Formulations and uses of retinoic acid receptor selective agonists

Abstract

The invention provides retinoic acid receptor (RAR) selective agonists and formulations thereof for the treatment of disease or for inducing a medically beneficial effect.

1 .- 30 . (canceled) 
     
     
         31 . A method of treating a disease or a condition associated with the disease in a subject, the method comprising: administering to a subject a formulation comprising a single active ingredient, wherein the active ingredient consists of a RAR selective agonist, wherein the RAR selective agonist is not more than 0.005% of the formulation, and wherein the RAR selective agonist has the structure: 
       
         
           
           
               
               
           
         
          wherein the dotted bond is either present and forms a double bond, or is absent; 
         R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl; 
         n is 1, 2 or 3; 
         X is —C(R 8 )(R 9 )— for n=1, 2 or 3; or X is oxygen for n=1;
 wherein R 8  and R 9  are independently hydrogen or alkyl; 
 
         R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
 wherein R 10  is hydrogen or alkyl; 
 
         m is 0 when the dotted bond is present; or m is 1 when the dotted bond is absent;
 wherein Ar is phenyl or a heteroarylic ring; 
 R 6  is hydrogen, halogen, alkoxy or hydroxy; 
 R 7  is hydrogen or alkyl; and 
 Y
 is —COO—, —OCO—, —CONR 10 —, —NR 10 CO—, —CH═CH—, —C≡C—, —COCH═CH—, —CHOHCH═CH—, —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 NR 10 —, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, 
 with the proviso that when Y
 is —OCO—, —NR 10 CO—, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, R 5  is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl; 
 
 
 
         or a pharmaceutically active salt of carboxylic acids of formula I. 
       
     
     
         32 . The method of  claim 31 , wherein the RAR selective agonist is administered by applying a cream, by applying an ointment, by applying a lotion, by applying a liquid, by foam, orally or intravenously comprising the RAR selective agonist. 
     
     
         33 . The method of  claim 31 , wherein the disease or disease condition is selected from the group consisting of a metabolic disease or condition associated with a metabolic disease and a carcinoma. 
     
     
         34 . The method of  claim 33 , wherein the condition associated with the metabolic disease is selected from hyperglycemia, hyperinsulinemia, hyperlipidemia, impaired glucose metabolism, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomeruloscerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, angina pectoris, myocardial infarction, stroke, skin or connective tissue disorders, scar tissue repair, wrinkle treatment, psoriasis, UV-damage skin, rosacea, metabolic acidosis, arthritis, osteoporosis, conditions of impaired glucose tolerance, diabetic ulcer, diabetes and cardiovascular disease. 
     
     
         35 . The method of  claim 33 , wherein the carcinoma is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma and leukemia. 
     
     
         36 . The method of  claim 31 , wherein R 8  and R 9  are H. 
     
     
         37 . The method of  claim 31 , wherein R 1 , R 2 , R 3  and R 4  are alkyl. 
     
     
         38 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3 , and R 4  are each methyl,   X n  is —CH 2 —CH 2 —,   R 5  is —CH 2 —CH 2 —CH 2 —CH 2 —CH 3 ,   Y is —COO—, and   R 6  and R 7  are each is H.   
     
     
         39 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 1 or 2;   X is —C(R 8 )(R 9 )— for n=1 or 2; or X is oxygen for n=1;   wherein R 8  and R 9  are independently hydrogen or alkyl; and   R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl;
 wherein R 10  is hydrogen or alkyl. 
   
     
     
         40 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 1 or 2;   X is —C(R 8 )(R 9 )— for n=1 or 2; or X is oxygen for n=1;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkylthio, alkyl-NR 10 —, alkenyl, alkynyl;   wherein R 10  is hydrogen or alkyl.   
     
     
         41 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl;
 wherein R 10  is hydrogen or alkyl. 
   
     
     
         42 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkylthio, alkyl-NR 10 —, alkenyl, alkynyl;   wherein R 10  is hydrogen or alkyl.   
     
     
         43 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; 
   R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl;
 wherein R 10  is hydrogen or alkyl; and 
   Y is —COO—, —OCO—, —CONR 10 —, —NR 10 CO—, —CH═CH—, —C≡C—, —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 NR 10 —, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —,
 with the proviso that when Y is —OCO—, —NR 10 CO—, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, R 5  is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl. 
   
     
     
         44 . The method of  claim 31 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkylthio, alkyl-NR 10 —, alkenyl, alkynyl;
 wherein R 10  is hydrogen or alkyl; and 
   Y is —COO—, —OCO—, —CONR 10 —, —NR 10 CO—, —CH═CH—, —C≡C—, —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 NR 10 —, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —,
 with the proviso that when Y is —OCO—, —NR 10 CO—, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, R 5  is hydrogen, alkyl, alkenyl, alkynyl. 
   
     
     
         45 . A method of treating acne vulgaris, the method comprising: administering to a subject a topical formulation comprising a single active ingredient, wherein the active ingredient consists of a RAR selective agonist, wherein the RAR selective agonist is not more than 0.05% of the formulation, and wherein the RAR selective agonist has the structure: 
       
         
           
           
               
               
           
         
          wherein the dotted bond is either present and forms a double bond, or is absent; 
         R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl; 
         n is 1, 2 or 3; 
         X is —C(R 8 )(R 9 )— for n=1, 2 or 3; or X is oxygen for n=1;
 wherein R 8  and R 9  are independently hydrogen or alkyl; 
 
         R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl;
 wherein R 10  is hydrogen or alkyl; 
 
         m is 0 when the dotted bond is present; or m is 1 when the dotted bond is absent;
 wherein Ar is phenyl or a heteroarylic ring; 
 R 6  is hydrogen, halogen, alkoxy or hydroxy; 
 R 7  is hydrogen or alkyl; and 
 Y
 is —COO—, —OCO—, —CONR 10 —, —NR 10 CO—, —CH═CH—, —C≡C—, —COCH═CH—, —CHOHCH═CH—, —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 NR 10 —, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, 
 with the proviso that when Y
 is —OCO—, —NR 10 CO—, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, R 5  is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, benzyl, cycloalkyl-alkyl or phenyl-alkyl; 
 
 
 
         or a pharmaceutically active salt of carboxylic acids of formula I. 
       
     
     
         46 . The method of  claim 45 , wherein the RAR selective agonist is not more than 0.01% of the formulation. 
     
     
         47 . The method of  claim 45 , wherein the RAR selective agonist is administered by applying a cream, ointment, lotion or liquid comprising the RAR selective agonist. 
     
     
         48 . The method of  claim 45 , wherein R 8  and R 9  are H. 
     
     
         49 . The method of  claim 45 , wherein R 1 , R 2 , R 3  and R 4  are alkyl. 
     
     
         50 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3 , and R 4  are each methyl,   X n  is —CH 2 —CH 2 —,   R 5  is —CH 2 —CH 2 —CH 2 —CH 2 —CH 3 ,   Y is —COO—, and   R 6  and R 7  are each is H.   
     
     
         51 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 1 or 2;   X is —C(R 8 )(R 9 )— for n=1 or 2; or X is oxygen for n=1;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl;
 wherein R 10  is hydrogen or alkyl. 
   
     
     
         52 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 1 or 2;   X is —C(R 8 )(R 9 )— for n=1 or 2; or X is oxygen for n=1;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkylthio, alkyl-NR 10 —, alkenyl, alkynyl;   wherein R 10  is hydrogen or alkyl.   
     
     
         53 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl;   wherein R 10  is hydrogen or alkyl.   
     
     
         54 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkylthio, alkyl-NR 10 —, alkenyl, alkynyl;   wherein R 10  is hydrogen or alkyl.   
     
     
         55 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; 
   R 5  is hydrogen, alkyl, alkoxy, alkoxy-alkyl-, alkylthio, alkyl-NR 10 —, alkenyl, alkenyloxy, alkynyl;
 wherein R 10  is hydrogen or alkyl; and 
   Y is —COO—, —OCO—, —CONR 10 —, —NR 10 CO—, —CH═CH—, —C≡C—, —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 NR 10 —, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —,
 with the proviso that when Y is —OCO—, —NR 10 CO—, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —, R 5  is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl. 
   
     
     
         56 . The method of  claim 45 , wherein
 R 1 , R 2 , R 3  and R 4  are independently hydrogen or alkyl;   n is 2;   X is —C(R 8 )(R 9 )— for n=2;
 wherein R 8  and R 9  are independently hydrogen or alkyl; and 
   R 5  is hydrogen, alkyl, alkylthio, alkyl-NR 10 —, alkenyl, alkynyl;
 wherein R 10  is hydrogen or alkyl; and 
   Y is —COO—, —OCO—, —CONR 10 —, —NR 10 CO—, —CH═CH—, —C≡C—, —CH 2 O—, —CH 2 S—, —CH 2 SO—, —CH 2 SO 2 —, —CH 2 NR 10 —, —OCH 2 —, —SCH 2 —, —SOCH 2 —, —SO 2 CH 2 — or —NR 10 CH 2 —,
 with the proviso that when Y is —OCO—, —NR10CO—, —OCH2-, —SCH2-, —SOCH2-, —SO2CH2- or —NR10CH2-, R5 is hydrogen, alkyl, alkenyl, alkynyl.