Pth prodrugs

Abstract

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

1 . A PTH prodrug or a pharmaceutically acceptable salt thereof comprising a conjugate D-L, wherein
 -D is a 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 PTH prodrug or the pharmaceutically acceptable salt thereof 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 PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -D has the sequence of SEQ ID NO:51. 
     
     
         4 . The PTH prodrug or the pharmaceutically acceptable salt thereof 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 PTH prodrug or the pharmaceutically acceptable salt thereof 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 PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -L 1 - is conjugated to a functional group of the side chain of a lysine of -D. 
     
     
         7 . The PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -L 1 - is conjugated to a functional group of the side chain of a serine of -D. 
     
     
         8 . The PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -L 1 - is conjugated to the N-terminal amine functional group of -D. 
     
     
         9 . The PTH prodrug or the pharmaceutical acceptable salt thereof 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 PTH prodrug or the pharmaceutical acceptable salt thereof of  claim 1 , wherein -L 1 - is a reversible prodrug linker from which the PTH is released in its free form. 
     
     
         11 . The PTH prodrug or the pharmaceutical acceptable salt thereof 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 alkenylalkyl, 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 PTH prodrug or the pharmaceutical acceptable salt thereof of  claim 1 , wherein -L 2 - is a chemical bond. 
     
     
         13 . The PTH prodrug or the pharmaceutical acceptable salt thereof of  claim 1 , wherein -L 2 - is a spacer moiety. 
     
     
         14 . The PTH prodrug or the pharmaceutically acceptable salt thereof 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 PTH prodrug or the pharmaceutically acceptable salt thereof 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 PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -L 2 - has a molecular weight in the range of from 14 g/mol to 750 g/mol. 
     
     
         17 . The PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -L 2 - has a chain length of 1 to 20 atoms. 
     
     
         18 . The PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 , wherein -Z′ is a hydrogel. 
     
     
         19 . The PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 18 , 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 PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 18 , wherein the hydrogel comprises PEG or hyaluronic acid. 
     
     
         21 . The PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 18 , wherein the hydrogel comprises PEG. 
     
     
         22 . A pharmaceutical composition comprising at least one PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1  and at least one excipient. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the pharmaceutical composition has a pH ranging from and including pH 4 to pH 6. 
     
     
         24 . A method of treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more diseases which can be treated with PTH, comprising the step of administering to said patient in need thereof a therapeutically effective amount of the PTH prodrug or the pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
         25 . The method of  claim 24 , wherein the disease is selected from the list consisting of hypoparathyroidism, hyperphosphatemia, osteoporosis, fracture repair, osteomalacia, osteomalacia and osteoporosis in patients with hypophosphatasia, steroid-induced osteoporosis, male osteoporosis, arthritis, osteoarthritis, osteogenesis imperfect, fibrous dysplasia, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy, osteopenia, periodontal disease, bone fracture, alopecia, chemotherapy-induced alopecia, and thrombocytopenia. 
     
     
         26 . The method of  claim 24 , wherein the disease is hypoparathyroidism. 
     
     
         27 . The method of  claim 24 , wherein the mammalian patient is a human patient. 
     
     
         28 . The method of  claim 24 , wherein the time period between two consecutive administrations is one week. 
     
     
         29 . The method of  claim 24 , wherein the prodrug or the pharmaceutically acceptable salt thereof is administered via injection. 
     
     
         30 . The method of  claim 24 , wherein the prodrug or the pharmaceutically acceptable salt thereof is administered via subcutaneous injection. 
     
     
         31 . The method of  claim 24 , wherein the subcutaneous injection is with a pen injector.