Glp-1 analogues

Abstract

The present invention is directed to peptide analogues of glucagon-like peptide-1, the pharmaceutically-acceptable salts thereof, to methods of using such analogues to treat mammals and to pharmaceutical compositions useful therefor comprising said analogues.

1 . A compound of formula (I),
   (R 2 R 3 )-A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -R 1 ,  (I)   
       wherein
 A 7  is L-His, Ura, Paa, Pta, D-His, Tyr, 3-Pal, 4-Pal, Hppa, Tma-His, Amp or deleted, provided that when A 7  is Ura, Paa, Pta or Hppa then R 2  and R 3  are deleted; 
 A 8  is Ala, D-Ala, Aib, Acc, N-Me-Ala, N-Me-D-Ala, Arg or N-Me-Gly; 
 A 9  is Glu, N-Me-Glu, N-Me-Asp or Asp; 
 A 10  is Gly, Acc, Ala, D-Ala, Phe or Aib; 
 A 11  is Thr or Ser; 
 A 12  is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, β-Nal, Cha, Trp or X 1 -Phe; 
 A 13  is Thr or Ser; 
 A 14  is Ser, Thr, Ala or Aib; 
 A 15  is Asp, Ala, D-Asp or Glu; 
 A 16  is Val, D-Val, Acc, Aib, Leu, Ile, Tle, Nle, Abu, Ala, D-Ala, Tba or Cha; 
 A 17  is Ser, Ala, D-Ala, Aib, Acc or Thr; 
 A 13  is Ser, Ala, D-Ala, Aib, Acc or Thr; 
 A 19  is Tyr, D-Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, β-Nal, Amp or X 1 -Phe; 
 A 20  is Leu, Ala, Acc, Aib, Nle, Ile, Cha, Tle, Val, Phe or X 1 -Phe; 
 A 21  is Glu, Ala or Asp; 
 A 22  is Gly, Acc, Ala, D-Ala, β-Ala or Aib; 
 A 23  is Gln, Asp, Ala, D-Ala, Aib, Acc, Asn or Glu; 
 A 24  is Ala, Aib, Val, Abu, Tle or Acc; 
 A 25  is Ala, Aib, Val, Abu, Tle, Acc, Lys, Arg, hArg, Orn, HN—CH((CH 2 ) n —NR 10 R 11 )—C(O) or HN—CH((CH 2 ) e —X 3 )—C(O); 
 A 26  is Lys, Ala, 3-Pal, 4-Pal, Arg, hArg, Orn, Amp, HN—CH((CH 2 ) n —NR 10 R 11 )—C(O) or HN—CH((CH 2 ) e —X 3 )—C(O); 
 A 27  is Glu, Ala, D-Ala or Asp; 
 A 28  is Phe, Ala, Pal, β-Nal, X 1 -Phe, Aic, Acc, Aib, Cha or Trp; 
 A 29  is Ile, Acc, Aib, Leu, Nle, Cha, Tle, Val, Abu, Ala, Tba or Phe; 
 A 30  is Ala, Aib, Acc or deleted; 
 A 31  is Trp, Ala, β-Nal, 3-Pal, 4-Pal, Phe, Acc, Aib, Cha, Amp or deleted; 
 A 32  is Leu, Ala, Acc, Aib, Nle, Ile, Cha, Tle, Phe, X 1 -Phe, Ala or deleted; 
 A 33  is Val, Acc, Aib, Leu, Ile, Tle, Nle, Cha, Ala, Phe, Abu, X 1 -Phe, Tba, Gaba or deleted; 
 A 34  is Lys, Arg, hArg, Orn, Amp, Gaba, HN—CH((CH 2 ), —NR 10 R 11 )—C(O), HN—CH((CH 2 ) e —X 3 )—C(O) or deleted; 
 A 35  is Gly or deleted; 
 A 36  is L- or D-Arg, D- or L-Lys, D- or L-hArg, D- or L-Orn, Amp, HN—CH((CH 2 ), —NR 10 R 11 )—C(O), HN—CH((CH 2 ) e —X 3 )—C(O) or deleted; 
 A 37  is Gly or deleted;
 X 1  for each occurrence is independently selected from the group consisting of (C 1 -C 6 )alkyl, OH and halo; 
 R 1  is OH, NH 2 , (C 1 -C 12 )alkoxy, or NH—X 2 —CH 2 -Z 0 , wherein X 2  is a (C 1 -C 12 )hydrocarbon moiety, and Z 0  is H, OH, CO 2 H or CONH 2 ; 
 X 3  is 
 
 
       
         
           
           
               
               
           
         
       
       or —C(O)—NHR 12 , wherein X 4  for each occurrence is independently —C(O)—, —NH—C(O)— or —CH 2 —, and f for each occurrence is independently an integer from 1 to 29;
 each of R 2  and R 3  is independently selected from the group consisting of H, (C 1 -C 30 )alkyl, (C 2 -C 30 )alkenyl, phenyl(C 1 -C 30 )alkyl, naphthyl(C 1 -C 30 )alkyl, hydroxy(C 1 -C 30 )alkyl, hydroxy(C 2 -C 30 )alkenyl, hydroxyphenyl(C 1 -C 30 )alkyl, and hydroxynaphthyl(C 1 -C 30 )alkyl; or one of R 2  and R 3  is C(O)X 5  in which X 5  is (C 1 -C 30 )alkyl, (C 2 -C 30 )alkenyl, phenyl(C 1 -C 30 )alkyl, naphthyl(C 1 -C 30 )alkyl, hydroxy(C 1 -C 30 )alkyl, hydroxy(C 2 -C 30 )alkenyl, hydroxyphenyl(C 1 -C 30 )alkyl, hydroxynaphthyl(C 1 -C 30 )alkyl, 
 
       
         
           
           
               
               
           
         
         
           where Y is H or OH, r is 0 to 4 and q is 0 to 4; 
           e for each occurrence is independently an integer from 1 to 4; 
           n for each occurrence is independently an integer from 1-5; and 
           R 10  and R 11  for each occurrence is each independently H, (C 1 -C 30 )alkyl, (C 1 -C 30 )acyl, (C 1 -C 30 )alkylsulfonyl, —C((NH)(NH 2 )) or 
         
       
       
         
           
           
               
               
           
         
       
       provided that when R 10  is (C 1 -C 30 )acyl, (C 1 -C 30 )alkylsulfonyl, —C((NH)(NH 2 )) or 
       
         
           
           
               
               
           
         
         R 11  is H or (C 1 -C 30 )alkyl; and
 R 12  is (C 1 -C 30 )alkyl; 
 
       
       with the proviso that:
 (i) at least one amino acid of a compound of formula (I) is not the same as the native sequence of hGLP-1 (7-36, or -37)NH 2  (SEQ ID NOS: 1, 2) or hGLP-1 (7-36, or -37)OH (SEQ ID NOS: 3, 4); 
 (ii) a compound of formula (I) is not an analogue of hGLP-1(7-36, or -37)NH 2  (SEQ ID NOS: 1,2) or hGLP-1(7-36, or -37)OH (SEQ ID NOS: 3, 4) wherein a single position has been substituted by Ala; 
 (iii) a compound of formula (I) is not [Lys 26 (N ε -alkanoyl)]hGLP-1(7-36, or -37)-E (SEQ ID NOS: 5-8), [Lys 34 (N ε -alkanoyl)]hGLP-1(7-36, or -37)-E (SEQ ID NOS: 9-12), [Lys 26,34 -bis(N ε -alkanoyl)]hGLP-1(7-36, or -37)-E (SEQ ID NOS: 13-16), [Arg 26 , Lys 34 (NE-alkanoyl)]hGLP-1(8-36, or -37)-E (SEQ ID NOS: 17-20), or [Arg 26,34 , Lys 36 (N ε -alkanoyl)]hGLP-1(7-36, or -37)-E, wherein E is —OH or —NH 2  (SEQ ID NOS: 21-24); 
 (iv) a compound of formula (I) is not Z 1 -hGLP-1(7-36, or -37)-OH, Z 1 -hGLP-1(7-36, or -37)-NH 2 , where Z 1  is selected from the group consisting of 
 (a) [Arg 26 ] (SEQ ID NOS: 25-28), [Arg 34 ] (SEQ ID NOS: 29-32), [Arg 26,34 ] (SEQ ID NOS: 33-36), [Lys 36 ] (SEQ ID NOS: 37-40), [Arg 26 , Lys 36 ] (SEQ ID NOS: 41-44), [Arg 34 , Lys 36 ] (SEQ ID NOS: 45-46), [D-Lys 36 ], [Arg 36 ] (SEQ ID NOS: 37-40), [D-Arg 36 ], [Arg 26,34 , Lys 36 ] (SEQ ID NOS: 49-52), or [Arg 26,36 , Lys 34 ] (SEQ ID NOS: 25-28); 
 (b) [Asp 21 ] (SEQ ID NOS: 53-56); 
 (c) at least one of [Aib 8 ] (SEQ ID NOS: 57-60), [D-Ala 8 ] and [Asp 9 ] (SEQ ID NOS: 61-64); and 
 (d) [Tyr 7 ] (SEQ ID NOS: 65-68), [N-acyl-His 7 ] (SEQ ID NOS: 69-72), [N-alkyl-His 7 ] (SEQ ID NOS: 73-76), [N-acyl-D-His 7 ] or [N-alkyl-D-His 7 ]; 
 (v) a compound of formula (I) is not a combination of any two of the substitutions listed in groups (a) to (d); and 
 (vi) a compound of formula (I) is not [N-Me-Ala 8 ]hGLP-1(8-36 or -37) (SEQ ID NOS: 77, 78), [Glu 15 ]hGLP-1(7-36 or -37) (SEQ ID NOS: 79, 80), [Asp 21 ]hGLP-1(7-36 or -37) (SEQ ID NOS: 53, 54) or [Phe 31 ]hGLP-1(7-36 or -37) (SEQ ID NOS: 81, 82). 
 
     
     
         2 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof wherein A 11  is Thr; A 13  is Thr; A 14  is Ser, Aib or Ala; A 17  is Ser, Ala, Aib or D-Ala; A 18  is Ser, Ala, Aib or D-Ala; A 21  is Glu or Ala; A 23  is Gln, Glu, or Ala; and A 27  is Glu or Ala. 
     
     
         3 . A compound according to  claim 2  or a pharmaceutically acceptable salt thereof wherein A 9  is Glu, N-Me-Glu or N-Me-Asp; A 12  is Phe, Acc or Aic; A 16  is Val, D-Val, Acc, Aib, Ala, Tle or D-Ala; A 19  is Tyr, 3-Pal, 4-Pal or D-Tyr; A 20  is Leu, Acc, Cha, Ala or Tle; A 24  is Ala, Aib or Acc; A 25  is Ala, Aib, Acc, Lys, Arg, hArg, Orn, HN—CH((CH 2 ), —NH—R 10 )—C(O); A 28  is Phe or Ala; A 29  is Ile, Acc or Tle; A 30  is Ala, Aib or deleted; A 31  is Trp, Ala, 3-Pal, 4-Pal or deleted; A 32  is Leu, Acc, Cha, Ala or deleted; A 33  is Val, Acc, Ala, Gaba, Tle or deleted. 
     
     
         4 . A compound according to  claim 3  or a pharmaceutically acceptable salt thereof wherein A 8  is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A 10  is Gly, Ala, D-Ala or Phe; A 12  is Phe, A6c or A5c; A 16  is Val, Ala, Tle, A6c, A5c or D-Val; A 20  is Leu, A6c, A5c, Cha, Ala or Tle; A 22  is Gly, Aib, β-Ala, L-Ala or D-Ala; A 24  is Ala or Aib; A 29  is Ile, A6c, A5c or Tle; A 32  is Leu, A6c, A5c, Cha, Ala or deleted; A 33  is Val, A6c, A5c, Ala, Gaba, Tle or deleted. 
     
     
         5 . A compound according to  claim 4  or a pharmaceutically acceptable salt thereof wherein R 1  is OH or NH 2 . 
     
     
         6 . A compound according to  claim 5  or a pharmaceutically acceptable salt thereof wherein R 2  is H and R 3  is (C 1 -C 30 )alkyl, (C 2 -C 30 )alkenyl, (C 1 -C 30 )acyl, 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound according to  claim 1  wherein said compound is
 [D-Ala 8 , Ala 17,22,23,27 , 3-Pal 19,31 , Gaba 34 ]-GLP-1(7-34)NH 2 ;   [D-Ala 8,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2 ;   [Ala 18,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2  (SEQ ID NO: 83);   [Ala 16,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2  (SEQ ID NO: 84);   [Ala 14,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2  (SEQ ID NO: 85);   [Ala 22,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2  (SEQ ID NO: 86);   [Hppa 7 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 87);   [Ala 15,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2  (SEQ ID NO: 88);   [Ala 17,23,27 , 3-Pal 19,31 ]hGLP-1(7-35)-NH 2  (SEQ ID NO: 89);   [Ala 22,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 90);   [Ala 15,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 91);   [Ala 17,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 92);   [Ala 18,22,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 93);   [Ala 21,22,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 94);   [Ala 22,23,26,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 95);   [Ala 22,23,27,32 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 96);   [Ala 22,23,26,27 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 97);   [Ala 22,23,27,31 , 3-Pal 19 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 98);   [Ala 22,23,27,28 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 99);   [Ala 22,23,27,29 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 100);   [Ala 23,27 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 101);   [Ala 20,22,23,27 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 102);   [Ala 22,23,27 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 103);   [Ala 17,22,23,27 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 104);   [D-Ala 10 , Ala 22,23,27 , 3-Pal 19,31 , Gaba 33 ]hGLP-1(7-33)-NH 2 ;   [D-Ala 8 , Ala 17,23,27 , 3-Pal 19,31 ]hGLP-1(7-34)-NH 2 ;   [Ala 17,23,27 , 3-Pal 19,26,31 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 105);   [D-Ala 8 , Ala 17 , 3-Pal 19,31 ]hGLP-1(7-34)-NH 2 ;   [Ala 17,23,27 , 3-Pal 19,31 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 106);   [D-Ala 8 , Ala 17,23,27 , 3-Pal 19,31 , Tle 29 ]hGLP-1(7-34)-NH 2 ;   [D-Ala 8 , Ala 17,23,27 , 3-Pal 19,31 , Tle 16 ]hGLP-1(7-34)-NH 2 ;   [D Ala 8 , Ala 17,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2 ;   [D-Ala 22 , Ala 17,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2 ;   [Aib 8 , Ala 17,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 107);   [D-Ala 8 , Ala 17,22,23,27 , 3-Pal 19,31 ]hGLP-1(7-33)-NH 2 ;   [Aib 8 , Ala 17,22,23,27 , 3-Pal 19,31 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 108);   [Ala 17,18,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 109);   [Ala 17,23,27 , 3-Pal 19,31 , Tle 33 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 110);   [Tle 16 , Ala 17,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 111);   [N-Me-D-Ala 8 , Ala 17,22,23,27 , 3-Pal 19,31 ]hGLP-1(7-33)-NH 2 ;   [Aib 8 , Ala 17,18,23,27 , 3-Pal 19,31 ]hGLP-1(7-33)-NH 2  (SEQ ID NO: 112);   [Ala 17,18,22,23,27 , 3-Pal 19,31 , Tle 16,20 , Gaba 34 ]hGLP-1(7-34)-NH 2  (SEQ ID NO: 113);   [D-Ala 8 , Ala 17,18,22,23,27 , 3-Pal 19,31 , Tle 16 , Gaba 34 ]hGLP-1(7-34)-NH 2 ;   [D-Ala 8,22 , Ala 17,18,23,27,3 -Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2 ;   [D-Ala 8,18 , Ala 17,22,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2 ;   [D-Ala 8,17 , Ala 18,22,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2 ; or   [D-Ala 8 , Ala 17,18,22,23,27 , 3-Pal 19,31 , Gaba 34 ]hGLP-1(7-34)-NH 2 ; or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A compound according to  claim 1  wherein said compound is
 [Aib 8 , A6c 32 ]hGLP-1(7-36)NH 2  (SEQ ID NO: 114);   [A6c 20,32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 115);   [Aib 8 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 116);   [(Tma-His) 7 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 117);   [A6c 8 ]hGLP-1(8-36)-NH 2  (SEQ ID NO: 118);   [A6c 8 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 119);   [A6c 16,20 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 120);   [A6c 29,32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 121);   [A6c 20 , Aib 24 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 122);   [Aib 24 , A6c 29,32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 123);   [A6c 16,29,32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 124);   [Ura 7 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 125);   [Paa 7 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 126);   [Pta 7 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 127);   [N-Me-Ala 8 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 128);   [N-Me-Ala 8 ]hGLP-1(8-36)-NH 2  (SEQ ID NO: ______);   [N-Me-D-Ala 8 ]hGLP-1(7-36)-NH 2 ;   [N-Me-D-Ala 8 ]hGLP-1(8-36)-NH 2 ;   [N-Me-Gly 8 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 129);   [A5c 8 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 130);   [N-Me-Glu 9 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 131);   [A5c 8 , A6c 20,32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 132);   [Aib 8 , A6c 32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 133);   [Aib 8,25 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 134);   [Aib 824 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 135);   [Aib 8.30 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 136);   [Aib 8 , Cha 20 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 137);   [Aib 8 , Cha 32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 138);   [Aib 8 , Glu 23 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 139);   [Aib 8 , A6c 20 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 140);   [Aib 8 , A6c 20.32 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 141);   [Aib 8,22 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 142);   [Aib 8 , β-Ala 22 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 143);   [Aib 8 , Lys 25 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 144);   [Aib 8 , A6c 12 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 145);   [Aib 8 , A6c 29 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 146);   [Aib 8 , A6c 33 ]hGLP-1(7-36)-NH 2  (SEQ ID NO: 147);   [Aib 8,14 ]hGLP-1(7-36)NH 2  (SEQ ID NO: 148);   [Aib 8,18 ]hGLP-1(7-36)NH 2  (SEQ ID NO: 149);   [Aib 8,17 ]hGLP-1(7-36)NH 2  (SEQ ID NO: 150); or   [Aib 8 , D-Arg; 26 ]hGLP-1(7-36)NH 2 ; or a pharmaceutically acceptable salt thereof.   
     
     
         9 . A pharmaceutical composition comprising an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. 
     
     
         10 . A method of eliciting an agonist effect from a GLP-1 receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A method of treating a disease selected from the group consisting of Type I diabetes, Type II diabetes, obesity, glucagonomas, secretory disorders of the airway, metabolic disorder, arthritis, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension, in a subject in need thereof which comprises administering to said subject an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method according to  claim 11  wherein said disease is Type I diabetes or Type II diabetes.