Abstract:
The present invention describes steroid antibiotic conjugates. These single drug entities are formed connecting a steroid moiety and two same antibiotics moieties, or a steroid moiety and two different antibiotics moieties. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual 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 antibiotic conjugates. These single drug entities are formed connecting a steroid moiety and two same antibiotics moieties, or a steroid moiety and two different antibiotics moieties. Upon topical application to the eye, the conjugate hybrid would undergo enzymatic and/or hydrolytic cleavage to release the individual drugs. 
       SUMMARY OF THE INVENTION 
       [0003]    The antibiotic moieties and the steroid moiety, of the compounds disclosed herein are connected via two covalent bonds to a linker such that said compound degrades in vivo to yield the respective antibiotic and the respective steroids. Each bond is an amide bond or an ester bond depending on the nature of the compound. In other words, the single drug entity has one amide bond connecting to the antibiotic and/or one ester bond connecting to the other antibiotic and/or one ester bond connecting to the steroid. 
         [0004]    Degradation of the ester or amide bonds generally, but not necessarily, yields the corresponding acid and alcohol or amine by hydrolysis or a related reaction. A compound which degrades in vivo to yield the antibiotic and steroid, produces the active drugs belonging to distinct classes at some point in the metabolic process of the claimed compound. In many cases, cleavage of the first amide or ester bond will release one active, and cleavage of the second amide or ester bond will release the second active and then the third active will be released if it is the case. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0005]    In one aspect, the present invention relates to a hybrid compound comprising a steroid moiety and two same antibiotics moieties, or a pharmaceutical salt thereof, which are connected via two covalent bonds to a linker such that said compound degrades in vivo to yield the respective two antibiotics independently and the respective steroid drug, wherein each bond is an amide bond or an ester bond. 
         [0006]    In another aspect, the present invention relates to a compound comprising a steroid moiety and two different antibiotics moieties, or a pharmaceutical salt thereof, which are connected via two covalent bonds to a linker such that said compound degrades in vivo to yield the respective two antibiotics independently and the respective steroid drug, wherein each bond is an amide bond or an ester bond. 
         [0007]    In another aspect, the present invention relates to a hybrid compound comprising a steroid moiety and two antibiotics moieties, which are connected via separate covalent bonds to at least one linker each such that said covalent bond degrade in vivo to yield the respective two antibiotics independently and the respective steroid drug. 
         [0008]    In another aspect, the present invention relates to a hybrid compound wherein the two antibiotics moieties are identical. 
         [0009]    In another aspect, the present invention relates to a hybrid compound wherein the two antibiotics moieties are different. 
         [0010]    In another aspect, the present invention relates to a hybrid compound wherein a first antibiotic moiety is directly linked to the steroid moiety and further linked to the other antibiotic moiety via a linker. 
         [0011]    In another aspect, the present invention relates to a hybrid compound a first antibiotic moiety is linked to the steroid moiety via a linker and further linked to the other antibiotic moiety via another linker. 
         [0012]    In another aspect, the present invention relates to a hybrid compound wherein a first antibiotic moiety is linked to the steroid moiety via a linker and further linked to the other antibiotic moiety via another linker. 
         [0013]    In another aspect, the present invention relates to a hybrid compound wherein the two antibiotic drug moieties are selected from the group consisting of: gatifloxacin, moxifloxacin, chloramphenicol, tobramycin and amikacin. 
         [0014]    In another aspect, the present invention relates to a hybrid compound wherein the steroid drug moiety is selected from the group consisting of: dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone. 
         [0015]    In another aspect, the present invention relates to a hybrid compound wherein said linker comprises an ester, a carboxylate, a carbonyl, a carbonate, an amido, a carbamate, a ketone, an amino, an oxo, an ethylene glycol, a polyethylene glycol moiety or an ethylene moiety. 
         [0016]    In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a hybrid compound, comprising two antibiotic moieties and one steroid drug moiety, which are connected via separate covalent bonds such that said covalent bonds degrade in vivo to yield the antibiotics and steroid drugs, and wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0017]    In another aspect, the present invention relates to a method comprising administrating to an eye of a mammal a pharmaceutical composition comprising a therapeutically effective amount of a hybrid compound comprising two antibiotic moieties and one steroid moiety, which are connected via separate covalent bonds such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, and wherein said method is effective in the treatment of an inflammatory condition or bacterial infection affecting said eye. 
         [0018]    In another aspect, the present invention relates to a method wherein said hybrid compound has topical antibiotic and anti-inflammatory activity upon a surface of an eye, and wherein the hybrid compound degrades on said surface into said active antibiotics and said steroid drug, which are capable of penetrating beyond tissue of said surface 
         [0019]    In another aspect, the present invention relates to a hybrid compound comprising at least one linker having at least two bonds, wherein said bonds are asymmetrically degraded in vivo to release the antibiotic and steroid drugs. 
         [0020]    The hybrid compounds of the invention have both antibacterial and anti-inflammatory activities and are very useful compounds capable of producing the effect of an antibacterial drug and anti-inflammatory drug in monotherapy. 
         [0021]    In another aspect, the present invention relates to a compound which is an active drug, which degrades in vivo into active antibacterial(s) and anti-inflammatory drug(s). 
         [0022]    The hybrid drugs of the invention provide a unique delivery of an antibiotic and a steroid for the treatment of ophthalmic bacterial infections and inflammation. A single drug entity is advantageous for individual dosing of each drug because of the ability for simultaneous dosing and elimination of washout concerns when applying each drug separately. 
         [0023]    The use of an antibiotic/anti-inflammatory hybrid drug is indicated where the risk of infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye. 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 combination of an antibiotic and anti-inflammatory is also useful in post-operative inflammation where there is an increased chance of bacterial infection. 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, red eye, hyperemia, 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. 
         [0024]    The hybrid drugs disclosed herein comprise antibiotics moieties belonging to distinct classes: fluoroquinolones, cephalosporins, chloramphenicol, aminoglycosides, penicillins, erythromycin, macrolide antibiotics and oxazolidionones. 
         [0025]    Fluoroquinolones include, but are not limited to: levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin, trovafloxacin, ofloxacin, ciprofloxacin, sparfloxacin, grepafloxacin, norfoxacin, enoxacin, lomefloxacin, fleroxacin, tosufloxacin, prulifloxacin, pazufloxacin, clinafloxacin, garenoxacin, and sitafloxacin. 
         [0026]    Cephalosporins include, but are not limited to: loracarbef, cephalexin, cefuroxime, ceftriaxone, ceftaxime, ceftizoxime, ceftibuten, ceftazidime, cefprozil, cefpodoxime, cefoxitin, cefotetan, cefotaxime, cefoperazone, cefixime, cefepime, cefditoren, cefdinir, cefoperaxone, moxalactam, cefazolin, cefamandole, cefadroxil, cefaclor, cephalothin, cephradine, cephacetrile, and cephalothin. 
         [0027]    Aminoglycosides include, but are not limited to: tobramycin, streptomycin, gentamicin, kanamycin, amikacin and netilmicin. 
         [0028]    Penicillins include, but are not limited to: penicillin G, ticarcillin, methicillin, phenthicillin, cloxacillin, dicloxacillin, nafcillin, oxacillin. 
         [0029]    Macrolide antibiotics include, but are not limited to: erythromycin and azithromycin. 
         [0030]    Oxazolidinones include, but are not limited to: linezolid. 
         [0031]    Further, the compounds disclosed herein comprise a steroidal drug selected from: dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone. 
         [0032]    In another embodiment the compounds disclosed herein comprise at least one antibiotic drug selected from levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin, trovafloxacin, ofloxacin, ciprofloxacin, sparfloxacin, grepafloxacin, norfoxacin, enoxacin, lomefloxacin, fleroxacin, tosufloxacin, prulifloxacin, pazufloxacin, clinafloxacin, garenoxacin, sitafloxacin, loracarbef, cephalexin, cefuroxime, ceftriaxone, ceftaxime, ceftizoxime, ceftibuten, ceftazidime, cefprozil, cefpodoxime, cefoxitin, cefotetan, cefotaxime, cefoperazone, cefixime, cefepime, cefditoren, cefdinir, cefoperaxone, moxalactam, cefazolin, cefamandole, cefadroxil, cefaclor, cephalothin, cephradine, cephacetrile, cephalothin, chloramphenicol, tobramycin, streptomycin, gentamicin, kanamycin, amikacin, netilmicin, penicillin g, ticarcillin, methicillin, phenthicillin, cloxacillin, dicloxacillin, nafcillin and oxacillin. 
         [0033]    In another embodiment the compounds disclosed herein comprise at least one steroidal drug selected from: dexmethasone, betamethasone, triamcinolone acetonide, prednisolone and hydrocortisone. 
         [0034]    Depending on the linking site, the hybrid compounds of the invention can be represented by Schemes 1, wherein the antibiotic moieties can be the same or different: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0035]    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. 
         [0036]    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 linker moieties are exemplified below and linker structures are exemplified in Table 1. 
         [0037]    Examples of ester moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0038]    Examples of carboxylate moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0039]    Example of a carbonyl moiety comprised in the linkers is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0040]    Example of a carbonate moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0041]    Examples of amido moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0042]    Example of carbamate moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0043]    Example of a ketone moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0044]    Examples of amino moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0045]    Example of an oxo moiety comprised in the linker is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0046]    Example of ethylene glycol moieties comprised in the linkers are: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0047]    Example of polyethylene glycol moiety comprised in the linkers is: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0048]    Further the compounds disclosed herein comprise a linker selected from Table 1: 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                   
                 Linker Number 
               
             
          
           
               
                 Linker Structure 
                   
                 n = 0 
                 n = 1 
                 n = 2 
                 n = 3 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L2 
                 L1 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L3 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L4 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L35 
                   
                 L5 
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L6 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L7 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 L14 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L15 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 L16 
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                 L46 
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 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 
                   
                   
                   
                   
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   
                   
                 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 
               
               
                   
               
             
          
         
       
     
         [0049]    Further the compounds disclosed herein comprise at least one pro-drug moiety selected from Table 2: 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Prodrug Structure 
                 Prodrug Number 
               
               
                   
               
             
             
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P1 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P2 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P3 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P4 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P5 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P6 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P7 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P8 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P9 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P10 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P11 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P12 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P13 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P14 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 P15 
               
               
                   
               
             
          
         
       
     
         [0050]    Compounds of the invention are shown in Table 3. 
         [0000]    
       
         
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Compound 
                   
               
               
                 number 
                 IUPAC NAME 
               
               
                   
               
             
             
               
                 10 
                 2-[(8R,9R,10S,11R,13R,14R,17S)-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-1- 
               
               
                   
                 cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7- 
               
               
                   
                 (octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4- 
               
               
                   
                 dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl} 
               
               
                   
                 octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy- 
               
               
                   
                 4-oxo-1,4-dihydroquinoline-3-carboxylate 
               
               
                 11 
                 2-[(8R,9R,10S,11R,13R,14R,17S)-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-1- 
               
               
                   
                 cyclopropyl-7-(4-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7- 
               
               
                   
                 (octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4- 
               
               
                   
                 dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-3- 
               
               
                   
                 methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4- 
               
               
                   
                 dihydroquinoline-3-carboxylate 
               
               
                 12 
                 [({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)- 
               
               
                   
                 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-oxoethoxy}carbonyl)-6- 
               
               
                   
                 fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2- 
               
               
                   
                 methylpiperazin-1-yl}carbonyl)oxy]methyl rel-7-[(3S)-3- 
               
               
                   
                 aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo- 
               
               
                   
                 1,4-dihydroquinoline-3-carboxylate 
               
               
                 13 
                 2-[(8R,9R,10S,11R,13R,14R,17S)-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-1- 
               
               
                   
                 cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3- 
               
               
                   
                 methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] 
               
               
                   
                 piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl] 
               
               
                   
                 oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro- 
               
               
                   
                 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 
               
               
                 14 
                 2-[(8R,9R,10S,11R,13R,14R,17S)-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-1- 
               
               
                   
                 cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy- 
               
               
                   
                 7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro- 
               
               
                   
                 6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3- 
               
               
                   
                 yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6- 
               
               
                   
                 fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 
               
               
                 15 
                 rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-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}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7- 
               
               
                   
                 yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl] 
               
               
                   
                 methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4- 
               
               
                   
                 dihydroquinoline-3-carboxylic acid 
               
               
                 16 
                 rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({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)-8-methoxy-4-oxo-1,4-dihydroquinolin- 
               
               
                   
                 7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl] 
               
               
                   
                 methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy- 
               
               
                   
                 4-oxo-1,4-dihydroquinoline-3-carboxylic acid 
               
               
                 17 
                 rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({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}carbonyl)-6- 
               
               
                   
                 fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2- 
               
               
                   
                 methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxo1-4-yl] 
               
               
                   
                 methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo- 
               
               
                   
                 1,4-dihydroquinoline-3-carboxylic acid 
               
               
                 18 
                 rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(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-oxoethoxy}-4- 
               
               
                   
                 oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]- 
               
               
                   
                 6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3- 
               
               
                   
                 yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]- 
               
               
                   
                 6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3- 
               
               
                   
                 carboxylic acid 
               
               
                 19 
                 rel-1-cyclopropyl-7[1-({[({1-cyclopropyl-7[4-({[(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-oxoethoxy}-4- 
               
               
                   
                 oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]- 
               
               
                   
                 6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3- 
               
               
                   
                 yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4- 
               
               
                   
                 b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4- 
               
               
                   
                 dihydroquinoline-3-carboxylic acid 
               
               
                 20 
                 rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(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-oxoethoxy}-4- 
               
               
                   
                 oxobutanoyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4- 
               
               
                   
                 b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin- 
               
               
                   
                 3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methylpiperazin- 
               
               
                   
                 1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline- 
               
               
                   
                 3-carboxylic acid 
               
               
                 21 
                 ({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7- 
               
               
                   
                 (2-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl] 
               
               
                   
                 carbonyl}oxy)methoxy]carbonyl}-6-fluoro-8-methoxy-4-oxo- 
               
               
                   
                 1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl}carbonyl} 
               
               
                   
                 oxy)methyl 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 
               
               
                 22 
                 ({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy- 
               
               
                   
                 7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3- 
               
               
                   
                 yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4- 
               
               
                   
                 b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin- 
               
               
                   
                 3-yl]carbony}oxy)methyl 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 
               
               
                 23 
                 ({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7- 
               
               
                   
                 (octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4- 
               
               
                   
                 dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl} 
               
               
                   
                 octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy- 
               
               
                   
                 4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl 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 
               
               
                 24 
                 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 2- 
               
               
                   
                 [(9S,10R,11R,13R,16S,17S)-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  
               
               
                   
                 re1-7,7′-{(2-oxo-1,3-dioxole-4,5-diyl)bis[methanediyl(3- 
               
               
                   
                 methylpiperazine-4,1-diyl)]}bis(1-cyclopropyl-6-fluoro-8- 
               
               
                   
                 methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate) 
               
               
                 25 
                 2-[(8R,9S,10R,11R,13R,14R,16R,17S)-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-1-cyclopropyl- 
               
               
                   
                 6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4-yl)propanoyl] 
               
               
                   
                 oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-8-methoxy- 
               
               
                   
                 4-oxo-1,4-dihydroquinoline-3-carboxylate 
               
               
                 26 
                 2-[(8R,10S,11R,13R,14R,17S)-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-1- 
               
               
                   
                 cyclopropyl-6-fluoro-7-{4-[({[2-(2-fluorobiphenyl-4- 
               
               
                   
                 yl)propanoyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}- 
               
               
                   
                 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate 
               
               
                 27 
                 1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3- 
               
               
                   
                 methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl] 
               
               
                   
                 carbonyl}oxy)propan-2-yl 2-[(8R,9S,10R,11R,13R,14R,16S, 
               
               
                   
                 17S)-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-benzene-1,4-dicarboxylate 
               
               
                 28 
                 1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3- 
               
               
                   
                 methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl] 
               
               
                   
                 carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)- 
               
               
                   
                 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 
               
               
                 29 
                 1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3- 
               
               
                   
                 methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl] 
               
               
                   
                 carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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 
               
               
                 30 
                 1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5- 
               
               
                   
                 methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo- 
               
               
                   
                 1,4-dihydroquinolin-3-yl)carbonyl]oxy}propan-2-yl 2- 
               
               
                   
                 [(8R,10S,11R,13R,14R,17S)-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 
               
               
                 31 
                 1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3- 
               
               
                   
                 methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl] 
               
               
                   
                 carbonyl}oxy)methoxy]carbonyl}oxy)propan-2-yl 2- 
               
               
                   
                 [(8R,10S,11R,13R,14R,17S)-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 
               
               
                 32 
                 1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4- 
               
               
                   
                 [(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo- 
               
               
                   
                 1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy} 
               
               
                   
                 propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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 
               
               
                 33 
                 1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl- 
               
               
                   
                 2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b] 
               
               
                   
                 pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl] 
               
               
                   
                 oxy}methoxy)carbonyl]oxy}propan-2-yl 2- 
               
               
                   
                 [(8R,10S,11R,13R,14R,17S)-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 
               
               
                 34 
                 2-({2-[(8R,10S,11R,13R,14R,17S)-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}carbonyl) 
               
               
                   
                 propane-1,3-diyl relbis(1-cyclopropyl-6-fluoro-8-methoxy- 
               
               
                   
                 7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl] 
               
               
                   
                 piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate) 
               
               
                   
               
             
          
         
       
     
         [0051]    In another embodiment the compounds disclosed herein comprise one steroid moiety and two antibiotic moieties. 
         [0052]    In another embodiment the compounds disclosed herein comprise one steroid moiety and two antibiotic moieties and at least one linker selected from Table 1. 
         [0053]    In another embodiment the compounds disclosed herein comprise one steroid moiety and two antibiotic moieties and at least one linker selected from Table 1 and one pro-drug moiety selected from Table 2. 
         [0054]    In another embodiment the compounds disclosed herein comprise one steroid moiety and two antibiotic moieties and two linkers selected from Table 1 and two pro-drug moieties selected from Table 2. 
         [0055]    In another embodiment the compounds disclosed herein comprise steroid moiety and two antibiotic moieties and least two linkers selected from Table 1 and one pro-drug moiety selected from Table 2. 
         [0056]    In another embodiment the compounds disclosed herein comprise steroid moiety and two antibiotic moieties and one linker selected from Table 1 and two pro-drug moieties selected from Table 2. 
         [0057]    In another embodiment the compounds disclosed herein comprise one prednisolone moiety and two moxifloxacin moieties, such as:
   2-[(8R,9R,10S,11R,13R,14R,17S)-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-1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;   ({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl 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.   
 
         [0060]    In another embodiment the compounds disclosed herein comprise one prednisolone moiety and one moxifloxacin moiety and one gatifloxacin moiety such as:
   2-[(8R,9R,10S,11R,13R,14R,17S)-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-1-cyclopropyl-7-(4-{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;   2-[(8R,9R,10S,11R,13R,14R,17S)-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-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;   rel-1-cyclopropyl-7-[1-({[({1-cyclopropyl-7-[4-({[(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-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;   rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[1-({[(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-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-2-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;   ({[1-cyclopropyl-7-(1-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methyl 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.   
 
         [0066]    In another embodiment the compounds disclosed herein comprise one prednisolone moiety and two gatifloxacin moieties such as:
   ({[4-(1-cyclopropyl-3-{[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl]carbonyl}oxy)methyl 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;   rel-1-cyclopropyl-7-[4-({[({1-cyclopropyl-7-[4-({[(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-oxoethoxy}-4-oxobutanoyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)oxy]methoxy}carbonyl)-3-methylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;   rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-3-({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}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;   2-[(8R,9R,10S,11R,13R,14R,17S)-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-1-cyclopropyl-7-{4-[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]-3-methylpiperazin-1-yl}-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate;   1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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;   1,3-bis{[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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.   
 
         [0073]    In another embodiment the compounds disclosed herein comprise one hydrocortisone moiety and one besifloxacin moiety and one gatifloxacin moiety such as:
   [({4-[1-cyclopropyl-3-({2-[(8R,9R,10S,11R,13R,14R,17S)-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-oxoethoxy}carbonyl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}carbonyl)oxy]methyl rel-7-[(3S)-3-aminoazepan-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate.   
 
         [0075]    In another embodiment the compounds disclosed herein comprise one dexamethasone and two gatifloxacin moieties such as:
   rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-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}carbonyl)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;   1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl 2-[(8R,9S,10R,11R,13R,14R,16S,17S)-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-benzene-1,4-dicarboxylate.   
 
         [0078]    In another embodiment the compounds disclosed herein comprise one bethasone and two gatifloxacin moieties such as:
   rel-1-cyclopropyl-7-(4-{[5-({4-[1-cyclopropyl-6-fluoro-3-({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)-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl]-2-methylpiperazin-1-yl}methyl)-2-oxo-1,3-dioxol-4-yl]methyl}-3-methylpiperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.   
 
         [0080]    In another embodiment the compounds disclosed herein comprise one hydrocortisone and two gatifloxacin moieties such as:
   1,3-bis({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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;   1,3-bis({[({[1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}oxy)methoxy]carbonyl}oxy)propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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;   1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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.   
 
         [0084]    In another embodiment the compounds disclosed herein comprise one hydrocortisone and two moxifloxacin moieties such as:
   1,3-bis{[({[(1-cyclopropyl-6-fluoro-8-methoxy-7-{1-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]oxy}methoxy)carbonyl]oxy}propan-2-yl 2-[(8R,10S,11R,13R,14R,17S)-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;   2-({2-[(8R,10S,11R,13R,14R,17S)-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}carbonyl)propane-1,3-diyl relbis(1-cyclopropyl-6-fluoro-8-methoxy-7-{3-methyl-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylate).   
 
         [0087]    In another embodiment the invention provides a hybrid compound comprising two antibiotic moieties and a steroid drug moiety, or a pharmaceutical salt thereof, which are connected via three separate covalent bonds to a linker such that said covalent bonds degrade in vivo to yield independently the antibiotics and steroid drugs. 
         [0088]    In another embodiment the invention provides a hybrid compound comprising two different antibiotic moieties and a steroid drug moiety, or a pharmaceutical salt thereof, which are connected via three separate covalent bonds to a linker such that said covalent bonds degrade in vivo to yield independently the antibiotics and steroid drugs. 
         [0089]    In another embodiment the invention provides a hybrid compound comprising two identical antibiotic moieties and a steroid drug moiety, or a pharmaceutical salt thereof, which are connected via three separate covalent bonds to a linker such that said covalent bonds degrade in vivo to yield independently the antibiotics and steroid drugs. 
         [0090]    In another embodiment the invention provides a hybrid compound comprising two different antibiotic moieties and a steroid drug moiety, or a pharmaceutical salt thereof, wherein the steroid is directly linked to one antibiotic which is connected via a linker to the other antibiotic and wherein the bonds degrade in vivo to yield independently the antibiotics and steroid drugs. 
         [0091]    In another embodiment the invention provides a hybrid compound comprising two identical antibiotic moieties and a steroid drug moiety, or a pharmaceutical salt thereof, which are connected via four separate covalent bonds to two different linkers such that said covalent bonds degrade in vivo to yield independently the antibiotics and steroid drugs. 
         [0092]    In another embodiment the invention provides a hybrid compound comprising two identical antibiotic moieties and a steroid drug moiety, or a pharmaceutical salt thereof, which are connected via four separate covalent bonds to two identical linkers such that said covalent bonds degrade in vivo to yield independently the antibiotics and steroid drugs. 
         [0093]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two antibiotic moieties and a steroid moiety, which are connected via three separate covalent bonds to a linker such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0094]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two antibiotic moieties and a steroid moiety, which are connected via four separate covalent bonds to two linkers such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0095]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two identical antibiotic moieties and a steroid moiety, which are connected via three separate covalent bonds to a linker such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0096]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two different antibiotic moieties and a steroid moiety, which are connected via three separate covalent bonds to a linker such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0097]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two antibiotic moieties and a steroid moiety, which are connected via four separate covalent bonds to two linkers such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0098]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two identical antibiotic moieties and a steroid moiety, which are connected via four separate covalent bonds to two linkers such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0099]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two different antibiotic moieties and a steroid moiety, which are connected via four separate covalent bonds to two linkers such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0100]    In another embodiment the invention provides a pharmaceutical composition comprising a hybrid compound comprising two different antibiotic moieties and a steroid moiety, which are connected via three separate covalent bonds to one linker such that said covalent bonds degrade in vivo to yield the antibiotics and the steroid drugs, wherein each bond is an ester bond or an amide depending on the nature of the linker, wherein said pharmaceutical composition is formulated for topical ophthalmic administration. 
         [0101]    In another embodiment the invention provides a hybrid compound comprising two linkers having four bonds, wherein said bonds are asymmetrically degraded in vivo to release the three active drugs. 
         [0102]    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. 
         [0103]    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. 
         [0104]    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). 
         [0105]    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-Zürich, 2002, 329-345). 
         [0106]    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. 
         [0107]    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. 
         [0108]    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, endophthalmitis, red eye, hyperemia, 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. 
         [0109]    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. 
         [0110]    The patient will 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. 
         [0111]    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. 
         [0112]    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. 
         [0113]    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. 
         [0114]    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. 
         [0115]    The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required. 
         [0116]    The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug. 
         [0117]    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. 
         [0118]    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. 
         [0119]    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. 
         [0120]    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. 
         [0121]    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. 
         [0122]    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. 
         [0123]    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. 
         [0124]    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. 
         [0125]    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. 
         [0000]    The ingredients are usually used in the following amounts: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Ingredient 
                 Amount (% w/v) 
               
               
                   
                   
               
             
             
               
                   
                 active ingredient 
                 about 0.001 to about 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% 
               
               
                   
                   
               
             
          
         
       
     
         [0126]    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. 
         [0127]    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. 
         [0128]    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. 
         [0129]    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, endophthalmitis, red eye, hyperemia, 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. 
         [0130]    Thus, in further embodiments of the invention, there are provided methods for treating conjunctivitis, keratitis, blepharitis, dacyrocystitis, endophthalmitis, red eye, hyperemia, 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. 
         [0131]    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. 
         [0132]    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. 
         [0133]    The present invention concerns also processes for preparing the compounds of the invention. The 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. Schemes A, B, C, D and E set forth below, illustrate how the compounds according to the invention can be made. 
         [0134]    It should be noted that the brief description on each of the arrows for each conversion has been added for illustration purpose sonly and should not be regarded as limiting with respect to the sequence of each individual step. 
         [0135]    The following abbreviations are used in the examples:
   CH 2 Cl 2  dichloromethane   EtOH ethanol   Na 2 SO 4  sodium sulfate   DMF N,N dimethylformamide   EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide   THF tetrahydrofuran   BOO tert-butyl carbamate   BOC 2 O di-tert-butyl pyrocarbonate   NaOH sodium hydroxide   HCl hydrochlorique acid   DMAP 4-Dimethylaminopyridine   NaHCO 3  sodium bicarbonate   CHCl 3  chloroform   Na 2 CO 3  sodium carbonate   (n-Bu) 4 NHSO 4  tetrabutylammonium hydrogen sulfate   
 
         [0151]    In Scheme A BOO protected gatifloxacin reacted with prednisolone to form a directly coupled steroid antibiotic hybrid compound, which was couple to a linker further coupled with a molecule of moxifloxacin. Scheme A is representative of a Scheme 1C hybrid compound. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0152]    In Scheme B BOO a gatifloxacin molecule was coupled with linker and further coupled with a prednisolone molecule, which was further coupled with a molecule of moxifloxacin via a linker. Scheme B is representative of a Scheme 1D hybrid compound. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0153]    Scheme C shows the formation of a hybrid compound according to Scheme 1 G. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0154]    Scheme D shows the formation of a hybrid compound according to Scheme 1G with a pro-drug moiety. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0155]    Scheme E shows the formation of a hybrid compound according to Scheme 1 E. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0156]    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. 
         [0157]    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 diastereisomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereisomers 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. 
         [0158]    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. 
         [0159]    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. 
         [0160]    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. 
         [0161]    Compound names were generated with ACDLabs version 12.5 or ChemBioDraw Ultra version 12.0.2. 
         [0162]    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. 
         [0163]    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 pro-drug 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 and pro-drug moiety numbers are as described in Table 1 and 2 respectively. 
         [0164]    It is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described. 
       Examples of Compounds 
       [0165]    Prednisolone reacted with two molecules of Moxifloxacin to form the following hybrid compounds as shown in Scheme 1 with the results described in Table 4; and as shown in Scheme 2 with the results described in Table 5. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2c * 
                 Mass 
               
               
                   
               
             
             
               
                 10 L46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.12 (dd) 
                 1201 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker1 
                   
                   
                   
               
               
                 Linker2 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 23 L 1 47 L 2 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.88 (in DMSO) 
                   
               
               
                   
               
             
          
         
       
     
         [0166]    Prednisolone reacted with one molecule of Gatifloxacin and one molecule of Moxifloxacin to form the following hybrid compounds as shown in Scheme 3 with the results described in Table 6; and as shown in Scheme 4 with the results described in Table 7; and as shown in Scheme 5 with the results described in Table 8; and as shown in Scheme 6 with the results described in Table 9; and as shown in Scheme 7 with the results described in Table 10. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker1 
                   
                   
                   
               
               
                 Linker2 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 19 L 1 52 L 2 46  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.98 (dd) 
                 1371 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 1 
                   
                   
                   
               
               
                 Linker2 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 20 L 1 52 L 2 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.00 
                 1371 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 1 
                   
                   
                   
               
               
                 Linker2 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 22 L 1 52 L 2 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.88 (in DMSO) 
                   
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 11 L46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.16 (dd) 
                 1176 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 10 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                   
                   
                   
               
               
                 Prodrug 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 14 L46 P3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.07 
                 1309 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0167]    Prednisolone reacted with two molecules Gatifloxacin to form the following hybrid compounds as shown in Scheme 8 with the results described in Table 11 and as shown in Scheme 9 with the results described in Table 12 and as shown in Scheme 10 with the results described in Table 13 and as shown in Scheme 11 with the results described in Table 14 and as shown in Scheme 12 with the results described in Table 15 and as shown in Scheme 13 with the results described in Table 16. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 11 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 1 
                   
                   
                   
               
               
                 Linker2 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 21 L 1 56 L 2 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.98 (dd) 
                 1301 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 1 
                   
                   
                   
               
               
                 Linker2 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 18 L 1 52 L 2 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.01 (dd) 
                 134 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 13 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 17 L12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.10 (dd) 
                 1225 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 14 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                   
                   
                   
               
               
                 Prodrug 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 13 L46 P3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.08 
                 1283 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 15 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 28 L50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.02-  4.73     (m) 
                 1249 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 16 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                   
                   
                   
               
               
                 Prodrug 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 30 L50 P3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.26-4.81 (m)  
                 1495 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0168]    Hydrocortisone reacted with Gatifloxacin and with Besifloxacin to form the following hybrid compounds as shown in Scheme 14 with the results described in Table 17. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 17 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 12 L46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.13 (dd) 
                 1167 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0169]    Dexmethasone reacted with two molecules of Gatifloxacin to form the following hybrid compounds as shown in Scheme 15 with the results described in Table 18 and as shown in Scheme 16 with the results described in Table 19. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 18 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 15 L12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.07 (dd) 
                 1257 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 19 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c * 
                 Mass 
               
               
                   
               
             
             
               
                 27 L51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.22 (dd) 
                 1329 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0170]    Betamethasone reacted with two molecules of Gatifloxacin to form the following hybrid compounds as shown in Scheme 17 with the results described in Table 20. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 20 
               
               
                   
               
             
             
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c*   
                 Mass 
               
               
                   
               
               
                 16 L12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.00 (dd) 
                 1257 (MNa + ) 
               
               
                   
               
             
          
         
       
     
         [0171]    Hydrocortisone reacted with two molecules of Gatifloxacin to form the following hybrid compounds as shown in Scheme 18 with the results described in Table 21 and as shown in Scheme 19 with the results described in Table 22. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 21 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                 Structure 
                 CH 2   c*   
                 Mass 
               
               
                   
               
             
             
               
                 31 L48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.03 (dd) 
                 1398 (MH + ) 
               
               
                   
               
               
                 29 L50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.06- 4.77 (m) 
                 1273 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 22 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                   
                   
                   
               
               
                 Prodrug 
                 Structure 
                 CH 2   c*   
                 Mass 
               
               
                   
               
             
             
               
                 32 L48 P3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.01 (dd) 
                 1642.8 (MH + ) 
               
               
                   
               
             
          
         
       
     
         [0172]    Hydrocortisone reacted with two molecules of Moxifloxacin to form the following hybrid compounds as shown in Scheme 20 with the results described in Table 23. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE 23 
               
               
                   
               
               
                 * 
                   
                   
                   
               
               
                 Comp. 
                   
                   
                   
               
               
                 No. 
                   
                   
                   
               
               
                 Linker 
                   
                   
                   
               
               
                 Prodrug 
                 Structure 
                 CH 2   c*   
                 Mass 
               
               
                   
               
             
             
               
                 34 L49 P3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 5.10 (dd) 
                 1401 (MH + ) 
               
               
                   
               
               
                 33 L48 P3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.98 (dd) 
                 1695 (MH + ) 
               
               
                   
               
             
          
         
       
     
       In vitro Metabolic Stability in Human Recombinant Carboxylesterases 
       [0173]    Human recombinant carboxylesterases were purchased from a commercial vendor (BD Gentest™, Bedford, Massachusettes). All metabolic stability experiments were performed in triplicate in 96-well plate format. The final incubation mixture contained 1 μM test compound, 0.3 mg/mL corneal protein homogenate or 0.1 mg/mL human recombinant carboxylesterase mixture in a final volume of 0.5 mL 0.1 M 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. 
         [0174]    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. 
         [0175]    Results 
         [0176]    Table 24 lists the rate of metabolite formation in human recombinant carboxylesterases. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 24 
               
               
                   
               
               
                   
                 Rate of  
                 Rate of  
                 Rate of 
               
               
                   
                 formation 
                 formation 
                 formation 
               
               
                 *Comp. 
                 Metabolite 1  
                 Metabolite 2 
                 Metabolite 3 
               
               
                 No. 
                 (nM/min/mg) 
                 (nM/min/mg) 
                 (nM/min/mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 28 
                 13.9 ± 1.1 
                 55.9 ± 4.4 
                 N/A 
               
               
                   
                 Gatifloxacin 
                 Prednisolone 
                   
               
               
                 10 
                 13.8 ± 1.5 
                 14.6 ± 1.1 
                 N/A 
               
               
                   
                 Moxifloxacin 
                 Prednisolone 
                   
               
               
                 11 
                  256 ± 29 
                 35.4 ± 5.0 
                 69.7 ± 14.2 
               
               
                   
                 Prednisolone 
                 Gatifloxacin 
                 Moxifloxacin 
               
               
                 12 
                  155 ± 31 
                 54.9 ± 8.1 
                 91.0 ± 22.2 
               
               
                   
                 Prednisolone 
                 Gatifloxacin 
                 Besifloxacin 
               
               
                 30 
                 41.8 ± 10.2 
                 6.16 ± 1.36 
                 N/A 
               
               
                   
                 Prednisolone 
                 Gatifloxacin 
                   
               
               
                 18 
                 81.2 ± 9.0 
                  107 ± 9 
                 N/A 
               
               
                   
                 Prednisolone 
                 Gatifloxacin 
                   
               
               
                   
               
               
                 N/A = Not applicable 
               
             
          
         
       
     
         [0177]    The data demonstrate that linkage of a fluoroquinolone (e.g. gatifloxacin, moxifloxacin, and besifloxacin) and a steroid (e.g. prednisolone) as a single hybrid compound was hydrolyzed enzymatically in human recombinant carboxylesterases to their respective individual antibiotic and steroid drugs.