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, wherein the prodrug is of formula (Ia) or (Ib)
   ZL 2 -L 1 -D) x   (Ia)
     DL 1 -L 2 -Z) y   (Ib),
   wherein   -D is a PTH moiety;   -L 1 - is a reversible prodrug linker moiety connected to the PTH moiety -D through a functional group of PTH;   -L 2 - is a single chemical bond or a spacer moiety;   —Z is a water-soluble carrier moiety;   x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; and   y is an integer selected from the group consisting of 1, 2, 3, 4 and 5.   
     
     
         2 . 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.   
     
     
         3 . The PTH prodrug or a pharmaceutically acceptable salt thereof of  claim 1  or  2 , 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. 
     
     
         4 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  to  3 , wherein -L 1 - is conjugated to the N-terminal amine functional group of -D. 
     
     
         5 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  to  4 , wherein -D has the sequence of SEQ ID NO:51. 
     
     
         6 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  to  5 , wherein the moiety -L 1 - is of formula (II): 
       
         
           
           
               
               
           
         
         wherein the dashed line indicates the attachment to a nitrogen, hydroxyl or thiol of -D which is a PTH moiety; 
         —X— is —C(R 4 R 4a )—; —N(R 4 )—; —O—; —C(R 4 R 4a )—C(R 5 R 5a )—; —C(R 5 R 5a )—C(R 4 R 4a )—; 
         —C(R 4 R 4a )—N(R 6 )—; —N(R 6 )—C(R 4 R 4a )—; —C(R 4 R 4a )—O—; —O—C(R 4 R 4a )—; or —C(R 7 R 7a )—; 
         X 1  is C; or S(O); 
         —X 2 — is —C(R 8 R 8a )—; or —C(R 8 R 8a )—C(R 9 R 9a )—; 
         ═X 3  is ═O; ═S; or ═N—CN; 
         —R 1 , —R 1a , —R 2 , —R 2a , —R 4 , —R 4a , —R 5 , —R 5a , —R 6 , —R 8 , —R 8a , —R 9 , —R 9a  are independently selected from the group consisting of —H; and C 1-6  alkyl; 
         —R 3 , —R 3a  are independently selected from the group consisting of —H; and C 1-6  alkyl, provided that in case one of —R 3 , —R 3a  or both are other than —H they are connected to N to which they are attached through an SP 3 -hybridized carbon atom; 
         —R 7  is —N(R 10 R 10a ); or —NR 10 —(C═O)—R 11 ; 
         —R 7a , —R 10 , —R 10a , —R 11  are independently of each other —H; or C 1-6  alkyl; 
         optionally, one or more of the pairs —R 1a /—R 4a , —R 1a /—R 5a , —R 1a /—R 7a , —R 4a /—R 5a , —R 8a /—R 9a  form a chemical bond; 
         optionally, one or more of the pairs —R 1 /—R 1a , —R 2 /—R 2a , —R 4 /—R 4a , —R 5 /—R 5a , —R/—R 8a , —R 9 /—R 9a  are joined together with the atom to which they are attached to form a C 3-10  cycloalkyl; or 3- to 10-membered heterocyclyl; 
         optionally, one or more of the pairs —R 1 /—R 4 , —R 1 /—R 5 , —R 1 /—R 6 , —R 1 /—R 7a , —R 4 /—R 5 , —R 4 /—R 6 , —RB/—R 9 , —R 2 /—R 3  are joined together with the atoms to which they are attached to form a ring A; 
         optionally, R 3 /R 3a  are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle; 
         A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; 
         tetralinyl; C 3-10  cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and 
         wherein -L 1 - is substituted with -L 2 -Z or -L 2 -Z′ and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L 2 -Z or -L 2 -Z′ or a substituent;
 wherein 
 -L 2 - is a single chemical bond or a spacer; 
 —Z is a water-soluble carrier; and 
 —Z′ is a water-insoluble carrier. 
 
       
     
     
         7 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  to  6 , 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 Yl )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 5y , —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. 
 
     
     
         8 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claim 1  or  3  to  7 , wherein —Z comprises a C 8-24  alkyl or a polymer. 
     
     
         9 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claim 1  or  3  to  8 , wherein —Z comprises a polymer, preferably 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. 
     
     
         10 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  and  3  to  9 , wherein —Z is a branched polymer. 
     
     
         11 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claim 1  or  3  to  10 , wherein —Z comprises a moiety of formula (a) 
       
         
           
           
               
               
           
         
         wherein 
         the dashed line indicates attachment to -L 2 - or to the remainder of —Z; 
         BP a  is a branching point selected from the group consisting of —N<, —CR< and >C<; 
         —R is selected from the group consisting of —H and C 1-6  alkyl; 
         a is 0 if BP a  is —N< or —CR< and n is 1 if BP a  is >C<; 
         —S a —, —S a′ —, —S a″ — and —S a′″ — are independently of each other a chemical bond or are selected from the group consisting of C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl; 
         wherein C 1-50  alkyl, C 2-50  alkenyl, and C 2-50  alkynyl are optionally substituted with one or more —R 1 , 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 2 )—, —S(O) 2 N(R 2 )—, —S(O)N(R 2 )—, —S(O) 2 —, —S(O)—, —N(R 2 )S(O) 2 N(R 2a )—, —S—, —N(R 2 )—, —OC(OR 2 )(R 2a )—, —N(R 2 )C(O)N(R 2a )—, and —OC(O)N(R 2 )—; 
         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 1 , which are the same or different; 
         each —R 1  is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR 3 , —OR 3 , —C(O)R 3 , —C(O)N(R 3 R 3a ), —S(O) 2 N(R 3 R 3a ), —S(O)N(R 3 R 3a ), —S(O) 2 R 3 , —S(O)R 3 , —N(R 3 )S(O) 2 N(R 3a R 3b ), —SR 3 , —N(R 3 R 3a ), —NO 2 , —OC(O)R 3 , —N(R 3 )C(O)R 3a , —N(R 3 )S(O) 2 R 3a , —N(R 3 )S(O)R 3a , —N(R 3 )C(O)OR 3a , —N(R 3 )C(O)N(R 3a R 3b ), —OC(O)N(R 3 R 3a ), and C 1-6  alkyl; wherein C 1-6  alkyl is optionally substituted with one or more halogen, which are the same or different; 
         each —R 2 , —R 2a , —R 3 , —R 3a  and —R 3b  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; and 
         P a′ , —P a″  and —P a′″  are independently a polymeric moiety. 
       
     
     
         12 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claim 1  or  3  to  11 , wherein the PTH prodrug is of formula (IIe-i): 
       
         
           
           
               
               
           
         
         wherein 
         the unmarked dashed line indicates the attachment to a nitrogen of -D which is a PTH moiety by forming an amide bond; and 
         the dashed line marked with the asterisk indicates attachment to a moiety 
       
       
         
           
           
               
               
           
         
         
           wherein 
           m and p are independently an integer ranging from and including 400 to 500. 
         
       
     
     
         13 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claim 1  or  3  to  11 , wherein the PTH prodrug is of formula (IIf-i): 
       
         
           
           
               
               
           
         
         wherein 
         the unmarked dashed line indicates the attachment to a nitrogen of -D which is a PTH moiety by forming an amide bond; and 
         the dashed line marked with the asterisk indicates attachment to a moiety 
       
       
         
           
           
               
               
           
         
         
           wherein 
           m and p are independently an integer ranging from and including 400 to 500. 
         
       
     
     
         14 . A pharmaceutical composition comprising at least one PTH prodrug of any one of  claims 1  to  13  and at least one excipient. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition has a pH ranging from and including pH 4 to pH 6. 
     
     
         16 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  to  13  or the pharmaceutical composition comprising of  claim 14  or  15  for use in the treatment of a disease which can be treated with PTH. 
     
     
         17 . The PTH prodrug or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of  claim 16 , wherein the disease is selected from the group 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. 
     
     
         18 . The PTH prodrug or a pharmaceutically acceptable salt thereof of any one of  claims 1  to  13  or the pharmaceutical composition of  claim 14  or  15  for use in the treatment of hypoparathyroidism via subcutaneous injection.