Tazarotene derivatives

Abstract

The presently described subject matter relates to new derivatives of tazarotene that also exhibit retinoid activity, pharmaceutical compositions comprising the derivatives, method of treating skin disorders with the pharmaceutical compositions, and process of making the derivatives.

1 . A compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein n is 0 or 1; 
         R 1  is hydrogen, optionally substituted C 1-18  alkyl, optionally substituted C 2-18  alkenyl, optionally substituted C 2-18  alkynyl, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted cycloalkyl group, or a optionally substituted heteroaryl group; and 
         R 2  is hydrogen, optionally substituted C 1-18  alkyl, optionally substituted C 2-18  alkenyl, optionally substituted C 2-18  alkynyl, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted cycloalkyl group, or a optionally substituted heteroaryl group; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein n is 1. 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is an optionally substituted C 1-18  alkyl. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is an optionally substituted aryl, heteroaryl or heterocyclic group. 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is an optionally substituted C 2-18  alkenyl. 
     
     
         6 . The compound according to  claim 1 , wherein when R 1  is an optionally substituted C 1-18  alkyl, C 2-18  alkenyl, C 2-18  alkynyl, aryl, heterocyclic, C 3-7  cycloalkyl or heteroaryl group, the group is optionally substituted one or more times, independently by halogen; hydroxy; NR 4 R 5 ; hydroxy substituted C 1-6  alkyl; C 1-6  alkoxy; halosubstituted C 1-6  alkoxy; halosubstituted C 1-6  alkyl; C 1-6  alkyl; —C(O)OR 6 , or —OC(O)R 6 ;
 R 4  and R 5  are independently selected from hydrogen or C 1-6  alkyl; and 
 R 6  is independently selected from hydrogen or C 1-6  alkyl. 
 
     
     
         7 . The compound according to  claim 6 , wherein R 1  is C 1-18  alkyl or C 1-18  alkyl substituted one or more times by hydroxy, NR 4 R 5 , C 1-6  alkoxy, or —C(O)OR 6 . 
     
     
         8 . The compound according to  claim 4 , wherein R 1  is an optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted tetrahydropyranyl, or optionally substituted piperidinyl. 
     
     
         9 . The compound according to  claim 1 , wherein R 2  is hydrogen or C 1-6  alkyl. 
     
     
         10 . The compound according to  claim 8 , wherein R 1  is phenyl. 
     
     
         11 . The compound according to  claim 1 , wherein R 2  is C 1-6  alkyl. 
     
     
         12 . The compound according to  claim 11 , wherein R 2  is ethyl. 
     
     
         13 . The compound according to  claim 1 , wherein n is 0. 
     
     
         14 . The compound according to  claim 13 , wherein R 1  is H and R 2  is H. 
     
     
         15 . The compound according to  claim 1  which is:
 6-[4,4-dimethyl-2-(pyridine-3-carbonyloxy)thiochroman-6-yl-ethynyl]nicotinic acid ethyl ester; 
 (S)-6-[4,4-dimethyl-2-(pyridine-3-carbonyloxy)thiochroman-6-yl-ethynyl]nicotinic acid ethyl ester; 
 (R)-6-[4,4-dimethyl-2-(pyridine-3-carbonyloxy)thiochroman-6-yl-ethynyl]nicotinic acid ethyl ester; 
 Ethyl 6-[(2-palmitoyl-4,4-dimethyl-3,4-dihydro-2-thiochromen-6-yl)ethynyl]pyridine-3-carboxylate; 
 6-[2-(2-Hydroxy-acetoxy)-4,4-dimethyl-thiochroman-6-yl-ethynyl]-nicotinic acid ethyl ester; 
 Ethyl 6-[(2-(2-methoxyacetyl)-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-acetyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-n-butyryloxyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-lauroyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-isobutyryloxy-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-linoeoyll-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-linleolyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-(N-methyl-4-piperidinylcarboxy-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-propionyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-salicylicyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-(4-pyranyloxy-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[(2-monomethyladopyl-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; 
 Ethyl 6-[2-(monomethylazelauate-4,4-dimethyl-3,4-dihydro-2-thiochroman-6-yl)ethynyl]pyridine-3-carboxylate; or 
 6-[2-((S)-2-Amino-3-methyl-butyryloxy)-4,4-dimethyl-thiochroman-6-yl-ethynyl]-nicotinic acid ethyl ester; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         16 . A pharmaceutical composition comprising a compound according to  claim 1 , and one or more pharmaceutically acceptable carriers or excipients. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , comprising a second pharmaceutically active agent. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the second pharmaceutically active agent is benzoyl peroxide. 
     
     
         19 . (canceled) 
     
     
         20 . A method of treating a skin disorder in a human in need thereof, said method comprising administering to said human an effective amount of a compound, or pharmaceutically acceptable salt thereof, according to  claim 1 . 
     
     
         21 - 31 . (canceled)