HK1104969A - Methods and compositions using selective cytokine inhibitory drugs for treatment and management of cancers and other diseases - Google Patents

Abstract

Methods of treating, preventing and/or managing cancer as well as and diseases and disorders associated with, or characterized by, undesired angiogenesis are disclosed. Specific methods encompass the administration of a selective cytokine inhibitory drug alone or in combination with a second active ingredient. The invention further relates to methods of reducing or avoiding adverse side effects associated with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy which comprise the administration of a selective cytokine inhibitory drug. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

Methods and compositions for treatment and management of cancer and other diseases using selective cytokine inhibitory drugs

1. Field of the invention

The present invention relates to methods of treating, preventing and/or managing certain cancers and other diseases, including but not limited to those associated with or characterized by undesired angiogenesis, by administering one or more selective cytokine inhibitory drugs, alone or in combination with other therapies. In particular, the present invention encompasses the use of specific combinations of drugs and other therapies, such as radiation therapy or "cocktail therapy" to treat these specific cancers, including cancers that are refractory to conventional treatments. The invention also relates to pharmaceutical compositions and dosage regimens.

2. Background of the invention

2.1 Pathology of cancer and other diseases

Cancer is mainly characterized by an increase in the number of abnormal cells derived from a normal tissue, invasion of adjacent tissues by these abnormal cells, or spread of malignant cells to regional lymph nodes and distant sites through lymph fluid or blood (metastasis). Clinical data and molecular biological studies have demonstrated that cancer is a multi-step process that begins with subtle preneoplastic changes that can in some cases progress to tumors. Neoplastic lesions can develop within allogeneic cells and increase the ability to invade, grow, metastasize, and become heterogeneous, especially if neoplastic cells escape host immune surveillance. Roitt, i., Brostoff, J and Kale, d., Immunology 17.1-17.12 (third edition, Mosby, st. louis, mo., 1993).

A large number of cancers have been described in detail in the medical literature. Examples thereof include lung cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, brain cancer and intestinal cancer. The incidence of cancer continues to rise as the population ages, new cancers emerge, and susceptible populations (e.g., people infected with AIDS or overly exposed to sunlight) increase. There is therefore an urgent need for new methods and compositions for treating cancer patients.

Many cancer types are associated with a process of neovascularization known as angiogenesis. Several mechanisms have been elucidated that are involved in tumor-induced angiogenesis. The most critical guide for these mechanisms is the secretion of cytokines with angiogenic properties by tumor cells. Examples of such cytokines include acidic and basic fibroblast growth factors (a, b-FGF), angiogenin, Vascular Endothelial Growth Factor (VEGF), and TNF- α. Alternatively, tumor cells can release angiogenic peptides by producing proteases that in turn disrupt the extracellular matrix that stores certain cytokines (e.g., b-FGF). Angiogenesis can also be induced indirectly by the recruitment of inflammatory cells (specifically macrophages), which subsequently release angiogenic cytokines (e.g., TNF- α, bFGF).

Many other diseases and conditions are also associated with or characterized by undesired angiogenesis. For example, enhanced or unregulated angiogenesis has resulted in a number of diseases and clinical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, flushing (neovascularization of the canthus), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrocrystallic fibroplasia and proliferative vitreoretinopathy.

Accordingly, compounds that control angiogenesis or inhibit the production of certain cytokines, including TNF- α, are useful in the treatment and prevention of various diseases and disorders.

2.2 methods of treating cancer

Current cancer therapies include surgery, chemotherapy, hormonal therapy and/or radiation therapy to eradicate neoplastic cells in a patient (see, e.g., Stockdale, 1998, Medicine, Vol.3, Rubenstein and Federman eds., Chapter 12, section IV). More recently, cancer treatment methods also include biological therapy or immunotherapy. All of these methods have significant drawbacks for the patient. For example, surgery may be contraindicated or unacceptable to the patient due to patient health issues. In addition, surgery cannot completely remove tumor tissue. Radiotherapy is only effective when the tumor tissue is more sensitive to radiation than normal tissue. Radiotherapy also often has serious side effects. Hormone therapy is rarely used alone. Although hormone therapy can be effective, it is often used to prevent or delay cancer recurrence after other treatments have removed a large proportion of the cancer cells. Biological and immunotherapy are limited in number and may cause side effects such as rashes or swelling, cold-like symptoms including fever, cold and fatigue, digestive tract problems or allergic reactions.

In the case of chemotherapy, there are many chemotherapeutic agents for the treatment of cancer. Cancer chemotherapy acts primarily by inhibiting DNA synthesis directly, or indirectly by inhibiting deoxynucleoside triphosphate precursor biosynthesis, to prevent DNA replication and concomitant cell division. Gilman et al, Goodman and Gilman's: the Pharmacological Basis of Therapeutics, eds (McGraw Hill, New York).

Although a variety of chemotherapeutic agents may be used, chemotherapy has a number of disadvantages. Stockdale, Medicine, Vol.3, Rubenstein and Federman eds, Chapter 12, section 10, 1998. Almost all chemotherapeutic agents are toxic and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. Furthermore, even when chemotherapeutic agents are used in combination, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. Indeed, those cells that are resistant to a particular chemotherapeutic agent used in a treatment regimen often demonstrate resistance to other drugs, even though those agents act by a different mechanism than the drug used in the particular treatment. This phenomenon is known as multiple drug resistance or multidrug resistance. Due to this resistance, many cancer evidences are refractory to standard chemotherapy.

Other diseases or conditions associated with or characterized by undesired angiogenesis are also difficult to treat. However, compounds such as protamine, heparin and steroids have been proposed for the treatment of certain specific diseases. Taylor et al, Nature 297: 307 (1982); folkman et al, Science 221: 719 (1983); and U.S. patent nos. 5,001,116 and 4,994,443. Thalidomide (thalidomide) and some of its derivatives have also been proposed for the treatment of such diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 to D' Amato.

There remains an urgent need for safe and effective methods for the treatment, prevention and management of cancer and other diseases and conditions, particularly those refractory to standard therapeutic approaches such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicity and/or side effects associated with conventional therapies.

2.3 Selective cytokine inhibitory drugs

Have been synthesized and tested to be called SelCIDs^TM(Celgene corporation) or a selective cytokine inhibitory drug. These compounds strongly inhibited TNF- α production, but showed moderate inhibition of LPS-induced IL1 β and IL12, but no inhibition of IL6, even at high drug concentrations. In addition, SelCIDs^TMCan moderately stimulate IL-10. L.g.corral et al, ann.rheum.dis.58: (supplement I) 1107-.

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

3. Summary of the invention

The present invention includes methods of treating and preventing certain types of cancer, including primary and metastatic cancers, as well as cancers that are refractory to conventional chemotherapy or resistant to conventional chemotherapy. The method comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods of managing certain cancers (e.g., preventing or delaying their recurrence, or prolonging their time to remission) which comprise administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In particular methods of the invention, selective cytokine inhibitory drugs are administered in combination with therapies conventionally used to treat, prevent or manage cancer. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy.

The invention also encompasses methods of treating, managing or preventing non-cancer diseases and disorders associated with or characterized by undesired angiogenesis, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In other methods of the invention, selective cytokine inhibitory drugs are administered in combination with therapies conventionally used to treat, prevent or manage diseases or conditions associated with or characterized by undesired angiogenesis. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy, and immunotherapy.

The invention encompasses pharmaceutical compositions, single unit dosage forms, dosage regimens and kits comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second or additional active agent. The second active agent comprises a particular combination of drugs or a "cocktail".

4. Detailed description of the invention

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

In particular methods encompassed by this embodiment, the selective cytokine inhibitory drug is administered in combination with another drug ("second active agent") or method of treating, managing and preventing cancer. Second active agents include small and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods or treatments that may be administered in combination with selective cytokine inhibitory drugs include, but are not limited to, surgery, blood transfusion, immunotherapy, biotherapy, radiation therapy, and other non-drug based therapies currently used to treat, prevent, or manage cancer.

Another embodiment of the invention encompasses methods of treating, managing or preventing non-cancer diseases and disorders characterized by undesired angiogenesis, which comprise administering a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Examples of diseases and conditions associated with or characterized by undesired angiogenesis include, but are not limited to: inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, and flushing (canthus neovascularisation). Specific examples of diseases and conditions associated with or characterized by undesired angiogenesis include, but are not limited to, endometriosis, Crohn's disease, heart failure, progressive heart failure, kidney injury, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary diseases, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, large cell anemia, refractory anemia, and 5 q-syndrome.

In particular methods encompassed by this embodiment, a selective cytokine inhibitory drug is administered in combination with a second active agent or method of treating, managing or preventing the disease or condition. Second active agents include small and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods or treatments that may be administered in combination with selective cytokine inhibitory drugs include, but are not limited to: surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies currently used to treat, prevent or manage diseases and conditions associated with or characterized by undesirable angiogenesis.

The invention also includes pharmaceutical compositions (e.g., single unit dosage forms) that can be used in the methods disclosed herein. Particular pharmaceutical compositions comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent.

4.1 Selective cytokine inhibitory drugs

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

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

Specific examples of selective cytokine inhibitory drugs include, but are not limited to: cyclic imines disclosed in U.S. Pat. nos. 5,605,914 and 5,463,063; cycloalkyl amides and cycloalkyl nitriles disclosed in U.S. Pat. nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644, and 6,518,281; arylamides disclosed in U.S. patents 5,801,195, 5,736,570, 6,046,221, and 6,284,780 (e.g., N-benzoyl-3-amino-3- (3 ', 4' -dimethoxyphenyl) -propionamide); imine/amide ethers and alcohols disclosed in U.S. patent 5,703,098 (e.g., 3-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propan-1-ol); succinimides and maleimides disclosed in U.S. patent 5,658,940 (e.g., methyl 3- (3 ', 4', 5 ', 6' -tetrahydrophthalimido) -3- (3 ", 4" -dimethoxyphenyl) propionate); imino and amino substituted alkanohydroxamic acids disclosed in U.S. patent 6,214,857 and WO 99/06041; substituted phenethylsulfones disclosed in U.S. Pat. nos. 6,011,050 and 6,020,358; fluoroalkoxy-substituted 1, 3-dihydro-isoindolyl compounds disclosed in U.S. patent application 10/748,085, filed on 29/12/2003; substituted imines disclosed in U.S. patent 6,429,221 (e.g., 2-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propane); substituted 1, 3, 4-oxadiazoles (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1, 3, 4-oxadiazol-2-yl) ethyl ] -5-methylisoindoline-1, 3-dione) disclosed in U.S. patent 6,326,388; cyano and carboxyl derivatives of substituted styrenes disclosed in U.S. Pat. nos. 5,929,117, 6,130,226, 6,262,101, and 6,479,554 (e.g., 3, 3-bis- (3, 4-dimethoxyphenyl) acrylonitrile); isoindolin-1-ones and isoindoline-1, 3-diones substituted in the 2-position with an α - (3, 4-disubstituted phenyl) alkyl group and in the 4-and/or 5-position with a nitrogen-containing group as disclosed in WO 01/34606 and U.S. patent 6,667,316; imino-and amino-substituted acylhydroxamic acids (e.g., (3- (1, 3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanolamino) propanoate) disclosed in WO 01/45702 and U.S. patent 6,699,899. Other selective cytokine inhibitory drugs include the diphenylethylene compounds disclosed in U.S. provisional application 60/452,460, filed 3/5/2003, the contents of which are incorporated herein by reference in their entirety. The contents of each of the patents and patent applications referred to herein are incorporated by reference.

Other selective cytokine inhibitory drugs belong to the family of synthetic chemical compounds, typical examples of which include 3- (1, 3-dioxobenzo- [ f ] isoindol-2-yl) -3- (3-cyclopentyloxy-4-methoxyphenyl) propionamide and 3- (1, 3-dioxo-4-azaisoindol-2-yl) -3- (3, 4-dimethoxyphenyl) -propionamide.

Other specific selective cytokine inhibitory drugs belong to the non-polypeptide cyclic imines disclosed in U.S. Pat. Nos. 5,698,579, 5,877,200, 6,075,041, and 6,200,987, and WO 95/01348, each of which is incorporated herein by reference. Representative cyclic imines include compounds having the formula:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid methyl ester. Other representative cyclic imines include compounds having the formula:

wherein Z is:

or R⁴-，

Wherein:

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

R²is-CO-or-SO₂-；

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

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

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

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

R⁶is-CO-, -CH₂-or-SO₂-；

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

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

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

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

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

Other representative imines include compounds having the formula:

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

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

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

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

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

Other specific selective cytokine inhibitory drugs include imino-and amino-substituted alkanohydroxamic acids disclosed in WO 99/06041 and U.S. Pat. No. 6,214,857, each of which is incorporated herein by reference. Examples of such compounds include, but are not limited to:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-nitrobenzodiimido) propanamide;

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

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

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

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

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

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

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

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

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

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

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophenyldicarboximido) propanamide.

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

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

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

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

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

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

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

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

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

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

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

Specific compounds are, wherein R¹、R²、R³And R⁴One is-NHCOCH₃And the balance being hydrogen compounds.

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

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

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

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

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

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

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

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

Specific compounds are, wherein R⁷A compound that is methyl.

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

Other selective cytokine inhibitory drugs include fluoroalkoxy-substituted 1, 3-dihydro-isoindolyl compounds disclosed in U.S. patent application 10/748,085, filed 12/29/2003, which is incorporated herein by reference in its entirety. Representative compounds are of the formula:

wherein:

y is-C (O) -, -CH₂、-CH₂C(O)-、-C(O)CH₂-or SO₂；

Z is-H, -C (O) R³、-(C_0-1-alkyl) -SO₂-(C_1-4Alkyl), C_1-8-alkyl, -CH₂OH、CH₂(O)(C_1-8-alkyl) or-CN;

R₁and R₂Are each independently-CHF₂、-C_1-8-alkyl, -C_3-18-cycloalkyl or- (C)_1-10-alkyl) (C_3-18-cycloalkyl), and R¹And R²At least one of which is CHF₂；

R³is-NR⁴R⁵-alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl;

R⁴and R⁵Are each independently-H, -C_1-8-alkyl, -OH, -OC (O) R⁶；

R⁶is-C_1-8-alkyl, -amino (C)_1-8-alkyl), -phenyl, -benzyl or-aryl;

X₁、X₂、X₃and X₄Are each independently-H, -halogen, -nitro, -NH₂、-CF₃、-C_1-6Alkyl, - (C)_0-4-alkyl) - (C_3-6-cycloalkyl), (C)_0-4-alkyl) -NR⁷R⁸、(C_0-4-alkyl) -N (H) C (O) - (R)⁸)、(C_0-4Alkyl) -N (H) C (O) N (R)⁷R⁸)、(C_0-4Alkyl) -N (H) C (O) O (R)⁷R⁸)、(C_0-4-alkyl) -OR⁸、(C_0-4-alkyl) -imidazolyl, (C)_0-4-alkyl) -pyrrolyl, (C)_0-4-alkyl) -oxadiazolyl or (C)_0-4-alkyl) -triazolyl, or X₁、X₂、X₃And X₄Two of which may be joined together to form a cycloalkyl or heterocycloalkyl ring (e.g., X)₁And X₂、X₂And X₃、X₃And X₄、X₁And X₃、X₂And X₄Or X₁And X₄May form a 3, 4,5, 6 or 7 membered ring, which may be aromatic, thereby forming a bicyclic ring system with an isoindolyl ring); and

R⁷and R⁸Independently of one another is H, C_1-9Alkyl radical, C_3-6Cycloalkyl group, (C)_1-6-alkyl) - (C_3-6-cycloalkyl), (C)_1-6-alkyl) -N (R)⁷R⁸)、(C_1-6-alkyl) -OR⁸Phenyl, benzyl or aryl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Other selective cytokine inhibitory drugs include enantiomerically pure compounds disclosed in the following references: U.S. patent application 10/392,195 filed on 3/19/2003; international patent applications PCT/US03/08737 and PCT/US03/08738 filed 3/20/2003; U.S. provisional patent applications 60/438,450 and 60/438,448 by g.muller et al, filed on 7/1/2003; U.S. provisional patent application 60/452,460 to g.muller et al, filed 3/5/2003; and U.S. patent application 10/715,184 filed on 17.11.2003, all of which are incorporated herein by reference. Preferred compounds include the enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione and the enantiomer of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

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

other specific selective cytokine inhibitory drugs include, but are not limited to: cycloalkyl amides and cycloalkyl nitriles disclosed in U.S. Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281 and WO 97/08143 and WO97/23457, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

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

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

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

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

R⁶is-CO-, -CH₂-or-CH₂CO-；

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

z is-NH₂、-OH、-NHR、-R⁹OR-OR⁹；

R⁸Is hydrogen or lower alkyl;

R⁹is lower alkyl or benzyl; and

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

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

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

x is-CH₂-or-O-;

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

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

(iii) vinylidene disubstituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, propisocarbonyl, acetyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxyl, hydroxyl, amino substituted with alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halogen;

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

R⁶is-CO-, -CH₂-or-CH₂CO-；

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

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

R⁸is hydrogen or lower alkyl;

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

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

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

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

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

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

R⁶is-CO-, -CH₂-or-CH₂CO-；

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

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

R⁸is hydrogen or lower alkyl;

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

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

Other representative compounds have the formula:

in the formula:

y is-C ═ N or CO (CH)₂)_mCH₃，

m is 0, 1,2 or 3;

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

R⁶is-CO-, -CH²-、-CH₂CO-or-SO₂-；

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

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

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

in the formula:

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

R⁶is-CO-, -CH₂-、-CH₂CO-or-SO₂-；

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

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

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

R⁸is hydrogen or lower alkyl;

R⁹is alkyl or benzyl; and

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

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

in the formula:

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

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

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

in the formula:

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

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

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

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

in the formula:

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

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

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

R⁴is-CX-, -CH₂-or-CH₂CX-；

X is O is S; and

n is 0, 1,2 or 3.

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

in the formula:

R¹is-CH₂-、-CH₂CO-or-CO-;

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

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

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

Wherein X is NH₂OH, NHR OR OR⁶，

Wherein R is lower alkyl; and

wherein R is⁶Is alkyl or benzyl.

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

in the formula:

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

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

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

R⁴is-CX or-CH₂-；

X is O or S.

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

in the formula:

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

y is C-O, CH₂、SO₂Or CH₂C＝O；

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

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

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

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

R⁸and R⁹Each independently hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or R⁸And R⁹One of which is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Or R is⁸And R⁹Together form tetramethylene, pentamethylene, hexamethylene, -CH-NCH-or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-;

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

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

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

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

Specific examples of such compounds have the formula:

in the formula:

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

y is C-O, CH₂、SO₂Or CH₂C＝O；

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

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

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

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

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

(ii)R⁸And R⁹One of which is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR¹¹R¹²Or CH₂NR¹⁴R¹⁵Wherein R is¹¹And R¹²Each independently hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, R¹⁴And R¹⁵Each independently hydrogen, methyl, ethyl or propyl; or

(iii)R⁸And R⁹Together form tetramethylene, pentamethylene, hexamethylene, -CH-NCH-or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-.

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

in the formula:

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

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

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

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

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

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

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

in the formula:

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

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

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

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

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

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

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

Particularly preferred nitriles are compounds having the formula:

in the formula:

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

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

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

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

Particularly preferred nitriles have the formula:

other specific selective cytokine inhibitory drugs include, but are not limited to: isoindolin-1-ones and isoindoline-1, 3-diones substituted at the 2-position with an α - (3, 4-disubstituted phenyl) alkyl group and at the 4-and/or 5-position with a nitrogen-containing group are disclosed in WO 01/34606 and U.S. Pat. No. 6,667,316, each of which is incorporated herein by reference. Representative compounds have the formula:

and including pharmaceutically acceptable salts and stereoisomers thereof,

in the formula:

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

n is 1,2 or 3;

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

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

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

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

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

R₇is H or (C)₁-C₄) An alkyl group;

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

R₈is CH₂O, NH, CH ═ CH, CH ═ N, or N ═ CH; or

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

in the formula:

z is 0 or 1;

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

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

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

R₄And R₅All have the structure of formula (A).

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

Specific compounds have the formula:

and enantiomers thereof. Other specific compounds have the formula:

and

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

Other specific selective cytokine inhibitory drugs include, but are not limited to: imino-and amino-substituted acylhydroxamic acids (e.g., (3- (1, 3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanolamino) propanoate) disclosed in WO 01/45702 and U.S. Pat. No. 6,699,899, each of which is incorporated herein by reference. Representative compounds have the formula:

in the formula:

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

R⁴is hydrogen or- (C ═ O) -R¹²，

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

CHR^*(CH₂)_nNR^*R⁰，

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

R⁵is C-O, CH₂、CH₂-CO-or SO₂；

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

R⁸、R⁹、R¹⁰and R¹¹Each independently is:

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

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

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

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

(v) Hydrogen, if R⁹And R¹⁰Together are benzo.

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

in the formula:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

X is H;

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

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

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

R⁴is H;

R⁵is-OH or-OC (O) R⁶；

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

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

in the formula:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

X is halogen, -CN, -NR₇R₈、-NO₂or-CF₃；

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

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

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

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

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

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

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

R₉is C_1-4Alkyl, (C)_0-4Alkyl) aryl, (C)_0-4Alkyl group) - (C_3-6-cycloalkyl), (C)_0-4Alkyl) -heterocyclyl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In other embodiments of the present invention, the substrate may be,w is

Or

In other embodiments, representative compounds have the formula:

in the formula:

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

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

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

in the formula:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

R₁And R₂Independently is C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cycloalkyl or (C)_1-8-alkyl) cycloalkyl;

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

Z₂Is H or C (O) R₅；

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

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

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

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

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

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

and pharmaceutically acceptable salts, solvates or hydrates thereof,

in the formula:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

R₉Independently for each occurrence-H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted cycloalkyl;

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

R₁₆and R₁₇Each occurrence is independently-H or halogen.

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

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

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

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

As used herein, unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (e.g., phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylaminoalkyl esters (e.g., acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

Various selective cytokine inhibitory drugs of the present invention contain one or more chiral centers and may exist as racemic mixtures of enantiomers or as mixtures of diastereomers. The invention includes the use of stereochemically pure forms of this compound, as well as the use of mixtures of those forms. For example, mixtures containing equal or unequal amounts of enantiomers of a particular selective cytokine inhibitory drug of the present invention may be used in the methods and compositions of the present invention. The pure (R) or (S) enantiomer of a particular compound disclosed herein may be substantially free of other enantiomers at the time of use.

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

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

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

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

4.2 second active Agents

In the methods and compositions of the present invention, the cytokine inhibitory drug may be combined with other pharmacologically active compounds ("second active agents"). It is believed that certain combinations will exert a synergistic effect in the treatment of specific cancer types, as well as certain diseases and conditions associated with or characterized by undesired angiogenesis. Cytokine inhibitory drugs may also alleviate adverse effects associated with certain second active agents, which may be used to alleviate adverse effects associated with cytokine inhibitory drugs.

One or more second active ingredients or agents may be used in the methods and compositions of the present invention with cytokine inhibitory drugs. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents are anti-CD 40 monoclonal antibodies (e.g., SGN-40); histone deacetylase (deaclyase) inhibitors (e.g., SAHA and LAQ 824); heat shock protein-90 inhibitors (e.g., 17-AAG); insulin-like growth factor-1 receptor kinase inhibitors; vascular endothelial growth factor receptor kinase inhibitors (e.g., PTK 787); an insulin growth factor receptor inhibitor; a lysophosphatidic acid acyltransferase inhibitor; an IkB kinase inhibitor; a p38MAPK inhibitor; EGFR inhibitors (e.g., gefitinib (gefitinib) and erlotinib hydrochloride (erlotinib HCL)); HER-2 antibodies (e.g. trastuzumab (Herceptin)^®) And pertuzumab (Omnitarg)^TM) ); VEGFR antibodies (e.g., bevacizumab (Avastin)^TM) ); VEGFR inhibitors (e.g., flk-1 specific kinase inhibitors, SU5416 and ptk787/zk 222584); P13K inhibitors (e.g., wortmannin); C-Met inhibitors (e.g., PHA-665752); monoclonal antibodies (e.g., rituximab (Rituxan)^®) Tositumomab (Bexxar)^®) Epilozumab (Panorex)^®) And G250); andanti-TNF-alpha antibodies.

Typical macromolecular active agents are biomolecules such as naturally occurring proteins or artificial proteins. Proteins particularly useful in the present invention include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunocompetent cells (pathogenic cells) in vitro or in vivo. Other proteins stimulate committed erythroid progenitor cells to divide and differentiate in vitro or in vivo. Specific proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL 2") and canarypox IL-2), IL-10, IL-12 and IL-18; interferons such as interferon alpha-2 a, interferon alpha-2 b, interferon alpha-nl, interferon alpha-n 3, interferon beta-Ia and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

Specific proteins that may be used in the methods and compositions of the invention include, but are not limited to: filgrastim, which is marketed in the United states under the Neupogen name^®Sold (Amgen, Thousand Oaks, CA); samoustin, which is marketed under the name Leukine in the United states^®Sold (Immunex, Seattle, WA); and recombinant EPO, available in the United states under the Epogen trade name^®Sold (Amgen, Thousand Oaks, Calif.).

Recombinant and mutant forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485, 5,393,870, and 5,229,496, all of which are incorporated herein by reference. Recombinant and mutant forms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643, 4,999,291, 5,528,823 and 5,580,755. All of these patents are incorporated herein by reference.

The present invention encompasses the use of natural proteins, naturally occurring proteins and recombinant proteins. The invention also includes mutants and derivatives (e.g., modified forms) of naturally occurring proteins that have at least a portion of the pharmacological activity of the protein on which they are based in vivo. Examples of mutants include, but are not limited to, proteins that contain one or more amino acid residues that differ from the corresponding residues in the naturally occurring form of the protein. The term "mutant" also includes proteins that lack the sugar moieties normally present in their naturally occurring form (e.g., non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to a protein or an active portion of a protein of interest. See, e.g., penechet, m.l. and Morrison, s.l., j.immunol.methods 248: 91-101(2001).

The macromolecular active agent may be administered in the form of an anti-cancer vaccine. For example, vaccines that secrete or secrete cytokines (e.g., IL-2, G-CSF, and GM-CSF) can be used in the methods, pharmaceutical compositions, and kits of the invention. See, e.g., emers, l.a., et al, curr. opinion mol. ther3 (1): 77-84(2001).

In one embodiment of the invention, the macromolecular active agent reduces, eliminates or prevents adverse effects associated with administration of cytokine inhibitory drugs. Depending on the particular cytokine inhibitory drug and the disease or condition being treated, adverse effects may include, but are not limited to, drowsiness and somnolence, dizziness, as well as orthostatic hypotension, neutropenia, infection by neutropenia, increased HIV viral load, bradycardia, Stevens-Johnson syndrome, and toxic epidermal necrolysis and seizures (e.g., grand mal spasm). A particular adverse effect is neutropenia.

The small molecule second active agent can be used to alleviate adverse effects associated with administration of cytokine inhibitory drugs. However, as with certain macromolecules, many small molecules are believed to provide a synergistic effect when administered with (e.g., before, after, or simultaneously with) a cytokine inhibitory drug. Examples of small molecule second active agents include, but are not limited to, anticancer drugs, antibiotics, immunosuppressive agents, and steroids.

Examples of anti-cancer drugs include, but are not limited to: semaxanib; (ii) a cyclosporin; etanercept; doxycycline; bordeaux (bortezomib); acivicin; aclarubicin; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; hexamethylmelamine; an apramycin; acetic acid dihydroamine anthraquinone; ansacholine; anastrozole; an atramycin; an asparaginase enzyme; a triptyline; azacytidine; a thiotepa; azomycin; batimastat; benztepa; bicalutamide; bishan mountain forest hydrochloride; bisnefaede iodonate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib; chlorambucil; a sirolimus; cisplatin; cladribine; cllinaltol mesylate; cyclophosphamide; cytarabine; (ii) a dacarbazine; dactinomycin; myeloid leukemia hydrochloride; decitabine; (ii) dexomaplatin; 2, dizagutanin; 1, dizagutinine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotandrosterone propionate; azomycin; edatrexae; (ii) nilisil hydrochloride; elsamitrucin; enloplatin; phenyl propinyl ester; a bis-epoxy piperidine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine phosphate; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; fadrozole hydrochloride; fazarabine; fenretinide; a fluorouracil deoxynucleoside; fludarabine phosphate; fluorouracil; fluorocyclocytidine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; an ifosfamide; emofosfam; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium; a cyclohexylnitrosourea; losoxantrone hydrochloride; -Marpropico; maytansine; mechlorethamine hydrochloride; megestrol acetate; (ii) estrene acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; chlorpheniramine; meltupipide; mitodomide; micacacine; mitorubin; mitogen; mitosin; mitomycin; mitosporin; mitotane; mitoxantrone hydrochloride; mycophenolic acid; thiaurethane pyridazinol; a noggin; ormaplatin; a sulfinylpyridine; paclitaxel; adding a parzyme; a calicheamicin; neostigmine bromide; pirlimycin sulfate; hyperphosphamide; bromopropylpiperazine; 1, azinpyram; piroxantrone hydrochloride; mithramycin; pramipexole; porfimer sodium; a podomycin; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; isopentene adenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium sperphosphate; sparsomycin; helical germanium hydrochloride; spiromustine; cis-spiroplatinum; streptonigrin; streptomyces lanceolatus; a sulfochlorophenylurea; talimox; sodium tegafur; d, D-Tylox; tegafur; tiloxanthraquinone hydrochloride; temoporfin; teniposide; a tiroxiron; a testosterone ester; (ii) a thiopurine; thioguanine; thiotepa; thiazolfurin; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; trimetrexate; triptorelin; tobramzole hydrochloride; uracil mustard; a urethane imine; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vincristine sulfate; vinorelbine tartrate; isovincamine sulfate; vinzolidine sulfate; (ii) vorozole; zenitheline; a neocarzinostatin; and zorubicin hydrochloride.

Other anti-cancer agents include, but are not limited to: 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecyenol; (ii) Alexanox; aldesleukin; an ALL-TK antagonist; altretamine; amifostine; sulphaisoxazole (amidox); amifostine; (ii) aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; an angiogenesis inhibitor; antagonist D; an antagonist G; anrlex; anti-dorsal formation of protein-1; anti-androgens, prostate cancer agents; an estrogen antagonist; anti-cancer peptides; an antisense oligonucleotide; aphidicolin; modifying apoptosis genes; a modulator of apoptosis; depurination nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; (ii) atrazine; axinatatin 1; axinatatin 2; axinatatin 3; azasetron; azatoxin; diazotyrosine; baccatin III derivatives; balanol; batimastat; a BCR/ABL antagonist; benzochlor; benzoyl staurosporine; beta lactam derivatives; betaalethine; betacylmycinB; betulinic acid; a bFGF inhibitor; bicalutamide;a bisantrene group; bisaziridinylsphermine; (ii) bisnefarde; bistetralene A; bizelesin; brefflate; briprimine; butootitanium; buthionine esulfoximine; calcipotriol; inhibin C; a camptothecin derivative; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole (carboxyyamidotriazole); CaRest M3; CARN 700; a cartilage derived inhibitor; folding to get new; casein kinase Inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; (ii) chlorolins; chloroquinoxaline sulfonamide; (ii) cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin a 4; combretastatin analogs; a concanagen; crambescidin 816; clinatot; cryptophycin 8; cryptophycin a derivatives; curve A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; a cytolytic factor; hexestrol phosphate; daclizumab; decitabine; dehydrogenine B; deslorelin; dexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; diazaquinone; dynastine B; didox; diethylnorstanol; dihydro-5-azacytidine; dihydrotaxol, 9-; a dioxamycin; diphenylspiromustine; docetaxel; behenyl alcohol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; etokomustine; edifulin; epidolumab; (ii) nilotinib; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine phosphate analogue; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flutemastine; a flashterone; fludarabine; fluoroaurorunornicin hydrochloride; fowler; 2, fulvestrant; fostrexed; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; (ii) a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; norethoxyquin; ioxifene; iloperidone; emofosfam; ilomastat; imatinib (e.g. Gleevec)^®) "Miquine" as a medicineMott; an immune promoting peptide; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; iomycin; sweet potato picrol, 4-; iprop; isoxagliadine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; a lamellar element triacetate; lancet; leinamycin; lenolatiri; mushroom polysaccharide sulfate; leptin statin; letrozole; a leukocyte inhibitory factor; leukocyte interferon-alpha; leuprorelin + estrogen + progesterone; leuprorelin; levamisole; liazole; a linear polyamine analog; a lipophilic glycopeptide; a lipophilic platinum compound; lissoclinamide 7; lobaplatin; earthworm phosphatide; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; a cytolytic peptide; maytansine; mannostatin A; marimastat; (ii) maxolone; maspin; a matrix dissolution factor inhibitor; a matrix metalloproteinase inhibitor; (ii) a melanoril; mebarone (merbarone); 1, meperiline; methioninase; metoclopramide; an inhibitor of MIF; mifepristone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofagotine; moraxest; abittus (Erbitux), human chorionic gonadotropin; monophosphoryl lipid a + mycobacteria (mycobactium) cell wall sk; mopidanol; mustard anticancer drugs; indian marine sponge (mycaperoxide) B; a mycobacterial cell wall extract; myriaporone; n-acetyldinaline; n-substituted benzamides; nafarelin; spraying naretide; naloxone + pentazocine; napavin; naphterpin; a nartostim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; quenching and tempering nitrous oxide; nitrous oxide antioxidant; nitrulyn; olimoesen (Genasense)^®)；O⁶-benzylguanine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; an oral cytokine inducer; ormaplatin; an oxateclone; oxaliplatin; oxanonomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; palauamine; soft esteroylcholic acid; pamidronic acid; ginseng alkyneA triol; panomifen; parabacterin (paramactin); pazeliptin; a pemetrexed; pedunculing; a wood polysulphide sodium; pentostatin; (ii) pentazole; perfluorobromoalkane; hyperphosphamide; perilla alcohol; phenazinomomycin; phenyl acetate; a phosphatase inhibitor; carrying out streptolysin; pilocarpine hydrochloride; pirarubicin; pirtroxine; placentinA; placentinB; a plasminogen activator inhibitor; a platinum complex; a platinum compound; a platinum-triamine complex; porfimer sodium; a podomycin; prednisone; propyldi-acridone; prostaglandin J2; a proteasome inhibitor; protein a-based immunomodulation; inhibitors of protein kinase C; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoline acridine; a glycohydroxyethylated hemoglobin polyoxyethylene conjugate; (ii) a raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated reteplatin; rhenium (Re) 186 etidronate (rhenium 186 ethidronate); rhizomycin; a ribozyme; RII viaminate; rohitukine; romurtide; loquimex; rubiginone B1; ruboxyl; safrog; saintopin; SarCNU; sarcophylol A; sargrastim; a Sdi 1 mimetic; semustine; senescence-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium boron carbonate; sodium phenylacetate; solverol; a growth regulator binding protein; sonaming; phosphono-winteric acid; spicamycin D; spiromustine; spleenetin; spongistatin 1; squalamine; stiiamide; a matriptase inhibitor; sulfinosine; a vasoactive intestinal peptide potent antagonist; (ii) surfasta; suramin; aloperine; tamustine; tamoxifen methyl iodide; bovine iodomustine; tazarotene; sodium tegafur; tegafur; telluropyrylium; a telomerase inhibitor; temoporfin; teniposide; tetrachlorodecaoxide (tetrachlorodecaoxide); tetrazomine; (ii) a thioablistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thyntotrinan; thyroid stimulating hormone; rubia purpurea (tin ethyl purpurin); tirapazamine; cyclopentadienyl titanium dichloride; topstein; tuoruiMifene; a translation inhibitor; tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; a tyrosine phosphorylation inhibitor; an UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitory factor; a urokinase receptor antagonist; vapreotide; variolin B; vilareol; veratramin; verdins; verteporfin; vinorelbine; vinxaline; vitaxin; (ii) vorozole; zanoteron; zeniplatin; benzal vitamin C; and neat stastatin ester.

Specific second active agents include, but are not limited to, 2-methoxyestradiol, telomeric acid (telomestatin), multiple myeloma apoptosis-inducing agents (e.g., TRAIL), statins (statins), semaxanib, cyclosporine, etanercept, doxycycline, pertuzumab, Olympic (Genasense)^®) Rituximab (remicade), docetaxel, celecoxib, melphalan, dexamethasone (Decadron)^®) Steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, Temodar, carboplatin, procarbazine, carmustine wafer capsule (gliadel), tamoxifen, topotecan, methotrexate, Arisa^®Paclitaxel, taxotere, fluorouracil, leucovorin, irinotecan, receptacle, CPT-11, interferon alphA, pegylated interferon alphA (e.g., PEGINTRON-A), capecitabine, cisplatin, thiotepA, fludarabine, carboplatin, doxorubicin liposomes, cytarabine, docetaxel (doxetaxol), paclitaxel (paclitaxel), vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, clarithromycin formulations, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil)^®) Paclitaxel, ganciclovir, doxorubicin, estramustine sodium phosphate (Emcyt)^®) Sulindac, and etoposide.

4.3 methods of treatment and prevention

The methods of the invention include methods of treating, preventing and/or managing various types of cancers and diseases and conditions associated with or characterized by undesired angiogenesis. The term "treating" as used herein, unless otherwise indicated, refers to the administration of a compound of the invention or other active agent after the onset of symptoms of a particular disease or condition. Unless otherwise indicated, the term "prevention" as used herein refers to administration prior to the onset of symptoms, particularly administration to patients suffering from cancer and other diseases and conditions associated with or characterized by undesired angiogenesis. The term "preventing" includes inhibiting the symptoms of a particular disease or disorder. Patients with cancer and a family history of diseases and disorders associated with or characterized by undesired angiogenesis are preferred candidates for prophylactic treatment. Unless otherwise indicated, the term "controlling" as used herein includes preventing the recurrence of a particular disease or disorder in a patient who has been afflicted with the disease or disorder, and/or prolonging the time that a patient who has been afflicted with the disease or disorder is at a reduced level of symptoms.

The term "cancer" as used herein includes, but is not limited to, solid tumors and blood borne tumors. The term "cancer" refers to diseases of skin tissues, organs, blood and blood vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, breast, colon, endometrium, esophagus, eye, head, kidney, liver, lymph node, lung, oral cavity, neck, ovary, pancreas, prostate, rectum, stomach, testis, pharynx, and uterus. Specific cancers include, but are not limited to, progressive malignancy, amyloidosis, neuroblastoma, meningioma, atypical meningioma, vascular involuntary tumor, multiple brain metastases, glioblastoma multiforme, brain stem glioma, pre-refractory malignant cerebroma, malignant glioma, recurrent malignant glioma, degenerative astrocytoma, degenerative oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes 'C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, nuclear acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-lymphomas, cutaneous B-lymphomas, diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma (local melanoma), Including but not limited to ocular melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma (scelroderma), cutaneous vasculitis, langerhans 'cell histiocytosis, leiomyosarcoma, progressive osteogenic fibrodysplasia, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable (unresectable) hepatocellular carcinoma, waldenstrom's macroglobulinemia, smoldering myeloma, occult myeloma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and leiomyoma. In a specific embodiment, the cancer is metastatic. In another embodiment, the cancer is refractory to or resistant to chemotherapy or radiation therapy; especially thalidomide, is difficult to treat.

When referring to diseases and conditions other than cancer, the terms "diseases and conditions associated with or characterized by undesired angiogenesis", "diseases and conditions associated with undesired angiogenesis" and "diseases and conditions characterized by undesired angiogenesis" herein refer to diseases, conditions and conditions caused, mediated or implicated in undesired, unwanted or uncontrolled angiogenesis, including, but not limited to, inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases and retinal neovascular diseases.

Examples of such diseases and conditions associated with undesired angiogenesis include, but are not limited to, endometriosis, crohn's disease, heart failure, progressive heart failure, kidney injury, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic fovea, epidemic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium keratitis, xerosis, rosacea, vesiculosis (phylectenulosis), syphilis, lipodegeneration, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoal infections, kaposi's sarcoma, predatory corneal ulcers, freon's cuticle degeneration, limbic detachment, rheumatoid arthritis, systemic lupus erythematosus, chronic keratosis, chronic inflammatory bowel disease, polyarteritis, trauma, wegener's sarcoidosis, scleritis, stevensis disease, periphigoid radiation keratoastigmatism, sickle cell anemia, sarcoid, elasto-pseudoxanthoma, paget's disease, venous occlusion, arterial occlusion, carotid artery occlusion, chronic uveitis, chronic vitritis, lyme disease, ilus disease, behcet disease, retinitis, choroiditis, suspected ocular histoplasmosis, bests disease, Stargarts disease, pars planaris, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, flushing, sarcoidosis, cirrhosis, soriatis, psoriasis, primary sclerosing cholangitis, proctitis, primary biliary srosis, idiopathic pulmonary fibrosis, alcoholic hepatitis, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, wasting, meningitis, and the like, Silica-induced fibrosis, asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, large cell anemia, refractory anemia, syndrome 5q, and veterinary diseases caused by feline immunodeficiency virus, equine infectious anemia virus, caprine arthritis virus, sheep myelinating virus, sydisovirus, or lentivirus.

In particular embodiments of the invention, the diseases and conditions associated with undesired angiogenesis do not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, HIV, hepatitis, adult respiratory distress syndrome, bone resorption diseases, chronic obstructive pulmonary disease, chronic inflammatory pulmonary disease, dermatitis, cystic fibrosis, septic shock, septicemia, endotoxic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, fibrotic disease, cachexia, transplant rejection, rheumatoid spondylitis, osteoporosis, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus (systemic lupus erythematosus), erythema nodosum leprosum occurring in leprosy, radiation injury, Asthma, hyperoxic alveolar injury (hyperoxic alveolar injury), malaria, mycobacterial infection, and opportunistic infection by HIV.

The invention includes methods of treating patients who have previously been treated for cancer or diseases and conditions associated with or characterized by undesired angiogenesis but which have not responded to standard therapy, as well as those patients who have not previously been treated. The invention also includes methods of treating patients of any age, but some diseases or conditions are more common in certain age groups. The invention also includes methods of treating patients who have undergone surgery at the tissue level to treat a disease or condition, as well as those who have not undergone surgery. Because patients with cancer and diseases and conditions characterized by undesired angiogenesis have different clinical manifestations and multiple clinical outcomes, the treatment given to a patient may vary depending on his/her prognosis. The specific second agent, type of surgery, and type of non-drug based standard therapy that is effective for treating an individual with cancer and other diseases or conditions can be readily determined by the skilled clinician without undue experimentation.

The methods encompassed by the present invention comprise administering to a patient (e.g., a human) having or at risk of having cancer or a disease or condition mediated by undesired angiogenesis one or more cytokine inhibitory drugs of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof.

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

In particular embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is administered to a patient with relapsed multiple myeloma at about 400 mg/day, 800 mg/day, or 1,200 mg/day. In particular embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is initially administered at a dose of 100 mg/day and then may be increased to 200 mg/day, 400 mg/day, 800 mg/day, 1,200 mg/day, and 2,500 mg/day weekly. In a specific embodiment, the compound is administered to a patient having a solid tumor at about 5,000 mg/day. In a particular embodiment, the compound is administered to a patient having a glioma at about 10,000 mg/day.

In particular embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide may be administered to a patient with crohn's disease at an initial dose of 400 mg/day, and may then be increased to 800 mg/day and 1,200 mg/day.

In particular embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is administered to a patient having a disease or condition associated with or characterized by undesired angiogenesis in an amount of from about 100 mg/day to about 5,000 mg/day or in a daily dosage of from about 1.5 to 2.5 times every other day, including, but not limited to: endotoxemia, toxic shock syndrome, osteoarthritis, reverse transcriptase replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, large cell anemia, refractory anemia, and 5 q-syndrome.

In another embodiment, (+) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline 1, 3-dione is administered to a patient having a disease or disorder associated with or characterized by undesired angiogenesis, including but not limited to: endotoxemia, toxic somite syndrome, osteoarthritis, reverse transcriptase replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorders, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, large cell anemia, refractory anemia, and 5 q-syndrome.

4.3.1 combination therapy with a second active agent

Particular methods of the invention comprise administering a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in combination with one or more second active agents, and/or in combination with radiation therapy, blood transfusion, or surgery. Examples of selective cytokine inhibitory drugs of the invention are disclosed herein (see, e.g., section 4.1). Examples of second active agents are also disclosed herein (see, e.g., section 4.2).

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

In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously in an amount of about 1-1000mg, about 5-500mg, about 10-350mg, or about 50-200mg once a day or twice a day. The specific dosage of the second active agent will depend upon the specific agent used, the type of disease being treated or controlled, the severity and stage of the disease, and the amounts of the selective cytokine inhibitory drug of the invention and any optional additional active agents concurrently administered to the patient. In a specific embodiment, the second active agent is oblimersen (Genasense)^®) GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, trans-retinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitors, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.

In one embodiment, GM-CSF, G-CSF or EPO is administered subcutaneously for about 5 days in a4 or 6 week circulation at a dose of about 1 to 750mg/m²A preferred dosage is about 25-500 mg/m/day²More preferably, the dosage is from about 50 to about 250mg/m²The most preferred dosage is about 50-200mg/m²The day is. In certain embodiments, GM-CSF may be about 60-500mcg/m²Is administered intravenously over at least 2 hours, or at about 5-12mcg/m²The amount per day was administered subcutaneously. In one embodiment, G-CSF can be administered subcutaneously in an initial amount of about 1 mcg/kg/day, and the dose can be adjusted based on an increase in total granulocyte count. Maintenance amounts of G-CSF can be administered subcutaneously in amounts of about 300 (for smaller patients) or 480 mcg. In certain embodiments, EPO may be administered subcutaneously in an amount of 10,000 units three times a week.

In another embodiment, the selective cytokine inhibitory drug is present in an amount of about 20 mg/day to about 1,200 mg/day, alone or in combination with a second active agentCo-administration to patients with metastatic malignant melanoma (localized malignant melanoma, including but not limited to ocular malignant melanoma). In one embodiment, about 800 mg/day to about 1,200 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide and about 200mg/m²A day to about 1000mg/m²Daily Dacarbazine (DTIC) was administered to patients with metastatic malignant melanoma (localized malignant melanoma, including but not limited to ocular malignant melanoma). In another embodiment, about 800 mg/day to 1,200 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide and temozolomide are administered to a patient having metastatic malignant melanoma (localized malignant melanoma, including but not limited to ocular malignant melanoma). In another embodiment, from about 200 mg/day to about 800 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is administered to a patient having metastatic melanoma or localized malignant melanoma whose disease worsens after treatment with temozolomide, Dacarbazine (DTIC), IL-2, and/or IFN. In particular embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is administered in an amount of about 400 mg/day twice a day or about 800 mg/day four times a day in combination with dexamethasone to a patient with relapsed or refractory multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with melphalan and dexamethasone to the subject suffering from amyloidosis. In a specific embodiment, the selective cytokine inhibitory drugs of the invention may be administered with a steroid to a patient suffering from amyloidosis.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine and cisplatin to a patient with locally progressive or metastatic transitional cell bladder cancer.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with a second active ingredient that is: temozolomideAdministering to a patient having a recurrent or progressive brain tumor or a recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide, to a patient with recurrent or progressive CNS cancer; temodar administered to a patient with recurrent or progressive meningioma, malignant meningioma, vascular involuntary tumor, multiple brain metastases, recurrent brain tumor, or newly diagnosed glioblastoma multiforme; irinotecan for administration to patients with relapsed glioblastoma; carboplatin, administered to a brain stem glioma patient; procarbazine administered to a patient with progressive malignant glioma; cyclophosphamide, given to patients with poor prognosis malignant brain tumors, newly diagnosed or relapsed glioblastoma multiforme; gliadel^®Administering to a patient with highly recurrent malignant glioma; temozolomide and tamoxifen administered to a patient with degenerative astrocytoma; or topotecan, to a patient having glioma, glioblastoma, degenerative astrocytoma, or degenerative oligodendroglioma.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with methotrexate and cyclophosphamide to a patient with metastatic breast cancer.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with temozolomide to a patient with a neuroendocrine tumor.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine to a patient with recurrent or metastatic head or neck cancer. In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine to a pancreatic cancer patient.

In another embodiment, the selective cytokine inhibitory drug is an Arisa^®Taxol and/or taxotere are administered in combination to a patient with colon cancer.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with capecitabine to a patient with refractory colorectal cancer or a patient who has failed the first treatment or who has poor performance in the treatment of colon cancer or colorectal cancer.

In another embodiment, the selective cytokine inhibitory drug is administered to patients with Duoxidepc and Digitel colorectal cancers in combination with fluorouracil, folinic acid, and irinotecan or to patients who have been treated for metastatic colorectal cancer.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with refractory colorectal cancer in combination with capecitabine, hiloda, and/or CPT-11.

In another embodiment, the selective cytokine inhibitory drugs of the invention are administered to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal cancer in combination with capecitabine and irinotecan.

In another embodiment, the selective cytokine inhibitory drug is administered alone or in combination with interferon alpha or capecitabine to a patient with unresectable or metastatic hepatocellular carcinoma; or in combination with cisplatin and thiotepa, to patients with primary or metastatic liver cancer.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with Kaposi's sarcoma in combination with pegylated interferon alfa.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with fludarabine, carboplatin and/or topotecan to a patient with refractory or relapsed or high risk acute myeloid leukemia.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with daunorubicin liposomes, topotecan, and/or cytarabine to a patient with an exacerbating nuclear acute myeloblastic leukemia.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with gemcitabine and irinotecan to a non-small cell lung cancer patient. In one embodiment, the selective cytokine inhibitory drug is administered in combination with carboplatin and irinotecan to a non-small cell lung cancer patient. In one embodiment, the selective cytokine inhibitory drug is administered with docetaxel in a non-small cell lung cancer patient treated with carbon/VP 16 and radiation therapy.

In another embodiment, the selective cytokine inhibitory drug is administered to a non-small cell lung cancer patient in combination with carboplatin and/or taxotere or in combination with carboplatin, paclitaxel, and/or chest radiotherapy. In a specific embodiment, the selective cytokine inhibitory drug is administered in combination with taxotere to a stage IIIB or stage IV non-small cell lung cancer patient.

In another embodiment, the selective cytokine inhibitory drugs of the invention are those associated with Olympic (Genasense)^®) In combination with small cell lung cancer.

In another embodiment, the selective cytokine inhibitory drug is administered to patients with various types of lymphoma, including but not limited to hodgkin's lymphoma, non-hodgkin's lymphoma, cutaneous T-lymphoma, cutaneous B-lymphoma, diffuse large B-cell lymphoma, or relapsed or refractory low-grade follicular lymphoma, either alone or in combination with a second active ingredient (e.g., vinblastine or fludarabine).

In another embodiment, the selective cytokine inhibitory drug is administered to patients with various types and stages of melanoma, including, but not limited to, localized melanoma or metastatic melanoma, such as ocular melanoma, in combination with taxotere, IL-2, IFN, GM-CSF and/or dacarbazine.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with malignant mesothelioma or a patient with stage IIIB non-small cell lung cancer with peritoneal implant or a patient with malignant pleural effusion mesothelioma syndrome, alone or in combination with vinorelbine.

In another embodiment, the selective cytokine inhibitory drug is administered to multiple myelomA patients of various types or stages in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, clarithromycin formulations, vinblastine, melphalan, busulfan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonates, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, doxil, decadron, or combinations thereof.

In another embodiment, the selective cytokine inhibitory drug is doxorubicin (Doxil)^®) Vincristine and/or dexamethasone (Decadron)^®) In combination with patients with relapsed or refractory multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug is administered to patients with various types or stages of ovarian cancer (e.g., peritoneal cancer, papillary serous carcinoma, refractory ovarian cancer, or recurrent ovarian cancer) in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, hiloda, taxol, dexamethasone, or a combination thereof.

In another embodiment, the selective cytokine inhibitory drug is administered to prostate cancer patients of various types or stages in combination with hiloda, 5FU/LV, gemcitabine, irinotecan + gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, taxol, doxorubicin, docetaxel, estramustine, Emcyt, or combinations thereof.

In another embodiment, the selective cytokine inhibitory drug is a compound selected from the group consisting of capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrexe^®Or combinations thereof, to patients with different types or stages of renal cell carcinoma.

In another embodiment, the selective cytokine inhibitory drug is an inhibitor of IFN, COX-2 such as Celebrex^®And/or sulindac in combination with different types or stages of patients with gynaecological, uterine or soft tissue sarcoma cancer.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with a solid tumor of a different type or stage in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apectibine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with scleroderma or cutaneous vasculitis in combination with celecoxib, etoposide, cyclophosphamide, docetaxel, apectibine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

The present invention also includes methods of increasing the dose of an anti-cancer agent or an anti-cancer agent that can be safely and effectively administered to a patient, comprising administering to the patient (e.g., a human) a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable derivative, salt, solvate, inclusion, hydrate, or prodrug thereof. Patients that may benefit from this method are patients who may suffer from adverse effects associated with anticancer drugs or combinations thereof for the treatment of specific cancers of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal gland, kidney, prostate, breast, colorectal. Administration of the selective cytokine inhibitory drugs of the present invention will alleviate or reduce the adverse effects of the amount of the anti-cancer drug that is so severe that it is limited.

In one embodiment, the selective cytokine inhibitory drugs of the invention may be administered orally in an amount of about 1mg to about 5,000mg, about 10mg to about 2,500mg, about 25mg to about 2,500mg, about 100mg to about 1,200mg, or about 100mg to about 800mg per day, before, during, or after the occurrence of the adverse effects associated with administration of an anti-cancer agent to a patient. In a specific embodiment, the selective cytokine inhibitory drugs of the invention are administered in combination with specific agents, such as heparin, aspirin, coumadin, or G-CSF, to avoid adverse effects associated with the anti-cancer drugs, including but not limited to neutropenia or cytopenia.

In one embodiment, the selective cytokine inhibitory drugs of the present invention may be administered to patients suffering from diseases and conditions associated with or characterized by undesired angiogenesis in combination with other active ingredients including, but not limited to, anticancer agents, anti-inflammatory agents, antihistamines, antibiotics, and steroids.

In another embodiment, the invention encompasses methods of treating, preventing and/or managing cancer, comprising administering a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in combination with (e.g., before, during or after) conventional therapy, including but not limited to surgery, immunotherapy, biologic therapy, radiation therapy or other non-pharmaceutical methods based on the therapies currently used to treat, prevent or manage cancer. The combination of the selective cytokine inhibitory drugs of the present invention and conventional therapies may provide a unique treatment regimen that is exceptionally effective in certain patients. Without being bound by theory, it is believed that the selective cytokine inhibitory drugs of the present invention may provide additive or synergistic effects when administered concurrently with conventional therapies.

In another embodiment, the invention encompasses methods of treating, preventing and/or managing diseases and disorders associated with or characterized by undesired angiogenesis, which comprise administering a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in combination with (e.g., before, during or after) conventional therapy, including but not limited to surgery, immunotherapy, biological therapy, radiation therapy, or other non-pharmaceutical methods based on therapies currently used to treat, prevent or manage diseases and disorders associated with or characterized by undesired angiogenesis. The combination of the selective cytokine inhibitory drugs of the present invention and conventional therapies may provide a unique treatment regimen that is exceptionally effective in certain patients. Without being bound by theory, it is believed that the selective cytokine inhibitory drugs of the present invention may provide additive or synergistic effects when administered concurrently with conventional therapies.

As discussed elsewhere herein, the present invention includes methods of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapies including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. One or more of the selective cytokine inhibitory drugs and other active ingredients of the present invention may be administered to a patient before, during, or after the occurrence of adverse effects associated with conventional therapies.

In one embodiment, the selective cytokine inhibitory drugs of the invention may be administered orally, alone or in combination with a second active agent disclosed herein (see, e.g., section 4.2), in an amount of about 1mg to about 5,000mg, about 10mg to about 2,500mg, about 25mg to about 2,500mg, about 100mg to about 1,200mg, or about 100mg to about 800mg per day, before, during, or after conventional therapy is used.

In a specific embodiment of this method, the selective cytokine inhibitory drug of the invention and docetaxel are administered to a non-small cell lung cancer patient who has been treated with carbon/VP 16 and radiation therapy.

4.3.2 use with transplantation therapy

The compounds of the invention may be used to reduce the risk of Graft Versus Host Disease (GVHD). Accordingly, the present invention includes methods of treating, preventing and/or managing cancer, comprising administering a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in combination with transplantation therapy.

As is well known to those of ordinary skill in the art, the treatment of cancer is often based on the stage and mechanism of the disease. For example, with the inevitable transformation of leukemia occurring at some stages of cancer, peripheral blood stem cells, hematopoietic stem cell preparations or bone marrow transplantation may be necessary. The combination of the selective cytokine inhibitory drugs of the present invention and transplantation therapy provides a unique and unexpected synergistic effect. In particular, the activities exhibited by the selective cytokine inhibitory drugs of the invention may provide additive or synergistic effects when used with transplantation therapies in cancer patients.

The selective cytokine inhibitory drugs of the present invention may be used in combination with transplantation therapies to alleviate complications associated with invasive transplantation procedures and the risk of GVHD. The present invention includes methods of treating, preventing and/or managing cancer, which comprise administering to a patient (e.g., a human) a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, before, during, or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow. Examples of stem cells suitable for use in the methods of the present invention are disclosed in U.S. patent application 10/411,655 filed 11.4.2003 by r.haririi et al, which is incorporated herein by reference in its entirety.

In another embodiment, the invention includes methods of treating, preventing and/or managing diseases and disorders associated with or characterized by undesired angiogenesis, comprising administering to a patient (e.g., a human) a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, before, during, or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow.

In one embodiment of the method, the selective cytokine inhibitory drugs of the invention are administered to multiple myeloma patients before, during or after autologous peripheral blood progenitor cell transplantation.

In another embodiment, the selective cytokine inhibitory drug is administered to relapsed multiple myeloma patients after stem cell transplantation with prednisone.

In another embodiment, the selective cytokine inhibitory drug is administered to multiple myeloma patients as maintenance therapy with prednisone after autologous stem cell transplantation.

In another embodiment, a selective cytokine inhibitory drug is administered with dexamethasone as a remedial treatment to multiple myeloma patients to reduce post-transplant risk.

In another embodiment, the selective cytokine inhibitory drug is administered with dexamethasone as a maintenance therapy to multiple myeloma patients following autologous bone marrow transplantation.

In another embodiment, a selective cytokine inhibitory drug is administered to multiple myeloma patients that are chemotherapy-responsive following administration of high dose melphalan and autologous stem cell transplantation.

In another embodiment, A selective cytokine inhibitory drug is administered with PEG INTRO-A as A maintenance therapy to multiple myelomA patients following autologous CD34 selective peripheral stem cell transplantation.

In another embodiment, a selective cytokine inhibitory drug is administered with a post-transplant booster chemotherapy to newly diagnosed multiple myeloma patients to evaluate anti-angiogenesis.

In another embodiment, a selective cytokine inhibitory drug and dexamethasone are administered as maintenance therapy following high dose melphalan and peripheral blood stem cell transplantation therapy after DCEP potentiation to multiple myeloma patients 65 years or older.

4.3.3 cycle treatment

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

Thus, in a particular embodiment of the invention, the selective cytokine inhibitory drugs of the invention are administered daily in a single or divided dose over a 4-6 week cycle, with discontinuation of the cycle for about 1 or 2 weeks. The invention also allows increasing the frequency, number and length of dosing cycles. Accordingly, another specific embodiment of the invention comprises administering more cycles of the selective cytokine inhibitory drug of the invention than are typical of administration alone. In another specific embodiment of the invention, the selective cytokine inhibitory drugs of the invention are administered at higher cycle numbers that typically cause dose-limiting toxicity in patients not administered the second active ingredient.

In one embodiment, the selective cytokine inhibitory drug of the invention is administered in an amount of about 1 mg/day to about 5,000 mg/day for 3 or 4 consecutive weeks per day, followed by 1 or 2 weeks of discontinuation. 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is preferably administered continuously daily at an initial dose of 1 mg/day to 5 mg/day, which is increased in increments of 10 mg/day to 100 mg/day (weekly) to a maximum dose of 5,000 mg/day, as long as the treatment is tolerated. In a particular embodiment, the compound is administered at a dose of about 400 mg/day, 800 mg/day, 1,200 mg/day, preferably about 800 mg/day for 3-4 weeks in a4 or 6 week cycle, followed by 1 or 2 weeks off.

In one embodiment of the invention, the selective cytokine inhibitory drug of the invention and the second active ingredient are administered orally and the selective cytokine inhibitory drug of the invention is administered 30-60 minutes before the second active ingredient in a 4-6 week cycle. In another embodiment of the invention, the combination of a selective cytokine inhibitory drug of the invention and a second active ingredient is administered within about 90 minutes per cycle by intravenous infusion. In one embodiment, a cycle comprises about 400-800 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide and about 50-200mg/m²The second active ingredient/day, is administered for 3-4 weeks, then discontinued for 1 or 2 weeks. In another embodiment, each cycle comprises about 200-400 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide and about 50-200mg/m²The second active ingredient/day, is administered for 3-4 weeks, then discontinued for 1 or 2 weeks. The number of cycles of combination therapy administered to a patient is typically about 1-24 cycles, more typically about 2-16 cycles, and still more typically about 4-3 cycles.

4.4 pharmaceutical compositions

The pharmaceutical compositions may be formulated for use in a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion compound or prodrug thereof. The pharmaceutical compositions and dosage forms of the present invention may also comprise one or more excipients.

The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise the active ingredients (e.g., selective cytokine inhibitory drugs and second active agents) described herein. Examples of optional additional active ingredients are disclosed in this specification (see e.g. section 4.2).

The single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular or intraarterial), transdermal or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules, such as elastic soft gelatin capsules; a cachet; keeping in mouth; a lozenge; a dispersant; suppositories; a powder agent; aerosols (e.g., nasal sprays or inhalants); gelling agent; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of dosage form of the present invention will vary depending on its use. For example, a dosage form for the acute treatment of a disease may contain an amount of one or more active ingredients that is greater than the amount contained in a dosage form for the chronic treatment of the same disease. Similarly, a parenteral dosage form will contain an amount of one or more active ingredients that is less than the amount contained in an oral dosage form used to treat the same disease. The manner in which these particular dosage forms of the invention are contained, as well as other manners, will be readily apparent to those skilled in the art. See, e.g., Remington's pharmaceutical sciences, 18 th edition, Mack Publishing, Easton PA (1990).

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

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

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

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

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

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

As with the amount and type of excipient, the type and amount of a particular active ingredient in a dosage form may vary depending upon a variety of factors including, but not limited to, the route of administration. However, a typical dosage form of the invention contains the selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion compound or prodrug thereof, in an amount of about 0.10 to about 150 mg. Typical dosage forms contain the selective cytokine inhibitory drugs of this invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion, or prodrug thereof, in an amount of about 0.1, 1,2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, or 200 mg. In one embodiment, preferred dosage forms contain 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide in an amount of about 5, 10, 25, or 50 mg. Typical dosage forms contain the second active ingredient in an amount of 1-1000mg, about 5-500mg, about 10-350mg, or about 50-200 mg. The particular amount of anti-cancer agent will, of course, depend upon the particular agent used, the type of cancer being treated or controlled, as well as the amounts of the selective cytokine inhibitory drug of this invention and any optional other active agents concurrently administered to the patient.

4.4.1 oral dosage forms

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

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

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

For example, tablets may be made by compression or molding. Compressed tablets may be manufactured by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder 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 may be used in the oral dosage forms of the present invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

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

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

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

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

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

The solid oral dosage form of the present invention preferably contains the selective cytokine inhibitory drug of the present invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide and gelatin.

4.4.2 sustained Release dosage forms

The active ingredients of the present invention may be administered by controlled release devices or by delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in the following patents: U.S. Pat. nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms may be used for slow or controlled release of one or more active agents by using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, isotonic systems, multilayer coatings, microparticles, liposomes, microspheres or combinations thereof to produce the desired release profile in varying proportions. Suitable controlled release formulations are well known to those skilled in the art, including those disclosed herein, and are readily selected for use with the active agents of the present invention. Thus, the present invention encompasses single unit dosage forms suitable for controlled release and for oral administration, including but not limited to tablets, capsules, gelcaps, and caplets.

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

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

4.4.3 parenteral dosage forms

Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since their administration typically bypasses the natural defenses of the patient against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to use in the patient. Examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry products dissolved or suspended in a pharmaceutically acceptable carrier for injection, suspensions for injection, and emulsions.

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

Compounds that increase the solubility of one or more of the active agents disclosed herein can also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of the selective cytokine inhibitory drugs and derivatives thereof of the present invention. See, for example, U.S. Pat. No.5,134,127, which is incorporated herein by reference.

4.4.4 topical and transmucosal 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 of ordinary skill in the art. See, e.g., Remington's pharmaceutical sciences, 16 and 18 th ed., Mack Publishing, Easton PA (1980 and 1990); and Introduction to Pharmaceutical Dose Forms, 4 th edition, Lea & Febiger, Philadelphia (1985). The preparation suitable for treating oral mucosa tissue can be made into collutory or oral gel.

Suitable excipients (e.g., carriers and diluents) and other materials that may be used in the topical and mucosal dosage forms of the invention are well known to those of ordinary skill in the pharmaceutical arts and depend on the particular tissue to which a given pharmaceutical composition or dosage form is administered. In fact, typical excipients include, but are not limited to, water, propanol, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form non-toxic and pharmaceutically acceptable solutions, emulsions or gels. Wetting agents or preservatives may also be added to the pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's pharmaceutical sciences, 16 and 18 th ed., Mack Publishing, Easton PA (1980 and 1990).

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

4.4.5 kits

It is generally preferred that the active agents of the invention are not administered at the same time or by the same route of administration. Thus, the present invention includes kits that, when used by medical personnel, can simplify the administration of an appropriate amount of an active agent to a patient.

A typical kit of the invention comprises a dosage form of a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or inclusion thereof. The kit of the invention may also comprise other active ingredients such as orlistat (Genasense)^®) Melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitors, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or pharmaceutically active mutants or derivatives thereof, or combinations thereof. Examples of other active ingredients include, but are not limited to, those disclosed herein (see, e.g., section 4.2).

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

The kits of the invention may also comprise cells or blood that can be used for transplantation and a pharmaceutically acceptable carrier for administering one or more active ingredients. For example, if the active ingredient is in solid form and must be formulated for parenteral administration, the kit may comprise a sealed container containing a suitable carrier in which the active agent can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: USP water for injection; aqueous vehicles such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. Examples of the embodiments

The following non-limiting examples further illustrate certain embodiments of the invention.

5.1 modulation of cytokine production

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

In a particular embodiment, the pharmacological properties of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide are characterized in an in vitro assay. Studies examined the effect of compounds on the production of various cytokines. The inhibitory effect of the compounds on TNF- α production after LPS stimulation in human PBMC and human whole blood was studied in vitro. In vitro studies have shown that the pharmacological activity of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is more than 5-50 times stronger than that of thalidomide. The pharmacological effect of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide derives from its inhibitory effect on the growth of inflammatory cytokines.

Inhibition of MM cell proliferation

The ability of selective cytokine inhibitory drugs to affect the proliferation of Multiple Myeloma (MM) cell lines was examined in vitro studies. Determination of the alignment of different MM cell lines (MM.1S, Hs Sultan, U266 and RPMI-8226)³H]-uptake of thymidine as an indication of cell proliferation. The cells are cultured in the presence of the compound for 48 hours, introduced during the last 8 hours of the culture period³H]-thymidine. In particular toIn embodiments, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is added to mm.1s and HsSultan cells. Determination of various MM cell line pairs³H]Uptake of thymidine.

5.3. In vivo LPS-induced TNF-alpha production assay

Male CD rats purchased from Charles River laboratory 7 weeks before use were acclimated one week before use. After brief isoflurane anaesthesia, the lateral tail vein was cannulated subcutaneously with a 22-gauge (gag) needle superior catheter. Rats were administered the selective cytokine inhibitory drugs of the present invention by intravenous injection via tail vein cannulation or oral gavage 15-180 minutes prior to injection of 0.05mg/kg LPS (E.coli 055: B5). The catheter was perfused with 2.5mL/kg of conventional injection saline. Blood was collected by cardiac puncture 90 minutes after LPS stimulation. Plasma was prepared using a lithium heparin separator tube and frozen at-80 ℃ until analysis. TNF-. alpha.levels were determined using a rat specific TNF-. alpha.ELISA kit (Busywork). ED (electronic device)₅₀Values are calculated as the dose of the selective cytokine inhibitory drug of the invention at which the production of TNF- α drops to 50% of the control value.

5.4. Villa of toxicology

The effect of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide on cardiovascular and respiratory function was studied in anesthetized dogs. Two groups of Beagle dogs (2/gender/group) were used. One group received only three doses of vehicle and the other group received three incremental doses of compound (200, 400 and 800 mg/kg). In all cases, doses of the compound or vehicle are administered at least 30 minutes apart, followed by infusion into the jugular vein.

Cardiovascular and respiratory changes induced by 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide were minimal at all doses compared to the vehicle control. The only significant differences between the vehicle and treatment groups were: there was a weak rise in arterial blood pressure following administration of a low dose of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide. This phenomenon lasted for about 15 minutes; and this phenomenon does not occur in the administration of higher doses. Deviations in thigh blood flow, respiratory parameters, and Qtc interval are common to both the control and treated groups and are not considered treatment-related.

5.5. Circulatory therapy in a patient

In a specific embodiment, the selective cytokine inhibitory drugs of the invention are cyclically administered to a cancer patient. Cycling therapy involves administering a first agent for a period of time, then discontinuing the administration for a period of time, and repeating this sequence of administrations. Cycling therapy may reduce resistance to one or more of the therapies, avoid or reduce side effects of one of the therapies, and/or improve treatment efficacy.

In a specific embodiment, the prophylactic or therapeutic agent is administered about once or twice daily for a cycle of about 4 to 6 weeks. A cycle may include administration of a therapeutic or prophylactic agent for 3-4 weeks, and discontinuation of the agent for at least 1 week or 2 weeks. The number of cycles employed is typically from about 1 to about 24 cycles, more typically from about 2 to about 16 cycles, and still more typically from about 4 to about 8 cycles.

For example, in a 4-week cycle therapy, on the first day, 800 mg/day of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is administered as a starting material. Compound administration was stopped on day 22 for 1 week as an interruption. On day 29, 800 mg/day of compound administration was resumed.

5.6. Clinical study of patients with relapsed multiple myeloma

Patients who had received at least three therapies but had no effect and had poor physical condition, neutropenia or thrombocytopenia with relapsed and refractory Dune-Salmon stage III multiple myeloma were treated every 4-6 weeks with melphalan (50mg administered intravenously), a selective cytokine inhibitory drug of the invention (about 1-5,000 mg administered orally per day), and dexamethasone (40 mg/day, administered orally on days 1-4) administered for up to 4 cycles. Followed by daily administration of the selective cytokine inhibitory drugs of the invention and monthly administration of dexamethasone for maintenance therapy until the disease is inhibited. The combination of the selective cytokine inhibitory drugs of the invention with melphalan and dexamethasone is highly active and well tolerated in pre-treatment of severe multiple myeloma patients, and the prognostic outcome is very poor if other therapies are used.

The embodiments of the invention described above are intended to be exemplary only. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and methods. All such equivalents are considered to be within the scope of this invention and are encompassed by the following claims.

Claims (32)

1. A method of treating, managing or preventing a specific cancer, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. A method of treating, managing or preventing a specific cancer, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active ingredient, radiation therapy, hormonal therapy, biological therapy or immunotherapy.

3. A method of treating, managing or preventing a disease associated with undesired angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

4. A method of treating, managing or preventing a disease associated with undesired angiogenesis, which comprises administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active ingredient.

5. The method of claim 1, wherein the cancer is a progressive malignancy, amyloidosis, neuroblastoma, meningioma, vascular involuntary tumor, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, pre-refractory malignant brain tumor, malignant glioma, degenerative astrocytoma, degenerative oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, colorectal carcinoma of the type C and type D, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype (karotype) acute myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, localized melanoma, multiple myeloma, cutaneous tumor, multiple myeloma, glioblastoma multiforme, colorectal carcinoma, metastatic carcinoma, colorectal carcinoma, or a, Malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, langerhans 'cell histiocytosis, leiomyosarcoma, progressive ossifying fibrodysplasia, hormone refractory prostate cancer, resected high risk soft tissue sarcoma, unresectable hepatocellular carcinoma, waldenstrom's macroglobulinemia, multiple myeloma, smoldering myeloma, occult myeloma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate, papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and leiomyoma.

6. The method of claim 2, wherein the cancer is a progressive malignancy, an amyloidosis, a locally progressive bladder cancer, a metastatic transitional cell bladder cancer, a recurrent brain tumor, a progressive brain tumor, a neuroblastoma, a meningioma, a vascular involuntary tumor, a multiple brain metastasis, a glioblastoma multiforme, a brain stem glioma, a pre-refractory malignant brain tumor, a malignant glioma, a degenerative astrocytoma, a degenerative oligodendroglioma, a metastatic breast cancer, a neuroendocrine tumor, a rectal adenocarcinoma, a Duke's C and D colorectal cancers, a non-resectable colorectal cancer, a metastatic hepatocellular carcinoma, a Kaposi's sarcoma, a nuclear acute myeloblastic leukemia, a Hodgkin's lymphoma, a non-Hodgkin's lymphoma, a cutaneous T-cell lymphoma, a cutaneous B-cell lymphoma, a malignant metastatic malignant brain tumor, a malignant brain stem glioma, a pre-refractory malignant glioma, a malignant glioma, Diffuse large B-cell lymphoma, low-grade follicular lymphoma, metastatic melanoma, local melanoma, malignant mesothelioma, stage IIIB non-small cell lung cancer, malignant pleural effusion mesothelioma syndrome, multiple myeloma, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans 'cell histiocytosis, leiomyosarcoma, progressive osteogenic fibrodysplasia, hormone-refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, occult myeloma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate papillary, thyroid cancer, Follicular thyroid cancer, medullary thyroid cancer, and leiomyoma.

7. The method of claim 3 or 4, wherein the disease or disorder is endometriosis, Crohn's disease, heart failure, progressive heart failure, kidney injury, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic fovea, epidemic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium keratitis, sjogrens, rosacea, phylectenulosis, syphilis, lipodegeneration, bacterial ulcers, fungal ulcers, herpes simplex infections, herpes zoster infections, protozoal infections, Kaposi sarcoma, predatory corneal ulcers, Tarrien marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease, chronic obstructive, Polyarteritis, trauma, Wegeners sarcoidosis, scleritis, Steven's Johnson disease, periphigoid radiation keratoastigmatism, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid artery obstruction, chronic uveitis, chronic vitritis, Lyme disease, Iris disease, Bechet's disease, retinitis, choroiditis, suspected histoplasmosis of the eye, Bests disease, Stargarts' disease, ciliary pars planarit, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, sclerosing cholangitis, flushing, endotoxemia, toxic shock syndrome, osteoarthritis, retroviral replication, marasmus, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, medical disorders, malignant tumor-associated hypercalcemia, Stroke, circulatory shock, periodontitis, gingivitis, large cell anemia, refractory anemia, or 5q syndrome.

8. The method of claim 2 or 4, wherein the second active ingredient is an anti-CD 40 monoclonal antibody, a histone deacetylase inhibitor, a heat shock protein-90 inhibitor, an insulin-like growth factor-1 receptor kinase inhibitor, a vascular endothelial growth factor receptor kinase inhibitor, an apoptosis-inducing agent in multiple myeloma cells, a statin, an insulin growth factor receptor inhibitor, a lysophosphatidic acid acyltransferase inhibitor, an IkB kinase inhibitor, a P38MAPK inhibitor, an EGFR inhibitor, a HER-2 antibody, a VEGFR inhibitor, a P13K inhibitor, a C-Met inhibitor, a monoclonal antibody, an anti-TNF- α antibody, a hematopoietic growth factor, a cytokine, an anticancer agent, an antibiotic, a cox-2 inhibitor, an immunomodulator, an immunosuppressant, a corticosteroid, or a pharmaceutically active mutant or derivative thereof, or a combination thereof.

9. The method of claim 8, wherein the second active ingredient is 2-methoxyestradiol, telomeric acid (telomestatin), gefitinib, erlotinib hydrochloride, trastuzumab, pertuzumab, bevacizumab, wortmannin, rituximab, tositumomab, edrecolomab, semaxanib, cyclosporin, etanercept, doxycycline, gemtuzumab, oblimersen, melphalan, G-CSF, GM-CSF, EPO, topotecan, pentoxifylline, taxotere, irinotecan, a COX-2 inhibitor, ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutically active mutant or derivative thereof, or a combination thereof.

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

11. The method of claim 10, wherein the selective cytokine inhibitory drug is enantiomerically pure.

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

13. The method of claim 12, wherein the selective cytokine inhibitory drug is enantiomerically pure.

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

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

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

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

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

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

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

15. The method of claim 14, wherein the selective cytokine inhibitory drug is enantiomerically pure.

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

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

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

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

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

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

n has a value of 0, 1 or 2.

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

18. A method of treating, preventing or managing a specific cancer, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before, during or after surgery to alleviate, alleviate or avoid the occurrence of the symptoms of the specific cancer in the patient.

19. A method of reducing or avoiding the adverse effects associated with the administration of a second active ingredient in a patient with a particular cancer, which method comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

20. A method of reducing or avoiding adverse effects associated with radiation therapy, hormonal therapy, biological therapy or immunotherapy in a specific cancer patient, which method comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

21. A method of treating, preventing or managing a specific cancer that is refractory to conventional therapy, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

22. A method of treating, preventing or managing a specific cancer which is refractory to conventional therapy, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active ingredient.

23. A method of treating, preventing or managing a specific cancer, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and performing umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow transplantation in the patient.

24. The method of claim 23, wherein the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the patient before, during, or after transplantation of umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparation, or bone marrow.

25. The method of any one of claims 1-4, wherein the selective cytokine inhibitory drug is administered in an amount of about 1 mg/day to about 10,000 mg/day.

26. The method of claim 2, wherein the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered before, during, or after the administration of the second active ingredient, radiation therapy, hormonal therapy, biological therapy, or immunotherapy.

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

28. The pharmaceutical composition of claim 27, wherein the second active ingredient is an anti-CD 40 monoclonal antibody, a histone deacetylase inhibitor, a heat shock protein-90 inhibitor, an insulin-like growth factor-1 receptor kinase inhibitor, a vascular endothelial growth factor receptor kinase inhibitor, an apoptosis-inducing agent in multiple myeloma cells, a statin, an insulin growth factor receptor inhibitor, a lysophosphatidic acid acyltransferase inhibitor, an IkB kinase inhibitor, a P38MAPK inhibitor, an EGFR inhibitor, a HER-2 antibody, a VEGFR inhibitor, a P13K inhibitor, a C-Met inhibitor, a monoclonal antibody, an anti-TNF- α antibody, a hematopoietic growth factor, a cytokine, an anticancer agent, an antibiotic, a cox-2 inhibitor, an immunomodulator, an immunosuppressant, a corticosteroid, or a pharmaceutically active mutant or derivative thereof.

29. The pharmaceutical composition of claim 28, wherein the second active ingredient is 2-methoxyestradiol, telomeric acid (telomestatin), gefitinib, erlotinib hydrochloride, trastuzumab, pertuzumab, bevacizumab, wortmannin, rituximab, tositumomab, edrecolomab, semaxanib, cyclosporin, etanercept, doxycycline, gemtuzumab, oblimersen, melphalan, G-CSF, GM-CSF, EPO, COX-2 inhibitor, topotecan, pentoxifylline, ciprofloxacin, taxotere, irinotecan, dexamethasone, doxorubicin, vincristine, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutically active mutant or derivative thereof.

30. A kit, comprising:

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

a pharmaceutical composition comprising an anti-CD 40 monoclonal antibody, a histone deacetylase inhibitor, a heat shock protein-90 inhibitor, an insulin-like growth factor-1 receptor kinase inhibitor, a vascular endothelial growth factor receptor kinase inhibitor, an apoptosis inducing agent in multiple myeloma cells, a statin, an insulin growth factor receptor inhibitor, a lysophosphatidic acid acyltransferase inhibitor, an IkB kinase inhibitor, a P38MAPK inhibitor, an EGFR inhibitor, a HER-2 antibody, a VEGFR inhibitor, a P13K inhibitor, a C-Met inhibitor, a monoclonal antibody, an anti-TNF- α antibody, a hematopoietic growth factor, a cytokine, an anticancer drug, an antibiotic, a cox-2 inhibitor, an immunomodulator, an immunosuppressant, a corticosteroid, or a pharmaceutically active mutant or derivative thereof, or a combination thereof.

31. A kit, comprising:

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

a pharmaceutical composition comprising 2-methoxyestradiol, telomestatin, gefitinib, erlotinib hydrochloride, trastuzumab, pertuzumab, bevacizumab, wortmannin, rituximab, tositumomab, edrecolomab, semaxanib, cyclosporin, etanercept, doxycycline, gemtuzumab, oblimersen, melphalan, G-CSF, GM-CSF, EPO, COX-2 inhibitor, topotecan, pentoxifylline, taxotere, irinotecan, ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutically active mutant or derivative thereof, or a combination thereof.

32. A kit, comprising:

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

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