MXPA01005763A

MXPA01005763A - Glp-1 analogues

Info

Publication number: MXPA01005763A
Application number: MXPA/A/2001/005763A
Authority: MX
Inventors: Zheng Xin Dong; David H Coy
Original assignee: Societe De Conseils De Recherches Et D'applications Scientifiques Sas
Priority date: 1998-12-07
Filing date: 2001-06-07
Publication date: 2002-02-26

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.

Description

ANGLAS STRUCTURES OF GLP- 1 BACKGROUND OF THE INVENTION The present invention is directed to analogous peptide-1 peptide structures similar to 'glucagon, its pharmaceutically acceptable salts, to the methods for using these analogous structures to treat mammals and to the pharmaceutical compositions useful therefor comprising these analogous structures. The amide of glucagon-like peptide-1 (7-36) (GLP-1) (SEQ ID NO: 1) is synthesized in intestinal L cells by post-translational tissue-specific processing of the glucagon precursor, preproglucagon (Varndell, JM, et al., J. Histochem Citochem, 1985: 33 : 1080-6) and is released into circulation in response to a meal. The plasma concentration of GLP-1 increases from a fasting level of approximately 15 pmol / L to a maximum postprandial level of 40 pmol / L. It has been shown that, for a given increase in plasma glucose concentration, the increase in plasma insulin is approximately three times higher when glucose is administered orally, compared to intravenous administration (Kreymann, B., et al. ., Lancet 1987: 2, 1300-4). This food improvement in insulin release, known as the effect of Incretin is mainly humoral and it is now believed that GLP-1 is the most potent physiological incretin in humans. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, slows gastric emptying (Wettergren A., et al., Dig Dis Sci 1993: 38: 665-73) and may improve peripheral glucose evacuation (D 'Alessio, DA et al., J Clin Invest 1994: 93: 2293-6). In 1994, the therapeutic potential of GLP-1 was suggested after the observation that a single subcutaneous (s / c) dose of GLP-1 could completely normalize postprandial glucose levels in patients with non-insulin dependent diabetes mellitus ( NIDDM) (Gutniak, MK, et al., Diabetes Care 1994: 17: 1039-44). It was believed that this effect was moderated both by a greater release of insulin and by a reduction in glucagon secretion. In addition, it has been demonstrated that an intravenous infusion of GLP-1 delays postprandial gastric emptying in patients with NIDDM (Williams, B., et al., J Clin Endo Metab 1996: 81: 327-32). In contrast to sulfonylureas, the insulinotropic action of GLP-1 depends on the concentration of plasma glucose (Holz, G.G. 4th, et al., Nature 1993: 361: 362-5). Therefore, the loss of insulin release mediated by GLP-1 at a low plasma glucose concentration protects against severe hypoglycaemia. This combination of actions offers therapeutic advantages unique to GLP-1 over other agents currently used to treat NIDDM. Numerous studies have shown that when administered to healthy people, GLP-1 strongly influences glycemic levels, as well as insulin and glucagon concentrations (Orskov, C, Diabetologia 35: 701-711, 1992; Holst, JJ, et al., Potential of GLP-1 in diabetes manaaement in Glucagon III, Manual of Experimental Pharmacology, Lefevbre PJ, Ed. Berlin, Springer Verlag, 1996, pages 311-326), whose effects depend on glucose (Kreymann, B. , et al., Lancet ii: 1300-1304, 1987; Weir, GC, et al., Diabetes 38: 338-342, 1989). In addition, it is also effective in patients with diabetes (Gutniak, M., N. Engl J Med 226: 1316-1322, 1992; Nathan, DM, et al., Diabetes Care 15: 270-276, 1992), normalizing the levels of blood glucose in people with type 2 diabetes (Nauck, MA, et al., Diabetologia 36: 741-744, 1993) and improving glycemic control in patients with type 1 diabetes (Creutzfeldt, WO, et al., Diabetes Care 19: 580-586, 1996), increasing the possibility of its use as a therapeutic agent. However, GLP-1 is metabolically unstable since it has a half-life (t ^) in the plasma of only 1-2 minutes in vivo. GLP-1 administered exogenously also degrades rapidly (Deacon, C.F., et. al., Diabetes 44: 1126-1131, 1995). This metabolic instability limits the therapeutic potential of native GLP-1. Therefore, there is a need for analogous structures of GLP-1 that are more active or more metabolically stable than native GLP-1.

SUMMARY OF THE INVENTION In one aspect, the present invention is directed to a compound of the formula (I), (R2R3) -A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18 -A19-A20-A21-A22- A23_A24_A25_A2S_A27_A28_A29_A30_A31_A32_A33_A3 _A35_A36_A37_Rlí (i) where A7 is L-His, Ura, Paa, Pta, D-His, Tyr, 3 -Pal, 4 -Pal, Hppa, Tma-His, Amp, or suppressed; in the assumption that when A7 is Ura, Paa, Pta or Hppa then R2 and R3 are suppressed; A8 is Ala, D-Ala, Aib, Acc, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A9 is Glu, N-Me-Glu, N-Me-Asp or Asp; A10 is Gly, Acc, Ala, D-Ala, Phe or Aib; A11 is Thr or Ser; A12 is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, ß-Nal, Cha, Trp or Xx-Phe; > 1 is Ser, Thr, Ala or Aib; A15 is Asp, Ala, D-Asp or Glu; A16 is Val, D-Val, Acc, Aib, Leu, Lie, Tie, Nle, Abu, Ala, D-Ala, Tba or "Cha; A17 is Ser, Ala, D-Ala, Aib, Acc or Thr; A18 is Ser, Ala, D-Ala, Aib, Acc or Thr; A19 is Tyr, D-Tyr, Cha , Phe, 3 -Pal, 4-Pal, Acc, ß-Nal, Amp or X1-Phe; A20 is Leu, Ala, Acc, Aib, Nle, lie, Cha, Tie, Val, Phe or X1-Phe; A21 is Glu, Ala or Asp; A22 is Gly, Acc, Ala, D-Ala, jS-Ala or Aib; A23 is Gln, Asp, Ala, D-Ala, Aib, Acc, Asn or Glu; A24 is Ala, Aib, Val, Abu, Tie or Acc; A25 is Ala, Aib, Val, Abu, Tie, Acc, Lys, Arg, hArg, Orn, HN-CH ((CH2) nN (R10R1: 1)) -C (O) O HN-CH ((CH2) e -X3) -C (O); A26 is Lys, Ala, 3 -Pal, 4-Pal, Arg, hArg, Orn, Amp, HN-CH ((CH2) nN (R10R1: L)) -C (O) or HN-CH ((CH2) e -X3) -C (O); A27 is Glu, Ala, D-Ala or Asp; A28 is Phe, Ala, Pal, jS-Nal, X1-Phe, Aic, Acc, Aib, Cha or Trp; A29 is Lie, Acc, Aib, Leu, Nle, Cha, Tie, Val, Abu, Ala, Tba or Phe; A30 is Ala, Aib, Acc or deleted; A31 is Trp, Ala, β-Nal, 3-Pal, 4-Pal, Phe, Acc, Aib, Cha, Amp or deleted; A32 is Leu, Ala,, Acc, Aib, Nle, lie, Cha, Tie, Phe, X1-Phe, Ala or suppressed; A33 is Val, Acc, Aib, Leu, Lie, Tie, Nle, Cha, Ala, Phe, Abu, Xx-Phe, Tba, Gaba or suppressed; A34 is Lys, Arg, hArg, Orn, Amp, Gaba, HN-CH ((CH2) n- N (R? OR? I)) -c (0), HN-CH ((CH2) e-X3) - C (O) or deleted; A35 is Gly or deleted; A3S is L- or D-Arg, D- or L-Lys, D- or L-hArg, D- or L-Orn, Amp, HN-CH ((CH2) aN (R10R1: L)) -C (O), HN-CH ((CH2) ß-X) -C (O) or deleted; A, 37 is Gly or suppressed; X1 each time it appears is independently selected from the group consisting of (C? -C6) alkyl, OH and halo; R1 is OH, NH2, (C? -C? A) alkoxy, or NH-X2-CH2-Z °, wherein X2 is an entity of (C? -C? 2) hydrocarbon and Z ° is H, OH, C02H or CONH2; -NH-C (O) -CH¿-N ~? N- (CH2) 2-NH-C (O) -R 13 • N N- (CH2) f -CH, or -C (0) -NHR12, where X4 is, independently each time which appears, -C (O) -, -NH-C (O) - or -CH2- and where f is, independently each time it appears, an integer from 1 to 29; each of R2 and R3 is independently selected from the group consisting of H, (C? -C30) alkyl, (C2-C30) alkenyl, phenyl (C? -C30) alkyl, naphthyl (C? -C30) alkyl , hydroxy (C? -C30) alkyl, hydroxy (C2-C30) alkenyl, hydroxy-phenyl (C1-C30) alkyl and hydroxy-naphthyl (C? -30) alkyl; or one of R2 and R3 is C (O) X5 wherein X5 is (C? -C30) alkyl, (C2-C30) alkenyl, phenyl (Cx-Cso) alkyl, naphthyl (C? -C30) alkyl, hydroxy ( C1-C30) alkyl, hydroxy (C2-C30) alkenyl, hydroxyphenyl (C? -C30) alkyl, hydroxynaphthyl (C? -C30) alkyl, (to) Y (CH2) r ~ N - (CH2) qSO2- Y (CH2) r-N N. (CH2) q-CO- (b) where Y is H or OH; r is 0 to 4; q is 0 to 4; n is, independently whenever it appears, an integer from 1 to 5; Y R, 1i0U and R11 is, independently whenever it appears, H, (C1-C30) alkyl, (C? -C30) acyl, (C? -C30) alkylsulfonyl, C ((NH) (NH2)) or -CCO-CH-N N- (CH2) f-CH3 in the supposition that when R (C1-C30) acyl, (d.-C30) alkylsulfonyl, -C ((NH) (NH2)) or -C (0) -CH2- N- (CH2) rCH3 R11 is H or (C1-C30) alkyl; and R12 is (C1-C30) alkyl; with the premise that: (i) at least one amino acid of a compound of the formula (I) is not the same as the native sequence of hGLP-l (7-36 or -37) NH2 (SEQ ID NOS: 1, 2) or hGLP-l (7-36 or -37) OH (SEQ ID NOS : 3. 4); (ii) a compound of the formula (I) is not an analogous structure of hGLP-1 (7-36 or -37) NH2 (SEQ ID NOS: 1, 2) or hGLP-1 (7-36 or -37) OH (SEQ ID NOS: 3, 4) where only one position has been replaced by Ala; (iii) a compound of the formula (I) is not, [Lys2G (Ne- alkanoyl)] hGLP-l (7-36 or -37) -E (SEQ ID NOS: 5-8), [Lys34 (Ne-alkanoyl)] hGLP-l (7-36 or -37) -E (SEQ ID NOS: 9-12), [Lys2S'34-bis (Ne-alkanoyl)] hGLP-l (7-36 or -37) -E (SEQ ID NOS: 13-16), [Arg2S, Lys34 (Ne-alkanoyl )] hGLP-1 (8-36 or -37) -E (SEQ ID NOS: 17-20), or [Arg25'34, Lys36 (Ne-alkanoyl)] hGLP-1 (7-36 or -37) - E, wherein E is -OH or -NH2 (SEQ ID NOS: 21-24); (iv) a compound of the formula (I) is not Z1-hGLP-I (7-36 or -37) -OH, Zx-hGLP-I (7-36 or -37) -NH2, wherein Z1 is selected from the group consisting of: (a) [Arg26] (SEQ ID NOS: 25-28), [Arg34] (SEQ ID NOS: 29-32), [Arg26'34] (SEQ ID NOS: 33-36), [Lys36] (SEQ ID NOS: 37-40), [Arg26, Lys36] (SEQ ID NOS: 41-44), [Arg34, Lys36] (SEQ ID NOS: 45-48), [D-Lys36], [ Arg36] (SEQ ID NOS: 3,4,1,2), [D-Arg36], [Arg26'34, Lys36] (SEQ ID NOS: 49-52) or [Arg26'36, Lys34] (SEQ ID NOS: 25-28); (b) [Asp21] (SEQ ID NOS: 53-56); (c) at least one of [Aib8] (SEQ ID NOS: 57-60), [D-Ala8] and [Asp9] (SEQ ID NOS: 61-64); and (d) [Tyr7] (SEQ ID NOS: 65-68), [N-acyl-His7] (SEQ ID NOS: 69-72), [N-alkyl -His7], [N-acyl-D-Hi 7] (SEQ ID NOS: 73-76) or [N-alkyl-D-His7]; (v) a compound of the formula (I) is not a combination of two of the substitutions included in the groups (a) to (d); Y (vi) a compound of the formula (I) is not [N-Me-Ala8] hGLP-1 (8-36 or -37) (SEQ ID NOS: 75.78), [Glu15] hGLP-1 (7- 36 o -37) (SEQ ID NOS: 79.80), [Asp21] hGLP-1 (7-36 or -37) (SEQ ID NOS: 53.54) or [Phe31] hGLP-1 (7-36 or -37) (SEQ ID NOS: 81.82). A preferred compound of the immediately preceding compound of formula (I) is where A 11 is Thr; A13 is Thr; A14 is Ser, Aib or Ala; A17 is Ser, Ala, Aib or D-Ala; A18 is Ser, Ala, Aib or D-Ala; A21 is Glu or Ala; A23 is Gln, Glu or Ala; A27 is Glu or Ala; or a pharmaceutically acceptable salt thereof. A preferred compound of the immediately preceding compound of the formula (I) is where A9 is Glu, N-Me-Glu or N-Me-Asp; A is Phe, Acc, or Aic; A, 16 is Val, D-Val, Acc, Aib, Ala, Tie or D-Ala; Ay is Tyr, 3 -Pal, 4-Pal or D-Tyr; A20 is Leu, Acc, Cha, Ala or Tie; A24 is Ala, Aib or Acc; A25 is Ala, Aib, Acc, Lys, Arg, hArg, Orn, HN-CH ((CH2) nN (R10R1: L)) -C (O) or HN-CH ((CH2) e-X3) -C ( O); A28 is Phe or Ala; A29 is Lie, Acc or Tie; A30 is Ala, Aib or deleted; A31 is Trp, Ala, 3-Pal, 4-Pal or deleted; A32 is Leu, Acc, Cha, Ala or suppressed; A33 is Val, Acc, Ala, Gaba, Tie or suppressed; or a pharmaceutically acceptable salt thereof. A preferred compound of the immediately preceding compound of formula (I) is where A8 is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; , 10 is Gly, Ala, D-Ala or Phe; A 12 is Phe, A6c or A5c; A, 1x6 is Val, Ala, Tie, A6c, A5c or D-Val; A20 is Leu, A6c, A5c, Cha, Ala or Tie; A22 is Gly, jS-Ala, Aib, L-Ala or D-Ala; A24 is Ala or Aib; A29 is lie, A6c, A5c or Tie; A32 is Leu, A6c, A5c, Cha, Ala or deleted; A33 is Val, A6c, A5c, Ala, Gaba, Tie or suppressed; or a pharmaceutically acceptable salt thereof. A preferred compound of the immediately preceding compound of formula (I) is where R1 is OH or NH2; or a pharmaceutically acceptable salt thereof. A preferred compound of the immediately preceding compound of the formula (I) or a pharmaceutically acceptable salt thereof is where R 2 is H and R 3 is (C 3 -C 30) alkyl, (C 2 -C 30) alkenyl, (C 1 -C 30) acyl , HO- (CH2) 2-N N- (CH2) 2SO2- H2N-. { CH2) 2-N N-CH2-CO- A preferred compound of the formula (I) is where [D-Ala8, A? A ", 22, 23, 27 ^ 3-Pal19'31, Gaba34] -GLP-1 (7-34) -NH2; [D- Ala8'23'27, 3-Pal19'31 ] hGLP-1 (7-35) -NH 2; [Ala 8'23'27, 3 Pal 19,31] hGLP-1 (7-35) -NH 2 (SEQ ID NO: 83) [Ala 16'23'27, 3- Pal19'31] hGLP-1 (7-35) -NH2 (SEQ ID NO: 84) [Ala14'23'27, Pal19'31] hGLP-1 (7-35) -NH2 (SEQ ID NO: 85 ) [Wing 22,23,27 Pal19'31] h.GLP-1 (7-35) -NH2 (SEQ ID NO: 86); [Hppa7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 87); [Ala15'23'27, 3 -Pal19'31] hGLP-1 (7-35) -NH2 (SEQ ID NO: 88); [Ala17'23'27, 3 -Pal19'31] hGLP-1 (7-35) -NH2 (SEQ ID NO: 89); [Ala22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 90); [Ala15'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 91); [Ala17'22'23'27, 3-Pal19'31, Gaba34] hGLP-l (7-34) -NH2 (SEQ ID NO: 92); [Ala18'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 93); [Ala21'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 94); [Ala22'23'26'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 95); [Ala 22'23'27'32, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 96); [Ala22 '3'26-27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 97); [Ala22'23'27'31, 3-Pal19, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 98); [Ala2, 23,27,28í 3-pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 99); [Ala 22'23'27'29, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 100); [Ala23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 101); [Ala, 22.23.27 ^ 3_ Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 102); [Ala22'23'27, 3-Pal 19.31 GabaJJ] hGLP-1 (7-33) -NH2 (SEQ ID NO: 103) [Ala17'22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 104); [D-Ala10, Ala22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; [D-Ala8, Ala17'23'27, 3-Pal19'31] hGLP-1 (7-34) -NH2; [Ala17'23'27, 3-Pal19'26'31, Gaba33] hGLP-1 (7-34) -NH2 (SEQ ID NO: 105); [D-Ala8, Ala17, 3-Pal19'31] hGLP-l (7-34) -NH2; [Ala17'23'27, 3 -Pal19'31] hGLP-1 (7-34) -NH2 (SEQ ID NO: 106); [D-Ala8, Ala17'23'27, 3-Pal19'31, Tie29] hGLP-1 (7-34) -NH2; [D-Ala8, Ala17'23'27, 3-Pal19'31 Tie16] hGLP-1 (7-34) -NH2; [D-Ala8, Ala17'23'27, 3-Pal19'31 Gaba34] hGLP-1 (7-34) -NH2; [D-Ala22, Ala17'23'27, 3-Pal19'31 Gaba34] hGLP-1 (7-34) -NH2; [Aib8, Ala17'23'27, 3-Pal19'31 Gaba34] h.GLP-1 (7-34) -NH2 (SEQ ID NO: 107); [D-Ala8 Ala17'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2; [Aib8, Ala17'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2 (SEQ ID NO: 108); [Ala 1: 7,18,23,27 Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 109); [Ala17'23'27, 3-Pal19'31, Tie33, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 110); [Tie16, Ala17'23'27, 3-Pal19'31, Gaba34] b.GLP-1 (7-34) -NH2 (SEQ ID NO: 111); [N-Me-D-Ala8, Ala17'22'23'27, 3-Pal19'31] b.GLP-1 (7-33) -NH2; [Aib8, Ala17'18'22'23'27, 3_pal19'31] hGLP-1 (7-33) -NH2 (SEQ ID NO: 112); [A? A17 < 18'22'23'27, 3-Pal19'31, Tie16'20, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 113); [D-Ala8, Ala17'18'22'23'27, 3-Pal19'31, Tie 16 Gaba34] hGLP-1 (7-34) -NH2; [D-Wing 8,22 Wing 17,18,23,27 Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; [D-Ala8'18, Ala17'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; [D-Ala8'17, Ala18'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; or [D-Ala8, A? a17 < 18'22'23'27, 3_ Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; or a pharmaceutically acceptable salt thereof. A more preferred compound of the formula (I) is where the compound is of the formula: [Aib8, A6c32] hGLP-l (7-36) -NH2 (SEQ ID NO: 114); [A6c20'32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 115); [Aib8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 116); [(Tma-His) 7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 117); [A6c8] hGLP-1 (8-36) -NH2 (SEQ ID NO: 118); [A6c8] hGLP-l (7-36) -NH2 (SEQ ID NO: 119); [A6c16'20] hGLP-1 (7-36) -NH2 (SEQ ID NO: 120); [A6c29'32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 121); [A6c20, Aib24] hGLP-1 (7-36) -NH2 (SEQ ID NO: 122); [Aib24, A6c29'32] hGLP-I (7-36) -NH2 (SEQ ID NO: 123); [A6c16'29'32] hGLP-l (7-36) -NH2 (SEQ ID NO: 124); [Ura7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 125); [Paa7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 126); [Pta7] hGLP-l (7-36) -NH2 (SEQ ID NO: 127); [N-Me-Ala8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 128); [N-Me-Ala8] hGLP-1 (8-36) -NH2 (SEQ ID NO:); [N-Me-D-Ala8] hGLP-1 (7-36) -NH2; [N-Me- Ala8] b.GLP-1 (8-36) -NH2; [N-Me-Gly8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 129); [A5c8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 130); [N-Me-Glu9] hGLP-l (7-36) -NH2 (SEQ ID NO: 131); [A5c8, A6c20'32] hGLP-l (7-36) -NH2 (SEQ ID NO: 132); [Aib8, A6c32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 133); [Aib8'25] hGLP-1 (7-36) -NH2 (SEQ ID NO: 134); [Aib8'24] hGLP-1 (7-36) -NH2 (SEQ ID NO: 135); [Aib8'30] hGLP-1 (7-36) -NH2 (SEQ ID NO: 136); [Aib8, Cha20] h.GLP-1 (7-36) -NH2 (SEQ ID NO: 137); [Aib8, Cha32] h.GLP-1 (7-36) -NH2 (SEQ ID NO: 138); [Aib8, Glu23] hGLP-1 (7-36) -NH2 (SEQ ID NO: 139); [Aib8, A6c20] hGLP-1 (7-36) -NH2 (SEQ ID NO: 140); [Aib8, A6c20'32] hGLP-l (7-36) -NH3 (SEQ ID NO: 141); [Aib8'22] hGLP-1 (7-36) -NH2 (SEQ ID NO: 142); [Aib8, ß-Ala22] hGLP-1 (7-36) -NH2 (SEQ ID NO: 143); [Aib8, Lys25] hGLP-1 (7-36) -NH2 (SEQ ID NO: 144); [Aib8, A6c12] hGLP-1 (7-36) -NH2 (SEQ ID NO: 145); [Aib8, A6c29] hGLP-l (7-36) -NH2 (SEQ ID NO: 146); [Aib8, A6c33] hGLP-1 (7-36) -NH2 (SEQ ID NO: 147); [Aib8'14] hGLP-1 (7-36) -NH2 (SEQ ID NO: 148); [Aib8'18] h.GLP-1 (7-36) -NH2 (SEQ ID NO: 149); or [Aib8'17] hGLP-1 (7-36) -NH2 (SEQ ID NO: 150); or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the formula (I) as defined herein above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. In another aspect, the present invention provides a method for producing an agonist effect of a GLP-1 receptor in a person in need thereof comprising administering to the aforementioned person an effective amount of a compound of formula (I) as is defined hereinbefore or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for treating a disease selected from the group consisting of: Type I diabetes, Type II diabetes, obesity, glucagonomas, airway secretion disorders, metabolic disorder, arthritis, osteoporosis, central nervous system, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension and disorders wherein the reduction of food consumption is desired, in a person in need thereof, comprising administering to the aforementioned person an effective amount of a compound of the formula (I) as defined hereinbefore or a pharmaceutically acceptable salt thereof. A preferred method of the immediately preceding method is where the condition being treated is Type I diabetes or Type II diabetes. With the exception of the N-terminal amino acid, all abbreviations (for example Ala) of amino acids in this disclosure mean the structure of -NH-CH (R) -CO-, where R is the side chain of an amino acid (for example CH3 for Ala). For the N-terminal amino acid, the abbreviation means the structure of (R2R3) -N-CH (R) -CO-, wherein R is a side chain of an amino acid and R2 and R3 are as defined above, except when A7 is Ura, Paa, Pta or Hppa, in which case R2 and R3 are not present since Ura, Paa, Pta and Hppa are considered here as de-amino amino acids. Amp, S-Nal, Nle, Cha, 3-Pal, 4-Pal and Aib are the abbreviations of the following α-amino acids: 4-amino-phenylalanine, β- (2-naphthyl) alanine, norleucine, cyclohexylalanine, β - (3-pyridinyl) alanine, β- (4-pyridinyl) alanine and a-aminoisobutyric acid, respectively. Other definitions of amino acids are: Ura is urocanic acid; Pta is (4-pyridylthio) acetic acid; Paa is trans-3 - (3-pyridyl) acrylic acid; Tma-His is N, N-tetramethylamidino-histidine; N-Me-Ala is N-methyl-alanine; N-Me-Gly is N-methyl-glycine; N-Me-Glu is N-methyl-glutamic acid; Tie is ter-butylglycine; Abu is a-aminobutyric acid; Tba is tert-butylalanine; Orn is ornithine; Aib is α-aminoisobutyric acid; 5-Ala is jS-alanine; Gaba is 7-aminobutyric acid; Ava is 5-aminovaleric acid and Aic is 2-amino-2,4-carboxylic acid. What is meant by Acc is an amino acid selected from the group of 1-amino-1-cyclopropanecarboxylic acid (A3c); 1-amino-1-cyclobutanecarboxylic acid (A4c); 1-amino-1-cyclopentanecarboxylic acid (A5c); 1-amino-1-cyclohexanecarboxylic acid (A6c); 1-amino-1-ccycclloohheeppttaannooccaarrbbooxxylliiccoo acid (A7c); 1-amino-1-cyclooctanecarboxylic acid (A8c); and 1-amino-1-cyclononanecarboxylic acid (A9c). In the above formula, hydroxyalkyl, hydroxyphenylalkyl and hydroxynaphtylalkyl can contain 1-4 hydroxy substituents. COX5 means -C = 0-X5. Examples of -C = 0-X5 include, in non-exclusive form, acetyl and phenylpropionyl. What is meant by Lys (Ne-alkanoyl) is represented by the following structure: What is meant by Lys (Ne-alkylsulfonyl) is represented by the following structure: What is meant by Lys (Ne- (2- (4-alkyl-1-piperazine) acetyl)) is represented by the following structure: What is meant by Asp (1- (4-alkyl-piperazine)) is represented by the following structure: What is meant by Asp (1-alkylamino) is represented by the following structure: The variable n in the following structures is 1-30. The complete names for other abbreviations used herein are as follows: Boc for tert-butyloxycarbonyl, HF for hydrogen fluoride, Fm for formyl, Xan for xanthyl, Bzl for benzyl, Tos for tosyl, DNP for 2,4-dinitrophenyl, DMF for dimethylformamide, DCM for dichloromethane, HBTU for 2- (1H-Benzotriazol-1-yl) -1,1,3, 3-tetramethyl uronium hexafluorophosphate, DIEA for diisopropylethylamine, HOAc for acetic acid, TFA for trifluoroacetic acid, 2CIZ for 2-chlorobenzyloxycarbonyl, 2BrZ for 2- bromobenzyloxycarbonyl and OcHex for O-cyclohexyl. A peptide of this invention is also denoted, in the present with another format, for example, [A5c8] h.GLP-1 (7-36) NH2 (SEQ ID NO: 130), with the substituted amino acids of the natural sequence placed between the first set of parentheses (for example, A5c8 for Ala8 in h.GLP-1). The abbreviation GLP-1 means glucagon-like peptide-1; h.GLP-1 means human peptide-1 similar to glucagon. The numbers between the parentheses refer to the number of amino acids present in the peptide (for example, hGLP-I (7-36) (SEQ ID NO: 3) is amino acids 7 to 36 of the peptide sequence for human GLP-1) . The sequence for hGLP-I (7-37) (SEQ ID NO: 4) is included in Mojsov, S., Int. J. Peptide Protein Res., 40, 1992, pages 333-342. The designation "NH2" in hGLP-1 (7-36) NH2 (SEQ ID NO: 1) indicates that the C-terminus of the peptide is amidated. hGLP-I (7-36) (SEQ ID NO: 2) means that the C-terminal is the free acid.

DETAILED DESCRIPTION OF THE INVENTION The peptides of this invention can be prepared by standard synthesis of solid phase peptides. See, for example, Ste art, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., second edition 1984). The substituents R2 and R3 of the above generic formula can binding to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, ie, (C? -C30) alkyl, can be joined using reductive alkylation. Hydroxyalkyl groups, for example, (C? -C30) hydroxyalkyl, can also be linked using reductive alkylation wherein the free hydroxy group is protected with a terbutyl ester. The acyl groups, for example, COE1, can be linked by coupling the free acid, i.e., E1COOH, to the free amine of the N-terminal amino acid by mixing the resin completed with 3 molar equivalents of both the free acid and the diisopropylcarbodiimide in methylene chloride for an hour. If the free acid contains a free hydroxy group, for example, p-hydroxyphenylpropionic acid, then the coupling would be carried out with 3 additional molar equivalents of HOBT. When R1 is NH-X2-CH2-CONH2, (ie, Z ° = CONH2), the synthesis of the peptide begins with BocHN-X2-CH2-COOH which is coupled to the MBHA resin. If R1 is NH-X2-CH2-COOH (ie, Z ° = COOH), the synthesis of the peptide begins with Boc-HN-X2-CH2-COOH which is coupled to the PAM resin. Next, a synthetic method for making a peptide of the invention is described, which is well known to a person skilled in the art. Other methods are also known to those skilled in the art. technique. The benzhydrylamine-polystyrene resin (Advanced ChemTech, Inc., Louisville, KY) (0.9 g, 0.3 mmol) in its chloride ion form is placed in a reaction vessel of the Advanced Chem Tech Model 200 peptide synthesizer, programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 15 min, respectively); (c) methylene chloride; (d) ethanol; (e) methylene chloride; (f) 10% diisopropylethylamine in methylene chloride. The neutralized resin is mixed with a Boc protected amino acid, which will be the C-terminal amino acid of the desired peptide to be synthesized and diisopropylcarbodiimide (3 mmoles each) in methylene chloride for 1 hour and the resulting amino acid resin is then subjected to to the cycle that includes steps (a) to (f) of the previous washing program. The other amino acids (3 mmoles) of the peptide of interest are then coupled by the same procedure. The finished peptide is separated from the resin, by mixing it with anisole (5 ml), dithiothreitol (100 mg) and hydrogen fluoride anhydride (35 ml) at about 0 ° C and stirring for about 45 min. The excess of hydrogen fluoride evaporates rapidly under a flow of dry nitrogen and the free peptide is precipitated and washed with ether. The crude peptide is dissolved in a minimum volume of acetic acid and eluted on a column (2.5 x 2.5 cm) of silica octadecylsilane VYDAC® (10 mM); it is eluted with a linear gradient of 20-60% acetonitrile for about 1 hour in 0.1% trifluoroacetic acid in water. The fractions are examined by thin layer chromatography and analytical high pressure chromatography (40-70% B at 1% / min, solution B is 80% acetonitrile / water containing 0.1% TFA) and combined to generate a maximum purity , instead of performance. Repeated lyophilization of the solution from water generates a product as a white powder. The produced peptide is analyzed by HPLC. The amino acid analysis of an acid hydrolyzate of a produced peptide can confirm the composition of the peptide. The MS laser desorption is used to determine the molecular weight of the peptide. The protected amino acid, 1- [N-tert-butoxycarbonyl-amino] -1-cyclohexane-carboxylic acid (Boc-A6c-OH) was synthesized as follows. 19.1 g (0.133 mol) of 1-amino-1-cyclohexanecarboxylic acid (Acros Organics, Fisher Scientific, Pittsburgh, PA) were dissolved in 200 ml of dioxane and 100 ml of water. To this was added 67 ml of 2N NaOH. The solution was cooled in a bath of ice water. HE they added 32.0 g (0.147 moles) of di-tert-butyl-dicarbonate to this solution. The reaction mixture was stirred overnight at room temperature. Then, the dioxane was removed under reduced pressure. 200 ml of ethyl acetate was added to the remaining aqueous solution. The mixture was cooled in a bath of ice water. The pH of the aqueous layer was adjusted to approximately 3 by adding 4 N HCl. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (1 x 100 ml). The two organic layers were combined and washed with water (2 x 150 ml), dried over anhydrous MgSO 4, filtered and concentrated for dehydration under reduced pressure. The residue was recrystallized from ethyl acetate / hexanes. 9.2 g of the pure product were obtained. Performance of 29%. Boc-A5c-0H was synthesized in a manner analogous to that of Boc-A6c-OH. Other protected Acc amino acids can be prepared in an analogous manner by a person of ordinary skill in the art as allowed by the teachings herein. In the synthesis of the peptide of this invention containing A5c, A6c and / or Aib, the coupling time is about 2 hours for these residues and the residue immediately after them. For the synthesis of [Tma-His7] hGLP-1 (7-36) NH2 (SEQ ID NO: 117), HBTU (2 mmoles) and DIEA (1.0 ml) in 4 ml DMF are used to react with the amine Free N-terminal resin peptides in the last coupling reaction. The coupling time is around 2 hours. The complete names for the abbreviations used above are as follows: Boc for tert-butyloxycarbonyl, HF for hydrogen fluoride, Fm for formyl, Xan for xanthyl, Bzl for benzyl, Tos for tosyl, DNP for 2,4-dinitrophenyl, DMF for dimethylformamide, DCM for dichloromethane, HBTU for 2- (1H-Benzotriazol-1-yl) -1, 1,3, 3-tetramethyl uronium hexafluorophosphate, DIEA for diisopropylethylamine, HOAc for acetic acid, TFA for trifluoroacetic acid, 2CIZ for 2- chlorobenzyloxycarbonyl, 2BrZ for 2-bromobenzyloxycarbonyl and OcHex for O-cyclohexyl. The substituents R2 and R3 of the above generic formula can be linked to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, ie, (C? -C30) alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups, for example, (C? -C30) hydroxyalkyl, can also be attached using reducing alkylation wherein the free hydroxy group is protected with a terbutyl ester. Acyl groups, for example, COX1, can be attached by coupling the free acid, i.e., X1COOH, to the free amine of the N-terminal amino acid, by mixing the resin completed with 3 molar equivalents of both the free acid and the diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxy group, for example, p-hydroxyphenylpropionic acid, then the coupling would be carried out with 3 additional molar equivalents of HOBT. A compound of the present invention can be tested for activity as a GLP-1 binder compound according to the following procedure. Cell culture: Insulinoma RIN cells from 5 female rats (ATCC- # CRL-2058, American Type Culture Collection, Manassas, VA) were cultured, expressing the GLP-1 receptor, in Eagle's medium modified by Dulbecco ( DMEM) containing 10% fetal calf serum and were maintained at approximately 37 ° C in a humidified atmosphere of 5% C02 / 95% air. Radioligant binding: Membranes were prepared for radioligant binding studies by homogenization of the RIN cells in 20 ml of 50 mM Tris-Hcl, cooled with ice with a Polytron Brinkman (Westbury, NY) (setting 6, 15 seconds). The homogenates were washed twice by centrifugation (39,000 g / 10 minutes) and the final beads were suspended again in 50 mM Tris-HCl, containing 2.5 mM MgCl2, 0.1 mg / ml bacitracin (Sigma Chemical, St. Louis, MO) and 0.1% BSA. For the assay, aliquots (0.4 ml) were incubated with (125I) GLP-I (7-36) (SEQ ID NO: 151) of 0.05 nM (-2200 Ci / mmol, New England Nuclear, Boston, MA), with and without 0.05 ml of unlabeled peptides of competition test. After an incubation of 100 min (25 ° C), bound (125I) GLP-1 (7-36) (SEQ ID NO: 151) was separated from the free acid by rapid filtration through GF / C filters (Brandel , Gaithersburg, MD), which had previously been soaked in 0.5% polyethyleneimine. The filters were then washed three times with 5 ml aliquots of 50 mM Tris-HCl cooled with ice and the radioactivity trapped in the filters was counted by gamma spectrometry (Wallac LKB, Gaithersburg, MD). The specific agglutination was defined as the total (125I) GLP-1 (7-36) (SEQ ID NO: 151) bound except the one bound in the presence of GLP-I (7-36) (SEQ ID NO: 3) of 1000 nM (Bachem, Torrence, CA). The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of these salts include, but are not limited to, those formed with organic acids (eg, acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acids), inorganic acids (eg. example, hydrochloric acid, sulfuric acid, or acid phosphoric) and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic acid, polyglycolic acid, or polylactic-glycolic acid copolymers). A characteristic method for making a salt of a peptide of the present invention is well known in the art and can be carried out by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt resulting from the purification of the peptide using HPLC in preparation, eluting with TFA containing regulatory solutions) can be converted to another salt, such as an acetate salt by dissolving the peptide in a small amount of 0.25 N aqueous acetic acid solution. The resulting solution is applied to a semipreparated HPLC column (Zorbax, 300 SB, C-8). The column is eluted with (1) 0.1N aqueous ammonium acetate solution for 0.5 hours, (2) 0.25N aqueous acetic acid solution for 0.5 hours and (3) a linear gradient (20% to 100% solution B for 30 minutes) at a flow rate of 4 ml / min (solution A is 0.25N aqueous acetic acid solution, solution B is 0.25N acetic acid in acetonitrile / water, 80:20). The fractions containing the peptide are harvested and freeze-dried until dehydrated. As is well known by people with experience in the technique, the known and potential uses of GLP-1 are varied and innumerable. (See, Todd, J.F., et al., Clinical Science, 1998, 95 pages 325-329.; and Todd, JF, et al., European Journal of Clinical Investigation, 1997, 27, pages 533-536.) Thus, administration of the compounds of this invention for the purpose of producing an agonist effect may have the same effects and uses that GLP-1 itself. These varied uses of GLP-1 can be summarized as follows, treatment of: Type I diabetes, Type II diabetes, obesity, glucagonomas, airway secretion disorders, metabolic disorder, arthritis, osteoporosis, central nervous system syndromes, restenosis, neurodegenerative diseases, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension and disorders where the reduction of food consumption is desired. The analogous GLP-1 structures of the present invention that produce an antagonistic effect of a person can be used to treat the following: hypoglycemia and malabsorption syndrome associated with gastrectomy or small bowel resection. Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the formula (I) in association with a pharmaceutically acceptable carrier. The dose of the active ingredient in the compositions of this invention can be varied. However, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The dose selected depends on the desired therapeutic effect, the route of administration and the duration of treatment. In general, an effective dose for the activities of this invention is in the range of lxl0 ~ 7 to 200 mg / kg / day, preferably lxlO "4 to 100 mg / kg / day, which can be administered as a single dose or divided into multiple doses The compounds of this invention can be administered by the following routes of administration: oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical. Compounds can be prepared with pharmaceutically acceptable carriers to provide the appropriate dosage forms for each route of administration Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules In these solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert carrier such as sucrose, lactose, or starch. These dosage forms may also comprise, according to normal practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise regulatory agents. Tablets and pills can also be prepared with enteric coatings. Liquid dosage forms for oral administration include emulsions, solutions, suspensions, pharmaceutically acceptable syrups, elixirs containing inert diluents frequently used in the art, such as water. In addition to these inert diluents, the compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents and sweetening agents, flavors and perfumes. Preparations according to this invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin and injectable organic esters such as ethyl oleate. These dosage forms can also contain adjuvants such as preservatives, moisturizers, emulsifiers and dispersants. They can be sterilized, for example, by filtration through a bacteria retainer filter, incorporating sterilization agents into the compositions, irradiating the compositions, or heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some sterile injectable medium immediately before use. Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art. In addition, a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications. U.S. Patent Number 5,672,659 explains sustained release compositions comprising a bioactive agent and a polyester. U.S. Patent Number 5,595,760 explains sustained release compositions comprising a bioactive agent in a castable form. Application Number 08 / 929,363 of the United States presented on September 9, 1997 explains the sustained release compositions comprising a bioactive agent and chitosan. The Application Number 08/740No. 778 of the United States filed on November 1, 1996 explains sustained release compositions comprising a bioactive agent and cyclodextrin. Application No. 09 / 015,394 of the United States filed January 29, 1998 explains the sustained release absorbable compositions of a bioactive agent. The Application Number 09 / 121,653 of the United States filed on July 23, 1998 explains a process for making microparticles comprising a therapeutic agent such as a peptide in an oil-in-water process. Application Number 09 / 131,472 of the United States filed on August 10, 1998 explains complexes comprising a therapeutic agent such as a peptide and a phosphorylated polymer. Application Number 09 / 184,413 of the United States filed on November 2, 1998 explains complexes comprising a therapeutic agent such as a peptide and a polymer carrying a non-polymerizable lactone. The teachings of the above patents and applications are incorporated herein by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which they belong. this invention. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference. The following examples describe synthetic methods for making a peptide of this invention, which are well known to those skilled in the art. These people also know other methods. The examples are provided for the purpose of illustration and in no way limit the scope of the present invention.

Example 1 [D-Ala8, Ala17'22'23'27, 3-Pal19'31, Gaba34] -GLP-1 (7-34) NH2 The benzhydrylamine-polystyrene resin (Advanced ChemTech, Inc., Louisville, KY) (0.9 g, 0.3 mmol) in its chloride ion form is placed in a reaction vessel of the Advanced Chem Tech Model 200 peptide synthesizer, programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 15 min, respectively); (c) methylene chloride; (d) ethanol; (e) methylene chloride; (f) 10% diisopropylethylamine in methylene chloride. The neutralized resin is mixed with Boc-Gaba and diisopropylcarbodiimide (3 mmoles each) in chloride of methylene for 1 hour and the resulting amino acid resin is then subjected to the cycle including steps (a) to (f) of the previous washing program. The following amino acids (3 mmoles) are then coupled successively by the same procedure: Boc-Val, Boc-Leu, Boc-3-Pal, Boc-Ala, Boc-Ile, Boc-Phe, Boc-Ala, Boc-Lys ( 2-C1-Z), Boc-Ala, Boc-Ala, Boc-Ala, Boc-Ala, Boc-Glu (Bzl), Boc-Leu, Boc-3-Pal, Boc-Ser (Bzl), Boc-Ala , Boc-Val, Boc-Asp (Bzl), Boc-Ser (Bzl), Boc-Thr (Bzl), Boc-Phe, Boc-Thr (Bzl), Boc-Gly, Boc-Glu (Bzl), Boc- D-Ala, Boc-His (Bom). The resin with the complete peptide sequence is mixed with anisole (5 ml), dithiothreitol (100 mg) and hydrogen fluoride anhydride (35 ml) at about 0 ° C and stirring for about 45 min. The excess of hydrogen fluoride evaporates rapidly under a flow of dry nitrogen; the free peptide is precipitated and washed with ether. The crude peptide is dissolved in a minimum volume of dilute acetic acid and eluted on a column (2.5 x 2.5 cm) of silica octadecylsilane VYDAC® (10 mM); it is eluted with a linear gradient of 20-60% acetonitrile for about 1 hour in 0.1% trifluoroacetic acid in water. The fractions are examined by thin layer chromatography and analytical high pressure liquid chromatography (40-70% B at 1% / min; r.t .: 14.1 min) and combined to generate maximum purity, instead of yield. Repeated lyophilization of the solution from water generates a product (49.9 mg) as a white powder. The product was found homogeneous by HPLC and by thin layer chromatography. The amino acid analysis of an acid hydrolyzate confirms the composition of the peptide.

The MS laser desorption gave a molecular weight of 2880 (Cale.M + H 2873).

Example 2 Synthesis of Peptide with Alkylamides The peptides were assembled in a 0-benzyl-polystyrene resin (commonly referred to as Merrifield resin) using the protocol for the amino acid Boc, as described in Example 1, except that the side chains carboxylic acids Asp and Glu are protected with an Fm (fluorenylmethyl ester) group. The complete peptide resins are suspended in a diluted solution of DMF of a suitable small alkylamine (such as ethylamine, propylamine, phenethylamine, 1,2-diaminoethane, etc.) and mixed at about 60 ° C (for about 18 hours), after which it is filtered, the solvents are removed under reduced pressure and the peptide oil exfoliated with ether is ground, which will generate a solid peptide protected with alkylamide. The above is subjected to exfoliation with HF to remove additional protective groups from the side chains and to HPLC purification as described in Example 1.

Examples 3-5 Examples 3-5 can be synthesized basically according to the procedure described for Example 1 using the appropriate protected amino acids to produce the peptides: Example 3: [Aib8, D-Ala17, Ala18'22'23'27 , 3-Pal19'31, Tie16, Gaba34] -GLP-1 (7-34) NH2 Example 4: [Aib8, D-Ala17, Ala22'23'27, 3-Pal19'31, Tie16] -GLP-1 ( 7-33) NH2 Example 5: [Aib8, D-Ala17, Ala22'23'27, 3-Pal19'31, Tie16'20] -GLP-1 (7-33) NH2 Examples 6-51 Examples 6-51 can be synthesized basically according to the procedure described for Example 1 using the appropriate protected amino acids to produce the peptides mentioned below. MS (ES) were obtained by MS laser desorption (NA means not available). Example 6: [D-Ala8'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2; MS = 2971.0; PM cale. = 2974.4 Example 7: [Ala18'23'27, 3-Pal19'31] h.GLP-1 (7-35) -NH2; (SEQ ID NO: 83); MS = 2954.4; PM cale. = 2958.4 Example 8: [Ala16'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2; (SEQ ID NO: 84); MS = 2943.0; PM cale. = 2946.3 Example 9: [Ala14'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2; (SEQ ID NO: 85); MS = 2956.0; PM cale. = 2958.4 Example 10: [Ala22'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2; (SEQ ID NO: 86); MS = 2981.0; PM cale. = 2988.4 Example 11: [Hppa7] hGLP-1 (7-36) -NH2; (SEQ ID NO: 87); MS = NA Example 12: [Ala15'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2; (SEQ ID NO: 88); MS = 2928.0; PM cale. = 2930.4 Example 13: [Ala17'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2; (SEQ ID NO: 89); MS = 2955.0; PM cale. = 2958.4 Example 14: [Ala22'23'27, 3-Pal19'31, Gaba34] h.GLP-1 (7-34) -NH2; (SEQ ID NO: 90); MS = 2896.0; PM cale. = 2888.3 Example 15: [Ala15'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 91); MS = 2852.0; PM cale. = 2844.3 Example 16: [Ala 17,22.23.27 3 -Pal 19.31 Gaba 4] hGLP-1 (7-34) NH2; (SEQ ID NO: 92); MS = 2880.0; PM cale. = 2872.3 Example 17: [Ala18'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 93); MS = 2870.0; PM cale. = 2872.3 Example 18: [Ala21'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 94); MS = NA Example 19: [Ala22'23'26'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 95); MS = 2832.0; PM cale. = 2831.2 Example 20: [Ala22'23'27'32, 3-Pal19'31, Gaba34] hGLP-1 (7-34) NH2; (SEQ ID NO: 96); MS = 2855.0; PM cale. = 2846.2 Example 21: [Ala22'23'26'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) NH2; (SEQ ID NO: 97); MS = 2729.0; PM cale. = 2732.0 Example 22 [Wing 22,23,27,31 3 -Pal 19 GabaJJ] hGLP-l (7-33) NH2; (SEQ ID NO: 98); MS = 2711.6; PM cale. = 2712.0 Example 23: [Ala22-23-27'28, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; (SEQ ID NO: 99); MS = 2712.0; PM cale. = 2713.0 Example 24: [A? A22 < 23'27'29, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; (SEQ ID NO: 100); MS = 2746.9; PM cale. = 2747.1 Example 25: [Ala23'27, 3-Pal19'31, Gaba33] b.GLP-1 (7-33) -NH2; (I KNOW THAT ID NO: 101); MS = 2777.0; PM cale. = 2775.1 Example 26: [Aia20'22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; (SEQ ID NO: 102); MS = 2742.0; PM cale. = 2747.1 Example 27: [Ala22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; (SEQ ID NO: 103); MS = 2786.7; PM cale. = 2789.1 Example 28: [Ala17'22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; (SEQ ID NO: 104); MS = 2771.0; PM cale. = 2773.1 Example 29: [D-Ala10, Ala22'23'27, 3-Pal19'31, Gaba33] h.GLP-1 (7-33) -NH2; MS = 2802.0; PM cale. = 2803.2 Example 30: [D-AJa8, Ala17'23'27, 3-Pal19'31] hGLP-1 (7-34) -NH2; MS = 2905.0; PM cale. = 2901.3 Example 31: [Ala17'23'27, 3-Pal16'26'31] hGLP-1 (7-34) -NH2; (SEQ ID NO: 105); MS = 2920.0; PM cale. = 2921.3 Example 32: [D-Ala8, Ala17, 3-Pal19'31] hGLP-1 (7-34) -NH2; MS = 2908. 0 (Na + salt); PM cale. = 2885.3 Example 33: [Ala17'23'27, 3 -Pal19'31] hGLP-1 (7-34) -NH2; (SEQ ID NO: 106); MS = 2907.0; PM cale. = 2901.3 Example 34: [D-Ala8, Ala17'23'27, 3-Pal19'31, Tie29] hGLP-1 (7-34) -NH2; MS = 2906.0; PM cale. = 2901.3 Example 35: [D-Ala8, Ala17'23'27, 3-Pal19'31, Tie16] h.GLP-1 (7-34) -NH2; MS = 2914.0; PM cale. = 2915.4 Example 36: [D-Ala8, Ala17'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; MS = 2856.8; PM cale. = 2858.2 Example 37: [D-Ala22, Ala17'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; MS = 2871.0; PM cale. = 2872.3 Example 38: [Aib8, Ala17'23'27, 3-Pal19'31, Gaba34] h.GLP-1 (7-34) -NH2; (SEQ ID NO: 107); MS = 2875.0; PM cale. = 2872.3 Example 39: [D-Ala8, t 3-Pal19'31] hGLP-1 (7-33) -NH2; MS = 2786.0; PM cale. = 2787.2 Example 40: [Aib8, Ala17'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2; (SEQ ID NO: 108); MS = 2800.0; PM cale. = 2801.2 Example 41: [Ala17'18'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 109); MS = 2842.5; PM cale. = 2842.2 Example 42: [Ala17'23'27, 3-Pal19'31, Tie33, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 110); MS = 2871.0; PM cale. = 2872.3 Example 43: [Tie16, Ala17'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; (SEQ ID NO: 111); MS = 2870.0; PM cale. = 2872.3 Example 44: [N-Me-D-Ala8, Ala17'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2; MS = 2795.0; PM cale. = 2801.2 Example 45: [Aib8, Ala17'18'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2; (SEQ ID NO: 112); MS = 2784.2; PM cale. = 2785.2 Example 46: [A? A17'18'22'23'27, 3-Pal19'31, Tie16'20, Gaba34] hGLP -l (7-34) -NH2; (SEQ ID NO: 113); MS = 2871.9; PM cale. = 2870.3 Example 47: [D-Ala8, Ala17'18'22'23'27, 3-Pal19'31, Tie16, Gaba34] hGLP-1 (7-34) -NH2; MS = 2870.0; PM cale. = 2870.3 Example 48: [D-Ala8'22, Ala17'18'23'27, 3-Pal19'31, Gaba34] hGLP-l (7-34) -NH2; MS = 2856.3; PM cale. = 2856.3 Example 49: [D-Ala8'18, Ala17'22'23'27, 3-Pal19'31, Gaba34] hGLP-l (7-34) -NH2; MS = NA Example 50: [D-Ala8'17, Ala18'22'23'27, 3-Pal19'31, Gaba3] hGLP-1 (7-34) -NH2; MS = NA Example 51: [D-Ala8, A? A17 < 18'22'23'27, 3-Pal19'31, Gaba34] hGLP-l (7-34) -NH2; MS = 2861.6; PM cale. = 2856.3 Example 52 [Aib8, A6c32] hGLP-1 (7-36) NH2 (SEQ ID NO: 114) The title peptide was synthesized on a peptide synthesizer model 430A from Applied Biosystems (Foster City, CA) which was modified to make the accelerated synthesis of solid phase peptides according to the Boc chemistry. See Schnolzer, et al., Int. J.

Peptide Protein Res., 90: 180 (1992). The 4-methylbenzhydrylamine resin (MBHA) (Peninsula, Belmont, CA) was used with the replacement of 0.91 mmole / g. The amino acids of Boc (Bachem, CA, Torrence, CA, Nova Biochem., La Jolla, CA) were used with the following side chain protection: Boc-Ala-OH, Boc-Arg (Tos) -OH, Boc-Asp (OcHex) -OH, Boc-Tyr (2BrZ) -OH, Boc-His (DNP) -OH, Boc-Val-OH, Boc-Leu-OH, Boc-Gly-OH, Boc-Gln-OH, Boc Ile-OH, Boc-Lys (2C1Z) -OH, Boc-Thr (Bzl) -OH, Boc-A6c-OH, Boc-Ser (Bzl) -OH, Boc-Phe-OH, Boc-Aib-OH, Boc -Glu (OcHex) -OH and Boc-Trp (Fm) -OH. The synthesis was performed on a scale of 0.20 mmoles. The Boc groups were removed by treatment with 100% TFA for 2 x 1 min. Boc amino acids (2.5 mmoles) were preactivated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF and were coupled without prior neutralization of the TFA salt of peptide resin. The coupling times were about 5 minutes except for the Boc-Aib-OH and Boc-A6c-OH residues and the following residues. Boc-Trp (Fm) -OH and Boc-His (DNP) -OH where the coupling times were approximately 2 hours. At the end of the assembly of the peptide chain, the resin was treated with a solution of 20% mercaptoethanol / 10% DIEA in DMF for 2 x 30 min to remove the DNP group in the His side chain. The N-terminal Boc group was then removed by treatment with 100% TFA for 2 x 2 min. After neutralization of the peptide resin with 10% DIEA in DMF (1 x min), the The formyl group in the Trp side chain was removed by treatment with a 15% ethanolamine / 15% water / 70% DMF solution for 2 x 30 min. The partially deprotected peptide resin was washed with DMF and DCM and dried under reduced pressure. The final exfoliation was performed by stirring the peptide resin in 10 mL of HF containing 1 mL of anisole and dithiothreitol (24 mg) at 0o C for 75 minutes. HF was removed by a flow of nitrogen. The residue was washed with ether (6 x 10 mL) and extracted with 4N HOAc (6 x 10 mL). The peptide mixture in the aqueous extract was purified in reverse phase preparative high pressure liquid chromatography (HPLC) using a reverse phase C? 8 column VYDAC? (Nest Group, Southborough, MA). The column was eluted with a linear gradient (20% to 50% of solution B for 105 minutes) at a flow rate of 10 mL / min (Solution A = water containing 0.1% TFA); Solution B = acetonitrile containing 0.1% TFA). Fractions were collected and checked in analytical HPLC. Those containing pure product were combined and lyophilized until dehydrated. 92 mg of a white solid were obtained. The purity was greater than 99% based on analytical HPLC. Electrostatic mass spectrometer (MS (ES)) S analysis gave the molecular weight in 3324.2 (in accordance with the calculated molecular weight of 3323. 7). The synthesis of other compounds of the present invention can be carried out in the same manner as described for the synthesis of [Aib8, A6c32] hGLP-1 (7-36) NH2 (SEQ ID NO: 114) in Example 52 above, using the appropriate protected amino acids depending on the desired peptide. [(Na-HEPES-His) 7] hGLP-1 (7-36) NH 2 (SEQ ID NO: 152). { HEPES is (4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid)} it can be synthesized as follows: after assembly of the long chain peptide in the MBHA resin (0.20 mmoles), the peptide resin is treated with 100% TFA (2 x 2 min) and washed with DMF and DCM. The resin is then neutralized with 10% DIEA in DMF for about 2 minutes. After washing with DMF and DCM, the resin is treated with 0.23 mmoles of 2-chloro-l-ethanesulfonyl chloride and 0.7 mmoles of DIEA in DMF for about 1 hour. The resin is washed with DMF and DCM and treated with 1.2 mmoles of 2-hydroxyethylpiperazine for about 2 hours. The resin is washed with DMF and DCM and treated with different reagents ((1) 20% mercaptoethanol / 10% DIEA in DMF and (2) 15% ethanolamine / 15% water / 70% DMF) to remove the DNP group in the side chain of His and formyl group in the side chain of Trp as described above before the final exfoliation of HF of the peptide of the resin. [(Na-HEPES-His) 7] hGLP-1 (7-36) NH 2 (SEQ ID NO: 153) ([(4- (2-hydroxyethyl) -1-piperazineacetyl) -His7] hGLP-1 (7- 36) NH2) can be done basically according to the procedure described above to make [(Na-HEPES-His) 7] hGLP-1 (7-36) NH2 (SEQ ID NO: 152) except that 2-anhydride is used. bromoacetic instead of 2-chloro-1-ethanesulfonyl chloride.

Examples 53-90 and 104 Examples 53-90 and 104 were synthesized basically in accordance with the procedure described in Example 52 using the appropriate protected amino acid. Example 53: [A6c20'32] h.GLP-1 (7-36) -NH2; (SEQ ID NO: 115); MS = 3322.3; PM cale. = 3321.7 Example 54: [Aib8] h.GLP-1 (7-36) -NH2; (SEQ ID NO: 116); MS = 3311. 7; PM cale. = 3311.7 Example 55: [(Tma-His) 7] h.GLP-1 (7-36) -NH2; (SEQ ID NO: 117); MS = 3395.9; PM cale. = 3396.9 Example 56: [A6c8] hGLP-1 (8-36) -NH2; (SEQ ID NO: 118); MS = 3214. 5; PM cale. = 3214.7 Example 57: [A6c8] hGLP-1 (7-36) -NH2; (SEQ ID NO: 119); MS = 3351. 5; PM cale. = 3351.8 Example 58: [A6c16'20] hGLP-1 (7-36) -NH2; (SEQ ID NO: 120); MS = 3335.9; PM cale. = 3335.8 Example 59: [A6c29'32] hGLP-1 (7-36) -NH2; (SEQ ID NO: 121); MS = 3321.7; PM cale. = 3321.7 Example 60: [A6c20, Aib24] hGLP-1 (7-36) -NH2; (SEQ ID NO: 122); MS = 3323.6; PM cale. = 3323.7 Example 61: [Aib24, A6c29'32] hGLP-1 (7-36) -NH2; (SEQ ID NO: 123); MS = 3335.7; PM cale. = 3335.8 Example 62: [A6c16'29'32] hGLP-1 (7-36) -NH2; (SEQ ID NO: 124); MS = 3347.7; PM cale. = 3347.8 Example 63: [Ura7] hGLP-1 (7-36) -NH2; (SEQ ID NO: 125); MS = 3279.5; PM cale. = 3280.7 Example 64: [Paa7] hGLP-1 (7-36) -NH2; (SEQ ID NO: 126); MS = 3290. 9; PM cale. = 3291.8 Example 65: [Pta7] hGLP-1 (7-36) -NH2; (SEQ ID NO: 127); MS = 3311. 2; PM cale. = 3311.8 Example 66: [N-Me-Ala8] b.GLP-1 (7-36) -NH2; (SEQ ID NO: 128); MS = 3311.4; PM cale. = 3311.7 Example 67: [N-Me-D-Ala8] hGLP-1 (7-36) -NH2; MS = 3311.6; PM cale. = 3311.7 Example 68: [N-Me-D-Ala8] hGLP-1 (8-36) -NH2; MS = 3174.0; PM cale. = 3174.6 Example 69: [N-Me-Gly8] hGLP-1 (7-36) -NH2; (SEQ ID NO: 129); MS = 3297.3; PM cale. = 3297.7 Example 70: [A5c8] hGLP-1 (7-36) -NH2; (SEQ ID NO: 130); MS = 3337. 3; PM cale. = 3337.8 Example 71: [N-Me-Glu9] hGLP-1 (7-36) -NH2; (SEQ ID NO: 131); MS = 3311.4; PM cale. = 3311.7 Example 72: [A5c8, A6c20'32] hGLP-1 (7 -36) -NH2 (SEQ ID NO: 132); MS = 3361.4; PM cale. = 3361.8 Example 73: [Aib8, A6c32] hGLP-1 (7-36) -NH2; (SEQ ID NO: 133) MS = 3323.2; PM cale. = 3323.7 Example 74: [Aib8'25] hGLP-1 (7-36) -NH2; (SEQ ID NO: 134); MS = 3325.8; PM cale. = 3325.7 Example 75: [Aib8'24] hGLP-1 (7-36) -NH2; (SEQ ID NO: 135); MS = 3325.8; PM cale. = 3325.7 Example 76: [Aib8'30] b.GLP-1 (7-36) -NH2; (SEQ ID NO: 136); MS 3326. 1; PM cale. = 3325.7 Example 77: [Aib8, Cha20] hGLP-1 (7-36) -NH 2 / (SEQ ID NO: 137) MS = 3351.8; PM cale. = 3351.8 Example 78: [Aib8, Cha32] hGLP-1 (7-36) -NH2; (SEQ ID NO: 138) MS = 3352.0; PM cale. = 3351.8 Example 79: [Aib8, Glu23] hGLP-1 (7-36) -NH2; (SEQ ID NO: 139) MS = 3311.7; PM cale. = 3312.7 Example 80: [Aib8, A6c20] hGLP-1 (7-36) -NH2; (SEQ ID NO: 140) MS = 3323.6; PM cale. = 3323.7 Example 81: [Aib8, A6c20'32] hGLP-1 (7 -36) -NH2; (SEQ ID NO: 141); MS = 3335.3; PM cale. = 3335.7 Example 82: [Aib8'22] hGLP-1 (7-36) -NH2; (SEQ ID NO: 142); MS = 3339.8; PM cale. = 3339.8 Example 83: [Aib8, ß-Ala22] hGLP-1 (7 -36) -NH2; (SEQ ID NO: 143); MS = 3325.6; PM cale. = 3325.8 Example 84: [Aib8, Lys25] hGLP-1 (7-36) -NH2; (SEQ ID NO: 144); MS = 3369.0; PM cale. = 3368.8 Example 85: [Aib8, A6c12] hGLP-1 (7-36) -NH2; (SEQ ID NO: 145); MS = 3289.8; PM cale. = 3289.7 Example 86: [Aib8, A6c29] b.GLP-1 (7-36) -NH2; (SEQ ID NO: 146); MS = 3323.9; PM cale. = 3323.7 Example 87: [Aib8, A6c33] b.GLP-1 (7-36) -NH2; (SEQ ID NO: 147); MS = 3338.0; PM cale. = 3337.8 Example 88: [Aib8'14] b.GLP-1 (7-36) -NH2; (SEQ ID NO: 148); MS = 3309. 8; PM cale. = 3309.7 Example 89: [Aib8'18] hGLP-1 (7-36) -NH2; (SEQ ID NO: 149); MS = 3309. 7; PM cale. = 3309.7 Example 90: [Aib8'17] h.GLP-1 (7-36) -NH2; (SEQ ID NO: 150); MS = 3309. 4; PM cale. = 3309.7 Example 104: [Aib8, D-Arg26] hGLP-1 (7-36) -NH2; MS = 3310.7; PM cale. = 3311.73 Example 91 [Aib8, A5c33] hGLP-l (7-36) NH2 (SEQ ID NO: 154) The title compound is synthesized basically according to the procedure described in Example 52 using the appropriate protected amino acid.

Example 92 [Aib8, A6c32, Lys36 (Ne-tetradecanoyl)] hGLP-l (7-36) NH2 (SEQ ID NO: 155) The amino acids of Boc used were the same as those in the synthesis of [Aib8, A6c32] hGLP-1 (7-36) NH2 (SEQ ID NO: 114) (Example 52) except that Fmoc-Lys (Boc) -OH was used in this example for the residue of Lys36 (Ne-tetradecanoyl). The first amino acid residue was attached to the resin manually on a shaker. 2.5 mmoles of Fmoc-Lys (Boc) -OH were dissolved in 4 L of 0.5N HBTU in DMF. To the solution was added 1 mL of DIEA. The mixture was stirred for about 2 minutes. To the solution was then added 0.2 mmoles of MBHA resin (substitution = 0.91 mmoles / g). The mixture was stirred for about 1 hour. The resin was washed with DMF and treated with 100% TFA for 2x2 min to remove the Boc protection group. The resin was washed with DMF. Myristic acid (2.5 mmol) was preactivated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 L DMF for 2 minutes and coupled to the Fmoc-Lys resin. The coupling time was around 1 hour. The resin was washed with DMF and treated with 25% piperidine in DMF for 2x20 min to remove the Fmoc protection group. The resin was washed with DMF and transferred to the reaction vessel of the peptide synthesizer. The following steps and methods of synthesis and purification for the peptide were the same as in the synthesis of [Aib8, A6c32] hGLP-1 (7-36) NH2 (SEQ ID NO: 114).

The synthesis of other compounds containing Lys residue (Ne-alkanoyl) can be carried out analogously to the procedure described for the synthesis of [Aib8, A6c32, Lys36 (Ne-tetradecanoyl)] hGLP-1 (7-36) NH2 ( SEQ ID NO: 155). The amino acid of Fmoc-Lys (Boc) -OH is used for the residue of Lys (Ne-alkanoyl) in the peptide, while the amino acid of Boc-Lys (2C1Z) -OH is used for the Lys residue. If the Lys residue (Ne-alkanoyl) is not in the C-terminus, the peptide fragment immediately preceding the Lys residue (Ne-alkanoyl) is first assembled in the resin in the peptide synthesizer.

Example 93-98 Examples 93-98 were synthesized basically according to the procedure described in Example 92 using the appropriate protected amino acid. Example 93: [Aib8, A6c32, Lys36 (Ne-tetradecanoyl)] h.GLP-1 (7-36) NH2 (SEQ ID NO: 155) Example 94: [Aib8, Arg26'34, A6c32, LysJb (N tetradecanoyl) ] hGLP-1 (7-36) NH 2 (SEQ ID NO: 156) Example 95 [Aib 8 Arg 26 A 6c 32 Lys 34 (Ne-tetradecanoyl)] hGLP-1 (7-36) NH 2 (SEQ ID NO: 157) Example 96 [Aib8, Lys (Ne-tetradecanoyl) A6c 32 Arg34] hGLP-1 (7-36) NH2 (SEQ ID NO: 158) Example 97: [Aib8, Lys36 (Ne-octanyl)] hGLP-1 (7 -36) NH2 (SEQ ID NO: 159) Example 98: [Aib8, A6c20'32, Lys36 (Ne-octanoyl)] hGLP-1 (7-36) NH2 (SEQ ID NO: 160) Example 99 [Aib8, Arg26'34, A6c32, Lys36 (Ne-tetradecanoyl)] hGLP-1 (7-36) -OH (SEQ ID NO: 161) The amino acids of Boc to be used are the same as those in the synthesis of [Aib8, A6c32, Lys36 (Ne-tetradecanoyl)] hGLP-l (7-36) NH2 (SEQ ID NO: 162) (Example 92). Fmoc-Lys (Boc) -OH (2.5 mmoles) was preactivated with HBTU (2.0 mmoles), HOBt (2.0 mmol) and DIEA (2.5 ml) in DMF (4 ml) for about 2 minutes. This amino acid is coupled to 235 mg of PAM resin (Chem-Impex, Wood Dale, IL; substitution = 0.85 mmoles / g) manually in a shaker. The coupling time is around 8 hours. The remainder of the synthesis and purification procedures for making the peptide are the same as those described in Example 52. The synthesis of other analogous structures of hGLP-1 (7-36) -OH (SEQ ID NO: 3) and hGLP-1 (7-37) -OH (SEQ ID NO: 4), which contain Lys residue (Ne-alkanoyl) can be performed in an analogous manner according to the procedure described for the synthesis of [Aib8, Arg26 ' 34, A6c32, Lys36 (Ne-tetradecanoyl)] hGLP-l (7-36) -OH (SEQ ID NO: 161). The amino acid of Fmoc-Lys (Boc) -OH is used for the residue of Lys (Ne-alkanoyl) in the peptide, while the amino acid of Boc-Lys (2C1Z) -OH is used for the Lys residue.

Examples 100-103 Examples 100-103 were synthesized basically according to the procedure described in Example 99 using the appropriate protected amino acid. Example 100 [Aib8 Arg 26 A6c 32 LysJ4 (Ne-tetradecanoyl)] hGLP-1 (7-36) -OH (SEQ ID NO: 162) Example 101: [Aib8, Lys26 (Ne-tetradecanoyl) A6c 32 Arg34] hGLP- l (7-36) -OH (SEQ ID NO: 163) Example 102 [Aib8 Arg 26.3 A6c 32 LysJb (N1 tetradecanoyl)] hGLP-1 (7-37) -OH (SEQ ID NO: 164) Example 103 [Aib8 Arg 26 A6c 32 LysJ4 (Ne-tetradecanoyl)] hGLP-l (7-37) -OH (SEQ ID NO: 165)

Claims

CLAIMS; 1. A compound of the formula (I), (R2R3) -A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24 -A25-A26-A27-A28-A29-A30-A31-A32-A33-A3 -A35-A36-A37-R1, (I) wherein A7 is L-His, Ura, Paa, Pta, D-His, Tyr, 3-Pal, 4-Pal, Hppa, Tma-His, Amp, or suppressed; in the supposition that when A7 is Ura, Paa, Pta or Hppa then R2 and R3 are suppressed; A8 is Ala, D-Ala, Aib, Acc, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A9 is Glu, N-Me-Glu, N-Me-Asp or Asp; A10 is Gly, Acc, Ala, D-Ala, Phe or Aib; A11 is Thr or Ser; A12 is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, S-Nal, Cha, Trp or X1-Phe; ? l3 is Thr or Ser; A?! 4, ± is Ser, Thr, Ala or Aib; A15 is Asp, Ala, D-Asp or Glu; A16 is Val, D-Val, Acc, Aib, Leu, Lie, Tie, Nle, Abu, Ala, D-Ala, Tba or Cha; A17 is Ser, Ala, D-Ala, Aib, Acc or Thr; A18 is Ser, Ala, D-Ala, Aib, Acc or Thr; A19 is Tyr, D-Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, jS-Nal, Amp or X ^ Phe; A20 is Leu, Ala, Acc, Aib, Nle, lie, Cha, Tie, Val, Phe or X1-Phe; A21 is Glu, Ala or Asp; A22 is Gly, Acc, Ala, D-Ala, jg-Ala or Aib; A23 is Gln, Asp, Ala, D-Ala, Aib, Acc, Asn or Glu; A24 is Ala, Aib, Val, Abu, Tie or Acc; A25 is Ala, Aib, Val, Abu, Tie, Acc, Lys, Arg, hArg, Orn, HN-CH ((CH2) nN (R10R?: L)) -C (O) or HN-CH ((CH2) e-X3) -C (O); A26 is Lys, Ala, 3-Pal, 4-Pal, Arg, hArg, Orn, Amp, HN-CH ((CH2) aN (R10RX1)) -C (O) or HN-CH ((CH2) e-X3 ) -C (O); A27 is Glu, Ala, D-Ala or Asp; A28 is Phe, Ala, Pal, jS-Nal, X1-Phe, Aic, Acc, Aib, Cha or Trp; A29 is Lie, Acc, Aib, Leu, Nle, Cha, Tie, Val, Abu, Ala, Tba or Phe; A30 is Ala, Aib, Acc or deleted; A31 is Trp, Ala, β-Nal, 3 -Pal, 4 -Pal, Phe, Acc, Aib, Cha, Amp or deleted; A32 is Leu, Ala, Acc, Aib, Nle, lie, Cha, Tie, Phe, X1-Phe, Ala or suppressed; A33 is Val, Acc, Aib, Leu, Lie, Tie, Nle, Cha, Ala, Phe, Abu, X1-Phe, Tba, Gaba or suppressed, -, 34 is Lys, Arg, hArg, Orn, Amp, Gaba, HN-CH ((CH2) n- N (RL? RJ "L)) -C (O), HN-CH ((CH2) e -XJ) -C (O) or deleted; A is Gly or deleted; A3"is L- or D-Arg, D- or L-Lys, D- or L-hArg, D- or L-Orn, Amp, HN-CH ((CH2) n-N (R10R1: L)) -C (0), HN-CH ((CH2) e-X3) -C (0) or deleted; A37 is Gly or suppressed; X1 each time it appears is independently selected from the group consisting of (C? -C6) alkyl, OH and halo; R1 is OH, NH2, (d-C12) alkoxy, or NH-X2-CH2-Z °, wherein X2 is an entity of (C? -CX2) hydrocarbon and Z ° is H, OH, C02H or C0NH2; -NH-C (O) -CH; "N- (CH2) 2-NH-C (O) -R13? -__ N N- (CH2) f -CH3 or -C (0) -NHR12, where X4 is, independently whenever it appears, -C (0) -, -NH-C (O) - or -CH2- and where f is, independently whenever it appears , an integer from 1 to 29; each of R2 and R3 is independently selected from the group consisting of H, (C? -C30) alkyl, (C2-C30) alkenyl, phenyl (C-30) alkyl, naphthyl (C1.-C30) alkyl, hydroxy (Cx-Cso) alkyl, hydroxy (C2-C30) alkenyl, hydroxyphenyl (C1-C30) alkyl and hydroxynaphthyl (C? -C30) alkyl; or one of R2 and R3 is C (0) X5 wherein X5 is (C? -C30) alkyl, (C2-C30) alkenyl, phenyl (C? -C30) alkyl, naphthyl (C? -C30) alkyl, hydroxy (C? -C30) alkyl, hydroxy (C2-C30) alkenyl, hydroxyphenyl (O.-C30) alkyl, hydroxynaphthyl (C? -C30) alkyl, (a) / \ Y (CH2) r-N N- (CH2) qS02- Y (CH2) f-N N- < CH2) q-CO- (b) where Y is H or OH; r is 0 to 4; q is 0 to 4; n is, independently whenever it appears, an integer from 1 to 5; and R10 and R11 is, independently whenever it appears, H, (C1-C30) alkyl, (C? -C30) acyl, (C? -C30) alkylsulfonyl, C ((NH) (NH2)) or -CÍO-CHj-N N-. { CH2) rCH2 in the assumption that when R (C? -C30) acyl, (Ci-C30) alkylsulfonyl, -C ((NH) (NH2)) or / \ -C (0) -CH¿-N N- - (CH2) rCH; R11 is H or (C1-C30) alkyl; and R12 is (C1-C30) alkyl; with the premise that: (i) at least one amino acid of a compound of the formula (I) is not the same as the native sequence of h.GLP-1 (7-36 or -37) NH2 (SEQ ID NOS: 1) , 2) or hGLP-1 (7-36 or -37) OH (SEQ ID NOS: 3, 4); (ii) a compound of the formula (I) is not an analogous structure of hGLP-I (7-36 or -37) NH2 (SEQ ID NOS: 1, 2) or hGLP-1 (7-36 or -37) OH (SEQ ID NOS: 3, 4) where only one position has been replaced by Ala; (iii) a compound of the formula (I) is not, [Lys26 (Ne-alkanoyl)] hGLP-l (7-36 or -37) -E (SEQ ID NOS: 5-8), [Lys34 (Ne-alkanoyl)] hGLP-l (7-36 or -37) -E (SEQ ID NOS: 9-12), [Lys26'34-bis (Ne-alkanoyl)] hGLP-l (7-36 or -37) -E (SEQ ID NOS: 13-16), [Arg26, Lys34 (Ne-alkanoyl)] hGLP-1 (8-36 or -37) -E (SEQ ID NOS: 17-20), or [Arg26'34, Lys36 (Ne-alkanoyl)] hGLP-1 (7-36 or -37) -E, where E is -OH or -NH2 (SEQ ID NOS : twenty-one- 24); (iv) a compound of the formula (I) is not Z1-hGLP-I (7-36 or -37) -OH, Zx-hGLP-I (7-36 or -37) -NH2, wherein Z1 is selected from the group consisting of: (a) [Arg26] (SEQ ID NOS: 25-28), [Arg34] (SEQ ID NOS: 29-32), [Arg26'34] (SEQ ID NOS: 33-36), [Lys36] (SEQ ID NOS: 37-40), [Arg26, Lys36] (SEQ ID NOS: 41-44), [Arg34, Lys36] (SEQ ID NOS: 45-48), [D-Lys36], [Arg36] (SEQ ID NOS: 3,4,1,2), [D-Arg36], [Arg26'34, Lys36 ] (SEQ ID NOS: 49-52) or [Arg26'36, Lys34] (SEQ ID NOS: 25-28); (b) [Asp21] (SEQ ID NOS: 53-56); (c) at least one of [Aib8] (SEQ ID NOS: 57-60), [D-Ala8] and [Asp9] (SEQ ID NOS: 61-64); and (d) [Tyr7] (SEQ ID NOS: 65-68), [N-acyl-His7] (SEQ ID NOS: 69-72), [N-alkyl-His7], [N-acyl-D-His7 ] (I KNOW THAT ID NOS: 73-76) or [N-alkyl-D-His7]; (v) a compound of the formula (I) is not a combination of two of the substitutions included in the groups (a) to (d), - Y (vi) a compound of the formula (I) is not [N- Me-Ala8] hGLP-1 (8-36 or -37) (SEQ ID NOS: 75.78), [Glu15] hGLP-1 (7-36 or -37) (SEQ ID NOS: 79.80), [ Asp21] hGLP-1 (7-36 or -37) (SEQ ID NOS: 53.54) or [Phe31] b.GLP-1 (7-36 or -37) (SEQ ID NOS: 81.82).
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A11 is Thr; A13 is Thr; A14 is Ser, Aib or Ala; A17 is Ser, Ala, Aib or D-Ala; A18 is Ser, Ala, Aib or D-Ala; A21 is Glu or Ala; A23 is Gln, Glu or Ala; and A27 is Glu or Ala. ,
3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein A9 is Glu, N-Me-Glu or N-Me-Asp; A12 is Phe, Acc or Aic; A16 is Val, D-Val, Acc, Aib, Ala, Tie or D-Ala; A19 is Tyr, 3 -Pal, 4-Pal or D-Tyr; A20 is Leu, Acc, Cha, Ala or Tie; A24 is Ala, Aib or Acc; A25 is Ala, Aib, Acc, Lys, Arg, hArg, Orn, HN-CH ((CH2) n-NH-R10) -C (O); A28 is Phe or Ala; A29 is He, Acc or Tie; A30 is Ala, Aib or deleted; A31 is Trp, Ala, 3-Pal, 4-Pal or deleted; A32 is Leu, Acc, Cha, Ala or suppressed; A33 is Val, Acc, Ala, Gaba, Tie or suppressed.
4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein A8 is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me- Gly; A10 is Gly, Ala, D-Ala or Phe; A12 is Phe, A6c or A5c; A16 is Val, Ala, Tie, A6c, A5c or D-Val; A20 is Leu, A6c, A5c, Cha, Ala or Tie; A22 is Gly, Aib, β-Ala, L-Ala or D-Ala; A24 is Ala or Aib; A29 is He, A6c, A5c or Tie; A32 is Leu, A6c, A5c, Cha, Ala or deleted; A33 is Val, A6c, A5c, Ala, Gaba, Tie or suppressed.
5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R1 is OH or NH2.
6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R2 is H and R3 is (C? -C30) alkyl, (C2-C30) alkenyl, (C? -C30) acyl, H2N- (CH2) 2-N N-CH2-CO-
7. A compound according to claim 1, wherein the compound is [D-Ala8, Ala17'22'23'27, 3-Pal19'31, Gaba34] -GLP-1 (7-34) -NH2; [D-Ala8'23'27, 3-Pal19'31] hGLP-l (7-35) -NH2; [Ala8'23'27, 3- Palxy'3-L] hGLP-l (7-35) -NH2 (SEQ ID NO: 83) [Al a, 1.6-23.27 3- Pal19'31] hGLP -1 (7-35) -NH2 (SEQ ID NO: 84) [Ala14'23'27, 3-Pal19'31] h.GLP-1 (7-35) -NH2 (SEQ ID NO: 85) [Ala22 '23'27, 3-Pal19'31] b.GLP-1 (7-35) -NH2 (SEQ ID NO: 86); [Hppa7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 87); [Ala15'23'27, 3 -Pal19'31] hGLP-1 (7-35) -NH2 (SEQ ID NO: 88); [Ala17'23'27, 3-Pal19'31] hGLP-1 (7-35) -NH2 (SEQ ID NO: 89); [Ala22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 90); [Ala15'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 91); [Ala17'22'23'27, 3-Pal19'31, Gaba34] hGLP-l (7-34) -NH2 (SEQ ID NO: 92); [Ala18'22'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 93); [Ala21'22'23'27, 3- Pal 19.31 Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 94) [Ala 22'23'26'27, 3 -Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 95); [Ala 22'23'27'32, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 96); [^ 322.23,26.27 ^ 3-pai19r21f Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 97); [Ala22'23'27'31, 3-Pal19, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 98); [Ala22'23'27 < 28, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 99); [Ala 22'23'27'29, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 100); [Ala23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 101); [Ala2o, 22.23.27 ^ 3_ Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 102); [Ala22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 103); [Ala17'22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2 (SEQ ID NO: 104); [D-Ala10, Ala22'23'27, 3-Pal19'31, Gaba33] hGLP-1 (7-33) -NH2; [D-Ala8, Ala17'23'27, 3-Pal19'31] hGLP-1 (7-34) -NH2; [Ala17'23'27, 3-Pal19'26'31, Gaba33] hGLP-1 (7-34) -NH2 (SEQ ID NO: 105); [D-Ala8, Ala17, 3-Pal19'31] hGLP-l (7-34) -NH2; [Ala17'23'27, 3-Pal19'31] hGLP-l (7-34) -NH2 (SEQ ID NO: 106); [D-Ala8, Ala 17,23.27 3-Pal19'31 Tie 29] hGLP-1 (7 -34) -NH 2; [D-Ala8, Ala17'23'27, 3-Pal19'31 Tie16] hGLP-1 (7-34) -NH2; [D-Ala8, Ala17'23'27, 3-Pal19'31 Gaba34] hGLP-1 (7-34) -NH2; [D-Ala22, Ala17'23'27, 3-Pal19'31 Gaba34] hGLP-1 (7-34) -NH2; [Aib8, Ala17'23'27, 3-Pal19'31 Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 107); [D-Ala8 Ala17'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2; [Aib8, Aia ^ 22-23 ^ 7 3-Pal19'31] hGLP-1 (7-33) -NH2 (SEQ ID NO: 108); [Ala17'18'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 109); [Ala17'23'27, 3-Pal19'31, Tie33, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 110); [Tie16, Ala17'23'27, 3-Pal19'31, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 111); [N-Me-D-Ala8, A? Ai7.22.23.27 ^ 3_pa? 19'31] GLP-1 (7-33) -NH2; [Aib8, Ala17'18'22'23'27, 3-Pal19'31] hGLP-1 (7-33) -NH2 (SEQ ID NO: 112); [A? A17 < 18'22'23'27, 3-Pal19'31, Tie16'20, Gaba34] hGLP-1 (7-34) -NH2 (SEQ ID NO: 113); [D-Ala8, A? A17'18'22'23'27, 3-Pal19'31, Tie 16 Gaba .3J44] hGLP-l (7-34) -NH2; [D-Ala 8.22 Ala 17.18.23.27 3- Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; [D-Wing 8,18 Wing 17,22,23,27 Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; [D-Ala8'17, Wing 18,22,23,27 Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; or [D-Ala8, A? a17'18 < 22 < 23 < 27, 3- Pal19'31, Gaba34] hGLP-1 (7-34) -NH2; or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1, wherein the compound is [Aib8, A6c32] hGLP-l (7-36) -NH2 (SEQ ID NO: 114); [A6c20'32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 115); [Aib8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 116); [(Tma-His) 7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 117); [A6c8] b.GLP-1 (8-36) -NH2 (SEQ ID NO: 118); [A6c8] hGLP-l (7-36) -NH2 (SEQ ID NO: 119); [A6c16'20] h.GLP-1 (7-36) -NH2 (SEQ ID NO: 120); [A6c29'32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 121); [A6c20, Aib24] hGLP-1 (7-36) -NH2 (SEQ ID NO: 122); [Aib24, A6c29'32] hGLP-I (7-36) -NH2 (SEQ ID NO: 123); [A6c16'29'32] hGLP-l (7-36) -NH2 (SEQ ID NO: 124); [Ura7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 125); [Paa7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 126); [Pta7] hGLP-1 (7-36) -NH2 (SEQ ID NO: 127); [N-Me- Ala8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 128); [N-Me-Ala8] hGLP-1 (8-36) -NH2 (SEQ ID NO:); [N-Me-D-Ala8] hGLP-1 (7-36) -NH2; [N-Me-Ala8] hGLP-1 (8-36) -NH2; [N-Me-Gly8] h.GLP-1 (7-36) -NH2 (SEQ ID NO: 129); [A5c8] hGLP-1 (7-36) -NH2 (SEQ ID NO: 130); [N-Me-Glu9] .hGLP-I (7-36) -NH2 (SEQ ID NO: 131); [A5c8, A6c20'32] hGLP-l (7-36) -NH2 (SEQ ID NO: 132); [Aib8, A6c32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 133); [Aib8'25] hGLP-1 (7-36) -NH2 (SEQ ID NO: 134); [Aib8'24] hGLP-1 (7-36) -NH2 (SEQ ID NO: 135); [Aib8'30] hGLP-1 (7-36) -NH2 (SEQ ID NO: 136); [Aib8, Cha20] hGLP-1 (7-36) -NH2 (SEQ ID NO: 137); [Aib8, Cha32] hGLP-1 (7-36) -NH2 (SEQ ID NO: 138); [Aib8, Glu23] h.GLP-1 (7-36) -NH2 (SEQ ID NO: 139); [Aib8, A6c20] hGLP-l (7-36) -NH2 (SEQ ID NO: 140); [Aib8, A6c20'32] hGLP-l (7-36) -NH2 (SEQ ID NO: 141); [Aib8'22] hGLP-1 (7-36) -NH2 (SEQ ID NO: 142); [Aib8, ß-Ala22] hGLP-1 (7-36) -NH2 (SEQ ID NO: 143); [Aib8, Lys25] hGLP-1 (7-36) -NH2 (SEQ ID NO: 144); [Aib8, A6c12] hGLP-l (7-36) -NH2 (SEQ ID NO: 145); [Aib8, A6c29] hGLP-l (7-36) -NH2 (SEQ ID NO: 146); [Aib8, A6c33] hGLP-1 (7-36) -NH2 (SEQ ID NO: 147); [Aib8'14] hGLP-1 (7-36) -NH2 (SEQ ID NO: 148); [Aib8'18] hGLP-1 (7-36) -NH2 (SEQ ID NO: 149); or [Aib8'17] hGLP-l (7-36) -NH2 (SEQ ID NO: 150); or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition containing an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a carrier or diluent acceptable in terms of pharmacists The use of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to produce an agonist effect of a GLP-1 receptor in a person in need thereof. 11. The use of an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of a disease selected from the group consisting of Type I diabetes, Type II diabetes, obesity, glucagonomas, secretory disorders, the respiratory tract, 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 person who needs it. 12. The use according to claim 11, wherein the disease is Type I diabetes or Type II diabetes.