Abstract:
The present invention describes steroid conjugates. These single drug entities are formed by connecting two or more steroids via a linker. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual steroid drugs.

Description:
RELATED APPLICATIONS 
       [0001]    This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/775,216 filed Mar. 8, 2013, the disclosure of which is hereby incorporated in its entirety by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention describes steroid conjugates. These single drug entities are formed by connecting two or more steroids via a linker. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual steroid drugs. 
       SUMMARY OF THE INVENTION 
       [0003]    A conjugate drug, also referred to as a co-drug, a pro-drug, or a hybrid drug, comprises two or more different or same drugs within one single chemical entity wherein each drug contains an appropriate chemical functionality to enable them to be connected together, either directly or by means of a covalent linker, which is cleavable, biologically labile. 
         [0004]    Hybrid structures can incorporate two drugs joined together by a linker moiety such as an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, which is cleaved enzymatically or hydrolytically in vivo to release the active drugs. 
         [0005]    By appropriate structural design of these linkers, it may be possible to control the release of each drug. When the drugs are chemically combined, the resulting hybrid will usually have different physicochemical properties compared to the individual parent drugs, which may provide superior properties for delivery when compared to delivery of a physical mixture of the drugs. The steroid moieties, of the compounds disclosed herein are connected via two covalent bonds to a linker such that said compound degrades in vivo to yield the individual steroids. Depending on the nature of the linker and depending on the nature of the compound, each bond has a chemical functionality such as an ester, a carbonate, an amide, a carbamate, an ether, an oxo, a ketone, an amine. In other words, the single drug entity can have one ether bond connecting to one steroid and one ester bond connecting to the other steroid or one ester bond connecting to each steroid or one ether bond connecting each steroid. 
         [0006]    Degradation of these covalent bonds generally, yields the corresponding acid, or alcohol by hydrolysis or a by related reaction. A compound which degrades in vivo to yield the individual steroids, produces the active steroid drugs at some point in the metabolic process of the claimed compound. In many cases, cleavage of the first ester bond will release one active, and cleavage of the second ester bond will release the second active. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0007]    The hybrid drugs of the invention provide a unique delivery of two steroids for the treatment of ophthalmic bacterial infections and for the prevention of inflammation and infection. A single drug entity is advantageous to individual dosing of each drug because of the ability for simultaneous dosing and elimination of washout concerns when applying each drug separately. 
         [0008]    The use of an anti-inflammatory hybrid drug is indicated where the risk of infection is high. The anti-inflammatory component of the composition is useful in treating inflammation associated with physical trauma to ophthalmic tissues, inflammation associated with bacterial infections and inflammation resulting from surgical procedures. The composition of the invention may also be used prophylactically in connection with various ophthalmic surgical procedures that create a risk of bacterial infection. Other examples of ophthalmic conditions which may be treated with the compositions of the present invention include infective conditions associated with inflammation and where the use of anti-inflammatory is acceptable. Such conditions may include, but are not limited to conjunctivitis, keratitis, blepharitis, endophthalmitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, red eye, hyperemia, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, red eye, hyperemia, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof. 
         [0009]    The compounds disclosed herein comprise at least one steroidal drug selected from, but not limited to: dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone. 
         [0010]    In one aspect the invention provides the compounds represented by a hybrid drug as described below. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0011]    In another aspect the invention provides compounds which may comprise a linker moiety selected from, but not limited to, an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol, an ethylene. 
         [0012]    In another aspect, the invention provides compounds which may comprise a linker moiety comprising any combination of an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an ethylene, an amino, an oxo, an ethylene glycol and/or a polyethylene glycol. Such linkers moieties and linker structures are exemplified in Table 1. 
         [0013]    Examples of ester moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0014]    Examples of carboxylate moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0015]    Example of a carbonyl moiety comprised in the linkers is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0016]    Example of a carbonate moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0017]    Examples of amido moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0018]    Example of carbamate moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0019]    Example of a ketone moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0020]    Examples of amino moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0021]    Example of an oxo moiety comprised in the linker is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0022]    Example of ethylene glycol moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0023]    Example of polyethylene glycol moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0024]    In another aspect, the invention provides compounds which may comprise a linker moiety or a linker structure selected from Table 1: 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                   
                 Linker Moiety Number or 
               
               
                   
                 Linker Structure Number 
               
             
          
           
               
                 Linker Moiety or Linker Structure 
                   
                 n = 0 
                 n = 1 
                 n = 2  
                 n = 3 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L2 
                 L1 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L3 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L4 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L35 
                   
                 L5 
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L6 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L7 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L14 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L15 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L16 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L46 
                 L17 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L8 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L9 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L10 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L18 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L11 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L19 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L12 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L13 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L20 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L21 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L22 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L23 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L24 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L25 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L26 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L27 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L28 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L29 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L30 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L31 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L32 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L33 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L34 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L35 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L36 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L37 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L38 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L39 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L40 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L41 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L42 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L43 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L44 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L45 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L47 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L48 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L49 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L50 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L51 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L52 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L53 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L54 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L55 
                 L58 
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L56 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L57 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L59 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L60 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L61 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L62 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L63 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L64 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L65 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L66 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L67 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L68 
                 L103 
                 L104 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L69 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L70 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L71 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L72 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L73 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L74 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L75 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L76 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L77 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L78 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L79 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L80 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L81 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L82 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L83 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L84 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L85 
                 L86 
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L87 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L88 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L89 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L90 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L91 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L92 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L93 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L94 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L95 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L96 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L97 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L98 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L99 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L100 
                 L101 
                 L102 
               
               
                   
               
             
          
         
       
     
         [0025]    Preferred linkers of the invention have a carbonyl functional group at each end, in order to form a carboxylate group with the oxygen atom of the steroid. Preferred linkers are: L41, L42, L44, L52, L53, L54, L55, L58, L56, L57, L60, L61, L62, L63, L64, L65, L66, L67, L68, L69, L70, L71, L76, L78, L79, L80, L81, L82, L83, L84, L90, L92, L93, L94, L95, L96, L97, L98, L99, L103, L104. 
         [0026]    Compounds of the invention are shown in Table 2. 
         [0000]    
       
         
               
               
             
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Com- 
                   
               
               
                 pound 
                   
               
               
                 number 
                 IUPAC Name 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 26 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-[(6-{2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- 
               
               
                   
                 oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl rel-butanedioate 
               
               
                 25 
                 6-[(6-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl- 
               
               
                   
                 3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6- 
               
               
                   
                 oxohexyl)oxy]-6-oxohexyl 2-[(9R,10S,11S,13S,16R,17R)-9- 
               
               
                   
                 fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 
               
               
                 24 
                 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′-{2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 
               
               
                   
                 4,4′-octane-1,8-diyl reldi-butanedioate 
               
               
                 23 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-4,21-dioxo-5,8,11,14,17,20-hexaoxatetracosane-1,24- 
               
               
                   
                 dioate 
               
               
                 22 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-4,18-dioxo-5,8,11,14,17-pentaoxahenicosane-1,21-dioate 
               
               
                 30 
                 2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17- 
               
               
                   
                 dihydroxy-10,13,16-trimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-butanedioate 
               
               
                 20 
                 2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17- 
               
               
                   
                 dihydroxy-10,13,16-trimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2- 
               
               
                   
                 [(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 
               
               
                 27 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,17R)-9-fluoro-11,17-dihydroxy-10,13- 
               
               
                   
                 dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate 
               
               
                 11 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate 
               
               
                 19 
                 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-4-({2-[(2-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13- 
               
               
                   
                 dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro- 
               
               
                   
                 3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-2- 
               
               
                   
                 oxoethyl)(methyl)amino]-2-oxoethyl}amino)-4-oxobutanoate 
               
               
                 18 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate 
               
               
                 2 
                 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-4,15-dioxo- 
               
               
                   
                 5,8,11,14-tetraoxaoctadecane-1,18-dioate 
               
               
                 10 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-2,2′-oxyd iacetate 
               
               
                 17 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-2,2′-oxyd iacetate 
               
               
                 21 
                 4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1-{2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 
               
               
                   
                 rel-(2R)-2-am inobutaned ioate 
               
               
                 9 
                 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4-{[({2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- 
               
               
                   
                 oxoethoxy}carbonyl)oxy]methyl} rel-(2R)-2-aminobutanedioate 
               
               
                 16 
                 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 
               
               
                   
                 1′,4-methanediyl reldi-butanedioate 
               
               
                 8 
                 1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 
               
               
                   
                 1′,4-methanediyl reldi-butanedioate 
               
               
                 29 
                 [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- 
               
               
                   
                 oxoethoxylcarbonyl)oxy]methyl 2-[(9R,10S,11S,13S,16R,17R)- 
               
               
                   
                 9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate 
               
               
                 7 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- 
               
               
                   
                 oxoethoxy}carbonyl)oxy]methyl rel-butanedioate 
               
               
                 15 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2- 
               
               
                   
                 oxoethoxy}carbonyl)oxy]methyl rel-butanedioate 
               
               
                 6 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-3-hydroxypentanedioate 
               
               
                 14 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-3-hydroxypentanedioate 
               
               
                 13 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-butanedioate 
               
               
                 5 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-pentanedioate 
               
               
                 12 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-pentanedioate 
               
               
                 3 
                 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-pentanedioate 
               
               
                 4 
                 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo- 
               
               
                   
                 6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2- 
               
               
                   
                 [(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy- 
               
               
                   
                 10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17- 
               
               
                   
                 dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 
               
               
                   
                 rel-butanedioate 
               
               
                 28 
                 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate 
               
               
                 1 
                 bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3- 
               
               
                   
                 oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H- 
               
               
                   
                 cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate 
               
               
                   
               
             
          
         
       
     
         [0027]    In another embodiment, the compounds of the invention comprise two of prednisolone moiety such as the compounds below:
   bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate;   bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate;   bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-pentanedioate.   
 
         [0031]    In another embodiment, the compounds of the invention comprise a prednisolone moiety and a betamethasone moiety as shown below:
   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-pentanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-3-hydroxypentanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl rel-butanedioate;   1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}4′-{2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′,4-methanediyl reldi-butanedioate;   1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4-{[({2-[(9R,10S,115,135,165,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl} rel-(2R)-2-aminobutanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-2,2′-oxydiacetate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate.   
 
         [0040]    In another embodiment, the compounds of the invention comprise a prednisolone moiety and a dexamethasone moiety as shown below:
   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-pentanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-3-hydroxypentanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl [({2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl rel-butanedioate;   1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4′-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′,4-methanediyl reldi-butanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-2,2′-oxydiacetate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate;   2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4-({2-[(2-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-2-oxoethyl)(methyl)amino]-2-oxoethyl}amino)-4-oxobutanoate;   2-amino-3-{2-[(9R,105,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;   4-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl}rel-(2R)-2-aminobutanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,18-dioxo-5,8,11,14,17-pentaoxahenicosane-1,21-dioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,21-dioxo-5,8,11,14,17,20-hexaoxatetracosane-1,24-dioate;   1-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 1′-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} 4,4′-octane-1,8-diyl reldi-butanedioate;   6-[(6-{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 6-[(6-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-6-oxohexyl)oxy]-6-oxohexyl rel-butanedioate.   
 
         [0056]    In another embodiment, the compounds of the invention comprise a prednisolone moiety and a hydrocortisone moiety as shown below:
   2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl 2-[(9R,10S,11S,13S,17R)-9-fluoro-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-4,15-dioxo-5,8,11,14-tetraoxaoctadecane-1,18-dioate.   
 
         [0058]    In another embodiment, the compounds of the invention comprise two hydrocortisone moieties as shown below:
   bis{2-[(10R,11S,13S,17R)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl} rel-butanedioate.   
 
         [0060]    In another embodiment, the compounds of the invention comprise a betamethasone moiety and a dexamethasone moiety as shown below:
   [({2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}carbonyl)oxy]methyl 2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate;   2-amino-3-{2-[(9R,10S,11S,13S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy}-3-oxopropyl 2-[(9R,10S,11S,13S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl rel-butanedioate.   
 
         [0063]    In another embodiment, the invention provides a hybrid compound comprising two steroid moieties, or a pharmaceutical salt thereof, which are separately connected via a covalent bond to a linker such that said compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond. 
         [0064]    In another embodiment, the invention provides a hybrid compound wherein at least one steroid is selected from the group consisting of dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone. 
         [0065]    In another embodiment, the invention provides a hybrid compound, comprising two prednisolone moieties. 
         [0066]    In another embodiment, the invention provides a hybrid compound, comprising one prednisolone moiety and one betamethasone moiety. 
         [0067]    In another embodiment, the invention provides a hybrid compound, comprising one prednisolone moiety and one dexamethasone moiety. 
         [0068]    In another embodiment, the invention provides a hybrid compound, comprising one prednisolone moiety and one hydrocortisone moiety. 
         [0069]    In another embodiment, the invention provides a hybrid compound, comprising one betamethasone moiety and one dexamethasone moiety. 
         [0070]    In another embodiment, the invention provides a hybrid compound, comprising two hydrocortisone moieties. 
         [0071]    In another embodiment, the invention provides a pharmaceutical composition comprising a hybrid compound comprising two steroid moieties, which are separately connected via a covalent bond to a linker, such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0072]    In another embodiment, the invention provides a method comprising administration to an eye of a mammal a hybrid compound comprising two steroid moieties, which are separately connected via a covalent bond to a linker such that said hybrid compound degrades in vivo to yield the two steroids, wherein each bond is an ester bond, wherein said method is effective in the treatment of an inflammation condition affecting said eye. 
         [0073]    In another embodiment, the invention provides a method wherein said hybrid compound has topical steroid activity upon a surface of an eye, and wherein the hybrid compound degrades on said surface into one or more of said smaller active steroids which are capable of penetrating beyond tissue of said surface. 
         [0074]    In another embodiment, the invention provides a hybrid compound comprising a linker having two bonds, wherein said bonds are asymmetrically degraded in vivo to release the two steroid moieties. 
         [0075]    Some compounds of the invention have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13. 
         [0076]    The term “pharmaceutically acceptable salts” refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The “pharmaceutically acceptable salts” according to the invention include therapeutically active, non-toxic base or acid salt forms, which the compounds of the invention are able to form. 
         [0077]    The acid addition salt form of a compound of the invention that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic acid and the like (Handbook of Pharmaceutical Salts, P. Heinrich Stahl &amp; Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345). 
         [0078]    The base addition salt form of a compound of the invention that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. (Handbook of Pharmaceutical Salts, P. Heinrich Stahl &amp; Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zurich, 2002, 329-345). 
         [0079]    Compounds of the invention and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. 
         [0080]    In still another embodiment of the invention, there are provided methods for treating or preventing eye conditions such as: conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, in a patient suffering thereof. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms thereof. 
         [0081]    The present invention concerns the use of a compound of the invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis. 
         [0082]    The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient&#39;s general physical condition, the cause of the condition, and the route of administration. 
         [0083]    The compounds of the invention may also be administered as pharmaceutical compositions in a form suitable for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid emulsions. 
         [0084]    Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound according to the present invention, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional ophthalmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations. 
         [0085]    For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants. 
         [0086]    Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. 
         [0087]    A preferred surfactant is, for example, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water. 
         [0088]    Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. 
         [0089]    Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed. 
         [0090]    In a similar manner an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. 
         [0091]    Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it. 
         [0092]    The ingredients are usually used in the following amounts: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Amount (% w/v) 
               
               
                   
                   
               
             
             
               
                   
                 active ingredient 
                 about 0.001-5 
               
               
                   
                 preservative 
                   0-0.10 
               
               
                   
                 vehicle 
                  0-40 
               
               
                   
                 tonicity adjustor 
                  0-10 
               
               
                   
                 buffer 
                 0.01-10   
               
               
                   
                 pH adjustor 
                 q.s. pH 4.5-7.8 
               
               
                   
                 antioxidant 
                 as needed 
               
               
                   
                 surfactant 
                 as needed 
               
               
                   
                 purified water 
                 to make 100% 
               
               
                   
                   
               
             
          
         
       
     
         [0093]    The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. 
         [0094]    The ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 μl. 
         [0095]    The patient may be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy. 
         [0096]    In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 
         [0097]    Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition. 
         [0098]    Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. 
         [0099]    In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. 
         [0100]    Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner. 
         [0101]    The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions such as conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof. 
         [0102]    Thus, in further embodiments of the invention, there are provided methods for treating conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulcers, anterior blepharitis, posterior blepharitis, meibomian gland dysfunction, dry eye disease (keratocojunctivitis sicca) ocular pain, ocular pain and inflammation post-ocular surgery, bacterial conjunctivitis, anterior uveitis, post-surgical inflammation, inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis, ocular rosacea, dry eye, blepharitis, meibomian gland dysfunction, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, corneal injury from chemical radiation, or thermal burns, penetration of foreign bodies, allergy, and combinations thereof. 
         [0103]    Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term “therapeutically effective amount” means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human. 
         [0104]    The present invention concerns also processes for preparing the hybrid compounds disclosed herein. The hybrid compounds according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The synthetic scheme set forth below, illustrates how compounds according to the invention can be made. Those skilled in the art will be able to routinely modify and/or adapt the following scheme to synthesize any compounds of the invention. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0105]    In this scheme the synthesis of hybrid compounds were started with a steroid R—CH 2 —OH. EDCI coupling of steroid R—CH 2 —OH with succinic anhydride gave a carboxylic acid intermediate. A second EDCI coupling of the carboxylic acid intermediate with steroid R′—CH 2 —OH yielded the desired hybrid compound. 
         [0106]    The carboxylic intermediate can be coupled with a polyethylene glycol to form a corresponding alcohol, which can be coupled with another succinic anhydride molecule and then with another steroid of formula R′—CH 2 —OH to form a hybrid with a polyethylene and ketone moieties. 
         [0107]    The following abbreviations are used in the general Scheme 1:
       EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide   DMAP 4-dimethylaminopyridine   CH 2 Cl 2  dichloromethane       
 
         [0111]    It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. 
         [0112]    It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention. 
         [0113]    The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium  2 H (or D) in place of hydrogen  1 H (or H) or use of  13 C enriched material in place of  12 C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents. 
         [0114]    The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention. 
         [0115]    As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed. 
         [0116]    Compound names were generated with ACDLabs version 12.5 or ChemBioDraw Ultra version 12.0.2. 
         [0117]    In general, characterization of the compounds is performed according to the following methods. Proton nuclear magnetic resonance ( 1 H NMR) and carbon nuclear magnetic resonance ( 13 C NMR) spectra were recorded on a Varian 300 or 600 MHz spectrometer in deuterated solvent. Chemical shifts were reported as δ (delta) values in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard (0.00 ppm) and multiplicities were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data were reported in the following format: chemical shift (multiplicity, coupling constant(s) J in hertz (Hz), integrated intensity). The mass spectrometry data were determined on a Shimadzu LCMS-IT-TOF instrument. 
         [0118]    The formation of the hybrid compounds was checked by  1 H-NMR, comparing the chemical shifts of the protons from the CH 2  group identified in the schemes shown below, and identified as “CH 2   c ” for the starting material and as “CH 2   c* ” or “c*” for of the corresponding protons on the newly formed hybrid molecule wherein “*” indicates the hybrid compound. Applicants have marked with arrows the location of these protons and the reaction site of the prodrug moiety, where available. Each scheme shows the formation of the new hybrid drug. Each table describes the results for the new hybrid drug and the linker number, where existing. The linker moiety numbers are as described in Table 1. 
         [0119]    The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention. 
       EXAMPLES 
       [0120]    Prednisolone reacted with another molecule of Prednisolone to form the following hybrid compounds as shown in Scheme 2 with the results described in Table 3. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 *Comp. 
                   
                 CH 2   c * 
                   
               
               
                 Linker 
                 Structure 
                 δ(ppm) 
                 Mass 
               
               
                   
               
             
             
               
                 1 L55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.00 (dd, 4H) 
                 825 (MNa + ) 
               
               
                   
               
               
                 2 L57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.99 (dd, 4H) 
                 1057  (MNa + ) 
               
               
                   
               
               
                 3 L58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.99 (dd, 4H) 
                 839 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0121]    Prednisolone reacted with one molecule of Betamethasone to form the following hybrid compounds as shown in Scheme 3 with the results described in Table 4. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 *Comp 
                   
                 CH 2   c * 
                   
               
               
                 Linker 
                 Structure 
                 δ(ppm) 
                 Mass 
               
               
                   
               
             
             
               
                 4 L55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.06-4.93 (m, 4H) 
                 857 (MNa + ) 
               
               
                   
               
               
                 5 L58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.05-4.92 (m, 4H) 
                 871 (MNa + ) 
               
               
                   
               
               
                 6 L62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.10-4.95 (m, 4H) 
                 887 (MNa + ) 
               
               
                   
               
               
                 7 L63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.09-4.85 (m, 4H) 
                 931 (MNa + ) 
               
               
                   
               
               
                 8 L59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.07-4.91 (m, 4H) 
                 963 (MH + ) 
               
               
                   
               
               
                 9 L60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.09-4.98 (m, 4H) 
                 946 (MNa + ) 
               
               
                   
               
               
                 10  L61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.16-4.99 (m, 4H) 
                 874 (MNa + ) 
               
               
                   
               
               
                 11  L57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.03-4.96 (m, 4H) 
                 1089  (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0122]    Prednisolone reacted with one molecule of Dexamethasone to form the following hybrid compounds as shown in Scheme 4 with the results described in Table 5. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp 
                   
                 CH 2   c * 
                   
               
               
                 Linker 
                 Structure 
                 δ(ppm) 
                 Mass 
               
               
                   
               
             
             
               
                 12 L58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.06-4.92  (m, 4H) 
                 871 (MNa + ) 
               
               
                   
               
               
                 13 L55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.06-4.97  (m, 4H) 
                 857 (MNa + ) 
               
               
                   
               
               
                 14 L62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.11-4.85  (m, 4H) 
                 887 (MNa + ) 
               
               
                   
               
               
                 15 L63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.10-4.86  (m, 4H) 
                 931 (MNa + ) 
               
               
                   
               
               
                 16 L59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.06-4.90  (m, 4H) 
                 987 (MNa + ) 
               
               
                   
               
               
                 17 L61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.16-5.02  (m, 4H) 
                 873 (MNa + ) 
               
               
                   
               
               
                 18 L57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.08-4.93  (m, 4H) 
                 1090  (MNa + ) 
               
               
                   
               
               
                 19 L64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.18-4.94  (m, 4H) 
                 985 (MNa + ) 
               
               
                   
               
               
                 20 L65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.07-4.91  (m, 4H) 
                 944 (MNa + ) 
               
               
                   
               
               
                 21 L66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.25-5.02  (m, 4H) 
                 892 (MNa + ) 
               
               
                   
               
               
                 22 L67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.08-4.96  (m, 4H) 
                 1133  (MNa + ) 
               
               
                   
               
               
                 23 L68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.08-4.95  (m, 4H) 
                 1177  (MNa + ) 
               
               
                   
               
               
                 24 L69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.08-4.91  (m, 4H) 
                 1133  (MNa + ) 
               
               
                   
               
               
                 25 L70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.03-4.91 (m, 4H) 
                 1085  (MNa + ) 
               
               
                   
               
               
                 26 L71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.08-4.91  (m, 4H) 
                 1085  (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0123]    Prednisolone reacted with one molecule of Hydrocortisone to form the following hybrid compounds as shown in Scheme 5 with the results described in Table 6. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp 
                   
                 CH 2   c * 
                   
               
               
                 Linker 
                 Structure 
                 δ(ppm) 
                 Mass 
               
               
                   
               
             
             
               
                 27 L57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.09-4.92  (m, 4H) 
                 1060 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0124]    Hydrocortisone reacted with another molecule of Hydrocortisone to form the following hybrid compounds as shown in Scheme 6 with the results described in Table 7. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp 
                   
                 CH 2   c * 
                   
               
               
                 Linker 
                 Structure 
                 δ (ppm) 
                 Mass 
               
               
                   
               
             
             
               
                 28 L55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.01 (dd, 4H) 
                 829 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0125]    Dexamethasone reacted with one molecule of Betamethasone to form the following hybrid compounds as shown in Scheme 7 with the results described in Table 8. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp 
                   
                 CH 2   c * 
                   
               
               
                 Linker 
                 Structure 
                 δ(ppm) 
                 Mass 
               
               
                   
               
             
             
               
                 29 L52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.09-4.94  (m, 4H) 
                 963  (MNa + ) 
               
               
                   
               
               
                 30 L65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.10-4.95  (m, 4H) 
                 954 (MNa + ) 
               
               
                   
               
             
          
         
       
     
       Biological Examples 
     In Vitro Metabolic Stability in Human Recombinant Carboxylesterases 
       [0126]    Human recombinant carboxylesterases were purchased from a commercial vendor (BD Gentest™, Bedford, Mass.). All metabolic stability experiments were performed in triplicate in 96-well plate format. The final incubation mixture contained 1 μM test compound and 0.1 mg/mL human recombinant carboxylesterase mixture in a final volume of 0.5 mL 0.1M potassium phosphate buffer (pH=6.0). The final percentage of solvent in the incubation was less than 1.0% to prevent inhibition of enzymatic activity. Following a pre-incubation at 37° C., test article was added to initiate the reaction. At designated time points (typically less than 60 minutes to capture the linear range of metabolite formation), 0.05 mL aliquots were removed from the incubation mixtures using a clean pipet tip and immediately placed in organic solvent to stop any esterase activity. The hydrolysis to the metabolites was confirmed to be due to esterase activity and not chemical lability. 
         [0127]    The samples were analyzed by liquid chromatography with mass spectrometry (LC-MS/MS) detection to determine the metabolite concentrations resulting from the metabolism of the hybrid compounds. Internal standards were used to compensate for variability from sample processing, chromatographic elution, mass spectrometer response and ion suppression by matrix components. 
         [0128]    Table 9 lists the rate of metabolite formation in human recombinant carboxylesterases. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                   
                   
                 Rate of 
                 Rate of 
               
               
                 * 
                   
                 formation 
                 formation 
               
               
                 Comp 
                   
                 Metabolite 1 
                 Metabolite 2 
               
               
                 No. 
                 Structure 
                 (nM/min/mg) 
                 (nM/min/mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 35.1 ± 7.6  Prednisolone 
                 74.8 ± 14.2 Betamethasone 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 54.5 ± 10.4 Prednisolone 
                 56.5 ± 7.5  Dexamethansone 
               
               
                   
               
             
          
         
       
     
         [0129]    The data demonstrate that linkage of two steroids (e.g. prednisolone, betamethasone, or dexamethasone) as a single hybrid compound was hydrolyzed enzymatically in human recombinant carboxylesterases to their respective individual steroid drugs.