2-oxo-2,3-dihydro-indoles for the treatment of CNS disorders
Inventors
Brunner, Daniela • Malberg, Jessica • Shankar, Bavani G. • Kolczewski, Sabine • Limberg, Anja • Prinssen, Eric • Riemer, Claus • Stoll, Theodor
Assignees
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Publication Number
US-9221816-B2
Publication Date
2015-12-29
Expiration Date
Abstract
The present invention is concerned with 2-oxo-2,3-dihydro-indoles of general formula wherein is phenyl or a heteroaryl group, selected from pyridinyl, pyrimidinyl, imidazolyl, isoxazolyl or pyrazolyl; is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be on all free positions; R1 is hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy or halogen; n is 1 or 2; if n is 2, R1 may be the same or not; R2/R2′ are independently from each other lower alkyl, or form together with the carbon atom to which they are attached a C3-6-cycloalkyl ring;R3 is lower alkyl, C3-6-cycloalkyl, CH2—C3-6-cycloalkyl, C3-6-cycloalkyl wherein one ring-carbon atom is replaced by —O—, (CH2)3—O—C3-6-cycloalkyl, lower alkyl substituted by hydroxy, lower alkyl substituted by halogen, (CH2)3—S(O)2—C3-6-cycloalkyl or (CH2)2—S(O)2-lower alkyl;R4 is hydrogen, halogen or lower alkyl; m is 1 or 2; if m is 2, R4 may be the same or not; as well as with a pharmaceutically acceptable salts thereof, with a racemic mixture, or with its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
Core Innovation
The invention relates to compounds of formula I and formula I-1, including pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and stereoisomers. The compounds are defined with phenyl or heteroaryl groups selected from pyridinyl, pyrimidinyl, imidazolyl, isoxazolyl or pyrazolyl, together with substituent variables R1, R2/R2′, R3, R4, n, and m, including restrictions on ring placement and ring-forming options for R2/R2′.
The disclosure describes indolinone-isonicotinamide, pyrimidine, carboxamide, and related 2-oxo-2,3-dihydro-indole compounds, including spiro-indolinone–isonicotinamides and non-spiro pyrrolo[2,3-b]pyridine/pyrrolo[3,2-c]pyridine isonicotinamides. The examples include substituted nicotinamide variants, oxetanyl substituents, cyclopropyl and cyclopropoxypropyl substituents, fluoro and chloro variants, and named compound examples spanning a broad heteroaromatic amide series.
The invention also frames synthetic routes that convert isatin derivatives into lactam or intermediate general formulas and install aryl substituents through multi-step transformations. Example compounds are accompanied by preparation and characterization information, including MS ESI and 1H NMR, and reaction notes referencing isonicotinic acid and acid chloride derivatives with corresponding indolinone intermediates.
Claims Coverage
The claims coverage centers on a broad compound of formula I with defined aromatic/heteroaryl options and detailed substitution rules for R1, R2/R2′, R3, R4, n, and m, including salts and stereochemical forms. Dependent claim language narrows specific heteroaryl choices, fixes selected pyridinyl substitution patterns, adds combination coverage with marketed psychiatric drugs, and includes a preparation concept using defined intermediates.
Formula I compound with defined aromatic and heteroaryl substituents
A compound of formula I wherein the aromatic/heteroaryl group is phenyl or a heteroaryl group selected from pyridinyl, pyrimidinyl, imidazolyl, isoxazolyl or pyrazolyl, with defined options for R1, R2/R2′, R3, R4, n and m, and including pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and stereoisomers thereof.
Heteroaryl selection narrows to pyrimidinyl or imidazolyl with phenyl substituent
A compound of formula I having a specified heteroaryl group that is either pyrimidinyl or imidazolyl and another specified substituent group that is phenyl.
Both N positions are pyridinyl groups
A compound corresponding to formula I such that the (N1-) and (N2-) substituents shown in the structure are both pyridinyl groups.
Combination with marketed psychiatric drugs
A combination of a compound defined by formula I or a specified N-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methyl-isonicotinamide with a known marketed psychiatric drug selected from antipsychotics, antidepressants, anxiolytics, or mood stabilizers.
Preparation process using defined intermediates and optional acid addition salts
A process prepares a compound of formula I by reacting a specified compound of one formula with another specified compound of a different formula, where X is hydroxy or chlorine and the substituent meanings follow the definition of formula I, and optionally converts the resulting compounds into pharmaceutically acceptable acid addition salts.
The claims are directed to formula I compounds with defined phenyl or heteroaryl selection and structured substitution rules for R1 through R4 plus n and m, together with pharmaceutically acceptable salts and stereochemical variants. The dependent coverage further narrows heteroaryl identity and pyridinyl substitution, and adds combination and preparation embodiments.
Stated Advantages
Compounds of formula I/I-1 reduce L-687,414-induced hyperlocomotion in mice.
Activity comparable to antipsychotics is suggested by SmartCube® similarity analyses.
Reported similarity/discrimination-rate results indicate that example compounds show similar neuropharmacological signatures to clinically approved atypical antipsychotics.
Documented Applications
Reduction of L-687,414-induced hyperlocomotion in mice.
Combination therapy context with marketed psychiatric drugs, including antipsychotics, antidepressants, anxiolytics, or mood stabilizers.
Treating central nervous system disorders including schizophrenia symptoms, substance abuse, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression and treatment resistant depression, anxiety disorders, and neurodegenerative and other disorders including Alzheimer’s disease and Parkinson’s disease.
Additional disorder use cases including autism, chronic pain, borderline personality disorder, sleep disturbances, chronic fatigue syndrome, arthritis antiinflammatory effects, and balance problems.
Use of SmartCube® behavioral profiling results to compare example compounds with atypical antipsychotics, supporting CNS indication context.
Pharmaceutical preparations and administration routes, including tablets and oral/parenteral administration.
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