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Definitions

• the invention encompasses novel compounds including compounds having an isoindole-imide moiety, pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, or mixtures of stereoisomers thereof, pharmaceutical compositions of these compounds, and methods of using these compounds and compositions in mammals for treatment or prevention of diseases.
• the present invention relates to isoindole-imide compounds and pharmaceutically acceptable salts, hydrates, solvate, clathrate, enantiomer, diastereomer, racemate, or mixture of stereoisomers thereof; pharmaceutical compositions comprising these isoindole-imide compounds; and methods for reducing the level of cytokines and their precursors in mammals.
• the invention includes isoindole-imide compounds that have one or more of the following activities: modulation of the production of TNF- ⁇ ; modulation of the production of IL-l ⁇ ; stimulation of the production of IL-10; or stimulation of the production T-cells.
• the isoindole-imides described herein are useful for treating or preventing diseases or disorders in mammals, for example, cancers, such as solid tumors and blood-born tumors.
• cancers treatable or preventable by compounds of the invention include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and AEDS-related cancers.
• the compounds are particularly useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias.
• the compounds of the invention are also useful to treat or prevent heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
• the compounds of the invention can also be used to treat or prevent viral, genetic, inflammatory, allergic, and autoimmune diseases.
• the compounds are useful to treat or prevent diseases including, but not limited to, HIN; hepatitis; adult respiratory distress syndrome; bone-resorption diseases; chronic pulmonary inflammatory diseases; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection including graft versus host disease; auto-immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis; Crohn's disease; ulcerative colitis; inflammatory-bowel disease; multiple sclerosis; systemic lupus erythrematosus; E ⁇ L in leprosy; radiation damage; asthma; and hyperoxic alveolar injury.
• the compounds of the invention are also useful for treating or preventing bacterial infections or the symptoms
• Tumor necrosis factor alpha (T ⁇ F- ⁇ ) is a cytokine that is released primarily by mono-nuclear phagocytes in response to immunostimulators. T ⁇ F- ⁇ is capable of enhancing most cellular processes, such as differentiation, recruitment, proliferation, and proteolytic degradation. At low levels, T ⁇ F- ⁇ confers protection against infective agents, tumors, and tissue damage. But T ⁇ F- ⁇ also has role in many disease processes. When administered to mammals or humans, T ⁇ F- ⁇ causes or aggravates inflammation, fever, cardiovascular effects, hemorrhage, coagulation, and acute phase responses similar to those seen during acute infections and shock states.
• Enhanced or unregulated T ⁇ F- ⁇ production has been implicated in a number of diseases and medical conditions, for example, cancers, such as solid tumors and blood-born tumors; heart disease, such as congestive heart failure; and viral, genetic, inflammatory, allergic, and autoimmune diseases.
• cancers such as solid tumors and blood-born tumors
• heart disease such as congestive heart failure
• viral, genetic, inflammatory, allergic, and autoimmune diseases for example, cancers, such as solid tumors and blood-born tumors; and viral, genetic, inflammatory, allergic, and autoimmune diseases.
• the interleukins are a subclass of the cytokine family and possess a wide spectrum of biological activities including involvement in cell activation, cell differentiation, cell proliferation, and cell-to-cell interactions.
• Interleukin 1 beta (IL-l ⁇ ) and interleukin 10 (IL- 10) in combination with other cytokines, play a central role in mediating inflammatory processes and IL-l ⁇ has been implicated as both a growth factor and growth suppressor in certain tumor cells.
• T-cells are a class of white blood cells that play an important role in the immune response, and help protect the body from viral and bacterial infections. Diminished T-cell levels strongly contribute to the inability of HIN patients to combat infections, and abnormally low T-cell levels are prominent in a number of other immune deficiency syndromes, including DiGeorge Syndrome, and in certain forms of cancer, such as T-cell lymphoma.
• Cancer is a particularly devastating disease, and increase in blood T ⁇ F- ⁇ levels are implicated in the risk of and the spreading of cancer.
• cancer cells Normally, in healthy subjects, cancer cells fail to survive in the circulatory system, one of the reasons being that the lining of blood vessels acts as a barrier to tumor-cell extravasation.
• increased levels of cytokines have been shown to substantially increase the adhesion of cancer cells to endothelium in vitro.
• cytokines such as TNF- ⁇ stimulate the biosynthesis and expression of a cell surface receptors called ELAM-1 (endothelial leukocyte adhesion molecule).
• ELAM-1 is a member of a family of calcium-dependent cell adhesion receptors, known as LEC-CAMs, which includes LEG AM- 1 and GMP-140. During an inflammatory response, ELAM-1 on endothelial cells functions as a "homing receptor" for leukocytes. Recently, ELAM-1 on endothelial cells was shown to mediate the increased adhesion of colon cancer cells to endothelium treated with cytokines (Rice et al., 1989, Science 246:1303-1306).
• IL-l ⁇ in combination with other cytokines, appears to stimulate the growth of human gastric and thyroid carcinoma cells (Ito et. al., 1993, Cancer Research 53: 4102-6).
• Inflammatory diseases such as arthritis, related arthritic conditions ⁇ e.g. osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, sepsis, psoriasis, and chronic inflammatory pulmonary diseases are also prevalent and problematic ailments.
• IL-10 is an anti-inflammatory cytokine and is responsible for down- regulating inflammatory responses and as such possesses anti-inflammatory ability, including the suppression of production of proinflammatory cytokines such as TNF- ⁇ and IL-l ⁇ Heart disease has caused wide-spread death and debilitation.
• TNF- ⁇ has been implicated in a broad variety of cardiac pathophysiological conditions, such as septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, and congestive heart failure (see e.g., Steadman et al., 1988, IEEE Trans. Biomed. Eng. 35:264-272; Tracey
• TNF- ⁇ 10 is a target of TNF- ⁇ and that myocardial TNF- ⁇ production may be a maladaptive mechanism that contributes to progressive heart failure (Torre- Amione et al, 1996, Circulation 93:704-711).
• TNF- ⁇ is produced in the myocardium portion of the heart upon endotoxin stimulation.
• TNF- ⁇ 15 of biologically active TNF- ⁇ may be produced in the heart during endotoxin-mediated septic shock. And that such local concentrations of TNF- ⁇ may be the primary instigator of myocardial-function depression during systemic sepsis (Kapadia et al, 1995, J. Clin. Invest. 96:1042-1052). Thus, inhibitors of TNF- ⁇ activity may prevent its deleterious effects on the heart. For example, it has been demonstrated that soluble TNF-binding proteins modulate
• Enhanced or unregulated TNF- ⁇ production has been implicated in viral, genetic, inflammatory, allergic, and autoimmune diseases, for example, HIN; hepatitis; adult respiratory distress syndrome; bone-resorption diseases; chronic pulmonary inflammatory
• compositions that can block the activity or inhibit the production of certain cytokines may be beneficial therapeutics.
• Many small- molecule inhibitors have demonstrated an ability to treat or prevent inflammatory diseases implicated by T ⁇ F- ⁇ (for a review see Lowe, 1998 Exp. Opin. Ther. Patents 8:1309-1332).
• compositions that can stimulate the activity or increase the production of certain cytokines, including IL-10, and immune response factors such as T- cells may be beneficial therapeutics.
• Thalidomide is an emerging immunotherapeutic agent and, in addition to utility in treating a variety of inflammatory disorders, it is projected to be useful in treating cancers
• Thalidomide has been shown to inhibit production of both T ⁇ F- ⁇ and IL-l ⁇ while simultaneously increasing the production of IL-10 and T-cells, and has been tested against a variety of autoimmune and inflammatory diseases, see e.g., Gutierrez-Rodriguez, 1984, Arth. and Rheum 27:1118; TJie Physician 's Desk Reference, 54th edition, 911-916, Medical Economics Company (2000).
• Thalidomide's teratogenic properties have limited its use and driven efforts to discover analogs or derivatives with reduced toxicity and improved therapeutic activity.
• the design of thalidomide analogs and derivatives attempts to maintain/enhance activity while subverting toxicity (for a discussion of some recent advances in T ⁇ F- ⁇ inhibitors structurally related to thalidomide see Marriott, 1997, Exp. Opin. Invest. Drugs 6:1105-
• the invention encompasses novel isoindole-imide compounds and compositions thereof that are useful to treat or prevent diseases in mammals, including humans.
• the invention further encompasses the use of these compounds for treating or preventing diseases or disorders including, but not limited to, cancer; viral, genetic, inflammatory, allergic, and autoimmune diseases; and bacterial infections.
• the compounds of the invention are particularly useful to treat or prevent diseases caused or aggravated by excessive or unregulated levels of TNF- ⁇ , or IL-l ⁇ ; or diminished or unregulated levels of IL-10 or T-cells.
• the invention relates to compounds encompassed by Formula I
• R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyHC j -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyHC 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3' , C(S)NR 3 R 3' or (C,-C 8
• R 2 is H, F, benzyl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;
• R 3 and R 3' are independently ( -C ⁇ alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;
• R 4 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
• R 5 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
• each occurrence of R 6 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group;
• n 0 or 1 ;
• * represents, in formula I and in the following formulas of the invention, a chiral-carbon center; with the proviso that when n is 0 then R 1 is not H.
• the compounds of the invention include compounds of formula I, wherein when n is 0 then R 1 is (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl,
• R 2 is H or (C ] -C 8 )alkyl
• R 3 is (C ! -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (Co-C ⁇ alkyHC j -C ⁇ heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 5 -C 8 )alkyl-N(R 6 ) 2 ; (C 0 -C 8 )alkyl-NH-C(O)O-R 5 ; (C 1 -C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; and the other variables are as described above.
• the compounds of formula I
• R 1 is (C r C 8 )alkyl or benzyl.
• R 1 is H, ( -C ⁇ alkyL benzyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or -CH-
• R 1 is
• R 7 is independently H,(C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, halogen, (Co-C ⁇ alkyH - heterocycloalkyl, (C 0 -C 4 )alkyi-(C 2 -C 5 )heteroaryl,
• R 1 is C(O)R 3 or C(O)OR 4 .
• R 3 is (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C,-C 8 )alkyl, aryl, or (C 0 -C 4 )alkyl-OR 5 .
• heteroaryl is pyridyl, furyl, or thienyl.
• the H of C(O)NHC(O) can be replaced with (C j -C 4 )alkyl, aryl, or benzyl.
• the invention encompasess compounds of Formula II:
• R 1 is H, (C ! -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C 1 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3' , C(S)NR 3 R 3' or
• R 2 is H or (Ci- alkyl
• R 3 and R 3' are independently (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;
• R 4 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (d-C ⁇ alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
• R 5 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )l ⁇ eteroaryl;
• each occurrence of R 6 is independently H, (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group; and
• the * represents a chiral-carbon center.
• R 1 is
• R 7 is independently H,(C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, halogen, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C ⁇ -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bicycl
• R 1 is C(O)R 3 or C(O)OR 4 .
• the invention encompasses compounds of Formula III:
• R 1 is H, (C ⁇ -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocyoloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3' , C(S)NR 3 R 3' or
• R 2 is H or ( -Cgjalkyl
• R 3 and R 3' are independently is (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (Co-C ⁇ alkyHCj-C ⁇ heterocycloalkyl, (C 0 -C 4 )alkyHC 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-Cg)alkyl-OR 5 , (C -C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;
• R 4 is (C -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C ⁇ C ⁇ alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
• R 5 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
• the * represents a chiral-carbon center.
• R 1 is H, (C r C 4 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or
• R 1 is
• R 7 is independently H,(C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, halogen, (Co-C ⁇ alkyHCj-C ⁇ heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C 1 -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bicyclic alkyl or aryl
• R 1 is C(O)R 3 or C(O)OR 4 .
• the invention encompasses compounds of Formula IN:
• R 1 is H, (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C I -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(0)R 3 , C(S)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR ⁇ C(O)NR 3 R 3' , C(S)NR 3 R 3' or (C,-C 8
• R 2 is H or (C,-C 8 )alkyl
• R 3 and R 3' are independently (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl 5 (C 2 -C 8 )alkenyl, (C 2 -C 8 ) alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 3 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;
• R 4 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C,-C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyHC 2 -C 5 )heteroaryl;
• R 5 is (Cj-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
• each occurrence of R 6 is independently H, (C j -C ⁇ alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group; and
• the * represents a chiral-carbon center.
• R 1 is H, (C,-C 4 )alkyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or
• R 1 is
• R 7 is independently H,(C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, halogen, (Co-C ⁇ alkyHC j -C ⁇ heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl,
• R 1 is C(O)R 3 or C(O)OR 4 .
• the invention encompasses compounds of Formula V:
• R 1 is H, (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )al HC,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3' , C(S)NR 3 R 3' or (C 1 -C 8
• R 4 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C,-C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
• each occurrence of R 6 is independently H, (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group; and
• the * represents a chiral-carbon center.
• R 1 is (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C I -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(O)OR 4 , (C 1 -C 8 )alkyl-N(R 6 ) 2 , (d-C ⁇ alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , or (C 1 -C 8 )alkyl-O(CO)R 5 ; and
• R 3 is (Q-C ⁇ alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 5 -C 8 )alkyl-N(R 6 ) 2 ; (C 0 -C 8 )alkyl-NH-C(O)O-R 5 ; (C 1 -C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C ! -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; and the other variables have the definitions above.
• R 1 is (C ⁇ -C 8 )alkyl or benzyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or
• R' is C(O)R 3 or C(O)OR 4 .
• R 3 is (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C,-C 8 )alkyl, aryl, or (C 0 -C 4 )alkyl-OR 5 .
• heteroaryl is pyridyl, furyl, or thienyl.
• the invention further provides compounds of Formula VI:
• R 1 is (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )a ⁇ kyl-OR 5 , (C,-C ⁇ a1k l-C(O)OR 5 , C(S)NHR 3 , or (C,-C 8 )alkyl-O(CO)R 5 ;
• R 3 is (Cj- alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl,
• R 4 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
• R 5 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
• each occurrence of R 6 is independently H, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group; and
• the * represents a chiral-carbon center.
• R 1 is (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 ,C(S)NHR 3 , or (C 1 -C 8 )alkyl-O(CO)R 5 ; and
• R 3 is (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl,
• R 1 is (C,-C 8 )alkyl, benzyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or
• R l is
• R 7 is independently H,(C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, halogen, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , (C 1 -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bi
• R 1 is C(O)R 3 or C(O)OR 4 .
• R 3 is (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C,-C 8 )alkyl, aryl, or (C 0 -C 4 )alkyl-OR 5 .
• heteroaryl is pyridyl, furyl, or thienyl.
• C(O)NHC(O) can be replaced with (Q-C alkyl, aryl, or benzyl.
• the invention encompasses compounds of Formula VII:
• R 1 is (C ⁇ -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl,
• R 3 is (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; R 4 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8
• R 5 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
• each occurrence of R 6 is independently H, (C[-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group; and
• the * represents a chiral-carbon center.
• R 1 is (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , C(S)NHR 3 , or (C,-C 8 )alkyl-O(CO)R 5 ; and
• R 3 is (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 5 -C 8 )alkyl-N(R 6 ) 2 ; (C 0 -C 8 )alkyl-NH-C(O)O-R 5 ; (C 1 -C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; and the other variables are as defined above.
• R 1 is (Q-C ⁇ alkyl, benzyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or
• R 1 is
• R 7 is independently H,(C ⁇ -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, halogen, (C 0 -C 4 )alkyl-(C,-C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 , or adjacent occurrences of R 7 can be taken together to form a bicyclic
• R 3 is (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C ⁇ -C 8 )alkyl, aryl, or (C 0 -C 4 )alkyl-OR 5 .
• heteroaryl is pyridyl, furyl, or thienyl.
• the phrase "compounds of the invention” means, collectively, compounds falling within Formulas I, II, III, IV, V, VI, and VII and include pharmaceutically acceptable salts, hydrates, solvates, and clathrates thereof.
• the compounds of the invention generally exist in solid form and can be recrystallized according to well-known methods affording high-purity crystals, preferably, in greater than 95% purity, more preferably, in greater than 98% purity.
• Narrow melting- point range is an indication of purity, thus, compounds of the invention generally have a melting point within a range of 3 °C to 4 °C, more preferably, within a range of 2 °C.
• the compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
• stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
• the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form ⁇ e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
• a compound of the invention is considered optically active or enantiomerically pure
• a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to all chiral centers in the molecule.
• the invention encompasses all enantiomerically pure, enantiomerically enriched, and racemic mixtures of compounds of Formulas I through VII.
• Enantiomeric and stereoisomeric mixtures of compounds of the invention can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• the invention further encompasses prodrugs of compounds falling within Formulas I, II, III, IV, V, VI, and VII.
• prodrug refers to a compound that, following administration in a mammal, converts, via a biotransformation, into a compound falling within Formulas I, II, III, IV, V, VI, and VII in vivo.
• Prodrugs of compounds falling within Formulas I, II, III, IV, V, VI, and VII can be synthesized using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995).
• the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
• the present invention further provides pharmaceutical compositions comprising a therapeutically effective or a prophylactically effective amount of one or more compounds of the invention and a pharmaceutically acceptable vehicle or carrier.
• a pharmaceutically acceptable vehicle or carrier can comprise an excipient, diluent, or a mixture thereof.
• therapeutically effective amount means the amount of a compound of the invention that will elicit the biological or medical response in a mammal that is being that is being treated by the veterinarian or clinician.
• prophylactically effective means the amount of a compound of the invention that will prevent or inhibit affliction or mitigate affliction of a mammal with a medical condition that a veterinarian or clinician is trying to prevent, inhibit, or mitigate.
• the invention concerns a method of modulating the production or lowering the levels of TNF- ⁇ in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• the invention concerns a method of modulating the production or lowering the levels of IL-l ⁇ in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• the invention concerns a method of modulating the production or increasing the levels of IL-10 in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• the invention concerns a method of modulating the production or increasing the levels of T-cells in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• the invention concerns a method of treating or preventing cancer in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
• the compounds of the invention can be used to treat or prevent any cancer, for example, solid tumors and blood-born tumors.
• cancers treatable or preventable by compounds of the invention include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and AIDS-related cancers.
• the compounds are particularly useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias.
• the compounds of the invention can be used for treating or preventing either primary or metastatic tumors.
• the invention provides methods of treating or preventing cancer in a mammal, comprising administering to a mammal in need thereof, a therapeutically effective amount of a compound of the invention and another cancer chemotherapeutic agent.
• the invention concerns a method of treating or preventing inflammatory disorders in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
• the compounds of the invention are especially effective to treat or prevent inflammatory diseases related to the up- regulation of TNF- ⁇ including, but not limited to, arthritic conditions, such as, rheumatoid arthritis, and osteoarthritis; rheumatoid spondylitis; psoriasis; post ischemic perfusion injury; inflammatory bowel disease; and chronic inflammatory pulmonary disease.
• the invention provides methods of treating or preventing inflammatory disorders in a mammal, comprising administering to a mammal in need thereof, a therapeutically effective amount of a compound of the invention and another anti-inflammatory agent.
• the invention concerns a method of treating or preventing heart disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
• the compounds of the invention can be used to treat or prevent congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
• the invention concerns a method of treating or preventing osteoporosis in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
• the invention relates to a method of treating or preventing viral, genetic, inflammatory, allergic, and autoimmune diseases.
• the compounds are useful to treat or prevent diseases including, but not limited to, HIN, hepatitis, adult respiratory distress syndrome, bone resorption diseases, chronic pulmonary inflammatory diseases, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft rejection, auto-immune disease, rheumatoid spondylitis, Crohn's disease, ulcerative colitis, inflammatory-bowel disease, multiple sclerosis, systemic lupus erythrematosus, E ⁇ L in leprosy, radiation damage, asthma, or hyperoxic alveolar injury in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
• diseases including, but not limited to, HIN, hepatitis, adult respiratory distress syndrome, bone resorption diseases,
• the invention concerns a method of treating or preventing malaria, mycobacterial infection, or an opportunistic infection resulting from HIN in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention.
• the invention relates to treating or preventing mammals having more than one of the conditions treatable by a compound of the invention.
• the mammal be in need of the treatment or prevention, that is, the mammal is actually suffering from a medical condition or at risk of a medical condition for which a compound of the invention can provide treatment or prevention.
• the compounds of the invention can also be administered to test animals that do not necessarily require such treatment or prevention.
• the invention encompasses a method of modulating the production or lowering the levels of T ⁇ F- ⁇ in a mammalian cell or tissue comprising contacting an effective amount of a compound of the invention with said mammalian cell or tissue.
• the invention encompasses a method of modulating the production or lowering the levels of IL-l ⁇ in a mammalian cell or tissue comprising contacting an effective amount of a compound of the invention with said mammalian cell or tissue.
• the invention encompasses a method of modulating the production or lowering the levels of JL- 10 in a mammalian cell or tissue comprising contacting an effective amount of a compound of the invention with said mammalian cell or tissue.
• the invention encompasses a method of modulating the production or lowering the levels of T-cells in a mammalian cell or tissue comprising contacting an effective amount of a compound of the invention with said mammalian cell or tissue.
• the term "effective amount” means the amount of the compound that will induce the biological response sought by the researcher, veterinarian, physician, or clinician. It should be understood that the cell can be in a cell culture or a tissue culture (in vitro) or in an organism ⁇ in vivo) including a human.
• phrases "pharmaceutically acceptable salt(s),” as used herein includes, but is not limited to, salts of acidic or basic groups that maybe present in the compounds of the invention.
• Compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• acids that may be used to prepare pharmaceutically acceptable salts of such basic compounds are those that form salts comprising pharmacologically acceptable anions including, but not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycoUylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, muscate, napsylate, nitrate, panthothenate, phosphate/diphosphate, polygalacturonate,
• Compounds of the invention that include an amino moiety also can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
• Compounds of the invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
• Examples of such salts include alkali- metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
• solvate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
• hydrate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
• the te ⁇ n "clathrate” means a compound of the invention or a salt thereof in the form of a crystal lattice that contains spaces ⁇ e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
• a guest molecule e.g., a solvent or water
• alkyl group means a saturated, monovalent, unbranched or branched hydrocarbon chain.
• alkyl groups include, but are not limited to, (C,-C 8 )alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-l -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l- propyl, 2-methyl-l -pentyl, 3-methyl-l -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l- butyl, butyl, isobutyl, t-butyl,
• alkenyl group means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein.
• the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
• Suitable alkenyl groups include, but are not limited to (C 2 -C 8 )alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2- methyl-3-butene)-pentenyl.
• An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
• alkynyl group means monovalent, unbranched or branched hydrocarbon chain having one or more triple bonds therein.
• the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
• Suitable alkynyl groups include, but are not limited to, (C 2 -C 8 )alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
• An alkynyl group can be unsubstituted or substituted with one or two suitable substituents.
• aryl group means a monocyclic or polycyclic-aromatic group comprising carbon and hydrogen atoms.
• suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzofused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
• An aryl group can be unsubstituted or substituted with one or more suitable substituents.
• the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryl".
• heteroaryl group means a monocyclic or polycyclic aromatic ring comprising carbon atoms and one or more heteroatoms, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
• Preferred heteroaryl-ring systems include 5 to 6 membered monocyclic, 8 to 11 membered bicyclic, and 11 to 15 membered tricyclic ring systems.
• heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character.
• heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, phienyl, isoxazolyl, and oxazolyl.
• a heteroaryl group can be unsubstituted or substituted with one or two suitable substituents.
• a heteroaryl group is a 5 or 6 membered monocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "(C 2 - C 5 )heteroaryl", which optionally can be fused to one or more other aryl, cycloalkyl, heteroaryl, or heterocyclic ring systems to form 7 to 10 membered bicyclic or 10 to 15 membered tricyclic ring systems.
• a "cycloalkyl group” means a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms.
• a cycloalkyl group can have one or more carbon- carbon double bonds in the ring so long as the ring is not rendered aromatic by their presence.
• cycloalkyl groups include, but are not limited to, (C 3 -C 8 )cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes and (C 3 -C 8 )cycloalkenyl groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl, and unsaturated cyclic and bicyclic terpenes.
• (C 3 -C 8 )cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl
• saturated cyclic and bicyclic terpenes saturated cyclic and bicyclic terpenes
• a cycloalkyl group can be unsubstituted or substituted by one or two suitable substituents.
• the cycloalkyl group is a monocyclic ring or bicyclic ring.
• a "heterocycloalkyl group” means a non-aromatic monocyclic or polycyclic ring comprising carbon atoms and at least one heteroatom, preferably, 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Preferred heterocyclic-ring systems include 3 to 8 membered monocyclic, 8 to 11 membered bicyclic, and 11 to 15 membered tricyclic ring systems.
• a heterocycloalkyl group can have one or more carbon- carbon double bonds or carbon-heteroatom double bonds in the ring as long as the ring is not rendered aromatic by their presence.
• heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomo holinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl.
• a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable substituents.
• the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a 3-7 membered monocyclic ring, wherein the ring comprises from 1 to 6 carbon atoms and from 1 to 3 heteroatoms, referred to herein as "(C 1 -C 6 )heterocycloalkyl", which optionally can be fused to one or more other aryl, cycloalkyl, heteroaryl, or heterocyclic ring systems to form 7 to 10 membered bicyclic or 10 to 15 membered tricyclic ring systems.
• alkoxy group means an -O-alkyl group, wherein alkyl is as defined above.
• An alkoxy group can be unsubstituted or substituted with one or two suitable substituents.
• the alkyl chain of an alkyloxy group is from 1 to 8 carbon atoms in length, referred to herein as "(C,-C 8 )alkoxy”.
• aryloxy group means an O-aryl group, wherein aryl is as defined above.
• An aryloxy group can be unsubstituted or substituted with one or two suitable substituents.
• the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryloxy”.
• benzyl means CH 2 -phenyl. A benzyl group can be unsubstituted or substituted with one or more suitable substituents.
• phenyl means C 6 H S .
• a phenyl group can be unsubstituted or substituted with one or more suitable substituents.
• a “carbonyl” group is a divalent group of the formula -C(O)-.
• An “alkoxycarbonyl” group means a monovalent group of the formula C(O)-alkoxy.
• the hydrocarbon chain of an alkoxycarbonyl group is from 1 to 8 carbon atoms in length, referred to herein as a "lower alkoxycarbonyl" group.
• halogen means fluorine, chlorine, bromine, or iodine.
• halo encompass fluoro, chloro, bromo, and iodo.
• a "suitable substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds of the invention or the intermediates useful for preparing them.
• substituents include, but are not limited to: (C,-C 8 )alkyl; (C 1 -C 8 )alkenyl; (C,-C 8 )alkynyl; aryl; (C 2 -C 5 )heteroaryl; (C j -C ⁇ heterocycloalkyl; (C 3 -C 7 )cycloalkyl; O-(C,-C 8 )alkyl; O-(C,-C 8 )alkenyl;
• the invention encompasses compounds of the formula:
• R 1 is H, (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (Co-C alkyHC ⁇ C ⁇ heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C,-C 8 )alkyl-N(R 6 ) 2 , (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3' , C(S)NR 3 R 3' or (C 1 -C 8 )alkyl-O(CO
• R 2 is H, F, benzyl, (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;
• R 3 and R 3' are independently (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C ⁇ C ⁇ alkyl-C ⁇ OR 5 , (C 1 -C 8 )alkyl-O(CO)R 5 ,
• R 4 is (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C,-C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
• R 5 is ( -C ⁇ alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
• each occurrence of R 6 is independently H, (C]-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5 or the R 6 groups can join to form a heterocycloalkyl group; n is 0 or l; and the * represents a chiral-carbon center; with the proviso that when n is 0 then R 1 is not H.
• R 2 is H or (C ⁇ C ⁇ alkyl
• R 3 is (C,-C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 5 -C 8 )alkyl-N(R 6 ) 2 ; (C 0 -C 8 )alkyl-NH-C(O)O-R 5 ; (C,-C 8 )alkyl-OR 5 , (C,-C 8 )alkyl-C(O)OR 5 , (C,-C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; and the other variables have the same definitions. Further,
• the compounds of the invention can be obtained via standard, synthetic methodology. Some convenient methods are illustrated in Schemes 1-8.
• Starting materials useful for preparing the compounds of the invention and intermediates therefor are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents. Such starting materials include, but are not limited to, methyl-2-(methoxycarbonyl)-3-nitrobenzoate; methyl-3-aminomethyl-2- (methoxycarbonyl)benzoate; substituted and unsubstituted aminoglutarimide hydrochloride; di-t-butyl dicarbonate; and cyclopropylcarbonyl chloride.
• Scheme 1 outlines one method to synthesize 4-(aminomethyl)-2-(2,6-dioxo(3- piperidyl))-isoindoline-l,3-dione (I, wherein R 1 is H and n is 1) from compound 10.
• reduction of 10 commercially available
• palladium on charcoal and 50 psi of hydrogen followed by standard isolation and purification gives arylamine 11.
• Arylamine 11 converts to nitrile 12 by diazonium salt formation effected by treatment with sodium nitrate then displacement of nitrogen with cyanide according to the classic Sandmeyer procedure.
• Scheme 2 outlines a convenient method to synthesize 4-amino-2-(2,6-dioxo -piperidin-3-yl)-isoindole-l,3-dione (I, wherein R 1 is H and n is 0) from 4-nitrophthalic anhydride (18).
• a mixture of 18 and 16 in an acidic medium e.g., sodium acetate in glacial acetic acid
• an acidic medium e.g., sodium acetate in glacial acetic acid
• 19 is isolated and characterized according to standard methods (see e.g., United States Patent No.
• Scheme 3 outlines a convenient synthesis of compounds of Formula I, wherein R 1 is C(O)R 3 or C(O)OR 4 .
• compound 13 as prepared as in Scheme 1 above, reacts with a compounds 20 or 21, depending on whether R 1 of C(O)R 3 or C(O)OR 4 is desired, to give compounds 22.
• E is a suitable leaving group, for example, but not limited to halides, such as chloride, bromide, and iodide; azido (N 3 ); arylsulfonyloxy or alkylsulfonyloxy ⁇ e.g., tosyloxy or mesyloxy); phenoxy; alkoxy; and oxycarbonyl groups.
• E is a halide, more preferably, chloride.
• compounds 20 are acid chlorides, such as acetyl chloride and cyclopropylcarbonyl chloride and compounds 21 are chloro formates, such as ethylchloroformate or benzylchloroformate.
• the reaction is carried out according to standard, well-known procedures, e.g. see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.417- 419, incorporated herein by reference.
• Treatment of 22 with 16 using the same procedure as outlined in Scheme 1 gives compounds of Formula I, wherein R 1 is C(O)R 3 or C(O)OR 4 .
• Scheme 4 outlines an alternative synthesis of compounds of Formula I, wherein R 1 is C(O)R 3 or C(O)OR 4 and a convenient synthesis of compounds of Formula I, wherein R 1 is CH 2 R 3 .
• E is a suitable leaving group.
• E is a halide, more preferably, chloride.
• compounds 20 are acid chlorides, such as chloroacetyl chloride and t-butylacetyl chloride.
• Aldehydes 23 are readily available commercially or synthesized by well-known methods The reaction of 20 or 21 with I, where R 1 is H is carried out according to standard, well-known procedures for nucleophilic displacement, e.g. see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp.417-419. The reaction of 23 with I, where R 1 is H is accomplished according to the well-known reductive-amination procedure between an aldehyde and a primary amine, e.g.
• Scheme 5 outlines one method for the synthesis of compounds of Formula I, wherein R 1 is C(O)CH 2 N(R 6 ) 2 .
• E is chloro and R 5 is (C r C 8 )alkyl, such as methyl.
• the reaction is performed according to standard, well-known procedures, e.g. see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 411-413, incorporated herein by reference.
• Scheme 6 shows one method to synthesize compounds of Formula I, wherein R 1 is C(O)NHR 5 .
• a compound of Formula I, where R 1 is H reacts with isocyanates 25 under routine conditions to give a compounds I, where R 1 is C(O)NHR 5 .
• the reaction is performed according to standard, well-known procedures, e.g. see March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, p. 903, incorporated herein by reference.
• Scheme 7 Synthesis of Compounds of Formula I, wherein R 2 is F
• the nitrogen- protecting group is stable in a basic reaction medium but can be cleaved by acid.
• all of PG 1 , PG 2 , and PG 3 protecting groups are tert-butyloxycarbonyl, attached by treatment of compounds of Formula I, where R 1 and R 2 are H with in excess of 3 equivalents of di-tert-butyl carbonate as described in United States Patent No. 5,874,448. 5
• the fluorination-reaction procedure, to give compounds 27, is described in detail in United States Patent No.
• 5,874,448 can be effected by treating deprotonated 26 with a variety of reagents, such as N-fluorobenzenesulfonimide, perchloryl fluoride, or N-fluorobenzenedisulfonimide.
• Deprotonated 26 can be prepared by treatment of 26 with strong base, such as n-butyl lithium, sodium b ⁇ (trimethylsilyl)amide, sodium hydride, or lithium diisopropylamide.
• strong base such as n-butyl lithium, sodium b ⁇ (trimethylsilyl)amide, sodium hydride, or lithium diisopropylamide.
• Deprotection of compounds 27 to give compounds I, where R 1 is H and R 2 is F is effected by standard procedures such as those described in Greene, T.W., Protective Groups in Organic Synthesis, 3rd edition 494-654 (1999) and United States Patent No. 5,874,448.
• compounds IA and IB can be prepared starting from compounds 28 or 29 respectively, for example, using the methodology described in WO 98/54170, inco ⁇ orated herein by reference.
• Compounds 28 and compounds 29 are available commercially or readily available through well-known synthetic methodology.
• methyl-2-methyl-3-nitrobenzoate (29, where alkyl is methyl) is commercially available from Aldrich Chemical Co., Milwaukee, WI.
• Compounds 28 and 29 are first brominated at the activated benzylic position with a brominating agent such as N-bromosuccinimide under the influence of light or other radical initiator to yield methylbromo-compounds 30.
• a brominating agent such as N-bromosuccinimide under the influence of light or other radical initiator
• Exemplary brominating procedures are reviewed in March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, pp. 694-697, incorporated herein by reference.
• Compounds 30 are then converted into compounds 31 or 32 and thereafter to IA or IB by adapting the synthetic methods presented in Schemes 1 to 5 above, including standard cyclization with compounds 16.
• Scheme 9 shows one method to synthesize compounds of Formula I, wherein R 1 is
• a compound of Formula I, where R 1 is H reacts with isothiocyanates 28 under routine conditions to give a compounds I, where R 1 is C(O)NHR 5 .
• the reaction is performed according to standard, well-known procedures, e.g. see March, J. Advanced
• a compound or composition of the invention is administered to a mammal, preferably, a human, with or at risk of a disease or medical condition, for example, cancer, such as solid tumors and blood-born tumors.
• cancers treatable or preventable by administering compounds of the invention include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectal; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and AIDS-related cancers.
• the compounds are particularly useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias.
• the compounds of the invention are also useful to treat or prevent heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
• heart disease such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
• the compounds of the invention can also be used to treat or prevent viral, genetic, inflammatory, allergic, and autoimmune diseases.
• the compounds are useful to treat or prevent diseases including, but not limited to, HIN; hepatitis; adult respiratory distress syndrome; bone-reso ⁇ tion diseases; chronic pulmonary inflammatory diseases; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection; auto-immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis, Crohn's disease; ulcerative colitis; inflammatory-bowel disease; multiple sclerosis; systemic lupus erythrematosus; E ⁇ L in leprosy; radiation damage; asthma; and hyperoxic alveolar injury.
• diseases including, but not limited to, HIN; hepatitis; adult respiratory distress syndrome; bone-
• the compounds of the invention are also useful for treating or preventing bacterial infections including, but not limited to, malaria, mycobacterial infection, and opportunistic infections resulting from HIN.
• treatment refers to an amelioration of a disease or disorder, or at least one discernible symptom thereof.
• treatment refers to an amelioration of at least one measurable physical parameter, not necessarily discernible by the mammal.
• treatment or “treating” refers to inhibiting the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
• treatment or “treating” refers to delaying the onset of a disease or disorder.
• the compounds of the invention or the compositions of the invention are administered to a mammal, preferably, a human, as a prophylactic.
• prevention or “preventing” refers to a reduction of the risk of acquiring a given disease or disorder.
• the compounds and compositions of the present invention are administered as a preventative measure to a mammal, preferably, a human, having a genetic or non-genetic predisposition to a medical condition, for example, cancers, such as solid tumors and blood-born tumors.
• cancers preventable by compounds of the invention include, but are not limited to, cancers of the skin, such as melanoma; lymph node; breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate; colon; rectal; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal passages; and AIDS-related cancers.
• the compounds are particularly useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and myelocytic leukemias.
• the compounds of the invention are also useful for preventing heart disease, such as congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, and myocardial infarction.
• the compounds of the invention can also be used to prevent viral, genetic, inflammatory, allergic, and autoimmune diseases.
• the compounds are useful to prevent diseases including, but not limited to, HIN; hepatitis; adult respiratory distress syndrome; bone-reso ⁇ tion diseases; chronic pulmonary inflammatory diseases; dermatitis; cystic fibrosis; septic shock; sepsis; endotoxic shock; hemodynamic shock; sepsis syndrome; post ischemic reperfusion injury; meningitis; psoriasis; fibrotic disease; cachexia; graft rejection; auto-immune disease; rheumatoid spondylitis; arthritic conditions, such as rheumatoid arthritis and osteoarthritis; osteoporosis, Crohn's disease; ulcerative colitis; inflammatory-bowel disease; multiple sclerosis; systemic lupus erythrematosus; E ⁇ L in leprosy; radiation damage; asthma; and hyperoxic alveolar injury.
• the compounds of the invention are also useful for preventing bacterial infections or symptoms including, but not limited to, malaria, my
• the invention provides methods of treatment and prevention by administration of a therapeutically effective amount of a compound or a composition of the invention to a mammal, preferably, a human.
• a mammal encompasses any mammal.
• a mammal is in need of such treatment or prevention.
• mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, etc., more preferably, a human.
• Administration of compounds of the invention can be systemic or local.
• Methods of administration include enteral routes, such as oral, buccal, sublingual, and rectal; topical administration, such as transdermal and intradermal; and parenteral administration.
• Suitable parenteral routes include injection via a hypodermic needle or catheter, for example, intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intraarterial, intraventricular, intrathecal, and intracameral injection and non-injection routes, such as intravaginal rectal, or nasal administration.
• the compounds and compositions of the invention are administered orally.
• This may be achieved, for example, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
• the compounds of the invention can be administered via typical as well as non- standard delivery systems, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.
• the compounds and compositions of the invention can be delivered in a vesicle, in particular a liposome ⁇ see Langer, 1990, Science 249:1527-1533; Treat et al, in Liposomes in Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
• the compounds and compositions of the invention can be delivered in a controlled release system.
• a pump may be used ⁇ see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng.
• polymeric materials can be used ⁇ see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Dnig Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol Sci. Rev. Macromol Chem. 23:61; see also Levy et al, 1985, Science 228:190; During et al, 1989, Ann. Neurol.
• a controlled-release system can be placed in proximity of the target area to be treated, e.g., the liver, thus requiring only a fraction of the systemic dose ⁇ see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
• Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) can be used.
• a compound of the invention When administered as a composition, a compound of the invention will be formulated with a suitable amount of a pharmaceutically acceptable .vehicle or carrier so as to provide the form for proper administration to the mammal.
• pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
• vehicle refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is formulated for administration to a mammal.
• Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
• auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
• the compounds and compositions of the invention and pharmaceutically acceptable vehicles, excipients, or diluents are sterile.
• An aqueous medium is a preferred vehicle when the compound of the invention is administered intravenously, such as water, saline solutions, and aqueous dextrose and glycerol solutions.
• the present compounds and compositions can take the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained-release formulations thereof, or any other form suitable for administration to a mammal.
• the compounds and compositions of the invention are formulated for administration in accordance with routine procedures as a pharmaceutical composition adapted for oral or intravenous administration to humans.
• the pharmaceutically acceptable vehicle is a hard gelatin capsule. Examples of suitable pharmaceutical vehicles and methods for formulation thereof are described in Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, PA, 19th ed., 1995, Chapters 86, 87, 88, 91, and 92, inco ⁇ orated herein by reference.
• Compounds and compositions of the invention formulated for oral delivery are preferably in the form of capsules, tablets, pills, or any compressed pharmaceutical form. Moreover, where in tablet or pill form, the compounds and compositions may be coated to delay disintegration and abso ⁇ tion in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
• Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds and compositions of the invention. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound that swells to displace the agent or agent composition through an aperture.
• These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
• a time delay material such as glycerol monostearate or glycerol stearate may also be used.
• Oral compositions can include standard vehicles, excipients, and diluents, such as magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidinone, water, syrup, and methyl cellulose, the formulations can additionally include lubricating agents, such as talc, magnesium stearate, mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydfoxybenzoates.
• lubricating agents such as talc, magnesium stearate, mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydfoxybenzo
• Such vehicles are preferably of pharmaceutical grade.
• Orally administered compounds and compositions of the invention can optionally include one or more sweetening agents, such as fructose, aspartame or saccharin; one or more flavoring agents such as peppermint, oil of wintergreen, or cherry; or one or more coloring agents to provide a pharmaceutically palatable preparation.
• a therapeutically effective dosage regimen for the treatment of a particular disorder or condition will depend on its nature and severity, and can be determined by standard clinical techniques according to the judgment of a medical practitioner.
• in vitro or in vivo assays can be used to help identify optimal dosages.
• the amount of a compound of the invention that constitutes a therapeutically effective dose also depends on the administration route.
• suitable dosage ranges for oral administration are about 0.001 milligrams to about 20 milligrams of a compound of the invention per kilogram body weight per day, preferably, about 0.7 milligrams to about 6 milligrams, more preferably, about 1.5 milligrams to about 4.5 milligrams.
• a mammal preferably, a human is orally administered about 0.01 mg to about 1000 mg of a compound of the invention per day, more preferably, about 0.1 mg to about 300 mg per day, or about 1 mg to about 250 mg in single or divided doses.
• the dosage amounts described herein refer to total amounts administered; that is, if more than one compound of the invention is administered, the preferred dosages correspond to the total amount of the compounds of the invention administered.
• Oral compositions preferably contain 10% to 95% of a compound of the invention by weight.
• Preferred unit oral-dosage forms include pills, tablets, and capsules, more preferably capsules.
• Such unit-dosage forms will contain about 0.01 mg, 0.1 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 100 mg, 250 mg, or 500 mg of a compound of the invention, preferably, from about 5 mg to about 200 mg of compound per unit dosage.
• the compounds and compositions of the invention can be administered parenterally (e.g., by intramuscular, intrathecal, intravenous, and intraarterial routes), preferably, intravenously.
• compositions of the invention for intravenous administration are solutions in sterile isotonic aqueous vehicles, such as water, saline, Ringer's solution, or dextrose solution. Where necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection.
• the compounds and compositions of the invention can be supplied as a sterile, dry lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampule or sachette, the container indicating the quantity of active agent.
• Such a powder or concentrate is then diluted with an appropriate aqueous medium prior to intravenous administration.
• An ampule of sterile water, saline solution, or other appropriate aqueous medium can be provided with the powder or concentrate for dilution prior to administration.
• the compositions can be supplied in pre- mixed form, ready for administration.
• a compound or composition of the invention is to be administered by intravenous infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical-grade water, saline, or other suitable medium.
• Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter, modified vegetable oils, and other fatty bases.
• Suppositories can be formulated by well-known methods using well-known formulations, for example see Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, PA, 19th ed., 1995, pp. 1591-1597, inco ⁇ orated herein by reference
• a reservoir type patch design can comprise a backing film coated with an adhesive, and a reservoir compartment comprising a compound or composition of the invention, that is separated from the skin by a semipermeable membrane ⁇ e.g., U.S. Patent 4,615,699, inco ⁇ orated herein by reference).
• the adhesive coated backing layer extends around the reservoir's boundaries to provide a concentric seal with the skin and hold the reservoir adjacent to the skin.
• the invention also provides pharmaceutical packs or kits comprising one or more containers filled with one or more compounds of the invention.
• Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
• the kit contains more than one compound of the invention.
• the kit comprises a compound of the invention and another biologically active agent.
• the compounds of the invention are preferably assayed in vitro and in vivo, for the desired therapeutic or prophylactic activity, prior to use in humans.
• in vitro assays can be used to determine whether administration of a specific compound of the invention or a combination of compounds of the invention is preferred.
• the compounds and compositions of the invention may also be demonstrated to be effective and safe using animal model systems. Other methods will be known to the skilled artisan and are within the scope of the invention.
• a compound of the invention is administered to a mammal, preferably, a human concurrently with one or more other biologically active agents, or with one or more other compounds of the invention, or with both.
• a compound of the invention and the other agent are administered to a mammal in a sequence and within a time interval such that the compound of the invention can act together with the other agent to provide an increased or synergistic benefit than if they were administered otherwise.
• each component may be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently closely in time so as to provide the desired treatment effect.
• all components are administered at the same time, and if not administered at the same time, preferably, they are all administered from about 6 hours to about 12 hours apart from one another.
• the compounds of the invention and the therapeutic agent can act additively or, more preferably, synergistically.
• a compound or a composition of the invention is administered concurrently with another therapeutic agent in the same pharmaceutical composition.
• a compound or a composition of the invention is administered concurrently with another therapeutic agent in separate pharmaceutical compositions.
• a compound or a composition of the invention is administered prior or subsequent to administration of another therapeutic agent.
• combination therapy involves alternating between administering a compound or a composition of the invention and a pharmaceutical composition comprising another therapeutic agent, e.g., to minimize the toxicity associated with a particular drug.
• the therapeutic agent when a composition of the invention is administered concurrently with another therapeutic agent that potentially produces adverse side effects including, but not limited to toxicity, can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
• the present compounds and compositions can be administered together with hormonal and steroidal anti-inflammatory agents, such as, estradiol, conjugated estrogens (e.g., PREMARIN, PREMPRO, AND PREMPHASE), 17 beta estradiol, calcitonin-salmon, levothyroxine, dexamethasone, medroxyprogesterone, prednisone, cortisone, flunisolide, and hydrocortisone; non-steroidal anti-inflammatory agents, such as tramadol, fentanyl, metamizole, ketoprofen, naproxen, nabumetone, ketoralac, tromethamine, loxoprofen, ibuprofen, aspirin, and acetaminophen; anti-TNF- ⁇ antibodies, such as infliximab (REMICADETM) and etanercept (ENBRELTM); AIDS and AIDS-related therapies, such as lamivudine, zi
• the compounds of the invention can be used, not only to directly treat the disorder, but also to reduce the dose or toxicity of another chemotherapeutic.
• the compounds of the invention can be administered to reduce gastrointestinal toxicity associated with a topoisomerase inhibitor, such as irinotecan.
• the compounds of the invention can be assayed for their ability to modulate the production of TNF- ⁇ by well-known methods in the art, see e.g., Corral et al, 1999, J. Immun. 163:380-386 and Muller et al, 1996, J. Med. Chem. 39:3238 (assay for the inhibition of production of TNF- ⁇ ) and Muller et al, 1998, Bioorg. Med. Chem. Lett. 8:2669, all three of which citations are inco ⁇ orated herein by reference.
• PBMC cells normal human donors — were obtained by Ficoll-Hypaque density centrifugation (Pharmacia Fine Chemicals, Piscataway, NJ).
• the cells (about 2 x 10 5 to 10 6 cells/ml) are cultured with RPMI (commercially available, e.g., from Gibco Laboratories, Grand Island, NY) supplemented with 10AB+ serum (commercially available, e.g., from Biocell, Collinso Dominguez, CA), about 2 mM L-glutamine, about 100 U/ml penicillin, and about 100 ⁇ g/ml streptomycin (Gibco).
• the test compounds are dissolved in DMSO at 20 mg/ml, further dilution can be done with culture medium.
• the final DMSO concentration in all samples including the controls should be about 0.25% by weight.
• Test compounds were added to cells 1 hour prior to the addition of LPS.
• the PBMC cells in triplicate, are stimulated by 1 ⁇ g/ml LPS from Salmonella Minnesota R595 (List Biological Labs, Campbell, CA) and incubated for about 18 to about 20 hours at 37 °C (5% CO 2 ) in 96-well flat-bottom polystyrene Costar tissue culture plates (Corning, Corning, NY) for the induction of TNF- ⁇ . Cells are incubated with or without compounds of the invention (negative controls). The supematants are collected for the determination of cytokine levels by ELISA (Endogen, Cambridge, MA).
• Percent inhibition can be determined as 100 x [1 - (TNF- ⁇ EXPERIMENTAL/ TNF- ⁇ CONTROL)]. Assays are performed, in accordance with the assay kit's manufacturer, in 96-well plates (Nunc Immunoplates, Roskilde, Denmark) coated with the affinity-purified rabbit anti-TNF- ⁇ antibody (0.5 ⁇ g/ml; 12-16 hours; 4 °C) and blocked for 2 hours at room temperature with PBS/0.05% Tween 20 (Sigma Chemical
• HRP horseradish peroxidase
• OPD substrate 0.4 mg/ml o-phenylenediamine [Sigma Chemical Co.] in 24 mM citric acid, 51 mM sodium phosphate, pH 5.0 [phosphate-citrate buffer: Sigma Chemical Co.] containing 0.012% hydrogen peroxide [Fisher Scientific Co., Pittsburgh, PA.]
• absorbance read at 492 nm in an automated ELISA reader (Dynatech Laboratories, Inc., Alexandria, Na.).
• PBMC peripheral blood monoclonal mouse anti-human CD3
• Orthoclone OKT3 monoclonal mouse anti-human CD3
• the anti-CD3 Ab is diluted to 10 ⁇ g/ml in 100 ⁇ l PBS and coated onto 48-well flat-bottom polystyrene Falcon tissue culture plates (Becton Dickinson, Franklyn Lakes, ⁇ J) by overnight incubation at 4°C. Appropriate dilutions of compounds of the invention are added at the start of the cell culture. Supematants are collected at 24, 43, and 72 hours and assayed for T ⁇ F- ⁇ levels.
• CD40L CD40 ligand
• CD3 surface expression by two-color flow cytometry (anti-CD40L, PharMingen, San Diego, CA; anti- CD3, Becton Dickinson, San Jose, CA).
• This assay can be performed according to the procedure outlined in Muller et. al ,
• IL- l ⁇ and IL-10 levels were measured by ELISA (Endogen, Cambridge, MA) as described by the manufacturer.
• the cold neutralized diazonium solution was then added in small portions at a time with vigorous stirring.
• the mixture was stirred at 60 °C for 1 hour and then cooled to room temperature.
• the mixture was extracted with dichloromethane (4 x 150 ml) and the combined dichloromethane extracts were washed with water (2 100 ml), brine (100 ml) and dried.
• Triethylamine (3.89 g, 38 mmol) was added dropwise to a stirred suspension of methyl-3-aminomethyl-2-(methoxycarbonyl)benzoate hydrochloride (4.0 g, 15 mmol) in dichloromethane (100 ml). The mixture was cooled in an ice bath to 8 °C. A solution of di- t-butyl dicarbonate (3J g, 16 mmol) in dichloromethane (20 ml) was added dropwise at 8 °C. After the addition was complete, the cooled mixture was stirred for an additional 30 minutes, and then warmed to room temperature for 1 hour.
• Diisopropylethylamine (3.20 g, 25 mmol) was added to a stirred suspension of methyl-3-[(t-butoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (8.00 g, 25 mmol) and aminoglutarimide hydrochloride (4.07 g, 25 mmol) in DMF (60 ml). The mixture was heated to 120 °C for 24 hours and then cooled to room temperature. The mixture was poured into cold water (300 ml) and extracted with ethyl acetate (4x100 ml each). The combined ethyl acetate extracts were washed with water (2 50 ml), brine (50 ml) and dried.
• Triethylamine (1.87 g, 18 mmol) was added slowly to a stirred suspension of methyl-3-(aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The resulting mixture was cooled in an ice bath to 4 °C. Acetyl chloride (0J3 g, 9 mmol) was added dropwise at a rate such that the temperature stayed between 4-7 °C. After addition was complete, the mixture was stirred in the ice bath for an additional 30 minutes and then allowed to warm to room temperature and maintained for 2 hours. The reaction mixture was washed with water (2 30 ml), brine (30 ml) and dried.
• Triethylamine (1.87 g, 18 mmol) was added dropwise to a stirred suspension of methyl-3- (aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 7 mmol) in dichloromethane (40 ml). The mixture was cooled in an ice bath to 4 °C.
• Diisopropylethylamine (0.92 g, 7 mmol) was added to a stirred suspension of methyl-3-[(cyclopropylcarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (2.08 g, 7 mmol) and amino glutarimide hydrochloride (1.17 g, 7 mmol) in DMF (15 ml). The mixture was heated to 120 °C for 24 hours. The mixture was concentrated in vacuo and the residue was stirred with water (40 ml) and ethyl acetate (15 ml). The resulting slurry was filtered to give 0.7 g (27%) of the product as a gray solid.
• Triethylamine (1.57 g, 18.5 mmol) was added to a stirred suspension of methyl-3- (aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4 °C. Ethyl chloroformate (1.0 g, 9 mmol) was added slowly keeping the mixture at 4-6 °C. After addition was complete, the mixture was stirred in an ice bath for 30 minutes and then warmed to room temperature for 2 hours. The mixture was washed with water (2 x 30 ml), brine (30 ml) and dried.
• Triethylamine (1.87 g, 18.5 mmol) was added to a stirred suspension of methyl-3- (aminomethyl)-2-(methoxycarbonyl)benzoate hydrochloride (2.0 g, 8 mmol) in dichloromethane (30 ml). The mixture was cooled in an ice bath to 4 °C. Benzyl chloroformate (1.66 g, 10 mmol) was added slowly keeping the temperature between 4-7 °C. After the addition was complete, the cooled mixture was stirred an additional 30 minutes and then warmed to room temperature for 4 hours. The mixture was washed with water (2 x 30 ml), brine (30 ml) and dried.
• Triethylamine (0.6 g, 6 mmol) was added to a stirred suspension of 4-
• reaction mixture was diluted with methylene chloride (50 ml) and washed with water (3x100 ml), saturated aqueous sodium bicarbonate (2x100 ml), brine (100 ml), and dried (MgSO 4 ).
• the solvent was evaporated in vacuo and the residue purified by chromatography (25% ethyl acetate/hexane) to give 2.24 g (84%) of product as an oil.
• the pH of the aqueous portion was adjusted to 11-12 by dropwise addition of saturated aqueous sodium carbonate.
• the aqueous mixture was washed with ethyl acetate (3 x 100 ml).
• the combined ethyl acetate extracts were washed with brine (100 ml), and dried (MgSO 4 ).
• the solvent was evaporated in vacuo leaving a white solid.
• the solid was dissolved in acetonitrile (15 ml) and 2M HCl in ether (2 ml) was added to the solution. The mixture was stirred for 1 h and the solvent was evaporated in vacuo leaving a white solid.
• Step 1 l,8-Diazabicyclo[5,4,0]undec-7-ene (OJg, 4.62 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-l,3-dione hydrochloride (0.6g, 1.85 mmol) in CH 3 CN (50 mL).
• Step 2 A 4N HCl solution in dioxane (1.5 mL) was added to a stirred solution of 7-

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