US 6,608,101 B1 · 1, 3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders

Abstract

It has been discovered certain 1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds of formula (I) inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.

A compound of the formula (I):

or its pharmaceutically acceptable salt, wherein:
i) the wavy line indicates that the compound can be in the form of the E or Z isomer;
ii) R22 and R23 are independently hydrogen or (C1-C4)alkyl;
iii) R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β and R6β are independently hydrogen, alkyl, carbocycle, aryl, heteroaryl, heterocycle, cycloalkyl, alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl, haloalkyl, aryloxy, amido, acylamino, amino, dialkylamino, aminodialkyl, trifluoroalkoxy, alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, alkenyl, alkynyl, halogen, hydroxyl, thiol, cyano, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide, sulfoxide, metal sulfinate, phosphate, phosphonate, metal phosphonate, phosphinate, alditol, carbohydrate, amino acid, OC(R1)2CO2H, SC(R1)2CO2H, NHC(R1)2CO2H, CO—R2, CO2R1, polyoxyalkylene, polyol alkyl, oxyalkylamino, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl;
hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower aikyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which can be optionally substituted with a moiety that does not adversely affect the biological properties of the molecule;
—C(O)(CH2)2CO2−M+, —SO3M+, or -lower alkyl-O—R, wherein R is PO2(OH)−M+, PO3(OH)−M+ or —SO3M+, wherein M+ is a pharmaceutically acceptable cation;
-lower alkylcarbonyl-lower alkyl;
carboxy lower alkyl;
-lower alkylamino-lower alkyl;
N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl;
iv) R1 is H, lower alkyl, an optionally substituted carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheteroaryl or alkylheterocycle;
v) R2 is an optionally substituted alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheteroaryl or alkylheterocycle;
vi) alternatively, R22 and R6α or R23 and R6α can join together to form a bridged carbocycle, aryl, heterocycle or heteroaromatic;
vii) R2α and R3α, R3α and R4α, R4α and R5α, R5α and R6α, R2β and R3β, R3β and R4β, R4β and R5β or R5β and R6β can independently join to form a bridged compound selected from the group consisting of an optionally substituted carbocycle, an optionally substituted cycloalkenyl, an optionally substituted cycloalkylcarbonyl, an optionally substituted cycloalkenylcarbonyl;
an optionally substituted aryl, an optionally substituted heterocylic or an optionally substituted heteroaromatic, or alkylenedioxy or wherein the ring can include a carbonyl, cyclic ester, amide, amine, sulfonate, or phosphonate;
viii) at least one of R2α, R3α, R4α, R5α, R6α, R2β, R3β, R4β, R5β or R6β is, or R2α and R3α, R3α and R4α, R4α and R5α, R5α and R6α, R2β and R3β, R3β and R4β, R4β and R5β or R5β and R6β come together to be, an optionally substituted saturated or unsaturated thienyl or benzothienyl;
and
ix) at least one of R2α, R3α, R4α, R5α, or R6α, and at least one of R2β, R3β, R4β, R5β or R6β is a substituent other than hydrogen.

15 more elements

1, 3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders

Life of this patent

1, 3-bis-(substituted-phenyl)-2-propen-1-ones and their use to treat VCAM-1 mediated disorders

Life of this patent

Abstract

Claims49