2-amino-benzimidazole derivatives and their use as 5-lipoxygenase and/or prostaglandin E synthase inhibitors
Inventors
Kim, Jaeseung • AHN, SEOHYUN • JEON, YEEJIN • PARK, Dongsik • Yang, Young-In • LEE, DOOHYUNG • Lee, Saeyeon • AHN, Jiye • Kim, Jeongjun • Nam, Kiyean • Kang, Sunhee • SEO, MINJUNG • SEO, Mooyoung • SEO, Jeongjea • Han, Sung-Jun • Kim, Jung Hwan • Lee, Sangchul • Choi, Gahee • LEE, YUNMI
Assignees
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Publication Number
US-11447486-B2
Publication Date
2022-09-20
Expiration Date
Abstract
The present invention relates to benzimidazole derivatives having the general formula I, wherein n is 0 or 1; X1 and X2 are independently, at each occurrence, CR5 or N; Y is C1-C6 alkylene, wherein alkylene is optionally substituted with one to two C1-C3 alkyl groups; R1 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, —NH2, —NHR6, —NR7R8 and —NH—(R9)n—R10, n being 0 or 1; R2 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, —NH2, —NHR6, —NR7R8 and —NH—(R9)n—R10; R3 is selected from the group consisting of hydrogen, hydroxyl, OR11, —NR7R8, C1-C6 alkoxy, C1-C6 alkyl, C3-C10 cycloalkyl, C1-C3 haloalkyl, —C(O)NHR11, aryl, heteroaryl and heterocyclyl, wherein each of said cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally and independently substituted with one to four Ra groups; and R4 is selected from the group consisting of —NH2, —N(R12)(V)pR13, —NH(V)p—OR14, —NHC(O)R15, and groups of formula 1a shown below, and their use in the treatment of diseases, in particular inflammatory diseases, cancer, stroke and/or Alzheimer's disease.
Core Innovation
The document describes substituted heteroaromatic compounds defined by general formulae I, II, and III, with embedded sub-structures Ia, Ib, IIa, and IIIa and extensive variable definitions across R-group positions. The compounds include fused heteroaromatic and fused polynitrogen heteroaromatic scaffolds, with substituent options such as halogen, alkyl, haloalkyl, alkoxy, hydroxyl, amino-like, aryl, heteroaryl, and heterocyclyl groups, together with pharmaceutically acceptable salts.
The disclosed structures also include specific numbered compounds represented by embedded chemical structure depictions and associated CDX/MOL files. Across the examples, the shared scaffold is linked to substituted phenyl, pyridine-like, aryl, and heteroaryl fragments through ether, amide/amine, and related linkages, with variation in halogens including Cl, F, and Br, as well as oxygen-containing and other heteroatom-containing substituents.
The partial content further states that the compounds are benzimidazole derivatives and other substituted heteroaromatic compounds intended to inhibit arachidonate 5-lipoxygenase and prostaglandin E synthase pathways. The document also includes assay readouts such as IC50, EC50, and percent inhibition, and ties the disclosed compounds to specific structure representations and pharmaceutically acceptable salt forms.
Claims Coverage
The consolidated claim coverage includes multiple independent compound claims directed to general formulas I, II, and III and to specific enumerated structures, with salt inclusion throughout. A further independent claim set recites treatment and enzyme-inhibition coverage, so the consolidated set includes structural, inhibitory, composition, and disease-treatment features.
General formula I with extensive substituent-variable scope
A compound having general formula I wherein n is 0 or 1; X1 and X2 are independently CR5 or N; Y is C1-C6 alkylene optionally substituted with one to two C1-C3 alkyl groups; and R groups are defined by the stated selections and constraints, including groups of formula Ia or Ib, with pharmaceutically acceptable salts thereof.
General formula II with defined substituent-variable scope
A compound having general formula II wherein n is 0 or 1; X1 is CR5 or N; Y is C1-C6 alkylene optionally substituted with one to two C1-C3 alkyl groups; and the defined R groups include groups of formula IIa, with pharmaceutically acceptable salts thereof.
General formula III with defined substituent-variable scope
A compound having general formula III wherein n is 0 or 1; X1 is CR5 or N; Y is C1-C6 alkylene optionally substituted with one to two C1-C3 alkyl groups; and the defined R groups include groups of formula IIIa, with pharmaceutically acceptable salts thereof.
Specific disclosed compound structures
A compound having one of the enumerated chemical formulae or numbered structures, including pharmaceutically acceptable salts thereof.
Inhibiting inflammatory-pathway enzymes
A method for inhibiting an enzyme involved in one or more inflammatory pathways using a compound according to claim 1 at a concentration between 0.001 and 50 μM, where the enzyme is selected from arachidonate 5-lipoxygenase, LTA4-synthase, LTA4-hydrolase, LTC4-synthase, glutamyltranspeptidase, cysteinylglycinase, 5-hydroxy-6,8,11,14-eicosatetraenoic acid dehydrogenase, cyclooxygenase-2, and prostaglandin E synthase.
Treatment of 5-LOX pathway and/or PGES pathway associated disease
A treatment method in which a suitable amount of a compound as defined in claim 1 is administered to a patient with a disease associated with the 5-LOX pathway and/or the prostaglandin E synthase pathway, where the disease is selected from inflammatory diseases, cancer, and Alzheimer’s disease.
Treating enumerated inflammatory diseases
The treatment method is specified for asthma, allergic rhinitis, dermatitis, chronic obstructive pulmonary disease, inflammation post infection, arthritis, atherosclerosis, an allergy, an autoimmune disease, an inflammatory bowel disease, celiac disease, acne, and pain.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
Overall, the claims are directed to structurally defined heteroaromatic compounds and specific enumerated structures, with dependent coverage extending to enzyme inhibition, treatment of diseases associated with 5-LOX and/or PGES pathways, enumerated inflammatory diseases, and pharmaceutical compositions with a pharmaceutically acceptable carrier.
Stated Advantages
The patent states objectives for more potent, better-tolerated, non-hepatotoxic inhibitors.
Documented Applications
Inhibiting enzymes involved in one or more inflammatory pathways.
Treatment of diseases associated with the 5-LOX pathway and/or the prostaglandin E synthase pathway, including inflammatory diseases, cancer, and Alzheimer’s disease.
Treatment of inflammatory diseases including asthma, allergic rhinitis, dermatitis, chronic obstructive pulmonary disease, inflammation post infection, arthritis, atherosclerosis, an allergy, an autoimmune disease, an inflammatory bowel disease, celiac disease, acne, and pain.
A pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
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