Immunomodulator and anti-inflammatory compounds
Inventors
Muthuppalaniappan, Meyyappan • BHAVAR, Prashant K. • Viswanadha, Srikant • Vakkalanka, Swaroop Kumar V. S. • Merikapudi, Gayatri S.
Assignees
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Publication Number
US-8686048-B2
Publication Date
2014-04-01
Expiration Date
Abstract
The present invention provides dihydroorotate dehydrogenase inhibitors, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders wherein the inhibition of Dihydroorotate dehydrogenase is known to show beneficial effect.
Core Innovation
The invention relates to compounds of formula (I) and formula (IA), including tautomers, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable esters, and N-oxides thereof. The compounds are characterized as IL-17 and/or DHODH-targeting therapeutic agents and as a class of structurally defined small molecules to achieve DHODH modulation, including DHODH inhibition in a mammal through administration of the compound.
The disclosure provides compounds useful for treating disorders where DHODH inhibition is beneficial, including immunological disorders, inflammatory disorders, cancers/proliferative diseases, angiogenesis-related disorders, viral and infectious diseases, and immune system-related indications. It also places the compounds in the context of immunosuppression for transplant rejection and graft-versus-host disease.
Pharmaceutical compositions are also disclosed, including the compound with a pharmaceutically acceptable carrier and an effective amount, and compositions that further comprise one or more further therapeutic agents selected from specified anti-inflammatory, immunosuppressive/immunomodulatory, steroid, non-steroidal anti-inflammatory, antihistamine, and analgesic agents.
Claims Coverage
The independent claims cover structurally defined DHODH inhibitor compounds and specific enumerated compound selections. Across the provided independent claims, the core coverage centers on chemical structure specification, with 4 inventive feature groupings for the compound and method claims, plus claim coverage for pharmaceutical compositions.
Defined compound of formula (IA) with ring selections and Cy substituent options
A compound of formula (IA), or a tautomer, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or N-oxide thereof, wherein Ring A including R1 is selected from the defined options, Ring B is selected from the defined options, L2 is absent or is O—CH2—, and Cy is phenyl, indole or indazole, unsubstituted or substituted with allowed substituents.
Selected substituted biphenyl/benzoic acid carbamoyl derivatives and salts
A compound selected from the group consisting of the specifically listed substituted biphenyl/benzoic acid carbamoyl derivatives and related structures, together with pharmaceutically acceptable salts thereof.
Selected pyrazine-2-carboxylic acid, benzamide, and nicotinic acid derivatives and salts
A compound selected from the group consisting of the specifically listed 3-(substituted biphenylcarbamoyl)pyrazine-2-carboxylic acid derivatives, N-(substituted biphenyl)-2-(hydroxymethyl)benzamide derivatives, and substituted nicotinic acid derivatives, together with pharmaceutically acceptable salts thereof.
Inhibiting DHODH activity in a mammal by administration
A method for inhibiting dihydroorotate dehydrogenase (DHODH) activity in a mammal by administering the compound of claim 1, wherein administering inhibits DHODH activity in the mammal.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier and an effective amount.
Pharmaceutical composition including optional additional therapeutic agents
A pharmaceutical composition further comprising one or more further therapeutic agents selected from specified anti-inflammatory, immunosuppressive/immunomodulatory, steroid, non-steroidal anti-inflammatory, antihistamine, and analgesic agents, or suitable mixtures thereof.
Overall, the claims coverage centers on structurally defined DHODH inhibitor compounds: a genus of formula (IA) with specified ring selections and Cy substituent classes, plus enumerated claims for substituted biphenyl/benzoic acid carbamoyl derivatives and for pyrazine-2-carboxylic acid, benzamide, and nicotinic acid derivatives. The claim family also extends to pharmaceutical compositions with a pharmaceutically acceptable carrier and optional further therapeutic agents, and to methods of inhibiting DHODH activity in a mammal by administering the compounds.
Stated Advantages
Compounds are described as IL-17 and/or DHODH-targeting therapeutic agents.
Use in treating disorders where DHODH inhibition is beneficial, including immunosuppression such as transplant rejection and graft-versus-host disease.
Therapeutic indications described across immunological disorders, inflammatory disorders, cancers/proliferative diseases, angiogenesis-related disorders, viral and infectious diseases, and immune system-related indications.
Provides an immunosuppressive/anti-inflammatory therapy rationale via DHODH inhibition, including pyrimidine de novo synthesis inhibition, reduction of rUMP, and G1 phase cell-cycle arrest.
Aims to address limitations and side effects associated with known DHODH inhibitors such as leukocytopenia and thrombocytopenia.
DHODH inhibition reported with IC50 values for multiple Examples.
IL-17 inhibition reported in mouse splenocytes and PBMC assays.
Single-dose oral hepatotoxicity evaluation in mice reported via ALT and AST measurements.
Documented Applications
Treatment of immunosuppression, including transplant rejection and graft-versus-host disease.
Treatment of immunological disorders and inflammatory disorders.
Treatment of cancers/proliferative diseases.
Treatment of tumor angiogenesis-related disorders.
Treatment of viral and infectious diseases.
Chemoprevention is mentioned as an application context in the document.
Pharmaceutical compositions comprising the compound with a pharmaceutically acceptable carrier and an effective amount.
Immunosuppressive/anti-inflammatory therapy rationale using DHODH inhibition, affecting lymphocytes and associated cytokine production and NF-kB signaling.
Inhibition of dihydroorotate dehydrogenase (DHODH) activity in a mammal by administering the claimed compound.
Anti-inflammatory/autoimmune animal model use, including a TNBS colitis model with dexamethasone and teriflunomide reference.
Biological activity assessment including DHODH inhibition and downstream IL-17 inhibition in mouse splenocytes and PBMC assays.
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