KR20070007203A - Methods of using and compositions comprising selective cytokine inhibitory drugs for the treatment and management of myeloproliferative diseases - Google Patents

Abstract

Methods of treating, preventing and/or managing a myeloproliferative disease are disclosed. Specific methods encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent, and/or the transplantation of blood or cells. Particular second active agent is capable of suppressing the overproduction of hematopoietic stem cells or ameliorating one or more of the symptoms of MPD. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed. ® KIPO & WIPO 2007

Description

METHODS OF USING AND COMPOSITIONS COMPRISING SELECTIVE CYTOKINE INHIBITORY DRUGS FOR THE TREATMENT AND MANAGEMENT OF MYELOPROLIFERATIVE DISEASES}

One. Field of invention

The present invention relates to methods of treating, preventing and / or managing myeloproliferative diseases and related syndromes, including administering selective cytokine inhibitory drugs alone or in combination with other therapies.

2. Background of the Invention

2.1. MPD Pathology of the

Myeloproliferative disease (MPD) refers to a group of diseases characterized by clonal abnormalities of hematopoietic stem cells (see, eg, Current Medical Diagnosis & Treatment , pp. 499 (37 ^th ed., Tierney). et al . ed, Appleton & Lange, 1998). Since stem cells are the source of myeloid, erythrocyte and platelet cells, qualitative and quantitative changes can be seen in all these cell lines ( Id . ).

MPD is further subdivided based on myeloid cell types that are significantly proliferative. Erythrocyte excess is either "polycythemia rubra vera (PRV)" or "polycythemia vera", and platelet excess is "primary (or essential) thrombocytopenia (PT)", and granulocyte excess is "chronic." Myeloid leukemia (CML). The fourth subcategory of MPD is "agnogenic myeloid metaplasia (AMM)" characterized by myeloid fibrosis and extramedullary hematopoiesis ( Cecil Textbook of Medicine , pp. 922 (20 ^th ed., Bennett and Plum ed., WB Saunders Company, 1996). These diseases are grouped together because the disease evolves from one form to another, and typically hybrid diseases appear (Tierney et. al ., supra , at pp. 499). As a result of all the myeloproliferative disease is naturally or mutagenic process may proceed to acute leukemia (Id.).

Most patients with PRV show symptoms associated with expanded blood volume and increased blood viscosity ( Id . At pp. 500). Common complains include headache, dizziness, tinnitus, dim vision, and fatigue ( Id . ). The spleen enlarges to facilitate in 75% of cases, and splenomegaly is almost always present when imaged ( Id . ). Thrombosis is the most common complication of PRV and is the leading cause of morbidity and mortality in this disease. Thrombosis appears to be associated with increased blood viscosity and abnormal platelet function (Id.). 60% of patients with PRV are male, with a representative median age of 60. This appears rarely ought to under 40 years of age (Id.).

Thrombosis is also a common complication in patients with PT (Cecil Textbook of Medicine, pp. 922 (20^th ed., Bennett and Plum ed., W.B. Saunders Company, 1996). Platelet count ≥6 × 10 per microliter⁵Set to diagnose this PT (Tefferiet al.,Mayo Clin Proc 69: 651 (1994). Most patients are usually asymptomatic when PT is diagnosed through a concomitant increase in the number of peripheral blood platelets (Bennett and Plum,supra, at pp. 922). However, approximately one quarter has a thrombotic or hemorrhagic phenomenon (Id .). PT rarely transforms into acute leukemia or AMM, and most patients have a normal life expectancy (Id . at pp. 923). However, at least one third of patients with PT eventually suffer major thrombohemorrhagic complications (Id .).

Normal bone marrow function in CML patients is generally maintained during the early stages (Tierney et. al ., supra , at pp. 503). The disease is typically modified in the following remain stable over the years, more apparent in the malignant disease, (Id.). CML proceeds eventually to the onset of acute leukemia fibroblasts (blast crisis) that is distinct from (Id.). CML is (the median age is 42 years old represented), generally a disease of middle-aged (Id.). Acceleration of the disease is often associated with fever in the absence of infection, bone pain and nystagmus ( Id . ). One of the hallmarks of CML laboratory findings is increased leukocyte count, and the median leukocyte count at diagnosis is 150,000 / μl ( Id. ). The median survival of CML is 3-4 years ( Id . At pp. 505). Once the disease advances to accelerated or blast crisis fibroblasts, survival is usually measured in months (Id.).

AMMs are characterized by a leukocytotic peripheral blood phase with fibrosis, gynecology, and tear-like deformed hematopoiesis of the bone marrow (Tierney et. al ., supra , at pp. 502). AMM is an insidious when there appears from adults over the age of 50, usually expressed (Id.). The second half of the course of the disease is a bone marrow failure caused according As the bone marrow is a progressively more fibrous (Id.). Anemia is a serious (Id.). Painful episodes of splenic infarction may occur. Severe bone pain and liver failure also appear later in AMM. The median survival time from diagnosis was about 5 years ( Id . At pp. 503).

The exact cause of MPD is not clear. Current data suggest that some growth accreditation is involved. For example, in both PRV and PT, as opposed to normal erythroid progenitor cells, true polycytic erythroid progenitor cells can grow in vitro in the absence of erythropoietin due to hypersensitivity to insulin-like growth factor I. ( Harrison's Principles of Internal Medicine , pp. 701 (15 ^th ed., Braunwald et al . ed., McGraw-Hill, 2001). Overproduction of type III collagen in AMM was due to platelet-induced growth factor or transforming growth factor β (TGF-β) (see also Id . At pp. 703; see also Martyr_, Leuk) Lymphoma 6: 1 (1991)).

Some forms of MPD show specific chromosomal changes. For example, non-probable chromosomal abnormalities such as 20q-, trisomy 8 or 9 have been demonstrated in a small proportion of untreated PRV patients, with 20q-, 13q- and trisomy 1q in AMM patients. Common ( Harrison's Principles of Internal Medicine , pp. 701-3 (15 ^th ed., Braunwald et al . ed., McGraw-Hill, 2001). Philadelphia chromosomes are present in more than 90% of patients with typical CML and bone marrow cells of some patients with PRV (see Kurzrock et. al ., N. Engl J Med 319: 990 (1988). The Philadelphia chromosome is due to the balance transfer of matter between the long arms of chromosomes 9 and 22. The break in the long arm band q34 of chromosome 9 allows the translocation of the cellular oncogene C-ABL to a location on chromosome 22 called a breakpoint cluster region (bcr). The apposition of these two gene sequences creates a new hybrid gene (BCR / ABL) that encodes a novel protein of molecular weight 210,000 kD (P210). P210 protein, a tyrosine kinase, may play a role in inducing uncontrolled proliferation of CML cells (see, eg, Daley et. al ., Science 247: 824 (1990)).

The risk of CML type of MPD also increases upon exposure to ionizing radiation. Survivors of the atomic bomb explosion in Japan in 1945 had an increased incidence of CML, with peaks appearing 5-12 years after exposure and appear to be dose related ( Cecil Textbook of Medicine , pp. 925-926 (20 ^th ed., Bennett and Plum ed., WB Saunders Company, 1996). Radiation therapy of ankylosing spondylitis and cancer have increased the incidence of CML (Id.).

The incidence of MPD varies with the type of disease. CML accounts for one fifth of all cases of leukemia in the United States ( Id . At pp. 920). Approximately 4,300 new cases of CML are diagnosed annually in the United States and account for more than half of MPD cases (eMedicine website, myeloproliferative disease). PRV is diagnosed in 1 million per, 5-17 people a year (Id.). True incidence (true incidence) of PT and AMM is not known because it is not suitable mechanical test for these diseases (Id.). Internationally, CML seems to affect approximately equal frequency for all races. PRV are reported to be lower in Japan, that is one million per year, 2 patients (Id.).

2.2. MPD  cure

The treatment of choice for PRV is phlebotomy ( Current Medical Diagnosis & Treatment , pp. 501 (37 ^th ed., Tierney et al . ed, Appleton & Lange, 1998). Blood (about 500 ㎖) of the first unit is hematoxylin grit is removed every week until less than 45% (Id.). Repeated sahyeol is because to generate iron deficiency, requirement for sahyeol has been gradually reduced to (Id.). Medical iron supplements, it is important to avoid these supplements because they may interfere with the objectives of the program sahyeol (Id.).

In more severe cases of bone marrow PRV inhibitory treatment is used (Id.). One kinds of bone marrow inhibitors widely used is a hydroxy urea (Id.). Hydroxyurea is an oral drug that inhibits ribonucleotide reductase (Bennett and Plum, supra , at pp. 924). Typical doses are 500-1500 mg / d orally adjusted to maintain platelets at <500,000 / μl without reducing neutrophil count to <2000 / μL (Tierney et. al ., supra , at pp. 501). Side effects of hydroxyurea include mild gastrointestinal signs, reversible neutropenia, and mucous skin lesions (Bennett and Plum, supra , at pp. 924). Busulfan can also be used at doses of 4-6 mg / d for 4-8 weeks (Tierney et. al ., supra , at pp. 501). Alpha interferon has been shown to have some ability to control this disease. A typical weekly dose, a 2-5 baekman unit with three times subcutaneously (Id.). Anagrelide has also been approved for use in the treatment of thrombocytopenia ( Id . ). Some of the bone marrow, such as alkylating agents, radioactive phosphorus ⁽³² P) has been shown to increase the risk of PRV is switched to acute leukemia (Id.). Using myelosuppressive agents for long periods of time can cause prolonged severe myelosuppression.

Most officials agree that the treatment of PT should be aimed at reducing platelet levels in patients with a history of thrombosis and in patients with cardiovascular risk factors (Bennett and Plum, supra , at pp. 923). However, the benefits of certain therapies have not been established and there is concern about the leukemia-causing potential of available therapeutics ( Id . ). Once treatment is determined, the initial drug is hydroxyurea or anagrelide ( Id . At pp. 924). Ana Grella Id is a medicament for the oral may involve the suppression of mature megakaryocytes (Id.). The starting dose is administered four times a day with 0.5 ㎎ (Id.). It is relatively contraindicated in elderly patients with heart disease (Id.). Alpha is interferon may also be used when the PT treatment (Id.).

At present, there is no specific treatment for AMM (Tierney et. al ., supra , at pp. 502). Management of AMM is about symptoms. Binhyeolseong patient is supported by the red blood cells during transfusion (Id.). Androgens, such as oxymetholone, or testosterone, which provide orally 200 mg daily, help to reduce the need for blood transfusions in one third of the cases, but are inferior to women ( Id . ). Splenectomy is indicated for splenic enlargement resulting in recurring painful episodes, severe thrombocytopenia or an unacceptable large red blood cell transfusion need ( Id . ). Alpha interferon (3-5 weekly subcutaneously administered 2-5 million units) induces improvement in some cases ( Id . ).

Immediate treatment of CML is not necessary unless the number of leukocytes exceeds 200,000 / μl, evidence of leukocytosis (persistent, venous thrombosis, confusion or dyspnea), or spleen infarction ( Id . At pp. 504 ). Standard therapy for CML is composed of a dose of the hydroxy-urea (Id.). Since the leukocyte count will be increased within a few days after stopping the administration, hydroxy urea has to be administered must be no interruption (Id.). Recombinant alpha interferon has largely replaced hydroxyurea as the initial treatment of choice and can prolong both chronic phase and overall survival ( Id . ). Unlike other palliative agents, interferon can inhibit the Philadelphia chromosome and allow cytogenetically normal cells to appear ( Id . ).

Although the response to the bone marrow-inhibiting treatment of chronic CML are on the satisfactory, treatment is only palliative, disease is invariably fatal (Id.). Therapeutic treatment is possible only using homologous bone marrow transplantation (Id.). This treatment is available for adults up to 60 years of age with HLA-matched siblings ( Id. ). Approximately 60% of adults survive long-term disease free after bone marrow transplantation ( Id. ). However, this treatment is limited by the donor's base and the patient's age. In the case of relapsed CML patients after transplantation, immunological therapies by infusion of T lymphocytes from bone marrow donors can provide long lasting relief ( Id. At pp. 504-5). Subcellular onset of CML can be treated with daunorubicin, cnccristine and prednisone, but remission is usually temporary ( Id . At pp. 505).

Constant efforts have been made to find new ways to treat CML. For example, ST1571, a synthetic inhibitor of BCR / ABL kinase, induces selective inhibition in the growth of t (9; 22) -bearing tumor cells and some responses in patients in vitro (see, eg, Buchdunger et. al ., Proc . Natl . Acad . Sci . USA 92: 2558-252 (1995); And Buchdunger et al ., Cancer Res . 56: 100-104 (1996); See also Harrison's Principles of Internal Medicine , pp. 714 (15 ^th ed., Braunwald et al . Ed., McGraw-Hill, 2001). Inhibition of RAS by a farnesyl transferase inhibitor that blocks the insertion of RAS into the membrane can have antitumor activity in CML based on early clinical trials (Braunwald et. al ., supra , at 714). Preclinical efforts to use BCR / ABL peptides as tumor vaccines seem promising ( Id . ). Use of BCR / ABL antisense oligonucleotides to remove residual leukemia cells from autologous hematopoietic progenitors before reinjection, and minimal residual without inducing GVHD (graft-versus-host disease) Approaches for inducing GVL (graft-versus-leukemia) in the setting of disease (reduction phase, where leukemia cell numbers can be detected by conventional techniques, typically <10 ¹⁰ malignant cells) Is currently underway ( Id . ).

Most of the therapies used to treat MPD only target symptoms, and since most drugs have serious side effects with the risk of causing severe myelosuppression or converting the disease to acute leukemia, There is a great need to find new treatments for MPD that target or improve the effectiveness and safety of current treatments.

2.3. Selective Cytokines Inhibitory  drug

Compounds called SelCIDs ™ (Celgene Corporation) or selective cytokine inhibitory drugs were synthesized and tested. These compounds strongly inhibit TNF-α production, but show a moderate inhibitory effect on LPS-induced IL1β and IL12 and do not inhibit IL6 even at high drug concentrations. In addition, SelCIDs ™ tend to produce appropriate IL10 stimuli (LG Corral, et. al ., Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999).

Further characterization of selective cytokine inhibitory drugs indicates that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes present in human myeloid and lymphoid lineage cells. This enzyme plays a critical role in regulating cellular activity by degrading the ubiquitous second messenger cAMP and maintaining it at low intracellular levels ( Id .). Inhibition of PDE4 activity provides increased cAMP levels leading to modulation of LPS induced cytokines, including inhibition of TNF-α production in monocytes and lymphocytes.

3. Summary of the Invention

The present invention provides a selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate thereof, to a patient in need of treatment or prevention of myeloproliferative diseases. ) Or a method for treating and preventing myeloproliferative diseases (“MPD”), including administering a therapeutically or prophylactically effective amount of a prodrug. The invention also provides a therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient in need thereof. Methods of administering (eg, prolonging the time of remission) of MPD, including administration.

One embodiment of the invention provides for one or more selective cytokine inhibitory drugs such as, but not limited to, hydroxyureas, anagrelides, interferons, kinase inhibitors, cancer chemotherapeutic agents, stem cell transplants and other transplants. But not limited to use with conventional therapies currently used to treat, prevent or manage MPD.

Another embodiment of the invention provides a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the side effects associated with MPD therapy in a patient in need of treatment or prevention of the side effects associated with MPD therapy, Methods for reducing or preventing side effects associated with MPD therapy, including administering solvates, hydrates, stereoisomers, clathrates or prodrugs. This embodiment includes the use of a selective cytokine inhibitory drug of the invention for preventing or treating side effects associated with the use of MPD therapy. This embodiment includes elevating the patient's resistance to MPD therapy.

Another embodiment of the present invention provides a selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable thereof, in an amount sufficient to increase the therapeutic efficacy of MPD treatment in a patient in need of increased therapeutic efficacy of MPD treatment. Methods of increasing the therapeutic efficacy of MPD treatment, including administering salts, sorbates, hydrates, stereoisomers, clathrates or prodrugs.

The present invention further provides for the treatment, prevention and / or management of MPD, including the selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. Pharmaceutical compositions suitable for use, single unit dosage forms, and kits.

4. Detailed description of the invention

A first embodiment of the present invention provides a therapeutic or prophylactic treatment of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a patient in need of treatment or prevention of MPD. Methods of treating or preventing MPD, including administering an effective amount. This embodiment includes certain sub-types of MPD such as, but not limited to, true erythrocytosis (PRV), primary thrombocytopenia (PT), chronic myeloid leukemia (CML), and idiopathic myeloid (AMM) Treatment, prevention or management.

As used herein, the term “myeloproliferative disease” or “MPD” means hematopoietic stem cell disease characterized by one or more of the following conditions: overproduction of one or more blood forming elements (eg, For example, clonal expansion of pluripotent hematopoietic progenitor cells, the presence of the Philadelphia chromosome or bcr-abl gene, teardrops on peripheral blood smears, with increased red blood cell count, increased white blood cell count and / or increased platelet count). Significant left-shifted myeloid system, lybiosis, thrombosis with deformed thrombosis, leukocytosis, giant aberrant platelets, hyperplastic bone marrow with reticular or collagen fibrosis, low percentage of promyelocytic cells and subcellular , Cellular bone marrow with risk or impaired morphology to progress to acute leukemia. The term “myeloproliferative disease” or “MPD” includes unless otherwise indicated: diabetes mellitus (PRV), primary thrombocytopenia (PT), chronic myelogenous leukemia (CML), and idiopathic myeloid ( AMM). In certain embodiments, the term "myeloproliferative disease" or "MPD" excludes leukemia. Specific types of MPDs are PRV, PT, CML and AMM.

Another embodiment of the invention provides a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient in need thereof. Methods of administering MPD, including administration.

Another embodiment of the present invention includes a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof.

Also included in the present invention are single unit dosage forms comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof.

Another embodiment of the present invention is directed to a method for treating, preventing and / or managing MPD of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. Methods of treating, preventing and / or managing MPD, including administering a therapeutically or prophylactically effective amount, and a therapeutically or prophylactically effective amount of a second active agent.

Examples of second active agents include cytokines, corticosteroids, ribonucleotide reductase inhibitors, platelet inhibitors, all-trans retinoic acid, kinase inhibitors, topoisomerase inhibitors, farnesyl transferase inhibitors, antisense oligonucleotides, vaccines , Anticancer agents, antifungal agents, anti-inflammatory agents, immunosuppressive or myelosuppressive agents, and conventional therapies for MPD.

While not being limited in theory, it is believed that certain selective cytokine inhibitory drugs can act in a complementary or synergistic manner with other therapies conventional in the treatment or management of MPD. In addition, certain selective cytokine inhibitory drugs are believed to act by mechanisms different from other therapies conventional in the treatment or management of MPD. In addition, certain selective cytokine inhibitory drugs are believed to be effective when administered to patients who are unresponsive to conventional therapies for myeloproliferative diseases and to treatment with thalidomide. As used herein, the term “refractory” means that the patient's response to MPD treatment is not satisfactory to clinical standards, eg, no or little improvement in symptoms or laboratory findings. .

In addition, certain therapies are believed to reduce or eliminate the particular side effects associated with some of the selective cytokine inhibitory drugs of the present invention, thereby allowing the patient to be administered larger quantities of selective cytokine inhibitory drugs and / or increasing patient compliance. Lose. In addition, it is believed that some selective cytokine inhibitory drugs may reduce or eliminate the particular side effects associated with other MPD therapies, thereby allowing patients to be administered larger amounts of these therapies and / or increase patient compliance. Lose.

Another embodiment of the invention is a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug and a second active agent thereof and / or Includes kits containing instructions for use. The invention further includes a kit comprising a single unit dosage form.

Another embodiment of the invention relates to administering to a patient in need thereof a therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. And methods of reversing, reducing or avoiding side effects associated with administration of the active agent used to treat MPD in a patient suffering from MPD. Examples of active agents include, but are not limited to, the second active agents described herein (see Section 4.2.).

Examples of side effects associated with active agents used to treat MPD include: conversion to acute leukemia; Severe myelosuppression; Gastrointestinal toxicities such as, but not limited to, early and late-forming diarrhea and breakdown; Gastrointestinal bleeding; miscarriage of justice; throw up; Loss of appetite; Leukopenia; anemia; Neutropenia; asthenia; Abdominal cramps; Fever; ache; Weight loss; dehydration; Alopecia; Dyspnea; insomnia; Dizziness, mucositis, dry mouth, mucous skin lesions and renal failure are included, but are not limited to these.

Since all leukemia transformations are expressed at certain stages of MPD, transplantation of peripheral blood stem cells, hematopoietic stem cell preparations or bone marrow may be necessary. Without being bound by theory, it is believed that the combination of selective cytokine inhibitory drugs with stem cell transplantation in patients with MPD provides a unique and unexpected synergy. In particular, it is believed that selective cytokine inhibitory drugs exhibit immunomodulatory activity that can provide additive or synergistic effects when given concurrently with transplantation therapy. Selective cytokine inhibitory drugs of the invention can work in conjunction with transplantation to reduce the risk of complications associated with the invasive process of transplantation and associated graft-versus-host disease (GVHD). Accordingly, the present invention provides a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient (eg, a human) before, during or after transplantation therapy. And methods of treating, preventing and / or administering MPD, including administering the same.

The invention also provides one or more selective cytokine inhibitory drugs of the invention, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs, second active ingredients, and / or graft therapy thereof. Pharmaceutical compositions comprising a blood or cell for the purpose, single unit dosage forms, and kits. For example, a kit may contain one or more compounds of the invention, stem cells for transplantation, and anti-inhibitors and antibiotics or other drugs.

4.1. Selective Cytokines Inhibitory  drug

The compounds used in the present invention are racemic, stereoisomerically pure, and stereoisomerically enriched selective cytokine inhibitory drugs, stereoisomerically and enantiomericly pure compounds, and medicaments thereof having selective cytokine inhibitory activity. Academically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs. Preferred compounds used in the present invention are known selective cytokine inhibitory drugs (SelCIDs ™) from Celgene Corporation (NJ).

Unless otherwise indicated, as used herein, the terms "selective cytokine inhibitory drug" and "SelCIDs ™" are small molecule drugs, eg, peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. organic small molecules that are not (macromolecules). Preferred compounds inhibit TNF-α production. The compound may also have an appropriate inhibitory effect on LPS induced IL1β and IL12. More preferably, the present invention is a potent PDE4 inhibitor.

Specific examples of selective cytokine inhibitory drugs include the cyclic imides described in US Pat. Nos. 5,605,914 and 5,463,063; Cycloalkyl amides and cycloalkyl nitriles of US Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281; Aryl amides (eg, N-benzoyl-3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide) of US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780; Imide / amide ethers and alcohols described in US Pat. No. 5,703098 (eg, 3-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propan-1-ol); Succinimides and maleimides described in US Pat. No. 5,658,940 (eg, methyl 3- (3 ', 4', 5 ', 6'-tetrahydrophthalimido) -3- (3 ", 4 "-Dimethoxyphenyl) propionate); Imido and amido substituted alkanohydroxamic acids as described in US Pat. No. 6,214,857 and WO 99/06041; Substituted phenethylsulfones described in US Pat. Nos. 6,011,050 and 6,020,358; Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds described in US patent application Ser. No. 10 / 748,085, filed December 29, 2003; Substituted imides described in US Pat. No. 6,429,221 (eg, 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane); Substituted 1,3,4-oxadiazoles described in US Pat. No. 6,326,388 (eg, 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,3, 4-oxadiazol-2-yl) ethyl] -5-methylisoindolin-1,3-dione); Cyano and carboxy derivatives of substituted styrenes described in US Pat. Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554 (eg, 3,3-bis- (3,4-dimethoxyphenyl) acrylonitrile); Isoyn substituted at the 2-position by the α- (3,4-disubstituted phenyl) alkyl group described in WO 01/34606 and U.S. Pat. Dolin-1-one and isoindolin-1,3-dione; And imido and amido substituted acylhydroxysamic acids described in WO 01/45702 and US Pat. No. 6,699,899 (eg, (3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate), but is not limited to these. Other selective cytokine inhibitory drugs include the diphenylethylene compounds described in US Provisional Patent Application No. 60 / 452,460, filed March 5, 2003, the contents of which are incorporated herein by reference in their entirety. do. Each patent and patent application cited herein is hereby incorporated by reference in its entirety.

Additional selective cytokine inhibitory drugs belong to the class of synthesized chemical compounds, typical of which include 3- (1,3-dioxobenzo- [f] isoindol-2-yl) -3- (3 -Cyclopentyloxy-4-methoxyphenyl) propionamide and 3- (1,3-dioxo-4-azaisoindol-2-yl) -3- (3,4-dimethoxyphenyl) -propionamide Included.

Other particular selective cytokine inhibitory drugs are classes of non-polypeptide cyclic amides described in US Pat. 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. Belongs to. Representative cyclic amides include compounds of the formula

Where

n has a value of 1, 2 or 3;

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

R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, 1 to 10 carbon atoms Phenyl substituted by one or more substituents each independently selected from the group consisting of alkyl, alkoxy and halo of 1 to 10 carbon atoms, (ii) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, Unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms and halo Benzyl, (iii) naphthyl, or (iv) benzyloxy;

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

ego;

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

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

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

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

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

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

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

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

3- (4-methoxyphenyl) -3- (1-oxoisoindolin-2-yl) propionamide;

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

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

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

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

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

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

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

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

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

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

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionate; And

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionate.

Other representative cyclic amides include compounds of the formula

Where

이며, 여기에서Z is

, Where

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

R ² is -CO- or SO ₂ ;

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

R ⁴ is alanyl, arginyl, glycyl, phenylglycyl, histidyl, leuyl, isoleyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoceryl, threonyl, tyronyl, Tyrosyl, valelyl, benzimidol-2-yl, benzoxazol-2-yl, phenylsulfonyl, methylphenylsulfonyl, or phenylcarbamoyl;

n has a value of 1, 2 or 3.

Other representative cyclic amides include compounds of the formula

Where

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

R ⁶ is —CO—, —CH ₂ — or —SO ₂ —;

R ⁷ is (i) hydrogen when R ⁶ is —SO ₂ —, (ii) straight, branched or cyclic alkyl having 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl, or nitro, cyano From trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 10 carbon atoms, respectively. Phenyl substituted by one or more substituents independently selected from each other, (v) alkyl of 1 to 10 carbon atoms, (vi) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, Benzyl unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halo, (vii) Naphthyl, (viii) benzyloxy, or (ix) Imidazole-4-yl methyl;

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

ego;

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

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

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

Other representative imides include compounds of the formula

Where

R ⁷ is straight, branched or cyclic alkyl of 1 to 12 carbon atoms, (ii) pyridyl, (iii) phenyl, or nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, Phenyl substituted by one or more substituents each independently selected from acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iv) nitro, Cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy and halo of 1 to 4 carbon atoms Benzyl, (v) naphthyl, (vi) benzyloxy, or (vii) imidazol-4-ylmethyl, unsubstituted or substituted by one to three substituents selected from the group consisting of:

이며, 여기에서R ¹² is —OH, alkoxy having 1 to 12 carbon atoms, —O—CH ₂ -pyridyl, —O-benzyl or

, Where

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

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

R ^{9 '} is hydrogen, alkyl of 1 to 10 carbon atoms, -CH ₂ -pyridyl, benzyl, -COR ¹⁰ , or -SO ₂ R ¹⁰ , wherein R ¹⁰ 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 described in WO 99/06041 and US Pat. No. 6,214,857, each of which is incorporated herein by reference. Examples of such compounds include, but are not limited to, compounds of the formula: and acid addition salts of such compounds containing nitrogen atoms that can be protonated.

Where

R ¹ and R ² are each hydrogen or lower alkyl when present independently of each other, or together with the illustrated carbon atoms to which they are attached nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbo Independently from the group consisting of propoxy, 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 O-phenylene, o-naphthylene or cyclohexene-1,2-diyl unsubstituted or substituted by 1 to 4 substituents selected;

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

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

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

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

n has a value of 0, 1 or 2.

Further specific selective cytokine inhibitory drugs used in the present invention include, but are not limited to, the following compounds:

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

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

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

N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide;

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

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide;

N-hydroxy-3- (3,4-dimethoxyphenyl) -3-phthalimidopropionamide;

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

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

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

3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-1H-benzo [f] isoindol-2-yl) Propionamide;

N-hydroxy-3- {3- (2-propoxy) -4-methoxyphenyl} -3-phthalimidopropionamide;

3- (3-ethoxy-4-methoxyphenyl) -3- (3,6-difluorophthalimido) -N-hydroxypropionamide;

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

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

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

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

N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide.

Additional selective cytokine inhibitory drugs used in the present invention include substituted phenethylsulfones substituted by oxoisoindine groups in the phenyl vapor phase. Examples of such compounds include, but are not limited to, the compounds described in US Pat. No. 6,020,358, which is incorporated herein by reference.

Where

Carbon atoms marked with * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or —NR ⁸ R ^9, or ^Two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms represent naphthylidene with the phenylene ring shown;

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

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

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

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

For convenience the compounds are designated as phenethylsulfone, but it will be understood that they include sulfonamides when R ⁷ is NR ^{8 '} R ^9' .

A particular group of such compounds are those wherein Y is C═O or CH ₂ .

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

Certain compounds are compounds in which ^one of R ¹ , R ² , R ³ and R ⁴ is -NH ₂ , and the remaining of R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Certain compounds are compounds wherein one of R ¹ , R ² , R ³ and R ⁴ is -NHCOCH ₃ and the remaining of R ¹ , R ² , R ³ and R ⁴ are hydrogen.

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

A further preferred group of such compounds are compounds wherein ^one of R ¹ , R ² , R ³ and R ⁴ is methyl and the remaining of R ¹ , R ² , R ³ and R ⁴ are hydrogen.

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

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

Particular compounds are those wherein R ⁵ is methoxy and R ⁶ is monocycloalkoxy, polycycloalkoxy or benzocycloalkoxy.

Particular compounds are those wherein R ⁵ is methoxy and R ⁶ is ethoxy.

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

Certain compounds are compounds in which R ⁷ is methyl, ethyl, phenyl, benzyl or NR ^{8 '} R ^9' , wherein R ^{8 '} and R ^9' are each, independently of one another, hydrogen or methyl.

Particular compounds are those wherein R ⁷ is methyl.

Certain compounds are compounds in which R ⁷ is NR ^{8 '} R ^9' , wherein R ^{8 '} and R ^9' are each, independently of one another, hydrogen or methyl.

Additional selective cytokine inhibitory drugs are incorporated herein by reference and include the fluoroalkoxy-substituted 1,3-dihydro- described in US patent application Ser. No. 10 / 748,085, filed Dec. 29, 2003. Isoindolyl compounds are included. Representative compounds are compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

Where

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

Z is ^{-H, -C (O) R 3} , - (C 0 -1 - _{alkyl) -SO 2 - (C 2 -4} - alkyl), -C _{1 -8} - alkyl, -CH ₂ OH, -CH ₂ (O) (C _1-8 -alkyl) or -CN;

R ₁ and R ₂ are each independently -CHF _2, C _{1 -8} - and - (cycloalkyl C _{3 -18),} alkyl, -C _{3 -18-cycloalkyl,} or - (C _1-10 alkyl) At least one of R ₁ and R ₂ is CHF ₂ ;

R ³ is —NR ⁴ R ⁵ , -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl;

R ⁴ and R ⁵ are each independently selected from -H, -C _{1 -8} - alkyl, -OH, -OC (O) R 6 , and;

R ⁶ is -C _{1 -8-alkyl,} amino (C _{1 -8-alkyl),} -phenyl, -benzyl, or-aryl;

X _1, X _2, X ₃ and X ₄ are each independently -H, - halogen, - _{nitro, -NH 2, -CF 3, -C} 1-6 - alkyl, - (C _{0 -4} - alkyl) - (C _{3 -6} - cycloalkyl), (C _{0 -4} - ^{alkyl) -NR 7 R 8, (C} 0 -4 - alkyl) -N (H) C (O ) - (R 8), (C 0 ₄ - alkyl) -N (H) C (O ) N (R 7 R 8), (C 0 -4 - alkyl) -N (H) C (O ) O (R 7 R 8), (C 0 ₄ - alkyl) -OR ^8, (C _{0 -4} - alkyl) - imidazolyl, (C _{0 4} - alkyl) pyrrolyl, (C _{0 4} - alkyl) oxadiazolyl, or (C _0-4 - alkyl) -, or triazolyl, X _1, X _2, X ₃ and X ₄ of the two may form a cycloalkyl or heterocycloalkyl ring in combination with (for example, X ₁ and X ₂ , X ₂ and X ₃ , X ₃ and X ₄ , X ₁ and X ₃ , X ₂ and X ₄ , or X ₁ and X _{4 form} a 3, 4, 5, 6 or 7-membered ring which may be aromatic Thereby forming a bicyclic system with an isoindoleyl ring);

R ⁷ and R ⁸ are each independently H, C _{1 -9} - alkyl, C _{3 -6} - cycloalkyl, (C _{1 -6} - alkyl) - (C _{3 -6} - cycloalkyl), (C _{1 -6} ^{-alkyl) -N (R 7 R 8)} , (C 1 -6 - alkyl) -OR ^8, phenyl, benzyl or aryl.

Additional selective cytokine inhibitory drugs are described in US patent application Ser. No. 10 / 392,195, filed March 10, 2003; International Patent Applications PCT / US03 / 08737 and PCT / US03 / 08738, filed March 20, 2003; Both US Provisional Patent Application Nos. 60 / 438,450 and 60 / 438,448, filed Jan. 7, 2003 (G. Muller et. al . ); United States Provisional Patent Application 60 / 452,460, filed March 5, 2003 (G. Muller et. al . ); And enantiomerically pure compounds described in US Patent Application No. 10 / 715,184, filed November 17, 2003, all of which are incorporated herein by reference. Preferred compounds are enantiomers of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione and 3- (3 Enantiomer of, 4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide.

Preferred selective cytokine inhibitory drugs used in the present invention are 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1, available from Celgene Corp., Warren, NJ). 3-dihydro-isoindol-2-yl) -propionamide and cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3- Oxo-2,3-dihydro-1H-isoindol-4-yl} -amide. 3- (3,4-Dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide has a structure of the following formula.

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

Where

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

R ³ is monocycloalkyl, bicycloalkyl, or benzocycloalkyl having 18 or less carbon atoms;

X is a carbon-carbon bond, -CH ₂ -or -O-;

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

R ⁶ is —CO—, —CH ₂ — or —CH ₂ CO—;

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

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

R ⁸ is hydrogen or lower alkyl;

R ⁹ is lower alkyl or benzyl;

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

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

R ³ is monocycloalkyl having 10 or less carbon atoms, polycycloalkyl having 10 or less carbon atoms, or benzocyclic alkyl having 10 or less carbon atoms;

X is -CH ₂ -or -O-;

R ⁵ is (i) adjacent divalent residues of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein two bonds of the divalent residue are on adjacent ring carbon atoms; (ii) nitro, cyano, halo, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, 1 to 10 carbon atoms Adjacent divalent cycloalkyl having 4 to 10 carbon atoms unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl, alkoxy having 1 to 10 carbon atoms and phenyl; (iii) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl, acetoxy, carboxy, hydroxy substituted by alkyl of 1 to 3 carbon atoms , Disubstituted vinylene substituted by amino, amino substituted by alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; Or (iv) carbamoyl, acetoxy, carboxy, hydroxy substituted by nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, alkyl having 1 to 3 carbon atoms Ethyl unsubstituted or substituted by hydroxy, amino, amino substituted by alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and 1 to 2 substituents each independently selected from halo. ego;

R ⁶ is —CO—, —CH ₂ — or —CH ₂ CO—;

Y is -COX, -C≡N, -OR ⁸ , alkyl or aryl having 1 to 5 carbon atoms;

X is -NH ₂ , -OH, -NHR, -R ⁹ , -OR ⁹ , or alkyl of 1 to 5 carbon atoms;

R ⁸ is hydrogen or lower alkyl;

R ⁹ is alkyl or benzyl;

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

In another embodiment, one of R ¹ and R ² is R ³ -X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carbo (lower) alkoxy, acetyl, carbamoyl, acetoxy, Carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, HF ₂ CO, F ₃ CO or R ³ -X-;

R ³ is monocycloalkyl, bicycloalkyl, benzocycloalkyl having 18 or less carbon atoms, tetrahydropyran, or tetrahydrofuran;

X is a carbon-carbon bond, -CH _2- , -O- or -N =;

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

R ⁶ is —CO—, —CH ₂ — or —CH ₂ CO—;

Y is -COX, -C≡N, -OR ⁸ , alkyl having 1 to 5 carbon atoms, or aryl;

X is -NH ₂ , -OH, -NHR, -R ⁹ , -OR ⁹ , or alkyl of 1 to 5 carbon atoms;

R ⁸ is hydrogen or lower alkyl;

R ⁹ is alkyl or benzyl;

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

Other representative compounds are compounds of the formula

Where

Y is —C≡N or CO (CH ₂ ) _m CH ₃ ;

m is 0, 1, 2, or 3;

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

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

R ⁷ is (i) straight or branched chain alkyl of 1 to 12 carbon atoms; (ii) cyclic or acyclic alkyl having 1 to 12 carbon atoms; (iii) pyridyl; (iv) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, branched, between From cyclic or acyclic alkyl, straight chain, branched, cyclic or acyclic alkoxy of 1 to 10 carbon atoms, CH ₂ R (where R is cyclic or acyclic alkyl of 1 to 10 carbon atoms), and from halo Phenyl each substituted with one or more substituents independently selected from each other; (v) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, 1 to C carbon Benzyl substituted by 1 to 3 substituents each independently selected from the group consisting of 10 alkoxy and halo; (vi) naphthyl; Or (vii) benzyloxy;

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

In another embodiment, the specific selective cytokine inhibitory drug is a compound of the formula

Where

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

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

R ⁷ is (i) cyclic or acyclic alkyl having 4 to 12 carbon atoms; (ii) pyridyl; (iii) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, straight, branched, between From cyclic or acyclic alkyl, straight chain, branched, cyclic or acyclic alkoxy of 1 to 10 carbon atoms, CH ₂ R (where R is cyclic or acyclic alkyl of 1 to 10 carbon atoms), and from halo Phenyl each substituted with one or more substituents independently selected from each other; (iv) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 4 carbon atoms, having 1 to carbon atoms Benzyl substituted by 1 to 3 substituents each independently selected from the group consisting of 10 alkoxy and halo; (v) naphthyl; Or (vi) benzyloxy;

Y is COX, -C≡N, OR ⁸ , alkyl or aryl having 1 to 5 carbon atoms;

X is -NH ₂ , -OH, -NHR, -R ⁹ , -OR ⁹ , or alkyl of 1 to 5 carbon atoms;

R ⁸ is hydrogen or lower alkyl;

R ⁹ is alkyl or benzyl;

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

Other specific selective cytokine inhibitory drugs include the aryl amides of US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780, each of which is incorporated herein by reference (eg, embodiments are N-benzoyl-3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide), but is not limited to these. Representative compounds are those of the formula

Where

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) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms Phenyl substituted by one or more substituents each independently selected from the group consisting of alkoxy and halo having 1 to 10 carbon atoms; (v) heterocycles; Or (vi) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 carbon Heterocycle substituted by one or more substituents each independently selected from alkoxy, and halo, from 10 to 10;

R is -H, alkyl of 1 to 10 carbon atoms, CH ₂ OH, CH ₂ CH ₂ OH or CH ₂ COZ, wherein Z is alkoxy, benzyloxy or NHR ¹ of 1 to 10 carbon atoms, wherein R ¹ is H or alkyl of 1 to 10 carbon atoms;

Y is i) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 carbon A phenyl or heterocyclic ring unsubstituted or substituted by one or more substituents each independently selected from alkoxy and halo of from 10 to 10; Or ii) naphthyl.

Specific examples of this compound are compounds of the formula

Where

Ar is 3,4-disubstituted phenyl, each substituent here being nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydr Independently from each other from the group consisting of oxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo;

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

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

Other specific selective cytokine inhibitory drugs include the imide / amide ethers and alcohols described in US Pat. No. 5,703,098 (eg, 3-phthalimido-3- (3 ′, 4'-dimethoxyphenyl) propan-1-ol), but is not limited to these. Representative compounds have the formula

Where

R ¹ 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) nitro, cyano, trifluoromethyl, carethoxy, 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 Phenyl substituted by one or more substituents each independently selected from the group consisting of, and halo;

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

R ³ represents (i) ethylene, (ii) vinylene, (iii) side chain alkylene having 3 to 10 carbon atoms, (iv) side chain alkenylene having 3 to 10 carbon atoms, (v) nitro, cyano, trifluoromethyl Carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted by alkyl of 1 to 6 carbon atoms, substituted by acyl of 1 to 6 carbon atoms Cycloalkylene of 4 to 9 carbon atoms, unsubstituted or substituted by one or more substituents each independently selected from the group consisting of amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vi) nitro, cya Furnace, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted by alkyl of 1 to 6 carbon atoms, 1 to 6 carbon atoms By acyl Cycloalkenylene having 4 to 9 carbon atoms which is unsubstituted or substituted by one or more substituents each independently selected from the group consisting of substituted amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 12 carbon atoms and halo, (vii) Nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted by alkyl of 1 to 6 carbon atoms, carbon number O-phenylene unsubstituted or substituted by one or more substituents each independently selected from the group consisting of amino substituted by acyl of 1 to 6, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 12 carbon atoms, and halo, ( viii) naphthyl, or (ix) pyridyl;

R ⁴ is —CX—, —CH ₂ — or —CH ₂ CX—;

X is O or S;

n is 0, 1, 2, or 3.

Other specific selective cytokine inhibitory drugs include succinimides and maleimides described in US Pat. No. 5,658,940, incorporated herein by reference (eg, methyl 3- (3 ', 4', 5 ', 6'-tetrahydrophthalimido) -3- (3 ", 4" -dimethoxyphenyl) propionate), including but not limited to these. Representative compounds are those of the formula

Where

R ¹ is —CH ₂ —, —CH ₂ CO— or —CO—;

R ² and R ³ bonded together and each independently selected from each other from the group consisting of (i) ethylene unsubstituted or substituted by alkyl or phenyl having 1-10 carbon atoms, (ii) alkyl and phenyl having 1-10 carbon atoms Or unsubstituted or substituted by vinylene substituted by a substituent of (iii) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, alkyl having 1 to 3 carbon atoms. One or more substituents each independently selected from the group consisting of carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, norbornyl, phenyl and halo C2-C10 divalent cycloalkyl unsubstituted or substituted by;

R ⁴ represents (i) straight or branched unsubstituted alkyl of 4 to 8 carbon atoms, (ii) nitro, cyano, trifluoromethyl, carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, One or more substituents each independently selected from the group consisting of acetoxy, carboxy, hydroxy, amino, substituted amino, branched, straight or cyclic alkyl of 1 to 10 carbon atoms, alkoxy, phenyl and halo of 1 to 10 carbon atoms Cycloalkyl or bicycloalkyl, unsubstituted or substituted by 5 to 10 carbon atoms, (iii) nitro, cyano, trifluoromethyl, carethoxy, 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, cycle of 3 to 10 carbon atoms Phenyl substituted by one or more substituents each independently selected from the group consisting of alkoxy or bicycloalkoxy, phenyl and halo, (iv) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopro One or more substituents each independently selected from the group consisting of foxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, phenyl and halo Pyridine or pyrrolidine unsubstituted or substituted by;

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

X is NH ₂ , OH, NHR or OR ⁶ , where

R is lower alkyl,

R ⁶ is alkyl or benzyl.

Other specific selective cytokine inhibitory drugs include the substituted imides described in US Pat. No. 6,429,221 (eg, 2-phthalimido-3- (3 ', 4'-), which is incorporated herein by reference. Dimethoxyphenyl) propane), but is not limited to these. Representative compounds have the formula

Where

R ¹ is (i) straight, branched or cyclic alkyl of 1 to 12 carbon atoms, (ii) phenyl, or nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carba Phenyl substituted by one or more substituents each independently selected from moyl, acetoxy, carboxy, hydroxy, amino, straight or branched chain alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) benzyl Or nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 to 10 carbon atoms Benzyl substituted by one or more substituents each independently selected from alkoxy and halo, or (iv) -Y-Ph, wherein Y is straight, branched or cyclic alkyl of 1 to 12 carbon atoms, and Ph is Nyl, or nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 to C carbon Phenyl substituted by one or more substituents each independently selected from alkoxy and halo of 10;

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

R ³ is i) ethylene, ii) vinylene, iii) branched alkylene of 3 to 10 carbon atoms, iv) branched alkenylene of 3 to 10 carbon atoms, v) nitro, cyano, trifluoromethyl, carethoxy, 1-2 independently selected from carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halo Cycloalkylene, unsubstituted or substituted by 4 substituents, vi) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, Between 4 to 9 carbon atoms unsubstituted or substituted by carboxy, hydroxy, amino, substituted amino, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, and 1 to 2 substituents each independently selected from halo. Roalkenylene, or vii) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, 1 carbon O-phenylene unsubstituted or substituted by 1 to 2 substituents each independently selected from alkyl of from 4 to 4, alkoxy of 1 to 4 carbon atoms, and halo;

R ⁴ is -CX or -CH _2- ;

X is O or S.

Other specific selective cytokine inhibitory drugs include the substituted 1,3,4-oxadiazoles described in US Pat. No. 6,326,388, which is incorporated herein by reference (eg, 2- [1- (3- Cyclopentyloxy-4-methoxyphenyl) -2- (1,3,4-oxadiazol-2-yl) ethyl] -5-methylisoindolin-1,3-dione) It is not limited. Representative compounds are acid addition salts of compounds of the formula: and compounds containing nitrogen atoms sensitive to protonation.

Where

Carbon atoms marked with * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

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

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

^Two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxol or 2-hydroxybenzimidazole together with the benzene ring shown;

R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of 18 or less carbon atoms, bicycloalkoxy of 18 or less carbon atoms, 18 carbon atoms Tricycloalkoxy below or cycloalkylalkoxy having 18 or less carbon atoms;

R ⁸ and R ⁹ are each, independently of one another, hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or one of R ⁸ and R ⁹ is hydrogen, and the other is -COR ¹⁰ or —SO ₂ R ^10, or R ⁸ and R ⁹ may be bonded together to form tetramethylene, pentamethylene, hexamethylene, —CH = NCH = CH— or —CH ₂ CH ₂ X ¹ CH ₂ CH ₂ , wherein X ¹ is —O—, —S— or —NH—;

R ¹⁰ is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of 6 or less carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR ¹¹ R ¹² , CH ₂ R ¹⁴ R ¹⁵ Or NR ¹¹ R ¹² ; From here

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

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

Specific examples of the compound are compounds of the formula

Where

Carbon atoms marked with * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

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

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

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

R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of 18 or less carbon atoms, bicycloalkoxy of 18 or less carbon atoms, 18 carbon atoms Tricycloalkoxy below or cycloalkylalkoxy having 18 or less carbon atoms;

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

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

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

Other specific selective cytokine inhibitory drugs include cyano and carboxy derivatives of substituted styrenes described in US Pat. Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554, respectively (eg, 3,3). -Bis- (3,4-dimethoxyphenyl) acrylonitrile), but is not limited to these. Representative compounds are those of the formula

Where

(a) X is -O- or-(C _n H _2n )-, where n has a value of 0, 1, 2, or 3, and R ¹ is alkyl having 1 to 10 carbon atoms, having 10 or less carbon atoms Monocycloalkyl, polycycloalkyl having 10 or less carbon atoms, or benzocyclic alkyl having 10 or less carbon atoms,

(b) X is -CH = and R ¹ is C10 or less alkylidene, C10 or less monocycloalkylidene, or C10 or less bicycloalkylidene;

R ² is hydrogen, nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, Lower alkoxy or halo;

R ³ is (i) nitro, cyano, halo, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy , Carboxy, hydroxy, amino, amino substituted by alkyl of 1 to 5 carbon atoms, alkyl of 10 or less carbon atoms, cycloalkyl of 10 or less carbon atoms, alkoxy of 10 or less carbon atoms, cycloalkoxy of 10 or less carbon atoms, carbon of 10 or less carbon atoms Phenyl unsubstituted or substituted by one or more substituents each independently selected from alkylidenemethyl, cycloalkylidenemethyl of 10 or less carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine, imidazole, naphthalene or thiophene; (iii) nitro, cyano, halo, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, 1 to 10 carbon atoms Cycloalkyl having 4-10 carbon atoms unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, alkoxy having 1 to 10 carbon atoms and phenyl;

R ⁴ and R ⁵ are each independently hydrogen or R ⁴ and R ⁵ together are a carbon-carbon bond;

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

Z is -OH, -NR ⁶ R ⁶ , -R ⁷ , or -OR ⁷ ;

R ⁶ is hydrogen or lower alkyl;

R ⁷ is alkyl or benzyl.

Specific examples of the compound are compounds of the formula

Where

(a) X is -O- or-(C _n H _2n )-, where n has a value of 0, 1, 2, or 3, and R ¹ is alkyl having 1 to 10 carbon atoms, having 10 or less carbon atoms Monocycloalkyl, polycycloalkyl having 10 or less carbon atoms, or benzocyclic alkyl having 10 or less carbon atoms,

(b) X is -CH = and R ¹ is C10 or less alkylidene, C10 or less monocycloalkylidene, or C10 or less bicycloalkylidene;

R ² is hydrogen, nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidenemethyl, Lower alkoxy or halo;

R ³ is nitro, cyano, halo, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, 1 to 10 carbon atoms Pyrrolidine, imidazole or thiophene unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl, alkoxy having 1 to 10 carbon atoms and phenyl;

R ⁴ and R ⁵ are each independently hydrogen or R ⁴ and R ⁵ together are a carbon-carbon bond;

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

Z is -OH, -NR ⁶ R ⁶ , -R ⁷ , or -OR ⁷ ;

R ⁶ is hydrogen or lower alkyl;

R ⁷ is alkyl or benzyl.

Particularly preferred nitriles are compounds of the formula

Where

(a) X is -O- or-(C _n H _2n )-, where n has a value of 0, 1, 2, or 3, and R ¹ is alkyl having 1 to 10 carbon atoms, having 10 or less carbon atoms Monocycloalkyl, polycycloalkyl having 10 or less carbon atoms, or benzocyclic alkyl having 10 or less carbon atoms,

(b) X is -CH = and R ¹ is C10 or less alkylidene, C10 or less monocycloalkylidene, or C10 or less bicycloalkylidene;

R ² is hydrogen, nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy or halo ;

R ³ represents (i) nitro, cyano, halo, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, or carbamoyl, acetyl substituted by alkyl of 1 to 3 carbon atoms. Phenyl or naphthyl unsubstituted or substituted by one or more substituents each independently selected from oxy, carboxy, hydroxy, amino, amino substituted by alkyl of 1 to 5 carbon atoms, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; Or (ii) nitro, cyano, halo, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, C1-C1 Cycloalkyl having 4 to 10 carbon atoms unsubstituted or substituted by one or more substituents each independently selected from the group consisting of alkyl of 10, alkoxy having 1 to 10 carbon atoms and phenyl.

Particularly preferred nitriles are compounds of the formula

Other specific selective cytokine inhibitory drugs are described in WO 01/34606 and US Pat. No. 6,667,316, incorporated herein by reference, by an α- (3,4-disubstituted phenyl) alkyl group in the 2-position. Isoindololin-1-one and isoindolin-1,3-dione substituted and substituted by nitrogen-containing groups in the 4- and / or 5-positions. Representative compounds are those of the formula: and include pharmaceutically acceptable salts and stereoisomers thereof.

Where

One of X and X 'is = C = O or = SO ₂ and the other of X and X' is = C = O, = CH ₂ , = SO ₂ or = CH ₂ C = O;

n is 1, 2 or 3;

R ₁ and R ₂ are each independently (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, cyano, (C ₃ -C ₁₈ ) cycloalkyl, (C ₃ -C ₁₈ ) cycloalkoxy or (C ₃ -C ₁₈ ) cycloalkyl-methoxy;

R ₃ is SO ₂ -Y, COZ, CN or (C ₁ -C ₆ ) hydroxyalkyl, wherein

Y is (C ₁ -C ₆ ) alkyl, benzyl or phenyl;

Z is -NR ₆ R ₇ , (C ₁ -C ₆ ) alkyl, benzyl or phenyl;

R ₆ is H, (C ₁ -C ₄ ) alkyl, (C ₃ -C ₁₈ ) cycloalkyl, (C ₂ -C ₅ ) alkanoyl, benzyl or phenyl, each of which is halo, amino or (C ₁ -C ₄ ) optionally substituted by alkyl-amino;

R ₇ is H or (C ₁ -C ₄ ) alkyl;

R ₄ and R ₅ combine together to provide —NH—CH ₂ —R ₈ —, —NH—CO—R ₈ — or —N═CH—R ₈ —, wherein

R ₈ is CH ₂ , O, NH, CH═CH, CH═N or N═CH; or

One of R ₄ and R ₅ is H, the other of R ₄ and R ₅ is imidazoyl, pyrrolyl, oxadiazolyl, triazolyl, or a structure of formula A:

<Formula A>

From here

z is 0 or 1;

R ₉ is H; (C ₁ -C ₄ ) alkyl, (C ₃ -C ₁₈ ) cycloalkyl, optionally substituted by halo, amino, (C ₁ -C ₄ ) alkyl-amino or (C ₁ -C ₄ ) dialkyl-amino, (C ₂ -C ₅ ) alkanoyl or (C ₄ -C ₆ ) cycloalkanoyl; Phenyl; benzyl; Benzoyl; (C ₂ -C ₅ ) alkoxycarbonyl; (C ₃ -C ₅ ) alkoxyalkylcarbonyl; N-morpholinocarbonyl; Carbamoyl; N-substituted carbamoyl substituted by (C ₁ -C ₄ ) alkyl; Or methylsulfonyl;

R ₁₀ is H, (C ₁ -C ₄ ) alkyl, methylsulfonyl or (C ₃ -C ₅ ) alkoxyalkylcarbonyl; or

R ₉ and R ₁₀ are bonded together to form —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, (C ₁ -C ₄ ) alkyl-amino or (C ₁ -C ₄ ) Or (C ₁ -C ₂ ) alkylidene optionally substituted by dialkyl-amino; or

R ₄ and R ₅ both represent the structure of Formula A.

In one embodiment, (i) z is not zero when R ₃ is -SO ₂ -Y, -COZ or -CN, and ( ii ) one of R ₄ and R ₅ is hydrogen. In another embodiment, R ₉ and R ₁₀ are bonded together to form —CH═CH—CH═CH—, —CH═CH—N═CH—, or amino, (C ₁ -C ₄ ) alkyl-amino or ( (C ₁ -C ₂ ) alkylidene substituted by C ₁ -C ₄ ) dialkyl-amino. In yet other embodiments, R ₄ and R ₅ are both structures of formula A.

Specific compounds are compounds of the formula and enantiomers thereof.

Further specific compounds are compounds of the formula

Further examples include, but are not limited to, the following compounds: 2- [1- (3-ethoxy-4-methokwanyl) -2-methylsulfonylethyl] -4,5-dinitroisoyne Doline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-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-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-dioxoisoindolin-4-yl} carboxamide; 2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-amino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-N, N-dimethylamino-N- {2- [1- (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-tri Fluoroacetamides; 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-methylsulfonylethyl] isoindoline-1,3-dione ; 4- [1-Aza-2- (dimethylamino) prop-1-enyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline- 1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (5-methyl-1,3,4-oxadiazol-2-yl) isoindolin -1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-pyrrolylisoindolin-1,3-dione; 4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -isoindolin-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [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-hydroxybutylisoindolin-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-pyrrolylisoindolin-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-pyrrolylisoindolin-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-pyrrolylisoindolin-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} carbox amides; 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-methoxyphenyl) -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-dimethyl Propanamide; (3R) -3- [7- (2-chloroacetylamino) -1-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxy-phenyl) -N, N-dimethylpropane amides; (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) isoindolin-1,3-dione; N-({2- [1- (3-ethoxy4-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- 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-methoxyphenyl) -3-hydroxybutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione; 2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione; N- {2- [1- (3-cyclopentyl-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-pyrrolylisoindolin-1,3-dione; 2- [1- (3,4-dimethoxyphenyl) -3-oxobutyl] -4- [bis (methylsulfonyl) amino] isoindolin-1,3-dione; And pharmaceutically acceptable salts, solvates and stereoisomers thereof.

Another particular selective cytokine inhibitory drug includes imido and amido substituted acylhydroxamic acids described in WO 01/45702 and US Pat. No. 6,699,899, incorporated herein by reference (eg, (3- ( 1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy4-methoxyphenyl) propanoylamino) propanoate), but is not limited to these. Representative compounds are those of the formula

Where

Carbon atoms marked with * constitute a chiral center;

R ⁴ is hydrogen or — (C═O) —R ¹² ;

R ¹ and R ¹² are each independently of each other alkyl, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl, imidazolyl methyl, or CHR ^* (CH ₂ ) _n NR ^* R ⁰ , Wherein R ^* and R ⁰ are independently of each other hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridyl methyl, pyridyl, imidazoyl or imidazolylmethyl, n is 0, 1 or 2 ;

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

R ⁶ and R ⁷ are each independently of each other nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, 1 to C Alkyl of 6, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, halo, bicycloalkyl of 18 or less carbon atoms, tricycloalkoxy of 18 or less carbon atoms, 1-indanyloxy, 2-indanyloxy, C ₄ -C ₈ -cycloalkylidenemethyl, or C ₃ -C ₁₀ -alkylidenemethyl;

R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently of the other

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

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

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

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

(v) hydrogen when R ⁹ and R ¹⁰ are bonded together to be benzo;

Further specific selective cytokine inhibitory drugs include the 7-amido-isoindoleyl compound described in US patent application Ser. No. 10 / 798,317, filed March 12, 2004, which is incorporated herein by reference. However, they are not limited thereto. Exemplary compounds are compounds of Formula 1, or pharmaceutically acceptable salts, sorbates, hydrates, stereoisomers, clathrates, or prodrugs thereof, or compounds of Formula 2, or pharmaceutically acceptable salts thereof, sol Bait, hydrate, stereoisomer, clathrate, or prodrug.

<Formula 1>

Where

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

X is H,

Z is (C _{0 -4} - ^{alkyl) -C (O) R 3,} C 1 -4 - alkyl, (C _{0 -4} - alkyl) -OH, (C _{1 -4} - alkyl) -O (C _{1 - 4-alkyl),} (C _{1 -4-alkyl)} -SO ₂ (C _{1 -4-alkyl),} (C _{0 -4} - alkyl) -SO (C _{1 -4-alkyl),} (C _{0 -4} - alkyl) -NH _2, (C _0-4 - alkyl) -N (C _{1 -8} - alkyl) _2, (C _{0 -4} - alkyl) -N (H) (OH) , or CH ₂ NSO ₂ (C alkyl), - _1-4

R ₁ and R ₂ are independently a C _{1 -8-alkyl,} cycloalkyl, or - a (C _{1 -4} alkyl) cycloalkyl,

R ³ is NR ⁴ R ^5, OH, O-, or - a (C _{1 -8} alkyl),

R ⁴ is H,

R ⁵ is —OH, or —OC (O) R ⁶ ,

R ⁶ is C _{1 -8} - alkyl, amino, - (C _{1 -8} - alkyl), (C _{1 -8} - alkyl) - (C _{3 -6} - cycloalkyl), C _{3 -6} - cycloalkyl, phenyl, Benzyl or aryl;

<Formula 2>

Where

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

X is halogen, -CN, -NR ₇ R ₈ , -NO ₂ or -CF ₃ ,

Z is (C _{0 -4} - alkyl) -SO ₂ (C _{1 -4} - alkyl), - (C _{0 -4} - _{alkyl) -CN, - (C 0 -4} - alkyl) -C (O) R ³ , C _{1 -4} - alkyl, (C _{0 -4} - alkyl) -OH, (C _{0 -4} - alkyl) O (C _{1 -4} - alkyl), (C _{0 -4} - alkyl) SO (C _{1 - 4-alkyl),} (C _{0 -4} - _{alkyl) NH 2, (C 0 -4} - alkyl) N (C _{1 -8-alkyl) 2,} (C _{0 -4} - alkyl) N (H) (OH) and (alkyl _{C 1 -4),, (C} 0 -4 - alkyl) - dichloropyridine, or (C _{0 -4} alkyl) ₂ NSO

W is -C _{3 -6} - cycloalkyl, - (C _{1 -8} - alkyl) - (C _{3 -6} - cycloalkyl), - (C _{0 -8} - alkyl) - (C _3-6 - cycloalkyl) _{-NR 7 R 8, (C 0} -8 - _{alkyl) -NR 7 R 8, (C} 0 -4 - _{alkyl) -CHR 9 - (C 0 -4} - alkyl) -NR ₇ R _8, and

R ₁ and R ₂ are independently a C _{1 -8-a} - (alkyl C _{1 -4)} alkyl, cycloalkyl, alkyl, cycloalkyl, or

R ³ is C _{1 -8-a} - (alkyl C _{1 -8),} alkyl, NR ⁴ R ^5, OH, or O-

And - (cycloalkyl C _{3 -6} -), OH, or ^{-OC (O) R 6, R} 4 and R ⁵ are independently H, C _{1 -8-alkyl,} (C _{0 -8-alkyl)}

R ⁶ is C _{1 -8} - alkyl, (C _{0 -8} - alkyl) - (C _{3 -6} - cycloalkyl), amino, - (C _{1 -8} - alkyl), phenyl, benzyl or aryl,

R ₇ and R ₈ are each independently H, C _{1 -8} - alkyl, (C _{0 -8} - alkyl) - (C _{3 -6} - cycloalkyl), phenyl, or benzyl, or aryl, together with the atoms connecting them Combine to form a 3-7 membered heterocycloalkyl or heteroaryl ring,

R ₉ is C _{1 -4-alkyl,} (C _{0 -4} - alkyl) aryl, (C _{0 -4} - alkyl) - (C _{3 -6-cycloalkyl),} (C _{0 -4} - alkyl) - heterocycle to be.

In another embodiment, W represents groups of the formula

In another embodiment, the representative compound is a compound of the formula: and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

Where

R _1, R ₂ and R ₃ are independently H or C _{1 -8} - alkyl, with the proviso that R _1, R ₂ and R _3, at least one is not H.

Further specific selective cytokine inhibitory drugs are disclosed in US Provisional Patent Application No. 60 / 454,149 (filed March 12, 2003) and Man et al., March 12, 2004, each of which is incorporated herein by reference. N-alkyl-hydroxamic acid described in its U.S. non-temporary application (named "N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses"), filed in US Patent Application, Isoindoleyl compounds, including but not limited to. Representative compounds are compounds of the formula: and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

Where

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

R ₁ and R ₂ are independently a C _{1 -8} - alkyl, CF ₂ H, CF _3, CH ₂ CHF _2, cycloalkyl, or (C _{1 -8} - alkyl) cycloalkyl;

Z ₁ is H, C _{1 -6} - alkyl, -NH _2, -NR ₃ R ₄ or OR _5, and;

Z ₂ is H or C (O) R ₅ ;

X _1, X _2, X ₃ and X ₄ are each independently H, _{halogen, NO 2, OR 3, CF} 3, C 1 -6 - alkyl, (C _0-4 - alkyl) - (C _{3 -6} - cycloalkyl), (C _{0 -4} - _{alkyl) -N- (R 8 R 9)} , (C 0 -4 - alkyl) -NHC (O) - (R 8), (C 0-4 - alkyl) - _{NHC (O) CH (R 8} ) (R 9), (C 0 -4 - alkyl) -NHC (O) N (R 8 R 9), (C 0 -4 - alkyl) -NHC (O) O ( _{R 8), (C 0 -4} - _{alkyl) -OR 8, (C 0 -4} - alkyl) - imidazolyl, (C _{0 -4} - alkyl) pyrrolyl, (C _0-4 - alkyl) - oxadiazolyl, (C _{0 -4} - alkyl) -, or triazolyl (C _{0 -4} - alkyl) -, and heterocyclyl;

R _3, R ₄ and R ₅ are each independently H, C _{1 -6} - alkyl, OC _{1 -6} - alkyl, phenyl, benzyl, or aryl;

R ₆ and R ₇ are independently H or C _{1 -6} - alkyl;

R ₈ and R ₉ are each independently H, C _{1 -9} - alkyl, C _{3 -6} - cycloalkyl, (C _{1 -6} - alkyl) - (C _{3 -6} - cycloalkyl), (C _{0 -6 -alkyl) -N (R 4 R 5)} , (C 1 -6 - alkyl) -OR _5, phenyl, benzyl, aryl, piperidinyl, piperidyl, piperazinyl, pyrrolidinyl, morpholino, or C _{3 - 7} -heterocycloalkyl.

Further particular selective cytokine inhibitory drugs include, but are not limited to, the diphenylethylene compounds described in US Patent Application No. 10 / 794,931, filed March 5, 2004, which is incorporated herein by reference. Does not. Representative compounds are compounds of the formula: and pharmaceutically acceptable salts, solvates, or hydrates thereof.

Where

R ₁ is —CN, lower alkyl, —COOH, —C (O) —N (R ₉ ) ₂ , —C (O) -lower alkyl, -C (O) -benzyl, -C (O) O-lower Alkyl, -C (O) O-benzyl;

R ₄ is —H, —NO ₂ , cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, halogen, —OH, —C (O) (R ₁₀ ) ₂ , —COOH, —NH ₂ , -OC (O) -N (R ₁₀ ) ₂ ;

R ₅ is substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkenyl;

X is substituted or unsubstituted phenyl, substituted or unsubstituted pyridine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted imidazole, substituted or unsubstituted naphthalene, substituted or unsubstituted thiophene, or substitution Or unsubstituted cycloalkyl;

R ₉ in each occurrence is independently —H or substituted or unsubstituted lower alkyl;

R ₁₀ in each occurrence is independently —H or substituted or unsubstituted lower alkyl.

In another embodiment, the representative compound is a compound of the formula: and pharmaceutically acceptable salts, sorbates or hydrates thereof.

Where

R ₁ and R ₂ are independently —H, —CN, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —COOH, —C (O) -lower alkyl, -C (O) O-lower alkyl, -C (O) -N (R ₉ ) ₂ , substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle;

R _a , R _b , R _c and R _d are independently at each occurrence -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cyclo Alkyl, substituted or unsubstituted alkoxy, halogen, cyano, -NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O) N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC (O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH ₂ ;

R ₃ 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 ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH _2, or R ₃ is combined with R _a , or combined with R ₄ , -OC (R ₁₆ R ₁₇ ) -O- or -O- (C (R ₁₆ R ₁₇ )) forms ₂ -O-;

R ₄ 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 ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or —NHC (O) —R ₁₀ -NH ₂ ;

R ₅ 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 ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH ₂ ;

R ₆ 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 ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or —NHC (O) —R ₁₀ -NH ₂ ;

R ₇ 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 ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH ₂ ;

R ₈ 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 ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH _2, or R ₈ is combined with R _c , or in combination with R ₇ , -OC (R ₁₆ R ₁₇ ) -O- or -O- (C (R ₁₆ R ₁₇ )) forms ₂ -O-;

R ₉ in each occurrence is independently —H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted cycloalkyl;

R ₁₀ in each occurrence is independently substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted lower hydroxyalkyl, or R ₁₀ and the nitrogen to which it is attached Is a substituted or unsubstituted heterocycle, or R ₁₀ is optionally -H;

R ₁₆ and R ₁₇ in each occurrence are independently -H or halogen.

The compounds of the present invention can be purchased commercially or prepared according to the methods described in the patents or patent publications described herein. In addition, optically pure compositions can be synthesized asymmetrically, or can be cleaved using known splitting agents or chiral columns as well as other standard synthetic organic chemistry techniques.

Unless otherwise indicated, the term "pharmaceutically acceptable salts" as used herein includes non-toxic acid and base addition salts of the compounds to which the term is mentioned. Acceptable nontoxic acid addition salts include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconic acid, salicylic acid, phthalic acid. And those derived from organic and inorganic acids or bases known in the art, including, but not limited to, emvolic acid, enanthic acid and the like.

Compounds that are acidic in nature can form salts with various pharmaceutically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds include, but are not limited to, non-toxic base addition salts, ie alkali metal or alkaline earth metal salts and especially calcium, magnesium, sodium or potassium salts, To form a salt containing a pharmaceutically acceptable cation. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine Do not.

Unless indicated otherwise, the term “prodrug” as used herein refers to a derivative of a compound capable of providing a compound by hydrolysis, oxidation or otherwise reacting (in vitro or in vivo) under physiological conditions. do. Examples of prodrugs include selective cytokine inhibitors including biohydrolyzable sites such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable uraids and biohydrolyzable phosphate homologs. Derivatives of the drug are included, but are not limited to these. Other examples of prodrugs include derivatives of selective cytokine inhibitory drugs that include -NO, -NO ₂ , -ONO, or -ONO ₂ sites. Prodrugs are generally described in 1 Burger's Medicinal. Chemistry and Drug Discovery , 172-178, 949-982 (Manfred E. Wolff ed ., 5th ed. 1995) and Design of Prodrugs (H. Bundgaard ed., Elsevier, New York 1985) can be prepared using well known methods.

Unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable uraide", as used herein, and "Biohydrolysable phosphate" 1) does not inhibit the biological activity of the compound, but can impart beneficial properties to the compound in vivo, such as absorption, duration of action or expression of the action; Or 2) an amide, ester, carbamate, carbonate, ureate or phosphate of a compound that is biologically inert but converted to a biologically active compound in vivo. Examples of biohydrolyzable esters include lower alkyl esters, lower acyloxyalkyl esters (eg, acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactose Nyl esters (eg phthalidyl and thiopridyl esters), lower alkoxyacyloxyalkyl esters (eg methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl Esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (eg, acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

Various selective cytokine inhibitory drugs contain one or more chiral centers and may be present in a racemic mixture of enantiomers or in a mixture of diastereomers. The present invention includes the use of stereoisomericly pure forms of these compounds, and the use of mixtures of these forms. For example, mixtures comprising equal or uneven amounts of enantiomers of selective cytokine inhibitory drugs can be used in the methods and compositions of the present invention. Purified (R) or (S) enantiomers of certain compounds described herein can be used substantially in the absence of other enantiomers thereof.

Unless indicated otherwise, the term “stereoisomerically pure” as used herein means a composition that includes one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. Stereoisomericly pure compositions of a compound having two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomeric pure compounds include one stereoisomer of more than about 80% by weight of the compound and other stereoisomers of less than about 20% by weight of the compound, more preferably one stereoisomer of more than about 90% by weight of the compound and Less than about 10% by weight of other stereoisomers of the compound, more preferably more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, most preferably about 97% by weight One stereoisomer of more compounds and another stereoisomer of less than about 3% by weight of the compound.

Unless indicated otherwise, the term “stereomericly rich” as used herein refers to one stereoisomer of a compound of more than about 60% by weight, preferably more than about 70% by weight, more preferably about 80% by weight. By a composition comprising more than one percent by weight of one stereoisomer of the compound.

Unless indicated otherwise, the term “enantiomerically pure” as used herein means a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically rich" means a stereoisomerically rich composition of a compound having one chiral center.

It should be noted that if there is a contradiction between the structure shown and the name given for that structure, the structure shown should be adopted more importantly. Also, if a stereochemistry of a structure or a portion of a structure is not indicated, for example by bold or dotted lines, it is understood that the structure or portion of the structure includes all stereoisomers thereof.

4.2. Second active ingredient

One or more second active ingredients may be used with the selective cytokine inhibitory drugs of the invention. Preferably, the second active ingredient or agent may inhibit overproduction of hematopoietic stem cells or ameliorate one or more symptoms of MPD.

The second active agent can be, but is not limited to, small molecules (eg, synthetic inorganic, organometallic, or organic molecules), large molecules, synthetic drugs, peptides, polypeptides, proteins, nucleic acids, antibodies, and the like. Any agent known to be useful for, used for, or currently used for the prevention, treatment or amelioration of one or more symptoms of MPD may be used with the present invention. Certain agents include anticancer agents (e.g., anti-metabolic agents, antibiotics, alkylating agents, microtubule inhibitors, steroid hormones, DNA-recovery enzyme inhibitors, kinase inhibitors, farnesyl transferase inhibitors, antisense oligonucleotides, immunomodulators, antibodies, vaccines and adenosine Deaminase inhibitors, all-trans retinoic acid (eg, arsenic trioxide), platelet inhibitors (eg, aspirin, dipyridamole, ticlopidine, anagrelide), anticoagulants (eg , Enoxaphrine, heparin, vaparin), thrombolytics (eg, alteplase (tPA), annitreplase, streptokinase, urokinase), antifibrotic agents (eg, penicillamine, water Lamin, clochicin), agents used to treat bleeding (eg, aminocaproic acid, protamine sulfate, vitamin K), and agents used to treat anemia (eg, vitamins) K, folic acid), but is not limited to these.

The present invention also encompasses natural, natural presence, and the use of recombinant proteins. The invention further includes mutants and derivatives (eg, modified forms) of naturally occurring proteins that exhibit at least a portion of the pharmacological activity of the proteins on which they are based in vivo. Examples of mutants include, but are not limited to, proteins having one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the protein. In addition, the term “mutants” includes proteins lacking carbohydrate moieties that normally exist in their naturally occurring forms (eg, aglycosylated forms). Examples of derivatives include, but are not limited to, phenylated derivatives, and fusion proteins such as proteins formed by fusing IgG1 or IgG3 to a protein or active moiety of the protein of interest (see, eg, Penichet, ML and Morrison). , SL, J. Immunol Methods 248: . 91-101 (2001)).

The invention further includes the use of immune cells or transplantation of blood and bone marrow stem cells. For example, CML patients can be treated by infusion of donor leukocytes that inhibit the growth of leukemia cells (Slavin et. al ., Transfus Apheresis Sci 27 (2): 159-66 (2002)).

Examples of anticancer drugs that can be used in various embodiments of the present invention, including methods of the present invention, dosing regimens, cocktails, pharmaceutical compositions, and dosage forms and kits, include , But not limited to: abyssin; Aclarubicin; Acodazole hydrochloride; Acronin; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Amethanetron acetate; Aminoglutetane immunomodulatory compounds of the present invention; Amsacrine; Anastrozole; Anthracycin; Asparaginase; Asperlin; Azacytidine; Azethepa; Azotomycin; Batimastad; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Bisnaphide dimesylate; Bizelesin; Bleomycin sulfate; Brequinar sodium; Bropyrimin; Busulfan; Cocktinomycin; Calusosterone; Carracemide; Carbetatimers; Carboplatin; Carmustine; Carrubicin hydrochloride; Carzelesin; Sedefingol; Celecoxib (COX-2 inhibitor); Chlorambucil; Sirolemycin; Cisplatin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diajikuon; Dacarbazine; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droroxifene citrate; Dromostanolone propionate; Duazomycin; Edda trexate; Eflornithine hydrochloride; Elsammitrusin; Enroplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; Erbulosol; Esorubicin hydrochloride; Esturamustine; Esthramustine phosphate sodium; Ethanidazol; Etoposide; Etoposide phosphate; Etorine; Padrosol hydrochloride; Pazarabine; Fenretinide; Phloxuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Phosquidone; Postriecin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Monomorphine; Intoleukin II (including recombinant interleukin II or rIL2); Interferon alfa-2a; Interferon alpha-2b; Interferon alpha-n1; Interferon alpha-n3; Interferon beta-I a; Interferon gamma-I b; Ifoplatin; Irinotecan; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarosol hydrochloride; Rometrexole sodium; Romustine; Roxanthrone hydrochloride; Plum wine; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melenzestrol acetate; Melparan; Menogaryl; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprin; Meteuredepa; Mythinamide; Mitocarcin; Mitochromen; Mitogiline; Mitomalcin; Mitomycin; Mitosper; Mitothene; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Oblimersen; Ormaplatin; Oxyshuran; Paclitaxel; Pegasparase; Peliomycin; Pentamustine; Pepleomycin sulfate; Perphosphamide; Fifobroman; Capulsulfan; Pyroxanthrone hydrochloride; Plicamycin; Plomethane; Porphymer sodium; Porphyromycin; Prednismustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazopurin; Ribophrine; Rogletane immunomodulatory compounds of the invention; Safingol; Safingol hydrochloride; Semustine; Simtragen; Sparfosate sodium; Spartomycin; Spirogermanium hydrochloride; Spiromostin; Spiroplatin; Streptonigrin; Streptozosin; Sulfofenur; Thalisomycin; Tecogallan sodium; Taxotere; Tegapur; Teloxtron hydrochloride; Temophorin; Teniposide; Theroxylone; Testosterone; Thiamiprine; Thioguanine; Thiotepa; Thiazopurin; Tyrapazamine; Toremifene citrate; Trestolone acetate; Trisiribin phosphate; Trimetrexate; Trimetrexate glucuronate; Tryptorelin; Tubulosol hydrochloride; Uracil mustard; Euredepa; Vapretide; Berteporphine; Vinblastine sulfate; Vincristine sulfate; Bindesin; Vindesine sulfate; Vinepidine sulfate; Vin glycinate sulfate; Binroyrosine sulfate; Vinorelbine tartrate; Binrocidine sulfate; Vinzolidine sulfate; Borosol; Geniplatin; Ginostatin; Zorubicin hydrochloride. Other anticancer drugs include, but are not limited to, the following drugs: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; Abiraterone; Aclarubicin; Acylpulbene; Adecayphenol; Adozelesin; Aldesleukin; ALL-TK antagonists; Altretamine; Ambamustine; Amidox; Amifostine; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitors; Antagonist D; Antagonist G; Antarelix; Anti-dorsalizing morphogenetic protein-1; Anti-androgens, prostate cancer; Antiestrogens; Antineoplasmon; Antisense oligonucleotides; Apidicholine glycinate; Apoptosis gene modulators; Apoptosis regulators; Apurinic acid; Ara-CDP-DL-PTBA; Arginine deaminase; Asulacrine; Atamesteine; Atrimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxins; Azatyrosine; Baccatin III derivatives; Balanol; Batimastad; BCR / ABL antagonists; Benzochlorine; Benzoylstaurosporin; Beta lactam derivatives; Beta-aletin; Betaclomycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnaphide; Bistratene A; Bizelesin; Breplates; Bropyrimin; Budotetiin; Butionine sulfoximine; Calcipotriol; Calfostine C; Camptothecin derivatives; Canarypox IL-2; Capecitabine; Carboxamide-amino-triazole; Carboxamidotriazoles; CaRest M3; CARN 700; Cartilage induced inhibitors; Carzelesin; Casein kinase inhibitors (ICOS); Castanospermine; Secropin B; Setlorellix; Chlorins; Chloroquinoxaline sulfonamides; Cicafrost; Cis-porphyrin; Cladribine; Clomiphene homologs; Clotrimazole; Cholismycin A; Cholismycin B; Combretastatin A4; Combretastatin homologues; Conazenin; Cramblesdine 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cyfemycin; Cytarabine oxphosphate; Cytolytic factor; Cytostatin; Daclicksimab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexiphosphamide; Dexlaonic acid; Dexverapamil; Diajikuon; Didemnin B; Dedox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenyl spiromostin; Docetaxel; Docosanol; Dolacetron; Doxyfluidine; Droloxifene; Dronabinol; Duocarmycin SA; Epselen; Echomustine; Edelfosine; Edrecolomab; Eflornithine; Element; Emitepur; Epirubicin; Epristeride; Esturamustine homologues; Estrogen agonists; Estrogen antagonists; Ethanidazol; Etoposide phosphate; Exemsteine; Padrosol; Pazarabine; Fenretinide; Filgrastim; Finasteride; Flavopyridols; Flezelastine; Fluasterone; Fludarabine; Fluorodaunorunycin hydrochloride; Porfenix; Formemsteine; Postriecin; Potemustine; Gadolinium texaphyrin; Gallium nitrate; Gallocitabine; Ganirelex; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hepsulpam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Udoxifen; Isdramantone; Monomorphine; Ilomatstat; Immunomodulatory compounds azoacridone of the invention; Imiquimod; Immunostimulant peptides; Insulin-positive growth factor-1 receptor inhibitors; Interferon agonists; Interferon; Interleukin; Iobenguan; Iododoxorubicin; Ifomianol, 4-; Ilopact; Irsogladine; Isobenazole; Iso homohalicondrin B; Itacrone; Jasplatinolides; Kahalide F; Lamelalin-N triacetate; Lanreotide; Reinamycin; Renograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitors; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuproreline; Levamizol; Liarosol; Linear polyamine homologues; Lipophilic disaccharide peptide; Lipophilic platinum compounds; Lysoclinamide 7; Lovaplatin; Rombrisin; Rometrexole; Rodidamine; Rooxanthrone; Lovastatin; Roxoribin; Lutetocan; Lutetium texaphyrin; Lysophylline; Soluble peptides; Maytansine; Mannostatin A; Marimastat; Plum wine; Maspin; Matrylysine inhibitors; Matrix metalloproteinase inhibitors; Menogaryl; Merbaron; Meterelin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Myrimos team; Mismatched double stranded RNA; Mitoguazone; Mitolactol; Mitomycin homologues; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofarotene; Molgramos team; Monoclonal antibodies, human chorionic gonadotropin; Monophosphoryl lipid A + myobacterium cell wall sk; Fur mall; Multiple drug resistance gene inhibitors; Multiple tumor suppressor 1-basic therapies; Mustard anticancer agent; Mycaperoxide B; Mycobacterial cell wall extract; Miraphorone; N-acetyldinaline; N-substituted benzamides; Naparelin; Nagre tip; Naloxone + pentazosin; Napabin; Naphterpine; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrile; O ⁶ -benzylguanine; Octreotide; Ocisenone; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Ormaplatin; Ostherone; Oxaliplatin; Oxaunomycin; Paclitaxel; Paclitaxel homologues; Paclitaxel derivatives; Palauamine; Palmitoylraicin; Pamidronic acid; Panaxitriol; Panomifen; Parabactin; Pazelliptin; Pegaspargase; Peldesin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubrones; Perphosphamide; Peryl alcohol; Phenazinomycin; Phenyl acetate; Phosphatase inhibitors; Fishvanyl; Pilocarpine hydrochloride; Pyrarubicin; Pyritrexime; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porphymer sodium; Porphyromycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immune modulators; Protein kinase C inhibitors; Protein kinase C inhibitors; Microalgal; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; Raltitrexide; Lamosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; Demethylated retelliptin; Rhenium Re 186 ethedronate; Lysine; Ribozyme; RII retinamide; Logeltan immunomodulatory compounds of the invention; Lohitukine; Lomurtide; Loquinimex; Rubiginone B1; Luboksil; Safingol; Seintopin; SarCNU; Sarcophytol A; Sargramos team; Sdi 1 analogues; Semustine; Aging induced inhibitor 1; Sense oligonucleotides; Signal transduction inhibitors; Signal transduction modulators; Single chain antigen binding protein; Sizopyran; Small tribe; Sodium borocaptate; Sodium phenylacetate; Solberol; Somatomedin binding protein; Sonermin; Spartoic acid; Spicamycin D; Spiromostin; Splinofentin; Spongestatin 1; Squalane; Stem cell inhibitors; Stem cell division inhibitors; Stiffamide; Stromelysine inhibitors; Sulfinosine; Hyperactive vasoactive intestinal peptide antagonists; Suradista; Suramin; Swainsonine; Synthetic glycosaminoglycans; Thalimustine; Tamoxifen methoxide; Tauromustine; Tazarotene; Tyrapazamine; Tecogallan sodium; Tegapur; Tellurium pyrilium; Telomerase inhibitors; Temophorpine; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Thaliblastine; Thiocoralin; Thrombopoietin; Thrombopoietin analogs; Thymalfasin; Thymopoietin receptor agonists; Thymotrinan; Thyroid stimulating hormone; Tin ethyl thiofurfurin; Tyrapazamine; Titanocene bichloride; Topsentin; Toremifene; Omnipotent stem cell factor; Detoxification inhibitors; Tretinoin; Triacetyluridine; Trisiribin; Trimetrexate; Tryptorelin; Trophysetron; Turosteride; Tyrosine kinase inhibitors; Tyrphostin; UBC inhibitors; Juvenimex; Urinary sinus-induced growth inhibitory factor; Urokinase receptor antagonists; Vapretide; Variolin B; Vector system; Erythrocyte gene therapy; Belaresol; Veramine; Verdin; Berteporphine; Vinorelbine; Vinxaltin; Nontaxin; Borosol; Zanoterone; Geniplatin; Zillascorb; And ginostatin stymalamer. Preferred anticancer drugs are drugs that have been shown to have therapeutic advantages in patients with MPD, such as interferon-α, hydroxyurea, busulfan, anagrelide, daunorubicin, cincristine, corticosteroid hormones (eg, Fred Nizone, beclomethasone, cortisone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone), kinase inhibitors, topoisomerase inhibitors, farnesyl transferase inhibitors, vaccines and antisense nucleotides.

Examples of kinase inhibitors include compound ST1571, imatinib mesylate (Kantarjian et al ., Clin Cancer Res . 8 (7): 2167-76 (2002)), and U.S. Pat. , 5,840,745, 5,728,868, 5,648,239, 5,587,459, all of which are incorporated herein by reference, include but are not limited to these. Preferred kinase inhibitors include, but are not limited to, compounds that directly target BCR / ABL kinases, or other kinases involved in MPD pathophysiology, such as ST1571 and imatinib mesylate.

Examples of topoisomerase inhibitors include camptothecins; Irinotecan; SN-38; Topotecan; 9-aminocamptothecins; GG-211 (GI 147211); DX-8951f; IST-622; Rubithecane; Pyrazoloacridine; XR-5000; Seintopin; UCE6; UCE1022; TAN-1518A; TAN-1518B; KT6006; KT6528; ED-110; NB-506; ED-110; NB-506; And levecamycin; Bulgarian; DNA minor groove binders such as Hoechst Dye 33342 and Chust Dye 33258; Nitidine; Pagaronin; Epiberberine; Coralline; Beta-rapacone; BC-4-1; And pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof (see, for example, Rothenberg, ML, Annals). of Oncology 8: 837-855 (1997); And Moreau, P., et al., J. Med . Chem . 41: 1631-1640 (1998). Examples of camptothecin derivatives that can be used in the methods and compositions of the present invention are described, for example, in US Pat. No. 6,043,367; 6,040,313; 5,932,588; 5,916,896; 5,889,017; 5,801,167; 5,674,874; 5,658,920; 5,646,159; 5,633,260; 5,604,233; 5,597,829; 5,552,154; 5,541,327; 5,525,731; 5,468,754; 5,447,936; 5,446,047; 5,401,747; 5,391,745; 5,364,858; 5,340,817; 5,244,903; 5,227,380; 5,225,404; 5,180,722; 5,122,606; 5,122,526; 5,106,742; 5,061,800; 5,053,512; 5,049,668; 5,004,758; 4,981,968; 4,943,579; 4,939,255; 4,894,456; And 4,604,463, each of which is incorporated herein by reference. Preferred topoisomerase inhibitors include, but are not limited to, DX-8951f, irinotecan, SN-38, and pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.

Examples of farnesyl transferase inhibitors include R115777, BMS-214662 (see for review: Caponigro, Anticancer Drugs 13 (8): 891-897 (2002)), and, for example, U.S. Pat. 6362188, 6342765, 6342487, 6300501, 6268363, 6265422, 6248756, 6.23914 million, 6232338, 6228865, 6228856, 6225322, 6218406, 6211193, 6187786, 6169096, 6159984, 6143766, 6133303, 6127366, 6124465, 6124295, 6102723, 6093737, 6090948, 6,080,870, 6,077,853, 6,071,935, 6,066,738, 6,063,930, 6,054,466, 6,051, 582, 6,061,582, 6,051,574, 6,040305, all of which are incorporated herein by reference, but are not limited to these. .

In one embodiment of the invention, the second active agent is a medicament used in gene therapy of MPD. For example, antisense oligonucleotides may block coding instructions of the tumor source such that the tumor source cannot direct the formation of the corresponding oncoprotein that causes the cells to convert into malignant cells. Examples of antisense oligonucleotides include, but are not limited to, those described in US Pat. Nos. 6,277,832, 5,998,596, 5,885,834, 5,734,033, and 5,618,709, all of which are incorporated herein by reference.

In another embodiment of the invention, the second active agent is a protein, a fusion protein thereof, or a vaccine that secretes the protein, wherein the protein is IL-2, IL-10, IL-12, IL18, G-CSF , GM-CSF, EPO, or a pharmacologically active mutant or derivative thereof. In some circumstances apparent to those skilled in the art, G-CSF, GM-CSF and EPO are undesirable. For example, G-CSF, GM-CSF and EPO are preferably not used in methods that do not utilize stem cell transplantation. In a preferred embodiment, the protein is an antibody or antibody linked to a chemical toxin or radioisotope that targets and kills overproduced cells specific in MPD patients. Such antibodies include rituximab (Rituxan ™), calicheamicin (Mylotarg ™), iburitumomab tiuxetane (Zevalin ™), and tocitumomab (Bexxar). ™)), but is not limited to these.

In certain embodiments of the invention, the second active agent is a vaccine capable of inducing antigen-specific anti-malignant cell immune responses in MPD patients. Non-limiting examples of such vaccines are described in US Pat. No. 6,432,925, which is incorporated herein by reference.

In another embodiment of the invention, the second active agent is one that can reverse multidrug resistance in an MPD patient. Overproduced cells in MPD patients have a mechanism that allows them to escape the damaging effects of chemotherapy. New drugs are being investigated to reduce resistance to important chemotherapeutic drugs used in the treatment of leukemia. Non-limiting examples of such agents are described in US Pat. No. 6,225,325, which is incorporated herein by reference.

Other medicaments of the foil that may be used with the present invention include U.S. Pat. 6,262,053, 6,258,779, 6,251,882, 6,231,893, 6,225,323, 6,221,873, 6,218,412, 6,204,364, 6,187,287, 6,183,988, 6,183,744, 6,172,112, 6,156,73, 6,143,06,6,121,6,06,121,6,121,6 And the like, but are not limited to these.

4.3. Treatment and Care

The methods of the present invention include methods for preventing, treating and / or managing various types of MPD. Unless indicated otherwise, the terms “treating” and “preventing” as used herein include inhibiting or reducing the severity or magnitude of one or more symptoms or laboratory findings associated with MPD. Symptoms associated with MPD include headache, dizziness, tinnitus, sunken vision, fatigue, cold sweats, low grade fever, systemic pruritis, nasal bleeding, sunken vision, nystagmus, abdominal fullness, thrombosis, increased bleeding , Anemia, spleen infarction, severe bone pain, hematopoiesis in the liver, ascites, esophageal varices, liver failure, dyspnea, and penile anorexia. It is not limited to these. Laboratory findings associated with MPD include clonal expansion of pluripotent hematopoietic progenitor cells with overproduction of one or more blood forming elements (eg, increased red blood cell count, increased white blood cell count, and / or increased platelet count), Presence of Philadelphia chromosome or bcr-abl gene, hyperplastic bone marrow with tear-like deformed thrombocytosis, leukocytosis, giant abnormal platelet, reticular or collagen fibrosis on peripheral blood smears, and low percentage of promyeloid cells And prominent left shifted myeloid system with blast cells. Unless otherwise indicated, the term "treating" as used herein means administering the composition after the manifestation of the symptoms of MPD, while "preventing" refers to the symptoms of symptoms, especially in patients at risk for MPD. Administration before expression is shown. Unless otherwise indicated, the term "managing" as used herein prevents the recurrence of MPD in patients who have had MPD, prolongs the time that patients with MPD maintain remission, and / or Preventing the occurrence of MPD in a patient at risk of suffering.

The present invention includes methods of treating or preventing patients with primary and secondary MPD. The invention further includes a method of treating a patient who has not been previously treated for MPD as well as a patient already treated for MPD. Because patients with MPD have heterogeneous clinical symptoms and variable clinical outcomes, it will be apparent that it may be necessary to stage patients according to their prognosis and to try treatments according to severity and stage. Indeed, the methods and compositions of the present invention include, but are not limited to, diabetes mellitus (PRV), primary thrombocytopenia (PT), chronic myelogenous leukemia (CML), and idiopathic myeloid (AMM) It can be used at various stages of treatment for patients with more than one type of MPD.

The methods encompassed by the present invention include a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer thereof, of a subject suffering from, or likely to suffer from, MPD (eg, a human). , Administration of a clathrate or prodrug. Certain patient populations include patients older than 35 years, as well as patients older than 60 years. Patients with a family history of MPD or leukemia are also preferred candidates for prophylactic regimens.

In one embodiment of the invention, the recommended daily dose range of selective cytokine inhibitory drugs for the conditions described herein is within the range of about 1 mg to about 10,000 mg per day, which is a single dose once a day Or preferably in divided doses throughout the day. More particularly, the daily dose is administered twice daily in equally divided doses. In particular, the daily dose range is from about 1 mg to about 5,000 mg per day, more particularly from about 10 mg to about 2,500 mg per day, from about 100 mg to about 800 mg per day, from about 100 mg to day Should be about 1,200 mg, or about 25 mg to about 2,500 mg per day. In managing a patient, the treatment should start at a low dose, perhaps from about 1 mg to about 2500 mg, depending on the patient's overall response as needed. The single dose or divided dose should be increased from about 200 mg to about 5,000 mg per day. In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is preferably divided twice The dose may be administered in an amount of about 400, 800, 1,200, 2,500, 5,000 or 10,000 mg per day.

4.3.1. 2nd With active agents  Combination Therapy

Certain methods of the present invention comprise 1) selective cytokine inhibitory drugs of the present invention, pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof, and 2) second active agents or active ingredients. It is administered. Examples of selective cytokine inhibitory drugs of the invention are described herein (see, eg, item 4.1); Examples of second active agents are also described herein (see Example 4.2).

In certain embodiments, one or more selective cytokine inhibitory drugs are administered in conjunction with the administration of one or more therapies used to treat, manage, or prevent myeloproliferative diseases. Non-limiting examples include the administration of anticancer cocktail regimens, such as but not limited to those containing cytarabine and anthracycline (eg, daunorubicin or idarubicin). It is to use selective cytokine inhibitory drugs.

Administration of the selective cytokine inhibitory drug and the second active agent to the patient may be performed simultaneously or sequentially by the same or different route of administration. The suitability of a particular route of administration used for a particular active agent may depend on the active agent itself (eg, whether it can be administered orally without degradation prior to entering the bloodstream) and the disease to be treated. . Preferred routes of administration for selective cytokine inhibitory drugs are oral. Preferred routes of administration for the second active agents or active ingredients of the invention are known to those of ordinary skill in the art (see, eg, Physicians'). Desk Reference , 1755-1760, 56 ^th ed., 2002).

In one embodiment, the second active agent intravenously or subcutaneously, in an amount of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg per day It is administered once or twice. The specific amount of the second active agent is the specific agent used, the type of MPD to be treated or administered, the severity and stage of the MPD, and the amount of the optional cytokine inhibitory drug of the present invention and any additional active agent administered simultaneously to the patient. It will depend on the (s). In certain embodiments, the second active agent is interferon-α, hydroxyurea, anagrelide, arsenic trioxide, ST1571, imatinib mesylate, DX-8951f, R115777, vincristine, daunorubicin, prednison, or these It is a combination of. Interferon-α is administered subcutaneously in an amount of 2 to 5 million units, three times a week. Hydroxyurea is administered orally in an amount of about 500 to about 1500 mg / d adjusted to keep platelets below 500,000 / μl without reducing neutrophil counts to <2000 / μl.

4.3.2. Use with transplantation

In another embodiment, the present invention comprises administering a selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof in combination with transplantation therapy. Methods of treating, preventing and / or managing MPD. As mentioned elsewhere herein, treatment of MPD is based on the stage and mechanism of the disease. Because unavoidable leukemia transformation is expressed at certain stages of MPD, transplantation of peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow may be necessary. The combination use of the selective cytokine inhibitory drugs and transplantation therapy of the present invention provides unique and unexpected synergy. In particular, the selective cytokine inhibitory drugs of the present invention exhibit immunomodulatory activity that can provide additive or synergistic effects when given concurrently with transplantation therapy in patients with MPD. Selective cytokine inhibitory drugs of the invention may work in conjunction with transplantation to reduce the risk of complications associated with transplant invasive procedures and associated graft-versus-host disease (GVHD). The present invention provides a selective cytokine inhibitory drug of the present invention to a patient (eg, a human) before, during or after transplantation of cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow, Methods of treating, preventing and / or managing MPD, including administering acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. Examples of stem cells suitable for use in the methods of the present invention are described in US Provisional Patent Application No. 60 / 372,348, filed April 12, 2002 (R. Hariri et. al .), the entire contents of which are incorporated herein by reference.

4.3.3. Periodic therapy ( cycling therapy )

In certain embodiments, the prophylactic or therapeutic agents of the invention are administered periodically to a patient. Periodic therapy involves repeating this sequential administration after administration of the active agent for a period of time, followed by a period of rest for a period of time. Periodic therapy may reduce the incidence of resistance to one or more therapies, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.

Thus, in one particular embodiment of the invention, the selective cytokine inhibitory drug of the invention is administered daily in single or divided doses on a 4-6 week cycle, with a pause of about 1 or 2 weeks. The present invention further allows for increasing the frequency, number and length of dosing cycles. Thus, another specific embodiment of the present invention involves administering the selective cytokine inhibitory drug for a greater number of cycles than usual when administering the selective cytokine inhibitory drug of the present invention alone. In another specific embodiment of the invention, the selective cytokine inhibitory drug of the invention is administered for a greater number of cycles which can generally cause dose-limiting toxicity in a patient who is not administered the second active ingredient.

In one embodiment, the selective cytokine inhibitory drug of the invention is administered continuously daily for three or four weeks at a dose of about 0.1 to about 150 mg / d, followed by discontinuation for one or two weeks.

In one embodiment of the present invention, the selective cytokine inhibitory drug and the second active ingredient of the present invention are administered orally during a cycle of 4 to 6 weeks, wherein the administration of the selective cytokine inhibitory drug of the present invention is a second active ingredient. 30 to 60 minutes before administration. In another embodiment of the invention, the combination of the selective cytokine inhibitory drug of the invention and the second active ingredient is administered by intravenous infusion over about 90 minutes every cycle. In general, the number of cycles in which the combination therapy is administered to a patient may be from about 1 to about 24 cycles, more generally about 2 to about 16 cycles, and more generally about 4 to about 8 cycles.

4.4. Pharmaceutical Compositions and Single Unit Dosage Forms

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

Pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the present invention may comprise the active ingredients described herein (eg, selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, sorbates, hydrates, stereoisomers, clathrates or Prodrugs, and second active ingredients). Examples of any additional active ingredients are described herein (see Example 4.2).

Single unit dosage forms of the invention can be used to provide oral, mucosal (eg, intranasal, sublingual, vaginal, oral, or rectal) or parenteral (eg, subcutaneous, intravenous, bolus injection, muscle) to a patient. Intra or intraarterial), transdermal or transcutaneous administration. Examples of dosage forms include tablets; Caplets; Capsules such as soft elastic gelatin capsules; Cachets; Troches; Lozenges; Dispersants; Suppositories; powder; Aerosols (eg, nasal sprays or inhalants); Gels; Liquid dosage forms suitable for oral or mucosal administration to a patient, including suspending agents (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs; Liquid dosage forms suitable for parenteral administration to a patient; And sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

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

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends upon a variety of factors well known in the art, including but not limited to, the manner in which the dosage form will be administered to the patient. For example, oral dosage forms such as tablets may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredient in the dosage form. For example, degradation of some active ingredients may be accelerated by some excipients, such as lactose, or upon exposure to water. Active ingredients comprising primary or secondary amines may be particularly sensitive to such accelerated degradation. Thus, the present invention includes pharmaceutical compositions and dosage forms that contain mono- or di-saccharides other than lactose even if present. As used herein, the term "lactose-free", if any, means that the amount of lactose present is insufficient to substantially increase the degradation rate of the active ingredient.

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

Since water can catalyze the degradation of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising the active ingredient. For example, the addition of water (eg 5%) is widely employed in the pharmaceutical arts as a means of simulating long term storage to determine such characteristics as shelf life or stability of the formulation over time. (See, eg, Jens T. Carstensen, Drug Stability: Principles & Practice , 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80). Indeed, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on the formulation can be very important, as moisture and / or humidity is commonly encountered during manufacture, handling, packaging, storage, transportation and use of the formulation.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture-containing components and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising primary or secondary amines are preferably anhydrous if significant contact with moisture and / or humidity is expected during manufacture, packaging and / or storage. to be.

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

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

As with the amount and type of excipient, the amount and specific type of active ingredient in the dosage form can vary depending on factors such as, but not exclusively, the route to be administered to the patient. However, typical dosage forms of the present invention contain a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof in an amount of about 1 to about 1,200 mg. Typical dosage forms include selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, sorbates, hydrates, stereoisomers, clathrates or prodrugs thereof in about 1, 2, 5, 10, 25, 50, 100, 200, In amounts of 400, 800, 1200, 2500, 5000 or 10000 mg. In certain embodiments, preferred dosage forms comprise 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide at about 400, In an amount of 800 or 1200 mg. Typical dosage forms contain the second active ingredient in an amount of 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. Of course, the specific amount of the second active ingredient will depend on the particular agent used, the type of MPD being treated or administered, and the optional cytokine inhibitory drug administered simultaneously to the patient and any additional amount (s) of the active ingredient.

4.4.1. Oral dosage form

Pharmaceutical compositions of the invention suitable for oral administration include, but are not limited to, tablets (eg, chewable tablets), caplets, capsules and liquids (eg, aromatic syrups) May be present in discrete dosage forms. Such dosage forms contain a predetermined amount of the active ingredient and may be prepared by pharmaceutical methods well known to those skilled in the art (general reference: Remington's Pharmaceutical Sciences , 18th ed., Mack Publishing Easton PA (1990).

Typical oral dosage forms of the invention are prepared by combining the active ingredient in intimate mixture with at least one excipient according to conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, fragrances, preservatives and colorants. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules and caplets) include starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants However, it is not limited to these.

Because of their ease of administration, tablets and capsules represent the most beneficial oral unit dosage forms, in which case solid excipients are used. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any pharmaceutical method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier or both, and then, if necessary, forming the product in the desired form.

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

Examples of excipients that can be used in the oral dosage form of the present invention include, but are not limited to, binders, fillers, disintegrants and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include corn starch, potato starch or other starches, gelatin, natural and synthetic rubbers such as acacia, sodium alginate, alginic acid, other alginates, powdered tra Gancan, guar gum, cellulose and derivatives thereof (e.g. ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl Methyl cellulose (eg, Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof, including but not limited to.

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

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powdered cellulose, dexrate, kaolin, mannitol , Silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the present invention is generally present in about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate upon storage, while tablets that contain too little cannot disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant must be used to form the solid oral dosage form of the present invention, not too much or too little to deleteriously change the release of the active ingredient. The amount of disintegrant used depends on the type of formulation and can be readily determined by those skilled in the art. Typical pharmaceutical compositions comprise about 0.5 to about 15 weight percent of disintegrant, preferably about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the present invention include agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polyacrylic potassium, sodium starch glycol Latex, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, rubbers, and mixtures thereof. .

Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include calcium stearate, magnesium stearate, mineral oil, diesel oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, Talc, hydrogenated vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof, but It is not limited to. Further lubricants include, for example, siloid silica gel (manufactured by AEROSIL 200, WR Grace Co., Baltimore, MD), agglomerated aerosols of synthetic silica (Degussa Co., Plano, TX). CAB-O-SIL (hot silicon dioxide sold by Cabot Co., Boston, MA), and mixtures thereof. Once used, lubricants are generally used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

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

4.4.2. Sustained release  Dosage type

The active ingredients of the present invention may be administered by controlled release means or by delivery devices well known to those skilled in the art. Examples thereof include U.S. Patent Nos. 3,845,770, each of which is incorporated herein by reference; 3,916,899; 3,536,809; 3,598,123; And 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566. For example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, particulates, liposomes, microspheres, or these to provide variable ratios of desired release profiles. Such dosage forms using combinations of can be used to provide sustained or controlled release of one or more active ingredients. Suitable controlled-release preparations known to those skilled in the art, including those described herein, can be readily selected for use by the active ingredients of the present invention. Accordingly, the present invention includes single unit dosage forms suitable for oral administration such as tablets, capsules, gelcaps and caplets suitable for controlled release.

All controlled-release pharmaceutical products have a common purpose to improve drug therapy beyond that achieved by their non-controlled counterparts. Ideally, the use of controlled-release preparations that are optimally designed in medical treatment is characterized in that the minimum drug component is used to treat or control the condition within the minimum amount of time. Advantages of controlled-release preparations include prolonged activity of the drug, reduced frequency of dosing, and elevated patient compliance. In addition, controlled-release agents can be used to influence other features, such as the time of onset of action, or the blood level of the drug, and thus affect the occurrence of adverse effects (eg, deleterious action). .

Most controlled-release preparations primarily release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and gradually and continuously release an additional amount of drug to produce a therapeutic or prophylactic effect over a long period of time. It is designed to maintain this level of. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that can replace the amount of drug that is metabolized and excreted from the body. Controlled-release of the active ingredient can be facilitated by a variety of conditions, including but not limited to pH, temperature, enzymes, water or other physiological conditions or compounds.

4.4.3. Parenteral  Dosage type

Parenteral dosage forms can be administered to a patient in a variety of ways including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial. Since their administration generally bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or may be sterilized prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, solutions for immediate injection, dry products prepared to be dissolved or suspended in pharmaceutically acceptable injectable vehicles, suspensions for immediate injection, and emulsions.

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

Compounds that increase the solubility of one or more active ingredients described herein may also be included within the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of selective cytokine inhibitory drugs and derivatives thereof (see, eg, US Pat. No. 5,134,127, incorporated herein by reference).

4.4.4. Topical and mucosal dosage forms

Topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to those skilled in the art (see, for example, Remington's). Pharmaceutical Sciences , 16 ^th and 18 ^th eds., Mack Publishing, Easton PA (1908 &1990); And Introduction to Pharmaceutical Dosage Forms , 4th ed., Lea & Febiger, Philadelphia (1985)). Dosage forms suitable for treating mucosal tissues in the oral cavity may be formulated as mouthwashes or oral gels.

Suitable excipients (eg, carriers and diluents) and other materials that can be used to provide the topical and mucosal dosage forms encompassed by the present invention are well known to those of ordinary skill in the pharmaceutical arts and The composition or dosage form depends on the particular tissue to which it is applied. In view of this fact, typical excipients include non-toxic and pharmaceutically acceptable water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, iso, which form solutions, emulsions or gels. Propyl palmitate, mineral oil, and mixtures thereof, including but not limited to. Moisturizers or humectants may also be added to the pharmaceutical compositions and dosage forms as needed. Examples of such additional ingredients are well known in the art (see, eg, Remington's). Pharmaceutical Sciences , 16 ^th and 18 ^th eds., Mack Publishing, Easton PA (1980 & 1990).

The pH of the pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, delivery can be improved by adjusting the polarity of the solvent carrier, its ionic strength or tonicity. Compounds such as stearates may also be added to the pharmaceutical composition or dosage form to advantageously change the hydrophilicity or lipophilic properties of one or more active ingredients to improve delivery. In this regard, stearates may act as lipid vehicles for formulations, as emulsifiers or surfactants, and as delivery-enhancing or penetration-enhancing agents. Other salts, hydrates or sorbates of the active ingredient may be used to further adjust the properties of the resulting composition.

4.4.5. Kit  ( kits )

In general, the active ingredients of the invention are preferably not administered to the patient at the same time or by the same route of administration. Accordingly, the present invention includes kits that, when used by a physician, can simplify the administration of an appropriate amount of active ingredient to a patient.

Typical kits of the invention include dosage forms of selective cytokine inhibitory drugs or pharmaceutically acceptable salts, sorbates, hydrates, stereoisomers, prodrugs or clathrates thereof. Kits included in the present invention are interferon-α, hydroxyurea, anagrelide, arsenic trioxide, ST1571, imatinib mesylate, DX-8951f, R115777, vincristine, daunorubicin, prednisone, or drugs thereof It may further comprise additional active ingredients such as, but not limited to, pharmaceutically active mutants or derivatives, or combinations thereof. Examples of additional active ingredients include, but are not limited to, those described herein (see, eg, Item 4.2).

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

Kits of the invention may further comprise a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients, as well as cells or blood for transplantation. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may be sealed with a suitable vehicle in which the active ingredient can be dissolved to form a particle-free sterile solution suitable for parenteral administration. It may comprise a container. Examples of pharmaceutically acceptable vehicles include water for injection USP; Aqueous vehicles such as, but not limited to, sodium chloride injections, Ringer's injections, dextrose injections, dextrose and sodium chloride injections, and lactated Ringer's injections; Water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; And non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

5. Example

The following tests are intended to further illustrate the present invention without limiting the scope thereof.

5.1. Pharmacological and Toxic  exam

A series of non-clinical pharmacological and toxicological tests are performed to support the clinical evaluation of selective cytokine inhibitory drugs in human subjects. These tests are carried out in accordance with internationally recognized guidelines for test design unless otherwise stated and in accordance with the requirements of Good Laboratory Practice (GLP).

Pharmacological properties of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide including activity comparison with thalidomide It is specified in in vitro tests. The test examines the effect of 3- (3,4-dimethoxy-phenyl) -3 (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide on the production of various cytokines. . In addition, safety pharmacological tests of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide were also performed in dogs, The effect of the compound on the ECG parameters is further tested as part of the three repeat-dose toxicity studies in primates.

5.2. Cytokines  Modulation of production

LPS-stimulation of human PBMCs and human whole blood by 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide Inhibition of TNF-α production in vitro (Muller et. al ., Bioorg . Med . Chem . Lett . 9: 1625-1630, 1999). 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole- to inhibit the production of TNF-α following LPS-stimulation of PBMCs and human whole blood IC ₅₀ of 2-yl) -propionamide is measured.

5.3. Toxic  exam

Effects of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide on cardiovascular and respiratory function in anesthetized dogs Investigate. Two groups of Beagle dogs (2 / sex / group) are used. One group administered three doses of vehicle only, and the other group administered three increased doses of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole. 2-yl) -propionamide (400, 800 and 1,200 mg / kg / day) is administered. In all cases, the dose of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide or vehicle is at least 30 minutes. Separated at intervals and administered continuously by infusion through the jugular vein.

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

All patents cited herein are incorporated by reference in their entirety. Embodiments of the invention described herein are merely sampling of the scope of the invention. The full scope of the invention is better understood by reference to the appended claims.

Claims (40)

Patients in need of treatment or prevention of myeloproliferative disorders are provided with a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. A method of treating or preventing myeloproliferative disorders, including administering. Administering a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient in need thereof. , How to manage myeloproliferative diseases. A therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in a patient in need of treatment or prevention of myeloproliferative diseases, And administering a therapeutically or prophylactically effective amount of at least one second active agent. Prophylactically effective amounts of selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof, and at least one agent in a patient in need of management of myeloproliferative diseases 2 A method of managing myeloproliferative disorders comprising administering a therapeutically or prophylactically effective amount of an active agent. 5. The method of claim 1, wherein the patient is nonresponsive to treatment of conventional myeloproliferative disease. 5. The method of claim 1, wherein the patient is nonresponsive to the treatment of myeloproliferative diseases comprising thalidomide. 6. The method of claim 3 or 4, wherein the second active agent is capable of inhibiting overproduction of hematopoietic stem cells or ameliorating one or more symptoms of myeloproliferative disease. 5. The method according to claim 3, wherein the second active agent is a cytokine, corticosteroid, ribonucleotide reductase inhibitor, platelet inhibitor, anticoagulant, thrombolytic agent, antifibrotic agent, all-trans retinoic acid, kinase A method that is an inhibitor, a topoisomerase inhibitor, a farnesyl transferase inhibitor, an antisense oligonucleotide, an antibody, a drug used to reverse multi-drug resistance, a vaccine, a myelosuppressive drug, or an anticancer agent. The method according to claim 8, wherein the second active agent is interferon-α, hydroxyurea, anagrelide, busulfan, arsenic trioxide, ST1571, imatinib mesylate, DX-8951f, R115777, vincristine, daunorubicin, Prednisone, or a pharmacologically active mutant or derivative thereof, or a combination thereof. The method according to any one of claims 1 to 4, wherein the myeloproliferative disease is diabetes mellitus, primary thrombocytopenia, chronic myeloid leukemia or idiopathic myeloid. 5. The method of claim 1, wherein the myeloproliferative disease is primary or secondary. The method according to any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole- 2-yl) -propionamide. The method of claim 12, wherein the selective cytokine inhibitory drug is enantiomerically pure. The method according to claim 1, wherein the selective cytokine inhibitory drug is cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl ] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} -amide. The method of claim 14, wherein the selective cytokine inhibitory drug is enantiomerically pure. 5. The method of claim 1, wherein the selective cytokine inhibitory drug is a compound of formula (I): 6. <Formula I>

Where n has a value of 1, 2 or 3; R ⁵ is nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, O-phenylene unsubstituted or substituted by 1 to 4 substituents each independently selected from the group consisting of alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms and halo; R ⁷ is (i) phenyl, or nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, 1 to 10 carbon atoms Phenyl substituted by one or more substituents each independently selected from the group consisting of alkyl, alkoxy and halo of 1 to 10 carbon atoms, (ii) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, Unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms and halo Benzyl, (iii) naphthyl, or (iv) benzyloxy; R ¹² is —OH, alkoxy having 1 to 12 carbon atoms, or

ego; R ⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; R ⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, -COR ¹⁰ , or -SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl. The method of claim 16, wherein the selective cytokine inhibitory drug is enantiomerically pure. 5. The method of claim 1, wherein the selective cytokine inhibitory drug is a compound of Formula II: 6. <Formula II>

Where R ¹ and R ² are each hydrogen or lower alkyl when present independently of each other, or together with the illustrated carbon atoms to which they are attached nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbo Independently from the group consisting of propoxy, 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 O-phenylene, o-naphthylene or cyclohexene-1,2-diyl unsubstituted or substituted by 1 to 4 substituents selected; R ³ is nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 to C 10 alkoxy, alkylthio having 1 to 10 carbon atoms, benzyloxy, cycloalkoxy having 3 to 6 carbon atoms, C ₄ -C ₆ -cycloalkylidenemethyl, C ₃ -C ₁₀ -alkylidenemethyl, indanyloxy and halo Phenyl substituted by 1 to 4 substituents selected from the group consisting of; R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R ^{4 '} is hydrogen or alkyl of 1 to 6 carbon atoms; R ⁵ is —CH ₂ —, —CH ₂ —CO—, —SO ₂ —, —S— or —NHCO—; n has a value of 0, 1 or 2. The method of claim 18, wherein the selective cytokine inhibitory drug is enantiomerically pure. The method of any one of claims 1-4, wherein the selective cytokine inhibitory drug is a compound of formula III. <Formula III>

Where Carbon atoms marked with * constitute a chiral center; Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O; R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or —NR ⁸ R ^{9 Two} of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms represent naphthylidene with the phenylene ring shown; R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano, or cycloalkoxy having 18 or less carbon atoms; R ⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR ^{8 ′} R ^{9 ′} ; R ⁸ and R ⁹ are each independently of each other hydrogen, alkyl having 1 to 8 carbon atoms, phenyl or benzyl, one of R ⁸ and R ⁹ is hydrogen, the other is —COR ¹⁰ or —SO ₂ R ^10, or R ⁸ and R ⁹ together represent tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , wherein X ¹ is -O-, -S- or -NH-; R ^{8 '} and R ^9' are each independently hydrogen, alkyl having 1 to 8 carbon atoms, phenyl or benzyl, or one of R ^{8 '} and R ^9' is hydrogen, the other is -COR ^{10 '} or -SO ₂ R ^{10 '} or R ^8' and R ^{9 '} together represent tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ² CH ₂ CH _2- , wherein X ² is -O-,- S- or -NH-. The method of claim 20, wherein the selective cytokine inhibitory drug is enantiomerically pure. Selective cytokine inhibitory drugs to such patients before, during or after transplantation of cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations or bone marrow in patients in need of treatment, prevention or management of myeloproliferative diseases, or A method of treating, preventing or managing myeloproliferative diseases, including administering a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug. Selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, sorbates, hydrates, stereoisomers, clathrates or prodrugs thereof, in patients with myeloproliferative disorders that need to reduce or avoid the side effects associated with the administration of the second active agent A method of reducing or avoiding side effects associated with the administration of a second active agent in a patient with myeloproliferative disease, comprising administering a therapeutically or prophylactically effective amount of. The method of claim 23, wherein the second active agent is capable of inhibiting overproduction of hematopoietic stem cells or ameliorating one or more symptoms of myeloproliferative disease. The method of claim 23, wherein the second active agent is a cytokine, corticosteroid, ribonucleotide reductase inhibitor, platelet inhibitor, anticoagulant, thrombolytic, antifibrotic, all-trans retinoic acid, kinase inhibitor, topoisomerase inhibitor, par A method that is a Nesyl Transferase Inhibitor, Antisense Oligonucleotide, Antibody, Agent, Vaccine, Myelosuppressive Agent, or Anticancer Agent used to reverse multi-drug resistance. The method of claim 25, wherein the second active agent is interferon-α, hydroxyurea, anagrelide, busulfan, arsenic trioxide, ST1571, imatinib mesylate, DX-8951f, R115777, vincristine, daunorubicin, Prednisone, or a pharmacologically active mutant or derivative thereof, or a combination thereof. The method of claim 23, wherein the side effect is conversion to acute leukemia; Severe myelosuppression; Gastrointestinal toxicities; Gastrointestinal bleeding; miscarriage of justice; throw up; Loss of appetite; Leukopenia; anemia; Neutropenia; asthenia; Abdominal cramps; Fever; ache; Weight loss; dehydration; Alopecia; Dyspnea; insomnia; Dizziness; Mucositis; Dry mouth; Mucous skin lesions; Or renal failure. A therapeutically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate, or prodrug thereof, in a patient in need of increased therapeutic efficacy of treating myeloproliferative disease; And administering a therapeutically or prophylactically effective amount of a second active agent. The method of claim 28, wherein the therapeutically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, is administered prior to administering the second active agent to the patient. How to be. The method of claim 28, wherein the therapeutically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate, or prodrug thereof, is administered during administration of the second active agent to the patient. How to be. The method of claim 28, wherein the therapeutically effective amount of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate, or prodrug thereof, is administered after the second active agent is administered to the patient. How to be. A pharmaceutical agent comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount effective to treat, prevent or manage myeloproliferative disease. Composition. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second active agent. The pharmaceutical composition of claim 33, wherein the second active agent is capable of inhibiting overproduction of hematopoietic stem cells or ameliorating one or more symptoms of myeloproliferative disease. The method of claim 33, wherein the second active agent is a cytokine, corticosteroid, ribonucleotide reductase inhibitor, platelet inhibitor, anticoagulant, thrombolytic, antifibrotic, all-trans retinoic acid, kinase inhibitor, topoisomerase inhibitor, par A pharmaceutical composition that is a necil transferase inhibitor, an antisense oligonucleotide, an antibody, a medicament used for reversing multidrug resistance, a vaccine, a myelosuppressive medicament, or an anticancer agent. 36. The method of claim 35, wherein the second active agent is interferon-α, hydroxyurea, anagrelide, busulfan, arsenic trioxide, ST1571, imatinib mesylate, DX-8951f, R115777, vincristine, daunorubicin, A pharmaceutical composition that is prednisone, or a pharmacologically active mutant or derivative thereof, or a combination thereof. Pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof; And Pharmaceutical composition comprising a second active agent capable of reversing and inhibiting overproduction of hematopoietic stem cells Kit comprising a. Pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof; And Umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow Kit comprising a. Pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof; Cytokines, corticosteroids, ribonucleotide reductase inhibitors, platelet inhibitors, anticoagulants, thrombolytics, antifibrotic agents, all-trans retinoic acid, kinase inhibitors, topoisomerase inhibitors, farnesyl transferase inhibitors, antisense oligonucleotides, antibodies, A pharmaceutical composition comprising a second active agent which is a medicament, a vaccine, a myelosuppressive agent, or an anticancer agent used to reverse multidrug resistance; And Umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow Kit comprising a. 40. The kit of any one of claims 37-39, further comprising a device for administering the pharmaceutical composition or a single unit dosage form.