Melanocortin-4 receptor binding compounds and methods of use thereof

Abstract

Provided are MC4-R binding compounds of the formula XVII: wherein L 2 is a linker group, and P 1 , P 2 , P 3 , P 4 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , t, s, and R are as described in the specification. Methods of using the compounds to treat MC4-R associated disorders, such as disorders associated with weight loss, are also provided.

1 . A method of treating an MC4-R associated state in a mammal comprising of administering a compound of the formula (XI), or a pharmaceutical salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 Ar and Ar′ are aromatic groups; 
 R 11  is selected independently for each position capable of substitution from the group hydrogen, halogen, alkyl, amino, cyano, or aryloxy. 
 R 12  is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl containing moiety; 
 X is NR 17 , S, O or a covalent bond; 
 R 17  is hydrogen, alkyl, alkenyl, alkynyl, acyl, heterocyclic, or carbonyl containing moiety; 
 R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, or aryl, for each occurrence; 
 R 22  and R 21  are each independently selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, halogen, nitro, cyano, amino, aryl, hydrogen, or carbonyl, and may optionally be linked to form a heterocycle; 
 v is 0, 1, 2, 3, 4, 5, or 6; 
 e is 0, 1, 2, or 3; 
 f is 0, 1, 2, or 3; 
 
       
       and pharmaceutically acceptable salts thereof.
 wherein: 
 alkyl is a C 1 -C 10  straight chain alkyl, C 3 -C 10  branched chain alkyl, C 4 -C 7 , cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups, optionally having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons and optionally being substituted with one or more substituents selected from alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aryl moiety, as defined herein; 
 alkenyl and alkynyl is each an unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond or at least one triple bond, respectively; 
 aryl is a 5- and 6-membered single-ring aromatic groups and multicyclic aryl groups comprised of two to three 5- and 6-membered ring aromatic groups, each of which may include from zero to four heteroatoms, forming a heteroaromatic ring, multicyclic aryl groups, optionally substituted at one or more ring positions with substituents selected from halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aryl moiety and optionally fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle; 
 aralkyl is an alkyl group substituted with an aryl group; 
 acyl is a group having the structure R—C(O)—, where R is an alkyl, alkenyl, alkynyl or aryl group as defined above; 
 alkoxy is a group of the structure RO—, where R is an alkyl, alkenyl, or alkynyl; and 
 aryloxy comprises a group of the structure Ar″RO—, where Ar″ is an aryl group as defined herein; 
 heterocyclic is a saturated, unsaturated, aromatic and polycyclic rings, as defined herein, which contain one or more heteroatoms selected from nitrogen, oxygen and sulfur; 
 amine or amino is a group of the structure R2N—, where each R is independently hydrogen or an alkyl, alkenyl, alkynyl or aryl group as defined above; and 
 carbonyl containing moiety is a moiety which contains a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof, including aldehydes, ketones, carboxylic acids, amides, esters, anhydrides comprised of alkyl groups as defined herein and including groups having a heteroatom selected from oxygen, nitrogen and sulfur attached to the carbon of the carbonyl group. 
 
     
     
         2 . A method of treating an MC4-R associated state in a mammal, comprising of administering a formula (X), or pharmaceutical salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar and Ar′ are aromatic groups; 
 R 11  is selected independently for each position capable of substitution from the group hydrogen, cyano, halogen, alkyl, amino, or aryloxy; 
 R 12  is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl containing moiety; 
 R 13  is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl, or acyl, carbonyl containing moiety, or SO 2 CH 3 , and may optionally be linked to an R 16  or an R 16′  group; 
 R 16  and R 16′  are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or acyl, and may optionally be connected through an alkyl chain to R 13  or another R 16  and R 16′  group, to form a fused or spiro ring system; 
 X is NR 7 , S, O or a covalent bond; 
 R 17  is hydrogen, alkyl, alkenyl, alkynyl, acyl, heterocyclic. or carbonyl containing moiety; 
 R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroaromatic, halogen, nitro, cyano, amino, or aryl, for each occurrence; 
 w is 0, 1, 2, 3, or 4; 
 e is 0, 1, 2, or 3; 
 f is 0, 1, 2, or 3, 
 and pharmaceutically acceptable salts thereof, 
 wherein: 
 wherein: 
 alkyl is a C 1 -C 10  straight chain alkyl, C 3 -C 10  branched chain alkyl, C 4 -C 7 , cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups, optionally having oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons and optionally being substituted with one or more substituents selected from alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aryl moiety, as defined herein; 
 alkenyl and alkynyl is each an unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond or at least one triple bond, respectively; 
 aryl is a 5- and 6-membered single-ring aromatic groups and multicyclic aryl groups comprised of two to three 5- and 6-membered ring aromatic groups, each of which may include from zero to four heteroatoms, forming a heteroaromatic ring, multicyclic aryl groups, optionally substituted at one or more ring positions with substituents selected from halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aryl moiety and optionally fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle; 
 aralkyl is an alkyl group substituted with an aryl group; 
 acyl is a group having the structure R—C(O)—, where R is an alkyl, alkenyl, alkynyl or aryl group as defined above; 
 alkoxy is a group of the structure RO—, where R is an alkyl, alkenyl, or alkynyl; and 
 aryloxy comprises a group of the structure Ar″RO—, where Ar″ is an aryl group as defined herein; 
 heterocyclic is a saturated, unsaturated, aromatic and polycyclic rings, as defined herein, which contain one or more heteroatoms selected from nitrogen, oxygen and sulfur; 
 amine or amino is a group of the structure R2N—, where each R is independently hydrogen or an alkyl, alkenyl, alkynyl or aryl group as defined above; and 
 carbonyl containing moiety is a moiety which contains a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereof, including aldehydes, ketones, carboxylic acids, amides, esters, anhydrides comprised of alkyl groups as defined herein and including groups having a heteroatom selected from oxygen, nitrogen and sulfur attached to the carbon of the carbonyl group. 
 
     
     
         3 . The method of  claim 1 , wherein Ar is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein R 1  is selected independently for each aromatic position capable of substitution from the group consisting of hydrogen, halogen, alkyl, amino, and benzyloxy. 
     
     
         5 . The method of  claim 4 , wherein each R 11  is independently hydrogen or halogen. 
     
     
         6 . The method of  claim 1 , wherein Ar′ is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein R 19  is hydrogen, alkyl, acyl, aryl, alkenyl, or alkynyl. 
     
     
         7 . The method of  claim 1 , wherein each R 12  is selected independently for each aromatic position capable of being substituted from the group consisting of hydrogen, alkoxy, halogen, or cyano. 
     
     
         8 . The method of  claim 7 , wherein each R 12  is hydrogen, C 1 -C 10  alkoxy, or halogen selected from bromine, fluorine, iodine, and chlorine. 
     
     
         9 . The method of  claim 1 , wherein X is NR 17  and R 17  is hydrogen, C 1 -C 10  alkyl, or acyl. 
     
     
         10 . The method of  claim 2 , wherein R 16  and R 16′  are independently selected for each position from the group consisting of hydrogen and alkyl. 
     
     
         11 . The method of  claim 1 , wherein R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl and phenyl for each occurrence. 
     
     
         12 . The method of  claim 2 , wherein said R 13  group is hydrogen, acyl, alkyl, acyl, carboxy, or SO 2 CH 3 . 
     
     
         13 . The method of  claim 12 , wherein R 13  is hydrogen, acyl, or alkyl that is an optionally substituted C 1 -C 10  alkyl. 
     
     
         14 . The method of  claim 2 , wherein w is 2 or 3. 
     
     
         15 . The method of  claim 1 , wherein R 22  and R 21  are each independently selected from the group consisting of substituted or unsubstituted alkyl, carbonyl, and may optionally be linked to form a heterocycle. 
     
     
         16 . The method of  claim 15 , wherein said heterocycle is piperazinyl or morpholinyl. 
     
     
         17 . The method of  claim 1 , wherein v is 1, 2, or 3. 
     
     
         18 . A pharmaceutical composition for the treatment of a MC4-R associated state in a mammal comprising a pharmaceutically acceptable carrier and an effective amount of an MC4-R binding compound of the formulate (XI): 
       
         
           
           
               
               
           
         
         wherein
 Ar and Ar′ are aromatic groups, as described above; 
 R 11  is selected independently for each position capable of substitution from the group hydrogen, halogen, alkyl, amino, cyano, or aryloxy; 
 R 12  is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl; 
 X is NR 17 , S, O, or a covalent bond; 
 R 17  is hydrogen, alkyl, acyl, heterocyclic, or carbonyl; 
 R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, or aryl for each occurrence; 
 R 20  and R 21  are each independently selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, hydrogen, or carbonyl, and may optionally be linked to form a heterocycle; 
 v is 0, 1, 2, 3, 4, 5, or 6; 
 e is 0, 1, 2, or 3; 
 f is 0, 1, 2, or 3, and pharmaceutically acceptable salts thereof. 
 
       
     
     
         19 . An MC4-R binding compound of the formula (XVIII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 Ar and Ar′ are aromatic groups; 
 R 11  is selected independently for each position capable of substitution from the group hydrogen, cyano, alkoxy, nitro, halogen, alkyl, amino, hydroxy or aryloxy; 
 R 12  is selected for each position capable of substitution from the group consisting of hydrogen, halogen, alkoxy, acetylenic, nitro, aryl, alkyl, alkenyl, alkynyl, cyano, acyl, or carbonyl containing moiety; 
 R 13  is hydrogen, alkenyl, alkynyl, aralkyl, nitro, cyano, alkyl, acyl, carbonyl containing moiety, or SO 2 CH 3 , and may optionally be linked to an R 16  or an R 16′  group; 
 R 16  and R 16′  are each independently selected for each position capable of substitution from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, cyano, aryl, heterocyclic, carbonyl containing moiety, or acyl, and may optionally be connected through an alkyl chain to R 13  or another R 16  or R 16′  group, to form a fused or Spiro ring system; 
 X is NR 17 , O or a covalent bond; 
 R 17  is hydrogen, alkyl, or carbonyl; 
 R 14  and R 15  are each independently hydrogen, halogen, or alkyl; 
 w is 1, 2, 3, or 4; 
 e is 0 or 1; 
 f is 0 or 1, wherein both e and f are not both 0 if X is a covalent bond; 
 
         wherein alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, alkoxy, heterocyclic, amine, amino and carbonyl containing moiety are as defined in  claim 1 . 
       
     
     
         20 . A pharmaceutical composition for the treatment of an MC4-R associated state in a mammal comprising a pharmaceutically acceptable carrier and an effective amount of an MC4-R binding compound according to  claim 19 .