US 12,133,883 B2
Polymeric hGH prodrugs
Thomas Kurpiers, Heidelberg (DE); Harald Rau, Dossenheim (DE); Evelyn Exner, Nussloch (DE); Steen Jensen, Dragoer (DK); Grethe Nørskov Rasmussen, Farum (DK); Torben Lessmann, Neustadt (DE); Thomas Wegge, Heidelberg (DE); Alina Hermann, Schriesheim (DE); Nina Schubert, Stuttgart (DE); Anna Splanemann, Heidelberg (DE); and Joachim Zettler, Heidelberg (DE)
Assigned to Ascendis Pharma Endocrinology Division A/S, Hellerup (DK)
Filed by Ascendis Pharma Endocrinology Division A/S, Hellerup (DK)
Filed on Aug. 28, 2020, as Appl. No. 17/006,589.
Application 17/006,589 is a continuation of application No. 15/527,744, granted, now 10,799,563, previously published as PCT/EP2015/076813, filed on Nov. 17, 2015.
Claims priority of application No. 14193603 (EP), filed on Nov. 18, 2014.
Prior Publication US 2020/0390864 A1, Dec. 17, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 38/27 (2006.01); A61K 9/08 (2006.01); A61K 47/12 (2006.01); A61K 47/20 (2006.01); A61K 47/26 (2006.01); A61K 47/60 (2017.01); C08G 65/334 (2006.01)
CPC A61K 38/27 (2013.01) [A61K 9/08 (2013.01); A61K 47/12 (2013.01); A61K 47/20 (2013.01); A61K 47/26 (2013.01); A61K 47/60 (2017.08); C08G 65/3348 (2013.01); C08G 2650/06 (2013.01)] 21 Claims
 
1. A container comprising a polymeric human growth hormone (hGH) prodrug or a pharmaceutically acceptable salt thereof of formula (Ia) or (Ib)

OG Complex Work Unit Chemistry
wherein
—D is a hGH moiety connected to the rest of the molecule through an amine functional group;
n is 0, 1, 2, 3, or 4;
—X— is a chemical bond or a spacer;
═Y1 is selected from the group consisting of ═O and ═S;
—Y2— is selected from the group consisting of —O— and —S—;
—Y3— is selected from the group consisting of —O— and —S—;
—Y4— is selected from the group consisting of —O—, —NR5— and —C(R6R6a)—;
═Y5 is selected from the group consisting of ═O and ═S;
—R1 comprises a moiety of formula (IIc):

OG Complex Work Unit Chemistry
wherein:
p1, p2, p3, and p4 are independently an integer ranging from 180 to 240;
—R2, —R3, —R5, —R6 —R6a are independently of each other selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl;
—R4 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and 3,3-dimethylpropyl;
—W— is selected from the group consisting of C1-20 alkyl optionally interrupted by one or more groups selected from the group consisting of C3-10 cycloalkyl, 8- to 30-membered carbopolycyclyl, 3- to 10-membered heterocyclyl, —C(O)—, —C(O)N(R7)—, —O—, S— and —N(R7)—;
—Nu is a nucleophile selected from the of group consisting of —N(R7R7a), —N(R7OH), —N(R7)—N(R7aR7b), —S(R7), —COOH,

OG Complex Work Unit Chemistry
—Ar— is selected from the group consisting of

OG Complex Work Unit Chemistry
wherein
dashed lines indicate attachment to the rest of the prodrug,
—Z1— is selected from the group consisting of —O—, —S— and —N(R7)—, and
—Z2 is —N(R7)—; and
—R7 —R7a, —R7b are independently of each other selected from the group consisting of —H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
wherein the prodrug of formula (Ia) and (Ib) is optionally further substituted.