RU2022116958A - CONTROLLED RELEASE PTH COMPOUND DOSING MODE - Google Patents

Claims (62)

1. Use of a pharmaceutical composition containing at least one controlled release PTH compound or a pharmaceutically acceptable salt, hydrate or solvate thereof for the treatment of hypoparathyroidism, wherein said pharmaceutical composition is administered by subcutaneous injection not more than once every 24 hours with a dose of the PTH compound controlled release that corresponds to no more than 70% of the molar equivalent dose of PTH 1-84 SEQ ID NO: 1, administered subcutaneously every 24 hours, required to maintain an albumin-adjusted serum calcium level above 8.5 mg/dL for the specified 24-hour period in humans and wherein the controlled release PTH compound is a water-soluble conjugate of formula (Ia) or (Ib)

where -D is the PTH component; where D has the sequence 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, SEQ ID NO: 115; -L ¹ - is a reversible prodrug linker moiety reversibly or covalently linked to the PTH moiety of -D via a PTH moiety; where -L ¹ - has the formula (II):

, where the dotted line denotes the attachment to the nitrogen atom of the -D component, which is the PTH component; -X- is selected from the group consisting of -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-; -OC(R ⁴ R ^4a )-; and -C(R ⁷ R ^7a )-; X ¹ is selected from the group consisting of C; and S(O); -X ² - selected from the group consisting of -C(R ⁸ R ^8a )-; and -C(R ⁸ R ^8a )-C(R ⁹ R ^9a )-; =X ³ is selected from the group consisting of =O; =S; and =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 , and - R ^9a are independently selected from the group consisting of -H; and C _1-6 alkyl; -R ³ and -R ^3a are independently selected from the group consisting of -H; and C _1-6 alkyl, with the proviso that if one of -R ³ , -R ^3a or both is other than hydrogen, they are connected to the N to which they are attached via an SP ³ hybridized carbon atom; -R ⁷ is selected from the group consisting of -N(R ¹⁰ R ^10a ); and -NR ¹⁰ -(C=O) -R ¹¹ ; -R ^7a , -R ¹⁰ , -R ^10a , and -R ¹¹ are independently selected from the group consisting of -H; and 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 , and -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 ⁸ /-R ^8a , and -R ⁹ /-R ^9a are connected together with the atom to which they are attached, with the formation of C _3-10 cycloalkyl; or 3-10 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 , -R ⁸ /-R ⁹ , and -R ² /-R ³ join together with the atoms to which they are attached to form ring A; optionally, R ³ /R ^3a join together with the nitrogen atom to which they are attached to form a 3-10 membered heterocycle; A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C _3-10 cycloalkyl; 3-10 membered heterocyclyl; and 8-11 membered heterobicyclyl; and where -L ¹ - is substituted with -L ² -Z, and where -L ¹ - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (II) is not substituted with -L ² -Z or a substituent; and from which at least one component of the PTH is released with a half-life in an aqueous buffer with pH 7.4 at 37°C for at least 12 hours; where -L ² - represents a simple chemical bond or spacer component; -Z is the water-soluble component of the carrier; 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. Use according to claim 1, wherein the pharmaceutical composition is administered once every 24 hours. 3. Use according to claim 1, wherein the pharmaceutical composition is administered once every 48 hours. 4. Use according to claim 1, wherein the pharmaceutical composition is administered once every week. 5. Use according to claim 1, wherein the dose of the controlled release PTH compound corresponds to no more than 40% of the molar equivalent dose of PTH 1-84. 6. Use according to claim. 1, where the pharmaceutical composition is administered using a syringe pen. 7. Use according to claim 1, wherein D has the sequence of SEQ ID NO: 51. 8. Use according to claim. 1, where -L ¹ - is conjugated to the N-terminal amine functional group -D. 9. Application according to claim 1, where -L ¹ - has the formula (IIb-iii):

where where the dotted line denotes the addition to the nitrogen atom of the D component, which is the PTH component, by forming an amide bond; and where -L ¹ - is substituted with -L ² -Z, and where -L ¹ - is optionally further substituted, provided that the hydrogen marked with an asterisk in formula (IIb-iii) is not substituted with -L ² -Z or a substituent. 10. Use according to claim 1, where -L ² is 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; where -T-, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted with one or more -R ^y2 that are the same or different, and where 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 selected from the group consisting of H, -T, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl; where -T, C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl are optionally substituted with one or more -R ^y2 that are the same or different, and where C _1-50 alkyl, C _2-50 alkenyl and C _2-50 alkynyl is 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, C3-10 cycloalkyl, _3-10 membered heterocyclyl, 8-11 membered heterobicyclyl, 8-30 membered carbopolycyclyl, and 8-30 membered heteropolycyclyl; where each T is independently optionally substituted with one or more -R ^y2 that 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; where C _1-6 alkyl is optionally substituted with one or more halogens that 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, where C _1-6 alkyl optionally substituted with one or more halogens which are the same or different. 11. The use according to claim 1, where -L ¹ -L ² - is selected from the group consisting of

where the unmarked dotted line denotes the attachment to the nitrogen atom of the D moiety, which is the PTH moiety, by forming an amide bond; and the dotted line marked with an asterisk means attaching to -Z. 12. Use according to claim 1, wherein -Z is a branched PEG-based polymer. 13. Use according to claim 1, wherein the pharmaceutical composition has a pH value in the range and including pH 3 - pH 8. 14. Application according to any one of paragraphs. 1-13, where the PTH prodrug has the formula (IIf-i):

where the unmarked dotted line denotes the addition to the nitrogen atom of the D component, which is the PTH component, by forming an amide bond; and the dotted line marked with an asterisk means the connection of the component:

where m and p independently of each other are an integer in the range and inclusive of 400 to 500.