Pyrrolopyrimidine nucleosides and analogs thereof
Inventors
Bougher, III, John Henry • Changalvala, Ramamurty V S • Downey, Aaron Leigh • Drach, John C. • Lanier, Jr., Ernest Randall • McIver, Andrew Louis • Robertson, Bradley David • Selleseth, Dean Wallace • Sethna, Phiroze Behram • Townsend, Leroy • Ware, Roy W.
Assignees
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Publication Number
US-9708359-B2
Publication Date
2017-07-18
Expiration Date
Abstract
The present disclosure provides pyrrolopyrimidine nucleoside analogs of the Formula I, Formula IA, Formula IB, or Formula II and phospholipid conjugates and pharmaceutical compositions thereof wherein Rc and A are defined herein. Also presented are methods of treating and/or preventing viral infection and/or viral infection-associated disease or disorder with one or more compounds of Formula I, Formula IA, Formula IB, or Formula II.
Core Innovation
The disclosure relates to compounds of Formula IB, including pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture thereof, and to pyrrolopyrimidine nucleoside analogs of Formula I, including Formula IA, Formula IB, and Formula II. The compounds are defined by variable substituent definitions for A and multiple R groups, together with structural linkage options denoted by X1, X2, and X3, and parameters such as v, n, p, and q.
The Formula IB compounds are characterized by a defined substituent A selected from specified structural alternatives in which the oxygen atom is distal to the RIB moiety in A. The X2 definition is absent, O, C(O)O, or OCH2, again with the oxygen atom distal to the RIB moiety in A, while the RIB moiety is independently hydrogen, C1-C6 alkyl, or an amino acid residue bound via the carbonyl group.
Additional structural constraints define Rz and multiple substituent sets, including Ra, Rb, Rx, Ry, R1, R45, R2, R3, R4, R44, R5, and Rc, with extensive allowable ranges and optional formation of larger ring systems such as spirocycloalkyl and spiroheterocycle. The disclosure also describes phospholipid (monoacyl) conjugates of the pyrrolopyrimidine nucleoside analogs, pharmaceutical compositions containing the described compounds, and methods of treating or preventing viral infections, including norovirus.
Claims Coverage
The independent claim coverage is centered on compounds of Formula IB with multiple inventive structural features, including defined A substituent options with oxygen distal to the RIB moiety, X2 and RIB definitions, and extensive enumerated substituent and parameter constraints for the chemical genus. The claim coverage also includes pharmaceutically acceptable variants such as salts, solvates, stereoisomers, racemates, and mixtures.
Formula IB compound scope with distal oxygen in A
A compound of Formula IB, or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, racemate or mixture, wherein A is selected from the specified alternatives, including cases where the oxygen atom is distal to the RIB moiety in A, and wherein R11 and R12 are independently hydrogen or C1-C4 alkyl optionally substituted with halogen, OH, SH, or NH2.
X2 and RIB moiety definition with amino-acid residue option
X2 is absent, O, C(O)O, or OCH2 where the oxygen atom is distal to the RIB moiety in A, and each RIB is independently hydrogen, C1-C6 alkyl, or an amino acid residue bound via the carbonyl group, with the alkyl optionally substituted with one or more halogen, OH, SH, or NH2.
Parameter-controlled structure constraints using v, n, p, and q
The compound has v equal to 0 or 1; n equal to 0, 1, 2, or 3 with the condition that when X2 is C(O)O then n is 0; p is selected from 2-11; and q is selected from 1-18.
Permitted substituent families with ring-forming and bond-forming constraints
Rz is hydrogen or selected substituent types; Ra, Rb, Rx, and Ry are each independently selected from hydrogen, halogen, OH, SH, C1-C6 alkoxy, aryloxy, C1-C6 alkylthio, arylthio, OC(O)C1-C6 alkyl, OC(O)aryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, C3-C8 cycloalkyl, or C4-C8 cycloalkenyl, each optionally substituted; and selected pairs can combine to form spirocycloalkyl or spiroheterocycle, form carbon-carbon double or triple bonds, or form larger ring systems, with optional replacements by O, S, S(O), or SO2.
Substituent constraints for R1/R45 and R2/R3/R4/R44 including carbon-carbon double bond condition
R1 and R45 are independently hydrogen, halogen, N3, OH, NH2, SH, or selected alkyl/cycloalkyl/alkenyl/cycloalkenyl/alkynyl/cycloalkynyl/alkoxy/alkylthio groups optionally substituted as specified; R2, R3, R4 and R44 are each independently hydrogen, halogen, N3, OH, NH2, SH, or selected alkyl/alkoxy/alkylthio groups; and R3 together with one of R4 and R44 can form a carbon-carbon double bond together with the atoms to which they are attached.
R5 selection with cations and not an amino acid restriction; Rc definition
R5 is independently hydrogen, RIB, M+, aryl, aralkyl, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, non-aromatic heterocyclic ring, or heteroaryl, where M+ is a cation and R5 is not an amino acid, with optional substitution of the selected aryl/alkyl/heteroaryl groups by halogen, N3, OH, NH2, or SH; and Rc is defined from C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C8-C12 cycloalkynyl, or aryl, each optionally substituted as specified.
Across the independent claim coverage, the inventive scope is built around Formula IB compounds whose genus is defined by the specific A substituent options with distal oxygen positioning, the coordinated X2 and RIB moiety definitions including an amino acid residue bound via the carbonyl group, parameter constraints on v, n, p, and q, and extensive, explicitly enumerated substituent allowances and structural formation constraints on multiple R-variables, together with restrictions governing R5, including M+ cations and excluding amino acid for R5.
Stated Advantages
Comparative efficacy/toxicity improvement.
Intended to improve intestinal absorption/uptake and enable intracellular release of active monophosphate and higher antiviral nucleotide levels.
Documented Applications
Method of treating or preventing viral infection, explicitly including norovirus infection.
Human and murine norovirus activity.
Treating viral infections and viral infection-associated disorders using pharmaceutical compositions comprising compounds of Formula IB and pharmaceutically acceptable variants.
Prophylaxis of viral infections using pharmaceutical compositions comprising compounds of Formula IB and pharmaceutically acceptable variants.
Treatment use explicitly associated with norovirus infection.
Treatment use with pharmaceutical compositions suitable for administration via oral and injectable routes, and other routes named in the document.
Combination therapy with other antiviral and/or immunosuppressant agents.
Treatment of diseases, particularly viral infections such as norovirus, via manufacture of a medicament.
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