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US 12,673,957 B2Granted
Inhibition of glial cell activation
AssigneeLapko Inc
InventorBruce Kovacs
Life of this patent
Estimating the term…
Abstract
Compounds and methods useful for inhibition of glial cell activation and for the treatment of diseases associated with increased glial cell activation in mammalian species including humans are presented.
Claims13
A method for the inhibition of glial cell activation in a human subject in need thereof comprising administering an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, or ester, thereof optionally in association with a pharmaceutically acceptable adjuvant, diluent, or carrier
- wherein:
- A is selected from 2,3-dihydro-1,4-benzodioxin-6-yl, 1,4-benzodioxin-6-yl, 2,3-dihydro-1,4-benzoxathiin-6-yl, 2,3-dihydro-1,4-benzoxathiin-6-yl, 1,4-benzoxathiin-6-yl, 1,4-benzoxathiin-6-yl, 7-(yl)chroman-4-one, 6-(yl)chroman-4-one, 7-(yl)chromen-4-one, 7-(yl)chromen-4-one, 2,3-dihydrobenzo[g][1,4]benzodioxin-7-yl, benzo[g][1,4]benzodioxin-7-yl, 2,3-dihydrobenzo[g][1,4]benzoxathiin-7-yl, 2,3-dihydrobenzo[g][1,4]benzoxathiin-8-yl, benzo[g][1,4]benzoxathiin-7-yl, benzo[g][1,4]benzoxathiin-8-yl, 8-(yl)2,3-dihydrobenzo[g]chromen-4-one, 7-(yl)2,3-dihydrobenzo[g]chromen-4-one, 8-(yl)benzo[g]chromen-4-one, 7-(yl)benzo[g]chromen-4-one, each of which may be optionally substituted;
- D is selected from COCH2, COCH2CH2, COCH2CH2CH2, CH2COCH2CH2, CHOHCH2CH2, COCHCH, COCH2CH(CH3), COCHC(CH3), COCH2CO, COSCH2CH2, COSCOCH2, COOCH2CH2, CONHCH2CH2, COCH2COCH2, COCOCH2, CHSCOCH2, COCOCH2CH2, SO2CH2CH2, SO2CH2CH2CH2, SO2CH2CH(CH3), SO2CHC(CH3), SO2CH2COCH2, CH2COCH2CH2, COC6H4CH2, C6H4COCH2CH2, C6H4COCH2, COCH2C6H4, COOCH2C6H4, COSCH2C6H4, COC5NH3CH2, C5NH3COCH2CH2, C5NH3COCH2, COCH2C5NH3, COOCH2C5NH3, COSCH2C5NH3, CH2NHCOCH2CH2, CH2CH(OH)CH2CH2;
- n is 1;
- R1, R2, R3, and R4 are independently selected from H, OH, F, Cl, Br, I, (halogen)alkyl, optionally substituted C1 to C8 straight chain or branched chain alkyl, optionally substituted C1 to C8 cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted C1 to C8 alkenyl, optionally substituted C1 to C8 alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl, O-alkyl, O-optionally substituted alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O-optionally substituted aryl, alkyl-O-aryl, alkyl-O-optionally substituted aryl, C(O)-aryl, C(O)-optionally substituted aryl, CH2C(O)-aryl, CH2C(O)-optionally substituted aryl, O-(halogen)alkyl, wherein adjacent substituents R1 and R3, R2 and R4, when present, may form a saturated or unsaturated 5 membered or 6-membered or 7 membered carbocyclic or heterocyclic ring;
- wherein alkenyl, if present, may refer to one or more double bond and each double bond may independently be cis or trans, E or Z, a cis/trans mixture or an E/Z mixture and wherein if an asymmetric center is present or asymmetric centers are present the compound may be in the form of a racemic mixture, a single enantiomer, a diastereoisomeric mixture, an enantiomeric diastereomer, a meso compound, a pure epimer, or a mixture of epimers thereof and wherein a hydrogen, several hydrogens or all hydrogens may be replaced with deuterium,
- wherein inhibition of glial cell activation treats a treatment of a disease or disorder selected from the group consisting of Alzheimer's disease, Amyotrophic lateral sclerosis, Frontotemporal lobar dementia, Parkinson's disease, Prion diseases, Ataxia, Multiple system atrophy, Corticobasal degeneration, Guillain-Barre syndrome, Lewy body dementia, Multiple sclerosis, Motor neuron disease, Retinopathy, Spinocerebellar ataxia, Huntington's disease, Autism Spectrum Disorder, Attention Deficit Hyperactivity disorder, Fragile X syndrome, Bipolar disorder, Post-Traumatic Stress disorder, Schizophrenia, Diabetic neuropathy, Neuropathic pain, Neuromyelitis Optica spectrum disorder, Post-Traumatic Brain Injury syndrome, and epilepsy.
4 more elements
A method to simultaneously inhibit the production by glial cells of at least two biomarkers selected from the group consisting of CCL2, CCL5, CXCL10, IL-1beta, IL-6, INF-beta, TNF-alpha, and VEGF, under conditions that produce activation of glial cells, comprising administering to a patient in need thereof an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, or ester, thereof optionally in association with a pharmaceutically acceptable adjuvant, diluent, or carrier
- wherein:
- A is selected from 2,3-dihydro-1,4-benzodioxin-6-yl, 1,4-benzodioxin-6-yl, 2,3-dihydro-1,4-benzoxathiin-6-yl, 2,3-dihydro-1,4-benzoxathiin-6-yl, 1,4-benzoxathiin-6-yl, 1,4-benzoxathiin-6-yl, 7-(yl)chroman-4-one, 6-(yl)chroman-4-one, 7-(yl)chromen-4-one, 7-(yl)chromen-4-one, 2,3-dihydrobenzo[g][1,4]benzodioxin-7-yl, benzo[g][1,4]benzodioxin-7-yl, 2,3-dihydrobenzo[g][1,4]benzoxathiin-7-yl, 2,3-dihydrobenzo[g][1,4]benzoxathiin-8-yl, benzo[g][1,4]benzoxathiin-7-yl, benzo[g][1,4]benzoxathiin-8-yl, 8-(yl)2,3-dihydrobenzo[g]chromen-4-one, 7-(yl)2,3-dihydrobenzo[g]chromen-4-one, 8-(yl)benzo[g]chromen-4-one, 7-(yl)benzo[g]chromen-4-one, each of which may be optionally substituted;
- D is selected from COCH2, COCH2CH2, COCH2CH2CH2, CH2COCH2CH2, CHOHCH2CH2, COCHCH, COCH2CH(CH3), COCHC(CH3), COCH2CO, COSCH2CH2, COSCOCH2, COOCH2CH2, CONHCH2CH2, COCH2COCH2, COCOCH2, CHSCOCH2, COCOCH2CH2, SO2CH2CH2, SO2CH2CH2CH2, SO2CH2CH(CH3), SO2CHC(CH3), SO2CH2COCH2, CH2COCH2CH2, COC6H4CH2, C6H4COCH2CH2, C6H4COCH2, COCH2C6H4, COOCH2C6H4, COSCH2C6H4, COC5NH3CH2, C5NH3COCH2CH2, C5NH3COCH2, COCH2C5NH3, COOCH2C5NH3, COSCH2C5NH3, CH2NHCOCH2CH2, CH2CH(OH)CH2CH2;
- n is 1;
- R1, R2, R3, and R4 are independently selected from H, OH, F, Cl, Br, I, (halogen)alkyl, optionally substituted C1 to C8 straight chain or branched chain alkyl, optionally substituted C1 to C8 cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted C1 to C8 alkenyl, optionally substituted C1 to C8 alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl, O-alkyl, O-optionally substituted alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O-optionally substituted aryl, alkyl-O-aryl, alkyl-O-optionally substituted aryl, C(O)-aryl, C(O)-optionally substituted aryl, CH2C(O)-aryl, CH2C(O)-optionally substituted aryl, O-(halogen)alkyl, wherein adjacent substituents R1 and R3, R2 and R4, when present, may form a saturated or unsaturated 5 membered or 6-membered or 7 membered carbocyclic or heterocyclic ring;
- wherein alkenyl, if present, may refer to one or more double bond and each double bond may independently be cis or trans, E or Z, a cis/trans mixture or an E/Z mixture and wherein if an asymmetric center is present or asymmetric centers are present the compound may be in the form of a racemic mixture, a single enantiomer, a diastereoisomeric mixture, an enantiomeric diastereomer, a meso compound, a pure epimer, or a mixture of epimers thereof and wherein a hydrogen, several hydrogens or all hydrogens may be replaced with deuterium.
3 more elements
A compound according to Formula 1
- wherein:
- A is selected from 2,3-dihydro-1,4-benzodioxin-6-yl, 1,4-benzodioxin-6-yl, 2,3-dihydro-1,4-benzoxathiin-6-yl, 2,3-dihydro-1,4-benzoxathiin-6-yl, 1,4-benzoxathiin-6-yl, 1,4-benzoxathiin-6-yl, 7-(yl) chroman-4-one, 6-(yl) chroman-4-one, 7-(yl) chromen-4-one, 7-(yl) chromen-4-one, 2,3-dihydrobenzo [g][1,4]benzodioxin-7-yl, benzo [g][1,4]benzodioxin-7-yl, 2,3-dihydrobenzo [g][1,4]benzoxathiin-7-yl, 2,3-dihydrobenzo [g][1,4]benzoxathiin-8-yl, benzo [g][1,4]benzoxathiin-7-yl, benzo [g][1,4]benzoxathiin-8-yl, 8-(yl) 2,3-dihydrobenzo [g]chromen-4-one, 7-(yl) 2,3-dihydrobenzo [g]chromen-4-one, 8-(yl) benzo [g]chromen-4-one, 7-(yl) benzo [g]chromen-4-one, each of which may be optionally substituted;
- D is selected from COCH2, COCH2CH2, COCH2CH2CH2, CH2COCH2CH2, CHOHCH2CH2, COCHCH, COCH2CH(CH3), COCHC(CH3), COCH2CO, COSCH2CH2, COSCOCH2, COOCH2CH2, CONHCH2CH2, COCH2COCH2, COCOCH2, CHSCOCH2, COCOCH2CH2, SO2CH2CH2, SO2CH2CH2CH2, SO2CH2CH(CH3), SO2CHC(CH3), SO2CH2COCH2, CH2COCH2CH2, COC6H4CH2, C6H4COCH2CH2, C6H4COCH2, COCH2C6H4, COOCH2C6H4, COSCH2C6H4, COC5NH3CH2, C5NH3COCH2CH2, C5NH3COCH2, COCH2C5NH3, COOCH2C5NH3, COSCH2C5NH3, CH2NHCOCH2CH2, CH2CH(OH) CH2CH2;
- nis 1;
- R1, R2, R3, and R4 are independently selected from H, OH, F, CI, Br, I, (halogen)alkyl, optionally substituted C1 to C8 straight chain or branched chain alkyl, optionally substituted C1 to C8 cycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, optionally substituted C1 to C8 alkenyl, optionally substituted C1 to C8 alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted heteroaryl, optionally substituted alkylheteroaryl, O-alkyl, O-optionally substituted alkyl, O-cycloalkyl, O-alkylcycloalkyl, O-aryl, O-optionally substituted aryl, alkyl-O-aryl, alkyl-O-optionally substituted aryl, C(O)-aryl, C(O)-optionally substituted aryl, CH2C(O)-aryl, CH2C(O)-optionally substituted aryl, O-(halogen) alkyl, wherein adjacent substituents R1 and R3, R2 and R4, when present, may form a saturated or unsaturated 5 membered or 6-membered or 7 membered carbocyclic or heterocyclic ring;
- wherein alkenyl, if present, may refer to one or more double bond and each double bond may independently be cis or trans, E or Z, a cis/trans mixture or an E/Z mixture and wherein if an asymmetric center is present or asymmetric centers are present the compound may be in the form of a racemic mixture, a single enantiomer, a diastereoisomeric mixture, an enantiomeric diastereomer, a meso compound, a pure epimer, or a mixture of epimers thereof and wherein a hydrogen, several hydrogens or all hydrogens may be replaced with deuterium,
- wherein the compound is selected from compounds 2-521;
- or a pharmaceutically acceptable salt, or ester thereof.
5 more elements
Dependencies are inferred from the claim text.