N-Acylated lipophilic amino acid derivatives

Abstract

Compounds of structural formula (I) where A is a lipophilic group including an aliphatic bridging group, B is a lipophilic group, D is a group having at least one amino or substituted amino group and R is hydrogen, alkyl or cycloalkyl, and pharmaceutically acceptable salts and individual isomers thereof, which have growth hormone releasing activity in humans or animals.

1 . A compound having a Formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 A is  
   A 1 -M 1 -  
 in which  
 A 1  is an indole ring, and  
 M is substituted or unsubstituted alkylene, and  
 B is a lipophilic group, and  
 D is a group having at least one amino or substituted amino group, and  
 R is hydrogen, alkyl or cycloalkyl,  
 and pharmaceutically acceptable salts and individual isomers thereof.  
 
   
   
       2 .- 32 . (canceled)  
   
   
       33 . A compound having the following formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 A 1  is  
                     
 R 14 =hydrogen or a halogen,  
 K=carbon or nitrogen  
 X═CH 2 , S, O or CH 2 -phenyl  
 Z=H,  
                     
 or COO-lower alkyl,  
 wherein  
 M is  
                     
 B is  
                     
 D is  
                     
 
   
   
       34 . A compound selected from: 
 N-(2-Aminoethyl)-3-phenyl-2 (R)-[2-(1,1,4-trioxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)-acetylamino]propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)propionamide;    3-(3-Acetylamino-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-N-[1(R)-(2-amino-ethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]propionamide;    N-[1(R)-(2-Aminoethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6-oxo-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl)propionamide;    N-[1(R)-(3-Amino-propylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6-oxo-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(4-oxo-2,3-dihydro[1,5]benzothiazepin-5-yl)propionamide;    N-[1(R)-(4-Aminobutylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(4-oxo-2,3-dihydro-[1,5benzothiazepin-5-yl)propionamide;    N-(4-Aminobutyl)-3-(naphthalen-2-yl)-2(R)-[2-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)-acetylamino]propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(11-oxo-11H-dibenzo [b,f][1,4]oxazepin-10-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(5,11-dioxo-2,3-dihydro-1H-(11aS)-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6-methoxy-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(4-Aminobutylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(4-methyl-2,5-dioxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl)propionamide;    N-[1(R)-(2-Aminoethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(3-oxo-2,3-dihydro-benzo [3,2-b][1,4]oxazin-4-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(2-oxo-3,4,5,6-tetrahydro-2H-benzo[b]azocin-1-yl)propionamide;    N-(2-Amino-2-methylpropyl)-3-(naphthalen-2-yl)-2(R)-[3-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)-propionylamino]propionamide    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(2-methyl-4-oxo-2,3-dihydro[1,5]benzothiazepin-5-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(6-oxo-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl)butyramide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)butyramide;    N-[1(R)-(3-Methylamino-propylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)propionamide;    N-[1(R)-(3-Methylamino-propylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-(1(R)-[(3-Aminopropyl)-methylcarbamoyl]-2-(naphthalen-2-yl)ethyl)-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-(3-Amino-2-hydroxypropyl)-3-(naphthalen-2-yl)-2(R)-[3-(4-oxo-2,3-dihydro-[1,5benzothiazepin-5-yl)-propionylamino]propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(2-Amino-ethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-(1(R)-[Bis-(3-aminopropyl)carbamoyl]-2-(naphthalen-2-yl)ethyl)-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Amino-propylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(1,1,4-trioxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(11-oxo-11H-dibenzo[b,f][1,4]oxazepin-10-yl)butyramide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-phenothiazin-10-yl-propionamide    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6-oxo-11,12-dihydro-6H-dibenzo[b,f]azocin-5-yl)propionamide;    N-(3-Amino-2-hydroxypropyl)-2(R)-[3-(6-methoxy-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)propionylamino]-3-(naphthalen-2-yl)propionamide;    N-(3-Amino-2-hydroxypropyl)-3-(naphthalen-2-yl)2(R)-[3-(2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)propionylamino]propionamide;    N-(3-Amino-2-hydroxypropyl)-3-(naphthalen-2-yl)-2(R)-[3-(2-oxo-3,4,5,6-tetrahydro-2H-benzo[b]azocin-1-yl)propionylamino]propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-5-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)pentanamide;    N-[1(R)-(2-aminoethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-5-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)pentanamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,5]-benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(11-oxo-11H-dibenzo[b,f][1,4]oxazepin-10-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(1,4-dioxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,5]-benzoxazepin-5-yl)butyramide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamyl)-2-(naphthalen-2-yl)ethyl]-3-(2-methyl-4-oxo-2,3-dihydro[1,5]benzothiazepin-5-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(7-fluoro-4-oxo-[1,5]benzothiazepin-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(5,11-dioxo-2,3-dihydro-1H,(11aS)-pyrrolo[2,1-c][1,4]diazepin-10-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(phenothiazin-10-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(6-methoxy-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)butyramide;    N-[1(R)-(2-Aminoethylcarbamoyl)-2-(naphthalene-2-yl)ethyl]-3-(8-fluoro-4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)propionamide;    N-(3-Amino-2-hydroxypropyl)-3-(naphthalene-2-yl)-2 (R)-[3-(4-oxo-7-trifluoromethyl-2,3-dihydro-[1,5]benzothiazepin-5-yl)propionylamino]propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-2,3-dihydro-[1,51-benzoxazepin-5-yl)butyramide;    N-(3-Amino-2-hydroxypropyl)-3-(naphthalen-2-yl)-2 (R)-[3-(4-oxo-2,3-dihydro-[1,5]-benzoxazepin-5-yl)propionylamino]propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(8-fluoro-4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide;    N-(3-Amino-2-hydroxypropyl)-2 (R)-[3-(8-fluoro-4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)propionylamino]-3-(naphthalen-2-yl)propionamide    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(8-fluoro-4-oxo-[1,5]-benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6-oxo-6,11-dihydro-dibenzo[b,e]azepin-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6-oxo-6,11-dihydro-dibenzo[b,e]-azepin-5-yl)propionamide;    N-[1(R)-(2-Aminoethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6,11-dioxo-6,11-dihydro-dibenzo[b,e]azepin-5-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6,11-dioxo-6,11-dihydro-dibenzo[b,e]azepin-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6,11-dioxo-6,11-dihydro-dibenzo-[b,e]-azepin-5-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-5-(6-oxo-6H-dibenzo[b,f]azocin-5-yl)pentanamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-5-(6-oxo-6H-dibenzo[b,f]azocin-5-yl)pentanamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(11-oxo-11H-dibenzo[b,f][1,4]thiazepin-10-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(11-oxo-11H-dibenzo[b,f][1,4]-thiazepin-10-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-5-(5,11-dioxo-5,11-dihydrodibenzo-[b,f][1,4]thiazepin-10-yl)pentanamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-5-(5,5,11-trioxo-5,11-dihydro-dibenzo[b,f][1,4]thiazepin-10-yl)pentanamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[1,5]thiazepin-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(7-chloro-5,11-dioxo-2,3,11,11a-tetrahydro-1H,5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(6,12-dioxo-6,6a,7,8,9,10-hexahydro-12H-benzo[e]pyrido [1,2-a][1,4]diazepine-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(9-fluoro-2-oxo-3,4,5,6-tetrahydro-2H-benzo[b]azocin-1-yl)propionamide;    N-[1(R)-(3-Aminopropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-2-methyl-3-(4-oxo-3,4-dihydro-2H-benzo[1,5]-thiazepin-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-2-methyl-3-(4-oxo-3,4-dihydro-2H-benzo[1,5]thiazepin-5-yl)propionamide;    N-[1(R)-(3-amino-2(S)-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-3,4-dihydro-[1,5]-benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-2-methyl-3-(5,11-dioxo-2,3,11,11a-tetrahydro-1H,5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10yl)propionamide;    N-[1(R)-(3-amino-2(R)-hydroxy-propylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-4-(4-oxo-3,4-dihydro-[1,5]-benzothiazepin-5-yl)buthanamide;    N-[1(R)-(3-Amino-2-hydroxypropylearbamoyl)-2-(naphthalen-2-yl)ethyl]-2,2-dimethyl-3-(5,11-dioxo-2,3,11,11a-tetrahydro-1H,5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxypropylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-2,2-dimethyl-3-(1,1,4-trioxo-benzo-[1,5]thiazepin-5-yl)propionamide;    N-[1(R)-(3-Aminoethylcarbamoyl)-2-(naphthalen-2-yl)ethyl]-2-methyl-3-(4-oxo-3,4-dihydro-[1,5]benzothiazepin-5-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxycarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(4-oxo-3,4-dihydro[1,5]benzothiazepin-5-yl)butyramide;    N-[1(R)-(3-Amino-2-hydroxycarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(3-cyano-5-isopropyl-2-oxo-2H-cyclohepta-4,6,8-trieno[b]pyrrol-1-yl)propionamide;    N-[1(R)-(3-Amino-2-hydroxycarbamoyl)-2-(naphthalen-2-yl)ethyl]-3-(5,11-dioxo-2,3,11,11a-tetrahydro-1H,5H-benzo[e]pyrrolo [1,2-a][1,4]diazepin-10-yl)propionamide; and    N-[1(R)-[2-Hydroxy-3-(2(R)-hydroxypropylamino)propylcarbamoyl]-2-naphthalen-2-yl-ethyl]-4-(4-oxo-2,3-dihydro-[1,5]benzothiazepin-5-yl)butyramide.    
   
   
       35 . A composition which comprises an inert carrier and a compound according to  claim 33 .  
   
   
       36 . A composition which comprises an inert carrier, a compound according to  claim 33  and at least one of the following components: 
 a growth hormone secretagogues selected from KP-102(GHRP-2), GHRP-6, Hexarelin, and GHRP-1, a growth hormone releasing factor (GRF) selected from IGF-1, IGF-2 and B-HT920.    
   
   
       37 . A method for increasing levels of endogenous growth hormones in a human or an animal which comprises administering to such human or animal an effective amount of a compound according to  claim 33 .  
   
   
       38 . A method for treating diseases or conditions which may be treated by growth hormone which comprises administering to a human or an animal of such treatment an amount of a compound according to  claim 33  which is effective in promoting release of said growth hormone.  
   
   
       39 . A method of  claim 38  wherein the disease or condition is selected from the group consisting of osteoporosis; catabolic illness; immune deficiency, hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; obesity; cachexia and protein loss due to chronic illness and treatment of patients recovering from major surgery, wounds and burns.  
   
   
       40 . A method for increasing the level of growth hormone in a human or an animal which comprises administering to a human or animal a compound according to  claim 33  in combination with any one of the following components: 
 an additional growth hormone secretagogue selected from KP-102(GHRP-2), GHRP-6, Hexarelin and GHRP-1, a growth hormone releasing factor(GRF) selected from IGF-1, IGF-2 and B-HT920, and a growth hormone.    
   
   
       41 . A method for the treatment of osteoporosis which comprises administering to a patient with osteoporosis a combination of a bisphosphonate compound and a compound according to  claim 33 .  
   
   
       42 . A method for the treatment of bone fractures, wounds or burns which comprises administering to a patient with bone fractures, wounds or burns a combination of fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF) and a compound of  claim 33 .  
   
   
       43 . A method to increase the rate and extent of growth of animals, to increase the milk or wool production of animals the method comprising administering to a subject in need thereof an effective amount of a compound according to  claim 33.