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.

1 .- 23 . (canceled) 
     
     
         24 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  independently represent a C 2 -C 28  fatty acid; 
         —X— is selected from —O—, —NH—, and —S—; 
         —Y— represents an unsubstituted, straight-chain —C 3 -C 6 alkyl-, —C 3 -C 6 alkenyl-, or —C 3 -C 6 alkynyl- group, wherein one or more of the carbon atoms in the alkyl, alkenyl, or alkynyl group are optionally replaced with NH, S, O, a C 5 -C 8  aromatic or aliphatic cyclic group, or a C 5 -C 8  aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl, or alkynyl group does not exceed a length equivalent to a linear C 6 alkyl group; 
       
       
         
           
           
               
               
           
         
       
       represents 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. 
 
     
     
         25 . The compound of  claim 24 , wherein R 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 24 , represented by the formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  independently represent H, or a C 2 -C 28  fatty acid; 
         —X— is selected from —O—, —NH— and —S—; 
         —Y— represents an unsubstituted, straight-chain —C 3 -C 6 alkyl-, —C 3 -C 6 alkenyl-, or —C 3 -C 6 alkynyl- group, wherein one or more of the carbon atoms in the alkyl, alkenyl, or alkynyl group may be replaced with NH, S, O, a C 5 -C 8  aromatic or aliphatic cyclic group, or a C 5 -C 8  aromatic or aliphatic heterocyclic group, provided that the alkyl, alkenyl, or alkynyl group does not exceed a length equivalent to a linear C 6 alkyl group; 
       
       
         
           
           
               
               
           
         
       
       represents a pharmaceutical agent;
 -L- is —X′— or —X′C(O)—; 
 X′ is O, S or N(R 4 ); 
 R 4  is H or C 1 -C 4 alkyl; and 
 —Z— is —C(O)— when -L- is —X′—; or 
 —Z— is absent when -L- is —X′C(O)—; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         27 . The compound of  claim 24 , represented by the formula (III): 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 2 , —X—, 
       
       
         
           
           
               
               
           
         
       
       and —Z— are as defined in claim  1 ;
 R 5  and R 6  are hydrogen; and 
 n is from 1 to 4; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         28 . The compound of  claim 24 , wherein the pharmaceutical agent is selected from testosterone, mycophenolic acid, oestrogens (estrogen), morphine, metoprolol, raloxifene, alphaxolone, atorvastatin, buprenorphine, pentazocine, propranolol, L-DOPA, midazolam, lidocaine, chlorpromazine, amitriptyline, nortriptyline, isosorbidedinitrate, oxprenolol, labetalol, verapamil, salbutamol, epitiostanol, melphalan or lovastatin. 
     
     
         29 . The compound of  claim 28  wherein the pharmaceutical agent is testosterone and the compound is represented by the formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and X are as defined in claim  1 ; 
         R 5  and R 6  are hydrogen; 
         —Z— is —C(O)— or —C(O)R 3 —; 
         R 3  is a self-immolative group; and 
         n is from 1 to 4; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The compound of  claim 24 , wherein -L- is —X′C(O)—. 
     
     
         31 . The compound of  claim 24 , wherein -L- is —X′—. 
     
     
         32 . The compound of  claim 24 , wherein —X— and —X′— are oxygen. 
     
     
         33 . The compound of  claim 24 , wherein —X— is —O— and R 1  and R 2  are independently selected from a C 2 -C 28  fatty acid. 
     
     
         34 . The compound of  claim 24 , wherein —Z— is —C(O)R 3 —. 
     
     
         35 . The compound of  claim 24 , wherein —Z— is —C(O)— or is absent. 
     
     
         36 . The compound of  claim 24 , wherein —Y— represents an unsubstituted, straight-chain —C 3 -C 6 alkyl-, wherein one or more of the carbon atoms in the alkyl group may be replaced with NH, S, or O. 
     
     
         37 . The compound of  claim 24 , wherein —Y— represents an unsubstituted, straight-chain —C 4 alkyl-. 
     
     
         38 . 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. 
     
     
         39 . 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, prednisone, pralatrexate, vinblastine, bortezomib, thiotepa, nelarabine, daunorubicin hydrochloride, clofarabine, cytarabine, dasatinib, imatinib mesylate, ponatinib hydrochloride, vincristine sulfate, bendamustine hydrochloride, fludarabine phosphate, bosutinib, nilotinib, omacetaxine mepesuccinate, 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, or cyclosporine. 
     
     
         40 . 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. 
     
     
         41 . A method of treating or preventing a disease or disorder in which increased testosterone levels are beneficial, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim  1 , or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The method of  claim 41 , 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. 
     
     
         43 . The method of  claim 41 , 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.