Creatine prodrugs, compositions and methods of use thereof
Inventors
CHAN, Yiumo • Kakkis, Emil D. • Trotier-Faurion, Alexandra • Brubaker, William F. • NATESAN, ARJUN • Lee, Paul • FYFFE-MARICICH, SHARYL • Lapointe, David • Lizarzaburu, Mike E.
Assignees
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Publication Number
US-11753369-B2
Publication Date
2023-09-12
Expiration Date
Abstract
The present disclosure provides creatine prodrug analogs and their compositions useful for the treatment of creatine deficiencies.
Core Innovation
The invention relates to a method for treating creatine deficiency in a patient in need thereof by administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. The Formula (I) compounds are defined by substituent selections for R, R2, R3, R4, R5, R6, and R1, including deuterated variants where R is selected from —CH3, —CH2D, —CHD2, or —CD3. The structural definitions additionally constrain the ring-forming alkylene group or alkenylene group and its optional heteroatom replacements, and permit optional substitution by R4.
The ring-forming portion of the Formula (I) compounds includes an alkylene group or an alkenylene group in which R6 and R1 together form a 12 to 25 membered ring with the atoms to which they are each bonded. The ring can have 1, 2, 3, or 4 —CH2-units, and those —CH2-units are optionally replaced with a heteroatom selected from —O—, —S—, or —N—, while no adjacent —CH2— is replaced. The alkylene or alkenylene group is optionally substituted with one or more R4.
In addition, two R4 on the same or adjacent carbon can form a 3 to 6 membered fused or spiro cycloalkyl ring or a 3 to 6 membered fused or spiro heterocyclic ring. The Formula (I) framework further specifies that R2 may be hydrogen, —C(O)NHR5, —C(O)OR5, —C(O)(linear or branched alkyl), or —C(O)(linear or branched alkenyl), and that R3 is —C(O)OR6. R4 is selected from halogen, —OH, —OR5, oxo, —NH2, —NHR5, —N(R5)2, —NO2, —CF3, —C1-C6 alkyl, or —C1-C6 haloalkyl, with R5 as linear or branched alkyl.
Claims Coverage
The independent claim coverage centers on administering a therapeutically effective amount of a Formula (I) compound to treat creatine deficiency, with pharmaceutically acceptable salts or solvates included. The inventive features comprise the Formula (I) structural definition, deuterated R options, the 12 to 25 membered ring-forming alkylene or alkenylene system, optional heteroatom replacement, optional fused/spiro ring formation, and patient selection for creatine-related disorders.
Treating creatine deficiency by administering a Formula (I) compound
A method for treating creatine deficiency in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
Deuterated and selected substituent definitions for R, R2, R3, and R4
R is —CH3, —CH2D, —CHD2, or —CD3; R2 is hydrogen, —C(O)NHR5, —C(O)OR5, —C(O)(linear or branched alkyl), or —C(O)(linear or branched alkenyl); R3 is —C(O)OR6; and R4 is halogen, —OH, —OR5, oxo, —NH2, —NHR5, —N(R5)2, —NO2, —CF3, —C1-C6 alkyl, or —C1-C6 haloalkyl.
12 to 25 membered ring-forming alkylene or alkenylene unit with optional heteroatom replacements
R6 and R1 together are an alkylene group or an alkenylene group which, with the atoms to which they are each bonded, forms a 12 to 25 membered ring, wherein 1, 2, 3, or 4 —CH2-units are optionally replaced with a heteroatom selected from —O—, —S—, or —N—, provided that no adjacent —CH2— is replaced, and the alkylene or alkenylene group is optionally substituted with one or more R4.
Optional fused or spiro 3 to 6 membered cycloalkyl or heterocyclic rings
Two R4 on the same or adjacent carbon can form a 3 to 6 membered fused or spiro cycloalkyl ring or a 3 to 6 membered fused or spiro heterocyclic ring.
Selected patient population based on creatine transporter or creatine synthesis disorders
The method is applied to a patient who has a creatine transporter disorder or a creatine synthesis disorder.
Overall, the claim coverage centers on administering therapeutically effective amounts of Formula (I) compounds to treat creatine deficiency, with structural constraints on deuterated R options, substituent groups, and a ring-forming alkylene or alkenylene system that permits optional heteroatom replacement and optional fused/spiro ring formation.
Stated Advantages
Conventional high-dose creatine is limited by gastrointestinal and brain delivery.
Conventional high-dose creatine does not provide improvement in transporter defects.
The disclosed membrane-permeable prodrugs enter cells and release creatine in the cytoplasm.
The disclosed prodrugs are described as capable of crossing the intestinal mucosa, the blood-brain barrier, and the blood-placental barrier.
Enhance creatine release upon prodrug cleavage.
Minimize cyclization to creatinine.
Increase BBB crossing and neuronal/glial uptake for creatine delivery.
Facilitate creatine delivery for creatine transporter deficiency (CTD) and broader energy-metabolism dysfunctions.
Documented Applications
Treating creatine deficiency in a patient in need thereof by administering a therapeutically effective amount of a compound of Formula (I).
Treating creatine transporter disorder or a creatine synthesis disorder in a patient in need thereof.
Treating conditions associated with ATP/creatine phosphate deficits, including ischemia and neurodegenerative diseases.
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