Treprostinil derivatives and their use in pharmaceutical compositions
Inventors
Batra, Hitesh • Guo, Liang • Poisson, Patrick • Jana, Susovan
Assignees
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Publication Number
US-12168071-B2
Publication Date
2024-12-17
Expiration Date
Abstract
Provided are treprostinil derivatives with a reduced ability to form undesired impurities in a pharmaceutical formulation, such as a dry powder formulation, further containing a carboxyl group containing inactive ingredient, such as fumaryl diketopiperazine.
Core Innovation
The invention relates to treprostinil-derived compounds in which X is a salt moiety or a promoiety and in which each OR2 and OR3 has a lower reactivity with a carboxyl group than the respective hydroxyl group of unsubstituted treprostinil. The compounds further include C(O)X having a lower reactivity with hydroxyl than the carboxyl group of unsubstituted treprostinil.
The compounds are defined by a chemical formula in which Z is O or CH2, and R2 and R3 are selected from CH2OBn and CH2OH or are joined together to form an 8-12 membered heterocyclyl comprising C(O) or SO2. Each R10 is H or optionally substituted C1-C6 alkyl, C1-C6 alkenyl, cycloalkyl, heteroaryl, or aryl.
The disclosure includes treprostinil di-substituted prodrugs and their salt forms, including treprostinil diacetate, dipropionate, dibutanoate, and dicarbonate, and corresponding salts. Exemplified counterions include L-arginine, L-lysine, and potassium, and the document describes treprostinil acetoxy acetate acid and treprostinil disubstituted benzyl ester intermediates that are hydrogenolyzed to di-substituted compounds and then converted to specific amino-acid salts.
The disclosure emphasizes reducing the formation of undesirable impurities during pharmaceutical storage and formulation. It specifically refers to impurity reduction in dry powder formulations containing a carboxyl-group containing ingredient such as FDKP, reactions involving hydroxyl-containing ingredients such as alcohols including methanol and ethanol, and improved storage stability at room temperature.
Claims Coverage
The independent claim coverage centers on treprostinil-derived compounds defined by a formula in which X is a salt moiety or a promoiety and where OR2, OR3, and C(O)X are configured to have lower reactivity than the corresponding functional groups of unsubstituted treprostinil. The inventive features also include selected R2/R3 configurations, Z selection, general R10 substitution limits, and water-soluble embodiments.
Reactivity-lowered treprostinil-derived prodrug and salt framework
X is a salt moiety or a promoiety, where each OR2 and OR3 has a lower reactivity with a carboxyl group than the respective hydroxyl group of unsubstituted treprostinil, and C(O)X has a lower reactivity with hydroxyl than the carboxyl group of unsubstituted treprostinil.
Selected R2 and R3 substituents with heterocyclyl option
R2 and R3 are each independently selected from CH2OBn and CH2OH, or R2 and R3 are joined together to form an 8-12 membered heterocyclyl comprising C(O) or SO2.
Z structural selection and general R10 substituent constraints
Z is O or CH2, and each R10 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted aryl.
Amino-acid salt embodiment for X
X includes L-arginine, L-lysine, and potassium in the disclosed salt forms.
Water-soluble compound limitation
The compound is characterized as a water-soluble compound.
Overall, the claim coverage centers on treprostinil-derived compounds where functional-group reactivity is lowered through the selection of OR2/OR3 and C(O)X relationships to carboxyl and hydroxyl groups, combined with defined R2/R3 configurations, a Z selection, and substitution limits on R10. Dependent features further include amino-acid and potassium salt embodiments and a water-soluble limitation.
Stated Advantages
Lowered reactivity of OR2 and OR3 with a carboxyl group relative to the hydroxyl group of unsubstituted treprostinil.
Lowered reactivity of C(O)X with hydroxyl relative to the carboxyl group of unsubstituted treprostinil.
Reduced impurities versus unsubstituted treprostinil in formulations with a carboxylic group containing ingredient such as FDKP.
Improved storage stability of a dry powder at room temperature.
Water solubility that avoids organic solvents.
Reduced formation of undesirable impurities during pharmaceutical storage and formulation.
Reduced impurity formation in the presence of hydroxyl-containing ingredients such as alcohols including methanol and ethanol.
Potential to allow milder storage conditions, including room temperature storage.
Documented Applications
Dry powder inhaler formulations that include a carboxyl-group containing ingredient such as FDKP, with storage stability at room temperature for the dry powder.
Pulmonary hypertension.
Pharmaceutical storage and formulation of treprostinil derivatives.
Formulations involving hydroxyl-containing alcohols such as methanol and ethanol, where impurity formation is addressed.
Use aimed at reducing undesirable impurity formation during storage, including room temperature storage.
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