Immunomodulator and anti-inflammatory compounds
Inventors
Muthuppalaniappan, Meyyappan • BHAVAR, Prashant K. • Viswanadha, Srikant • VAKKALANKA, Swaroop K. • Merikapudi, Gayatri S.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9758474-B2
Publication Date
2017-09-12
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 inhibitors of dihydroorotate dehydrogenase (DHODH), where DHODH participates in de novo pyrimidine biosynthesis by converting dihydroorotate to orotate. The pathway is associated with immune-cell proliferation, including lymphocytes such as T cells and B cells, and is linked to immunosuppressant and anti-inflammatory effects.
The disclosure describes known DHODH inhibitors and their immunosuppressive and anti-inflammatory mechanisms, while identifying clinical limitations such as side effects, a narrow therapeutic window, and long half-life for agents including leflunomide and teriflunomide, and other compounds such as brequinar and maritimus (FK778). The invention addresses the need for DHODH inhibitors in the context of immune-cell effects.
The invention provides DHODH inhibitors comprising compounds of formula (I), including embodiments of formula IA, together with tautomer, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable ester, and N-oxide forms. The compounds are defined by structural variable definitions for Ring A and Ring B selection and substitution patterns, including substituent R1 on Ring A and X1, X2, and X3 on Ring B, as well as constraints such as L1 and L2 being absent and defined options for Cy, Ra, Rb, Y, and q.
Preferred embodiments and representative named compounds, including salt forms, are introduced, and the disclosure is organized around these formula (I) embodiments and selected substituted benzoic acid carbamoyl derivatives. The compounds are presented as DHODH inhibitor compound claims in the context of immune-cell proliferation and related therapeutic effects.
Claims Coverage
The independent claims cover broad compound-formula DHODH inhibitors of formula (I) with defined structural constraints, specific exemplified compounds selected by name, and related pharmaceutical composition and DHODH-inhibition use methods. Across the independent claims, the inventive features focus on compound structure definition and on DHODH activity inhibition in a mammal via administration and formulation.
Formula (I) DHODH inhibitor compound definition
A compound of formula (I), or a tautomer, stereoisomer, pharmaceutically acceptable salt, pharmaceutically acceptable ester, or N-oxide thereof, wherein Ring A includes substituent R1 and Ring B includes X1, X2 and X3 are selected according to the defined structural rules, L1 and L2 are absent, and Cy, Ra, Rb, Y, and q are defined by the listed groups and constraints, with optional substitution patterns defined by the substituted terminology.
Pharmaceutical composition with compound of formula (I)
A pharmaceutical composition comprising the compound of formula (I) (or defined form), together with a pharmaceutically acceptable carrier.
Combination with additional therapeutic agents
The pharmaceutical composition further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, or suitable mixtures thereof.
Method for inhibiting DHODH activity in a mammal
A method of inhibiting dihydroorotate dehydrogenase (DHODH) activity in a mammal by administering a compound of formula (I) that inhibits DHODH activity in the mammal.
Selected exemplified compounds as DHODH inhibitors
A compound selected from a listed set of named substituted benzoic acid carbamoyl derivatives, and pharmaceutically acceptable salts thereof.
Pharmaceutical composition with a selected exemplified compound
A pharmaceutical composition comprising a compound selected from the listed set of named substituted benzoic acid carbamoyl derivatives and a pharmaceutically acceptable carrier.
Combination with additional therapeutic agents for selected exemplified compounds
The pharmaceutical composition further comprising one or more additional therapeutic agents selected from anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, or suitable mixtures thereof.
Method for inhibiting DHODH activity using selected exemplified compounds
A method of inhibiting DHODH activity in a mammal by administering to the mammal a compound selected from the listed set of named substituted benzoic acid carbamoyl derivatives that inhibits DHODH activity in the mammal.
Selected substituted benzoic acid carbamoyl derivatives
A compound selected from the specifically listed named substituted benzoic acid carbamoyl derivatives, together with pharmaceutically acceptable salts thereof, including compounds of the form 2-(arylcarbamoyl)benzoic acid bearing substituents such as methoxy, ethoxy, fluoro, chloro, trifluoromethoxy, ethylthio, perfluorinated patterns, and substituted biphenyl, pyridinyl, or indolyl substituents.
Overall, the independent claims cover a wide-ranging formula (I) defined by Ring A and Ring B substituent selection rules and substituent parameters, specific selected substituted benzoic acid carbamoyl derivatives listed by name, pharmaceutical compositions including pharmaceutically acceptable carriers and optional additional therapeutic-agent classes, and methods of inhibiting DHODH activity in a mammal by administration of the defined compounds.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Inhibiting dihydroorotate dehydrogenase (DHODH) activity in a mammal by administering a compound of formula (I).
Inhibiting DHODH activity in a mammal by administering a compound selected from the listed exemplified substituted benzoic acid carbamoyl derivatives.
Pharmaceutical compositions with a pharmaceutically acceptable carrier and optional additional therapeutic agents selected from anti-inflammatory agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, and analgesics.
Immunological assays measuring IL-17 release or production and PBMC proliferation and cytokine readouts in the context of anti-inflammatory or autoimmune relevance, including ConA lymphocyte or IL-17 effects and TNBS colitis.
Single-dose oral hepatotoxicity assessment in mice reporting ALT and AST.
Interested in licensing this patent?