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1. WO2000034331 - ANALOGUES OF GLP-1

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[ EN ]

ANALOGUES OF GLP-1

Background of the Invention

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.

Glucagon-like peptide-1 (7-36) amide (GLP-1 ) is synthesized in the intestinal L-cells by tissue-specific post-translational processing of the glucagon precursor preproglucagon (Vamdell, J.M., et al., J. Histochem Cytochem, 1985:33:1080-6) and is released into the circulation in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. It has been demonstrated that, for a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann, B., et al., Lancet 1987:2, 1300-4). This alimentary enhancement of insulin release, known as the incretin effect, is primarily humoral and GLP-1 is now thought to be the most potent physiological incretin in humans. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, delays gastric emptylng (Wettergren A., et al., Dig Dis Sci 1993:38:665-73) and may enhance peripheral glucose disposal (D'Alessio, D.A. et al., J. Clin Invest 1994:93:2293-6).

In 1994, the therapeutic potential of GLP-1 was suggested following 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, M.K., et al., Diabetes Care 1994:17:1039-44). This effect was thought to be mediated both by increased insulin release and by a reduction in glucagon secretion. Furthermore, an intravenous infusion of GLP-1 has been shown to delay postprandial gastric emptylng in patients with NIDDM (Williams, B., et al., J. Clin Endo Metab 1996:81 :327-32). Unlike sulphonylureas, the insulinotropic action of GLP-1 is dependent on plasma glucose concentration (Holz, G.G. 4th, et al., Nature 1993:361 :362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe

hypoglycemia. This combination of actions gives GLP-1 unique potential therapeutic advantages over other agents currently used to treat NIDDM.

Numerous studies have shown that when given to healthy subjects, GLP-1 potently influences glycemic levels as well as insulin and glucagon concentrations (Orskov, C, Diabetoiogia 35:701-711 , 1992; Hoist, J.J., et al., Potential of GLP-1 in diabetes management in Glucagon III, Handbook of Experimental Pharmacology, Lefevbre PJ, Ed. Berlin, Springer Verlag, 1996, p. 311-326), effects which are glucose dependent (Kreymann, B., et al., Lancet ii: 1300-1304, 1987; Weir, G.C., et al., Diabetes 38:338-342, 1989). Moreover, it is also effective in patients with diabetes (Gutniak, M., N. Engl J Med 226:1316-1322, 1992; Nathan, D.M., et al., Diabetes Care 15:270-276, 1992), normalizing blood glucose levels in type 2 diabetic subjects (Nauck, M.A., et al., Diagbetologia 36:741-744, 1993), and improving glycemic control in type 1 patients (Creutzfeldt, W.O., et al., Diabetes Care 19:580-586, 1996), raising the possibility of its use as a therapeutic agent.

GLP-1 is, however, metabolically unstable, having a plasma half-life (t1/2) of only 1-2 min in vivo. Exogenously administered GLP-1 is also rapidly degraded (Deacon, OF., et al., Diabetes 44:1126-1131 , 1995). This metabolic instability limits the therapeutic potential of native GLP-1. Hence, there is a need for GLP-1 analogues that are more active or are more metabolically stable than native GLP-1.

Summary of the Invention

In one aspect, the present invention is directed to a compound of formula

(I),

(R2R3)-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27- A 28- A 29- A 30- A 31 - A 32- A 33- A 34- A 35- A 36- A 37- A 38- A 39-R1 ,

(I)

wherein

A7 is L-His, Ura, Paa, Pta, Amp, Tma-His, des-amino-His, or deleted;

A8 is Ala, D-Ala, Aib, Ace, 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, Ace, β-Ala or Aib;

A11 is Thr or Ser;

A12 is Phe, Ace, Aic, Aib, 3-Pal, 4-Pal, β-Nal, Cha, Trp or X1-Phe;

A13 is Thr or Ser;

A14 is Ser or Aib;

A15 is Asp or Glu;

A16 is Val, Ace, Aib, Leu, lie, Tie, Nle, Abu, Ala or Cha;

A17 is Ser or Thr;

A18is Ser or Thr;

A19 is Tyr, Cha, Phe, 3-Pal, 4-Pal, Aec, β-Nal or X1-Phe;

A20 is Leu, Ace, Aib, Nle, lie, Cha, Tie, Val, Phe or X1-Phe;

A21 is Glu or Asp;

A22 is Gly, Aec, β-Ala, Glu or Aib;

A23 is Gin, Asp, Asn or Glu;

AA22 is Ala, Aib, Val, Abu, Tie or Aec;

A25 is Ala, Aib, Val, Abu, Tie, Aec, Lys, Arg, hArg, Orn, HN-CH((CH2)n-N(R10R11))-C(O) or HN-CH((CH2)e-X3)-C(O);

A26 is Lys, Arg, hArg, Orn, HN-CH((CH2)n-N(R10R11))-C(O) or HN-CH((CH2)e-X3)-C(O);

A27 is Glu Asp, Leu, Aib or Lys;

A28 is Phe, Pal, β-Nal, X1-Phe, Aic, Aec, Aib, Cha or Trp;

A29 is lie, Aec, Aib, Leu, Nle, Cha, Tie, Val, Abu, Ala or Phe;

A30 is Ala, Aib or Ace;

A31 is Trp, β-Nal, 3-Pal, 4-Pal, Phe, Ace, Aib or Cha;

A32 is Leu, Ace, Aib, Nle, lie, Cha, Tie, Phe, X1-Phe or Ala;

A33 is Val, Aec, Aib, Leu, lie, Tie, Nle, Cha, Ala, Phe, Abu, Lys or X1-Phe;

A34 is Lys, Arg, hArg, Orn, HN-CH((CH2)n-N(R10R11))-C(O) or HN-CH((CH2)e-X3)-C(O);

A35 is Gly, β-Ala, D-Ala, Gaba, Ava, HN-(CH2)m-C(O), Aib, Aec or a D-amino acid; A36 is L- or D-Arg, D- or L-Lys, D- or L-hArg, D- or L-Orn, HN-CH((CH2)n-N(R10R11))-C(O), HN-CH((CH2)e-X3)-C(O) or deleted;

A37 is Gly, β-Ala, Gaba, Ava, Aib, Ace, Ado, Arg, Asp, Aun, Aec, HN-(CH2)m-C(O), HN-CH((CH2)n-N(R10R11))-C(O), a D-amino acid, or deleted;

A38 is D- or L-Lys, D- or L-Arg, D- or L-hArg, D- or L-Orn, HN-CH((CH2)n-N(R10R11))-C(O), HN-CH((CH2)e-X3)-C(O) Ava, Ado, Aec or deleted;

A39 is D- or L-Lys, D- or L-Arg, HN-CH((CH2)n-N(R10R11))-C(O), Ava, Ado, or Aec; X1 for each occurrence is independently selected from the group consisting of (C,-C6)alkyl, OH and halo;

R1 is OH, NH2, (C1-C30)alkoxy, or NH-X2-CH2-Z0, wherein X2 is a (C1- C12)hydrocarbon moiety, and Z° is H, OH, CO2H or CONH2;

or -C(O)-NHR12, wherein X4 is, independently for each occurrence, -C(O)-, -NH- C(O)- or -CH2-, and wherein f is, independently for each occurrence, an integer from 1 to 29 inclusive;

each of R2 and R3 is independently selected from the group consisting of H, (C1- C30)alkyl, (C2-C30)alkenyl, phenyl(C1-C30)alkyl, naphthyl(C1-C30)alkyl, hydroxy(C1- C30)alkyl, hydroxy(C2-C30)alkenyl, hydroxypheny(C1-C30) alkyl, and

hydroxynaphthyl(C1-C30)alkyl; or one of R2 and R3 is
r

C30)acyl, (C1-C30) alkylsulfonyl, C(O)X5,

; wherein Y is H, OH or NH2; r is 0 to 4; q is 0 to 4; and X5 is (C1-C30)alkyl, (C2-C30)alkenyl, phenyl(C1-C30)alkyl, naphthyl(C1-C30)alkyl, hydroxy(C1-C30)alkyl, hydroxy(C2-C30)alkenyl, hydroxypheny(C1-C30) alkyl or hydroxynaphthyl(C1-C30)alkyl;

e is, independently for each occurrence, an integer from 1 to 4 inclusive;

m is, independently for each occurrence, an integer from 5 to 24 inclusive;

n is, independently for each occurrence, an integer from 1 to 5, inclusive;

each of R10 and R11 is, independently for each occurrence, H, (C1-C30)alkyl, (C1- C30)acyl, (C1-C30)alkylsulfonyl, -C((NH)(NH2)) or

;

R12 and R13 each is, independently for each occurrence, (C1-C30)alkyl;

provided that:

when A7 is Ura, Paa or Pta, then R2 and R3 are deleted;

when R10 is (C1-C30)acyl, (C1-C30)alkylsulfonyl, -C((NH)(NH2)) or

, then R11 is H or (C1-C30)alkyl;

(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, -37 or -38)NH2 or hGLP-1 (7-36, -37 or -38)OH; (ii) a compound of formula (I) is not an analogue of hGLP-1 (7-36, -37 or -38)NH2 or hGLP-1 (7-36, -37 or -38)OH wherein a single position has been substituted by Ala; (iii) a compound of formula (I) is not (Arg26,34, Lys38)hGLP-1 (7-38)-E, (Lys26(Nέ- alkanoyl))hGLP-1 (7-36, -37 or -38)-E, (Lys34(Nε-alkanoyl))hGLP-1 (7-36, -37 or - 38)-E, (Lys26,34-bis(NE-alkanoyl))hGLP-1 (7-36, -37 or -38)-E, (Arg26, Lys34(Nε- alkanoyl))hGLP-1 (8-36, -37 or -38)-E, (Arg26,34, Lys36(Nε-alkanoyl))hGLP-1 (7-36, -37 or -38)-E or (Arg26,34, Lys38(Nε-alkanoyl))hGLP-1 (7-38)-E, wherein E is -OH or -NH2; (iv) a compound of formula (I) is not Z1-hGLP-1 (7-36, -37 or -38)-OH, Z1-hGLP-1 (7- 36, -37 or -38)-NH2, wherein Z1 is selected from the group consisting of:

(a) (Arg26), (Arg34), (Arg26,34), (Lys36), (Arg26, Lys36), (Arg34, Lys36), (D-Lys36), (Arg36), (D-Arg36), (Arg26,34, Lys36) or (Arg26,36, Lys34);

(b) (Asp21);

(c) at least one of (Aib8), (D-Ala8) and (Asp9); and

(d) (Tyr7), (N-acyl-His7), (N-alkyl-His7), (N-acyl-D-His7) or (N-alkyl-D-His7);

(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-Ala8)hGLP-1 (8-36 or -37), (Glu15)hGLP- 1 (7-36 or -37), (Asp21)hGLP-1(7-36 or -37) or (Phe31)hGLP-1 (7-36 or -37) or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing compound is where A11 is Thr; A13 is Thr; A15 is Asp; A17 is Ser; A18 is Ser or Lys; A21 is Glu; A23 is Gin or Glu; A27 is Glu, Leu, Aib or Lys; and A31 is Trp, Phe or β-Nal; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A9 is Glu, N-Me-Glu or N-Me-Asp; A12 is Phe, Ace, β-Nal or Aic; A16 is Val, Aec or Aib; A19 is Tyr or β-Nal; A20 is Leu, Aec or Cha; A24 is Ala, Aib or Aec; A25 is Ala, Aib, Ace, Lys, Arg, hArg, Orn, HN-CH((CH2)n-N(R10R11))-C(O) or HN-CH((CH2)e-X3)-C(O); A28 is Phe or β-Nal; A29 is lie or Ace; A30 is Ala or Aib; A32 is Leu, Ace or Cha; and A33 is Val, Lys or Ace; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A8 is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A10 is Gly; A12 is Phe, β-Nal, A6c or A5c; A16 is Val, A6c or A5c; A20 is Leu, A6c, A5c or Cha; A22 is Gly, β-Ala, Glu or Aib; A24 is Ala or Aib; A29 is lle, A6c or A5c; A32 is Leu, A6c, A5c or Cha; A33 is Val, Lys, A6c or A5c; A35 is Aib, β-Ala, Ado, A6c, A5c, D-Arg or Gly; and A37 is Gly, Aib, β-Ala, Ado, D-Ala Ava, Asp, Aun, D-Asp, D-Arg, Aec, HN-CH((CH2)n-N(R10R11))-C(O) or deleted; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where X4 for each occurrence is -C(O)-; and R1 is OH or NH2; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds or a pharmaceutically acceptable salt thereof is where R2 is H and R3 is (C1-C30) alkyl, (C2-C30)alkenyl, (C1-C30)acyl, (C1-C30)alkylsulfonyl,


A preferred compound of the formula (I) is where A8 is Ala, D-Ala, Aib, A6c,

A5c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A10 is Gly; A12 is Phe, β-Nal A6c or A5c; A16 is Val, A6c or A5c; A20 is Leu, A6c, A5c or Cha; A22 is Gly, β-Ala, Glu or Aib; A24 is Ala or Aib; A29 is lie, A6c or A5c; A32 is Leu, A6c, A5c or Cha; A33 is Val, Lys, A6c or A5c; A35 is Aib, β-Ala, Ado, A6c, A5c D-Arg or Gly; and A37 is Gly, Aib, β-Ala, Ado, D-Ala, Ava, Asp, Aun, D-Asp, D-Arg, Aec, HN-CH((CH2)n-N(R10R11))-C(O) or deleted; X4 for each occurrence is -C(O)-; e for each occurrence is independently 1 or 2; R1 is OH or NH2; R10 is (C1-C30)acyl, (C1-C30)alkylsulfonyl or

, and R11 is H; or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing compounds is where R10 is (C4-

C20)acyl, (C4-C20)alkylsulfonyl or
, or a pharmaceutically acceptable salt thereof.

A more preferred compound of formula (I) is where said compound is of the formula:

(Aib8,35)hGLP-1 (7-36)NH2,

((Nα-HEPES-His)7, Aib8,35)hGLP-1 (7-36)NH2,

((Nα-HEPA-His)7, Aib8,35)hGLP-1 (7-36)NH2,

(Aib8, β-Ala35)hGLP-1 (7-36)NH2,

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2,

(Aib8,35, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2,

(Aib8,35,37, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1(7-38)NH2,

(Aib8,35, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2,

(Aib8 ,35, Arg26,34, Lys36(Nε-dodecanesulfonyl))hGLP-1 (7-36)NH2,

(Aib8 ,35, Arg26,34, Lys36(Nε-(2-(4-tetradecyl-1 -piperazine)-acetyl)))hGLP-1 (7-36)NH2,

(Aib8,35, Arg26,34, Asp36(1-(4-tetradecyl-piperazine)))hGLP-1 (7-36)NH2,

(Aib8 ,35, Arg26,34, Asp36(1-tetradecylamino))hGLP-1 (7-36)NH2,

(Aib8 ,35, Arg26,34, Lys36(Nε-tetradecanoyl),β-Ala37)hGLP-1 (7-37)-OH or

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)-OH,

or a pharmaceutically acceptable salt thereof .

More preferred of the immediately foregoing group of compounds is a compound of the formula:

(Aib8,35)hGLP-1 (7-36)NH2,

(Aib8, β-Ala35)hGLP-1 (7-36)NH2,

(Aib8,35, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2,

(Aib8,35,37, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)NH2,

(Aib8,35, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2, or

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl),β-Ala37)hGLP-1 (7-37) -OH, or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) is where said compound is of the formula:

(Aib8,35, A6c32)hGLP-1 (7-36)NH2;

(Aib8,35, Glu23)hGLP-1 (7-36)NH2;

(Aib8,24,35)hGLP-1 (7-36)NH2;

(Aib8,35, Glu23, A6c32)hGLP-1 (7-36)NH2;

(Aib8, Glu23, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8,35, Arg26,34)hGLP-1 (7-36)NH2;

(Aib8,35, Arg26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2;

(Aib8,35, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)OH;

(Aib8,35, Lys25, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)OH;

(Aib8, Arg26,34, β-Ala35, Lys36(Nε-Aec-decanoyl))hGLP-1 (7-36)NH2;

(Aib8,35,Arg26'34, Ava37, Ado38)hGLP-1 (7-38)NH2;

(Aib8,35,Arg26,34, Asp37, Ava38, Ado39)hGLP-1 (7-39)NH2;

(Aib8,35,Arg26,34, Aun37)hGLP-1 (7-37)NH2;

(Aib8,17,35,)hGLP-1 (7-36)NH2;

(Aib8 ,Arg26,34, β-Ala35, D-Asp37, Ava38, Aun39)hGLP-1 (7-39)NH2;

(Gly8, β-Ala35)hGLP-1 (7-36)NH2;

(Ser8, β-Ala35)hGLP-1(7-36)NH2;

(Aib8, Glu22,23, β-Ala35)hGLP-1(7-36)NH2;

(Gly8, Aib35)hGLP-1 (7-36)NH2;

(Aib8, Lys18, β-Ala35)hGLP-1(7-36)NH2;

(Aib8, Leu27, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8, Lys33, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8, Lys18, Leu27, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8, D-Arg36)hGLP-1 (7-36)NH2;

(Aib8, β-Ala35, D-Arg37)hGLP-1 (7-37)NH2;

(Aib8,27, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8,27, β-Ala35,37, Arg38)hGLP-1 (7-38)NH2;

(Aib8,27, β-Ala35,37, Arg38,39)hGLP-1 (7-39)NH2;

(Aib8, Lys18,27, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8, Lys27, β-Ala35)hGLP-1 (7-36)NH2;

(Aib8, β-Ala35, Arg38)hGLP-1 (7-38)NH2;

(Aib8, Arg26,34, β-Ala35,)hGLP-1 (7-36)NH2;

(Aib8, D-Arg35)hGLP-1 (7-36)NH2;

(Aib8, β-Ala35, Arg37)hGLP-1 (7-37)NH2;

(Aib8, Phe31, β-Ala35)hGLP-1(7-36)NH2;

(Aib8,35, Phe31)hGLP-1 (7-36)NH2;

(Aib8,35, Nal31)hGLP-1(7-36)NH2;

(Aib8,35, Nal28,31)hGLP-1 (7-36)NH2;

(Aib8,35, Arg26,34, Nal31)hGLP-1 (7-36)NH2;

(Aib8,35, Arg26,34, Phe31)hGLP-1 (7-36)NH2;

(Aib8,35, Nal19,31)hGLP-1 (7-36)NH2;

(Aib8,35, Nal12,31)hGLP-1 (7-36)NH2;

(Aib8,35, Lys36(Nε-decanoyl))hGLP-1 (7-36) NH2;

(Aib8,35, Arg34, Lys26(Nε-decanoyl))hGLP-1(7-36)NH2;

(Aib8,35, Arg26,34, Lys36(Nε-dodecanoyl))hGLP-1 (7-36)NH2;

(Aib8,B-Ala35, Ser37 O-decanoyl)) hGLP1 (7-37)-NH2;

(Aib827, β-Ala35,37, Arg38, Lys39(Nε-octanoyl))hGLP-1 (7-39)NH2;

(Aib8, Arg26,34, β-Ala35, Lys37(Nε-octanoyl))hGLP-1 (7-37)NH2;

(Aib8, Arg26,34, β-Ala35, Lys37(Nε-decanoyl))hGLP-1 (7-37)NH2; or

(Aib8, Arg26,34, β-Ala35, Lys37(Nε-tetradecanoyl))hGLP-1 (7-37)NH2;

or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula (I) is each of the compounds that are specifically enumerated hereinbelow in the Examples section of the present disclosure, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

In yet another aspect, the present invention provides 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 of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides 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, hypertension, and disorders wherein the reduction of food intake is desired, in a subject in need thereof which comprises administering to said subject an effective amount of a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof. A preferred method of the immediately foregoing method is where the disease being treated is Type I diabetes or Type II diabetes.

With the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure of -NH-CH(R)-CO-, wherein R is the side chain of an amino acid (e.g., CH3 for Ala). For the N-terminal amino acid, the abbreviation stands for 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 or Pta, in which case R2 and R3 are not present since Ura, Paa and Pta are considered here as des-amino amino acids. Amp, β-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 α-aminoisobutyric acid, respectively. Other amino acid definitions are: Ura is urocanic acid; Pta is (4-pyridylthio) acetic acid; Paa is frans-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 tert-butylglycine; Abu is α-aminobutyric acid; Tba is tetf-butylalanine; Orn is omithine; Aib is α-aminoisobutyric acid; β-Ala is β-alanine; Gaba is γ-aminobutyric acid; Ava is 5-aminovaleric acid; Ado is 12-aminododecanoic acid, Aic is 2-aminoindane-2-carboxylic acid; Aun is 11-aminoundecanoic acid; and Aec is 4-(2-aminoethyl)-1-carboxymethyl-piperazine,


represented by the structure:

What is meant by Aec 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-cyciohexanecarboxylic acid (A6c); 1-amino-1-cycloheptanecarboxylic acid (A7c); 1-amino-1-

cyclooctanecarboxylic acid (A8c); and 1-amino-1-cyclononanecarboxylic acid (A9c). In the above formula, hydroxyalkyl, hydroxyphenylalkyl, and hydroxynaphthylalkyl may contain 1-4 hydroxy substituents. COX5 stands for -C=O ·X5. Examples of -C=O ·X5 include, but are not limited to, acetyl and phenylpropionyl.

What is meant by Lys(Nε-alkanoyl) is represented by the following structure:


What is meant by Lys(Nε-alkylsulfonyl) is

represented by the following structure:
. What is meant by Lys(Nε-(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:
What is meant by Lys(Nε-Aec-alkanoyl) is represented by the structure:

The variable n in the foregoing structures is 1-30. What is meant by Lys (Nε-ace-alkanoyI) is represented by the structure:


The full names for other abbreviations used herein are as follows: Boc for t-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-(1 H-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, OcHex for O-cyclohexyl, Fmoc for 9-fluorenylmethoxycarbonyl, HOBt for N-hydroxybenzothazole and PAM resin for 4-hydroxymethylphenylacetamidomethyl resin.

The term "halo" encompasses fluoro, chloro, bromo and iodo.

The term "(C1-C30)hydrocarbon moiety" encompasses alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there are C2-C30.

A peptide of this invention is also denoted herein by another format, e.g., (A5c8)hGLP-1 (7-36)NH2, with the substituted amino acids from the natural sequence placed between the first set of parentheses (e.g., A5c8 for Ala8 in hGLP-1 ). The abbreviation GLP-1 means glucagon-like peptide-1 ; hGLP-1 means human glucagon-like peptide-1. The numbers between the parentheses refer to the number of amino acids present in the peptide (e.g., hGLP-1 (7-36) is amino acids 7 through 36 of the peptide sequence for human GLP-1 ). The sequence for hGLP-

1 (7-37) is listed in Mojsov, S., Int. J. Peptide Protein Res,. 40, 1992, pp. 333-342. The designation "NH2" in hGLP-1 (7-36)NH2 indicates that the C-terminus of the peptide is amidated. hGLP-1 (7-36) means that the C-terminus is the free acid. In hGLP-1 (7-38), residues in positions 37 and 38 are Gly and Arg, respectively.

Detailed Description

The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R2 and R3 of the above generic formula may be attached to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, e.g., (C1-C30)alkyl, may be attached using reductive alkylation. Hydroxyalkyl groups, e.g., (d-C30)hydroxyalkyl, may also be attached using reductive alkylation wherein the free hydroxy group is protected with a t-butyl ester. Acyl groups, e.g., COE1, may be attached by coupling the free acid, e.g., E1COOH, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxy group, e.g., p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBT.

When R1 is NH-X2-CH2-CONH2, (i.e., Z0=CONH2), the synthesis of the peptide starts with BocHN-X2-CH2-COOH which is coupled to the MBHA resin. If R1 is NH-X2-CH2-COOH, (i.e., Z0=COOH) the synthesis of the peptide starts with Boc-HN-X2-CH2-COOH which is coupled to PAM resin. For this particular step, 4 molar equivalents of Boc-HN-X2-COOH, HBTU and HOBt and 10 molar equivalents of DIEA are used. The coupling time is about 8 hours.

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) was dissolved in 200 ml of dioxane and 100 ml of water. To it was added 67 ml of 2N NaOH. The solution was cooled in an ice-water bath. 32.0 g (0.147 mol) of di-tert-butyl-dicarbonate was added to this solution. The reaction mixture was stirred overnight at room temperature. Dioxane was then removed under reduced pressure. 200 ml of ethyl acetate was added to the remaining aqueous solution. The mixture was cooled in an ice-water bath. The pH of the aqueous layer was adjusted to about 3 by adding 4N 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 MgSO4, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized in ethyl acetate/hexanes. 9.2 g of the pure product was obtained. 29% yield.

Boc-A5c-OH was synthesized in an analogous manner to that of Boc-A6c-OH. Other protected Aec amino acids can be prepared in an analogous manner by a person of ordinary skill in the art as enabled by the teachings herein.

In the synthesis of a GLP-1 analogue of this invention containing A5c, A6c and/or Aib, the coupling time is 2 hrs. for these residues and the residue immediately following them. For the synthesis of (Tma-His7)hGLP-1 (7-36)NH2, HBTU (2 mmol) and DIEA (1.0 ml) in 4 ml DMF are used to react with the N-terminal free amine of the peptide-resin in the last coupling reaction; the coupling time is about 2 hours.

The substituents R2 and R3 of the above generic formula can be attached to the free amine of the N-terminal amino acid by standard methods known in the art. For example, alkyl groups, e.g., (C1-C30)alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups, e.g., (C1-C30)hydroxyalkyl, can also be attached using reductive alkylation wherein the free hydroxy group is protected with a t-butyl ester. Acyl groups, e.g., COX1, can be attached by coupling the free acid, e.g., X1COOH, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for about one hour. If the free acid contains a free hydroxy group, e.g., p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBT.

A compound of the present invention can be tested for activity as a GLP-1 binding compound according to the following procedure.

Cell Culture:

RIN 5F rat insulinoma cells (ATCC-# CRL-2058, American Type Culture Collection, Manassas, VA), expressing the GLP-1 receptor, were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum, and maintained at about 37 °C in a humidifed atmosphere of 5% CO2/95% air.

Radioligand Binding:

Membranes were prepared for radioligand binding studies by

homogenization of the RIN cells in 20 ml of ice-cold 50 mM Tris-HCl with a Brinkman Polytron (Westbury, NY) (setting 6, 15 sec). The homogenates were washed twice by centrifugation (39,000 g / 10 min), and the final pellets were resuspended in 50 mM Tris-HCl, containing 2.5 mM MgCI2, 0.1 mg/ml bacitracin (Sigma Chemical, St. Louis, MO), and 0.1% BSA. For assay, aliquots (0.4 ml) were incubated with 0.05 nM (125l)GLP-1 (7-36) (-2200 Ci/mmol, New England Nuclear, Boston, MA), with and without 0.05 ml of unlabeled competing test peptides. After a 100 min incubation (25 °C), the bound (125l)GLP-1 (7-36) was separated from the free by rapid filtration through GF/C filters (Brandel, Gaithersburg, MD), which had been previously soaked in 0.5% polyethyleneimine. The filters were then washed three times with 5 ml aliquots of ice-cold 50 mM Tris-HCl, and the bound radioactivity trapped on the filters was counted by gamma spectrometry (Wallac LKB, Gaithersburg, MD). Specific binding was defined as the total (125l)GLP-1 (7-36) bound minus that bound in the presence of 1000 nM GLP1 (7-36) (Bachem, Torrence, CA).

The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids). A typical method of making a salt of a peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax, 300 SB, C-8). The column is eluted with (1 ) 0.1 N ammonium acetate aqueous solution for 0.5 hrs., (2) 0.25N acetic acid aqueous solution for 0.5 hrs. and (3) a linear gradient (20% to 100% of solution B over 30 min.) at a flow rate of 4 ml/min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile/water, 80:20). The fractions containing the peptide are collected and lyophilized to dryness.

As is well known to those skilled in the art, the known and potential uses of GLP-1 is varied and multitudinous (See, Todd, J.F., et al., Clinical Science, 1998, 95, pp. 325-329; and Todd, J.F. et al., European Journal of Clinical Investigation, 1997, 27, pp.533-536). Thus, the administration of the compounds of this invention for purposes of eliciting an agonist effect can have the same effects and uses as GLP-1 itself. These varied uses of GLP-1 may be summarized as follows, treatment of: Type I diabetes, Type II diabetes, obesity, glucagonomas, secretory disorders of the airway, metabolic disorder, arthritis, osteoporosis, central nervous system diseases, restenosis, neurodegenerative diseases, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake is desired. GLP-1 analogues of the present invention that elicit an antagonist effect from a subject can be used for treating the following: hypoglycemia and malabsorption syndrome associated with gastroectomy 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 formula (I) in association with a pharmaceutically acceptable carrier.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. In general, an effective dosage for the activities of this invention is in the range of 1x10-7 to 200 mg/kg/day, preferably 1x10-4 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 oral, parenteral

(e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating

agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or 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. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other 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 coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.

Further, 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 No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. Application No. 08/929,363 filed September 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. Application No. 08/740,778 filed November 1 , 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextrin. U.S. Application No. 09/015,394 filed January 29, 1998, teaches absorbable sustained release

compositions of a bioactive agent. U.S. Application No. 09/121 ,653 filed July 23, 1998, teaches a process for making microparticles comprising a therapeutic agent such as a peptide in an oil-in-water process. U.S. Application No. 09/131 ,472 filed August 10, 1998, teaches complexes comprising a therapeutic agent such as a peptide and a phosphorylated polymer. U.S. Application No. 09/184,413 filed November 2, 1998, teaches complexes comprising a therapeutic agent such as a peptide and a polymer bearing a non-polymerizable lactone. The teachings of the foregoing 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 one of ordinary skill in the art to which this invention belongs. 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 methods are well-known to those skilled in the art. Other methods are also known to those skilled in the art. The examples are provided for the purpose of illustration and is not meant to limit the scope of the present invention in any manner.

Boc-βAla-OH, Boc-D-Arg(Tos)-OH and Boc-D-Asp(OcHex) were purchased from Nova Biochem, San Diego, California. Boc-Aun-OH was purchased from Bachem, King of Prussia, PA. Boc-Ava-OH and Boc-Ado-OH were purchased from Chem-lmpex International, Wood Dale, IL. Boc-Nal-OH was purchased from Synthetech, Inc. Albany, OR.

Example 1

(Aib8,35)hGLP-1 (7-36)NH2

The title peptide was synthesized on an Applied Biosystems (Foster City,

CA) model 430A peptide synthesizer which was modified to do accelerated Boc-chemistry solid phase peptide synthesis. See Schnolzer, et al., Int. J. Peptide Protein Res., 90:180 (1992). 4-methylbenzhydrylamine (MBHA) resin (Peninsula, Belmont, CA) with the substitution of 0.91 mmol/g was used. The Boc amino acids (Bachem, CA, Torrance, CA; Nova Biochem., LaJolla, 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-lle-OH, Boc-Lys(2CIZ)-OH, Boc-Thr(Bzl)-OH, Boc-Ser(Bzl)-OH, Boc-Phe-OH, Boc-Aib-OH, Boc-Glu(OcHex)-OH and Boc-Trp(Fm)-OH. The

synthesis was carried out on a 0.20 mmol scale. The Boc groups were removed by treatment with 100% TFA for 2 x 1 min. Boc amino acids (2.5 mmol) were pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF and were coupled without prior neutralization of the peptide-resin TFA salt. Coupling times were 5 min. except for the Boc-Aib-OH residues and the following residues, Boc-Lys(2CIZ)-OH and Boc-His(DNP)-OH wherein the coupling times were 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 on 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 1 min), the formyl group on the side chain of Trp was removed by treatment with a solution of 15% ethanolamine/ 15% water/ 70% DMF for 2 x 30 min. The peptide-resin was washed with DMF and DCM and dried under reduced pressure. The final cleavage was done by stirring the peptide-resin in 10 mL of HF containing 1 mL of anisole and dithiothreitol (24 mg) at 0°C for 75 min. 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 on reverse-phase preparative high pressure liquid chromatography (HPLC) using a reverse phase VYDAC® C18 column (Nest Group, Southborough, MA). The column was eluted with a linear gradient (20% to 50% of solution B over 105 min.) at a flow rate of 10 mL/min (Solution A = water containing 0.1 % TFA; Solution B = acetonithle containing 0.1% of TFA). Fractions were collected and checked on analytical HPLC. Those containing pure product were combined and lyophilized to dryness. 135 mg of a white solid was obtained. Purity was 98.6% based on analytical HPLC analysis. Electro-spray mass spectrometer (MS(ES))S analysis gave the molecular weight at 3339.7 (in agreement with the calculated molecular weight of 3339.7).

Example 2

((Nα-HEPES-His)7, Aib8,35)hGLP-1 (7-36)NH2 The title compound (HEPES is (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid)) can be synthesized as follows: after assembly of the peptide (Aib8,35)hGLP-1 (7-36)NH2 on MBHA resin (0.20 mmol) according to the procedure of Example 1 , 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 2 min.

After washing with DMF and DCM, the resin is treated with 0.23 mmol of 2-chloro-1-ethanesulfonyl chloride and 0.7 mmol of DIEA in DMF for about 1 hour. The resin is washed with DMF and DCM and treated with 1.2 mmol 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 on the His side chain and formyl group on the Trp side chain as described above before the final HF cleavage of the peptide from the resin.

Example 3

((Nα-HEPA-His)7, Aib8,35)hGLP-1 (7-36)NH2

The title compound (HEPA is (4-(2-hydroxyethyl)-1-piperazineacetyl)) can be made substantially according to the procedure described in Example 2 for making ((Nα-HEPES-His)7, Aib8,35)hGLP-1(7-36)NH2 except that 2-bromoacetic anhydride is used in place of 2-chloro-1-ethanesulfonyl chloride.

Example 4

(Aib8, β-Ala35)hGLP-1 (7-36)NH2

The title compound was synthesized substantially according to the procedure described for Example 1 using the appropriate protected amino acids. MS (ES) gave the molecular weight at 3325.7, calculated MW = 3325.8, purity = 99%, yield = 85 mg.

The synthesis of other compounds of the present invention can be accomplished in substantially the same manner as the procedure described for the synthesis of (Aib8'35)hGLP-1(7-36)NH2 in Example 1 above, but using the appropriate protected amino acids depending on the desired peptide.

Example 5

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 The Boc amino acids used were the same as those in the synthesis of (Aib8,35)hGLP-1(7-36)NH2 described in Example 1 except that Fmoc-Lys(Boc)-OH was used in this example. The first amino acid residue was coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OH was dissolved in 4 mL of 0.5N HBTU in DMF. To the solution was added 1 mL of DIEA. The mixture was shaken for about 2 min. To the solution was then added 0.2 mmol of MBHA resin (substitution = 0.91 mmol/g). The mixture was shaken for about 1 hr. The resin was washed with DMF and treated with 100% TFA for 2x2 min to remove the Boc

protecting group. The resin was washed with DMF. Myristic acid (2.5 mmol) was pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF for 2 min and was coupled to the Fmoc-Lys-resin. The coupling time was about 1 hr. The resin was washed with DMF and treated with 25% pipehdine in DMF for 2x20 min to remove the Fmoc protecting group. The resin was washed with DMF and transferred to the reaction vessel of the peptide synthesizer. The following steps synthesis and purification procedures for the peptide were the same as those in the synthesis of (Aib8,35)hGLP-1 (7-36)NH2 in Example 1. 43.1 mg of the title compound were obtained as a white solid. Purity was 98% based on analytical HPLC analysis. Electro-spray mass spectrometer analysis gave the molecular weight at 3577.7 in agreement with the calculated molecular weight 3578.7.

Examples 6-8

Examples 6-8 were synthesized substantially according to the procedure described for Example 5 using the appropriate protected amino acid and the appropriate acid in place of the Myristic acid used in Example 5.

Example 6: (Aib8,35, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2; Yield = 89.6 mg; MS(ES) = 3577.2, Calculated MW = 3578.7; Purity 96%.

Example 7: (Aib8,35,37, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)NH2; Yield = 63.3 mg; MS(ES) = 3818.7; Calculated MW = 3819.5; Purity 96%.

Example 8: (Aib8,35, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2; Yield = 57.4 mg; MS(ES) = 3521.5; Calculated MW = 3522.7; Purity 98%; Acid = decanoic acid.

The syntheses of other compounds of the present invention containing Lys(Nε-alkanoyl) residue can be carried out in an analogous manner to the procedure described for Example 5, (Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1(7-36)NH2. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(Nε-alkanoyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. If the Lys(Nε-alkanoyl) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(Nε-alkanoyl) residue is assembled on the resin on the peptide synthesizer first. The appropriate acid corresponding to the desired alkanoyl can be purchased from Aldrich Chemical Co., Inc. Milwaukee, Wl, USA, e.g., octanoic acid, decanoic acid, lauric acid and palmitic acid.

Example 9

(Aib8,35, Arg26,34, Lys36(Nε-dodecanesulfonyl))hGLP-1 (7-36)NH2

The Boc amino acids to be used in this synthesis are the same as those used in the synthesis of Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OH is dissolved in 4 mL of

0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA resin(substitution

= 0.91 mmol/g). The mixture is shaken for about 1 hr. The resin is washed with

DMF and treated with 100% TFA for 2x2 min to remove the Boc protecting group. The resin is washed with DMF and to it is added 0.25 mmol of 1-dodecanesulfonyl chloride in 4 mL of DMF and 1 mL of DIEA. The mixture is shaken for about 2 hrs.

The resin is washed with DMF and treated with 25% piperidine in DMF for 2 x 20 min to remove the Fmoc protecting group. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer. The synthesis of the rest of the peptide and purification procedures are the same as those described in

Example 1.

The syntheses of other compounds of the present invention containing Lys(Nε-alkylsulfonyl) residue can be carried out in an analogous manner to the procedure described in Example 9. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(Nε-alkylsulfonyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. If the Lys(Nε-alkylsulfonyl) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(Nε-alkylsulfonyl) residue is assembled on the resin on the peptide synthesizer first. The appropriate akylsulfonyl chloride can be obtained from Lancaster Synthesis Inc., Windham, NH, USA, e.g., 1-octanesulfonyl chloride, 1-decanesulfonyl chloride, 1-dodecanesulfonyl chloride, 1-hexadecanesulfonyl chloride and 1-octadecylsulfonyl chloride.

Example 10

(Aib8,35, Arg26,34, Lys36(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2 The Boc amino acids to be used for this example are the same as those used in the synthesis of Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Lys(Boc)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution =

0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2x2 min to remove the Boc protecting group. The resin is washed with DMF. The 2-bromoacetic acid (2.5 mmol) is pre-activated with HBTU (2.0 mmol) and DIEA (1 mL) in 4 mL of DMF for about 2 min and is added to the resin. The mixture is shaken for about 10 min and washed with DMF. The resin is then treated with 1.2 mmol of piperazine in 4 mL of DMF for about 2 hrs. The resin is washed with DMF and treated with 2 mmol of 1 -iodotetradecane for about 4 hrs. After washing with DMF, the resin is treated with 3 mmol of acetic anhydride and 1 mL of DIEA in 4 mL of DMF for about 0.5 hr. The resin is washed with DMF and treated with 25% piperidine in DMF for 2x20 min. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide are the same as the procedures described for Example 1.

The syntheses of other compounds of the present invention containing Lys(Nε-(2-(4-alkyl-1-piperazine)-acetyl)) residue are carried out in an analogous manner as the procedure described for the synthesis of Example 10. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(Nε-(2-(4-alkyl-1-piperazine)-acetyl)) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. The corresponding iodoalkane is used for the residue of Lys(Nε-(2-(4-alkyl-1-piperazine)-acetyl)) during the alkylation step. If the Lys(Nε-(2-(4-alkyl-1-piperazine)-acetyl)) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(Nε-(2-(4-alkyl-1-piperazine)-acetyl)) residue is assembled on the resin on the peptide synthesizer first.

Example 11

(Aib8,35, Arg26,34, Asp36(1-(4-tetradecyl-piperazine)))hGLP-1 (7-36)NH2

The Boc amino acids to be used in this example are the same as the amino acids used in synthesis of Example 5 except Fmoc-Asp(O-tBu)-OH is used at position 36. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution = 0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2x15 min to remove the tBu protecting group. The resin is washed with DMF and is treated with HBTU (0.6 mmol) and DIEA (1 mL) in 4 mL of DMF for about 15 min. 0.6 mmol of piperazine is added to the reaction mixture and the mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 3 mmol of 1-iodotetradecane for about 4 hrs. After washing with DMF, the resin is treated with 3 mmol of acetic anhydride and 1 mL of DIEA in 4 mL of DMF for about 0.5 hr. The resin is washed with DMF and treated with 25% piperidine in DMF for 2x20 min to remove the Fmoc protecting group. The resin is washed with DMF and transferred to the reaction vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide are the same as those for the synthesis of Example 1.

The syntheses of other compounds of the present invention comprising

Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue are carried out in an analogous manner as the procedure described for the synthesis of Example 11. Fmoc-Asp(O-tBu)-OH or Fmoc-Glu(O-tBu)-OH amino acid is used for the residue of Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) in the peptide, while Boc-Asp(OcHex)-OH or Boc-Glu(OcHex)-OH amino acid is used for the residue of Asp or Glu. The corresponding iodoalkane is used for the residue of Lys(Nε-(2-(4-alkyl-1-piperazine)-acetyl)) during the alkylation step. If the Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue is not at the C-terminus, the peptide fragment immediately prior to the Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue is assembled on the resin on the peptide synthesizer first.

Example 12

(Aib8,35, Arg26,34, Asp36(1-tetradecylamino))hGLP-1 (7-36)NH 2

The Boc amino acids to be used for this example are the same as those used in Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution = 0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2x15 min to remove the t-Bu protecting group. The resin is washed with DMF and is treated with HBTU (0.6 mmol) and DIEA (1 mL) in 4 mL of DMF for about 15 min. 0.6 mmol of 1-tetradecaneamine is added to the reaction mixture and the mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 25% piperidine in DMF for 2x20 min to remove the Fmoc protecting group. The resin is washed with DMF and transferred to the reaction

vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide of this example are the same as those described for the synthesis of Example 1.

The syntheses of other compounds of the present invention containing Asp(1-alkylamino) or Glu(1-alkylamino) residue are carried out in an analogous manner as described for the synthesis of Example 12. Fmoc-Asp(O-tBu)-OH or Fmoc-Glu(O-tBu)-OH amino acid is used for the residue of Asp(1-alkylamino) or Glu(1-alkylamino), respectively, in the peptide, while Boc-Asp(OcHex)-OH or Boc-Glu(OcHex)-OH amino acid is used for the residue of Asp or Glu, respectively. If the Asp(1-alkylamino) or Glu(1-alkylamino) residue is not at the C-terminus, the peptide fragment immediately prior to the Asp(1-alkylamino) or Glu(1-alkylamino) residue is assembled on the resin on the peptide synthesizer first.

Example 13

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl),β-Ala37)hGLP-1 (7-37)-OH

The Boc amino acids used are the same as those in the synthesis of

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 (Example 5). 270 mg of Boc-β-Ala-PAM resin (Novabiochem, San Diego, California, substitution=0.74 mmol/g) was used. The Boc protecting group on Boc-β-Ala-PAM resin was deblocked on a shaker with 100%TFA for 2x2 min first. The remainder of the synthesis and purification procedures were the same as that in Example 5. 83.0 mg of the title peptide was obtained as white solid. Purity was 99% based on analytical HPLC analysis. Electro-spray mass spectrometer analysis gave the molecular weight at 3650.5 in agreement with the calculated weight 3650.8.

Example 14

(Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)-OH

The Boc amino acids to be used are the same as those in the synthesis of (Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1(7-36)NH2 (Example 5). Fmoc-Lys(Boc)-OH (2.5 mmol) is pre-activated with HBTU (2.0 mmol), HOBt (2.0 mmol and DIEA (2.5 ml) in DMF (4 ml) for about 2 min. This amino acid is coupled to 235 mg of PAM resin (Chem-lmpex, Wood Dale, IL; substitution = 0.85 mmol/g) manually on a shaker. The coupling time is about 8 hrs. The remainder of the synthesis and purification procedures are the same as those in Example 5. Electro-spray mass spectrometer analysis gave the molecular weight at 3579.15 in agreement with the calculated weight 3579.5.

The syntheses of other analogs of hGLP-1 (7-36)-OH, hGLP-1 (7-37)-OH and hGLP-1 (7-38)-OH of the instant invention which contain Lys(Nε-alkanoyl) residue can be carried out in an analogous manner according to the procedure described for the synthesis of Example 14. Fmoc-Lys(Boc)-OH amino acid is used for the residue of Lys(Nε-alkanoyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys.

Example 366

(Aib8, β-Ala35, Aec37)hGLP-1(7-37)NH2

A mixture of MBHA resin (0.2mmol, substitution=0.91 mmol/g), Fmoc-Aec-OH (0.40g, 0.829 mmol), HBTU (1.5 mL @ 0.5M in DMF) and DIEA (0.5mL) in a reaction vessel was shaken on a shaker for 4h at room temperature. The resin was then washed with DMF and treated with 25% piperidine in DMF for 2X20min. The resin was washed with DMF and DCM and transferred to the reaction vessel of the peptide synthesizer to continue the assembly of the rest of the peptide according the procedure described for Example 1. The purification procedure was also the same as the one described in Example 1. Electro-spry mass spectrometer analysis gave the molecular weight at 3494.8 in agreement with the calculated molecular weight 3494.99. Purity 93%; Yield 79.1mg.

Example 367

(Aib8, β-Ala35, Aec38)hGLP-1 (7-38)NH2

Example 367 was synthesized substantially according to the procedure described for Example 366. MS(ES)=3551.7, calculated MW=3552.04; Purity 97%; Yield 97.4mg.

Example 368:

(Aib8, β-Ala35, Aec37,38)hGLP-1 (7-38)NH2

A mixture of MBHA resin (0.2mmol, substitution=0.91 mmol/g), Fmoc-Aec- OH (0.289g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA (0.4mL) in a reaction vessel was shaken on a shaker for 2h at room temperature. The resin was then washed with DMF and treated with 30% piperidine in DMF for 2X15min. The resin was washed with DMF. To the reaction vessel were added Fmoc-Aec-OH

(0.289g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA (0.4mL). The mixture was shaken at room temperature for 2h. The resin was washed with DMF and treated with 30% piperidine in DMF for 2X15min. The resin was washed with DMF and DCM and transferred to the reaction vessel of the peptide synthesizer to continue the assembly of the rest of the peptide according the procedure described for Example 1. The purification procedure was also the same as the one described in Example 1. Electro-spry mass spectrometer analysis gave the molecular weight at 3663.9 in agreement with the calculated molecular weight 3664.26. Purity 100%; Yield 75.3mg.

Example 369

(Aib8, Arg26,34, β-Ala35, Lys36(Nε-Aec-decanoyl))hGLP-1 (7-36)NH2

A mixture of MBHA resin (0.2mmol, substitution=0.91 mmol/g), Boc-Lys(Fmoc)-OH (1.17g, 2.5mmol), HBTU (4 mL @ 0.5M in DMF) and DIEA (1 mL) in a reaction vessel was shaken on a shaker at room temperature for 10min. The resin was washed with DMF and treated with 25% piperidine in DMF for 2X15min. The resin was washed with DMF. To the reaction vessel were added Fmoc-Aec-OH (0.289g, 0.6 mmol), HBTU (1.12 mL @ 0.5M in DMF) and DIEA (0.4mL). The mixture was shaken at room temperature for 10min. The resin was washed with DMF and treated with 30% piperidine in DMF for 2X15min. The resin was washed with DMF and treated with a mixture of decanoic acid (431 mg, 2.5 mmol), HBTU (4 mL @ 0.5M in DMF) and DIEA (1mL) for 10 min. The resin was washed with DMF and treated with 100% TFA for 2X2 min. The resin was washed with DMF and DCM and transferred to the reaction vessel of the peptide synthesizer to continue the assembly of the rest of the peptide according the procedure described for Example 1. The purification procedure was also the same as the one described in Example 1. Electro-spry mass spectrometer analysis gave the molecular weight at 3677.0 in agreement with the calculated molecular weight 3677.25. Purity 97.6%;Yield 44.8mg.

The following examples can be made according to the appropriate procedures described hereinabove.

Example 15 : (Aib35)hGLP-1 (7-36)NH2

Example 16: (β-Ala35)hGLP-1 (7-36)NH2

exempt 17: ((Nα-Me-His)7, Aib8,35)hGLP-1 (7-36)NH2

Example 18: ((Nα-Me-His)7, Aib8, β-Ala35)hGLP-1 (7-36)NH2

Example 19: ((Nα-Me-His)7, Aib8,35, Arg26,34)hGLP-1 (7-36)NH2

Example 20: ((Nα-Me-His)7, Aib8, Arg26,34, β-Ala35)hGLP-1 (7-36)NH2

Example 21 : (Aib8, A6c35)hGLP-1 (7-36)NH2

Example 22: (Aib8, A5c35)hGLP-1 (7-36)NH2

Example 23: (Aib8, D-Ala35)hGLP-1(7-36)NH2

Example 24: (Aib8,35, A6c32)hGLP-1 (7-36)NH2

Example 25: (Aib8,35, A5c32)hGLP-1(7-36)NH2

Example 26: (Aib8,35, Glu23)hGLP-1 (7-36)NH2

Example 27 : (Aib8,24,35)hGLP-1(7-36)NH2

Example 28: (Aib8,30,35)hGLP-1 (7-36)NH2

Example 29 : (Aib8,25,35)hGLP-1 (7-36)NH2

Example 30: (Aib8,35, A6c16,20)hGLP-1 (7-36)NH2

Example 31 : (Aib8,35, A6c16,29,32)hGLP-1 (7-36)NH2

Example 32: (Aib8,35, A6c20,32)hGLP-1 (7-36)NH2

Example 33: (Aib8,35, A6c20)hGLP-1(7-36)NH2

Example 34: (Aib8,35, Lys25)hGLP-1 (7-36)NH2

Example 35: (Aib8 ,24,35, A6c20)hGLP-1 (7-36)NH2

Example 36: (Aib8,35, A6c29,32)hGLP-1(7-36)NH2

Example 37: (Aib8,24 ,35, A6c29,32)hGLP-1 (7-36)NH2

Example 38: (Aib8,35, A6c12)hGLP-1(7-36)NH2

Example 39: (Aib8,35, Cha20)hGLP-1(7-36)NH2

Example 40: (Aib8,35, A6c33)hGLP-1 (7-36)NH2

example 41: (Aib8,35, A6c20,32)hGLP-1 (7-36)NH2

Example 42: (Aib8, A6c16,20, β-Ala35)hGLP-1 (7-36)NH2

Example 43: (Aib8,35, β-Ala22)hGLP-1 (7-36)NH2

Example 44 (Aib8,22,35)hGLP-1 (7-36)NH2

Example 45: (Aib8,35, Glu23, A6c32)hGLP-1(7-36)NH2

Exampie 46: (Aib82435, Glu23, A6c32)hGLP-1 (7-36)NH2

Exampie 47: (Aib8,24,25,35, Glu23, A6c32)hGLP-1 (7-36)NH2

Example 48: (Aib8,24,25,35, A6c16,20,32, Glu23)hGLP-1 (7-36)NH2

Example 49: (Aib8, A6c32, β-Ala35)hGLP-1 (7-36)NH2

Example 50: (Aib8, A5c32, β-Ala35)hGLP-1(7-36)NH2

Example 51 : (Aib8, Glu23, β-Ala35)hGLP-1 (7-36)NH2

Example 52: (Aib8,24, β-Ala35)hGLP-1 (7-36)NH2

Example 53: (Aib8,30, β-Ala35)hGLP-1 (7-36)NH2

Example 54: (Aib8,25, β-Ala35)hGLP-1 (7-36)NH2

Example 55: (Aib8, A6c16,20, β-Ala35)hGLP-1 (7-36)NH2

Example 56: (Aib8, A6c16,29,32, β-Ala35)hGLP-1 (7-36)NH2

Example 57: (Aib8, A6c20,32, β-Ala35)hGLP-1 (7-36)NH2

Example 58: (Aib8, A6c20, β-Ala35)hGLP-1 (7-36)NH2

Example 59: (Aib8, Lys25, β-Ala35)hGLP-1 (7-36)NH2

Example 60: (Aib8,24, A6c20, β-Ala35)hGLP-1(7-36)NH2

Example 61 : (Aib8, A6c29,32, β-Ala35)hGLP-1 (7-36)NH2

Example 62 : (Aib8 ,24, A6c29,32, β-Ala35)hGLP-1 (7-36)NH2

Example 63: (Aib8, A6c12, β-Ala35)hGLP-1 (7-36)NH2

Example 64: (Aib8, Cha20, β-Ala35)hGLP-1 (7-36)NH2

Example 65: (Aib8 , A6c33, β-Ala35)hGLP-1 (7-36)NH2

Example 66: (Aib8, A6c20,32, β-Ala35)hGLP-1 (7-36)NH2

Example 67: (Aib8, β-Ala22,35)hGLP-1(7-36)NH 2

Example 68: (Aib8,22, β-Ala35)hGLP-1 (7-36)NH2

Example 69: (Aib8, Glu23, A6c32, β-Ala35)hGLP-1(7-36)NH2

Example 70: (Aib8,24, Glu23, A6c32, β-Ala35)hGLP-1 (7-36)NH2

Example 71: (Aib8,24, Glu23, A6c32, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 72: (Aib8,24 ,25, Glu23, A6c32, β-Ala35)hGLP-1 (7-36)NH2

Example 73: (Aib8,24,25, A6c16,20,32, Glu23, β-Ala35)hGLP-1 (7-36)NH2

Example 74: (Aib8,24, D-Arg36)hGLP-1 (7-36)NH2

Example 75: (Aib8,35, D-Lys36)hGLP-1 (7-36)NH2

Example 76: (Aib8, β-Ala35, D-Arg36)hGLP-1 (7-36)NH2

Example 77: (Aib8, β-Ala35, D-Lys36)hGLP-1 (7-36)NH2

Example 78: (Aib8 35, Arg26,34)hGLP-1 (7-36)NH2

Example 79: (Aib8, Arg26,34, β-Ala35)hGLP-1 (7-36)NH2

Example 80: (Aib8,35, Arg25,26,34)hGLP-1 (7-36)NH2

Example 81: (Aib8, Arg25,26,34, β-Ala35)hGLP-1 (7-36)NH2

Example 82 : (Aib8, Arg26,34, β-Ala35, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)OH Example 83: (Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-37)OH

Example 84: (Aib8,35,37, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-37)OH

Example 85: (Aib8,35, Arg26,34, Lys36(Nε-tetradecanoyl), D-Ala37)hGLP-1(7-37)OH

Example 86: (Aib8,35,37, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)OH

Example 87: (Aib8,35, Arg26,34, β-Ala37, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)OH Example 88: (Aib8,35, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)OH

Example 89 : (Aib8, Arg26,34, Lys36(Nε-tetradecanoyl), β-Ala37)hGLP-1 (7-37)OH

Example 90: (Aib8,37, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-37)OH

Example 91: (Aib8,35, Arg26,34, Ado37)hGLP-1(7-37)OH

Example 92: (Aib8,35, Arg26,34, Ado37)hGLP-1 (7-37)NH2

Example 93: (Aib8, Arg26,34, Lys36(Nε-tetradecanoyl), D-Ala37)hGLP-1 (7-37)OH

Example 94 (Aib8 ,37, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1(7-38)OH

Example 95: (Aib8, Arg26,34, β-Ala37, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)OH Example 96: (Aib8,35, Lys26(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 97 : (Aib8,35, Lys26(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 98: (Aib8,35, Lys26(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 99: (Aib8, Lys26(Nε-octanoyl), β-Ala35)hGLP-1(7-36)NH2

Example 100: (Aib8, Lys26(Nε-tetradecanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 101 : (Aib8, Lys26(Nε-hexadecanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 102: (Aib8,35, Lys26(Nε-octanoyl), Arg34)hGLP-1 (7-36)NH2

Example 103: (Aib8,35, Lys26(Nε-tetradecanoyl), Arg34)hGLP-1 (7-36)NH2 Example 104: (Aib8,35, Lys26(Nε-hexadecanoyl), Arg34)hGLP-1(7-36)NH2

Example 105: (Aib8 35, Lys26(Nε-decanoyl), Arg34)hGLP-1 (7-36)NH2

Example 106: (Aib8,35, Lys25, Lys26(Nε-octanoyl), Arg34)hGLP-1 (7-36)NH2 Example 107: (Aib8,35, Lys25, Lys26(Nε-tetradecanoyl), Arg34)hGLP-1 (7-36)NH2 Example 108 : (Aib8 35, Lys25, Lys26(Nε-hexadecanoyl), Arg34)hGLP-1(7-36)NH2 Example 109: (Aib8 35, Arg25'34, Lys26(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 110: (Aib8 35, Arg2534, Lys26(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 111: (Aib8 35, Arg2534, Lys26(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 112 : (Aib8,35, Arg2534, Lys26(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 113: (Aib8, Lys26(Nε-octanoyl), Arg34, β-Ala35)hGLP-1 (7-36)NH2 Example 1 14: (Aib8, Lys26(Nε-tetradecanoyl), Arg34, β-Ala35)hGLP-1 (7-36)NH2 Example 115: (Aib8, Lys26(Nε-hexadecanoyl), Arg34, β-Ala35)hGLP-1 (7-36)NH2 Example 116: (Aib8, Lys26(Nε-decanoyl), Arg34, β-Ala35)hGLP-1 (7-36)NH2 Example 1 17: (Aib8,35, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 1 18: (Aib8,35, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 1 19: (Aib8,35, Lys34(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 120: (Aib8,35, Arg26, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 121 : (Aib8 ,35, Arg26, Lys34(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 122: (Aib8,35, Arg26, Lys34(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 123: (Aib8,35, Arg25,26, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 124: (Aib8,35, Arg25,26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 125: (Aib8,35, Arg25,26, Lys34(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 126: (Aib8,35, Arg25,26, Lys34(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 127: (Aib8,35, Lys25, Arg26, Lys34(Nε-octanoyl))hGLP-1(7-36)NH2 Example 128: (Aib8,35, Lys25, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 129: (Aib8,35, Lys25, Arg26, Lys34(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 130: (Aib8,35, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 131 : (Aib8,35, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 132: (Aib8,35, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 133: (Aib8,35, Arg26, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 134: (Aib8,35, Arg26, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 135: (Aib8,35, Arg26, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 136: (Aib8,35, Arg26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 137 : (Aib8,35, Arg26,34, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 138: (Aib8,35, Arg26,34, LyS38(Nε-octanoyl))hGLP-1 (7-38)NH2

Example 139 : (Aib8,35, Arg2634, Lys38(Nε-decanoyl))hGLP-1 (7-38)NH2

Example 140: (Aib8,35, Arg26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)NH2 Example 141: (Aib8,35, Arg26,34, Lys38(Nε-hexadecanoyl))hGLP-1 (7-38)NH2

Example 142 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-octanoyl))hGLP-1 (7-38)NH2

Example 143 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-decanoyl))hGLP-1 (7-38)NH2

Example 144: (Aib8,35,37, Arg25,26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)NH2 Example 145: (Aib8,35,37, Arg25,26,34, Lys38(Nε-hexadecanoyl))hGLP-1 (7-38)NH2 Example 146: (Aib8 ,35 ,37, Arg26,34, Lys38(Nε-octanoyl))hGLP-1 (7-38)NH2

ExamPle 147: (Aib8,35,37, Arg26,34, Lys38(Nε-decanoyl))hGLP-1 (7-38)NH2

Example 148 : (Aib8,35,37, Arg26,34, Lys38(Nε-hexadecanoyl))hGLP-1 (7-38)NH2 Example 149 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-octanoyl))hGLP-1 (7-38)NH2

Example 150 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-decanoyl))hGLP-1 (7-38)NH2

Example 151 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-tetradecanoyl))hGLP-1 (7-38)NH2 Example 152 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-hexadecanoyl))hGLP-1 (7-38)NH2

Example 153: (Aib8,35, Lys25, Arg26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 154: (Aib8,35, Lys25, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 155: (Aib8,35, Lys25, Arg26,34, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 156: (Aib8,35, Arg25,26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 157: (Aib8,35, Arg2526,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 158 : (Aib8,35, Arg25,26,34, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 159: (Aib8,35, Arg25,26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 160: (Aib8, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 161 : (Aib8, Lys34(Nε-tetradecanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 162: (Aib8, Lys34(Nε-hexadecanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 163: (Aib8, A6c32, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 164: (Aib8, Glu23, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 165: (Aib8, Glu23, A6c32, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 166: (Aib8, Arg26, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 167 : (Aib8, Arg26, Lys34(Nε-tetradecanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 168 : (Aib8, Arg26, Lys34(Nε-hexadecanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 169 : (Aib8, Arg26, Lys34(Nε-decanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 170: (Aib8, Arg25,26, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 171 : (Aib8, Arg25,26, Lys34(Nε-tetradecanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 172 : (Aib8, Arg25,26, Lys34(Nε-hexadecanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 173: (Aib8, Arg25,26, Lys34(Nε-decanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 174: (Aib8, Lys25, Arg26, Lys34(Nε-octanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 175: (Aib8, Lys25, Arg26, Lys34(Nε-tetradecanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 176: (Aib8, Lys25, Arg26, Lys34(Nε-hexadecanoyl), β-Ala35)hGLP-1 (7-36)NH2 Example 177: (Aib8, β-Ala35, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 178: (Aib8, β-Ala35, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 179: (Aib8, β-Ala35, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 180: (Aib8, Arg26, β-Ala35, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 181 : (Aib8, Arg26, β-Ala35, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 182: (Aib8, Arg26, β-Ala35, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 183: (Aib8, Arg26,34, β-Ala35, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 184: (Aib8, Arg26,34, β-Ala35, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 185: (Aib8, Arg26,34, β-Ala35, Lys36(Nε- hexadecanoyl))hGLP-1 (7-36)NH2 Example 186: (Aib8, Arg26,34, β-Ala35, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 187: (Aib8, Lys25, Arg26,34, β-Ala35, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 188: (Aib8, Lys25, Arg26,34, Lys36(Nε-tetradecanoyl), β-Ala35)hGLP-1 (7-36)NH2

Example 189 : (Aib8, Lys25, Arg26,34, β-Ala35, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 190: (Aib8, Arg25,26,34, β-Ala35, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 191 : (Aib8, Arg25,26,34, β-Ala35, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 192 : (Aib8, Arg25,26,34, β-Ala35, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 193 : (Aib8, Arg25,26,34, β-Ala35, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 194: (Aib8 35, Lys26(Nε-octanoyl), A6c32, Arg34)hGLP-1 (7-36)NH2 Example 195 : (Aib8,35, Lys26(Nε-tetradecanoyl), A6c32, Arg34)hGLP-1 (7-36)NH2

Example 196: (Aib8,35, Lys26(Nε-hexadecanoyl), A6c32, Arg34)hGLP-1 (7-36)NH2 Example 197: (Aib8,35, A6c32, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 198: (Aib8,35, A6c32, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 199: (Aib8,35, A6c32, Lys34(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 200: (Aib8,35, Arg26, A6c32, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 201 : (Aib8,35, Arg26, A6c32, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 202: (Aib8,35, A6c32, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 203: (Aib8,35, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 204: (Aib8,35, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 205: (Aib8,35, Arg26, A6c32, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 206: (Aib8,35, Arg26, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 207: (Aib8,35, Arg26, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 208 : (Aib8,35, Arg2634, A6c32, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 209: (Aib8,35, Arg26,34, A6c32, Lys36(Nε-decanoyl))hGLP-1 (7-36)NH2 Example 210: (Aib8,35, Arg26,34, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 21 1 : (Aib8,35, Arg26,34, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 212: (Aib8,24,35, Lys26(Nε-octanoyl), Arg34)hGLP-1 (7-36)NH2

Example 213 : (Aib8,24,35, Lys26(Nε-tetradecanoyl), Arg34)hGLP-1 (7-36)NH2

Example 214: (Aib8,24,35, Lys26(Nε-hexadecanoyl), Arg34)hGLP-1 (7-36)NH2

Example 215: (Aib8,24,35, Arg26, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 216: (Aib8,24,35, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 217: (Aib8,24,35, Arg26, Lys34(Nε-hexadecanoyl))hGLP-1(7-36)NH

Example 218: (Aib8,24,35, Arg26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH

Example 219 : (Aib8 ,24 ,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 220: (Aib8,24,35, Arg26,34, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 221 : (Aib8,24,35, Glu23, A6c32, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 222: (Aib8,35, Glu23, Lys26(Nε-octanoyl), Arg34)hGLP-1 (7-36)NH2 Example 223 : (Aib8,35, Glu23, Lys26(Nε-tetradecanoyl), Arg34)hGLP-1 (7-36)NH2 Example 224: (Aib8,35, Glu23, Lys26(Nε-hexadecanoyl), Arg34)hGLP-1(7-36)NH2 Example 225: (Aib8,35, Glu23, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 226: (Aib8,35, Glu23, A6c32, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 227: (Aib8,35, Glu23, Arg26, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 228: (Aib8,35, Glu23, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 229: (Aib8,35, Glu23, Arg26, Lys34(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 230: (Aib8,35, Glu23, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

ExamPle 231 : (Aib8,35, Glu23, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 232 : (Aib8,35, Glu23, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 233: (Aib8,35, Glu23, Arg26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 234 : (Aib8,35, Glu23, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 235: (Aib8,35, Glu23, Arg26,34, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 236: (Aib8,30,35, Lys26(Nε-octanoyl), Arg34)hGLP-1 (7-36)NH2

Example 237 : (Aib8,30,35, Lys26(Nε-tetradecanoyl), Arg34)hGLP-1 (7-36)NH2

Example 238: (Aib8,30,35, Lys26(Nε-hexadecanoyl), Arg34)hGLP-1 (7-36)NH2 Example 239: (Aib8,30,35, Arg26, Lys34(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 240: (Aib8,30,35, Arg26, Lys34(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 241 : (Aib8,30,35, Arg26, Lys34(Nε-hexadecanoyl))hGLP-1(7-36)NH2 Example 242: (Aib8,30,35, Arg26,34, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2

Example 243: (Aib8,30,35, Arg26,34, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2

Example 244: (Aib8,30,35, Arg26,34, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2 Example 245: (Aib8,35, Glu23, A6c32, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 246 : (Aib8,35, Glu23, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Exampie 247 : (Aib8,35, Glu23, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 248: (Aib8,35, Glu23, Arg26,34, A6c32, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 249: (Aib8,35, Glu23, Arg26,34, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 250: (Aib8,35, Glu23, Arg26,34, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1(7-36)NH2

Example 251 : (Aib8,24,35, Glu23, Arg26,34, A6c32, Lys36(Nε-octanoyl))hGLP-1 (7-36)NH2 Example 252 : (Aib8,24,35, Glu23, Arg26,34, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 253: (Aib8 ,24,35, Glu23, Arg26,34, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1 (7-36)NH2

Example 254: (Aib8,24,30,35, Glu23, Arg26,34, A6c32, Lys36(Nε-octanoyl))hGLP-1(7-36)NH2 Example 255 : (Aib8,24,30,35, Glu23, Arg26,34, A6c32, Lys36(Nε-tetradecanoyl))hGLP-1 (7-36)NH2 Example 256: (Aib8,24,30,35, Glu23, Arg26,34, A6c32, Lys36(Nε-hexadecanoyl))hGLP-1(7-36)NH2

Example 257: ((Nα-HEPES-His)7, Aib35)hGLP-1 (7-36)NH2

Example 258: ((Nα-HEPES-His)7, β-Ala35)hGLP-1 (7-36)NH2

Example 259: ((Nα-HEPES-His)7, Aib8, β-Ala35)hGLP-1 (7-36)NH2

Example 260: ((Nα-HEPA-His)7, Aib35)hGLP-1 (7-36)NH2

Example 261: ((Nα-HEPA-His)7, β-Ala35)hGLP-1 (7-36)NH2

Example 262: ((Nα-HEPA-His)7, Aib8, β-Ala35)hGLP-1 (7-36)NH2

Example 263 : ((Nα-tetradecanoyl-His)7, Aib35)hGLP-1 (7-36)NH2

Exampie 264 : ((Nα-tetradecanoyl-His)7, β-Aia35)hGLP-1 (7-36)NH2

Example 265: ((Nα-tetradecanoyl-His)7, Aib8,35)hGLP-1 (7-36)NH2

Example 266: ((Nα-tetradecanoyl-His)7, Aib8, β-Ala35)hGLP-1 (7-36)NH2

Example 267 : ((Nα-tetradecanoyl-His)7, Arg26,34, Aib35)hGLP-1 (7-36)NH2

Example 268 : ((Nα-tetradecanoyl-His)7, Arg26,34, β-Ala35)hGLP-1 (7-36)NH2

Example 269: ((Nα-tetradecanoyl-His)7, Aib8,35 , Arg26,34)hGLP-1 (7-36)NH2

Example 270: ((Nα-tetradecanoyl-His)7, Aib8, Arg26 ,34, β-Ala35)hGLP-1 (7-36)NH2 Example 271 : ((Nα-tetradecanoyl-His)7, Arg25,26,34, β-Ala35)hGLP-1 (7-36)NH2

Example 272: ((Nα-tetradecanoyl-His)7, Aib8,35 , Arg25,26,34)hGLP-1 (7-36)NH2 Example 273: ((Nα-tetradecanoyl-His)7, Aib8, Arg25,26,34, β-Ala35)hGLP-1 (7-36)NH2 Example 274: (Aib8,35, Lys26(Nε-octanesulfonyl), Arg34)hGLP-1 (7-36)NH2

Example 275: (Aib8,35, Lys26(Nε-dodecanesulfonyl), Arg34)hGLP-1 (7-36)NH2

Example 276: (Aib8,35, Lys26(Nε-hexadecanesulfonyl), Arg34)hGLP-1 (7-36)NH2

Example 277: (Aib8,35, Arg26, Lys34(Nε-octanesulfonyl))hGLP-1(7-36)NH2

Example 278 : (Aib8,35, Arg26, Lys34(Nε-dodecanesulfonyl))hGLP-1 (7-36)NH2

Example 279: (Aib8,35, Arg26, Lys34(Nε-hexadecanesulfonyl))hGLP-1 (7-36)NH2 Example 280: (Aib8,35, Arg26,34, Lys36(Nε-octanesulfonyl))hGLP-1(7-36)NH2

Example 281 : (Aib8,35, Arg26,34, Lys36(Nε-hexadecanesulfonyl))hGLP-1 (7-36)NH2 Example 282 : (Aib8,35, Asp26(1-(4-decylpiPerazine)), Arg34)hGLP-1 (7-36)NH2

Example 283 : (Aib8,35, Asp26(1-(4-dodecylpiperazine)), Arg34)hGLP-1 (7-36)NH2

Example 284: (Aib8,35, Asp26(1-(4-tetradecylpiperazine)), Arg34)hGLP-1 (7-36)NH2 Example 285: (Aib8,35, Asp26(1-(4-hexadecylpiperazine)), Arg34)hGLP-1 (7-36)NH2 Example 286 : (Aib8,35, Arg26, Asp34(1-(4-decylpiperazine)))hGLP-1 (7-36)NH2

Example 287 : (Aib8,35, Arg26, Asp34(1-(4-dodecylpiperazine)))hGLP-1 (7-36)NH2

Example 288: (Aib8,35, Arg26, Asp34(1-(4-tetradecylpiperazine)))hGLP-1 (7-36)NH2 Example 289: (Aib8,35, Arg26, Asp34(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH2 Example 290 : (Aib8,35, Arg26 ,34, Asp36(1-(4-decylpiperazine)))hGLP-1 (7-36)NH2

Example 291 : (Aib8,35, Arg26,34, Asp36(1-(4-dodecylpiperazine)))hGLP-1 (7-36)NH2

Example 292: (Aib8,35, Arg26,34, Asp36(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH2 Example 293 : (Aib8,35, Arg26,34, Asp38(1-(4-decylpiperazine)))hGLP-1 (7-38)NH2

Example 294 : (Aib8,35, Arg26,34, Asp38(1-(4-dodecylpiperazine)))hGLP-1 (7-38)NH2

Example 295: (Aib8,35, Arg26,34, Asp38(1-(4-tetradecylpiperazine)))hGLP-1 (7-38)NH2 Example 296: (Aib8,35, Arg26,34, Asp38(1-(4-hexadecylpiperazine)))hGLP-1 (7-38)NH2 Example 297: (Aib8,35,37, Arg26,34, Asp38(1-(4-decylpiperazine)))hGLP-1 (7-38)NH2

Example 298 (Aib8 ,35,37, Arg26,34, Asp38(1-(4-dodecylpiperazine)))hGLP-1 (7-38)NH2 Example 299: (Aib8,35,37, Arg26,34, Asp38(1-(4-tetradecylpiperazine)))hGLP-1 (7-38)NH2 Example 300: (Aib8,35,37, Arg26,34, Asp38(1 -(4-hexadecylpiperazine)))hGLP-1 (7-38)NH2

Example 301 : (Aib8,35, Arg25,34, Asp26(1-(4-decylpiperazine)))hGLP-1(7-36)NH2

Example 302 : (Aib8,35, Arg25,34, Asp26(1-(4-dodecylpiperazine)))hGLP-1 (7-36)NH2

Example 303: (Aib8,35, Arg25,34, Asp26(1-(4-tetradecylpiperazine)))hGLP-1 (7-36)NH2 Example 304: (Aib835, Arg25,34, Asp26(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH2 Example 305 : (Aib8,35, Arg25,26, Asp34(1-(4-decylpiperazine)))hGLP-1 (7-36)NH2

Example 306 : (Aib8,35, Arg25,26, Asp34(1-(4-dodecylpiPerazine)))hGLP-1 (7-36)NH2

Example 307: (Aib835, Arg25,26, Asp34(1-(4-tetradecylpiperazine)))hGLP-1 (7-36)NH2 Example 308: (Aib8 ,35, Arg25,26, Asp34(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH2 Example 309 : (Aib8,35, Arg25,26,34, Asp36(1-(4-decylpiperazine)))hGLP-1 (7-36)NH2

Example 310 : (Aib8,35, Arg25,26,34, Asp36(1-(4-dodecylpiperazine)))hGLP-1 (7-36)NH2 Example 311 : (Aib8,35, Arg25,26,34, Asp36(1-(4-tetradecylpiperazine)))hGLP-1 (7-36)NH2 Example 312: (Aib8,35, Arg25,26,34, Asp36(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH2

Example 313 : (Aib8,35, Arg25,26,34, Asp38(1-(4-decylpiperazine)))hGLP-1 (7-38)NH2

Example 314 : (Aib8 , 35, Arg25,26,34, Asp38(1-(4-dodecylpiperazine)))hGLP-1 (7-38)NH2 Example 315: (Aib8,35, Arg25,26,34, Asp38(1-(4-tetradecylpiperazine)))hGLP-1 (7-38)NH2 Example 316: (Aib8,35, Arg25,26,34, Asp38(1-(4-hexadecylpiperazine)))hGLP-1 (7-38)NH2

Example 317: (Aib8,35,37, Arg25,26,34, Asp38(1-(4-decylpiperazine)))hGLP-1 (7-38)NH2 Example 318 : (Aib8,35,37, Arg25,26,34, Asp38(1-(4-dodecylpiperazine)))hGLP-1 (7-38)NH2 Example 319: (Aib8,35,37, Arg25,26,34, Asp38(1-(4-tetradecylpiperazine)))hGLP-1(7-38)NH2

Example 320 : (Aib8,35,37, Arg25,26,34, Asp38(1-(4-hexadecylpiperazine)))hGLP-1(7-38)NH2 Example 321 : (Aib8,35, Arg26,34, Glu36(1-dodecylamino))hGLP-1(7-36)NH2

Example 322: (Aib8,35, Glu26(1-dodecylamino), Arg34)hGLP-1 (7-36)NH2

Example 323 : (Aib8,35, Arg26, Glu34(1-dodecylamino))hGLP-1 (7-36)NH2

Example 324: (Aib8,35,37, Arg26'34, Glu38(1-dodecylamino))hGLP-1 (7-38)NH2

Example 325 : (Aib8,35, Arg34, Lys26(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2 Example 326 : (Aib8,35, Arg34, Lys26(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH2

Example 327: (Aib8,35, Arg34, Lys26(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 328: (Aib8,35, Arg34, Lys26(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 329 : (Aib8,35, Arg26, Lys34(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2 Example 330 : (Aib8,35, Arg26, LyS34(Nε-(2-(4-dodecyl-1 -piperazine)-acetyl))hGLP-1 (7-36)NH2

Example 331. (Aib8,35, Arg26, Lys34(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP- 1 (7-36)NH2

Example 332 (Aib8,35, Arg26, Lys34(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP- 1(7-36)NH2

Example 333 : (Aib8,35, Arg26,34, Lys36(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 334: (Aib8,35, Arg26,34, Lys36(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 335: (Aib8,35, Arg26,34, Lys36(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH2

Example 336, (Aib8,35, Arg26,34, Lys38(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 38)NH2

Example 337: (Aib8,35, Arg26,34, Lys38(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 338: (Aib8,35, Arg26,34, Lys38(Nε-(2-(4-tetradecyl-1 -piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 339: (Aib8,35, Arg26,34, Lys38(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1(7-38)NH2

Example 340 : (Aib8,35,37, Arg26,34, Lys38(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 38)NH2

Example 341 : (Aib8,35,37, Arg26,34, Lys38(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7- 38)NH2

Example 342: (Aib8,35,37, Arg26,34, Lys38(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 343: (Aib8,35,37, Arg26,34, Lys38(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 344 : (Aib8 ,35, Arg25,34, LyS26(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 345: (Aib8,35, Arg25,34, Lys26(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 346: (Aib8,35, Arg25,34, Lys26(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1(7-36)NH2

Example 347: Aib8,35, Arg25,34, Lys26(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 348 : (Aib8,35, Arg25,26, Lys34(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 349 : (Aib8,35, Arg25,26, Lys34(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 350: (Aib8,35, Arg25,26, Lys34(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 351 : (Aib8,35, Arg25,26, Lys34(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 352 : (Aib8,35, Arg25,26,34, Lys36(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 36)NH2

Example 353 : (Aib8,35, Arg25,26,34, Lys36(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 354: (Aib8,35, Arg25,26,34, Lys36(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Example 355: (Aib8,35, Arg25,26,34, Lys36(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-36)NH2

Exampie 356: (Aib8,35, Arg25,26,34, Lys38(Nε-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP-1 (7- 38)NH2

Example 357 : (Aib8,35, Arg25,26,34 , Lys38(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP-1 (7- 38)NH2

Example 358: (Aib8,35, Arg25,26,34, Lys38(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 359: (Aib8,35, Arg25,26,34, Lys38(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 360 : (Aib8,35,37, Arg25,26,34, Lys38(Nε-(2-(4-decyl-1-piperazine)-acetyl)))hGLP-1 (7- 38)NH2

Exampie 361 : (Aib8 ,35,37, Arg25,26,34, Lys38(Nε-(2-(4-dodecyl-1-piperazine)-acetyl)))hGLP- 1 (7-38)NH2

Example 362: (Aib8,3537, Arg25,26,34, Lys38(Nε-(2-(4-tetradecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 363: (Aib8 ,35,37, Arg25,26,34, Lys38(Nε-(2-(4-hexadecyl-1-piperazine)-acetyl)))hGLP-1 (7-38)NH2

Example 364: (Aib8,35, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)OH

Example 365: (Aib8,35, Lys25, Arg26,34, Lys36(Nε-decanoyl))hGLP-1 (7-36)OH

Example 370 (Aib8,35,Arg26,34, Ava37, Ado38)hGLP-1 (7-38)NH2

Example 371 (Aib8,35,Arg26,34, Asp37, Ava38, Ado39)hGLP-1 (7-39)NH2

Example 372 (Aib8,35,Arg26,34, Aun37)hGLP-1 (7-37)NH2

Example 373 (Aib8,17,35,)hGLP-1 (7-36)NH2

Example 374 (Aib8 ,Arg26,34, β-Ala35, D-Asp37, Ava38, Aun39)hGLP-1 (7-39)NH2 Example 375 (Gly8, β-Ala35)hGLP-1 (7-36)NH2

Example 376 (Ser8, β-Ala35)hGLP-1 (7-36)NH2

Example 377 (Aib8, Glu22,23, β-Ala35)hGLP-1 (7-36)NH2

Example 378 (Gly8, Aib35)hGLP-1 (7-36)NH2

Example 379 (Aib8, Lys18, β-Ala35)hGLP-1 (7-36)NH2

Example 380 (Aib8, Leu27, β-Ala35)hGLP-1 (7-36)NH2

Example 381 (Aib8, Lys33, β-Ala35)hGLP-1 (7-36)NH2

Example 382 (Aib8, Lys18, Leu27, β-Ala35)hGLP-1 (7-36)NH2

Example 383 (Aib8, D-Arg36)hGLP-1 (7-36)NH2

Example 384 (Aib8, β-Ala35, D-Arg37)hGLP-1(7-37)NH2

Example 385 (Aib8,27, β-Ala35)hGLP-1(7-36)NH2

Example 386 (Aib8,27, β-Ala35,37, Arg38)hGLP-1(7-38)NH2

Example 387 (Aib8,27, β-Ala35,37, Arg38,39)hGLP-1 (7-39)NH2

Example 388 (Aib8, Lys18,27, β-Ala35)hGLP-1 (7-36)NH2

Example 389 (Aib8, Lys27, β-Ala35)hGLP-1 (7-36)NH2

Example 390 (Aib8, β-Ala35, Arg38)hGLP-1 (7-38)NH2

Example 391 (Aib8, Arg26,34, β-Ala35,)hGLP-1 (7-36)NH2

Example 392 (Aib8, D-Arg35)hGLP-1 (7-36)NH2

Example 393 (Aib8, β-Ala35, Arg37)hGLP-1(7-37)NH2

Example 394 (Aib8, Phe31, β-Ala35)hGLP-1 (7-36)NH2

Example 395 (Aib8,35, Phe31)hGLP-1(7-36)NH2

Example 396 (Aib8,35, Nal31)hGLP-1 (7-36)NH2

Example 397 (Aib8,35, Nal28,31)hGLP-1(7-36)NH 2

Example 398 (Aib8,35, Arg26,34, Nal31)hGLP-1 (7-36)NH2

Example 399 (Aib8,35, Arg26,34, Phe31)hGLP-1 (7-36)NH2

Example 400 (Aib8,35, Nal19,31)hGLP-1(7-36)NH2

Example 401 (Aib8,35, Nal12,31)hGLP-1 (7-36)NH2

Example 402 (Aib8,35, Lys36(Nε-decanoyl))hGLP-1 (7-36) NH2

Example 403 (Aib8,35, Arg34, Lys26(Nε-decanoyl))hGLP-1 (7-36)NH2

Example 404 (Aib8,35, Arg26,34, Lys36(Nε-dodecanoyl))hGLP-1 (7-36)NH2

Example 405 (Aib8,B-Ala35,Ser37(O-decanoyl))hGLP1 (7-37)-NH2

Example 406 (Aib8,27, β-Ala35,37, Arg38, Lys39(Nε-octanoyl))hGLP-1 (7-39)NH2

Example 407 (Aib8, Arg26,34, β-Ala35, Lys37(Nε-octanoyl))hGLP-1 (7-37)NH2

Example 408 (Aib8, Arg26,34, β-Ala35, Lys37(Nε-decanoyl))hGLP-1 (7-37)NH2

Example 409 (Aib8, Arg26,34, β-Ala35, Lys37(Nε-tetradecanoyl))hGLP-1 (7-37)NH2

Example 410 (Aib8, Arg26,34, β-Ala35, Lys37(Nε-dodecanoyl))hGLP-1 (7-37)NH2

Example 411 (Aib8, Arg26,34, β-Ala35, Lys37(Nε-dodecanoyl))hGLP-1 (8-37)NH2

Physical data for a representative sampling of the compounds exemplified herein are given in Table 1.