Methods for making retinoids and uses thereof

Abstract

Described herein are methods for making retinoids. Also described herein are retinoids and methods of use thereof.

1 . A method for making a compound having the formula III 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula I 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; 
         and R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula I can optionally be replaced with a heteroatom, 
         with a compound having the formula II, 
       
       
         
           
           
               
               
           
         
         wherein R 4 -R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group, and X comprises a halogen, wherein the stereochemistry about the carbon-carbon double bond in formula II is substantially E or Z, or an E,Z-mixture, 
         in the presence of a coupling agent, wherein the coupling agent comprises a zero-valent metal atom, a metal salt, or a mixture thereof, wherein the coupling agent is not zinc metal alone. 
       
     
     
         2 . The method of  claim 1 , wherein the compound having the formula I comprises the formula XI 
       
         
           
           
               
               
           
         
         wherein R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         R 9  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the cycloalkyl ring and/or aryl ring in formula XI can optionally be substituted with a heteroatom. 
       
     
     
         3 . The method of  claim 2 , wherein n is 1. 
     
     
         4 . The method of  claim 3 , wherein R 3  and R 9  are hydrogen. 
     
     
         5 . The method of  claim 3 , wherein R 3  is hydrogen and R 9  is one or more methyl groups. 
     
     
         6 . The method of  claim 3 , wherein R 9  is hydrogen and R 3  is one or more methyl groups. 
     
     
         7 . The method of  claim 3 , wherein R 3  and R 9  are one or more methyl groups. 
     
     
         8 . The method of  claim 1 , wherein the compound having the formula II is 4-methyl-1-tetralone, 5-methyl-1-tetralone, 6-methyl-1-tetralone, 7-methyl-1-tetralone, 8-methyl-1-tetralone, or 7-isopropyl-1-tetralone. 
     
     
         9 . The method of  claim 1 , wherein n is 1, and R 1  and R 2  are a C 1 -C 15  branched or straight chain alkyl group or a substituted or unsubstituted cycloalkyl group. 
     
     
         10 . The method of  claim 1 , wherein n is 1, R 1  is a C 5  or greater branched or straight chain alkyl group or a substituted or unsubstituted cycloalkyl group, and R 2  is a C 1 -C 15  branched or straight chain alkyl group. 
     
     
         11 . The method of  claim 1 , wherein n is 1; R 1  is an isopentyl group, R 2  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl; and R 3  is hydrogen. 
     
     
         12 . The method of  claims 1 - 11 , wherein R 4  is a methyl group and X is bromide or chloride. 
     
     
         13 . The method of  claim 12 , wherein R 5 , R 6 , and R 7  are hydrogen. 
     
     
         14 . The method of  claims 1 - 13 , wherein the coupling agent comprises a mixture of (1) a zinc compound and (2) a rhodium compound or iron compound. 
     
     
         15 . The method of  claims 1 - 13 , wherein the coupling agent comprises a mixture of a zinc compound and a copper compound. 
     
     
         16 . The method of  claims 1 - 13 , wherein the coupling agent comprises a mixture of zinc metal and a copper salt. 
     
     
         17 . A method for making a compound having the formula VI 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula V 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula V can optionally be replaced with a heteroatom, 
         in the presence of an oxidant, wherein the oxidant comprises a compound capable of oxidizing a primary alcohol to the corresponding aldehyde, wherein the oxidant is not MnO 2 . 
       
     
     
         18 . The method of  claim 17 , wherein the compound having the formula V comprises the formula XII 
       
         
           
           
               
               
           
         
         wherein R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 9  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the aryl ring or cycloalkyl ring in formula XII can optionally be replaced with a heteroatom. 
       
     
     
         19 . The method of  claim 18 , wherein n is 1. 
     
     
         20 . The method of  claim 19 , wherein R 3  and R 9  are hydrogen. 
     
     
         21 . The method of  claim 19 , wherein R 3  is hydrogen and R 9  is one or more methyl groups. 
     
     
         22 . The method of  claim 19 , wherein R 9  is hydrogen and R 3  is one or more methyl groups. 
     
     
         23 . The method of  claim 19 , wherein R 3  and R 9  are one or more methyl groups. 
     
     
         24 . The method of  claims 18 - 23 , wherein R 4  is methyl. 
     
     
         25 . The method of  claims 18 - 24 , wherein R 6  and R 7  are hydrogen. 
     
     
         26 . The method of  claim 17 , wherein the compound having the formula V is (2Z,4E)-4-(3′,4′-dihydro-4′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-5′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-6′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-7′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, (2Z,4E)-4-(3′,4′-dihydro-8′-methyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol, or (2Z,4E)-4-(3′,4′-dihydro-7′-isopropyl-1′(2′H)-naphthalen-1′-ylidene))-3-methyl-2-buten-1-ol. 
     
     
         27 . The method of  claim 17 , wherein n is 1, and R 1  and R 2  are C 1 -C 15  branched or straight chain alkyl group. 
     
     
         28 . The method of  claim 17 , wherein n is 1, R 1  is C 5  or greater branched or straight chain alkyl group, and R 2  is C 1 -C 15  branched or straight chain alkyl group. 
     
     
         29 . The method of  claim 17 , wherein n is 1; R 1  is an isopentyl group, R 2  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl; R 3  is hydrogen; and R 4  is methyl. 
     
     
         30 . The method of  claims 27 - 29 , wherein R 6  and R 7  are hydrogen. 
     
     
         31 . The method of  claims 17 - 30 , wherein the oxidant comprises H 2 CrO 4 , CrO 3 -pyridine, pyridinium chlorochromate, pyridinium dichromate, Fe(VI), a reagent for the Swern oxidation, dimethyl sulfide and N-chlorosuccinimide, tetramethyl piperidine nitroxide, acetic anhydride in DMSO, P 2 O 5  in DMSO, tosyl chloride/triethyl amine, or Dess-Martin reagent. 
     
     
         32 . The method of  claims 17 - 30 , wherein the oxidant is 2-iodoxybenzoic acid. 
     
     
         33 . A method for making a compound having the formula VIII 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula VI 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula VIa or VIb can optionally be replaced with a heteroatom, 
         with a compound having the formula VII 
       
       
         
           
           
               
               
           
         
         wherein R 8 , R 10 , and R 11  are, independently, hydrogen or a C 1 -C 15  branched or straight chain alkyl group, wherein the stereochemistry about the carbon-carbon double bond in formula VII is substantially E or Z, or an E,Z-mixture, 
         in a solvent system comprising tetrahydrofuran and hexamethylphosphoramide, wherein the volumetric ratio of tetrahydrofuran to hexamethylphosphoramide is from 1:1 to 40:1. 
       
     
     
         34 . The method of  claim 33 , wherein the compound having the formula VIa comprises the formula 
       
         
           
           
               
               
           
         
         wherein R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 9  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the aryl ring or cycloalkyl ring in formula XV can optionally be replaced with a heteroatom. 
       
     
     
         35 . The method of  claim 34 , wherein n is 1. 
     
     
         36 . The method of  claim 35 , wherein R 3  and R 9  are hydrogen. 
     
     
         37 . The method of  claim 35 , wherein R 3  is hydrogen and R 9  is one or more methyl groups. 
     
     
         38 . The method of  claim 35 , wherein R 9  is hydrogen and R 3  is one or more methyl groups. 
     
     
         39 . The method of  claim 35 , wherein R 3  and R 9  are one or more methyl groups. 
     
     
         40 . The method of  claims 34 - 39 , wherein R 4  and R 10  are methyl, R 6  and R 7  are hydrogen, and R 11  is hydrogen or a C 1 -C 15  branched or straight chain alkyl group. 
     
     
         41 . The method of  claim 33 , wherein n is 1, and R 1  and R 2  are a C 1 -C 15  branched or straight chain alkyl group. 
     
     
         42 . The method of  claim 33 , wherein n is 1, is a C 5  or greater branched or straight chain alkyl group, and R 2  is a C 1 -C 15  branched or straight chain alkyl group. 
     
     
         43 . The method of  claim 33 , wherein n is 1; R 1  is an isopentyl group; R 2  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl; R 3  is hydrogen; and R 4  is methyl. 
     
     
         44 . The method of  claims 41 - 43  wherein R 6  and R 7  are hydrogen, R 10  is methyl, and R 11  is hydrogen or a C 1 -C 15  branched or straight chain alkyl group. 
     
     
         45 . The method of  claims 33 - 44 , wherein the volumetric ratio of tetrahydrofuran to hexamethylphosphoramide is from 5:1 to 15:1. 
     
     
         46 . A method for purifying a compound produced in  claims 33 - 45  comprising
 (a) dissolving the compound in a solvent to produce a homogeneous solution;   (b) cooling the homogeneous solution to produce crystals of the compound and a second solution; and   (c) removing the second solution.   
     
     
         47 . The method of  claim 46 , wherein the solvent comprises an organic solvent. 
     
     
         48 . The method of  claim 46 , wherein the solvent comprises one or more branched or straight chain aliphatic compounds. 
     
     
         49 . The method of  claim 46 , wherein the solvent comprises pentane, heptane, octane, or nonane. 
     
     
         50 . The method of  claim 46 , wherein the solvent is hexanes. 
     
     
         51 . The method of  claim 46 , wherein the cooling step (b) is conducted at from 0° C. to −78° C. 
     
     
         52 . The method of  claim 46 , wherein the cooling step (b) is from 10 minutes to 48 hours. 
     
     
         53 . A method for making a compound having the formula XX 
       
         
           
           
               
               
           
         
         comprising 
         (a) reacting a compound having the formula XXI 
       
       
         
           
           
               
               
           
         
         with a compound having the formula XXII, 
       
       
         
           
           
               
               
           
         
         wherein R 5  is hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group, and X is a halogen, wherein the stereochemistry about the carbon-carbon double bond in formula XXII is substantially E or Z, or an E,Z-mixture, 
         in the presence of a coupling agent, wherein the coupling agent comprises a zero-valent metal atom, a metal salt, or a mixture thereof, wherein the coupling agent is not zinc metal alone to produce a first compound having the formula XXIII 
       
       
         
           
           
               
               
           
         
         (b) reacting the first compound XXIII with a base to produce a second compound having the formula XXIV 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         (c) reacting the second compound XXIV with a reducing agent to produce a third compound having the formula XXV 
       
       
         
           
           
               
               
           
         
         (d) reacting the third compound XXV with an oxidant, wherein the oxidant comprises a compound capable of oxidizing a primary alcohol to the corresponding aldehyde, wherein the oxidant is not MnO 2 , to produce a fourth compound having the formula XXVI 
       
       
         
           
           
               
               
           
         
         (e) reacting the fourth compound XXVI with a compound having the formula XXVII 
       
       
         
           
           
               
               
           
         
         wherein R 8  and R 11  are, independently, a C 1 -C 15  branched or straight chain alkyl group, wherein the stereochemistry about the carbon-carbon double bond in formula XXVII is substantially E or Z, or an E,Z-mixture, 
         in a solvent system comprising tetrahydrofuran and hexamethylphosphoramide, wherein the volumetric ratio of tetrahydrofuran to hexamethylphosphoramide is from 1:1 to 40:1 to produce a fifth compound having the formula XXVIII 
       
       
         
           
           
               
               
           
         
         (f) hydrolyzing the fifth compound XXVIII to convert the ester to the compound having the formula XX or the pharmaceutically-acceptable salt thereof; and 
         (g) purifying the compound having the formula XX comprising
 (i) dissolving compound in a solvent to produce a homogeneous solution; 
 (ii) cooling the homogeneous solution to produce crystals of the compound and a second solution; and 
 (iii) removing the second solution. 
 
       
     
     
         54 . A method for making a compound having the formula V 
       
         
           
           
               
               
           
         
         comprising reacting a compound having the formula IX 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula V can optionally be replaced with a heteroatom, 
         with a reducing agent in an alkyl ether. 
       
     
     
         55 . The method of  claim 54 , wherein the reducing agent is LiAlH 4 , DIBAH, or diborane. 
     
     
         56 . The method of  claim 54 , wherein the alkyl ether is diethyl ether. 
     
     
         57 . A compound having the formula XXX 
       
         
           
           
               
               
           
         
         wherein R 1  is a C 5  or greater branched or straight chain alkyl group; 
         R 2  is hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; and 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 6  and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; R 11  is hydrogen or a C 1 -C 15  branched or straight chain alkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula XXX can optionally be replaced with a heteroatom, 
         or the pharmaceutically-acceptable salt or ester thereof, 
         wherein the compound is not (2E,4E,6Z,8E)-8-(3′,4′-dihydro-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid or an ester thereof; (2E,4E,6E,8E)-8-(3′,4′-dihydro-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid or an ester thereof; (2E,4E,6Z,8E)-8-(3′,4′-dihydro-4′ methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid or an ester thereof; and (2E,4E,6Z,8E)-8-(3′,4′-dihydro-5′,7′-dimethyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid or an ester thereof. 
       
     
     
         58 . The compound of  claim 57 , wherein the compound having the formula XXX comprises the formula XXXI 
       
         
           
           
               
               
           
         
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 6  and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 9  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 11  is hydrogen or a C 1 -C 15  branched or straight chain alkyl group; and 
         n is from 0 to 3. 
       
     
     
         59 . The compound of  claim 58 , wherein n is 1. 
     
     
         60 . The compound of  claim 58 , wherein R 3  is hydrogen and R 9  is one or more methyl groups. 
     
     
         61 . The compound of  claim 58 , wherein R 9  is hydrogen and R 3  is one or more methyl groups. 
     
     
         62 . The compound of  claims 57 - 61 , R 6 , R 7 , and R 11  are hydrogen 
     
     
         63 . The compound of  claim 57 , wherein the compound is (2E,4E,6E,8E)-8-(3′,4′-dihydro-5′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid; (2E,4E, 6E, 8E)-8-(3′,4′-dihydro-6′-methyl-1′ (2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid; (2E,4E,6E,8E)-8-(3′,4′-dihydro-7′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid; (2E,4E,6E,8E)-8-(3′,4′-dihydro-7′-isopropyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid; or (2E, 4E, 6E, 8E)-8-(3′,4′-dihydro-8′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid. 
     
     
         64 . The compound of  claim 57 , wherein n is 1, and R 2  is a C 1 -C 15  branched or straight chain alkyl group. 
     
     
         65 . The compound of  claim 57 , wherein n is 1, and R 1  is pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, or decyl. 
     
     
         66 . The compound of  claim 57 , wherein R 1  is an isopentyl group; R 2  is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or benzyl; and R 6 , R 7 , and R 11  are hydrogen. 
     
     
         67 . A compound having the formula XXXII 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 10  and R 11  are, independently, hydrogen or a C 1 -C 15  branched or straight chain alkyl group; and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula XXXII can optionally be replaced with a heteroatom, 
         or the pharmaceutically-acceptable salt or ester thereof, 
         wherein R 4  and R 10  are not both a methyl group. 
       
     
     
         68 . A pharmaceutical composition comprising the compound of  claims 57 - 67  and a pharmaceutically-acceptable carrier. 
     
     
         69 . A method for treating a subject having a neoplastic condition comprising administering to the subject an effective amount of a compound or composition of  claims 57 - 68 . 
     
     
         70 . A method for reducing or preventing the occurrence of a neoplastic condition in a subject comprising administering to the subject an effective amount of a compound or composition of  claims 57 - 68 . 
     
     
         71 . The method of  claim 69  or  70 , wherein the neoplastic condition comprises breast cancer, lung cancer, colon cancer, or leukemia. 
     
     
         72 . The method of  claim 71 , wherein the compound is administered at a dosage of from 1 mg/kg of body weight to 300 mg/kg of body weight. 
     
     
         73 . A method for treating a subject having squamous cell carcinoma comprising administering to the subject an effective amount of a compound having the formula VIII or a composition thereof. 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; and 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         wherein R 10  and R 11  are, independently, hydrogen or a C 1 -C 15  branched or straight chain alkyl group, 
         and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula VIII can optionally be replaced with a heteroatom. 
       
     
     
         74 . A method for treating a subject having basal cell carcinoma comprising administering to the subject an effective amount of a compound having the formula VIII or a composition thereof 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; and 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         wherein R 10  and R 11  are, independently, hydrogen or a C 1 -C 15  branched or straight chain alkyl group, 
         and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula VIII can optionally be replaced with a heteroatom. 
       
     
     
         75 . The method of  claim 72  or  74 , wherein the compound is administered orally. 
     
     
         76 . The method of  claim 72  or  74 , wherein the compound is administered topically. 
     
     
         77 . The method in any of  claims 72 - 76 , wherein the compound has the formula XXXV 
       
         
           
           
               
               
           
         
         wherein R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 9  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 10  and R 11  are, independently, hydrogen or a C 1 -C 15  branched or straight chain alkyl group, 
         and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula XXXV can optionally be replaced with a heteroatom. 
       
     
     
         78 . The method of  claim 77 , wherein n is 1 and R 4  and R 10  are methyl. 
     
     
         79 . The method in any of  claims 72 - 76 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         80 . A method for reducing serum triglycerides in a subject comprising administering to the subject an effective amount of a compound having the formula VIII or a composition thereof. 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group, or R 1  and R 2  collectively form a substituted or unsubstituted fused aryl group; and 
         R 3  is one or more groups comprising, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted cycloalkyl group; 
         R 4 , R 6 , and R 7  are, independently, hydrogen, a C 1 -C 15  branched or straight chain alkyl group, or a substituted or unsubstituted cycloalkyl group; 
         wherein R 10  and R 11  are, independently, hydrogen or a C 1 -C 15  branched or straight chain alkyl group, 
         and 
         n is from 0 to 3, 
         wherein one or more carbon atoms in the ring in formula VIII can optionally be replaced with a heteroatom. 
       
     
     
         81 . The method of  claim 80 , wherein the compound is (2E,4E,6E, 8E)-8-(3′,4′-dihydro-8′-methyl-1′(2′H-naphthalen-1′-ylidene))-3,7-dimethy 1-2,4,6-octatrienoic acid or (2E,4E,6Z)-8-(3′-cyclopropyl-2′-(3-methylbutyl)-2′-cyclohexen-1′-ylidene))-3,7-dimethyl-2,4,6-octatrienoic acid.