Bicyclic pyrazolone cytokine inhibitors

Abstract

The present invention relates to 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 6,7-dihydro-5H-pyrazolo[1,2a]pyrazol-1-ones and methods for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.

1 . A compound, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula: 
     
       
         
         
             
             
         
       
     
     wherein R is:
 a) —O[CH 2 ] k R 3 ; or 
 b) NR 4a R 4b ; 
 R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
 the index k is from 0 to 5; 
 R 4a  and R 4b  are each independently: 
 a) hydrogen; or 
 b) -[C(R 5a R 5b )] m R 6 ; 
 each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
 R 1  is: 
 a) substituted or unsubstituted aryl; or 
 b) substituted or unsubstituted heteroaryl; 
 L is a linking group chosen from: 
 i) -[C(R 12 )] n -; 
 ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
 iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n —; 
 R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
 each R 2  unit is independently chosen from: 
 a) hydrogen; 
 b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
 c) -(CH 2 ) j NR 9a R 9b ; 
 d) -(CH 2 ) j CO 2 R 10 ; 
 e) -(CH 2 ) j OCO 2 R 10    
 f) -(CH 2 ) j CON(R 10 ) 2 ; 
 g) —(CH 2 ) j OCON(R 10 ) 2 ; 
 h) two R units can be taken together to form a carbonyl unit; 
 i) and mixtures thereof; 
 R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
 Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl. 
 
   
   
       2 . A compound according to  claim 1  wherein R is chosen from 2-methyl-2-hydroxy-1-(S)-methylpropylamine, 1-(S)-methylbenzylamine, 2-methoxy-1-(S)-methylethylamine, 2-methyl-2-cyano-1-(S)-methylpropylamine, 2-methyl-2-hydroxy-1-(R)-methylpropyl-amine, 1-(R)-methylbenzylamine, 2-methoxy-1-(R)-methylethylamine, 2-methyl-2-cyano-1-(R)-methylpropylamine, pyran-4-ylamino, piperidin-4-ylamino, pyridin-2-ylamino, pyridin-3-ylamino, pyridin-4-ylamino, pyrimidin-2-ylamino, pyrimidin-4-ylamino, and pyrimidin-5-ylamino. 
   
   
       3 . A compound according to  claim 1  wherein R 1  is chosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,6-dimethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and 2,6-difluorophenyl. 
   
   
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       30 . A composition comprising:
 one or more bicyclic pyrazolones including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:   
     
       
         
         
             
             
         
       
     
     wherein R is:
 a) —O[CH 2 ] k R 3 ; or 
 b) —NR 4a R 4b ; 
 R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
 the index k is from 0 to 5; 
 R 4a  and R 4b  are each independently: 
 a) hydrogen; or 
 b) -[C(R 5a R 5b )] m R 6 ; 
 each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
 R 1  is: 
 a) substituted or unsubstituted aryl; or 
 b) substituted or unsubstituted heteroaryl; 
 L is a linking group chosen from: 
 i) -[C(R 12 ) 2 ] n —; 
 ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
 iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n —; 
 R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
 each R 2  unit is independently chosen from: 
 a) hydrogen; 
 b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
 c) -(CH 2 ) j NR 9a R 9b ; 
 d) -(CH 2 ) j CO 2 R 10 ; 
 e) -(CH 2 ) j OCO 2 R 10    
 f) -(CH 2 ) j CON(R 10 ) 2 ; 
 g) -(CH 2 ) j OCON(R 10 ) 2 ; 
 h) two R 2  units can be taken together to form a carbonyl unit; 
 i) and mixtures thereof; 
 R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
 Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl. 
 
   
   
       31 . A pharmaceutical composition comprising:
 a) an effective amount of one or more bicyclic pyrazolones including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:   
     
       
         
         
             
             
         
       
       wherein R is: 
       a) —O[CH 2 ] k R 3 ; or 
       b) —NR 4a R 4b ; 
       R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; the index k is from 0 to 5; 
       R 4a  and R 4b  are each independently: 
       a) hydrogen; or 
       b) -[C(R 5a R 5b )] m R 6 ; 
       each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
       R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
       R 1  is: 
       a) substituted or unsubstituted aryl; or 
       b) substituted or unsubstituted heteroaryl; 
       L is a linking group chosen from: 
       i) -[C(R 12 ) 2 ] n —; 
       ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
       iii) -[C(R 12 ) 2 ] n O[C(R 2 ) 2 ] n -; 
       R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
       each R 2  unit is independently chosen from: 
       a) hydrogen; 
       b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
       c) -(CH 2 ) j NR 9a R 9b ; 
       d) -(CH 2 ) j CO 2 R 10 ; 
       e) -(CH 2 ) j OCO 2 R 10    
       f) -(CH 2 ) j CON(R 10 ) 2 ; 
       g) -(CH 2 ) j OCON(R 10 ) 2 ; 
       h) two R 2  units can be taken together to form a carbonyl unit; 
       i) and mixtures thereof; 
       R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 1b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
       Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl; and 
     
     b) one or more pharmaceutically acceptable excipients. 
   
   
       32 . A method for controlling the extracellular release of cycloxygenase-2 (COX-2) cytokines in human and higher mammals, said method comprising the step of administering to said humans or higher mammals a pharmaceutical composition comprising one or more of the compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, having the formula: 
     
       
         
         
             
             
         
       
     
     wherein R is:
 a) —O[CH 2 ] k R 3 ; or 
 b) —NR 4a R 4b ; 
 R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
 the index k is from 0 to 5; 
 R 4a  and R 4b  are each independently: 
 a) hydrogen; or 
 b) -[C(R 5a R 5b )] m R 6 ; 
 each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
 R 1  is: 
 a) substituted or unsubstituted aryl; or 
 b) substituted or unsubstituted heteroaryl; 
 L is a linking group chosen from: 
 i) -[C(R 12 ) 2 ] n —; 
 ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
 iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n —; 
 R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
 each R unit is independently chosen from: 
 a) hydrogen; 
 b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
 c) -(CH 2 ) j NR 9a R 9b ; 
 d) -(CH 2 ) j CO 2 R 10 ; 
 e) -(CH 2 ) j OCO 2 R 10    
 f) -(CH 2 ) j CON(R 10 ) 2 ; 
 g) -(CH 2 ) j OCON(R 10 ) 2 ; 
 h) two R 2  units can be taken together to form a carbonyl unit; 
 i) and mixtures thereof; 
 R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
 Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl. 
 
   
   
       33 . A method for controlling the extracellular release of Tumor Necrosis Factor-α (TNF-α), in human and higher mammals, said method comprising the step of administering to said humans or higher mammals a pharmaceutical composition comprising one or more of the compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, having the formula: 
     
       
         
         
             
             
         
       
       wherein R is: 
       a) —O[CH 2 ] k R 3 ; or 
       b) —NR 4a R 4b ; 
       R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
       the index k is from 0 to 5; 
       R 4a  and R 4b  are each independently: 
       a) hydrogen; or 
       b) -[C(R 5a R 5b )] m R 6 ; 
       each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —O 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
       R 1  is: 
       a) substituted or unsubstituted aryl; or 
       b) substituted or unsubstituted heteroaryl; 
       L is a linking group chosen from: 
       i) -[C(R 12 ) 2 ] n —; 
       ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
       iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n -; 
       R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
       each R 2  unit is independently chosen from: 
       a) hydrogen; 
       b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
       c) -(CH 2 ) j NR 9a R 9b ; 
       d) -(CH 2 ) j CO 2 R 10 ; 
       e) -(CH 2 ) j OCO 2 R 10    
       f) -(CH 2 ) j CON(R 10 ) 2 ; 
       g) -(CH 2 ) j OCON(R 10 ) 2 ; 
       h) two R 2  units can be taken together to form a carbonyl unit; 
       i) and mixtures thereof; 
       R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
       Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl. 
     
   
   
       34 . A method for controlling a disease or disease state in humans or higher mammals, said disease or disease state chosen from congestive heart failure; hypertension; chronic obstructive pulmonary disease (COPD) and septic shock syndrome; tuberculosis, adult respiratory distress, and asthma; atherosclerosis; muscle degeneration and periodontal disease; cachexia, Reiter's syndrome, gout, acute synovitis, anorexia, bulimia nervosa; fever, malaise, myalgia and headaches, said method comprising the step of administering to said humans or higher mammals a pharmaceutical composition comprising one or more of the compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, having the formula: 
     
       
         
         
             
             
         
       
       wherein R is: 
       a) —O[CH 2 ] k R 3 ; or 
       b) —NR 4a R 4b ; 
       R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
       the index k is from 0 to 5; 
       R 4a  and R 4b  are each independently: 
       a) hydrogen; or 
       b) -[C(R 5a R 5b )] m R 6 ; 
       each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
       R 1  is: 
       a) substituted or unsubstituted aryl; or 
       b) substituted or unsubstituted heteroaryl; 
       L is a linking group chosen from: 
       i) -[C(R 12 ) 2 ] n -; 
       ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
       iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n —; 
       R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
       each R 2  unit is independently chosen from: 
       a) hydrogen; 
       b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
       c) -(CH 2 ) j NR 9a R 9b ; 
       d) -(CH 2 ) j CO 2 R 10 ; 
       e) -(CH 2 ) j OCO 2 R 10    
       f) -(CH 2 ) j CON(R 10 ) 2 ; 
       g) -(CH 2 ) j OCON(R 10 ) 2 ; 
       h) two R 2  units can be taken together to form a carbonyl unit; 
       i) and mixtures thereof; 
       R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
       Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl. 
     
   
   
       35 . A method for preventing elevated plasma levels of inflammatory cytokines in humans and higher mammals wherein said cytokines are chosen from TNF-α, IL-1β, and IL-6, thereby controlling or treating congestive heart failure in humans and higher mammals, said method comprising the step of administering to said humans or higher mammals a pharmaceutical composition comprising one or more of the compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, having the formula: 
     
       
         
         
             
             
         
       
     
     wherein R is:
 a) —O[CH 2 ] k R 3 ; or 
 b) —NR 4a R 4b ; 
 R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
 the index k is from 0 to 5; 
 R 4a  and R 4b  are each independently: 
 a) hydrogen; or 
 b) -[C(R 5a R 5b )] m R 6 ; 
 each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
 R 1  is: 
 a) substituted or unsubstituted aryl; or 
 b) substituted or unsubstituted heteroaryl; 
 L is a linking group chosen from: 
 i) -[C(R 12 ) 2 ] n —; 
 ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
 iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n —; 
 R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
 each R 2  unit is independently chosen from: 
 a) hydrogen; 
 b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
 c) -(CH 2 ) j NR 9a R 9b ; 
 d) -(CH 2 ) j CO 2 R 10 ; 
 e) -(CH 2 ) j OCO 2 R 10    
 f) -(CH 2 ) j CON(R 10 ) 2 ; 
 g) -(CH 2 ) j OCON(R 10 ) 2 ; 
 h) two R 2  units can be taken together to form a carbonyl unit; 
 i) and mixtures thereof; 
 R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
 Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl. 
 
   
   
       36 . A method for treating Crohn's disease or alleviating the symptoms thereof in humans by controlling the extracellular release of cytokines, said method comprising the step of administering to said humans a pharmaceutical composition comprising one or more of the compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, having the formula: 
     
       
         
         
             
             
         
       
       wherein R is: 
       a) —O[CH 2 ] k R 3 ; or 
       b) —NR 4a R 4b ; 
       R 3  is substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or alkylenearyl, substituted or unsubstituted heteroaryl or alkyleneheteroaryl; 
       the index k is from 0 to 5; 
       R 4a  and R 4b  are each independently: 
       a) hydrogen; or 
       b) -[C(R 5a R 5b )] m R 6 ; 
       each R 5a  and R 5b  are independently hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; C 1 -C 4  linear, branched, or cyclic alkyl, and mixtures thereof; R 6  is hydrogen, —OR 7 , —N(R 7 ) 2 , —CO 2 R 7 , —CON(R 7 ) 2 ; substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7  is hydrogen, a water-soluble cation, C 1 -C 4  alkyl, or substituted or unsubstituted aryl; the index m is from 0 to 5; 
       R 1  is: 
       a) substituted or unsubstituted aryl; or 
       b) substituted or unsubstituted heteroaryl; 
       L is a linking group chosen from: 
       i) -[C(R 12 ) 2 ] n —; 
       ii) -[C(R 12 ) 2 ] n NR 12 [C(R 12 ) 2 ] n —; and 
       iii) -[C(R 12 ) 2 ] n O[C(R 12 ) 2 ] n —; 
       R 12  is hydrogen, C 1 -C 4  alkyl, and mixtures thereof; or two R 12  units can be taken together to form a carbonyl unit; the index n is a unit from 0 to 2; 
       each R 2  unit is independently chosen from: 
       a) hydrogen; 
       b) -(CH 2 ) j O(CH 2 ) j R 8 ; 
       c) -(CH 2 ) j NR 9a R 9b ; 
       d) -(CH 2 ) j CO 2 R 10 ; 
       e) -(CH 2 ) j OCO 2 R 10    
       f) -(CH 2 ) j CON(R 10 ) 2 ; 
       g) -(CH 2 ) j OCON(R 10 ) 2 ; 
       h) two R 2  units can be taken together to form a carbonyl unit; 
       i) and mixtures thereof; 
       R 8 , R 9a , R 9b , and R 10  are each independently chosen from hydrogen, C 1 -C 4  alkyl, and mixtures thereof; R 9a  and R 9b  can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R 10  units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; 
       Z is O, S, NR 11 , or NOR 11 ; R 11  is hydrogen or C 1 -C 4  alkyl.