Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
Inventors
Lançois, David Francis Alain • Guillemont, Jérôme Émile Georges • Raboisson, Pierre Jean-Marie Bernard • Roymans, Dirk André Emmy • RIGAUX, Peter • Michaut, Antoine Benjamin
Assignees
Janssen Pharmaceutica NV • Janssen Cilag SAS • Novalix SAS • Janssen Sciences Ireland ULC
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Publication Number
US-11491157-B2
Publication Date
2022-11-08
Expiration Date
Abstract
The invention concerns compounds of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment of respiratory syncytial virus infection. (Formula I).
Core Innovation
The invention provides stereochemically isomeric compounds of formula (I), including pharmaceutically acceptable acid addition salts. The compounds are defined with selectable values for A, n=1, X1 and X2, and substituents R1 through R7, including the condition that when R6 is −NH(CO)-cyclopropyl, X1 is CH and X2 is CH.
The disclosure includes representative compounds and intermediates in pyrazolo[1,5-a]pyrimidine and related heteroaryl core series, with cyclopropyl substituents, fluorinated aryl components, and functional-group variations including carboxamide, urea, carbamate, acetamide, sulfonamide, tetrazolyl, oxazolyl, and oxadiazolyl functionalities. It also describes synthetic intermediates and final compounds with stereochemical descriptors such as (1S,2S), (1R,2R), and trans/cis relationships.
The patent further reports synthesis of multiple intermediates and final compounds, including Pd-catalyzed cross-coupling with boron-derived coupling partners and conversion to tetrazole-containing structures. It also presents characterization data for selected compounds, including 1H-NMR spectra, DSC melting point values, optical rotation measurements, and reported purification yields for several intermediates and final compounds.
Claims Coverage
The claim coverage includes broad Formula (I) stereochemically isomeric compounds with pharmaceutically acceptable acid addition salts, and a separately defined set of specific stereochemically defined compounds and salts. Across the independent claims, the coverage centers on selectable substituents at A, n, X1/X2, and R2–R7, with multiple heteroaryl, cyclopropyl, and functional-group variants.
Formula (I) stereochemically isomeric compound with acid addition salts
A compound of formula (I) or any stereochemically isomeric form thereof, including pharmaceutically acceptable acid addition salts, with A defined and n=1.
Selectable X1/X2 combination constraints
X1 and X2 are selected from the defined CH and N combinations, with the additional condition that when R6 is −NH(CO)-cyclopropyl then X1 is CH and X2 is CH.
Defined core substituent set R2–R7
R1 is CH3; R2 is hydrogen or fluoro; R3 is fluoro; R4 is cyclopropyl or phenyl; R5 is hydrogen; and R7 is hydrogen or fluoro.
N-substituted cyclopropane-1-carboxamide substituent options at R6
R6 is selected from an explicitly listed set including multiple carboxamide and related groups such as −CH2OH, −C(O)NHCH2CCH, −C(O)NHCH2CH2CN, −C(O)NH-oxetanyl, −C(O)NHCH2CH2OH, −C(O)NHSO2C1-4alkyl, −C(O)NHSO2-cyclopropyl, −NHC(O)NH−cyclopropyl, −NHCO2CH3, −NHC(O)CH3, −NHC(O)-cyclopropyl, −NHSO2CH3, −NHP(O)(CH3)2, and −OC(O)NH2.
Selected specific stereochemically defined compounds and pharmaceutically acceptable salts
A compound selected from a listed set of specific structures, each with explicit stereochemistry and functional-group variants including cyclopropyl-substituted pyrazolo[1,5-a]pyrimidine, tetrahydroisoquinoline carbonyl-containing frameworks, carboxamide, urea, carbamate, acetamide, sulfonamide, and related N-substituted functionalities.
Treating respiratory syncytial virus infection
A method for treating a respiratory syncytial virus (RSV) infection by administering to a subject an antivirally effective amount of a compound of formula (I).
Pharmaceutical composition including an RSV inhibiting compound
A pharmaceutical composition that includes an antiviral agent that is a respiratory syncytial virus (RSV) inhibiting compound.
Overall, the claim coverage spans broad Formula (I) stereochemically isomeric compounds with fixed n=1 and detailed substituent selection, together with a narrower set of specifically enumerated stereochemically defined compounds and pharmaceutically acceptable salts. Additional coverage includes RSV treatment and pharmaceutical compositions containing an RSV inhibiting compound.
Stated Advantages
Improved pharmacokinetic properties, including bioavailability and half-life/AUC improvements.
Antiviral activity against respiratory syncytial virus (RSV), including mutated strains.
Documented Applications
Treatment of an RSV infection by administering a therapeutically/antivirally effective amount of a compound of formula (I) to a subject in need.
Pharmaceutical composition use for RSV treatment, including preferred oral unit dosage forms, and combination therapy with other RSV antivirals such as ribavirin and RSV fusion/polymerase inhibitors.
Evaluation of antiviral activity against RSV using in vitro and cotton-rat in vivo testing approaches described in the document.
Antiviral activity evaluation against respiratory syncytial virus using rgRSV224 in HeLa cells, with EC50 based on GFP expression and CC50 based on ATP-based cytotoxicity.
Pharmaceutical compositions in dosage-form examples including tablets, suspension, injectable, and ointment containing an active ingredient corresponding to Formula (I) compounds and pharmaceutically acceptable salts, solvates, isomers, or tautomers.
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