Pth prodrugs

Abstract

The present invention relates to PTH prodrugs, pharmaceutical compositions comprising such PTH prodrugs and their uses.

1 . A method of treating hypoparathyroidism comprising administering to a subject in need thereof a pharmaceutically effective amount of a conjugate comprising a moiety D-L, wherein
 -D is the PTH moiety; and   -L comprises a reversible prodrug linker moiety -L 1 -, which moiety -L 1 - is connected to the PTH moiety -D through a functional group of PTH;
 wherein -L 1 - is substituted with -L 2 -Z′ and is optionally further substituted; 
 wherein 
 -L 2 - is a single chemical bond or a spacer moiety; and 
 —Z′ is a water-insoluble carrier moiety to which a multitude of moieties -L 2 -L 1 -D is connected. 
   
     
     
         2 . The method of  claim 1 , wherein -D has the sequence of SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:114 or SEQ ID NO:115. 
     
     
         3 . The method of  claim 1 , wherein -D has the sequence of SEQ ID NO:51. 
     
     
         4 . The method of  claim 1 , wherein the moiety -L 1 - is either conjugated to a functional group of the side chain of an amino acid residue of -D, to the N-terminal amine functional group or to the C-terminal carboxyl functional group of -D or to a nitrogen atom in the backbone polypeptide chain of -D. 
     
     
         5 . The method of  claim 1 , wherein -L 1 - is conjugated to a functional group of the side chain of a proteinogenic amino acid residue of -D selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine. 
     
     
         6 . The method of  claim 1 , wherein -L 1 - is conjugated to a functional group of the side chain of a lysine of -D. 
     
     
         7 . The method of  claim 1 , wherein -L 1 - is conjugated to a functional group of the side chain of a serine of -D. 
     
     
         8 . The method of  claim 1 , wherein -L 1 - is conjugated to the N-terminal amine functional group of -D. 
     
     
         9 . The method of  claim 1 , wherein -L 1 - is connected to -D through a linkage selected from the group consisting of amide, ester, carbamate, acetal, aminal, imine, oxime, hydrazone, disulfide and acylguanidine. 
     
     
         10 . The method of  claim 1 , wherein -L 1 - is a reversible prodrug linker from which the PTH is released in its free form. 
     
     
         11 . The method of  claim 1 , wherein wherein -L 1 - is of formula (IV): 
       
         
           
           
               
               
           
         
         wherein 
         the dashed line indicates attachment to -D and wherein attachment is through a functional group of -D selected from the group consisting of —OH, —SH and —NH 2 ; 
         m is 0 or 1; 
         at least one or both of —R 1  and —R 2  is/are independently of each other selected from the group consisting of —CN, —NO 2 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, —C(O)R 3 , —S(O)R 3 , —S(O) 2 R 3 , and —SR 4 , 
         one and only one of —R 1  and —R 2  is selected from the group consisting of —H, optionally substituted alkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; 
         —R 3  is selected from the group consisting of —H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —OR 9  and —N(R 9 ) 2 ; 
         —R 4  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; 
         each —R 5  is independently selected from the group consisting of —H, optionally substituted alkyl, optionally substituted alkynylalkyl, optionally substituted alkynylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         —R 9  is selected from the group consisting of —H and optionally substituted alkyl; 
         —Y— is absent and —X— is —O— or —S—; or 
         —Y— is —N(Q)CH 2 — and —X— is —O—; 
         Q is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         optionally, —R 1  and —R 2  may be joined to form a 3 to 8-membered ring; and 
         optionally, both —R 9  together with the nitrogen to which they are attached form a heterocyclic ring; 
         wherein -L 1 - is substituted with -L 2 -Z′ and wherein -L 1 - is optionally further substituted. 
       
     
     
         12 . The method of  claim 1 , wherein -L 2 - is a chemical bond. 
     
     
         13 . The method of  claim 1 , wherein -L 2 - is a spacer moiety. 
     
     
         14 . The method of  claim 1 , wherein -L 2 - selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—, —N(R y1 )S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 ), C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl; wherein -T-, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally substituted with one or more —R y2 , which are the same or different and wherein C 1-50  alkyl, C 2-50  alkenyl; and C 2-50  alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y3 )—, —S(O) 2 N(R y3 )—, —S(O)N(R y3 )—, —S(O) 2 —, —S(O)—, —N(R y3 )S(O) 2 N(R y3A )—, —S—, —N(R y3 )—, —OC(OR y3 )(R y3a ), —N(R y3 )C(O)N(R y3a )—, and —OC(O)N(R y3 )—;
 —R y1  and —R y1a  are independently of each other selected from the group consisting of —H, -T, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl; wherein -T, C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally substituted with one or more —R y2 , which are the same or different, and wherein C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y4 )—, —S(O) 2 N(R y4 )—, —S(O)N(R y4 )—, —S(O) 2 —, —S(O)—, —N(R y4 )S(O) 2 N(R y4a )—, —S—, —N(R y4 )—, —OC(OR y4 )(R y4a ), —N(R y4 )C(O)N(R y4a )—, and —OC(O)N(R y4 )—; 
 each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10  cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more —R y2 , which are the same or different; 
 each —R y2  is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR y5 , —OR y5 , —C(O)R y5 , —C(O)N(R y5 R y5a ), —S(O) 2 N(R y5 R y5a ), —S(O)N(R y5 R y5a ), —S(O) 2 R y5 , —S(O)R y5 , —N(R y5 )S(O) 2 N(R y5a R y5b ), —SR y5 , —N(R y5 R y5a ), —NO 2 , —OC(O)R y5 , —N(R y5 )C(O)R y5a , —N(R y5 )S(O) 2 R y5a , —N(R y5 )S(O)R y5a , —N(R y5 )C(O)OR y5a , —N(R y5 )C(O)N(R y5a R y5b ), —OC(O)N(R y5 R y5a ), and C 1-6  alkyl; wherein C 1-6  alkyl is optionally substituted with one or more halogen, which are the same or different; and 
 each —R y3 , —R y3a , —R y4 , —R y4a , —R y5 , —R y5a  and —R y5b  is independently selected from the group consisting of —H, and C 1-6  alkyl, wherein C 1-6  alkyl is optionally substituted with one or more halogen, which are the same or different. 
 
     
     
         15 . The method of  claim 1 , wherein -L 2 - is a C 1-20  alkyl chain, which is optionally interrupted by one or more groups independently selected from —O—, -T- and —C(O)N(R y1 )—; and which C 1-20  alkyl chain is optionally substituted with one or more groups independently selected from —OH, -T and —C(O)N(R y6 R y6a ); wherein —R y1 , —R y6 , —R y6a  are independently selected from the group consisting of H and C 1-4  alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10  cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl. 
     
     
         16 . The method of  claim 1 , wherein -L 2 - has a molecular weight in the range of from 14 g/mol to 750 g/mol. 
     
     
         17 . The method of  claim 1 , wherein -L 2 - has a chain length of 1 to 20 atoms. 
     
     
         18 . The method of  claim 1 , wherein —Z′ is a hydrogel. 
     
     
         19 . The method of  claim 1 , wherein the hydrogel comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof. 
     
     
         20 . The method of  claim 1 , wherein the hydrogel comprises PEG or hyaluronic acid. 
     
     
         21 . The method of  claim 1 , wherein the hydrogel comprises PEG. 
     
     
         22 . The method of  claim 1 , wherein the subject is a human patient. 
     
     
         23 . The method of  claim 1 , wherein the prodrug or the pharmaceutically acceptable salt thereof is administered via injection. 
     
     
         24 . The method of  claim 1 , wherein the prodrug or the pharmaceutically acceptable salt thereof is administered via subcutaneous injection. 
     
     
         25 . The method of  claim 1 , wherein the subcutaneous injection is with a pen injector.