Macrocyclic modulators of the ghrelin receptor

Abstract

The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.

1. The compound of the formula (II): 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein:
 R 50  is —(CH 2 ) ss CH 3 , —CH(CH 3 )(CH 2 ) tt CH 3 , —(CH 2 ) uu CH(CH 3 ) 2 , —C(CH 3 ) 3 , —(CHR 55 ) vv —R 56 , or —CH(OR 57 )CH 3 , 
 wherein ss is 0, 1, 2 or 3; tt is 1 or 2; uu is 0, 1 or 2; and vv is 0, 1, 2, 3 or 4; R 55  is hydrogen or C 1 -C 4  alkyl; R 56  is cycloalkyl substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and when vv is 1, 2 or 3, R 56  is also amino, hydroxy or alkoxy; and R 57  is hydrogen or lower alkyl;  
 and R 50′  is hydrogen; or R 50  and R 50′ , taken together with the carbon to which they are attached, form a C 3 -C 6  ring;  
 
 R 51  is hydrogen, C 1 -C 4  alkyl or C 1 -C 4  alkyl substituted with hydroxy or alkoxy; and R 51′  is hydrogen; or R 51  and R 51′ , taken together with the carbon to which they are attached, form a C 3 -C 6  ring, optionally comprising O, S or NH in the ring;  
 R 52  is —(CHR 58 ) ww R 59 , 
 wherein ww is 0, 1, 2 or 3; R 58  is hydrogen, C 1 -C 4  alkyl and when ww is 1, 2 or 3, R 58  is also amino, hydroxy or alkoxy; R 59  is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl;  
 
 R 53  is hydrogen or C 1 -C 4  alkyl;  
 X 2  is NR 9  or N(R 10 ) 2   + ; 
 wherein R 9  and R 10  are independently hydrogen or lower alkyl;  
 
 Z 5  is NR 12 , wherein R 12  is hydrogen or lower alkyl; and  
 T 2  is selected from the group consisting of the following: 
                 
 wherein (Z 5 ) is the site of a covalent bond of T 2  to Z 5 , and Z 5  is NR 12 , wherein R 12  is hydrogen or lower alkyl, and wherein (X 2 ) is the site of a covalent bond of T 2  to X 2 , and X 2  is NR 9  or N(R 10 ) 2   + , wherein R 9  and R 10  are independently hydrogen or lower alkyl;  
 U 2  is —CR 95 R 96 — or —C(═O)—;  
 L 6a-n  is —CH 2  or —O—;  
 R 90  is alkyl, substituted alkyl, aryl or substituted aryl;  
 R 91 , R 92 , R 93 , R 95  and R 96  are each independently hydrogen or lower alkyl; and  
 
 R 94  is hydrogen, lower alkyl, substituted lower alkyl or oxo,  
 with the proviso that when T 2  is 
                 
 
 
       at least one of R 50 , R 51  and R 52  is not selected from the group consisting of the following: 
                 
 
       wherein Rp is selected from the group consisting of H and a protecting group. 
     
     
       2. The compound of  claim 1 , wherein the compound is a ghrelin receptor agonist. 
     
     
       3. The compound of  claim 1 , wherein the compound is a GHS-R1a receptor agonist. 
     
     
       4. A compound represented by the following structures: 
                 
                 
                 
                 
                 
                 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound of  claim 4 , wherein the compound is a ghrelin receptor agonist. 
     
     
       6. The compound of  claim 4 , wherein the compound is a GHS-R1a receptor agonist. 
     
     
       7. A pharmaceutical composition comprising:
 (a) a compound of formula (II) of  claim 1 ; and  
 (b) a pharmaceutically acceptable carrier, excipient or diluent.  
 
     
     
       8. The pharmaceutical composition of  claim 7  further comprising a growth hormone secretagogue. 
     
     
       9. The pharmaceutical composition of  claim 8 , wherein the growth hormone secretagogue is hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, RC-1291, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187, NNC-26-1291, growth hormone releasing factor, IGF-I or IGF-II. 
     
     
       10. A pharmaceutical composition comprising:
 (a) any one of the compounds of  claim 4 ; and  
 (b) a pharmaceutically acceptable carrier, excipient or diluent.  
 
     
     
       11. The pharmaceutical composition of  claim 10  further comprising a growth hormone secretagogue. 
     
     
       12. The pharmaceutical composition of  claim 11 , wherein the growth hormone secretagogue is hexarelin, GHRP-1, GHRP-2, GHRP-6, ipamorelin, MK-0677, NN703, capromorelin, G7039, G7134, G7203, G7502, SM-130686, RC-1291, L-692429, L-692587, L-739943, L-163255, L-163540, L-163833, L-166446, CP-424391, EP-51389, LY-444711, NNC-26-0235, NNC-26-0323, NNC-26-0610, NNC-26-0722, NNC-26-1089, NNC-26-1136, NNC-26-1137, NNC-26-1187, NNC-26-1291, growth hormone releasing factor, IGF-I or IGF-II. 
     
     
       13. A kit comprising one or more containers containing pharmaceutical dosage units comprising an effective amount of one or more compounds having the following structure: 
                 
                 
                 
                 
                 
                 
 
       or a pharmaceutically acceptable salt thereof, wherein the container is packaged with optional instructions for the use thereof. 
     
     
       14. The kit of  claim 13 , wherein the kit further comprises a growth hormone secretagogue.