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Publication Number
US-12077531-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The present invention aims to provide a novel compound which has prolyl hydroxylase (PHDs) inhibitory effect and which is useful for the treatment of inflammatory bowel diseases such as ulcerative colitis and the like. The present invention relates to a imidazopyridinone compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. The compounds of the present invention or pharmaceutically acceptable salts thereof which have prolyl hydroxylase inhibitory effect and, are useful as agents for the treatment of inflammatory bowel diseases such as ulcerative colitis and the like. In an embodiment, the present invention relates to a method for treating an inflammatory bowel disease
Core Innovation
The invention relates to a compound represented by formula (I), including a pharmaceutically acceptable salt thereof. Ring W is selected from C6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and ring Z is selected from groups (a) to (c).
The structural definition further specifies substituent groups Ra, Rb, Rc, Rd, R1 to R8, and group A, together with integer parameters m, n, u, p, q, and r. The allowable substituents include hydrogen, halogen, C1-6 alkyl, cyano, hydroxy, carboxy, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, nitro, and carbonyl- or amide-containing groups, with multiple substituents permitted at defined positions when m, n, or u is 2 or 3.
The invention is directed to PHD2 inhibitors represented by formula (I), with characterized compounds and assay context provided for exemplified compounds. The compounds are described as having an excellent PHD2 inhibitory effect, an asserted effect on the HIF-1α degradation pathway, and large-intestine tissue selective action to limit HIF-α off-target effects.
The disclosure includes analytical characterization and biological activity data for multiple example compounds, including 1H NMR, MS, IC50 values, in vivo TNBS-induced colitis model results, intestinal permeability inhibition, and PK data indicating higher colon tissue concentrations than plasma. The compounds are also described for therapeutic use in inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, and for pharmaceutical composition and administration/use for IBD therapy.
Claims Coverage
The consolidated claim coverage centers on a formula (I) compound or pharmaceutically acceptable salt defined by ring W and ring Z selections, detailed substituent definitions through Ra to Rd and R1 to R8, group A and substituent group B, and constrained integer parameters m, n, u, p, q, and r. The provided claim content also includes therapeutic use limited to inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.
Formula (I) compound with ring W and ring Z selection
A compound represented by formula (I), wherein ring W is selected from C6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, and ring Z is selected from the group consisting of following (a) to (c).
Substituent framework for Ra to Rd and R1 to R8
Ra, Rb, and Rc are each independently hydrogen, halogen, C1-6 alkyl, cyano, hydroxy, or carboxy; Rd is hydrogen or C1-6 alkyl; R1 is hydrogen, halogen, C1-6 alkyl, cyano, hydroxy, or carboxy; R2 includes hydrogen, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, hydroxy, CO2R4, or CONR5R5'; and R3 includes hydrogen, halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfanyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, hydroxy, cyano, nitro, NR6R6', CO2R7, CONR8R8', or group A.
Group A and substituent group B definitions
Group A is selected from groups (a) to (h), including C6-10 aryl, 5- or 6-membered heteroaryl, C6-10 aryl C1-6 alkyl, C6-10 aryloxy, 5- or 6-membered heteroaryl C1-6 alkyl, 5- or 6-membered heteroaryloxy, C3-8 cycloalkyl, and 3- to 8-membered heterocycloalkyl, each unsubstituted or substituted with 1 to 3 groups selected from substituent group B; substituent group B consists of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, hydroxy, cyano, NR9R9', NR9SO2R10, CO2R10, and CONR11R11'.
Integer constraints on m, n, u, p, q, and r
m, n, and u are each independently an integer number 1 to 3; p and q are each independently 1 or 2; and r is an integer number 0 to 6, with inclusion of pharmaceutically acceptable salts.
Therapeutic use for inflammatory bowel disease
A method for treating inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.
Overall, the claims center on a formula (I) compound or pharmaceutically acceptable salt defined by ring W and ring Z choices, detailed substituent definitions through Ra to Rd and R1 to R8, group A and substituent group B, constrained integer parameters m, n, u, p, q, and r, and therapeutic use for inflammatory bowel disease.
Stated Advantages
Compounds have an excellent PHD2 inhibitory effect.
Preference for large-intestine tissue selective action to limit HIF-α off-target effects.
Higher colon tissue concentrations than plasma.
Intestinal permeability inhibition in a TNBS-induced colitis model.
Documented Applications
Therapeutic use for inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.
Pharmaceutical composition and administration/use for IBD therapy.
Use in a TNBS-induced colitis model, with intestinal permeability inhibition described.
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