Compositions and methods for treating inflammatory conditions

Abstract

The present invention relates to compositions containing signal transduction modulator compounds, to methods for treating or preventing inflammation, or promoting healthy joints, using the compounds and to kits for the same.

1 . A composition for treating or preventing inflammation comprising:
 a. at least one signal transduction modulator compound or a pharmaceutically acceptable salt thereof;   b. a carrier; and   c. optionally, an additional active ingredient.   
   
   
       2 . The composition according to  claim 1 , wherein the composition is administered by a route selected from oral, buccal, cutaneous, nasal, parenteral, vaginal and rectal. 
   
   
       3 . The composition according to  claim 1 , wherein the at least one signal transduction modulator compound is selected from the group consisting of:
 a. a compound of Formula (I) or a pharmaceutically acceptable salt of Formula (I):   
     
       
         
         
             
             
         
       
       
         wherein:
 R 1  is a C 1 -C 3  alkyl; 
 R 2  is —COX, wherein X is —OH, —OCH 3 , —NH 2 , —NHR 4 , —N(R 4 ) 2 , or a halogen; 
 R 3  is a C 10 -C 25  alkyl or a C 10 -C 25  alkene; and 
 R 4  is a C 1 -C 3  alkyl; 
 
       
       b. when R 2  is —COOH, a pharmaceutically acceptable salt of Formula (I) selected from the group consisting of an alkali metal salt, alkaline earth metal salt, ammonium salt, and substituted ammonium salt; 
       c. a compound of Formula (II) or a pharmaceutically acceptable salt of Formula (II):
   W—Y-Q-Z  (II) 
 wherein:
 W is a farnesyl group, geranylgeranyl group, substituted farnesyl group or substituted geranylgeranyl group; 
 Y is —S—, —O—, —Se—, —SO—, 
 
 
     
     
       
         
         
             
             
         
       
       
         
           —SeO—, —SO 2 —, or —SeO 2 —; and 
           Q is 
         
       
     
     
       
         
         
             
             
         
       
       
         
           
             wherein: 
             n, n′ and n″=1, 2, 3, 4, 5, or 6; 
             T 1′ , T 1″ , T n∝  and T n″  are each, independently, H, F, Br, —NHCOCH 3 , —NH 2 , a peptide, an alkane group, an alkene group, an polyethyleneglycol group, a saturated fatty acid, an unsaturated fatty acid, a monosaccharide, or a disaccharide; 
           
           Z is —CN, —CONH 2 , —NO 2 , —COOH or salts and esters thereof, —PO 3  or salts or esters thereof or —SO 3  or salts or esters thereof; 
         
       
       provided that when W is farnesyl, Y is —S—, n is 2, and either T 2′ , or T 2″  is —NHCOCH 3 , then Z is not —COOH; 
       d. a compound of Formula (III) or a pharmaceutically acceptable salt of Formula (III):
   W—Y-Z  (III) 
 wherein W, Y, and Z are as previously defined; 
 
       e. a compound of Formula (IV) or a pharmaceutically acceptable salt of Formula (IV) 
     
     
       
         
         
             
             
         
       
       
         wherein:
 Z is C—R 12  or N; 
 X is —O—, —S—, —SO—, —SO 2 —, —NH—, or —Se—; 
 R 7  is a C 10 -C 25  alkyl or a C 10 -C 25  alkene; 
 R 8  is H, CN, COOR 13 , SO 3 R 13 , CONR 13 R 14 , or SO 2 N(R 13 ) 2 , wherein R 13  and R 14  are each, independently, hydrogen, alkyl, alkenyl, —COOM or —SO 3  M, wherein M is a cation; and 
 R 9 , R 10 , R 11  and R 12  are each, independently, hydrogen, carboxyl, alkyl, alkenyl, aminoalkyl, nitroalkyl, nitro, halogen, amino, mono-alkylamino, di-alkylamino, mercapto, mercaptoalkyl, azido, or thiocyanato; 
 
       
       f. the quaternary ammonium salts or N-oxides of Formula (I), wherein Z is N; 
       g. a compound of Formula (V) or a pharmaceutically acceptable salt of Formula (V): 
     
     
       
         
         
             
             
         
       
       
         wherein:
 Z is geranyl, farensyl, geranylgeranyl, phytyl or 3,7-dimethyloctyl; 
 R 15  is butane, butene, methylbutene, CF 3 , CF 3 CF 2 , CF 3 CH 2 , CHBr 2 , 
 
       
     
     
       
         
         
             
             
         
       
       h. a compound of Formula (VI) or a pharmaceutically acceptable salt of Formula (VI): 
     
     
       
         
         
             
             
         
       
       
         wherein:
 R 17  and R 18  are each independently H, CH 3 , OCH 3 , CN, NO 2  or halogen; and 
 R 19  is H or halogen; 
 
       
       i. a compound of Formula (VII) or a pharmaceutically acceptable salt of Formula (VII): 
     
     
       
         
         
             
             
         
       
       
         wherein:
 R 17 , R 18  and R 19  are as previously defined; 
 
       
       j. a compound of Formula (VIII) or a pharmaceutically acceptable salt of Formula (VIII): 
     
     
       
         
         
             
             
         
       
       k. a compound of Formula (IX) or a pharmaceutically acceptable salt of Formula (IX): 
     
     
       
         
         
             
             
         
       
       l. a compound of Formula (X) or a pharmaceutically acceptable salt of Formula (X): 
     
     
       
         
         
             
             
         
       
       m. a compound of Formula (XI) or a pharmaceutically acceptable salt of Formula (XI): 
     
     
       
         
         
             
             
         
       
       
         wherein:
 X is 3,7-dimethyloctyl, 3,7-dimethylhexadecene, geranyl, geranylgeranyl or farnesyl; and 
 X′ is propene, 2-methylbutene or triphenylmethane. 
 
       
     
   
   
       4 . The composition according to  claim 1 , wherein the at least one signal transduction modulator compound is selected from the group consisting of:
 a. N-acetyl-S-farnesylcysteine;   b. 3-farnesylhomocysteine;   c. N-acetyl-S-oxo-farnesylcysteine;   d. 3-farnesylthio-trans-acrylic acid;   e. 3-farnesylthio-cis-acrylic acid;   f 3-farnesyloxypropionic acid;   g. 3-farnesylthiobutyric acid;   h 2-farnesylthioacetic acid sulfoxide;   i. 3-farnesylthiopropionamide;   j. 2-methyl-3-farnestylthiopropionic acid;   k. 2-farnesylthio-1-nitroethane;   l. 2-farnesylthio-S-methyl acetothiohydroximate;   m. 3-farnesylthio-2-methylenepropionic methyl ester,   n. S-farnesylcysteine;   o. N-acetylgeranylgeranylcysteine;   p. 3-farnesylthio-2-nitropropane;   q. 3-farnesylthio-2-methylenepropionic acid;   r. N-benzoyl-5-farnesylcysteine;   s. disodium 2-farnesylthioethyl phosphate;   t. 3-farnesylthiopropionitrile N-acetyl-Se-farnesyl-D,L-cysteine;   u. N-acetyl-S-farnesyl-D-cysteine;   v. 3-farnesylselenopropionic acid;   w. N-acetyl-S-geranyl-L-cysteine;   x. 3-farnesylthiononanoic acid;   y. 3-farnesylthiocyclohexanecarboxylic acid;   z. farnesyl-thiosalicyclic acid;   aa. 2-chloro-5-farnesylaminobenzoic acid;   bb. farnesyl thionicoatinic acid;   cc. 5-fluoro-farnesyl-thiosalicyclic acid;   dd. 5-chloro-farnesyl-thiosalicyclic acid;   ee. 4-chloro-farnesyl-thiosalicyclic acid;   ff. S-farnesyl-methylthiosalicylic acid;   gg. N-Fmoc-S-farnesyl-cysteine;   hh. N-Boc-S-farnesyl-cysteine;   ii. N-phthaloyl-5-farnesyl-cysteine; and   a pharmaceutically acceptable salt thereof.   
   
   
       5 . The composition according to  claim 1 , wherein the at least one signal transduction modulator compound is N-acetyl farnesyl-cysteine or N-acetylgeranylgeranylcysteine. 
   
   
       6 . The composition according to  claim 1 , wherein the at least one signal transduction modulator compound is N-acetyl farnesyl-cysteine. 
   
   
       7 . The composition according to  claim 1 , wherein the signal transduction modulator comprises N-acetyl farnesyl-cysteine and N-acetylgeranylgeranylcysteine. 
   
   
       8 . The composition according to  claim 1  further comprising at least one penetration enhancer or propellant. 
   
   
       9 . The composition according to  claim 1 , wherein the inflammation is associated with a joint condition, an inflammation of the airways, or an inflammatory bowel disease. 
   
   
       10 . The composition according to  claim 9 , wherein the joint condition comprises an arthritis or a joint injury. 
   
   
       11 . The composition according to  claim 9 , wherein the inflammation of the airways comprises an asthma or chronic obstructive pulmonary disease. 
   
   
       12 . The composition according to  claim 11 , wherein the asthma is chronic. 
   
   
       13 . The composition according to  claim 11 , wherein the chronic obstructive pulmonary disease comprises chronic bronchitis and emphysema. 
   
   
       14 . The composition according to  claim 13 , wherein the chronic obstructive pulmonary disease comprises chronic bronchitis. 
   
   
       15 . The composition according to  claim 9 , wherein the inflammatory bowel disease comprises ulcerative colitis and Crohn's disease. 
   
   
       16 . The composition according to  claim 15 , wherein the inflammatory bowel disease comprises ulcerative colitis. 
   
   
       17 . The composition according to  claim 15 , wherein the inflammatory bowel disease comprises Crohn's disease. 
   
   
       18 . The composition according to  claim 10 , wherein the composition is administered by a route selected from the group consisting of oral, cutaneous and parenteral. 
   
   
       19 . The composition according to  claim 11 , wherein the composition is administered by a route selected from the group consisting of oral and parenteral. 
   
   
       20 . The composition according to  claim 15 , wherein the composition is administered by a route selected from the group consisting of oral, parenteral and rectal. 
   
   
       21 . A composition for promoting healthy joints comprising:
 a. at least one signal transduction modulator compound or a pharmaceutically acceptable salt thereof   b. a carrier; and   c. optionally, an additional active ingredient.   
   
   
       22 . The composition according to  claim 1 , wherein the at least one signal transduction modulator compound is contained within a botanical extract. 
   
   
       23 . The composition according to  claim 1 , wherein the at least one signal transduction modulator compound is contained within a microbial extract. 
   
   
       24 . The composition according to  claim 1 , wherein the optional additional active ingredient is selected from a group consisting of a protective agent, a demulcent, an emollient, an astringent, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an antioxidant, a chemotherapeutic agent, an antihistamine agent and a cleansing agent. 
   
   
       25 . The composition according to  claim 1 , wherein the composition comprises a mixture selected from the group consisting of a solution, an emulsion, a suspension and a powder. 
   
   
       26 . The composition according to  claim 1 , wherein the signal transduction modulator compound comprises from about 0.01% to about 50% w/w of the composition. 
   
   
       27 . The composition according to  claim 1 , wherein the signal transduction modulator compound comprises from about 0.01% to about 5% w/w of the composition. 
   
   
       28 . A method of treating or preventing inflammation in a mammal in need thereof the method comprising administering to the mammal a pharmaceutically effective amount of a composition comprising:
 a. at least one signal transduction modulator compound or a pharmaceutically acceptable salt thereof;   b. a carrier, and   c. optionally, an additional active ingredient.   
   
   
       29 . The method according to  claim 28 , wherein the inflammation is associated with a joint condition, an inflammation of the airways or an inflammatory bowel disease. 
   
   
       30 . The method according to  claim 29 , wherein the joint condition comprises an arthritis or a joint injury. 
   
   
       31 . The method according to  claim 30 , wherein the composition further comprises a penetration enhancer. 
   
   
       32 . The method according to  claim 29 , wherein the inflammation of the airways comprises an asthma or a chronic pulmonary obstructive disease. 
   
   
       33 . The method according to  claim 29 , wherein the inflammation is associated with an inflammatory bowel disease. 
   
   
       34 . The method according to  claim 28 , wherein the composition is administered by a route that is oral, buccal, parenteral, nasal, vaginal or rectal. 
   
   
       35 . A method of promoting healthy joints in a mammal in need thereof, the method comprising administering to the mammal a pharmaceutically effective amount of a composition for treating inflammation comprising:
 a. at least one signal transduction modulator compound or a pharmaceutically acceptable salt thereof;   b. a carrier; and   c. optionally, an additional active ingredient.   
   
   
       36 . A kit comprising a composition for treating or preventing inflammation or for promoting healthy joints, the kit comprising:
 a. a composition comprising:
 i. at least one signal transduction modulator compound or a pharmaceutically acceptable salt thereof; 
 ii. a carrier, and 
   iii. optionally, an additional active ingredient; and   b. a needle.   
   
   
       37 . The kit according to  claim 36  further comprising a plurality of individual dosage units of the composition and a plurality of needles. 
   
   
       38 . The kit according to  claim 37 , wherein the plurality of individual dosage units and the plurality of needles provides for an administration regimen selected from the group consisting of daily, weekly or monthly.