Lymph directing prodrugs

Abstract

The present invention relates to compounds and their uses, in particular, compounds in the form of prodrugs that promote transport of a pharmaceutical agent to the lymphatic system and subsequently enhance release of the parent drug.

We claim: 
     
         1 - 23 . (canceled) 
     
     
         24 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  independently represent H or a residue of a C 2 -C 28  fatty acid; 
         —X— is —O—; 
         —Y— represents an optionally substituted —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl-group, wherein one or more of the carbon atoms in the alkyl, alkenyl, or alkynyl group may be replaced with NH, S, or O, provided that the alkyl, alkenyl, or alkynyl group does not exceed a length equivalent to a linear C 20 alkyl group; 
       
       
         
           
           
               
               
           
         
       
       represents a residue of a pharmaceutical agent;
 -L- is —X′— or —X′C(O)—; 
 X′ is O, S, N, N(R 4 ), or S(O) 2 NH; 
    represents a single bond when X′ is O, S, N(R 4 ), or S(O) 2 NH; or 
    represents two separate bonds when X′ is N; 
 —Z— is —C(O)— or —C(O)R 3 — when -L- is —X′—; or 
 —Z— is absent when -L- is —X′C(O)—; 
 R 3  is a self-immolative group; and 
 R 4  is H or C 1 -C 4 alkyl; 
 provided that —Y— is substituted or —Z— is —C(O)R 3 —; 
 or —Y— is substituted and —Z— is —C(O)R 3 —; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         25 . The compound of  claim 24 , wherein R 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 24 , wherein —Y— is substituted. 
     
     
         27 . The compound of  claim 24 , wherein —Z— is —C(O)R 3 —. 
     
     
         28 . The compound of  claim 24 , wherein —Y— is substituted and —Z— is —C(O)R 3 —. 
     
     
         29 . The compound of  claim 24 , wherein —Y— represents a —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group optionally substituted with one or more groups selected from hydroxyl, alkyl, alkoxy, alkoxycarbonyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, acylamino, carboxy, cyano, halogen, nitro, sulfo, phosphono, phosphorylamino, phosphinyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocycloxy, trihalomethyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl, amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl, and heterocyclyl, wherein one or more of the carbon atoms in the —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group of —Y— may be replaced with NH, S, or O. 
     
     
         30 . The compound of  claim 25 , wherein —Y— represents a —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group optionally substituted with one or more C 1 -C 20  alkyl groups, wherein one or more of the carbon atoms in the —C 3 -C 20 alkyl-, —C 3 -C 20 alkenyl-, or —C 3 -C 20 alkynyl- group of —Y— may be replaced with NH, S, or O. 
     
     
         31 . The compound of  claim 25 , wherein —Y— represents a —C 3 -C 20 alkyl- group optionally substituted with one or more groups selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or hexyl. 
     
     
         32 . The compound of  claim 24 , wherein —Y— represents an optionally substituted —C 9 -C 20 alkyl-, wherein one or more of the carbon atoms in the alkyl group may be replaced with NH, S, or O. 
     
     
         33 . The compound of  claim 24 , wherein the pharmaceutical agent is selected from non-steroidal anti-inflammatory medications, COX-2 inhibitors, corticosteroid anti-inflammatory medications, anti-malarial medications, nitrosoureas, platinum, anthracyclines, drugs acting on immunophilins, opioids, immunosuppressants, or pharmaceutically active peptides. 
     
     
         34 . The compound of  claim 24 , wherein the pharmaceutical agent is selected from aspirin, ibuprofen, naproxen, celecoxib, rofecoxib, prednisolone, dexamethasone, hydroxychloroquine, cyclophosphamide, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, mitomycin C, bleomycin, mithramycin, sulfasalazine, leflunomide, mycophenolate, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxinemepe succinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, daunarubicin, ciclosporin, tacrolimus, sirolimus, mycophenolic acid, and cyclosporine. 
     
     
         35 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  independently represent H or a residue of a C 2 -C 28  fatty acid; 
         —X— is —O—; 
         —Y— represents a —C 7 -C 20 alkyl-, —C 7 -C 20 alkenyl-, or —C 7 -C 20 alkynyl- group, wherein one or more of the carbon atoms in the alkyl, alkenyl, or alkynyl group may be replaced with NH, S, or O, provided that the alkyl, alkenyl, or alkynyl group does not exceed a length equivalent to a linear C 20 alkyl group; 
       
       
         
           
           
               
               
           
         
       
       represents a residue of a pharmaceutical agent;
 -L- is —X′— or —X′C(O)—; 
 X′ is O, S, N, N(R 4 ), or S(O) 2 NH; 
    represents a single bond when X′ is O, S, N(R 4 ), or S(O) 2 NH; or 
    represents two separate bonds when X′ is N; 
 —Z— is —C(O)— or —C(O)R 3 — when -L- is —X′—; or 
 —Z— is absent when -L- is —X′C(O)—; 
 R 3  is a self-immolative group; and 
 R 4  is H or C 1 -C 4 alkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         36 . The compound of  claim 35 , wherein R 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 35 , wherein —Y— represents a —C 7 -C 20 alkyl-, wherein one or more of the carbon atoms in the alkyl group may be replaced with NH, S, or O. 
     
     
         38 . The compound of  claim 35 , wherein —Y— represents a —C 9 -C 20 alkyl-. 
     
     
         39 . The compound of  claim 36 , wherein -L- is —X′— and —Z— is —C(O)R 3 —. 
     
     
         40 . The compound of  claim 36 , wherein X′ is O. 
     
     
         41 . The compound of  claim 35 , wherein the pharmaceutical agent is selected from non-steroidal anti-inflammatory medications, COX-2 inhibitors, corticosteroid anti-inflammatory medications, anti-malarial medications, nitrosoureas, platinum, anthracyclines, drugs acting on immunophilins, opioids, immunosuppressants, or pharmaceutically active peptides. 
     
     
         42 . The compound of  claim 35 , wherein the pharmaceutical agent is selected from aspirin, ibuprofen, naproxen, celecoxib, rofecoxib, prednisolone, dexamethasone, hydroxychloroquine, cyclophosphamide, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, mitomycin C, bleomycin, mithramycin, sulfasalazine, leflunomide, mycophenolate, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxinemepe succinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, daunarubicin, ciclosporin, tacrolimus, sirolimus, mycophenolic acid, and cyclosporine. 
     
     
         43 . A compound of formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  independently represent H or a residue of a C 2 -C 28  fatty acid; 
         —X— is —O—; 
       
       
         
           
           
               
               
           
         
       
       represents a residue of a pharmaceutical agent;
 -L- is —X′— or —X′C(O)—; 
 X′ is O, S, or N(R 4 ); 
 —Z— is —C(O)— or —C(O)R 3 — when -L- is —X′—; or 
 —Z— is absent when -L- is —X′C(O)—; 
 R 3  is a self-immolative group; and 
 R 4  is H or C 1 -C 4 alkyl; 
 R 5  and R 6  are individually selected from hydrogen and C 1 -C 4 alkyl; and 
 n is from 1 to 18; 
 provided that one or both of R 5  and R 6  are C 1 -C 4 alkyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         44 . The compound of  claim 43 , wherein R 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of  claim 43 , wherein R 5  is H and R 6  is methyl; or R 5  is methyl and R 6  is H. 
     
     
         46 . The compound of  claim 44 , wherein X′ is O. 
     
     
         47 . The compound of  claim 43 , wherein the pharmaceutical agent is selected from non-steroidal anti-inflammatory medications, COX-2 inhibitors, corticosteroid anti-inflammatory medications, anti-malarial medications, nitrosoureas, platinum, anthracyclines, drugs acting on immunophilins, opioids, immunosuppressants, or pharmaceutically active peptides. 
     
     
         48 . The compound of  claim 43 , wherein the pharmaceutical agent is selected from aspirin, ibuprofen, naproxen, celecoxib, rofecoxib, prednisolone, dexamethasone, hydroxychloroquine, cyclophosphamide, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, mitomycin C, bleomycin, mithramycin, sulfasalazine, leflunomide, mycophenolate, fingolimod, myriocin, chlorambucil, doxorubicin, nelarabine, cortisone, dexamethasone, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxinemepe succinate, anastrozole, capecitabine, letrozole, paclitaxel, gemcitabine, fulvestrant, tamoxifen, lapatinib, toremifene, ixabepilone, eribulin, albendazole, ivermectin, diethylcarbamazine, albendazole, doxycycline, closantel, maraviroc, enfuvirtide, deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, tenofovir, nevirapine, delavirdine, efavirenz, rilpivirine, raltegravir, elvitegravir, lopinavir, indinavir, nelfinavir, amprenavir, ritonavir, acyclovir, daunarubicin, ciclosporin, tacrolimus, sirolimus, mycophenolic acid, and cyclosporine. 
     
     
         49 . A pharmaceutical composition comprising a compound of  claim 24 , or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent. 
     
     
         50 . A method of treating or preventing a disease or disorder in which increased testosterone levels are beneficial, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of  claim 24 , or a pharmaceutically acceptable salt thereof. 
     
     
         51 . The method according to  claim 50 , wherein the disease or disorder is hypogonadism, anemia due to bone marrow failure, anemia due to renal failure, chronic respiratory failure, chronic cardiac failure, a steroid-dependent autoimmune disorder, AIDS wasting, hereditary angioedema or urticaria, terminal breast cancer, or menopause. 
     
     
         52 . The method according to  claim 50 , wherein the compound is administered orally with food to promote transport to the intestinal lymph, or is co-administered orally with a lipid based formulation to promote transport to the intestinal lymph.