Cycloalkyl-hydroxyl compounds and compositions for cholesterol management and related uses

Abstract

The present invention relates to novel cycloalkyl-hydroxyl compounds, compositions comprising hydroxyl compounds, and methods useful for treating and preventing a variety of diseases and conditions such as, but not limited to aging, Alzheimer's Disease, cancer, cardiovascular disease, diabetic nephropathy, diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia, dyslipoproteinemia, hypertension, impotence, inflammation, insulin resistance, lipid elimination in bile, obesity, oxysterol elimination in bile, pancreatitis, Parkinson's disease, a peroxisome proliferator activated receptor-associated disorder, phospholipid elimination in bile, renal disease, septicemia, Syndrome X, thrombotic disorder. Compounds and methods of the invention can also be used to modulate C reactive protein or enhance bile production in a patient. In certain embodiments, the compounds, compositions, and methods of the invention are useful in combination therapy with other therapeutics, such as hypocholesterolemic and hypoglycemic agents.

1 - 57 . (canceled) 
     
     
         58 . A method for treating a cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate or a mixture thereof, wherein:
 (a) each occurrence of m is independently an integer ranging from 0 to 5; 
 (b) each occurrence of n is independently an integer ranging from 3 to 7; 
 (c) X is (CH 2 ) z  or Ph, wherein z is an integer from 0 to 4; 
 (d) R 1  and R 2  and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group; 
 (e) each occurrence of R 11  and R 12  and the carbon to which they are both attached are taken together to form a (C 3 -C 7 )cycloalkyl group; and 
 
       
         
           
           
               
               
           
         
         (f) each occurrence of Y 1  and Y 2  is independently COOH, COOR 3 , SO 3 H, 
       
       wherein:
 (i) R 3  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C 1 -C 6 )alkoxy, or phenyl groups, and 
 (ii) each occurrence of R 4  is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl and is unsubstituted or substituted with one or two halo, OH, C 1 -C 6  alkoxy, or phenyl groups. 
 
     
     
         59 . The method  claim 58 , wherein each occurrence of Y 1  and Y 2  is independently COOR 3  or COOH. 
     
     
         60 . The method of  claim 59 , wherein m is 0. 
     
     
         61 . The method of  claim 59 , wherein m is 1. 
     
     
         62 . The method of  claim 59 , wherein n is 4. 
     
     
         63 . The method of  claim 59 , wherein n is 5. 
     
     
         64 . The method of  claim 59 , wherein X is (CH2) z  and z is 0. 
     
     
         65 . The method of  claim 58 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         66 . The method of  claim 58 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         67 . The method of  claim 58 , the method further comprising administering to a patient in need of such treatment a therapeutically effective amount of a second therapeutic agent. 
     
     
         68 . The method of  claim 67 , wherein the second therapeutic agent is selected from the group consisting of a chemotherapeutic agent, an alkylating agent, a plant alkaloid, a DNA topoisomerase inhibitor, a mitomycin, an anti-folate, a pyrimidine analog, a purine analog, a hormonal therapy, a retinoid, a deltoid, a vitamin D3 analog, a photodynamic therapy, a cytokine, a isoprenylation inhibitor, a dopaminergic neurotoxin, a cell cycle inhibitor, an actinomycine, a bleomycin, an anthracycline, a MDR inhibitor, and a Ca 2+  ATPase inhibitor. 
     
     
         69 . The method of  claim 58 , wherein the cancer is selected from group consisting of a solid tumor cancer, a blood-borne cancer, a leukemia, and a lymphoma. 
     
     
         70 . The method of  claim 69 , wherein the solid tumor cancer is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophogeal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, and retinoblastoma. 
     
     
         71 . The method of  claim 69 , wherein the blood-borne cancer is selected from the group consisting of acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and multiple myeloma. 
     
     
         72 . The method of  claim 69 , wherein the leukemia is an acute leukemia or a chronic leukemia. 
     
     
         73 . The method of  claim 72 , wherein the acute leukemia or chronic leukemia is selected from the group consisting of lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia, and a myelocytic leukemia. 
     
     
         74 . The method of  claim 69 , wherein the lymphoma is selected from the group consisting of Hodgkin's disease, non-Hodgkin's Lymphoma, multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease, and polycythemia vera.