KR20070011564A - 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. ® KIPO & WIPO 2007

Description

METHODS AND COMPOSITIONS USING SELECTIVE CYTOKINE INHIBITORY DRUGS FOR TREATMENT AND MANAGEMENT OF CANCERS AND OTHER DISEASES

One. Field of invention

The present invention includes, but is not limited to, certain cancers and diseases associated with or characterized by angiogenesis by administering one or more selective cytokine inhibitory drugs alone or in combination with other therapies. To treat, prevent and / or manage other diseases. In particular, the present invention contemplates the use of drugs and other therapies, such as specific combinations of radiation or "cocktails," to treat these specific cancers, including cancers that are unresponsive to conventional therapies. Include.

2. Background of the Invention

2.1. Pathology in Cancer and Other Diseases

Cancer is primarily due to an increase in the number of abnormal cells derived from certain normal tissues, invasion of adjacent tissues by these abnormal cells, or lymphoid or blood-mediated spreading (metastasis) to local lymph nodes and distal sites of malignant cells. It is characterized by. Clinical data and molecular biological testing suggest that cancer is a multistep process that begins with a slight pre-tumoral change that can progress to neoplasm under certain conditions. Oncological lesions can evolve clonally, showing tumor cells with synergistic capacity for invasion, growth, metastasis and heterogeneity under conditions that circumvent host's immune surveillance (Roitt, L., Brostoff, J and Kale, D Immunology , 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There are various types of cancers described in detail in the medical literature. Examples include cancers of the lung, colon, rectum, prostate, breast, brain and intestine. The incidence of cancer continues to rise as the entire population ages, as new cancers develop, and as the susceptibility population (eg, those infected with AIDS or excessive exposure to sunlight) increases. Thus, there is a great need for new methods and compositions that can be used to treat patients with cancer.

Many types of cancer are associated with new blood vessel formation, a process known as angiogenesis. Several mechanisms involved in tumor-induced angiogenesis are known. The most direct of these mechanisms is the secretion of cytokines with angiogenic properties by tumor cells. Examples of these 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 through the production of proteases and subsequent destruction of the extracellular matrix in which some cytokines (eg b-FGF) are stored. Angiogenesis may also be induced indirectly through recruitment of inflammatory cells (especially macrophages) followed by release of their angiogenic cytokines (eg, TNF-α, bFGF).

Various other diseases and disorders are also associated with or are characterized by unwanted angiogenesis. For example, enhanced or uncontrolled angiogenesis may include neovascular diseases of the eye, neovascular diseases of the choroid, neovascular diseases of the retina, dermal scarring (angiogenesis of angles), viral diseases, genetic diseases, It has been linked to a number of diseases and clinical conditions, including but not limited to inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include diabetic retinopathy; Retinopathy of prematurity; Corneal graft rejection; Neovascular glaucoma; Posterior capsular fibrosis; And proliferative vitreoretinopathy, but are not limited to these.

Thus, compounds that can modulate angiogenesis or inhibit the production of certain cytokines, including TNF-α, can be useful for the treatment and prevention of various diseases and conditions.

2.2. Treatment method

Current cancer therapies may include surgery, chemotherapy, hormone therapy and / or radiation therapy to eradicate tumor cells from the patient (see, eg, Stockdale, 1998, Medicine , vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recent cancer therapies may also include biological or immunotherapy. All of these methods have significant disadvantages for patients. For example, surgery may be contraindicated due to the patient's health or may not be acceptable to the patient. In addition, surgery cannot completely remove tumor tissue. Radiation therapy is only effective if the tumor tissue exhibits greater sensitivity to radiation than normal tissue. Radiation therapy can also often cause serious side effects. Hormonal therapies are rarely given as a single drug. Although hormonal therapy can be effective, it is often used to prevent or delay the recurrence of cancer after other treatments remove most of the cancer cells. Biological therapies and immunotherapy are limited in number and can cause side effects such as influenza-sheep syndrome, digestive system problems or allergic reactions including swelling or swelling, fever, chills and fatigue.

With regard to chemotherapy, there are a variety of chemotherapeutic agents available for the treatment of cancer. Most cancer chemotherapeutic agents act directly by inhibiting DNA synthesis or indirectly by inhibiting biosynthesis of deoxyribonucleotide triphosphate precursors to prevent DNA replication and coexisting cell division (Gilman et al, m Goodman). and Gilman's : The Pharmacological Basis of Therapeutics , Tenth Ed. (McGraw Hill, New York).

Despite the availability of various chemotherapy agents, chemotherapy has a number of disadvantages (Stockdale, Medicine , vol. 3, Rubenstein and Federman, eds., Ch. 12, sect. 10, 1998). Almost all chemotherapy agents are toxic and chemotherapy causes significant and often dangerous side effects, including severe nausea, bone marrow suppression and immunosuppression. In addition, even when administering a combination of chemotherapeutic agents, many tumor cells are resistant to or develop resistance to chemotherapeutic agents. Indeed, cells that are resistant to certain chemotherapeutic agents used in treatment protocols are often demonstrated to be resistant to other drugs, even if these chemotherapeutic agents act by a mechanism different from that of the drug used in a particular treatment. . This phenomenon is called pleiotropic drug or multidrug resistance. Because of drug resistance, many cancers have proven to be nonresponsive to standard chemotherapy protocols.

Other diseases or conditions associated with or characterized by unwanted angiogenesis are also difficult to treat. However, some compounds, such as protamine, hepine and steroids, have been suggested to be useful in the treatment of certain specific diseases (Taylor et al., Nature 297: 307 (1982); Folkman et al., Science 221: 719 (1983); And US Pat. Nos. 5,001,116 and 4,994,443). Thalidomide and certain derivatives thereof have also been proposed for the treatment of such diseases and conditions (US Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355; D'Amato).

It also treats cancer and other diseases and conditions, particularly those that are unresponsive to standard therapies such as surgery, radiation, chemotherapy and hormone therapy, while reducing or avoiding the toxicity and / or side effects associated with conventional therapies. There is a significant need for safe and effective ways to prevent, control and manage.

2.3. Selective Cytokines Inhibitory  drug

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

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

3. Summary of the Invention

The present invention includes methods for treating and preventing certain types of cancer, including primary and metastatic cancers, as well as cancers that are unresponsive or resistant to conventional chemotherapy. This method provides selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof in patients in need of such treatment or prevention. Administering a therapeutically or prophylactically effective amount of. The invention also provides for administering a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient in need thereof. Including administering (eg, preventing or prolonging their recurrence or prolonging remission).

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

The invention also provides a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt thereof, for a patient in need of treatment, management, or prevention of diseases and disorders other than cancer associated with or characterized by unwanted angiogenesis, Treating, managing, or otherwise treating a disease and disorder other than cancer associated with or characterized by unwanted angiogenesis, including administering a therapeutically or prophylactically effective amount of a solvate, hydrate, stereoisomer, clathrate or prodrug It includes how to prevent it.

In another method of the invention, the selective cytokine inhibitory drug is administered in combination with therapies commonly used to treat, prevent or manage diseases and disorders associated with or characterized by unwanted angiogenesis. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy and immunotherapy.

The present invention provides a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second or additional active agent, a single Unit dosage forms, dosage regimens and kits. Second active agents include particular combinations of drugs or “cocktails”.

4. Detailed description of the invention

A first embodiment of the present invention is directed to a therapeutic agent of a selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof, for a patient in need thereof. Or methods of treating, managing or preventing cancer, including administering a prophylactically effective amount.

In certain methods encompassed by the present invention, the selective cytokine inhibitory drug is administered in conjunction with another drug ("second active agent") or method for treating, managing or preventing cancer. Second active agents include small and large molecules (eg, proteins and antibodies) (examples of which are provided herein) as well as stem cells. Methods or therapies that may be used in conjunction with the administration of selective cytokine inhibitory drugs include surgery, transfusion, immunotherapy, biological therapy, radiation therapy, and other non-drug basic therapies currently used to treat, prevent, or manage cancer. However, it is not limited to these.

Another embodiment of the invention includes a method of treating, managing or preventing a disease and disorder other than cancer characterized by unwanted angiogenesis. These methods include administering a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof.

Examples of diseases and disorders associated with or characterized by unwanted angiogenesis include inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, neovascular diseases of the eye, choroidal neoplasms Vascular diseases, neovascular diseases of the retina, and cutaneous redness (each angiogenesis), but are not limited to these. Specific examples of diseases and disorders associated with or characterized by unwanted angiogenesis include endometriosis, Crohn's disease, heart failure, advanced heart failure, kidney failure, endotoxins, toxic shock syndrome, osteoarthritis, retrovirus replication , Wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorders, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q-syndromes include, but are not limited to these.

In certain methods included in the present invention, the selective cytokine inhibitory drug is administered in conjunction with a second active agent or method for treating, managing or preventing a disease or condition. Second active agents include small and large molecules (eg, proteins and antibodies) (examples of which are provided herein) as well as stem cells. Methods or therapies that may be used in conjunction with the administration of selective cytokine inhibitory drugs include surgery, transfusion, immunotherapy, and biological procedures currently used to treat, prevent or manage diseases and conditions associated with or characterized by unwanted angiogenesis. Therapies, radiation therapy and other non-drug basic therapies are included, but are not limited to these.

The invention also encompasses pharmaceutical compositions (eg, single unit dosage forms) that can be used in the methods described herein. Certain pharmaceutical compositions include a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug, and a second active agent thereof.

4.1. Selective Cytokines Inhibitory  drug

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

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

Specific examples of selective cytokine inhibitory drugs include the cyclic imides described in US Pat. Nos. 5,605,914 and 5,463,063; Cycloalkyl amides and cycloalkyl nitriles of US Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281; Aryl amides (eg, N-benzoyl-3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide) of US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780; Imide / amide ethers and alcohols described in US Pat. No. 5,703,098 (eg, 3-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propan-1-ol); Succinimides and maleimides described in US Pat. No. 5,658,940 (eg, methyl 3- (3 ', 4', 5 ', 6'-tetrahydrophthalimido) -3- (3 ", 4 "-Dimethoxyphenyl) propionate); Imido and amido substituted alkanohydroxamic acids as described in US Pat. No. 6,214,857 and WO 99/06041; Substituted phenethylsulfones described in US Pat. Nos. 6,011,050 and 6,020,358; Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds described in US patent application Ser. No. 10 / 748,085, filed December 29, 2003; Substituted imides described in US Pat. No. 6,429,221 (eg, 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane); Substituted 1,3,4-oxadiazoles described in US Pat. No. 6,326,388 (eg, 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,3, 4-oxadiazol-2-yl) ethyl] -5-methylisoindolin-1,3-dione); Cyano and carboxy derivatives of substituted styrenes described in US Pat. Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554 (eg, 3,3-bis- (3,4-dimethoxyphenyl) acrylonitrile); Isoyn substituted at the 2-position by the α- (3,4-disubstituted phenyl) alkyl group described in WO 01/34606 and U.S. Pat. Dolin-1-one and isoindolin-1,3-dione; And imido and amido substituted acylhydroxysamic acids described in WO 01/45702 and US Pat. No. 6,699,899 (eg, (3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate), but is not limited to these. Other selective cytokine inhibitory drugs include the diphenylethylene compounds described in US Provisional Patent Application No. 60 / 452,460, filed March 5, 2003, the contents of which are incorporated herein by reference in their entirety. do. Each patent and patent application cited herein is hereby incorporated by reference in its entirety.

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

Other particular selective cytokine inhibitory drugs are classes of non-polypeptide cyclic amides described in US Pat. Nos. 5,698,579, 5,877,200, 6,075,041 and 6,200,987 and WO 95/01348, each of which is incorporated herein by reference. Belongs to. Representative cyclic amides include compounds of the formula

Where

n has a value of 1, 2 or 3;

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

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

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

ego;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other representative cyclic amides include compounds of the formula

Where

이며, 여기에서Z is

, Where

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

R ² is -CO- or SO ₂ ;

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

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

n has a value of 1, 2 or 3.

Other representative cyclic amides include compounds of the formula

Where

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

R ⁶ is —CO—, —CH ₂ — or —SO ₂ —;

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

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

ego;

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

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

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

Other representative imides include compounds of the formula

Where

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

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

, Where

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

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

R ^{9 '} is hydrogen, alkyl of 1 to 10 carbon atoms, -CH ₂ -pyridyl, benzyl, -COR ¹⁰ , or -SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl .

Other specific selective cytokine inhibitory drugs include the imido and amido substituted alkanohydroxamic acids described in WO 99/06041 and US Pat. No. 6,214,857, each of which is incorporated herein by reference. Examples of such compounds include, but are not limited to, compounds of the formula: and acid addition salts of such compounds containing nitrogen atoms that can be protonated.

Where

R ¹ and R ² are each hydrogen or lower alkyl when present independently of each other, or together with the illustrated carbon atoms to which they are attached nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbo Independently from the group consisting of propoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo O-phenylene, o-naphthylene or cyclohexene-1,2-diyl unsubstituted or substituted by 1 to 4 substituents selected;

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

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

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

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

n has a value of 0, 1 or 2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Where

Carbon atoms marked with * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Particular compounds are those wherein R ⁷ is methyl.

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

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

Where

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

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

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

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

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

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

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

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

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

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

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

Where

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

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

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

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

R ⁶ is —CO—, —CH ₂ — or —CH ₂ CO—;

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

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

R ⁸ is hydrogen or lower alkyl;

R ⁹ is lower alkyl or benzyl;

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

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

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

X is -CH ₂ -or -O-;

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

R ⁶ is —CO—, —CH ₂ — or —CH ₂ CO—;

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

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

R ⁸ is hydrogen or lower alkyl;

R ⁹ is alkyl or benzyl;

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

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

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

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

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

R ⁶ is —CO—, —CH ₂ — or —CH ₂ CO—;

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

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

R ⁸ is hydrogen or lower alkyl;

R ⁹ is alkyl or benzyl;

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

Other representative compounds are compounds of the formula

Where

Y is —C≡N or CO (CH ₂ ) _m CH ₃ ;

m is 0, 1, 2, or 3;

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

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

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

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

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

Where

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

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

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

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

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

R ⁸ is hydrogen or lower alkyl;

R ⁹ is alkyl or benzyl;

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

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

Where

Ar is (i) straight, branched or cyclic unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched or cyclic substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; (iv) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms Phenyl substituted by one or more substituents each independently selected from the group consisting of alkoxy and halo having 1 to 10 carbon atoms; (v) heterocycles; Or (vi) nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 carbon Heterocycle substituted by one or more substituents each independently selected from alkoxy, and halo, from 10 to 10;

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

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

Specific examples of this compound are compounds of the formula

Where

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

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

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

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

Where

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

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

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

R ⁴ is —CX—, —CH ₂ — or —CH ₂ CX—;

X is O or S;

n is 0, 1, 2, or 3.

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

Where

R ¹ is —CH ₂ —, —CH ₂ CO— or —CO—;

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

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

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

X is NH ₂ , OH, NHR or OR ⁶ , where

R is lower alkyl,

R ⁶ is alkyl or benzyl.

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

Where

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

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

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

R ⁴ is -CX or -CH _2- ;

X is O or S.

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

Where

Carbon atoms marked with * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

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

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

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

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

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

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

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

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

Specific examples of the compound are compounds of the formula

Where

Carbon atoms marked with * constitute a chiral center;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

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

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

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

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

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

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

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

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

Where

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

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

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

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

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

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

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

R ⁶ is hydrogen or lower alkyl;

R ⁷ is alkyl or benzyl.

Specific examples of the compound are compounds of the formula

Where

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

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

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

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

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

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

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

R ⁶ is hydrogen or lower alkyl;

R ⁷ is alkyl or benzyl.

Particularly preferred nitriles are compounds of the formula

Where

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

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

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

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

Particularly preferred nitriles are compounds of the formula

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

Where

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

n is 1, 2 or 3;

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

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

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

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

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

R ₇ is H or (C ₁ -C ₄ ) alkyl;

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

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

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

<Formula A>

From here

z is 0 or 1;

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

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

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

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

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

Specific compounds are compounds of the formula and enantiomers thereof.

Further specific compounds are compounds of the formula

Further examples include, but are not limited to, the following compounds: 2- [1- (3-ethoxy-4-methokwanyl) -2-methylsulfonylethyl] -4,5-dinitroisoyne Doline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindolin-1,3-dione; 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-e] benzimidazole-6,8-dione; 7- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] hydro-3-pyrrolino [3,4-e] benzimidazole-2,6,8-dione ; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-f] quinoxaline-1,3-dione; Cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} carboxamide; 2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-amino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-N, N-dimethylamino-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl Acetamide; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} -2,2,2-tri Fluoroacetamides; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} methoxycarboxamide; 4- [1-Aza-2- (dimethylamino) vinyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline-1,3-dione ; 4- [1-Aza-2- (dimethylamino) prop-1-enyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] isoindoline- 1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (5-methyl-1,3,4-oxadiazol-2-yl) isoindolin -1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-pyrrolylisoindolin-1,3-dione; 4- (aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -isoindolin-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1S- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutylisoindolin-1,3-dione; 4-amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolylisoindolin-1,3-dione; 2-chloro-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindol-4-yl} acetamide; 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] isoindoline-1,3-dione; 4-amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] isoindoline-1,3-dione; 2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolylisoindolin-1,3-dione; 2- (dimethylamino) -N- {2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; Cyclopentyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxamide ; 3- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl } Propanamide; 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl } Propanamide; N- {2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2 -(Dimethylamino) acetamide; N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2 -(Dimethylamino) acetamide; 4- {3-[(dimethylamino) methyl] pyrrolyl} -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3 -Dione; Cyclopropyl-N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl } Carboxamide; 2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -4-pyrrolylisoindolin-1,3-dione; N- {2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2- (dimethylamino) acetamide ; Cyclopropyl-N- {2- [1- (3,4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} carboxamide; Cyclopropyl-N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; 2- (dimethylamino) -N- {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} acetamide ; Cyclopropyl-N- {2-[(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carbox amides; Cyclopropyl-N- {2-[(1R) -1 (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide ; (3R) -3- [7- (acetylamino) -1-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; (3R) -3- [7- (cyclopropylcarbonylamino) -1-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide ; 3- {4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethyl Propanamide; (3R) -3- [7- (2-chloroacetylamino) -1-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxy-phenyl) -N, N-dimethylpropane amides; (3R) -3- {4- [2- (dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N , N-dimethylpropanamide; 3- (1,3-dioxo-4-pyrrolylisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- (imidazolyl-methyl) isoindolin-1,3-dione; N-({2- [1- (3-ethoxy4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide; 2-chloro-N-({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl Acetamide; 2- (dimethylamino) -N-({2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4- Methyl} acetamide; 4- [bis (methylsulfonyl) amino] -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione; 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4-[(methylsulfonyl) amino] isoindoline-1,3-dione; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxypentyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxopentyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione; 2-[(1R) -1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4- (pyrrolylmethyl) isoindolin-1,3-dione; N- {2- [1- (3-cyclopentyl-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N- {2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolylisoindolin-1,3-dione; 2- [1- (3,4-dimethoxyphenyl) -3-oxobutyl] -4- [bis (methylsulfonyl) amino] isoindolin-1,3-dione; And pharmaceutically acceptable salts, solvates and stereoisomers thereof.

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

Where

Carbon atoms marked with * constitute a chiral center;

R ⁴ is hydrogen or — (C═O) —R ¹² ;

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

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

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

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

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

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

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

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

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

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

<Formula 1>

Where

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

X is H,

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

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

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

R ⁴ is H,

R ⁵ is —OH, or —OC (O) R ⁶ ,

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

<Formula 2>

Where

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

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

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

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

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

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

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

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

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

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

In another embodiment, W represents groups of the formula

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

Where

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

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

Where

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

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

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

Z ₂ is H or C (O) R ₅ ;

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

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

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

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

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

Where

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

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

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

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

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

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

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

Where

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

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

R ₃ is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, — NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH _2, or R ₃ is combined with R _a , or combined with R ₄ , -OC (R ₁₆ R ₁₇ ) -O- or -O- (C (R ₁₆ R ₁₇ )) forms ₂ -O-;

R ₄ is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, — NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or —NHC (O) —R ₁₀ -NH ₂ ;

R ₅ is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, — NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH ₂ ;

R ₆ is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano,- NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or —NHC (O) —R ₁₀ -NH ₂ ;

R ₇ is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano,- NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH ₂ ;

R ₈ is —H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, — NO ₂ , -OH, -OPO (OH) ₂ , -N (R ₉ ) ₂ , -OC (O) -R ₁₀ , -OC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -C (O N (R ₁₀ ) ₂ , -NHC (O) -R ₁₀ , -NHS (O) ₂ -R ₁₀ , -S (O) ₂ -R ₁₀ , -NHC (O) NH-R ₁₀ , -NHC ( O) N (R ₁₀ ) ₂ , -NHC (O) NHSO ₂ -R ₁₀ , -NHC (O) -R ₁₀ -N (R ₁₀ ) ₂ , -NHC (O) CH (R ₁₀ ) (N (R ₉ ) ₂ ) or -NHC (O) -R ₁₀ -NH _2, or R ₈ is combined with R _c , or in combination with R ₇ , -OC (R ₁₆ R ₁₇ ) -O- or -O- (C (R ₁₆ R ₁₇ )) forms ₂ -O-;

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

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

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

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

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

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

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

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

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

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

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

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

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

4.2. Second active agent

Selective cytokine inhibitory drugs may be combined with other pharmacologically active compounds (“second active agents”) in the methods and compositions of the present invention. It is believed that certain combinations act synergistically in the treatment of certain types of cancer and certain diseases and conditions associated with or characterized by unwanted angiogenesis. Selective cytokine inhibitory drugs may also act to alleviate the side effects associated with certain second active agents, and some second active agents may be used to mitigate the side effects associated with selective cytokine inhibitory drugs.

In the methods and compositions of the present invention, one or more second active ingredients can be used in conjunction with selective cytokine inhibitory drugs. The second active ingredient may be a large molecule (eg a protein) or a small molecule (eg a synthetic inorganic, organometallic or organic molecule).

Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents include anti-CD40 monoclonal antibodies (eg, SGN-40); Histone deacetylase inhibitors (eg, SAHA and LAQ 824); Heat-shock protein-90 inhibitors (eg, 17-AAG); Insulin-positive growth factor-1 receptor kinase inhibitors; Vascular endothelial growth factor receptor kinase inhibitors (eg PTK787); Insulin growth factor receptor inhibitors; Lysophosphatidic acid acyltransferase inhibitors; IkB kinase inhibitors; p38MAPK inhibitors; EGFR inhibitors (eg, gefitinib and erlotinib HCL); HER-2 antibodies (eg, Trastuzumab (Herceptin ™) and Pertuzumab (Omnitarg ™)); VEGFR antibodies (eg, Bevacizumab (Avastin ™)); VEGFR inhibitors (eg, flk-1 specific kinase inhibitors, SU5416 and ptk787 / zk222584); P13K inhibitors (eg, buttmannins); C-Met inhibitors (eg PHA-665752); Monoclonal antibodies (eg, Rituxan ™, Toxxtumomab, and G250); And anti-TNF-α antibodies.

Typical large molecule active agents are biological molecules such as proteins that exist naturally or are made artificially. Particularly useful proteins in the present invention include proteins that promote the survival and / or proliferation of hematopoietic progenitor cells and immunologically active cells in vitro or in vivo. Others promote the division and differentiation of committed erythrocyte progenitors within cells in vitro or in vivo. Certain proteins include interleukins such as IL-2 (including recombinant IL-II (“rIL2”) and canaripox IL-2), IL-10, IL-12 and IL-18; Interferons such as interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia and interferon gamma-Ib; GM-CF and GM-CSF; And EPO, but are not limited to these.

Certain proteins that can be used in the methods and compositions of the present invention include Philgrass Tim, sold in the United States under the trade name Neuupogen (Amgen, Thousand Oaks, Calif.); Sargramostim, sold in the United States under the trade name Leukine ™; Immunex, Seattle, WA; And recombinant EPO sold in the United States under the trade name Epogen ™ (Amgen, Thousand Oaks, Calif.).

Recombinant and mutated forms of GM-CSF are described in US Pat. Nos. 5,391,485; 5,393,870; And 5,229,496, all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF are described in US Pat. Nos. 4,810,643; 4,999,291; 5,528,823; And 5,580,755, all of which are incorporated herein by reference.

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

Large molecule active agents can be administered in the form of anticancer vaccines. For example, vaccines that secrete or cause secretion of cytokines such as IL-2, G-CSF and GM-CSF can be used in the methods, pharmaceutical compositions and kits of the invention (see, eg, Emens, LA, et al ., Curr . Opinion Mol . Ther . 3 (1): 77-84 (2001).

In one embodiment of the invention, the large molecule active agent reduces, eliminates or prevents side effects associated with the administration of selective cytokine inhibitory drugs. Depending on the particular selective cytokine inhibitory drug and the disease or disorder to be treated, side effects may include drowsiness and drowsiness, dizziness and orthostatic hypotension, neutropenia, neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson syndrome ( Stevens-Johnson Syndrome) and addictive epidermal detachment, and seizures (eg, large seizure cramps) may be included, but are not limited to these. Specific side effect is neutropenia.

Small molecule second active agents can also be used to mitigate the side effects associated with the administration of selective cytokine inhibitory drugs. However, as with some macromolecules, it is believed that most can provide a synergistic effect when administered with (eg, before, after or concurrently) with selective cytokine inhibitory drugs. Examples of small molecule second active agents include, but are not limited to, anticancer agents, antibodies, immunosuppressants, and steroids.

Examples of anticancer agents include cemaksanib; Cyclosporin; Etanercept; Doxycycline; Bortezomib; Abyssin; Aclarubicin; Acodazole hydrochloride; Acronin; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Amethanetron acetate; Amsacrine; Anastrozole; Anthracycin; Asparaginase; Asperlin; Azacytidine; Azethepa; Azotomycin; Batimastad; Benzodepa; Bicalutamide; Bisantrene hydrochloride; Bisnaphide demesylate; Bizelesin; Bleomycin sulfate; Brequinar sodium; Bropyrimin; Busulfan; Cocktinomycin; Calusosterone; Carracemide; Carbetatimers; Carboplatin; Carmustine; Carrubicin hydrochloride; Carzelesin; Sedefingol; Celecoxib (COX-2 inhibitor); Chlorambucil; Sirolemycin; Cisplatin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diajikuon; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droroxifene citrate; Dromostanolone propionate; Duazomycin; Edda trexate; Eflornithine hydrochloride; Elsammitrusin; Enroplatin; Enpromate; Epipropidine; Epirubicin hydrochloride; Erbulosol; Esorubicin hydrochloride; Esturamustine; Esthramustine phosphate sodium; Ethanidazol; Etoposide; Etoposide phosphate; Etorine; Padrosol hydrochloride; Pazarabine; Fenretinide; Phloxuridine; Fludarabine phosphate; Fluorouracil; Flurocitabine; Phosquidone; Postriecin sodium; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride; Ifosfamide; Monomorphine; Ifoplatin; Irinotecan; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarosol hydrochloride; Rometrexole sodium; Romustine; Roxanthrone hydrochloride; Plum wine; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melenzestrol acetate; Melparan; Menogaryl; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprin; Meteuredepa; Mythinamide; Mitocarcin; Mitochromen; Mitogiline; Mitomalcin; Mitomycin; Mitosper; Mitothene; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Ormaplatin; Oxyshuran; Paclitaxel; Pegasparase; Peliomycin; Pentamustine; Pepleomycin sulfate; Perphosphamide; Fifobroman; Capulsulfan; Pyroxanthrone hydrochloride; Plicamycin; Plomethane; Porphymer sodium; Propyromycin; Prednismustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pyrazopurin; Ribophrine; Safingol; Safingol hydrochloride; Semustine; Simtragen; Sparfosate sodium; Spartomycin; Spirogermanium hydrochloride; Spiromostin; Spiroplatin; Streptonigrin; Streptozosin; Sulfofenur; Thalisomycin; Tecogallan sodium; Taxotere; Tegapur; Teloxtron hydrochloride; Temophorin; Teniposide; Theroxylone; Testosterone; Thiamiprine; Thioguanine; Thiotepa; Thiazopurin; Tyrapazamine; Toremifene citrate; Trestolone acetate; Trisiribin phosphate; Trimetrexate; Trimetrexate glucuronate; Tryptorelin; Tubulosol hydrochloride; Uracil mustard; Euredepa; Vapretide; Berteporphine; Vinblastine sulfate; Vincristine sulfate; Bindesin; Vindesine sulfate; Vinepidine sulfate; Vin glycinate sulfate; Binroyrosine sulfate; Vinorelbine tartrate; Binrocidine sulfate; Vinzolidine sulfate; Borosol; Geniplatin; Ginostatin; And zorubicin hydrochloride, but are not limited to these.

Other anticancer drugs include, but are not limited to, the following drugs: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; Abiraterone; Aclarubicin; Acylpulbene; Adecayphenol; Adozelesin; Aldesleukin; ALL-TK antagonists; Altretamine; Ambamustine; Amidox; Amifostine; Aminolevulinic acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis inhibitors; Antagonist D; Antagonist G; Antarelix; Anti-dorsalizing morphogenetic protein-1; Anti-androgens, prostate cancer; Antiestrogens; Antineoplasmon; Antisense oligonucleotides; Apidicholine glycinate; Apoptosis gene modulators; Apoptosis modulators; Apurinic acid; Ara-CDP-DL-PTBA; Arginine deaminase; Asulacrine; Atamesteine; Atrimustine; Axinastatin 1; Axinastatin 2; Axinastatin 3; Azasetron; Azatoxins; Azatyrosine; Baccatin III derivatives; Balanol; Batimastad; BCR / ABL antagonists; Benzochlorine; Benzoylstaurosporin; Beta lactam derivatives; Beta-aletin; Betaclomycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Bisnaphide; Bistratene A; Bizelesin; Breplates; Bropyrimin; Budotetiin; Butionine sulfoximine; Calcipotriol; Calfostine C; Camptothecin derivatives; Capecitabine; Carboxamide-amino-triazole; Carboxamidotriazoles; CaRest M3; CARN 700; Cartilage induced inhibitors; Carzelesin; Casein kinase inhibitors (ICOS); Castanospermine; Secropin B; Setlorellix; Chlorins; Chloroquinoxaline sulfonamides; Cicafrost; Cis-porphyrin; Cladribine; Clomiphene homologs; Clotrimazole; Cholismycin A; Cholismycin B; Combretastatin A4; Combretastatin homologues; Conazenin; Cramblesdine 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cyfemycin; Cytarabine oxphosphate; Cytolytic factor; Cytostatin; Daclicksimab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexiphosphamide; Dexlaonic acid; Dexverapamil; Diajikuon; Didemnin B; Dedox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenyl spiromostin; Docetaxel; Docosanol; Dolacetron; Doxyfluidine; Doxorubicin; Droloxifene; Dronabinol; Duocarmycin SA; Epselen; Echomustine; Edelfosine; Edrecolomab; Eflornithine; Element; Emitepur; Epirubicin; Epristeride; Esturamustine homologues; Estrogen agonists; Estrogen antagonists; Ethanidazol; Etoposide phosphate; Exemsteine; Padrosol; Pazarabine; Fenretinide; Filgrastim; Finasteride; Flavopyridols; Flezelastine; Fluasterone; Fludarabine; Fluorodaunorunycin hydrochloride; Porfenix; Formemsteine; Postriecin; Potemustine; Gadolinium texaphyrin; Gallium nitrate; Gallocitabine; Ganirelex; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hepsulpam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Udoxifen; Isdramantone; Monomorphine; Ilomatstat; Imatinib (eg, Gleevec ™); Imiquimod; Immunostimulant peptides; Insulin-positive growth factor-1 receptor inhibitors; Interferon agonists; Interferon; Interleukin; Iobenguan; Iododoxorubicin; Ifomianol, 4-; Ilopact; Irsogladine; Isobenazole; Iso homohalicondrin B; Itacrone; Jasplatinolides; Kahalide F; Lamelalin-N triacetate; Lanreotide; Reinamycin; Renograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitors; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuproreline; Levamizol; Liarosol; Linear polyamine homologues; Lipophilic disaccharide peptide; Lipophilic platinum compounds; Lysoclinamide 7; Lovaplatin; Rombrisin; Rometrexole; Rodidamine; Rooxanthrone; Roxoribin; Lutetocan; Lutetium texaphyrin; Lysophylline; Soluble peptides; Maytansine; Mannostatin A; Marimastat; Plum wine; Maspin; Matrylysine inhibitors; Matrix metalloproteinase inhibitors; Menogaryl; Merbaron; Meterelin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Myrimos team; Mitoguazone; Mitolactol; Mitomycin homologues; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofarotene; Molgramos team; Erbitux, human chorionic gonadotropin; Monophosphoryl lipid A + myobacterium cell wall sk; Fur mall; Mustard anticancer agent; Mycaperoxide B; Mycobacterial cell wall extract; Miraphorone; N-acetyldinaline; N-substituted benzamides; Naparelin; Nagre tip; Naloxone + pentazosin; Napabin; Naphterpine; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrile; Oblimersen (Genasense ™); O ⁶ -benzylguanine; Octreotide; Ocisenone; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Ormaplatin; Ostherone; Oxaliplatin; Oxaunomycin; Paclitaxel; Paclitaxel homologues; Paclitaxel derivatives; Palauamine; Palmitoylraicin; Pamidronic acid; Panaxitriol; Panomifen; Parabactin; Pazelliptin; Pegaspargase; Peldesin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubrones; Perphosphamide; Peryl alcohol; Phenazinomycin; Phenyl acetate; Phosphatase inhibitors; Fishvanyl; Pilocarpine hydrochloride; Pyrarubicin; Pyritrexime; Placetin A; Placetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porphymer sodium; Porphyromycin; Prednisone; Propyl bis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immune modulators; Protein kinase C inhibitors; Protein kinase C inhibitors; Microalgal; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; Raltitrexide; Lamosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; Demethylated retelliptin; Rhenium Re 186 ethedronate; Lysine; Ribozyme; RII retinamide; Lohitukine; Lomurtide; Loquinimex; Rubiginone B1; Luboksil; Safingol; Seintopin; SarCNU; Sarcophytol A; Sargramos team; Sdi 1 analogues; Semustine; Aging induced inhibitor 1; Sense oligonucleotides; Signal transduction inhibitors; Sizopyran; Small tribe; Sodium borocaptate; Sodium phenylacetate; Solberol; Somatomedin binding protein; Sonermin; Spartoic acid; Spicamycin D; Spiromostin; Splinofentin; Spongestatin 1; Squalane; Stiffamide; Stromelysine inhibitors; Sulfinosine; Hyperactive vasoactive intestinal peptide antagonists; Suradista; Suramin; Swainsonine; Thalimustine; Tamoxifen methoxide; Tauromustine; Tazarotene; Tecogallan sodium; Tegapur; Tellurium pyrilium; Telomerase inhibitors; Temophorpine; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Thaliblastine; Thiocoralin; Thrombopoietin; Thrombopoietin analogs; Thymalfasin; Thymopoietin receptor agonists; Thymotrinan; Thyroid stimulating hormone; Tin ethyl thiofurfurin; Tyrapazamine; Titanocene bichloride; Topsentin; Toremifene; Detoxification inhibitors; Tretinoin; Triacetyluridine; Trisiribin; Trimetrexate; Tryptorelin; Trophysetron; Turosteride; Tyrosine kinase inhibitors; Tyrphostin; UBC inhibitors; Juvenimex; Urinary sinus-induced growth inhibitory factor; Urokinase receptor antagonists; Vapretide; Variolin B; Belaresol; Veramine; Verdin; Berteporphine; Vinorelbine; Vinxaltin; Nontaxin; Borosol; Zanoterone; Geniplatin; Zillascorb; And ginostatin stymalamer.

Certain second active agents include 2-methoxyestradiol, telomestatin, inducers of apoptosis in multiple myeloma cells (e.g. TRAIL), statins, cemaksanib, cyclosporin, etanercept, doxycycline, bortezomib , Oblimersen (Genasense ™), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron ™), steroids, gemcitabine, cisplatinum, temozolomide, eto Foursides, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, arisa ™, taxol, taxotere, fluorouracil, leucoborin, irinotecan, geloda , CPT-11, interferon alpha, pegylated interferon alpha (eg PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposome daunorubicin , Cytarabine, docetaxol, pasilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednison, bisphosphonate, Arsenic trioxide, vincristine, doxorubicin (Doxil ™), paclitaxel, gancyclovir, adriamycin, esturamustine sodium phosphate (Emcyt ™), sulindac and etoposide, including but not limited to It doesn't work.

4.3. Treatment and Prevention

The methods of the present invention include methods of treating, preventing and / or managing various types of cancers and diseases and disorders associated with or characterized by unwanted angiogenesis. Unless indicated otherwise, the term “treating” as used herein means administering a compound of the invention or other additional active agent after the manifestation of a particular disease or disorder. Unless otherwise indicated, the term "preventing" as used herein refers to the development of symptoms in patients at risk of cancer, and other diseases and disorders associated with or characterized by unwanted angiogenesis. Means to administer before. The term "prevention" includes the suppression of the symptoms of a particular disease or disorder. Patients with a family history of diseases and disorders associated with or characterized by cancer and unwanted angiogenesis are preferred candidates for prophylactic regimens. Unless otherwise indicated, the term "managing" as used herein prevents the recurrence of such a disease or disorder in a patient who has had a particular disease or disorder, and / or relieves a patient having that disease or disorder. Extending the time to maintain.

The term "cancer" as used herein includes, but is not limited to, solid tumors and blood born tumors. The term "cancer" refers to the bladder, bone or blood, brain, breast, oral cavity, thorax, crystal, endometrium, esophagus, eye, head, kidney, liver, lymph node, lung, oral cavity, cervix, ovary, pancreas, prostate, rectum, By diseases of the skin tissue, organs, blood and blood vessels, including but not limited to cancer of the stomach, testicles, throat and uterus. Specific cancers include advanced malignancies, amyloidosis, neuroblastoma, meningiomas, atypical meningiomas, pericarcinomas, multiple brain metastases, glioblastoma multiforms, gliomas, brainstem glioma, malignant brain tumors with poor prognosis, malignant glioma, Recurrent malignant glioma, degenerative astrocytoma, degenerative glioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, irresistible colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, Karyotype acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse versus B-cell lymphoma, low grade follicular lymphoma, metastatic melanoma ( Localized melanoma, including but not limited to melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal cancer, papillary serous cancer , Gynecologic sarcoma, Soft tissue sarcoma, Scleroderma, Cutaneous vasculitis, Langerhans cell histiocytosis, Leiomyosarcoma, Progressive osteoplastic fibrosis, Hormone-responsive prostate cancer, Resected high-risk soft tissue sarcoma, Can be resected Hepatocellular carcinoma, Waldenstrom's macroglobulinemia, Subacute myeloma, Painless myeloma, Tubal cancer, 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, medulla thyroid cancer, and leiomyoma.

As used herein to refer to diseases and conditions other than cancer, the terms “disease or disorder associated with or characterized by unwanted angiogenesis”, “disease or disorder associated with unwanted angiogenesis” and “primary Diseases or disorders characterized by non-angiogenic "include inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, neovascular diseases of the eye, neovascular diseases of the choroid and neovascular diseases of the retina. (But not limited to these) refers to diseases, disorders and conditions caused, mediated or accompanied by undesirable, unwanted or uncontrolled angiogenesis.

Examples of such diseases or disorders associated with unwanted angiogenesis include endometriosis, Crohn's disease, heart failure, advanced heart failure, renal failure, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, angiogenic glaucoma, posterior lens fibrosis, proliferation Sexual vitreoretinopathy, trachoma, myopia, orbit, epidemic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium dry keratitis, sjogrens, strawberry nose, phylectenulosis, syphilis, lipid degeneration , Bacterial ulcers, fungal ulcers, herpes simplex infections, shingles infections, protozoan infections, Kaposi's sarcoma, Mooren ulcer, Terrien's marginal degeneration, borderline keratitis, rheumatoid arthritis , Systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, scleritis, Steven's Johnson disease, Periphigoid radial keratotomy, sickle cell anemia, sarcoidosis, resilient fibrous pulmonary melanoma, Pagets disease, vein occlusion, arterial occlusion, carotid atresia, chronic uveitis, chronic vitreitis, Lyme disease ( Lyme's disease, Eales disease, Bechet's disease, retinitis, choroiditis, putative ocular histoplasmosis, Bests disease, Stargarts disease, flatulitis , Chronic retinal detachment, hyperviscotic syndrome, toxoplasmosis, cutaneous redness, sarcodisis, sclerosis, soriatis, psoriasis, primary sclerotic cholangitis, proctitis, primary cholangiosclerosis, idiopathic pulmonary fibrosis, Alcoholic hepatitis, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, weakness, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, malignancy-associated hypercalcemia, stroke, mild Veterinary medicine caused by ventilatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, 5q-syndrome, and feline immunodeficiency virus, equine infectious anemia virus, goat arthritis virus, visna virus, maedi virus or lenti virus Enemy disorders, including but not limited to.

In certain embodiments of the invention, the disease or disorder associated with unwanted angiogenesis is 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 disease, chronic obstructive pulmonary disease, chronic lung inflammatory disease, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxin shock, hemodynamic shock, sepsis syndrome, ischemia reperfusion injury , Fibrotic disease, cachexia, transplant rejection, rheumatoid spondylitis, osteoporosis, ulcerative colitis, inflammatory-intestinal disease, multiple sclerosis, systemic lupus erythematosus, leprosy nodules in leprosy, radiation damage, asthma, peroxal alveolar injury It does not include malaria, mycobacterial infections, and opportunistic infections caused by HIV.

The present invention includes methods of treating patients who have previously been treated for a disease or disorder associated with or characterized by cancer or unwanted angiogenesis, but who are previously unresponsive to standard therapies, and who have not been previously treated. . Although some diseases or disorders are more common in certain age groups, the invention also includes methods of treating a patient regardless of the age of the patient. The invention further includes a patient who has undergone surgery in an attempt to treat a disease or condition in question, and a method of treating a patient who does not. Since patients with cancer and diseases and disorders associated with or characterized by unwanted angiogenesis have heterogeneous clinical symptoms and variable clinical outcomes, the treatment provided to the patient may vary depending on their prognosis. have. The skilled clinician will be able to identify certain second agents, types of surgery, and types of non-drug basic standard therapies that can be effectively used to treat each patient with cancer and other diseases or disorders without undue experimentation. You can easily decide.

The methods encompassed by the present invention include one or more selective cytokine inhibitory drugs of the present invention in a patient (eg, a human) suffering from or likely to be suffering from a disease or disorder associated with or characterized by cancer or unwanted angiogenesis. Or administering a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof.

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

In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is used in patients with recurrent multiple myeloma May be administered in an amount of about 400, 800 or 1,200 mg per day. In a particular embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is primarily about 100 mg / day The dose can be raised to 200, 400, 800, 1,200 and 2,500 mg / day every week. In certain embodiments, the compound may be administered to a patient with a solid tumor in an amount up to about 5,000 mg / day. In a particular embodiment, the compound may be administered to a patient with glioma in an amount up to about 10,000 mg / day.

In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is administered to a patient with Crohn's disease. It may be administered in an amount of about 400 mg / day, and may be raised to 800 mg and 1,200 mg daily.

In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is endotoxin, toxic shock Syndrome, osteoarthritis, retroviral replication, weakness, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorders, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macromolecular anemia, refractory From about 100 mg to about 5,000 mg per day to a patient with a disease or disorder associated with or characterized by, but not limited to, sexual anemia, and 5q-syndrome Amount, or from about 1.5 to 2.5 times the daily dose may be administered every other day.

In another specific embodiment, (+)-2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin 1,3-dione is Endotoxin, toxic shock syndrome, osteoarthritis, retrovirus replication, debilitating, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorders, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, About 1 to about 200 in patients with a disease or disorder associated with or characterized by, but not limited to, macrocytic anemia, refractory anemia, and 5q-syndrome Mg / day, preferably about 10 to about 50 mg / day or more, preferably about 1.5 to 2.5 times the daily dose every other day.

4.3.1. 2nd With active agents  Combination Therapy

Certain methods of the present invention provide a selective cytokine inhibitory drug of the present invention, a pharmaceutically acceptable salt thereof, a solvate, hydrate, stereoisomer, clathrate or prodrug together with one or more second active agents, and / or radiation. Administration with therapy, transfusion, or surgery. Examples of selective cytokine inhibitory drugs of the invention are described herein (see Example 4.1). Examples of second active agents are also described herein (see Example 4.2).

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

In one embodiment of the invention, the second active agent is intravenously or subcutaneously, in an amount of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg It is administered once or twice a day. The specific amount of the second active agent is determined by the specific agent used, the type of disease to be treated or managed, the severity and stage of the disease, and the amount of the selective cytokine inhibitory drug of the present invention and any additional active agent administered simultaneously to the patient ( Will depend on In certain embodiments, the second active agent is oblimersen (Genasense ™), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxy Filin, ciprofloxacin, dexamethasone, vincristine, doxorubicin, cox-2 inhibitors, IL2 IL8, IL18, IFN, Ara-C, vinorelbine, or combinations thereof.

In a particular embodiment, the GM-CSF, G-CSF or EPO is in an amount of about 1 to about 750 mg / m 2 / day, preferably about 25 to about 500 mg / day, for about 5 days in a 4 or 6 week cycle. In an amount of m 2 / day, more preferably in an amount of about 50 to about 250 mg / m 2 / day, most preferably in an amount of about 50 to about 200 mg / m 2 / day subcutaneously. In certain embodiments, GM-CSF may be administered intravenously in an amount of about 60 to about 500 mg / m 2 or subcutaneously in an amount of about 5 to about 12 mcg / m 2 / day. In certain embodiments, G-CSF may be administered subcutaneously, primarily in an amount of about 1 mcg / kg / day, and may be adjusted according to an increase in the total granulocyte count. The maintenance dose of G-CSF may be administered subcutaneously in an amount of about 300 (in smaller patients) or 480 mcg. In certain embodiments, the EPO can be administered subcutaneously in an amount of 10,000 units three times per week.

In another embodiment, the selective cytokine inhibitory drug is from about 20 mg to about 1,200 mg / d to a patient with metastatic melanoma (limited to but not limited to melanoma including eye melanoma) Amounts alone or in combination with a second active agent. In one embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) in an amount from about 800 to about 1,200 mg / d -Patients with propionamide and dacarbazine (DTIC) in an amount from about 200 to about 1000 mg / m 2 / d with metastatic melanoma (including but not limited to melanoma) limited melanoma) To administer. In another embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) in an amount of about 800 to 1,200 mg / d Propionamide, and temozolomide, are administered to patients with metastatic melanoma (limited, but not limited to, melanoma including ocular melanoma). In another embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide has temozolomide whose disease is , Dacarbazine (DTIC), IL-2 and / or IFN is administered to patients with advanced metastatic melanoma or localized melanoma in an amount of about 200 to about 800 mg / d. In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is a relapsed or nonreactive multiple Patients with myeloma are administered with dexamethasone in an amount of twice daily, about 400 mg / d or four times a day, about 800 mg / d.

In another embodiment, the selective cytokine inhibitory drug is administered in combination with melphalan and dexamethasone to a patient with amyloidosis. In certain embodiments, the selective cytokine inhibitory drugs and steroids of the invention can be administered to a patient with amyloidosis.

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

In another embodiment, the selective cytokine inhibitory drug is administered with a second active ingredient as follows: temozolomide in pediatric patients with recurrent or advanced brain cancer or recurrent neuroblastoma; Celecoxib, etoposide and cyclophosphamide for recurrent or advanced CNS cancers; Temodar in patients with recurrent or progressive meningioma, malignant meningioma, pericarcinoma, multiple brain metastases, recurrent brain tumors, or newly diagnosed polymorphic gliomas; Irinotecan to patients with recurrent gliomas; Carboplatin in pediatric patients with brainstem glioma; Procarbazine in pediatric patients with advanced malignant glioma; Cyclophosphamide in patients with malignant brain tumors of poor prognosis, newly diagnosed or recurrent polymorphic gliomas; Gliadel ™ for high grade recurrent malignant glioma; Temozolomide and tamoxifen for degenerative astrocytoma; Or topotecan for glioma, glioblastoma, degenerative astrocytoma or degenerative glioma.

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

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

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

In another embodiment, the selective cytokine inhibitory drug is administered with Arisa ™, Taxol and / or Taxotere to a patient with colon cancer.

In another embodiment, the selective cytokine inhibitory drug is administered with capecitabine in patients with unresponsive colorectal cancer, or in patients with failed first line treatment or inferior results in colon or rectal adenocarcinoma.

In another embodiment, the selective cytokine inhibitory drug is administered with fluorouracil, leucoboline, and irinotecan to patients with Dukes C & D colorectal cancer or patients who have already been treated for metastatic colorectal cancer.

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

In another embodiment, the selective cytokine inhibitory drug of the present invention is administered with capecitabine and irinotecan to patients with unresponsive colorectal cancer or patients with intractable or metastatic colorectal cancer.

In another embodiment, the selective cytokine inhibitory drug is cisplatin and thiote alone or in combination with interferon alpha or capecitabine in patients with incontinent or metastatic hepatocellular carcinoma, or in patients with primary or metastatic liver cancer. Administered with leeks.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with Kaposi's sarcoma with pedsylated interferon alpha.

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

In another embodiment, the selective cytokine inhibitory drug is administered with liposome daunorubicin, topotecan and / or cytarabine to a patient with undesirable karyotype acute myeloid leukemia.

In another embodiment, the selective cytokine inhibitory drug is administered with gemcitabine and irinotecan to a patient with non-small cell lung cancer. In one embodiment, the selective cytokine inhibitory drug is administered with carboplatin and irinotecan to a patient with non-small cell lung cancer. In one embodiment, the selective cytokine inhibitory drug is administered with doxtaxol to a patient with non-small cell lung cancer that has previously been treated with carbo / vp 16 and radiation therapy.

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

In another embodiment, the selective cytokine inhibitory drug is administered with oblimersen (Genasense ™) to a patient with small cell lung cancer.

In another embodiment, the selective cytokine inhibitory drug is Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse versus B-cell lymphoma or relapsed or non-responsive low grade follicular It is administered to patients with various types of lymphoma, including but not limited to lymphoma, alone or in combination with a second active agent such as vinblastine or fludarabine.

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

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

In another embodiment, the selective cytokine inhibitory drug is dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, laying down in patients with multiple myeloma of various types or stages. It is administered with a plate, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, doxyl, decadron or combinations thereof.

In another embodiment, the selective cytokine inhibitory drug is combined with doxorubicin (Doxil ™), vincristine and / or dexamethasone (Decadron ™) in patients with multiple myeloma that is relapsed or unresponsive. Administered.

In another embodiment, the selective cytokine inhibitory drug is taxol, carboplatin, doxorubicin, in a patient with various types or stages of ovarian cancer such as peritoneal cancer, papillary serous cancer, unreactive ovarian cancer or recurrent ovarian cancer, Is administered with gemcitabine, cisplatin, geloda, paclitaxel, dexamethasone, or combinations thereof.

In another embodiment, the selective cytokine inhibitory drug is geloda, 5 FU / LV, gemcitabine, irinotecan + gemcitabine, cyclophosphamide, vincristine, dexamethasone in patients with various types or stages of prostate cancer. , GM-CSF, celecoxib, taxotere, cancyclovir, paclitaxel, adriamycin, docetaxel, esturamustine, Emcit or combinations thereof.

In another embodiment, the selective cytokine inhibitory drug is combined with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex ™ or combinations thereof in patients with various types or stages of renal cell carcinoma. Are administered together.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with various types or stages of gynecological, uterine or soft tissue sarcoma cancer with IFN, COX-2 inhibitors such as Celebrex ™ and / or sulindac. .

In another embodiment, the selective cytokine inhibitory drug is used in patients with solid tumors of various types or stages of celecrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF Or a combination thereof.

In another embodiment, the selective cytokine inhibitory drug is selebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF or Together with their combination.

The invention also includes administering to a patient (eg, a human) a selective cytokine inhibitory drug of the invention, or a pharmaceutically acceptable derivative, salt, sorbate, clathrate, hydrate or prodrug thereof. Methods of increasing the dosage of an anticancer drug or anticancer agent that can be safely and effectively administered to a patient. Patients who may benefit from this method may be characterized by skin, subcutaneous tissue, lymph nodes, brain, lungs, liver, bone, intestine, colon, heart, pancreas, adrenal gland, kidney, prostate, breast, colon, or a combination thereof. The patient is likely to suffer from side effects associated with anticancer drugs to treat cancer. Administration of the selective cytokine inhibitory drugs of the invention alleviates or reduces side effects with severity, which in other cases may limit the amount of anticancer drug.

In one embodiment, the selective cytokine inhibitory drug of the invention is about 1 to about 5,000 mg, about 10 to about 2,500 mg, about 25 to about 2,500 before, during or after a side effect associated with the administration of the anticancer drug to the patient. Mg, about 100 to about 1,200 mg, or about 100 to about 800 mg, orally daily. In certain embodiments, the selective cytokine inhibitory drugs of the invention may be combined with heparin, aspirin, coumadine or G-CSF to avoid side effects associated with anticancer drugs such as, but not limited to, neutropenia or thrombocytopenia. Administered with the same specific agent.

In one embodiment, the selective cytokine inhibitory drugs of the invention comprise anticancer drugs, anti-inflammatory agents, antihistamines, antibiotics and steroids in patients with diseases and disorders associated with or characterized by unwanted angiogenesis, But not limited to these).

In another embodiment, the present invention is directed to treating, preventing or managing cancer of the selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. In combination with (eg, before, during or after) conventional treatments, including but not limited to the currently used surgery, immunotherapy, biological therapy, radiation therapy or other non-drug base therapies ) Treatment, prevention and / or management of cancer, including administration. The combination use of the selective cytokine inhibitory drugs of the present invention and conventional therapies can provide a unique therapeutic regimen that is unexpectedly effective in some patients. Although not theoretically limited, it is believed that the selective cytokine inhibitory drugs of the invention can provide an additive or synergistic effect when administered concurrently with conventional therapies.

In another embodiment, the invention relates to or is characterized by an unwanted cytokine of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. Conventional therapies, including but not limited to surgery, immunotherapy, biological therapy, radiation therapy or other non-drug base therapies currently used to treat, prevent or manage diseases and disorders; Methods of treating, preventing and / or managing diseases and disorders associated with or characterized by unwanted angiogenesis, including administration together (eg, before, during or after). The combination use of selective cytokine inhibitory drugs and conventional therapies can provide a unique therapeutic regimen that is unexpectedly effective in some patients. Although not theoretically limited, it is believed that selective cytokine inhibitory drugs can provide an additive or synergistic effect when administered concurrently with conventional therapies.

As discussed elsewhere herein, the invention is detrimental to or associated with conventional therapies, including but not limited to surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. Methods of reducing, treating and / or preventing undesirable side effects. One or more selective cytokine inhibitory drugs of the invention may be administered to a patient before, during or after the side effects associated with conventional therapies occur.

In one embodiment, the selective cytokine inhibitory drug of the invention is orally about 1 to about 5,000 mg, about 10 to about 2,500 mg, about 25 to about 2,500 orally per day before, during or after using conventional therapies. Mg, about 100 to about 1,200 mg, or about 100 to about 800 mg, alone or in combination with a second active agent as described herein (see, eg, Item 4.2).

In certain embodiments of this method, the selective cytokine inhibitory drug and docetaxol of the invention are administered to a patient with carbo / VP 16 and non-small cell lung cancer previously treated by radiation therapy.

4.3.2. Use with transplantation

Compounds of the invention can be used to reduce the risk of graft-versus-host disease (GVHD). Accordingly, the present invention provides a method of treating cancer comprising administering a selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof in combination with transplantation therapy, Prevention and / or management.

As recognized by those of ordinary skill in the art, the treatment of cancer is often based on the stage and mechanism of the disease. For example, because inevitable leukemia transformation is expressed at certain stages of cancer, transplantation of peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow may be necessary. The combination use of the selective cytokine inhibitory drugs and transplantation therapy of the present invention provides unique and unexpected synergy. In particular, the selective cytokine inhibitory drugs of the invention exhibit activity that can provide an additive or synergistic effect when given concurrently with transplantation therapy in patients with cancer.

Selective cytokine inhibitory drugs of the invention can work in conjunction with transplantation to reduce the risk of GVHD and complications associated with invasive procedures of transplantation. The present invention provides a selective cytokine inhibitory drug of the present invention to a patient (eg, a human) before, during or after transplantation of cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow, Methods of treating, preventing and / or managing cancer, including administering acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. Examples of stem cells suitable for use in the methods of the present invention are described in US Patent Application No. 10 / 411,655 filed April 11, 2003 (R. Hariri et. al .), the entire contents of which are incorporated herein by reference.

In another embodiment, the invention provides a selective cytokine inhibitory drug to a patient (eg, a human) before, during or after transplantation of cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow, or Treating, preventing and / or managing diseases and disorders associated with or characterized by unwanted angiogenesis, including the administration of pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs It includes a method.

In one embodiment of this method, the selective cytokine inhibitory drug of the invention is administered before, during or after transplanting autologous peripheral blood progenitor cells into a patient with multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug is administered after transplanting stem cells to a patient with recurrent multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug and prednisone are administered as maintenance therapy after transplanting autologous stem cells to a patient with multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug and dexamethasone are administered to a patient with multiple myeloma as salvage therapy for low risk after transplantation.

In another embodiment, the selective cytokine inhibitory drug and dexamethasone are administered as maintenance therapy after transplanting autologous bone marrow to a patient with multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug is administered to a patient with chemotherapy reactive multiple myeloma after administration of high doses of melphalan and transplantation of autologous stem cells.

In another embodiment, the selective cytokine inhibitory drug and PEG INTRO-A are administered as maintenance therapy after transplantation of autologous CD34-selected peripheral stem cells to a patient with multiple myeloma.

In another embodiment, the selective cytokine inhibitory drug is administered by consolidation chemotherapy after transplantation to a patient with newly diagnosed multiple myeloma to assess anti-angiogenesis.

In another embodiment, the selective cytokine inhibitory drug and dexamethasone are administered to patients 65 years of age or older with multiple myeloma as maintenance therapy following DCEP notification following high doses of melphalan and transplantation of peripheral blood stem cells.

4.3.3. Periodic therapy ( cycling therapy )

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

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

In one embodiment, the selective cytokine inhibitory drug of the invention is administered continuously daily for 3 or 4 weeks at a dose of about 1 to about 5,000 mg / d, followed by discontinuation for 1 or 2 weeks. 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is continuously daily at an initial dose of 1 to 5 mg / d. And doses are increased by 10 to 100 mg / d up to a maximum dose of 5,000 mg / d (weekly) as long as treatment is acceptable. In certain embodiments, the compound is administered in an amount of about 400, 800 or 1,200 mg / day, preferably about 800 mg / day, for 3-4 weeks in a 4 or 6 week cycle, followed by 1 week or 2 weeks Leave a break.

In one embodiment of the invention, the selective cytokine inhibitory drug and the second active ingredient of the present invention are administered orally, wherein during the 4-6 week cycle the selective cytokine inhibitory drug of the present invention is administered the second active ingredient Administration 30 to 60 minutes before. In another embodiment, the combination of the selective cytokine inhibitory drug of the invention and the second active ingredient is administered by intravenous infusion over about 90 minutes every cycle. In certain embodiments, one cycle is about 400 to about 500 mg / day of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-di daily for 3-4 weeks Hydro-isoindol-2-yl) -propionamide and about 50 to about 200 mg / m 2 / day of the second active ingredient followed by a 1 or 2 week rest period. In another specific embodiment, each cycle is about 200 to about 400 mg / day of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3 for 3-4 weeks) -Dihydro-isoindol-2-yl) -propionamide and about 50 to about 200 mg / m 2 / day of the second active ingredient followed by a 1 or 2 week rest period. In general, the number of cycles in which the combination therapy is administered to a patient may be from about 1 to about 24 cycles, more generally about 2 to about 16 cycles, and more generally about 4 to about 8 cycles.

4.4. Pharmaceutical composition

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

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

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

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

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

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

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

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

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

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

As with the amount and type of excipient, the amount and specific type of active ingredient in the dosage form can vary depending on factors such as, but not exclusively, the route to be administered to the patient. However, a typical dosage form of the present invention may comprise a selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof in an amount of about 0.10 to about 150 mg. It contains. Typical dosage forms contain about 0.1, 1, 2, 5, 7.5, 10, 12.5 of the selective cytokine inhibitory drug of the present invention, or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, clathrate or prodrug thereof. , 15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In certain embodiments, preferred dosage forms comprise 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide at about 5, In an amount of 10, 25 or 50 mg. Typical dosage forms contain the second active ingredient in an amount of 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. Of course, the specific amount of anticancer drug will depend on the particular agent used, the type of cancer being treated or administered, and the amount (s) of the optional cytokine inhibitory drug of the invention and any additional active agent administered simultaneously to the patient. will be.

4.4.1 Oral dosage form

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

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

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

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

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

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

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

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

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

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

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

4.4.2. Sustained release  Dosage type

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

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

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

4.4.3. Parenteral  Dosage type

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

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

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

4.4.4. Topical and mucosal dosage forms

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

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

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

4.4.5. Kit  ( kits )

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

Typical kits of the invention include dosage forms of the selective cytokine inhibitory drug of the invention or a pharmaceutically acceptable salt, sorbate, hydrate, stereoisomer, prodrug or clathrate thereof. Kits included in the present invention are oblimersen (Genasense ™), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor , Pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or pharmacologically active mutants or derivatives thereof, or combinations thereof It may further comprise such additional active ingredients. Examples of additional active ingredients include, but are not limited to, those described herein (see, eg, Item 4.2).

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

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

5. Example

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

5.1. Cytokines  Modulation of production

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

In certain embodiments, the pharmacological properties of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is in vitro Is specified in the test. This test examines the effect of compounds on the production of various cytokines. Inhibition of TNF-α production following LPS-stimulation of human PBMCs and human whole blood by this compound is investigated in vitro. In vitro tests showed that the pharmacological activity profile for 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide was higher than thalidomide. 5 to 50 times more potent. The pharmacological effect of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide has been shown to act as an inhibitor of the production of inflammatory cytokines. Can be derived from the action.

5.2. MM  Inhibition of cell proliferation

The ability of selective cytokine inhibitory drugs to affect the proliferation of multiple myeloma (MM) cell lines is investigated in in vitro tests. Uptake of [ ³ H] -thymidine by various MM cell lines (MM.1S, Hs Sultan, U266 and RPMI-8226) is measured as an indicator of cell proliferation. The cells are incubated in the presence of the compound for 48 hours; [ ³ H] -thymidine is included during the last 8 hours of the incubation period. In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is MM.1S and Hs sultan Added to Sultan cells. The uptake of [ ³ H] -thymidine by various MM cell lines is measured.

5.3. In vivo LPS -Induced TNF -α production test

Seven week old male CD rats obtained from Charles River Laboratories are purified one week prior to use. The cannula is inserted percutaneously using a 22-gauge needle-top catheter under simple isoflurane anesthesia into the lateral tail vein. The rat is administered the selective cytokine inhibitory drug of the invention via a tail vein catheter or oral gavage prior to injection of 0.05 mg / kg LPS (E. Coli 055: B5). The catheter is washed with 2.5 ml / kg of saline for injection. 90 minutes after the LPS attack, blood is collected through cardiac puncture. Plasma is prepared using lithium heparin separation tubes and frozen at −80 ° C. until analysis. TNF-α levels are measured using a rat specific TNF-α ELISA kit (Busywork). The ED ₅₀ value is calculated as the dose of the selective cytokine inhibitory drug of the invention that reduces TNF-α production to 50% of the control.

5.4. Toxic  exam

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

Cardiovascular and respiratory changes induced by 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide compared to vehicle control If at all doses are minimal. The only statistically significant difference between the vehicle group and the treatment group was low dose 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) A small increase in arterial blood pressure following administration of propionamide. This effect lasts for about 15 minutes and does not appear at higher doses. Deviations in femoral blood flow, respiratory parameters, and Qtc intervals are common in both the control and treatment groups and are not considered treatment-related.

5.5. In the patient  Periodic therapy

In certain embodiments, the selective cytokine inhibitory drugs of the invention are administered periodically to a patient with cancer. Periodic therapy involves administering the first agent for a period of time, followed by a period of rest, and repeating this sequential administration. Periodic therapy may reduce the incidence of resistance to one or more therapies, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.

In certain embodiments, the prophylactic or therapeutic agent is administered approximately once or twice daily per cycle of about 4 to 6 weeks. One cycle may consist of administering a therapeutic or prophylactic agent for three to four weeks, with a rest period of at least one or two weeks. The number of cycles administered may be about 1 to about 24 cycles, more generally about 2 to about 16 cycles, and even more generally about 4 to about 8 cycles.

For example, in a 4-week cycle, 800 mg / d of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl per day Start administration of) -propionamide. On day 22, administration of the compound is discontinued for a one week rest period. On day 29 the administration of 800 mg / d compound is started.

5.6. Relapsed  I have multiple myeloma In the patient  Clinical trial

Melphalan every four to six weeks for patients with relapsed and unresponsive Dunne-Salmon stage III multiple myeloma who have failed or have inferior egress, neutropenia or thrombocytopenia at least three previous regimens (50 mg intravenously), a combination of a selective cytokine inhibitory drug of the present invention (about 1 to 5,000 mg, orally daily) and dexamethasone (orally 40 mg / day on 1-4 days) 4 Treat until cycle. Maintenance therapy consisting of the selective cytokine inhibitory drug of the invention administered daily and dexamethasone administered monthly, continues until the disease progresses. Therapies comprising the administration of the selective cytokine inhibitory drug of the present invention in combination with melphalan and dexamethasone are very active and are generally accepted in severely pretreated multiple myeloma patients with poor prognosis.

The above-described embodiments of the present invention are merely illustrative and those skilled in the art will be able to recognize and identify many equivalents of particular compounds, materials and methods using only routine experimentation. All such equivalents are considered to be within the scope of the present invention and are included in the appended claims.

Claims (32)

Certain cancers, including administering to a patient in need thereof a therapeutic, prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof How to treat, manage or prevent it. A therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a therapeutic or prophylactically effective amount for a patient in need of treatment, management or prevention of a particular cancer A method of treating, managing or preventing certain cancers, including administering a second active ingredient, radiation therapy, hormone therapy, biological therapy or immunotherapy. A therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for a patient in need thereof for the treatment, management, or prevention of a disease associated with unwanted angiogenesis. A method of treating, managing or preventing a disease associated with unwanted angiogenesis, including administration. A therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, or stereoisomer thereof, for a patient in need of treatment, management, or prevention of a disease associated with unwanted angiogenesis, and a second A method of treating, managing or preventing a disease associated with unwanted angiogenesis, comprising administering a therapeutically or prophylactically effective amount of an active ingredient. 2. The cancerous malignancy, amyloidosis, neuroblastoma, meningioma, pericarcinoma, multiple brain metastasis, glioblastoma multiforme, glioblastoma, brainstem glioma, malignant brain tumor of inferior prognosis, malignant glioma, degenerative characteristics of claim 1 Hematoma, degenerative glioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, irresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotypic acute myeloid leukemia, Hodgkin's lymphoma, non- Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low grade follicular lymphoma, metastatic melanoma, localized melanoma, malignant mesothelioma, malignant Pleural effusion mesothelioma syndrome, peritoneal cancer, papillary serous cancer, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, langerhans cell histiocytosis, leiomyosarcoma, progressive osteoplastic fiber Dysplasia, hormonal unresponsive prostate cancer, resected high-risk soft tissue sarcoma, incontinent hepatocellular carcinoma, Waldenstrom's macroglobulinemia, multiple myeloma, smoldering myeloma, painless myeloma, fallopian cancer , 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, medulla thyroid cancer, or leiomyoma . The method of claim 2, wherein the cancer has advanced malignancy, amyloidosis, locally advanced bladder cancer, metastatic transitional cell bladder cancer, recurrent brain tumor, advanced brain tumor, neuroblastoma, meningioma, pericarcinoma, multiple brain metastasis, glioblastoma multiforme, glioblastoma Subspecies, brainstem glioma, malignant brain tumor of inferior prognosis, malignant glioma, degenerative astrocytoma, degenerative glioma, metastatic breast cancer, neuroendocrine tumor, rectal adenocarcinoma, Duke C & D colorectal cancer, incontinent colorectal cancer, metastatic Hepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse versus B-cell lymphoma, low grade follicular lymphoma, metastatic melanoma Carcinoma, localized melanoma, malignant mesothelioma, stage IIIB non-small cell lung cancer, malignant pleural effusion mesothelioma syndrome, multiple myeloma, peritoneal cancer, papillary serous cancer, Causal Sarcoma, Soft Tissue Sarcoma, Scleroderma, Cutaneous Vasculitis, Langerhans Cell Histiocytosis, Leiomyosarcoma, Progressive Osteofibrosis, Hormone-Reactive Prostate Cancer, Resected High-Risk Soft Tissue Sarcoma, Unresectable Hepatocellular Carcinoma, Waldenst 룀 Macroglobulinemia, subacute myeloma, painless myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary A thyroid cancer, follicular thyroid cancer, medulla thyroid cancer, or leiomyoma. The disease or disorder according to claim 3 or 4, wherein the disease or disorder is endometriosis, Crohn's disease, heart failure, advanced heart failure, kidney failure, diabetic retinopathy, prematurity retinopathy, corneal graft rejection, angiogenic glaucoma, posterior lens fibrosis, proliferation. Sexual vitreoretinopathy, trachoma, myopia, orbit, epidemic keratoconjunctivitis, atopic keratitis, superior keratoconjunctivitis, pterygium dry keratitis, sjogrens, strawberry nose, phylectenulosis, syphilis, lipid degeneration, bacterial ulcer , Fungal ulcer, herpes simplex infection, shingles infection, protozoan infection, Kaposi's sarcoma, Mooren ulcer, Terrien's marginal degeneration, borderline keratinous fusion, rheumatoid arthritis, systemic lupus, Multiple arteritis, trauma, Wegeners sarcoidosis, scleritis, Steven's Johnson disease, periphigoid radial Keratotomy, Sickle Cell Anemia, Sarcoidosis, Elastic Fibrous Vulcanoma, Paget's Disease, Vein Occlusion, Arterial Occlusion, Carotid Obstructive Disease, Chronic Uveitis, Chronic Vitreitis, Lyme's Disease, Eales Disease, Behcet's disease, retinitis, choroiditis, putative ocular histoplasmosis, Bests disease, Stargarts disease, flatulitis, chronic retinal detachment, hyperviscotic syndrome, toxoplasmosis, sclerotic canal Salts, scarring, endotoxins, toxic shock syndrome, osteoarthritis, retroviral replication, weakness, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorders, malignancy-associated hypercalcemia, stroke, circulatory shock , Periodontitis, gingivitis, macrocytic anemia, refractory anemia, or 5q-syndrome. 5. The method according to claim 2, wherein the second active ingredient is an anti-CD40 monoclonal antibody, a histone deacetylase inhibitor, a heat-shock protein-90 inhibitor, an insulin-positive growth factor-1 receptor kinase inhibitor, vascular endothelial Growth factor receptor kinase inhibitors, inducers of apoptosis in multiple myeloma cells, statins, insulin growth factor receptor inhibitors, lysophosphatidic acid acyltransferase inhibitors, IkB kinase inhibitors, p38MAPK inhibitors, EGFR inhibitors, HER-2 antibodies , VEGFR antibody, VEGFR inhibitor, P13K inhibitor, C-Met inhibitor, monoclonal antibody, anti-TNF-α antibody, hematopoietic growth factor, cytokine, anticancer, antibiotic, cox-2 inhibitor, immunomodulator, immunosuppressant, cortico A steroid, or a pharmacologically active mutant or derivative thereof, or a combination thereof. The method of claim 8, wherein the second active ingredient is 2-methoxyestradiol, telomestatin, zephytinib, erlotinib HCL, trastuzumab, pertuzumab, bevacizumab, buttmannin, ritux Shimab, Tositumomab, Edrecolomab, Cemakanib, Cyclosporine, Etanercept, Doxycycline, Bortezomib, Oblimersen, Melphalan, G-CSF, GM-CSF, EPO, Topotecan, Pentoxifylline , Taxotere, irinotecan, COX-2 inhibitor, ciprofloxacin, dexamethasone, doxorubicin, vincristine, IL 2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically acceptable salt thereof, sol A bait or stereoisomer, or a pharmacologically active mutant or derivative thereof, or a combination thereof. The method according to any one of claims 1 to 4, wherein the selective cytokine inhibitory drug is 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole- 2-yl) -propionamide. The method of claim 10, wherein the selective cytokine inhibitory drug is enantiomerically pure. The method according to claim 1, wherein the selective cytokine inhibitory drug is cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl ] -3-oxo-2,3-dihydro-1H-isoindol-4-yl} -amide. The method of claim 12, wherein the selective cytokine inhibitory drug is enantiomerically pure. 5. The method of claim 1, wherein the selective cytokine inhibitory drug is a compound of formula (I): 6. <Formula I>

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

ego; R ⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; R ⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, -COR ¹⁰ , or -SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl. The method of claim 14, wherein the selective cytokine inhibitory drug is enantiomerically pure. 5. The method of claim 1, wherein the selective cytokine inhibitory drug is a compound of Formula II: 6. <Formula II>

Where R ¹ and R ² are each hydrogen or lower alkyl when present independently of each other, or R ¹ and R ² together with the depicted carbon atoms to which they are attached to nitro, cyano, trifluoromethyl, carb Methoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy and halo of 1 to 10 carbon atoms O-phenylene, o-naphthylene or cyclohexene-1,2-diyl unsubstituted or substituted by 1 to 4 substituents each independently selected from the group consisting of; R ³ is nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, 1 to C 10 alkoxy, alkylthio having 1 to 10 carbon atoms, benzyloxy, cycloalkoxy having 3 to 6 carbon atoms, C ₄ -C ₆ -cycloalkylidenemethyl, C ₃ -C ₁₀ -alkylidenemethyl, indanyloxy and halo Phenyl substituted by 1 to 4 substituents selected from the group consisting of; R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R ^{4 '} is hydrogen or alkyl of 1 to 6 carbon atoms; R ⁵ is —CH ₂ —, —CH ₂ —CO—, —SO ₂ —, —S— or —NHCO—; n has a value of 0, 1 or 2. The method of claim 16, wherein the selective cytokine inhibitory drug is enantiomerically pure. Selective cytokine inhibitory drugs, or pharmaceutically acceptable thereof, to the patient before, during or after surgery directed to alleviate, reduce or avoid the symptoms of a particular cancer in a patient in need of treatment, prevention or management of the particular cancer. A method of treating, preventing or managing a particular cancer, including administering a therapeutically or prophylactically effective amount of a salt, solvate or stereoisomer. A second in a patient suffering from a particular cancer, including administering to the patient suffering from the specific cancer a therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof A method of reducing or avoiding side effects associated with the administration of the active ingredient. Radiation therapy in patients with certain cancers, including administering to the patient suffering from certain cancers a therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof , Reducing or avoiding side effects associated with hormone therapy, biological therapy or immunotherapy. A therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate, or stereoisomer thereof, for a patient in need of treatment, prevention or management of certain cancers that are nonresponsive to conventional therapies. A method of treating, preventing or managing a particular cancer that is nonresponsive to conventional therapies, including administration. A therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, sorbate or stereoisomer thereof, for a patient in need of treatment, prevention or management of certain cancers that are nonresponsive to conventional therapies. And a method for treating, preventing or managing certain cancers that are nonresponsive to conventional therapies, including administering a therapeutically or prophylactically effective amount of a second active ingredient. Administering a therapeutic or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to a patient in need of treatment, prevention, or management of a particular cancer, A method of treating, preventing or managing certain cancers, including transplanting blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow. The method of claim 23, wherein the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before implanting cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparation, or bone marrow in the patient. Administered during, during or after. 5. The method of claim 1, wherein the selective cytokine inhibitory drug is administered in an amount of about 1 to about 10,000 mg per day. 6. The method of claim 2, wherein the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, before, during or after administration of the second active ingredient, radiation therapy, hormone therapy, biological therapy or immunotherapy Administered later. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a second active ingredient. The method of claim 27, wherein the second active ingredient is an anti-CD40 monoclonal antibody, a histone deacetylase inhibitor, a heat-shock protein-90 inhibitor, an insulin-positive growth factor-1 receptor kinase inhibitor, a vascular endothelial growth factor receptor kinase Inhibitors, inducers of apoptosis in multiple myeloma cells, statins, insulin growth factor receptor inhibitors, lysophosphatidic acid acyltransferase inhibitors, IkB kinase inhibitors, p38MAPK inhibitors, EGFR inhibitors, HER-2 antibodies, VEGFR antibodies, VEGFR inhibitors, P13K inhibitors, C-Met inhibitors, monoclonal antibodies, anti-TNF-α antibodies, hematopoietic growth factors, cytokines, anticancer agents, antibiotics, cox-2 inhibitors, immunomodulators, immunosuppressants, corticosteroids, or pharmacologics thereof Pharmaceutical composition which is an active mutant or derivative. The method of claim 28, wherein the second active ingredient is 2-methoxyestradiol, telomestatin, zephytinib, erlotinib HCL, trastuzumab, pertuzumab, bevacizumab, buttmannin, ritux Shimab, tocitumomab, edrecolomab, cemaksanib, cyclosporine, etanercept, doxycycline, bortezomib, oblimersen, melphalan, G-CSF, GM-CSF, EPO, cox-2 inhibitors, topo Tecan, pentoxifylline, siflofloxacin, taxotere, irinotecan, dexamethasone, doxorubicin, vincristine, IL 2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or a pharmaceutically thereof Pharmaceutical compositions which are acceptable salts, solvates or stereoisomers, or pharmacologically active mutants or derivatives thereof. Pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; And Anti-CD40 monoclonal antibodies, histone deacetylase inhibitors, heat-shock protein-90 inhibitors, insulin-positive growth factor-1 receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, inducers of apoptosis in multiple myeloma cells , Statins, insulin growth factor receptor inhibitors, lysophosphatidic acid acyltransferase inhibitors, IkB kinase inhibitors, p38MAPK inhibitors, EGFR inhibitors, HER-2 antibodies, VEGFR antibodies, VEGFR inhibitors, P13K inhibitors, C-Met inhibitors, monoclonal Antibodies, anti-TNF-α antibodies, hematopoietic growth factors, cytokines, anticancer agents, antibiotics, cox-2 inhibitors, immunomodulators, immunosuppressants, corticosteroids, or pharmacologically active mutants or derivatives thereof, or their Pharmaceutical Compositions Containing Combinations Kit comprising a. Pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; And 2-methoxyestradiol, telomestatin, zephytinib, erlotinib HCL, trastuzumab, pertuzumab, bevacizumab, bortmannin, rituximab, tocitumomab, edrecolomab , Cemaksanib, cyclosporine, etanercept, doxycycline, bortezomib, oblimersen, melphalan, G-CSF, GM-CSF, EPO, cox-2 inhibitors, topotecan, pentoxifylline, taxotere, irinotecan, Siflofloxacin, dexamethasone, doxorubicin, vincristine, IL 2, IFN, dacarbazine, Ara-C, vinorelbine, isotretinoin, or their pharmaceutically acceptable salts, solvates or stereoisomers, or their Pharmaceutical compositions comprising pharmaceutically active mutants or derivatives, or combinations thereof Kit comprising a. Pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; And Umbilical cord blood, placental blood, peripheral blood stem cells, hematopoietic stem cell preparations, or bone marrow Kit comprising a.