Boropeptide inhibitors of enteropeptidase and their uses in treatment of obesity, overweight and/or diseases associated with an abnormal fat metabolism

Abstract

The present invention relates to novel compounds, particularly derivatives of boroarginine, boroornithine and borolysine that selectively modulate, regulate, and/or inhibit enteropeptidase. The invention also relates to compositions, particularly pharmaceutical compositions, as well as methods to treat excess weight, obesity and diseases associated with an abnormal fat metabolism.

1 . A compound having the following formula (I): 
       
         
           
           
               
               
           
         
         wherein
 B represents a boron atom; 
 W is a nitrogen-containing functionality group, sustaining a positive charge either through protonation or quaternization, this group being selected from: 
 
         (i) an amino group of the formula: 
       
       
         
           
           
               
               
           
         
         wherein G 1  and G 2  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates the N atom and that contains a total of up to 15 atoms; 
         (ii) a quaternary ammonium group of formula: 
       
       
         
           
           
               
               
           
         
         wherein G 1 , G 2  and G 3  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates the N atom and that contains a total of up to 15 atoms; or 
         (iii) a guanidine group of formula: 
       
       
         
           
           
               
               
           
         
         wherein G 1 , G 2 , G 3 , G 4  and G 5  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates one or more of the guanidine N atoms and that contains a total of up to 15 atoms;
 X is a linker unit having the formula (CX 1 X 2 ) p , wherein 1<p<10, and wherein X 1  and X 2  are, independently, H, or linear or branched alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring residue containing from 3 to 10 atoms; 
 Y is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms; 
 Z is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms, or is a linear or branched or cyclic alkyl group containing from 1 to 15 carbon atoms; 
 R1 is chosen among:
 (i) an aminoacyl residue derived from an amino acid. 
 (ii) a derivative of the aminoacyl residue of option (i), in which the amino group is additionally acylated, or sulfonylated, or phosphorylated to form an amide, or peptide, or sulfonamide, or phosphoramide bond; 
 (iii) an acyl group of general formula R′—CO, wherein R′ is:
 a. a linear, branched or cyclic alkyl group that contains from 1 to 10 C atoms; 
 b. a saturated heterocyclic ring incorporating up to 20 atoms chosen from C, O, N, and S atoms; 
 c. an aryl group selected from phenyl or a substituted variant thereof bearing any combination, at any one ring position, of one or more substituents selected from halogen, alkyl groups containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy groups; or 
 d. a heteroaryl group; 
 
 
 R 2  is either H, or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms, or an OR group wherein R may be H or a or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein groups G 1  and G 2  of the amino group of W are selected, independently, from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein groups G 1 , G 2  and G 3  of the quaternary ammonium group of W are selected, independently, from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein groups G 1 , G 2 , G 3 , G 4  and G 5  of the guanidine group of W are selected, independently, from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein group X is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 1 , wherein group Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 , wherein group Z is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound according to  claim 1 , having the formula II: 
       
         
           
           
               
               
           
         
         wherein
 B represents a boron atom. 
 W is a nitrogen-containing functionality group, sustaining a positive charge either through protonation or quaternization, this group being selected from: 
 
         (i) an amino group of the formula: 
       
       
         
           
           
               
               
           
         
         wherein G 1  and G 2  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates the N atom and that contains a total of up to 15 atoms; 
         (ii) a quaternary ammonium group of formula: 
       
       
         
           
           
               
               
           
         
         wherein G 1 , G 2  and G 3  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates the N atom and that contains a total of up to 15 atoms; or 
         (iii) a guanidine group of formula: 
       
       
         
           
           
               
               
           
         
         wherein G 1 , G 2 , G 3 , G 4  and G 5  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates one or more of the guanidine N atoms and that contains a total of up to 15 atoms;
 X is a linker unit having the formula (CX 1 X 2 ) p , wherein 1<p<10, and wherein X 1  and X 2  are, independently, H, or linear or branched alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring residue containing from 3 to 10 atoms; 
 Y is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms; 
 Z is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms, or is a linear or branched or cyclic alkyl group containing from 1 to 15 carbon atoms; 
 R 2  is either H, or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms, or an OR group wherein R may be H or a or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms; and 
 “aa” refers to any amino acid residue or derivative thereof, and n is at least two. 
 
       
     
     
         9 . The compound according to  claim 1 , wherein the W—X—C—N(C═O)—R 2  is an amino acid positively charged. 
     
     
         10 . The compound according to  claim 9 , wherein said positively charged amino acid is arginine, lysine, ornithine or a derivative thereof. 
     
     
         11 . The compound according  claim 8 , having the following formula III: 
       
         
           
           
               
               
           
         
         wherein
 B represents a boron atom; 
 Y is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms; 
 Z is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms, or is a linear or branched or cyclic alkyl group containing from 1 to 15 carbon atoms; 
 R 2  is either H, or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms, or an OR group wherein R may be H or a or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms; 
 
         G 1 , G 2  and G 3  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates one or more of the guanidine N atoms and that contains a total of up to 15 atoms
 “aa” refers to any amino acid residue or derivative thereof, and n is at least two. 
 
       
     
     
         12 . The compound according to  claim 11 , wherein at least one of R 2 , G 1 , G 2  and G 3  is H. 
     
     
         13 . The compound according to  claim 12 , wherein G 1 , G 2  and G 3  is H. 
     
     
         14 . The compound according to  claim 12 , wherein R 2 , G 1 , G 2  and G 3  are H. 
     
     
         15 . The compound according to  claim 8 , having the following formula IV: 
       
         
           
           
               
               
           
         
         wherein
 B represents a boron atom; 
 Y is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms; 
 Z is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms, or is a linear or branched or cyclic alkyl group containing from 1 to 15 carbon atoms; 
 R 2  is either H, or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms or an OR group, wherein R may be H or a or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms; 
 G 1 , G 2  and G 3  or G 1  and G 2  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates one or more of the guanidine N atoms and that contains a total of up to 15 atoms; 
 “aa” refers to any amino acid residue or derivative thereof, and n is at least two; and 
 m equals 3 or 4. 
 
       
     
     
         16 . A compound according to  claim 15  having the following formula V: 
       
         
           
           
               
               
           
         
         wherein
 B represents a boron atom; 
 Y is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms; 
 Z is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms, or is a linear or branched or cyclic alkyl group containing from 1 to 15 carbon atoms; 
 R 2  is either H, or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms, or an OR group wherein R may be H or a or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms; 
 G 1  and G 2  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates the N atom and that contains a total of up to 15 atoms; and 
 “aa” refers to any amino acid residue or derivative thereof, and n is at least two. 
 
       
     
     
         17 . A compound according to  claim 8 , having the following formula VI: 
       
         
           
           
               
               
           
         
         wherein
 B represents a boron atom; 
 Y is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms; 
 Z is an OH, or is an OR group wherein R is a linear, branched or cyclic alkyl group incorporating from 1 to 10 carbon atoms, or is a branch of a homocyclic or heterocyclic structure, which incorporates the B atom and which contains up to 20 atoms chosen from C, O, N, and S atoms, or is a linear or branched or cyclic alkyl group containing from 1 to 15 carbon atoms; 
 R 2  is either H, or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms, or an OR group wherein R may be H or a or a linear or branched or cyclic alkyl group containing from 1 to 10 carbon atoms; 
 G 1  and G 2  are, independently, H, or linear or branched or cyclic alkyl groups containing from 1 to 10 carbon atoms, or branches of a ring system that incorporates the N atom and that contains a total of up to 15 atoms; and 
 “aa” refers to any amino acid residue or derivative thereof, and n is at least two. 
 
       
     
     
         18 . The compound according to  claim 15 , wherein at least one of R 2 , G 1  and G 2  is H. 
     
     
         19 . The compound according to  claim 15 , wherein G 1  and G 2  are H. 
     
     
         20 . The compound according to  claim 15 , wherein R 2 , G 1  and G 2  are H. 
     
     
         21 . The compound according to  claim 8 , wherein n is comprised between 2 and 5. 
     
     
         22 . The compound according to  claim 21 , wherein n equals 2, 3 or 4. 
     
     
         23 . The compound according to  claim 21 , wherein n equals 2. 
     
     
         24 . The compound according to  claim 23 , wherein said two amino acids residues are Tyr and Pro, Ala and Phe, Arg and Glu, Glu and Gly, Trp and Glu, Thr and Pro or Leu and Leu. 
     
     
         25 . The compound according to  claim 8 , wherein n equals 3. 
     
     
         26 . The compound according to  claim 25 , wherein said three amino acids residues are Phe, Arg and Val, Arg, Cys and Thr, Gly, Cys and Pro, Gly, Cys and Asn or Lys, Gly, Asp. 
     
     
         27 . The compound according to  claim 8 , wherein the amino group of the first N-terminal amino acid residue bears a protecting group selected from the group consisting of acyl, sulfonyl or phosphoryl. 
     
     
         28 . The compound according to  claim 8 , wherein the amino group of the first N-terminal amino acid residue is derivatized with an acyl, sulfonyl, or phosphoryl group to form an amide, or carbamate, or urea, or N-substituted urea, or peptide, or sulfonamide, or phosphoramide bond. 
     
     
         29 . The compound according to  claim 1 , wherein at least one of Y or Z is OH. 
     
     
         30 . The compound according to  claim 1 , wherein Y and Z are OH. 
     
     
         31 . The compound according to  claim 1 , which is Glu-Gly-BoroArg, Ala-Phe-BoroArg, Ac-Glu-Gly-BoroArg and Ac-Ala-Phe-BoroArg. 
     
     
         32 . The compound according to  claim 1 , which inhibits the enzymatic activity of the enteropeptidase. 
     
     
         33 . The compound according to  claim 32 , wherein the enteropeptidase activity inhibition is selective over other serine proteases. 
     
     
         34 . The compound according to  claim 1 , which is non-absorbable. 
     
     
         35 . The compound according to  claim 1 , which is in a free base form or is a pharmaceutically acceptable salt thereof. 
     
     
         36 . A composition comprising at least one compound according to  claim 1 . 
     
     
         37 . The composition according to  claim 36 , further comprising at least one pharmaceutically acceptable carrier. 
     
     
         38 . The composition according to  claim 36 , formulated for oral or enteral administration. 
     
     
         39 . The composition according to  claim 36 , further comprising at least one other drug. 
     
     
         40 . A method for treating a mammal having obesity, comprising administrating, in said patient in need of said treatment, at least one compound according to  claim 1  or a composition according to  claim 36 . 
     
     
         41 . The method according to  claim 40 , wherein the mammal is a human being. 
     
     
         42 . The method according to  claim 41 , wherein obesity results from environmental causes, from genetic alterations, from medical illness, from smoking cessation, from medications or from neurological disorders. 
     
     
         43 . A method for treating a mammal having excess weight, comprising administrating, to said mammal in need of said treatment, at least one compound according to  claim 1  or a composition according to  claim 36 . 
     
     
         44 . A method for treating a mammal suffering from abnormal fat metabolism comprising administrating, to said mammal in need of said treatment, at least one compound according to  claim 1  or a composition according to  claim 36 . 
     
     
         45 . The method according to  claim 44 , wherein the mammal is a human being. 
     
     
         46 . The method according to  claim 44 , wherein said abnormal fat metabolism disease is selected from the group consisting of: gout disease, type II diabetes, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, syndrome X, diabetic complications, dysmetabolic syndrome and related diseases, hypercholesterolemia, atherosclerosis, hypertension, pancreatitis, hypertriglyceridemia, hyperlipidemia, stroke, coronary heart diseases, peripheral vascular diseases, peripheral arterial diseases, vascular syndromes, cholesterol-related disorders or drug-induced lipodystrophy. 
     
     
         47 . (canceled) 
     
     
         48 . The compound according to  claim 17 , wherein at least one of R 2 , G 1  and G 2  is H. 
     
     
         49 . The compound according to  claim 17 , wherein G 1  and G 2  are H. 
     
     
         50 . The compound according to  claim 17 , wherein R 2 , G 1  and G 2  are H. 
     
     
         51 . The compound according to  claim 8 , wherein at least one of Y or Z is OH. 
     
     
         52 . The compound according to  claim 8 , wherein Y and Z are OH. 
     
     
         53 . A composition comprising at least one compound according to  claim 8 . 
     
     
         54 . A method for treating a mammal having obesity, comprising administrating, in said patient in need of said treatment, at least one compound according to  claim 8  or a composition according to  claim 53 . 
     
     
         55 . A method for treating a mammal having excess weight, comprising administrating, to said mammal in need of said treatment, at least one compound according to  claim 8  or a composition according to  claim 53 . 
     
     
         56 . A method for treating a mammal suffering from abnormal fat metabolism comprising administrating, to said mammal in need of said treatment, at least one compound according to  claim 8  or a composition according to  claim 53 .