Methods and compositions for the treatment of metabolic disorders

Abstract

Embodiments described herein are directed to methods for the treatment and control of hyperlipidemia, hypercholesterolemia, dyslipidemia, and other lipid disorders, and in delaying the onset of or reducing the risk of conditions and sequelae that are associated with these diseases, including atherosclerosis and non-insulin dependent diabetes. In addition, embodiments are directed to methods of treating coronary heart disease and metabolic syndrome. Embodiments are also directed to neurotensin analogs. In embodiments, the neurotensin analogs may be capable of binding to neurotensin receptors and, upon binding, may modulate the levels of lipids in subjects.

1 . A pharmaceutical composition comprising:
 an effective amount of a compound of Formula I:   
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or —C α HR 2 R 3 ; 
         R 2  and R 4  are independently H, —(CH 2 ) m NR 9 R 10 , —(CH 2 ) m N(CH 3 )R 9 R 10 , —(CH 2 ) m NR 9 C(═NR 9 )NR 9 R 10 , or —(CH 2 ) m -imidazolidin-2-imin-1-yl; 
         R 3  is H, —NR 9 R 10 , —N(CH 3 )R 9 R 10 , —N(R 9 )—C(═O)R 9 , —C φ HR 9 R 10 , —C φ H(R 9 )—C(═O)R 10 , or —C φ H(C(═O)R 9 )(C(═O)R 10 ; 
         R 5  is phenyl, benzyl, —CH 2 -(4-hydroxy-phenyl), —CH 2 -(indol-3-yl), —CH 2 -(indol-4-yl), —CH 2 -(napht-1-yl), —CH 2 -(napht-2-yl), —CH 2 -(aryl), —CH 2 -(heteroaryl), napht-1-yl, or napht-2-yl; 
         R 6  is methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, (2S)-butyl, (2R)-butyl, C 5-6  alkyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, or cyclohexylmethyl; 
         R 7  is —O— or —N(R 9 )—; 
         R 8 , R 9  and R 10  are, independently in each instance, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, or (CH 2 CH 2 O) n CH 3 ; 
         m is 2, 3, 4 or 5; 
         n is an integer of from 1 to 20; 
         C α , C β , C γ , C ε  and C φ  are carbon atoms, and the stereochemistries at C α , C β , C γ , C ε  and C φ  are independently either R or S; 
         or pharmaceutically acceptable salt, hydrate, solvate, pro-drug or solvate thereof; and 
         a pharmaceutically acceptable excipient. 
       
     
     
         2 . The composition of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The composition of  claim 1 , wherein the compound is HPI-501. 
     
     
         4 . The composition of  claim 1 , wherein the compound is HPI-363. 
     
     
         5 . A method of treating a lipid disorder comprising administering a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or —C α HR 2 R 3 ; 
         R 2  and R 4  are independently H, —(CH 2 ) m NR 9 R 10 , —(CH 2 ) m N(CH 3 )R 9 R 10 , —(CH 2 ) m NR 9 C(═NR 9 )NR 9 R 10 , or —(CH 2 ) m -imidazolidin-2-imin-1-yl; 
         R 3  is H, —NR 9 R 10 , —N(CH 3 )R 9 R 10 , —N(R 9 )—C(═O)R 9 , —C φ HR 9 R 10 ,—C φ H(R 9 )—C(═O)R 10 , or —C φ H(C(═O)R 9 )(C(═O)R 10 ; 
         R 5  is phenyl, benzyl, —CH 2 -(4-hydroxy-phenyl), —CH 2 -(indol-3-yl), —CH 2 -(indol-4-yl), —CH 2 -(napht-1-yl), —CH 2 -(napht-2-yl), —CH 2 -(aryl), —CH 2 -(heteroaryl), napht-1-yl, or napht-2-yl; 
         R 6  is methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, (2S)-butyl, (2R)-butyl, C 5-6  alkyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, or cyclohexylmethyl; 
         R 7  is —O— or —N(R 9 )—; 
         R 8 , R 9  and R 10  are, independently in each instance, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, or (CH 2 CH 2 O) n CH 3 ; 
         m is 2, 3, 4 or 5; 
         n is an integer of from 1 to 20; 
         C α , C β , C γ , C ε  and C φ  are carbon atoms, and the stereochemistries at C α , C β , C γ , C ε  and C φ  are independently either R or S; 
         or pharmaceutically acceptable salt, hydrate, solvate, pro-drug or solvate thereof. 
       
     
     
         6 . The method of  claim 5 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 5 , wherein the compound is in a pharmaceutical composition. 
     
     
         8 . The method of  claim 5 , wherein the lipid disorder is selected from hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertrigyceridemia, hyperglycemia, or obesity. 
     
     
         9 . A method of treating non-insulin dependent diabetes mellitus comprising administering a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or —C α HR 2 R 3 ; 
         R 2  and R 4  are independently H, —(CH 2 ) m NR 9 R 10 , —(CH 2 ) m N(CH 3 )R 9 R 10 , —(CH 2 ) m NR 9 C(═NR 9 )NR 9 R 10 , or —(CH 2 ) m -imidazolidin-2-imin-1-yl; 
         R 3  is H, —NR 9 R 10 , —N(CH 3 )R 9 R 10 , —N(R 9 )—C(═O)R 9 , —C φ HR 9 R 10 , —C φ H(R 9 )—C(═O)R 10 , or —C φ H(C(═O)R 9 )(C(═O)R 10 ; 
         R 5  is phenyl, benzyl, —CH 2 -(4-hydroxy-phenyl), —CH 2 -(indol-3-yl), —CH 2 -(indol-4-yl), —CH 2 -(napht-1-yl), —CH 2 -(napht-2-yl), —CH 2 -(aryl), —CH 2 -(heteroaryl), napht-1-yl, or napht-2-yl; 
         R 6  is methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, (2S)-butyl, (2R)-butyl, C 5-6  alkyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, or cyclohexylmethyl; 
         R 7  is —O— or —N(R 9 )—; 
         R 8 , R 9  and R 10  are, independently in each instance, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, or (CH 2 CH 2 O) n CH 3 ; 
         m is 2, 3, 4 or 5; 
         n is an integer of from 1 to 20; 
         C α , C β , C γ , C ε  and C φ  are carbon atoms, and the stereochemistries at C α , C β , C γ , C ε  and C φ  are independently either R or S; 
         or pharmaceutically acceptable salt, hydrate, solvate, pro-drug or solvate thereof. 
       
     
     
         10 . The method of  claim 9 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 12 , wherein the compound is in a pharmaceutical composition. 
     
     
         12 . A method of treating conditions associated with non-insulin dependent diabetes mellitus comprising administering a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic or —C α HR 2 R 3 ; 
         R 2  and R 4  are independently H, —(CH 2 ) m NR 9 R 10 , —(CH 2 ) m N(CH 3 )R 9 R 10 , —(CH 2 ) m NR 9 C(═NR 9 )NR 9 R 10 , or —(CH 2 ) m -imidazolidin-2-imin-1-yl; 
         R 3  is H, —NR 9 R 10 , —N(CH 3 )R 9 R 10 , —N(R 9 )—C(═O)R 9 , —C φ HR 9 R 10 , —C φ H(R 9 )—C(═O)R 10 , or —C φ H(C(═O)R 9 )(C(═O)R 10 ; 
         R 5  is phenyl, benzyl, —CH 2 -(4-hydroxy-phenyl), —CH 2 -(indol-3-yl), —CH 2 -(indol-4-yl), —CH 2 -(napht-1-yl), —CH 2 -(napht-2-yl), —CH 2 -(aryl), —CH 2 -(heteroaryl), napht-1-yl, or napht-2-yl; 
         R 6  is methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, (2S)-butyl, (2R)-butyl, C 5-6  alkyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, or cyclohexylmethyl; 
         R 7  is —O— or —N(R 9 )—; 
         R 8 , R 9  and R 10  are, independently in each instance, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, or (CH 2 CH 2 O) n CH 3 ; 
         m is 2, 3, 4 or 5; 
         n is an integer of from 1 to 20; 
         C α , C β , C γ , C ε  and C φ  are carbon atoms, and the stereochemistries at C α , C β , C γ , C ε  and C φ  are independently either R or S; 
         or pharmaceutically acceptable salt, hydrate, solvate, pro-drug or solvate thereof. 
       
     
     
         13 . The method of  claim 12 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 15 , wherein the compound is in a pharmaceutical composition. 
     
     
         15 . The method of  claim 13 , wherein the condition associated with non-insulin dependent diabetes mellitus is selected from hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertrigyceridemia, hyperglycemia, obesity, atherosclerosis, hyperinsulinemia, cardiovascular disease, coronary heart disease and metabolic syndrome. 
     
     
         16 . A compound having the formula: