Compounds for treatment of inflammation, diabetes and related disorders

Abstract

Novel acyl urea, thiourea, carbamate, thiocarbamate and related compounds are provided which are effective in inhibiting the cytokine-mediated inflammatory response in cultured cells, in ameliorating bone destruction in an animal model of arthritis and in lowering blood glucose levels in animal models of Type II diabetes mellitus. The compounds are disclosed as useful for a variety of treatments including the treatment of diabetes mellitus, insulin resistance, inflammation, inflammatory, diseases, immunological diseases and cancer.

1 . A compound, or salt, hydrate or solvate thereof, represented by at least one of the following Formulas I-XIII: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein the stereocenters marked with an asterisk (*) are R- or S-; the bond represented by a dashed line plus a solid line is a double bond or a single bond; and wherein
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 20  aryl, linear or branched alkylaryl, linear or branched alkenylaryl; COOR where R independently represents a hydrogen atom, or an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, tromethamine; CONR′R″, where R′ and R″ independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl or where NR′R″ represents a cyclic moiety selected from morpholine, piperidine, piperazine; optionally substituted C 1 -C 6  amidoalkyl; NH 2 ; C 1 -C 20  alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; optionally substituted C 1 -C 20  alkoxy, optionally substituted C 1 -C 20  alkanoyl; optionally substituted C 1 -C 20  acyloxy; halo; optionally substituted C 1 -C 20  alkylcarboxylamino; cyano; nitro; SO 2 NR′″R″″ where R′″ and R″″ are independently H, C 1 -C 20  alkyl or aryl; SO 2 R′″ where R′″ is H, C 1 -C 20  alkyl or aryl; SO 3 R′″ where R′″ is H, C 1 -C 20  alkyl or aryl; and C 4 -C 8  heterocycles selected from tetrazolyl, imidazolyl, pyrrolyl, pyridyl or indolyl; 
 R 8  and R 9  independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; COOR where R is H, optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, or tromethamine; CONR′R″, where R′ and R″ are independently H, alkoxy, optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl, optionally substituted C 3 -C 10  cycloalkyl or cycloalkenyl or optionally substituted C 6 -C 10  aryl or heteroaryl, or where NR′R″ represents a cyclic moiety selected from morpholine, piperidine, hydroxypiperidine, imidazole, piperazine, or methylpiperazine; NH 2 ; C 1 -C 20  alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; C 1 -C 20  alkoxy; C 1 -C 20  alkanoyl; C 1 -C 20  acyloxy; halo; C 1 -C 20  alkylcarboxylamino; cyano; nitro; SO 2 NR′″R″″ where R′″ and R″″ are independently H, C 1 -C 20  alkyl or aryl; SO 2 R′″ where R′″ is H, C 1 -C 20  alkyl or aryl; SO 3 R′″ where R′″ is H, C 1 -C 20  alkyl or aryl; or tetrazolyl; 
 R 10  and R 11  independently represent a hydrogen atom or an optionally substituted C 1 -C 20  linear or branched alkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; COOR where R represents a hydrogen atom or an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, or tromethamine; CONR′R″, where R′ and R″ independently represent a hydrogen atom, optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl or where NR′R″ represents a cyclic moiety selected from morpholine, piperidine, or piperazine; NH 2 ; C 1 -C 20  alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; C 1 -C 20  alkoxy; C 1 -C 20  alkanoyl; C 1 -C 20  acyloxy; halo; C 1 -C 20  alkylcarboxylamino; cyano; nitro; SO 2 NR′″R″″ where R′″ and R″″ independently represent a hydrogen atom, C 1 -C 20  alkyl or aryl; SO 2 R′″ where R′″ represents a hydrogen atom, C 1 -C 20  alkyl or aryl; SO 3 R′″ where R′″ represents a hydrogen atom, C 1 -C 20  alkyl or aryl; or tetrazolyl; 
 R 12 , R 13 , R 18 , R 19  and R 20  independently represent a hydrogen atom; or an optionally substituted C 1 -C 20  linear or branched alkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; COOR where R represents an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, or tromethamine; CONR′R″, where R′ and R″ independently represent a hydrogen atom, optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl or where NR′R″ represents a cyclic moiety selected from morpholine, piperidine and piperazine; C 1 -C 20  alkanoyl; C 1 -C 20  alkylamido; C 6 -C 20  aroyl or heteroaroyl; SO 2 R′″ where R′″ represents a hydrogen atom, C 1 -C 20  alkyl or aryl; morpholinocarbonylmethyl; piperazinocabonylmethyl; or piperadinocabonylmethyl; 
 R 12  and R 13  may be absent, or R 12  and R 13  together may be an optionally substituted heterocyclic ring selected from morpholine, piperidine, piperazine, and N-methylpiperidine; 
 R 14  represents a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl including chloroalkyl and fluoroalkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; COOR where R represents a hydrogen atom, optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, or tromethamine; CONR′R″, where R′ and R″ independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl or where NR′R″ represents a cyclic moiety selected from morpholine, piperidine and piperazine; cyano; and tetrazolyl 
 R 15 , R 16  and R 17  independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl including chloroalkyl and fluoroalkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; COOR where R represents a hydrogen atom, or an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, and tromethamine; CONR′R″, where R′ and R″ independently represent a hydrogen atom, an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl or where NR′R″ represents a cyclic moiety selected from morpholine, piperidine, and piperazine; NH 2 ; C 1 -C 20  alkylamino, bis(alkylamino), cycloalkylamino or cyclic amino; OH; C 1 -C 20  alkoxy; C 1 -C 20  alkanoyl; C 1 -C 20  acyloxy; halo; C 1 -C 20  alkylcarboxylamino; cyano; nitro; SO 2 NR′″R″″ where R′″ and R″″ independently represent a hydrogen atom, C 1 -C 20  alkyl or aryl; SO 2 R′″ where R′″ independently represents a hydrogen atom, C 1 -C 20  alkyl or aryl; SO 3 R′″ where R′″ independently represents a hydrogen atom, C 1 -C 20  alkyl or aryl; or tetrazolyl 
 X independently represents O; N; S; S═O; SO 2 ; or NR′″″, where R′″″ independently represents a hydrogen atom or optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl, optionally substituted C 1 -C 20  acyl, optionally substituted C 1 -C 20  acyloxy and optionally substituted C 1 -C 20  alkoxycarbonyl; 
 Y independently represents an oxygen atom, sulfur atom or NH radical; 
 Z independently represents
 OR a , wherein R a  represents a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl, optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; optionally substituted C 6 -C 20  aroyl or heteroaroyl; optionally substituted C 1 -C 20  alkanoyl; or SO 2 R′″ where R′″ represents a hydrogen atom, C 1 -C 20  alkyl or aryl; 
 NR b R c , wherein R b  and R c  independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; optionally substituted C 3 -C 10  cycloalkyl or cycloalkenyl; COOZ 1  where Z 1  represents an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl; optionally substituted C 6 -C 20  aroyl or heteroaroyl; optionally substituted C 1 -C 20  alkanoyl; or SO 2 R′″ where R′″ represents a hydrogen atom, or an C 1 -C 20  alkyl or aryl; or wherein R b  and R c  together may be joined to form a 3-6 membered ring selected from aziridine, morpholine, piperidine or piperazine; and 
 CR d R e R f , wherein R d , R e  and R f  independently represents represent a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl, optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; optionally substituted C 3 -C 10  cycloalkyl or cycloalkenyl; COOR where R represents a hydrogen atom, or an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl, sodium, potassium, calcium, magnesium, ammonium, or tromethamine; NH 2 ; C 1 -C 20  alkylamino, bis(alkylamino); cycloalkylamino or cyclic amino; OH; optionally substituted C 1 -C 20  alkoxy, trifluoromethoxy; optionally substituted C 1 -C 20  alkanoyl; optionally substituted C 1 -C 20  acyloxy; optionally substituted C 6 -C 20  aroyl or heteroaroyl; halo; cyano; nitro; optionally substituted C 1 -C 20  alkylcarboxylamino; SO 2 NR′″R″″ where R′″ and R″″ independently represent a hydrogen atom, C 1 -C 20  alkyl or aryl; SO 2 R′″ where R′″ independently represents a hydrogen atom, C 1 -C 20  alkyl or aryl; or SO 3 R′″ where R′″ independently represents a hydrogen atom, C 1 -C 20  alkyl or aryl; or 
 
 the grouping —C(═Y)Z may represent hydrogen or R 12  or may be absent 
 Q is selected from the group consisting of
 OR a  where R a  independently represents a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; optionally substituted C 6 -C 20  aroyl or heteroaroyl; optionally substituted C 1 -C 20  alkanoyl; and SO 2 R′″ where R′″ independently represents a hydrogen atom, C 1 -C 20  alkyl or aryl; and 
 NR b R c  where R b  and R c  independently represent a hydrogen atom, or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 10  aryl or heteroaryl; optionally substituted C 3 -C 10  cycloalkyl or cycloalkenyl; COOZ 1  where Z 1  represents an optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl or optionally substituted C 6 -C 10  aryl; optionally substituted C 6 -C 20  aroyl or heteroaroyl; optionally substituted C 1 -C 20  alkanoyl; or SO 2 R′″ where R′″ independently represents a hydrogen atom, or an C 1 -C 20  alkyl or aryl; or herein R b  and R c  represent together a 3-6 membered ring such as aziridine, morpholine, piperidine, piperazine and the like; and 
 SR g , SOR g  or SO 2 R g  where R g  represents a hydrogen atom or an optionally substituted C 1 -C 20  linear or branched alkyl, chloroalkyl or fluoroalkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 1 -C 20  acyl; optionally substituted C 1 -C 20  alkoxycarbonyl; C 2 -C 20  alkoxy; optionally substituted C 6 -C 10  aryl or heteroaryl; and optionally substituted C 6 -C 10  aroyl or heteroaroyl; 
 
 Group A represents an optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 20  aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally substituted heteroaryl selected from pyridine, indole, morpholine, piperidine, tetrazolyl and piperazine; COR h  where R h  represents an optionally substituted C 1 -C 20  linear or branched alkyl; optionally substituted C 2 -C 20  linear or branched alkenyl; optionally substituted C 6 -C 20  aryl, linear or branched alkylaryl, linear or branched alkenylaryl; optionally substituted heteroaryl selected from pyridine, indole, morpholine, piperidine, piperazine, or tetrazolyl; 
 Group B represents a OH, C 1 -C 20  alkoxy; SO 2 R i  where R i  represents a hydrogen atom or linear or branched C 1 -C 20  alkyl. 
 Group Het represents a heterocyclic ring selected from pyridyl, indolyl, tetrazolyl, imidazolyl, morphonyl, piperidinyl, piperazinyl or thiophenyl. 
 
     
     
         2 .- 65 . (canceled)