Phosphorus prodrugs of pyrazolo-substituted pyrimidine sGC stimulators
Inventors
SHEPPECK, James Edward • Renhowe, Paul Allan • Mermerian, Ara • Barden, Timothy Claude • RENNIE, Glen Robert • Iyengar, Rajesh R. • Nakai, Takashi
Assignees
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Publication Number
US-10927136-B2
Publication Date
2021-02-23
Expiration Date
Abstract
The present patent application discloses the compounds according to Formula (I) shown below, or pharmaceutically acceptable salts thereof wherein JB, n, R1, R2, R3, R4, R5, m and X as defined herein.
Core Innovation
The invention relates to phosphorus-containing phosphate ester prodrugs of soluble guanylate cyclase (sGC) stimulators, defined by Formula I and pharmaceutically acceptable salts. The compounds include variable substituents JB, R1-R5, and a phosphate/oxyphosphate ionic group X, where X corresponds to phosphate forms associated with pharmaceutically acceptable cations, including monovalent and divalent cations, with m and n parameters specified for the ionic group. Exemplary compounds are provided as Table I compounds I-1 to I-5.
The prodrug is designed to release a parent Formula IA upon cleavage, thereby linking the phosphorus-containing phosphate ester structure to activation of the sGC stimulator through release of the corresponding parent compound. Related structural variants are described in terms of Formula IA/IB/IC and further sub-variants II-VI, including Formula V and Formula VI. The structural scope is expanded through multiple formula-defined embodiments that preserve the prodrug concept of cleavage to generate the parent entity.
The disclosure also provides phosphate ester prodrugs and related salts, including disodium salt forms and phosphorus-containing intermediates within the Formula I framework. The document describes biological performance using HEK293 soluble guanylate cyclase (sGC)/cGMP assays, including a sGC-HEK-cGMP assay and a GloSensor™ 40F cGMP assay, with Absolute EC50 values and prodrug versus parent activity comparisons supported by LC/MS methods and assay readouts.
Claims Coverage
The independent claim defines a compound of Formula I, or a pharmaceutically acceptable salt, with a large set of substituent and ionic-group definitions. Overall, the claim coverage includes the core Formula I scaffold with constrained substituent options and optional ring formation, and the phosphate/oxyphosphate ionic group X with specified cation types and parameters m and n. Dependent claims further narrow allowable ionic parameters, restrict halogen choices for JB, specify named phosphorus oxyacid/oxyphosphate structures for X, and define pharmaceutical compositions with excipients.
Formula I sGC stimulator phosphate ester prodrug compound
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein JB is independently halogen; R1, R2, R3, R4, R5 are defined with allowed values including optional cycloaliphatic or heterocyclic ring formation from R1 and R2; X is a phosphorus-containing phosphate/oxyphosphate ionic group with M+ as a pharmaceutically acceptable monovalent cation, D2+ as a pharmaceutically acceptable divalent cation, and parameters m (0 or 1) and n (0, 1, 2, 3, or 4).
Restrained ionic parameter n values
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
Halogen restriction for JB (fluoro/chloro combinations)
The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein each JB is independently fluoro, or each JB is independently chloro, or each JB is independently chloro or fluoro.
Named phosphate oxyacid/oxyphosphate ionic group with specified monovalent cations
A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a depicted phosphorus oxyacid/oxyphosphate structure and M+ is Na+, K+, Cs+, or the monovalent cation of an organic amine.
Named phosphate/oxyphosphate ionic group with specified divalent cations
A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D2+ is Mg2+, Ca2+, Zn2+, or the divalent cation of an organic amine.
Pharmaceutical composition including excipients
A pharmaceutical composition including one or more excipients and a compound of claim 1, or a pharmaceutically acceptable salt of the compound.
The claim set centers on Formula I phosphorus-containing phosphate ester prodrug compounds of sGC stimulators, with defined substituent options and an ionic group X that specifies cation types and the parameters m and n. Dependent claims narrow the ionic parameter range for n, restrict the halogen identity for JB, instantiate X as depicted phosphorus oxyacid/oxyphosphate structures, and include a pharmaceutical composition claim defined by the addition of excipients.
Stated Advantages
Improved aqueous solubility at pH 7.
Improved aqueous solubility versus the parent compounds.
Unexpected rapid cleavage relative to the parent Intermediate 3.
Unexpected rapid cleavage and release in ex-vivo rat intestinal fluid and in vivo preclinical animals.
Documented Applications
Biological evaluation of the phosphate ester prodrugs and related salts in HEK293 sGC/cGMP assays, including reporting Absolute EC50 values and comparing prodrug activity to parent activity against Compound Y.
Use of cGMP assay platforms in the document context, including a sGC-HEK-cGMP assay and a GloSensor™ 40F cGMP assay, with reported assay readouts supported by LC/MS methods.
Treating NO/sGC/cGMP-mediated diseases, including cardiovascular and inflammatory/fibrotic disorders.
Therapeutic use for diseases benefiting from NO/sGC/cGMP modulation, including cardiovascular disease and pulmonary hypertension (PH), and other disorders.
Use of sGC-stimulator related prodrugs/compounds and combinations for therapeutic treatment in the described disease categories.
Drug-eluting stent coated with an sGC stimulator.
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