AU2003202533B2

AU2003202533B2 - Analogues of GLP-1

Info

Publication number: AU2003202533B2
Application number: AU2003202533A
Authority: AU
Inventors: Zheng Xin Dong
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1998-12-07
Filing date: 2003-03-27
Publication date: 2005-04-21
Anticipated expiration: 2019-12-07

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES SAS Invention Title: ANALOGUES OF GLP-1 The following statement is a full description of this invention, including the best method of performing it known to me/us: -la- 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 (Varndell, 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 pmot/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, 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 emptying (Wettergren et al., Dig Dis Sd 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 dose of GLP-1 could completely normalize postprandial glucose levels in patients with non-insuiin-dependent diabetes mellitus (NIDDM) (Gutniak, 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 emptying in patients with NIDDM (Williams, 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. 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, Diabetologia 35:701-711, 1992; Hoist, 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, 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, N. EngI J Med 226:1316-1322, 1992; Nathan, et al., Diabetes Care 15:270-276, 1992), normalizing blood glucose levels in type 2 diabetic subjects (Nauck, et al., Diagbetologia 36:741-744, 1993), and improving glycemic control in type 1 patients (Creutzfaldt, et 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 of only 1-2 min in vivo. Exogenously administered GLP-1 is also rapidly degraded (Deacon, 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

(R

2

R

3

)-A-A

8 -ASA -A'-A-A 1

-A

1 7

-A

l 6

-A

1

-A

1

-A-A

2 1

-A

2

-AA

2 A z

-A

2t

A"-A"

9 -A0-A'-A"-A 33

-A

3 4 A-A -A-A3-A-R' (1) wherein

A

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

A

8 is Ala, D-Ala, Aib, Atc, N-Me-Ala, N-Me-D-Ala or N-Me-Gly;

A

9 is Glu, N-Me-Glu, N-Me-Asp or Asp;

A'

0 is Gly, Acc, 8-Ala or Aib; A" is Thr or Ser;

A'

2 is Phe, Acc, Aic, Aib. 3-Pal, 4-Pal, 3-Nal, Cha. Trp or X'-Phe; is Thr or Ser; A" is Ser or Aib:

A'

5 is Asp or Glu:

A'

6 is Val, Acc, Aib, Leu, Ile, Tie, Nie, Abu, Ala or Cha; A' is Ser or Thr;

A'

8 is Ser or Thr;

A'

9 is Tyr. Cha, Phe. 3-Pai, 4-Pal, Aco, f3-Nal or X'-Phe; A' is Leu, Aco, Aib, Nie, Ile, Cha, Tie, Val, Phe or X'-Phe;

A

2 is Glu or Asp; A7 is Gly, Acc, -Ala, Glu or Aib;

A

23 is Gin, Asp, Asn or Glu;

A

2 is Ala, Aib, Val, Abu, Tie or Acc;

A

25 is Ala. Aib, Val, Abu, Tie. Aco, Lys, Arg. hArg, Om, HN-CH((CH 2 0 C(O) or HN-CH((CH 2 A2 is Lys, Arg, hArg, Gm, HN-CH((CH2)r-N(R' 1 or HN-CH((CH)-X 3

C(O);

A2T is Glu Asp. Leu, Aib or Lys;

A

2 8 is Phe, Pal, 13-Nai, X'-Phe. Aic, Acc, Aib, Cha or Trp; Al is lie, Acc, Aib, Leu, Nie, Cha, Tie, Val, Abu, Aia or Phe; is Ala, Aib or Acc;

A

3 is Trp, 13-Nal, 3-Pal, 4-Pal, Phe. Acc, Aib or Cha;

A

32 is Leu, Acc, Aib, Nie, lie, Cha, Tie, Phe, X'-Phe or Ala; A33 is Val. Acc, Aib, Leu, Ile, Tie, Nie, Cha, Ala, Phe, Abu, Lys or X'-Phe;

A

3 4 is Lys, Arg, hArg, Om, HN-CH((CH 2 or HN-CH((CH 2 4

-X

3

C(O);

A-1 is Gly, IA-Ala, 0-Ala. Gaba, Ava, HN-(CHt),C(O). Aib. Acc or a 0-amino acid: A3 M is L- or D-Arg, D- or L-Lys. D- or L-hArg, D- or L-Orn, HN-CH((CH 2

HN-CH((CH

2

)-X

3 )-CCO) or deleted;

A

37 is Giy, 8-Ala, Gaba, Ava, Aib, Acc, Ado. Arg. Asp, Aun, Aec. HN-CH((CH,)-N(R'R'j a 0-amino acid, or deleted; A3 is D- or L-Lys, 0- or L-Arg, D- or L-hArg, D- or L-Om,

HN-CH((CH

2

,-X

3 Ava. Ado, Aec or deleted;

A

39 is 0- or L-Lys. 0- or L-Arg, Ava, Ado, or Aec: X' for each occurrence is independently selected from the group consisting of (C- C,)alkyi. OH and halo; R' is OH. NH,, (0 1 -%3)alkoxy, or NH-X 2 -CHr-Z, wherein X 2 is a 0 12 )hydrocarbon moiety, and Z" is H, OH, CO 2 H or CONH 2 N-(CHf -CH 3

X

3 is\2I -N H-C(O)-CHj-N \N-(CH 2 2 -NH-C(O)-R 1 or -C(O)-NHR 12 wherein X 4 is. independently for each occurrence, -NHor -OH 2 and wherein f is. independently for each occurrence, an integer from 1 to 29 inclusive; each of R 2 and R 3 is independently selected from the group consisting of H, (Ci- C3,)alkyI, (CrC3)alkenyl. phenyl (C 1 -C30)alkyl, naphthyI(C,-C3,)alkyI, hydroxy(C 1 C3)alkyl, hydroxy(C.-C,,)alkenyI, hydroxyphenyl(C-C 3 3 )alkyl, and hydroxynaphthyl(C 1 -C,,)alkyl; or one of R' and R 3 is (CH 3 )rN0N(0H 3 )2 Y(CH 2 )rN N-(CH 2

),ISO

2 C,,)acyl. (C 1

-C

31 )alkylsulfonyl, C(0)X 5 ,or Y(C 2),N j H 2 q_ O w herein Y is H ,O H orN H ris 0to 4; q is 0to 4; and X 5 is (C 1 -C30)alkyI, (Cr-Cs,)alkenyl. phenyl(0 1

-C,

0 )alkyl, naphthyl(C 1 -C3,)akyl.

hydroxy(C-C 3 0,)alkyl, hydroxy(C 2 -C,3,)alkenyI, hydroxyphenyql(C-C30)alkyI or hyd e is, independently for each occurrence, an integer from 1 to 4 inclusive; m is, independenty 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 and R 11 is, independently for each occurrence, H, (C 1 -C3)alkyl.

C

3 ,jacyl, (C,-C~o)alkylsulfonyl, or -C(0)-CHr-N N (0H 2 )rCH 3 an

R"

2 and R 1 each is, independently for each occurrence. (C 1

-C,

0 )alkyl; provided that: when A' is Ura. Paa or Pta, then R 2 and R 3 are deleted; when R' 0 is (C,-C3,)acyl, (C,-C,)alkylsulfonyi, or N-(CH2 )fCH 3 ,then R" is H or (C,-C)alkyl; at least one amino acid of a compound of formula is not the same as the native sequence of hGLP-1(7-36, -37 or -38)NH, or hGLP-1(7-36, -37 or -38)OH; (ii) a compound of formula is not an analogue of hGLP-1(7-36. -37 or -38)NH, or hGLP-1 (7-36, -37 or -38)OH wherein a single position has been substituted by Ala; (iii) a compound of formula is not (ArgI-I, LysI)hGLP-1(7-38)-E, (Lys"(N,alkanoyl))hGLP-1(7-36, -37 or (Lys"(N.-alkanoyl))hGLP-1(7-36, -37 or 38)-E, (Lys2m--bis(Nr-alkanoyl))hGLP-1(7-36. -37 or (Arg', Lys 3 (Nealkanoyl))hGLP-1 (8-36, -37 or (Args"', Lys (N.-alkanoyl))hGLP-1(7-3 6 -37 or -38)-E or Lys(N-alkanoyl))hGLP-1 wherein E is -OH or -NH 2 (iv) a compound of formula is not Z'-hGLP-1(7-36, -37 or -38)-OH, Z'-hGLP-1(7- 36, -37 or wherein Z' is selected from the group consisting of: (Arg), (Arg 3 (Args, Lysf), (Arg", Lysf), (D-Lys), (D-Argf), (Arg2 3 t, Lys") or (ArgA. Lys); (Asp 21 at least one of (D-Ala') and and (Tyr), (N-acyl-His'), (N-alkyl-His'), (N-acyl-D-His') or (N-alkyl-D-His'); a compound of formula is not a combination of any two of the substitutions listed in groups to and (vi) a compound of formula is not (N-Me-Ala)hGLP-1 (8-36 or (Glu')hGLP- 1(7-36 or (Asp 2 '')hGLP-1(7-36 or (Phe ')hGLP-1(7-36 or -37) or (Aib 835 )hGLP-1 (7-36)NH 2 or a pharmaceutically acceptable salt thereof.

A preferred grup of compounds of the immediately foregoing compound is where A" is Thr; A' is Thr A" 5 is Asp; A" is Ser; A' is Ser or Lys; is Glu; A" is Gin or Glu; A 2 1 is Glu, Leu, Aib or Lys; and A 3 is Trp, Phe or 13-Nal; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A' is Glu, N-Me-Glu or N-Me-Asp;

A'

2 is Phe, Acc, 3-Nal or Aic; A" is Val, Acc or Aib; A" is Tyr or t3-Nal; A" is Leu. Acc or Cha; A" is Ala. Alb or Acc; A25 is Ala, Aib, Acc, Lys, Arg, hArg, Ornm, or

HN-CH((CH),-X

3 A 2 is Phe or -Nal; A 29 is lie or Acc; A1O is Ala or Aib; A" is Leu, Acc or Cha; and A- is Vat, Lys or Acc; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A' is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N- Me-Gly; A'O is Gly; A' 2 is Phe, 3-Nal, A6c or A5c; A" is Val, A6c or A5c; A1 is Leu, A6c, A5c or Cha; A2 is Gly, 13-Ala, Glu or Ab; A21 is Ala or Aib; A20 is lie, A6c or A32 is Leu, A6c, A5c or Cha; A" is Val, Lys, A6c or A5c; A" is Aib, B-Ala, Ado.

A6c. A5c, D-Arg or Gly; and A' 7 is Gly, Aib, B-Ala, Ado, D-Ala Ava, Asp, Aun, D- Asp, D-Arg, Aec, or deleted; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing gruup of compounds is where X' for each occurrence is and R' is OH or NH,; 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 R' is H and R' is (C,-Cso)alkyl, (Cz-C3o)alkenyl, (C,-C3o)acyrl (C,-Co)alkyisulfonyl,

HO-(CH

2 -N N-(CH 2 2

SO

2

N-CH

2

-CO-

or

H

2

N-(CH,

2 -N N-CH,-CO- A preferred compound of the formula is where A' is Ala, D-Ala, Ab, A6c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A'O is Gly; A" is Phe, a-Nal A6c or A1" is Val, A6c or A5c; A2 is Leu, A6c A5c or Cha; A22 is Gly B-Ala, Glu or Aib; A24 is Ala or Aib; Ag is Ile, Aqc or A5c; A2 is Leu, A6c, ASc or Cha; A" is Val, Lys, A6c or A5c; A' is Aib, 3-Ala, Ado, A6c, A5c D-Arg or Gly; and A"3T is Gly, Aib, 1-Ala.

Ado, D-Ala, Ava, Asp. Aun, D-Asp, D-Arg, Aec, or deleted; X 4 for each occurrence is e for each occurrence is independently 1 or 2; R' is OH or NH,; R' 0 is (C,-C,)acyl, 4 )alkylsulfonyl or 7 O -C H Z N C H )f-C 3 and .R 11 is H or a pharm aceutically acceptable salt thereof.

More preferred of the immediately foregoing compounds is where R" 0 is C,)acyl, (C 4 -C2,)alkylsulfoflyl or COCi-\ /N (H2)t H31oa pharmaceutically acceptable salt thereof.

A more preferred compound of formula is where said compound is of the formula: ((N.-HEPES-HiSY., Aib' 25 ")hGLP- 1(7-36)N H 2 ((Ne-H EPA-His) 7 AibO-')hGLP-1I(7-36)NH 2 (Aib B-Alt-)hGLP-1 (7-36)NH 2 (Aib',3, Arg2G 3 tU Lyst'4NtetradecaIoy))hGLP-1 (7-36)NH 2 (Aiba-' Arg26. Lys'4(Nr tetrade-aloyl))hGLP-1 (7-36)NH 2 (Aib 53 Arg26M-, LysM'(NrtetradecalOyl))hGLP-1 (7-38)NH 2 (Aib'--h Arg2- 3 t Lysm(N.-decanoyI))hGLP-1 (7-36)N- 2 (Aib't 5 Arg6'" Lyse(N.-dOdecaleSufOlY1))hGLP-1 (7-36)NH 2 (AibBM-', Arg"At Lys

M

6(Nr-(2-(4-tetradecyl-l1-piperazine)-acetyl)))hGLP- 1(7-36)N H 2 (Aib 3 15 Argm', Asp-'( 1 (4-tetradecy-piperazife)))hGLPi (7-36)N H 2 (Aib 8 Th5 Arg-" 3 t Asp

M

-tetradecylamino))hGLP-1 (7-36)NH 2 (Aib"- 5 Arg25 3 t Lys'(N.-tetradecaflOYl).B3-Aa 1hGLP'l (7-37)-OH or Arg, 3 Ly9'-(Nr-tetradecaloyl) )hG LP-1 (7-36>0 H, or a pharmaceutically acceptable salt thereof More preferred of the immediately foregoing group of compounds is a compound of the formula: (Aib 8 (3-AIaflhGLP-1 (7-36)NH 2 (Aib 8 11 35 Arg 25 Lysi4N.tetradecanoy))hGLP-1 (7-36)NH 2 (Aib 3 5, 3 7, Arg 5 LysM'(Nc-tetradecanoyl))hGLP-1 (7-38)NH 2 (Aib t .35t Arg 26 Lys'(N.-decaflOYl))hGLP- 1 (7-36)NH 2 or (Aid' 35 Arg'-t LYS(Nr-tetradecanoyl)I3-Ala 31)hGLP-1(7-37) -OH, or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula is where said compound is of the formula: (Aid 8 9 3 1, A6c')hGLP-1(7-36)NH 2 (Aid" GI U 23 )hGLP-1 (7-36)NH 2 (Aib 8 '.1 4 ")hGLP-1 (7-36)NH 2 (Aid 8 35 Gl U 2 3 A~t)hGLP- 1(7-36 )NH 2 (Aid 8 GlIu 23 I3-Ala 3 )hGLP- 1 (7-36)NH 2 (Aid', Arg26-3)hGLP- 1(7-36)NH 2 (Ai Arg 2 4 Lys-'(N'-octanoyl))hGLP-1 (7-36)NH (Aib1- 5 Arg6t Lys36(N'-decanoyI))hGLP-1 (7-36)OH; Lys 2 5 Argm6 3 t, LysN(NtI decanoyI))hGLP-1 (7-36)OH; (Aid', B1-Ala', Lys"(N'-Aec-decanoyl))hGLP-1 (7-36)NH 2 (Aib"Th'Arg"'t4 Ava 3 7 Ado&')hGLP-1 (7-38)NH 2 (Aib'tArg6t4 Asp" 7 Ava', Ado')hGLP-1(7-39)NH 2 (AibSM.5Argm-34 Aun37hGLP-1 (7-37)NH 2 (Aibs-' 7 )hGLP-1 (7-36)NH 2 (Aid 5 ,Ar2" 13-Ala 3 s, D-Asp 3T Ava

M

Aun39hGLP-1 (7-39)NH 2 (Gly', I3-Aa"5)hGLP-1 (7-36)N- 2 (Sera, I3-AaflhGLP-1 (7-36)NH 2 (Aid', Glua' 3 I-AafhGLP-1 (7-36)NH 2 (Gly', Aib 35 )hGLP-1 (7-36)NH 2 (Aib, Lys" 1 I3-Aa')hGLP-1I(7-36)NH 2 (Aib', Leu 2 7 i-Ala" )hGLP-1 (7-36)NH 2 (Aiba, Lys"a, 3-Ala--lhGLP-1I(7-36)NH 2 (Aid', Lys" 8 Leu-"h I3-Aafl5hGLP-1 (7-36)NH-1; (Aid', D-ArgflhGLP- 1(7-36 )NH 2 (Aibs, D-Arg 37 )hGLP-1 (7-37)NH 2 (Ab' 2 7 i3-Ala"5)hGLP-1 (7-36)NH 2 (Aid'11 27 B-Ala M 37 Arg"')hGLP-1 (7-38)NH 2 (Aid'11 2 7 13-Ala"15 37 Arg '-3)hGLP-1 (7-39)N H 2 (AiV. Lys'"", 7 (3-Aafl5hGLP-1 (7-36)N,- 2 (Atb', Lys",. 13-Aa")hGLP-1(7-36)NH 2 (Aib, 1-Ala", Argm)hGLP-1(7-38)NH,; (Aib, Arg1", 3-Ala",)hGLP-1 (7-36)NH, 2 (Aib', D-Arg5)hGLP-1(7-36)NH,; (Aib, (3-Ala", Argf)hGLP-1(7-37)NH,; (Aib, Phe", 3-Alat)hGLP-1(7-36)NH,; (Aib 8 3 Phe" 3 )hGLP-1 (7-36)NH 2 Nal")hGLP-1 (7-36)NH,; (Aib' 5 Nal 2 3 )hGLP-1(7-36)NH 2 Arg-'5.3 Nal")hGLP-1(7-36)NH 2 (Aib-5, Arg2t, Phe t )hGLP-1(7-36)NH 2 Nal' 9 1 ')hGLP-1(7-36)NH 2 (Aiba'", Nal'2 3 ')hGLP-1(7-36)NH,; Lys38(N'-deCanCyi))hGLP-1(7-36) NH 2 (Aib'Th, Arg Lys (N'-decanoyl))hGLP-1 (7-36)NH,; (Aib 8 x, Arg 2 Lys (N'-dodecanoyl))hGLP-1(7-36)NH,; (Aib,B-Ala 3 Ser(O-decanoyl))hGLPl (7-37)-NH (Aib&27, a-Ala-"; Arg', Lys'(N'-octanoyl))hGLP-1(7-39)NH2; (Aib', Arg2", I-Ala, Lys 3 "(N'-octanoyl))hGLP-1(7-37)NH,; (Aib, Arg26, t-Ala", Lysa 7 (N-decanoyl))hGLP-1(7-37)NH,; or (Aib', Argl, I3-Ala", Lys 7 (N'-tetradecanoyl))hGLP-1(7-37)NH,; or a pharmaceutically acceptable salt thereof.

Another more preferred compound of formula 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 as defined hereinabove por 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 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 1 diabetes. Type 11 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 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 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 add CH, for Ala). For the N-terminal amino acid, the abbreviation stands for the structure of (RZR 3 wherein R is a side chain of an amino acid and R 2 and R 3 are as defined above, except when A 7 is Ura, Paa or Pta, in which case R and R 3 are not present since Ura, Paa and Pta are considered here as des-amino amino adds. Amp, 8-Nal, Nle, Cha, 3-Pal, 4-Pal and Aib are the abbreviations of the following a-amino acids: 4-aminophenylalanine, 3-(2-naphthyl)alanine, norieucine, cyclohexylalanine, pyridinyl)alanine, 13-(4-pyridinyl)alanine and a-aminoisobutyric acid, respectively.

Other amino acid definitions are: Ura is urocanic acid; Pta is (4-pyridylthio) acetic acid; Paa is trans-3-(3-pyridyl) acrylic acid; Tma-His is N,N-tetramethylamidinohistidine; N-Me-Ala is N-methyl-alanine; N-Me-Gly is N-methyl-glycine; N-Me-Glu is N-methyl-gluiamic acid; Tie is tert-butytglycne; Abu is a-aminobutyric acid; Tba is tert-butylalanine; Om is omithine; Aib is a-aminoisobutyric acd; 3-Ala is /-alanine; Gaba is ;7-aminobutyric add; Ava is 5-aminovaleric acid; Ado is 12aminododecanoic acd, Aic is 2-aminoindane-2-carboxylic acid; Aun is 11aminoundecanoic acid; and Aec is 4-(2-aminoethyl)-l-carboxymethyl-piperazine,

N

0 represented by the structure: What is meant by Acc is an amino acid selected from the group of 1-amino- 1-cyclopropanecarboxylic acid (A3c); 1-amino-l-cyclobutanecarboxylic acid (A4c); 1-amino-l-cyclopentanecarboxylic acid (A5c); 1-amino-l-cyclohexanecarboxylic acid (A6c); 1 -amino-1-cycloheptanecarboxylic acid (A7c); 1-amino-1cyclooctanecarboxylic acid (A8c); and 1-amino-l-cyclononanecarboxylic acid (A9c).

In the above formula, hydroxyalkyl, hydroxyphenylalkyl, and hydroxynaphthylalkyl may contain 1-4 hydroxy substituents. COX 5 stands for Examples of C=0-X 5 include, but are not limited to, acetyl and phenylpropionyl.

What is meant by Lys(N-alkanoyl) is represented by the following structure: 0 N CH H 0 SWhat is meant by Lys(N-alkylsulfonyl) is 00 NS .fCH 3 NH h H 0 A/hnt LL-- I-ll^ ~CllrL representea oy me rollowing ~uuurtu; is meant by Lys(N,-(2-(4-alkyl-1-piperazine)-acetyl)) is represented by the following 0

/CH

3 -NH H 0 structure: Asp(1 -(4-alkyl-piperazine)) by SWhat is meant by the following is represented N KCH

N

structure: SWhat is meant by Asp(1-alkylamino) 0

H

N CH 3

AN

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

-12- 0 N N N N-

CH,

N 0 H O The variable n in the foregoing structures is 1-30. What is meant by Lys (Ne-ace-alkanoyl) is represented by the structure: 0 0 N N N C H N H H 0 The full names for other abbreviations used herein are as follows: Boc for tbutyloxycarbonyl, 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 diisopropytethylamine, HOAc for acetic acid, TFA for trifluoroacetic acid, 2CIZ for 2-chlorobenzyloxycarbonyl, 2BrZ for 2bromobenzyloxycarbonyl, OcHex for O-cyclohexyl, Fmoc for 9fluorenylmethoxycarbonyl, HOBt for N-hydroxybenzotriazole and PAM resin for 4hydroxymethylphenylacetamidomethyl resin.

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

The term "(C,-C,)hydrocarbon moiety" encompasses alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there are Cz-C,- A peptide of this invention is also denoted herein by another format, e.g..

(A5c)hGLP-1(7-36)NH 2 with the substituted amino acids from the natural sequence placed between the first set of parentheses A5c' for Ala* in hGLP- 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 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, Int. J. Peptide Protein Res,. 40, 1992, pp. 333-342.

The designation in hGLP-1(7-36)NH 2 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, Stewart, et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984). The substituents R 2 and R 3 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, (C,-CO)alkyl, may be attached using reductive alkylation. Hydroxyalkyl groups, C,)hydroxyalkyl, may also be attached using reductive alkylation wherein the free hydroxy group is protected with a t-butyl ester. Acyl groups, COE'. may be attached by coupling the free acid, E'COOH, to the free amine of the Nterminal amino acid by mixing the completed resin with 3 molar equivalents of both the free add and diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxy group, p-hydroxyphenylpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBT.

When R' is NH-X 2 -CH,-CONH2, ZO=CONH,), the synthesis of the peptide starts with BocHN-X-CHz-COOH which is coupled to the MBHA resin. If R' is NH-X-CHz-COOH, Z°=COOH) the synthesis of the peptide starts with Boc-HN-X 2

-CH

2 -COOH which is coupled to PAM resin. For this particular step, 4 molar equivalents of Boc-HN-X 2 -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)-l-cyclohexanecarboxylic acid (Boc-A6c-OH) was synthesized as follows. 19.1 g (0.133 mol) of 1amino-1-cyclohexanecarboxylic acid (Acros Organics, Fisher Scientific, Pittsburgh, PA) was dissolved in 2d0 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 HC1. The organic layer was separated. The j 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,, 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.

was synthesized in an analogous manner 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 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-His )hGLP-1(7-36)NH 2 HBTU (2 mmol) and DIEA (1.0 ml) in 4 ml DMF are used to react with the Nterminal free amine of the peptide-resin in the last coupling reaction; the coupling time is about 2 hours.

The substituents R 2 and R 3 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, (C,-C3)alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups, hydroxyalkyl, can also be attached using reductive alkylation wherein the free hydroxy group is protected with a t-butyl ester. Acyl groups, COX 1 can be attached by coupling the free acid, e.g., X'COOH, 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, 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% CO9 5% 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-HCt 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-HCI, containing 2.5 mM MgCIz, 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 ('"I)GLP-1(7-36) (-2200 Ci/mmol, New England Nuclear, Boston, MA), with and without 0.05 mi of unlabeled competing test peptides. After a 100 min incubation (25 the bound ('lI)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- HCI, and the bound radioactivity trapped on the filters was counted by gamma spectrometry (Wallac LKB, Gaithersburg, MD). Specific binding was defined as the total ('51)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 acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids 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 acetit acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax, 300 SB, The column is eluted with (1) 0.1N ammonium acetate aqueous solution for 0.5 hrs., 0.25N acetic acid aqueous solution for 0.5 hrs. and 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.

-16- As is well known to those skilled in the art, the known and potential uses of GLP-1 is varied and multitudinous (See, Todd, et al., Clinical Science, 1998, 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 malabs-orption 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 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 to 200 mglkg/day, preferably 1x1 0' 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 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, Lubricating 0: -17agents 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 eLhyl 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 bioactiveagent 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. 081929,363 filed September 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S.

Application No. 081740,778 filed November 1, 1996, teaches sustained release compositions comprising a bioactive agent and cyctodextrin. U.S. Application No.

091015,394 filed January 29, 1998, teaches absorbable sustained release 1.

-18compositions 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-BAla-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 (Aiba'5)hGLP-1 (7-36)NH The title peptide was synthesized on an Applied Biosystems (Foster City.

CA) model 430A peptide synthesizer which was modified to do accelerated Bocchemistry solid phase peptide synthesis. See Schnolzer, et al., Int. J. Peptide Protein Res., 90:180 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-tle-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 i" -19synthesis 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 preactivated with HBTU (2.0 mmol) and D1EA (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 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 mL of HF containing 1 mL of anisole and dithiothreitol (24 mg) at OOC for 75 min.

HF was removed by a flow of nitrogen. The residue was washed with ether (6 x 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® C, 1 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 mLimin (Solution A water containing 0.1% TFA; Solution B acetonitrile 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 ((No-HEPES-His)', Aibs.)hGLP-1 (7-36)NH 2 The title compound (HEPES is (4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid)) can be synthesized as follows: after assembly of the peptide (Aib'-")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% OIEA in DMF for 2 mn.

I'

After washing with DMF and DCM, the resin is treated with 0.23 mmol of 2-chioro- 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 2hydroxyethylpiperazine for about 2 hours. The resin is washed with DMF and DCM and treated with different reagents 20% mercaptoethanot 10% DIEA in DMF and 15% ethanolamine 15% water/ 70% DMF) to remove the DNP group on the His side chain and formy group on the Trp side chain as described above before the final HF cleavage of the peptide from the resin.

Example 3 ((N.-HEPA-His)', Aib'-")hGLP-1 (7-36)NH 2 The title compound (HEPA is (4-(2-hydroxyethyl)-1-piperazineacetyl)) can be made substantially according to the procedure described in Example 2 for making ((Na-HEPES-His) 7 Aib'")hGLP-1(7-36)NH, except that 2-bromoacetic anhydride is used in place of 2-chloro-1-ethanesulfonyl chloride.

Example 4 (Aib', ,-Alat)hGLP-1(7-36)NH, 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 (Aib"-)hGLP-1(7-36)NH, in Example 1 above, but using the appropriate protected amino adds depending on the desired peptide.

Example (Aib-" Arg 2 Lysm(Ne-tetradecanoyl))hGLP-1(7-36)NH 2 The Boc amino acids used were the same as those in the synthesis of (Aib' 3 )hGLP-1(7-36)N1 i 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 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

V

-21protecting group. The resin was washed with DMF. Myristic acid (2.5 mmol) was pre-activated with HBTU (2.0 mmol) and D1EA (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% piperidine 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 (Aiba'-)hGLP-1(7-36)NH 2 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 add in place of the Myristic acid used in Example Example 6: (Aib'"5, Arg", Lys(N.-tetradecanoyl))hGLP-1(7-36)NH,; Yield 89.6 mg; MS(ES) 3577.2, Calculated MW 3578.7; Purity 96%.

Example 7: (Aib' o 3 Arg" 6 Lys3(N.-tetradecanoyl))hGLP-1(7-38)NH,; Yield 63.3 mg; MS(ES) 3818.7; Calculated MW 3819.5; Purity 96%.

Example 8: (Aib'- 5 Arg4", Lys"(N.decanoyl))hGLP-1(7-36)NH,; 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(N.-alkanoyl) residue can be carried out in an analogous manner to the procedure described for Example 5, (Aib' 5 Arg 4 Lys 3 (N-tetradecanoyl))hGLP- 1(7-36)NH. Fmoc-Lys(Boc)-OH amino add is used for the residue of Lys(N.alkanoyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. If the Lys(NrallVanoyl) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(N.-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, WI, USA, octanoic acid, decanoic acid, lauric acid and palmitic acid.

Example 9 (Aib 8 s Arg 2 6 Lys

M

(N-dodecanesulfonyl))hGLP-1(7-36)NH, 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 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 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(N.-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(N.-alkylsulfonyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys. If the Lys(N.-alkylsutfonyl) residue is not at the Cterminus, the peptide fragment immediately prior to the Lys(N,-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, 1-octanesulfonyl chloride, 1-decanesulfonyl chloride, 1dodecanesulfonyl chloride, 1-hexadecanesulfonyl chloride and 1-octadecylsulfonyl chloride.

Example (Aib 8 35 Arg 2 Lys"(N.-(2-(4-tetradecyl-l-piperazine)-acetyt)))hGLP-1 (7-36)NH, 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 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 2

W

-23- 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 mmot) 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 t-he peptide are the same as the procedures described for Example 1.

The syntheses of other compounds of the present invention containing Lys(Nc-(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(N,-(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(N.-(2-(4-alkyl- 1-piperazine)-acetyl)) during the alkylation step. If the Lys(NC-(2-(4-alkyl-1piperazine)-acetyl)) residue is not at the C-terminus, the peptide fragment immediately prior to the Lys(N.-(2-(4-alkyl-1-piperazine)-acetyl)) residue is assembled on the resin on the peptide synthesizer first.

Example 11 (Aib a Arg 2 6 S, Asp(1 -(4-tetradecyl-piperazine)))hGLP-1(7-36)NH, The Boc amino acds 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 (1mL) in 4 mL -l B-' -24of 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(N.-(2-(4-alkyl- 1-piperazine)-acety)) 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 (Aib- 3 5, Arg 2 3 AspM(1 -tetradecylamino))hGLP-1 (7-36)NH, 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 (1mL) 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 (Aib s 5 Arg 2 4 Lys"(N.-tetradecanoyl),f-Ala7)hGLP-1 (7-37)-OH The Boc amino acids used are the same as those in the synthesis of Arg"-, Lys(N.-tetradecanoyl))hGLP-1(7-36)NH2 (Example 270 mg of Boc-13-Ala-PAM resin (Novabiochem, San Diego, California, substitution=0.74 mmol/g) was used. The Boc protecting group on Boc-3-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 (Aib 8 Arg", Lys(N.-tetradecanoyl))hGLP-1(7-36)-OH The Boc amino acids to be used are the same as those in the synthesis of Arg.", Lys(N.-tetradecanoyt))hGLP-1(7-36)NH, (Example Fmoc- Lys(Boc)-OH (2.5 mmd) 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, 1L; 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 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(N,-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(Nt-alkanoyl) in the peptide, while Boc-Lys(2CIZ)-OH amino acid is used for the residue of Lys.

Example 366 (Aib", fB-Ala 3 Aec 7 )hGLP-1 (7-37)NH, A mixture of MBHA resin (0.2mmol, substitution=0.91mmol/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 (Aib 8 3-Ala", Aec')hGLP-1 (738)NH, 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: (Aib', 13-A la Aec"3)hGLP-1(7-38)NH 2 A mixture of MHI-A resin (0.2mmol, substitution=0.91mmol/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 .1 -27and 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 (Aib' Arg s 13-Ala", Lys 3 (N'-Aec-decanoyl))hGLP-1 (7-36)NHz A mixture of MBHA resin (0.2mmol, substitution=0.91mmol/g). Boc- Lys(Fmoc)-OH (1.17g, 2.5mmol), HBTU (4 mL 0.5M in DMF) and DIEA (1mL) 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 (431mg, 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.

E,,5:(Aibf)hGLP-1 (7-36)NH, Example 16: (i3-Alat)hGLP-1(7-36)NH Ex.ame ,7 ((N-Me-His) 7 Aib'-)hGLP 1 (7-36)NH 2 Eu. ((N-Me-His) 7 Aib', S-Ala 3 )hGLP-1(7-36)NH, Em 19: ((N"-Me-His) 7 Aib' 6 Arg"-)hGLP-1 (7-36)NH 2 -28- Example 20: ((No-Me-His)?, Aibs, Arg 2 1 t fl/-Ala 35 )hGLP- 1(7-36)NH, Exap~ 2: Ai 8 .A6Cfl5hGLPd (7-36)NH 2 Exarnoe n: (AibV, A5c 35 )h GLP-I (7-36)N H2 Example 23: (Aib', D-Aafl)hGLP- 1(7-36)NH 2 Example 24: (Aib t t"5 A6c 32 )hGLP-1(7-36)NH 2 Example 25: (Aib't-4 A5ce)hGLP-1(7-36)NH 2 Example 26: (Aib't35 Glu-7)hGLP-1 (7-36)NH 2 Enmco 27: (Aib-"-')hGLP-1 (7-36)NH 2 Errpie 28 ,(Aib 8 -3' 21 )hGLP-1 (736)NH 2 Ex,e 29: (Aib"--M3)hGLP-1 (7-36)NH 2 Example 30: (Aib3Th A6c' 8 -4)hGLP-1 (7-36)N- 2 Example 31: (Aib 6 A6cIZ.ZZ-3)hGLP-1 (7-36)NH 2 Example 32: (AibIZ', A6&9.-2 hGLP-i (7-36)NH 2 Example 33: (Aiblss. A6&'o)hGLP-1(7-36)NH 2 Example 34: (Aib" 5 4, Lysfl)hGLP-1 (7-36)NH 2 Example 35: (Aib', 2 A6cm)hGLP-1 (7-36)NH 2 Example 36: (.Aib-t A692-3)hGLP-1 (7-36)NH 2 Ezrwdea 37 (Aib'8 24 3 t A~c 2 2 )hGLP-1 (7-36)NH 2 Example 38: (Aib" 5 A~c' 2 )hGLP-1(7-36)NH 2 Example 39:, (Ajb 8m Cha 2 ')lGLP-1 (7-36)NH 2 exanvge 4o: (Aib'-w Aee)hGLP-1 (7-36)N H 2 exflg 4 1 (Aiba 21 A6cD-3 2 )hGLP-1 (7-36)NH 2 Exzrfo 42 (Aib 8 A6c SZ2, 3-AJtm)hGLP-1 (7-36)NH 2 Example 43: (Aib-'s, J3-Aia2)hGLP-1 (7-36)NH 2 (Aib 8 22'3)hGLP-1 (7-36)NH 2 Example 45: (AibBM0, Glu 2 3, A6c 32 )hGLP-1 (7-36)NH 2 Enmffe 48: (Aib' 2 4 3 Glu23, A6c 32 )hGLP-1 (7-36)NH 2 Exnl 47 (Aib 8 9 24 5 5 Glu A6c9 2 )hGLP-1 (7-36)N-1 Eaoe4:(Aib 8 24 A6c' 8 ,z.

2 I, Glu 2 ")hGLP-1 (7-36)NH, Example 49: (Aib 8 A6c 32 I-Aa5lhGLP-1 (7-36)NH 2 Example 50: (Aib", A5c 32 3-Alt-)hGLP-1(7-36)NH 2 Example 51: (Aiba. Glu 23 I3-Aa)hGLP-1(7-36)NH 2 Exa'nOe 52: (Aib 8 t3-Aafl5hGLP-1 (7-36)NH 2 Ex.-m-We13: /3Ala-5)hGLPd (7-36)NH 2

W

-29- Exri *(Aib 625 B3-Aat")hGLP-1 (7-36)NH 2 Example 55: (Aib', AMc' 1 13-Aafl5hGLP-1(7-36)NH 2 Example 56: (Aib, AMc 16 2932 3-AIafl5hGLP- 1 (7-36)NH 2 Example 57: (Aib', Aet 32 i3-Ala 35 )hGLP-1 (7-36)NH 2 Example 58: (Aib 5 Aftc', 13-Alt')hGLP-1(7-36)NH 2 Example 59: (Aib'. Lys 25 I-Aa4hGLP-1 (7-36)NH 2 Example 60: (Aib' 2 t, A6czO, i3-Alt-)hGLP-1 (7-36)NH 2 Example 61: (Aib', AS&" 2 3, J3-Ala )hGLP- 1(7-36)N- 2 Enam~e 62: (Aib 8 9 24 A6c29- 2 ,13-Alt-1)hGLP-1(7-36 )N lH2 io Example 63: (Aib Afct", /3-A~a-")hGLP-1(7-36)NH 2 Example 64: (Aib, Cha', t3-Aa')hGLP-1 (7-36)N- 2 .(Aib 8 A6c33, (3-Ala-5)hGLP-1 (7-36)NH 2 Exrce W,(Aib 6 A6cP- 32 1I-AIa

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5)hGLP-1 (7-36)NH 2 Example 67: (Aib'. 13-Ala 2 "1 5 )hGLP-1 (7-36)NH 2 Ei.weM: (Aib 6 -2,/3sAlaflshGLP-1 (7-36)NH 2 Example 69: (Aib. Glum. A6e, II-Aait)hGLP-1 (7-36)NH 2 EzxamqU 70 (Ailb"' Glu- 3 AMe. f3-Aa5hGLP-1 (7-36)NH 2 ExnV 71: Glue, A6 3 2 Lyt(NoctanoyQ., 13-AIaflhGLP-1 (7-36)NH 2 ExoeM Aia 24 r, Glu 23 A6&I2 L-AW)hGLIP-1 (7-36)NH 2 ea 3(Aib' 242 5 A6l 8 1, Gluz, &3Aat)hGLP-1 (7-36)NH 2 ExrM W74,(Aiba-w D-Arg36lhGLP-1 (7-36)NH 2 ExaffL M (Alba-3* D-LyS-flhGLP- I (7-36)N H 2 TexrS (Aib I-Al-m D-ArgM%)hGLP-1(7-36)NH 2 Ezaiwa. 7,~(Aib 8 D-LysflhGLP-1(7-36)NH 2 afo4(AIb'Th, Argflk-3)hGLP-1 (7-36)NH 2 ExirfvW 7M (Aib', Arg26M, I3-Alt)hGLP-1 (7-36)NH 2 Exarfo 0: (Aib 6 -35, Arg5'")hGLP-1 (7-36)NH 2 Exv 82: (Aib', Arg-'.4 ti-AltIIL- Ls (7ttraecnoy)h L- 7-6O Exarrol. 8 z Aib, Arg-14 Lys(NI-tetradecanoyl))hGLP-1 (7-3)OH Example 84: (Aib s-.7 Arg~o 3 LysN(Nc-tetradecaflOyl))hGLP-1 (7-37)OH Fxsncta a5. (Akb 8 Arg~fi.34, LysMo(N'-tetradecanoyl). D-Aa )hGLP-1 (7-37)OH Example 86: (Aib'- 3 5 Arg26 3 4, Lysfls(Nt-tetradecanoyl))hGLP- 1 (7-38)OH Example 87: (Aib 83 Arg25-34 a-Ala" 7 Lys-'8(N"-tetraciecaloyl))hGLP-1 (7-3-8)OH Example 88: (Ab"t Argot" Lys'(N'-tetradecanoyl))hGLP-1 (7-38)OH (Aib', Arg 't14 Lys 3 (Nc-tetradecanoyl). f3-Ala' 7 ")hGLP-i (7-37)0K Example 90. (Aib ArgflS34 LysX6(Nc-tetradecanoyl))hGLp-1 (7-37)OH Example 91: (Ajb" 5 Arg" t Ado')hGLP-1(7-37)OH- Example 92: (Aib" 5 Argd't4 Adofl)hGLP-1I(7-37)NH 2 Ejwnpte 93: (Aib', Argm6 3 t. Lys-4(N'-tetradecanoyl), D-A~a 37 )hG LP- 1(7-37)0K Example 94: (Aib' 7 Arg~aM3, Lys38(Nt-tetradecanoyQ))hG LP-1 (7-38)0 H Example 95: (Aib 8 Arg"t a3-Ala'1 7 Lys"a(N'-tetradecanoyl))hGLP- 1(7-38)0 H Example 96: (Aib 8 Lys2(N'-octanoyl))h GLP-11 (7-36)N H 2 (Ailb" 5 Lys'(N'-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 98: (AMbSX, Lysfl'(Nthexadecanoyl ))hG LP-1 (7-36)N H 2 Example 99: Lys25(N-octanoyl), 13-Aa5,hGILP-1 (7-36)NH 2 Example 100: (Ailb', Lys~o(N'-tetradecanoyl), 13-Aafl)hGLP-1 (7-36)NH 2 Example 101: (Aiba, Lys'(N'-hexadecanoyl), 3-Aa5hGLP-1 (7-36)NH 2 Example 102: (Aiba-', Lysfl(Nt-actanoyI). Arg'4)hGLP-1 (7-36)NH 2 Example 103: (Ailb'" Lys m (N'tetradlecanoyl), flg')hGLP-1 (7-36)NH 2 Exnnfl twc(Aibl-m, Lys m *(N'-hexadecanoyl), ArgflhGLP-1 (7-36)NH 2 Example 105: (Aib-t5 Lys N-decanoyJ), ArgflhGLP-1 (7-36)NH 2 Example 106: (Aib"15h Lys25. Lys sNc-octanoyl), ArgU)hGLP-1(7-36)NH 2 Example 107: (Aib 8 Th-5 Lys', Lysn(N'-tetradecanoy), Arg')hGLP-1 (7-36)NH, Emi *(Aib 8 -5 Lys~s, Lys"(N'hexadecanoyl), Arr)hGLP-1 (7-36)NH 2 Example 109: (Ait' -5 Arg4-3 Lyslo(Nt-ctanoyl))hGLP-1 (7-36)NH 2 Example 1 10: (Ai Arg-3"t Lys-"(N'-tetradecanoyl))hG LP-1 (7-36)N H 2 Exro i 11 (Aib'T.5h Arg 3.

4 Lys26(Nc-hexadecanoyl ))hGLP-1 {7-36)N H 2 Exanole 1t2: (Ailb 83 t Arg25-3, Lys26(N'-decanoyl))hGLP-1(7-36)NH 2 Example 113: (AVb, LysO(N'octanoyl), Argut J1-Ala3 5 )hGLP-1(7-36)NH 2 Example 114: (Ailb 8 Lys'(Nt-tetradecanoyl). Arg', i3-AIa' 5 )IGLP-1 (7-36)NH 2 Enam~e IM: (Aib&. Lys-6(N'-hexadecanoyl). Arg' 4 a-AlaflhGLP-1 (7-36 )NH 2 Example 116: (Aib', Lysm(NI-decanoyl), Arg

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13-AlaflhG LP- 1(7-36 )N H 2 Example 117: Lys 4 (N'-octanoyl))hG LP- 1(7-36)NH 2 Example 118: (Aib"Th5 Lys'NN-tetradecanoyl))hGLP-1 (7-36)NH, Example 119: Lysi(N'-hexadecanoyl))hGLP-1 (7-36)N8 2 -31- Example 120: (Aib 825 Arg' 6 Lysi4N'-octanoy))hGLP-1 (7-36)NH 2 Enolc 121: (Aib''1 5 Arg26, Lyt3(N'-hexadecaoyl))hGLP- I (7-36)NH 2 Example 122: (Ailb 83 Arg 2 Ly"N-eany)hL (7-36)NH 2 Example 123: (Aib 63 5 Arg 252 r' Lysfl(NE-octanoyl))hGLP-1 (7-36)NH 2 Example 124: (Ab-'t Argz2sa0, Lys&(Nt-tetradecanoyl))hGLP-1 (7-36)NH 2 Fxampte 125: (Aib't35 Arg 2 sm2, Lys 34 (Nchexadecanoyl))hGLP-1 (7-36)NH 2 Example 126: (AibBA3. Arg5 5 Lyt-(N-decanoy))hGLP-1 (7-36)NH 2 Example 127: (Aibts Lys 25 Arg25, Lysm(Ng-octanoy))hGLP-1 (7-36)NH 2 Example 125: (Aib 25 Lys 25 Arg26, Lys 3 4(N'-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 129: (Aib 8 Th LYS' 5 Arg'. LysM(Nt-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 130: (Aib'3, LysM4(Nc-octanoyl))hGLP-1 (7-36)NH 2 Enmfqe 13 1: (Aib" 5 .3 Lyt-(N'-tetmdcaOy))hG LP- 1 (7-36)NH 2 Example 132: (AibaM1, Lys'(N'-hexadecanOyt))hGLP-1 (7-36)NH 2 Example 133: (Aiba--15 Arg 3 Lys-'(N'-octanoyl))hGLP-1 (7-36)NH 2 Example 134: (Aib'-35 Arg". Lys

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6(N'-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 135: (Aib" 3* Arg 2 Lysm(N-hexadecalOyI))hGLP-1 (7-36)NH, Example 136: (Abt5 Arg 2 M t Lys NM-odanoyl))hGLP-1 (7-36)N-1 Exargoe 137: (Alb", Arg-3t Lys'(N-hexadecalOyI)hGLP-1 (7-36)NH 2 EafW13:(Aiba,3, Argut Lys sN-octanoyl))hGLP-1 (7-38)NH 2 er.1:(Aib 8 -3 Arg"-t4 Lys N-decnoy))hGLP-1(7-35)NH 2 Example 140: (Aib 8 Arg". Lysw(NN'tetradecanoyI))hGLP-1(7-38)NH2 Eznline 141: (Aib", 5 Arg 2 "t34 Lys~s(N'-hexadecanoy))hGLP- I (7-38)NH 2 Exr~ 4 :(Aib-3-3. Ag5..3 Lys'(N'-actanoyl)fl1GLP-1 (7-38)NH 2 Ewr0.A 1 43 Ajb 5.5.7 ArgS"t3 Lys-'(N'4-ec-anoyl))hGLP-1 (7-38)NH 2 Example 144: (AibJSA? Arg25-" Lys3(Ng-tetradecanoy))hG LP- 1(7-38)NH 2 Examoe 143: (Aib 8 5- 7 Arg5"t'.4 Lysu8(Nt-hexadecanoYl))hGLP-1 (7-38)NH 2 Example i48: (Aib 8 Akrg6., Ly9~(N'-octanoyl))hGLP-1 (7-38)N l-1 E~mw 147- (Aib', 3 t7 Arg 5,M Lys aN'-decanOyl))hGLP-1 (7-38)NH 2 (AibS-3fl.7 Arg6t4 Lysm(N'-hexadecanoyl))hGLP-1 (7-38)N 82 149O. (Ailb 8 1 3

S

37 1 Lys gN-octanoyl))hGLP-1 (7-38)NH 2 F~.0 ls. (Aib 8 3 5.

3 7, Argn.4 Lys-a(N'-decanoyl))hGLP-1 (7-38)NH 2 Example 151: (Aib" .1 3 1. Arg-25 m 't Lysm(NI-tetradecafloyl))hGLP-1(7-38)NH 2 -32- Exarr~1e 152: (Aib 8 3537 ArgzsNa 4 Lys~a(Nc-hexadecanoyI))hG LP-1 (7-35)NH 2 Example 1 53: (Aib"t, Lys 2 Arg'', Lys I(NI-octanoyi))hG LP- 1(7-36)NH 2 Example 1 54: Lys 25 A rg 2 "t34 Lys-6N-tetradecanoyI))hGLP-1 (7-36)NH, Example 155: (Aib'Th35 Lys" 5 Arg'-t Lys~r(N'-hexadecanoy))hGLP- 1(7-36)NH 2 Example 156: (Aib 8 Arg5 2 4 Lys~o(N'-cctanoy))hGLP-1 (7-36)NH 2 Example 157: (Aib 5 35, Arg"-. Lysm(Nc-tetradecanoy))hGL-P-1 (7-36)NH 2 Exam~s t58: (Aib 8 3 5 Arg 2t34 Lysm(N'-hexadecanyl))hGLP-1 (7-36)N- 2 Exml 159 (Aib", 5 Arg Lys 3 (NN-decanoyl))hGLP-1 (7-36)NH 2 Example 160: Example 161: Example 162: Ex,,ample 163: Example 164: Example 165: Example 166: ExamplIe 1S?: (Aiba enxxcij lee: (Aib', Example 169: (Aibo Example 170: Example 171: Eunmloe IM (Aibc, Exmpe13 (Aib Example 174: Example 175: Example 176: Example 177: Exnrcie I78: (Aibs Example 179: Example 180: Example 181: Example 182: Example 183: (Aib', Lys

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(N'octanoyl), 13-Ala5hGLP-1 (7-36)NH 2 (Aib 8 Lys 3 (N-tetradecanoyl), 13-Ala3flhGLP- 1(7-36)NH 2 (Aibl, Lys 3 4NN-hexadecanoyl), f3-Ala"4)hG LP-1I(7-36)NH 2 AMe, Lys-'N.-octanoyl), 1-Alt-)hGLP-1 (7-36)NH 2 (Aib', Glum, Lys'NNroctanoyl), I3-Aa")hGLP- 1(7-36)NH 2 (Aib', Glum, A6e, Lys

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N-octanoyl), i3-Alt3)hGLP-1 (7-36)NH, (Aib', Arg' Lys 3 NN'-octanoyl), 13-Alt3)hGLP-1(7-36)NH 2 Argm. LysM4(Nt-tetradecanoyO. t3-AlashG LP-1 (7-36)N H 2 Are, Lys(Nt-hexadecanoyl), I3-Aal)hGLP-1 (7-36)NH 2 Arge, Lyst(N-decanoyl), i3-Ala-"')hGLP-1 (7-36)N- 2 (At'b, Arg25Z2, Lyt(Ntoctanoyl), A-Ala 3 5 )hGLP-1 (7-36)NH 2 (AbV, Arg-1', Lys"4(N'-tetradecanoyl), /3-AltI)hGLP-1 (7-36)NH 2 Arg5 5 LysJ(Nz-hexadecanoyfl. B3-Alafl)hGLP-1 (7-36)NH 2 ArgflZ2, Lys34(N'-decanoyl), i3-Alt3)hGLP-1 (7-36)NH 2 (Ailba, Lys 2 t. Argm, LysM(Nt-octanoyl), 1-Alt--)hGLP-1 (7-36)NH 2 (Aib', Lys2, ArgZ, Lys'(N-tefradecanoyl), I3-Ait-')hGLP- 1 (7-36)NH2 (Aib', Lys2I, Arg 2 Lys"(N'hexadlecanoyl), B3-Aafl5hGLP-1 (7-36)NH 2 I3-Ale", Lys~'(N'-octanoyl ))hGLP-1 (7-36 )NH 2 13-Alt' Lys3'( N'-tetradecanoyl))hGLP- 1(7-36)N H 2 (Aib t3-Ala 3 5 Lysw'(N'-hexadec-anoyl))h GLP- 1(7-36)NH 2 (Aib Argz, B3-Alt3, Lys-'(N'-octanoy))hGLP-1 (7-36)NH 2 (Aib-, Arg-. B3-Alt-, Lys& 8N'-tetradecanoyl))hGLP- 1 (7-36)N H 2 (Aib', Argn, B3-Ala 35 Lys '(N'-hexad ecanoy))hGLP-1I (7-36)NH 2 (iba, Argn-- 4 B-ANat 5Lys- 6N-octanoyl ))hG LP- 1(7-36)NH H 2 Example 184: (Aib 8 Arg 2 13-Ala 3 1, Lys&'(N'-tetradecanoyl))hGLP- 1 (7-36)NH 2 E~n~ .(Aibt. Arg 2 6.3t 13-Ala 35 Lys'(N'- hexadecanoyl))hGLP-1 (7-36)NH 2 Exinmpl 188: (Aibe. Arg26.. (-Al3t, Lys&6(N'-decanoyl))hGLP- 1 (7-36)NH 2 Example 187: (Aib', Lys25, Arjt /,3-Ala-'s Lys-'(N'-octanoyI))hGLP-1 (7-36 )NH 2 188: Lys 2 5, Arge-4 LysMa(Na-tetradecanoyl). 13-Aa')hGLP-1 (7- 36)NH 2 Ea~ 1 8 Lys" 5 Arg'* 3 t fl-Ala 3 5 Lys- NL-hexadecanoyI))hGLP-1 (7-36)NH 2 Example 190: (Aib Arg25-'t4 (3-Ala 3 Lys 6N-octanoyl))hGLP-1 (7-36)NH 2 Example 19 1: (Aibt, Arg" 3 t i-Ala5t Lysr(Nc-tetradecanoyl))hGLP-1 (7-36)NH 2 Er~L 9 (Aib'. Arg 2 B3-Als. Lys3 N-hexadecanoyl))hGLP-1 (7-36)NH,2 EwnrfAc 19:(Ab'. Arg5263t 13-Al35 Lys 16N'-decanoyl)hGLP-1 (7-36)NH 2 Example 19.4: Lyz 5N'-octanoyl), Afct", Arg')hGLP-1 (7-36)NH 2 (AibV-35 Lys26NI-tetradec-anoyl), A661. Arg') hGLP- 1 (7-36)N H 2 Example 196: Lys(N'hexadecaioyl). A6cP, ArgM)hGLP-1(7-36)NH 2 Example 197: (Aib". A6e2. Ly(cotny)hL- (7-36)N- 2 Example 198: AMe, Lys 4N-tetradecanoyl))hG LP-1 (7-36)NH 2 Example 199: (Aib25t A6e. Lys(N-hexadecalOyl))hGLPd1(7-36)NH 2 Example 200: (AittZ. Arg~o, AMe, Lys (NI-octafloyl))hGLP-1(7-36)NH2 Example 201: (Aibs'3, Arg 3 s. A66e, Lys 3 4NN-tetradecanOyl))hGLP-1(7-36)NHz Example 202: (Aib'" A6&. Lys oN-octanoyl))hGLP-1 (7-36)N- 2 Envrp.203: (Aib'-3, AMe, Lys (N-tetradecaloyl))hGLP-1 (7-36)NH 2 Example 204: (Aib'Th AMe, Lys

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'(N'-hexadecanoyl ))hGLP-1 (7-36 )N H 2 Example 205:. Arg 2 AMe, Lys-'(N'-octanoyl))hGLP- 1(7-36)NH2 Example 206: (Aib'5, Arg 3 A6& 2 Lyst(N-tetradecanoy )hGLP-1 (7-36) NH 2 Example 207: (Aiber-, Arga6, A6e, Lys aN'-hexadecanoYl))hGLP-l (7-36)NH 2 E.rf (Aib't" ArgmM *u.A6c 3 2 Lys3(N-ctanoyl))hGLP- 1 (7-36)N H 2 Example 209: Arg'-

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A6c', Lys 3 '6NN'decanoyl))hGLP-1 (7-36)NH-1 Example 210: (Ait'-"5 Arg' 0 't A6c', LysM(Nc-tetradecanOY))hGLP1(7- 3 G)NH2 Example 211 -1(Aib' 35, ArgfM-3, AWc2, Lys3(NN'hexacdecanOYl))hGLP-I (7-36)NH 2 Example 212: (Aib""2435 Lys 6(N'-octanoyI). ArgflhGLP-1 (7-36)NH 2 ExnVW 213: (Aib 3 t35 Lys'(N'-tetradecanoyl). Arg')hGLP-1 (7-36)NH 2 Example 214:. Lysr(N-hexadecaloyl). ArgflhGLP-1I(7-36)N-12 Example 215: (Ait9 2 4 tI Arg 26 Lys 34 (N'-octanoyl))hGLP- 1(7-36)NH 2 Example 216: (Aiba*,4.t Arg 2 Lys 34 (N'-Letradecanoy))hGLP-1 (7-36)NH 2 Example 217:, (Aib'a 2435 Arg 2 1 L ys 3t (N'-hexadecanoyl))hGLP.1 (7-36)NH 2 Example 218: (Aib 8 2 Argaat, Lys36(N'-caoI)GL 73)H Examle 19:(Ai .24-3Ag1 L 3 N'-teteanoyl))hGLp-1 (7-36)NN 2 Examle20: (Aib 8 r 243 A rg m 6- L yS

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(N'-hexadaecanoyl)GLP- 1(7-36)N ft Example 221: (Aib 2 .5 AG 3 Lys(N-odcanyl))hGLP-1(7-36)NH 2 Example 222: (Aib Glu',A 3 ,Lys s'(NN-octa noyl), Ar M GLP- (7-36)N H 2 Eampl 223: (Ab"-5 Glu3, Lys-'-ttrdcanoyl), ArgflhGLP-1 (7-36)NH Exampl 224: (Aib' 5 Glu 2 L s('-exadecanoy1), ArgM)GL.1 (7-36)NH 2 Example 225: (Aib 8 1t Glu 23 Lys 14 Ut-o ctanoy)P 173 Ag)H 2 L-(-3 Example 226: (Aib m GlU1 3 ALys' 9(N.octanoyl))hGLP- 1(7 3)NH 2 Example 227: (Aib t Glu 23 Arg 2 Lys,'(N'octanoyl))hGLP-1(7-36)NH 2 Example 226: (AWb" 5 01u 23 Arg-2, Lys-1(N'-oteaanoyl))hGLP-1 (7-36)NH 2 229: (AV-bM, Glu 2 3 ArgZ', Lyt3(NthexradecanoyI))hGLP-1 (7-36)NH 2 Example 230: (Aib 8 -3 Glu 23 Lyr(Nt LactanoyIhGLPecnoI)hG1 (7-36)NH 2 ESamp. 20 (Ab- Glu3 Lys6(N-trdcanoyl))hGLP 1 (7-36)N 2 Ezana 232: (Aib 8 Glu 23 LysM(Nt-hexadecanoy))hGLP-1 (7-36)NH 2 Exa mple 233: (Aib" '5 G lu 23 Argm- 5 Lys 2 (N'-octan oyl))hG LP- 1 (7-36)NH 2 Exfo 234: (Aib 8 Glu 23 Arg614 Lys 4N-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 235: (AjbSM. Glu23, Arg6-4 Lysm(N -hexadecanoyl))hGLP-1(7-36)NH 2 Example 236: (AMiax. Lys2O(N--octanayl), ArgflhGLP-1 (7-36)NH, Canml 237: (Aib&--O*t4 Lys26(N'-tetradecanoy), ArgflhGLP-1 (7-36)NH 2 Example 238: (AibGOM. Lysm NI-hexadecanoyl), Arg

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)hGLP- 1(7-36 )NH 2 Example 239: (Aib 8 23 Arg 2 Lys-',(NL-octanoyl)ytGLP-1 (7-36)NH 2 Example 240: (Aib'"Th Arg m Lyt-(N-tetradecanoyl))hGLP- 1(7-36)NH 2 Example 241: Argmo, Lys-"(N-he xadeca noyl))hGLP- I (7-36)NH, Example 242: (Pdb 8 Argmt-" Lys

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"(N'-octanoyl))hGLP- 1(7-36)NH 2 Example 243: (Ad? 8,3035 Arg6.4t Lys'"(N-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 244: (Aib t "30" 5 Arg2-M, Lysm(N'-hexadecanoyl))hGLP-1 (7-36)NI-l Example 2457 (Aib 83 5 Glum, A6c

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Lys -'(N'-actanoyl))hG LP- 1(7-36)NH 2 Exampee 246 (Ai b6 35h Glu"3. A6c1 2 Lys 36 '(N'-tetradecanoyl))hGLP-1 (7-36)NH 2 Examele 247: (Aib 5 a 2 t3 ,0GIU 23 A6 C 2 Lysm(N'-hexadecanoyl))hGLP-1I(7-36)NH 2 Example 248: (Alb'8T5h Glut,. Arg- 4 A6C 3 2 Lys'(N'-octanoy$))hGLP-l (7-36)NH, Example 249: (Aib68 3 5, Glu' 3 Arg 26 A6 C 32 Lys36(Nc-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 250: (Aib' 35 GIu 23 Arg~o't A6c', Lys'(N'-hexadecanoy))hGLP-1 (7- 36)NH 2 Example 251: (Aib 8 6 24 35

GIU

23 Arg26 3 U A6c0 2 LysX6(Nt-octanoy1))hGLP-1 (7-36 )NH 2 Example 252: (Aib 524 Th5 Glu 23 Argd"3, A6c 32 Lys-(Nt-tetradecanoyl))hGL.P-1(7-36) NH 2 Example 253: GlU"3, Arg"' A6c32, LysX(N'-hexadecanoyl))hGLP-1(7- 36)NH 2 Exampl e 254: (Aib 524 03 Glu23, Argl'. A6c 32 Lys- N-octanoyl))hGLP- 1(7-36)N H 2 (Aibg 2 3 1 Glum3, Arg~ m Aft, Lys'( N'-tetradecanoyl))hGLP- 1(7-36)NH2 Example 256: (Aib 8 24 .3035 Glu3, ArgMUt Aft", LysM(Nc-hexadecanoyl))hGLP-. 1 (7- 36)NH 2 Example 257: ((Na-HEPES-His)Y. Aib 35 )hGLP-1 (7-36)NH 2 ,,l..,((NI-HEPES-His)I. I3-AaI~hGLP-1 (7-36)NH 2 Example 252: ((N-HEPES-His)', AVb, 13-Aa35hGLP-1 (7-36)NH 2 .,mlezo ((Na-HEPA-His) 7 Aibfl)hGLP-1 (7-36)NH 2 Exam'ple Mo: ((NO-HEPA41is) 7 aiAlt)hGLPI1 (7-36)NZ- Example ((N--HEPA-His)'. Aib i3-AI&3 5 )hGLP-1 (7-36)NH 2 EIO 253. ((Na-tetradecanoy-His)Y, Aib33)hGLP-1 (7-36)NK 2 Example 254: ((NO-tetradecanoyl-HisY'. t3-AaflhGLP-1 (7-36)NH 2 Example 265: ((No-tetradecanoyl-His)Y. Aib"- 35 )hGLP-1 (7-36 )NH 2 Example 266: ((Na-tetradecanoy-HisY, Aib 8 I3-AaflhGLP- 1 (7-36)NH 2 Example 267: ((N~tefradecanoylkHis)', Aib'5hGLP-1 (7-36)NH 2 Exm,. ((NII-tetradecanoyl-His)Y, Arg 2 6 t. B-Altl)hGLP-1 (7-36)NH 2 Example 269: ((NI-tetradec-anoyl-HisV. AibSM4, ArgflM)hGLP-1(7-36)NH2 Example 270: ((N"-tetradecanoyl-His) 7 AMb, Arg-t4 (-Aafl)hGLP-1 (7-36)NH2 Euampi 2 71: ((NO-tetradecanoyl-His) 7 Arg" m 3-Aa5lhGLP- 1(7-36 )NH 2 Example 272: ((Na-tetradecanoyl-His) 7 Aib">s Arg 25 -IO.U)hGLP-1 (7-36)NH 2 Example 273: -tetrad eca noyl-His)', Aib', Arg'ozoM, 13-Aa')hGLP-1 (7-36)NH, Example 274: (Aib-ts Lysz*(N'-octanesulfonyI). ArgflhGLP-1 (7-36)NH 2 E1.. 215 (Aib 8 Lys 2 (N-dodecanesulfonyl), ArgulhGLP-1I(7-36)NH, Example 276:- (Aib t 5 Lys 2 (N-hexadecanesuIfonyI), Arg

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")hGLP-1 (7-36)NH 2 Example 277: (Aib'iS. Arg 26 Lys34N'c-octanesulfonyI))hGLP-1I(7-36)NH 2 Exarptc 278. (Aib 825 Arg 2 6 Lys(N'-dodecanesulfonyl))hGLP-1 (7-36)NH 2 Example 279: (AV1 83 5 Arg 28 Lys'4(N'-hexadecanesufonyl))hGLP-1 (7-36)NH 2 Example 280: (Aib' 3 Th Arg 26 3 t Lys'6NN'-octanesuifonyI))hGLP- 1(7-36)NH 2 Example 281:- (Aib' 3 t, Arg26 3 t Lys3(N'-hexadecaiesulony))hGLP- 1 (7-36)NH 2 Fxmo 28 P Ab' 3 T Asp 2 5( 1 -(4-dfecylpiperazine)). Argfl)hGLP-1 (7-36)NH 2 Exampw 281: (Ai bt, Asp'( 1 -(4-dodecylpi perazine)), ArgflhG LP- 1(7-36 )NH 2 Example 284: Asp'(l1-(4-tetradecylpiperazine)), Arg- )hGLP- 1(7-36 )NH2 Example 285: (Aibt"5 Asp2 1 -(4-hexaclecylpiperazine)), Arg

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)hGLP-1 (7-36)NH 2 Enmv. 28W: (Aib'-Th5 Arg'6, As&4( 1 -(4-decypiperazine)))hGLP- I (7-36)NH 2 Exam0.c 257: (Aib 83 Arg 2 1, Asp"'(l -(4-dodecylpiperazine)))hGLP- 1(7-36 )NH 2 Example 288: (Aib 8 3 Arg-', Asp 3 4(1 -(4-tetradecylpiperazine)))hGLP-1 (7-36)NH 2 Example 289: (Aib' 30 Arg 2 Asp

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(1 -(4-hexadecylpiperazine)))hGLP-l (7-36)NH 2 Eram~ MCI (Aib'T.5h Arg26 3 t, AspZ(1 -(4-decylpiperazine)))hGLP-1 (7-36)N H 2 Exarce 291: (Aib 8 Arg Mspm(1 -(4-dodecylpiperazine)))hGLP- 1 (7-36)NH 2 Exampte 292: (Aib'Th5 Argst Asp

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(l1-(4-hexadecylpiperazine)))hG LP-1 (7-36)N H 2 Ewao 293: (AIb 6 Th5 Arg,"t Asp38(1-(4-decylpiperezine)))hGLP-1 (7-38)NH 2 Eanoe (Aib"'3 5 Arg26

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3, Asp'(1 -(4-dodecylpiperazine)))hGLP-1 (7-38)NH 2 Example 295: (AibM-. Arg"t Asp' (1 -(4-tetradecylp iperazine)))h GLP- 1 (7-38)N H 2 Example 296: (Aib8M3, Arg6-u Aspm(1 -(4-hexadecylpiperazine)))hG LP-1 (7-38 )N H 2 Enmrole 297 2 (Aib g0.7, Arf 6, 4 AspI( 1 -(4-decyl pipe razi ne)))hGLP- 1 (7-38)NH 2 Exro 298 (Aib 8 ,3S 37 Mrg~,U, AspN(l1-(4-'dodecylpiperazine)))hGLP-1 (7-38)N H 2 Example 299: (Aib 6 Arg"', Asp-3(1 -(4-tetradecylpiperazine)) )hGLP-1 (7-38 )NH 2 Example 300: (Aib' 53 ArgX 3 4, Asp-u(l1-(4-hexadecylpiperazine)) )hGLP- 1(7- 38)NH 2 (Aibt5 Arg 25 't Asp~o(1-(4-decylpiperazine)))hGLP-l (7-36)NH 2 Exrv 302i (Aib 8 Th, Arg'-t Asp'( 1 -(4-dodecylpiperazine)))hGLP- 1 (7-36)NH 2 Example 303: Arg"-t Asp 30 1-(4-tetradecylpiperazine)))hGLP-1 (7-36)N H 2 Example 304: (Aib'5, Arg- 5 t4 Asp2'( I-(4-hexadecylpiperazine)))hGLP- 1(7-36)NH 2 Exa~qM (ib 5 5 ,Arg 2 5 Asp 14 (1 -(4-clecylpiperazine)) )hGLP-1 (7-36)NH 2 T Arg 252 8 Asp-u(1 -(4-dodecylpiperazine)))hGLP-1 (7-36)NH 2 Example 307:. (Aib', Arg 2 1.2, Asp34( 1 -tetradecylp iperazine)))h GLP 1(7-36)NH2 Example 308: (Aib 8 s, Arg'.2. Aspu( 1-(4-hexadecylpiperazine)))hGLP-1 (7k36)NH 2 -37- Exampic M09: (Aib 8 35 Arg5.203 Asp 1 -(4-decylpiperazine)))hGLP-1 (7-36)NH 2 (Aib" 3, Arg 25 6 ,34. Aspm( 1 -(4-dodecylpiperazine)))hGLP- 1 (7-36)NH 2 Example 311. (Aibl' T Arg 252 "t34 Asp'(l -(4-tetradecylpiperazifle)))hGLP- 1(7-36 )NH 2 Example 312: (AlbA 3 t, Arg 2 9 t-4 Aspm( 1 -(4-hexadecylpiperazifle)))hGLP-1 (7- 36)NH 2 Exampi 313- (Aib 835 Arg5--34 Asp

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3( I -(4-decylpiperazine)))hGLP-1 (7-38)NH 2 ExnV 314: (Aib 83 -1 Arg' 29 3 t Asp 1 -(4-dodecylpiperazine)))hGLP-1 (7-38)NH 2 Example 315: (Aib 8 3 t. Arg 252 "t34 Asp 3 l -(4-LetradecylpiperaZifle)))hGLP- 1 (7-38)NH 2 Example 316. (Aiba- 3 t Arg-152' 3 t, Asp"(1 -(4-hexadecylpiperazifle))hGLP-1 (7- 38)NH 2 innxa 317: (Aib 6 35 .3 7 Args25"3, Asp 'I -(4-decylpiperazine)))hGLP- 1(7-38)NH2 ExavOoe 3 15: (Ai ba.

5 5 3 Arj""'634, Asp~a(1-(4-dodecylpiperazine)))bGLP-1 (7-38)NH 2 Example 319: (Ab 5.7 Arg25,2.3t ASp38(1-(4-tetradecylpiperazine LP- 1(7- 38)NH 2 Etaiwa (Aib 63537 Arg5-" 3 t Aspm(l1-(4-hexadecylpiperazine)))hG LP- 1(7-38 )N H 2 Example 321: (AjbBA5, Argd"t4 Gli9N1-dodecylamin0))hGLP-1 (7-36)NH 2 Example 322: (AibSZ. Glu2 1 -dodecylamino), Arg34)hGLP-1 (7-36)NH 2 czanoo (Aib'- 3 t Arge, GluM4(1 -dodecylamino))hGLP-1 (7-36)NH 2 Example 324: (Aib" 7 Argat34 Glu 1l-dodecylamilO))hGLP-1(7-38)NH 2 E.,ra (Aib'- 2 5 ArgM, Ly2N-2(-ecllpprzn)-c l)hL-(7-36)NH 2 Exro 326 (Aib-Th5 ArgM., Lys 25 (N'-(2-(4-dodclyl-1 -piperazine)-acetyl)))hG LP- 1 (7- 36)NH 2 Example 327: (Aib 825 g. Arg"4, Lysr(Nt-(2-(4-tetradecyl- I -pipe razine)-acetyl G LP 1 (7-36)NH 2 Example 328: (Aib 82 Arg't Lys"(N'-(2-(4-hexadecyl-1 -piperazirie)-acetyl )h GLP 1 (7-36)NH 2 Ejcanfve 329: (Aib 8 35 Arg 29 Lys 34 N'-(2-(4-clecyl- 1 -pipe razirie)-acetyl) G LP- 1 (7-36) N H Eafu3:(Aib'- 3 t Arg~s. Lys 1 (N'-(2-(4-dOdCCYl-1 -piperazine)-acetyl))bGLP-l1 (7- 36)NH, Example 331:- (Aib't Mrg 2 Lys-u(N'-(2-(4-tetradCYl-1 -piperazine)-acetyt )hGLP- I (7-36)NH 2 Example 332: (Aib"t Arg m Lys 3 4(N'-(2-(4-hexadecy-1 -piperazirie)-acetyl) ))hGLP 1(7-36)NH 2 -38- Examole 333: (Aib 8 Arg6t4 Lys- N'-(2-(4-decyl- 1-piperazine)-acetyl)))hGLP- 1(7- 38)NH 2 Examfoe 334: (Aib 8 ,3 5 Arg 2 t4 Lys'O(N'-(2-(4-dodecyl-l1-piperazine )-acetyl) ))hGLP-1 (7- 36)NH 2 Example 335: (Aib-t Arg" Lys'( Nc-(2-(4-hexadecyl 1 -piperazine)acetyl)))hGLP-1 (7-36)NH 2 E.ampl 336: (Ab"1 Arg~s 3 t Lys3 IP-(2-(4-decyl-l1-piperazine)-acetyl) )ft'GLP- 1(7- 38 )NHF 2 Exampl 337: (Aib 6 5, Arg--u. Lys

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(N'-(2-(4-dodecyl- 1 -piperazine)-acetyl)) )hG LP- 1(7- 38)NH 2 Example 338: (Aib't35 Args"t4 Ly~(N(-41 rdey--piperazi ne)acetyl)))hGLP-1 (7-38)NH 2 Example 339: (AibsM3, Arg"' 3 Lys 'sN'-(2-(4-hexadecyl-1 -piperazine)acetyl)))hGLP-1 (7-38)NH 2 Entre 340: (Aib 8 M35 37 Arg 2 "t34 Lys~a(N'-(2-(4-decy-1 -piperazine)-acetyl )))hGLP-1 (7- 38)NH 2 Exm~ 341: (Aib 8 '3s 37 Arg", Lys

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(N'-(2-(4-dodecyl-1 -piperazine)-acetyl)))hGLP- 1(7- 38)NH 2 Example 342: (Aib""5.

7 Arg25 3 4, Lys~a(N'-(2-(4-tetradecy-1 -piperazine)acetyl)))hGLP-1 (7-38)NH 2 Example 343: (Aib: 5r. Argmsad, Lys 3 (N-(2-(4-hexadecyl-1 -piperazine)acetyl)))hGLP-1 (7-38)NH 2 (Aib 8 -33 ArgflM.4 Lys26N'-(2-(4-decyl-1 -piperazine)-acetyl )))hGLP- 1(7- 36)NH 2 Er34 Ab 3 ,Arg~r-

M

Lys 2 (N'-(2-(4-dodecyl-lI-piperazine)-acetyl )))hGLP-1 (7- 36)NH 2 Example 346: (AibhM., Aorg-'S. Lys 5N'-(2-(4-tetradecyl- 1 -piperazine)acetyl)))hGLP-1 (7-36 )N H, Example 347: Aibt5 Arg-s 34 Lys~s(N-(2-(4-hexadecyl-l1-piperazine)-acetyl ))hGLP- 1(7-36)NH 2 Enrnoie 348 (Ai b 8 -1 Arq 252 Lys 34 (N-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP- 1(7- 36)NH 2 EnampWc 349 (AVb Arg 22 Lys'(N'-(2-(4-dodecyl- I -piperazine)-acetyI)))hGLP-1 (7- 36)NH 2 Example 350: (Aib 8 35 Arg 2 5 t Lys' (Nr-(2-(4-tetrad ecyl- 1 -piperazine)acetyl)))hGLP-1 (7-36)NH 2 Example 351: (Aib"'t Arg 352 Lys"(N'-(2-(4-hexadecyl-1-piperazine)acetyl)))hGLP-1 (7-36)NH 2 Eajnvl 3,27 (Aib& 3 Arg 35 'o-ut L ys3 N-(2-(4-lecy-l1-piperazine)-acetyl)))hGLP- 1(7- 36)NH 2 Exam'e 3W3: (Aib-t krg25,26' 3 U Lys-"(N'-(2-(4-dodecyl- 1 -pipe razi ne)-acetyl hG LP- 1 (7- 36)NH 2 Example 354: (Aib'Ths Arg26tA Lys36(N'-(2-(4-tetradecyI- 1 -piperazine)acetyl)))hGLP-1 (7-36)NH 2 Example 355: (Aiba,35 Args26t4 LysM6(Nt(2-(4-hexadecy-1 -piperazine)acetyl)))h GLP- 1 (7-36)N H 2 e.yi,, 3w, (Aib" 33 Arg 2 Lys-4(N',-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP-1 (7- 38)NH 2 Sample u7: (Aib- 3 Th Argz-"t LysamN't-(2-(4-dodecyl1 -piperazine)-acetyl)))hGLP-1 (7- 38)NH 2 Example 358: (Aibz5, Arg 2 Lys36(N'-(2-(4tetadecyl-1 -PiPerazifle)acetyl)))hGLP-1 (7-38)NH 2 Example 359: (Aib", Arg3".3t LyuN-2(-eaey- pprzn) acetyl)))hGLP- 1 (7-38)N H 2 Example 360: (Aib 6 3537 Arg 2 2634 Lysw N-(2-(4-decyl-1 -piperazine)-acetyO)))h GLP- 1 (7- 38)NH 2 Eni.O. Aib 8 7 Arg't34 Lys38(N'-(2-(4-dodecy-1 -pip erazine)-ac-etyI )))hGLP 1 (7-38)NH 2 Example 362: (Aib"" 3 ArgfliflM., Lys- N-(2-(4-tetradeCyl-l1-piperazine acetyfl)))hGLP-1 (7-38)NH 2 Exa~ 3W (Aib' 37 Arg 526.34 Lys aN-(2-(4-hexadecy-1 -piperazine)-acetyl )hGLP 1(7-38)NH 2 Example 364: (Aib& 3 5 Arg 263 t, Lys m (N-decanoyl))hGLP-1 (7-36)OH Example 365: (Ab M3 LYS 25 Argfl.4 Lys-u(Nt-decanoy ))hGLP- 1(7-36)0 H Example 370 (AibS 35 .Argfl--1. Avt3, Adofl)hGLP-1 (7-38)NH 2 Exampie 371 Example 372 Example 373 Example 374 Example 375 Example 376 Example 377 Example 378 Example 379 Example 380 Example 381 Example 382 Example 383 Example 384 Example 385 Example 386 Example 387 Example 388 Example 359 Example 390 Example 391 Example 392 Example 393- Example 394 Example 395 Example 396 Example 397 Example 398 Example 399 Example 400 Example 401 Example 402 (Aib 8 35Arg 2 Asp' 7 Ava'. Ado' 9 )hGLP-1 (7-39)N-4 (Aib 8 '.35Arg Aun3 7 )hGLP-1 (7-37)NH 2 (Aib t 17 35,)hGLP-1 (7-36)NH 2 (Aib 8 ,Arg'- t 1-Alam, D-Asp3 7 Ava', Aun")bGLP- 1(7-39)NH, (Sly 8 I3-Ala5)hG LP- 1(7-36 )N H 2 (See, i3-Aa,5)hGLP-1 (7-36)NH 2 (Sly', AibflhGLP-1 (7-36)NH 2 (Aibt, Lys", f3AlaM1-)hGLr-1 (7-36)NH 2 (Aib, Leu' 7 13-Aafl)hGLP-1 (7-36)NH2 (AVb, Lys-3, 3-Alt2)hGLP- 1 (7-36)NH 2 (Aib Lys", Leu 27 13-AJaflIhGLP-1 (7-36)NH 2 (Aibt D-Argfl6hGLP-1 (7-36)NH 2 (Aib 8 -Ala', D-Arg 37 )hGLP-1 (7-37)NH 2 (Aib 82 T B3-Adt3)hGLP-1 (7-36)NH 2 (AibIZ, B-Ala 3 r Arr3)hGLP-1 (7-35)NH2 (Aib'8 2 7 1, 1-Ala 5 3 7 Arg-m-NibGLP-1 (7-39)NH 2 (Ailb', LysIU?2, 1-Ala3)hGLP-1 (7-36)NH 2 (Aiba. Lys 2 7 13-AiaflhGLP-1 (7-:36)NH 2 (AIM, 1-Alt, Arga)hGLP- 1 (7-38)NH 2 (Aib', Arg"t I-Al ,)hGLP-1 (7-36)NH 2 (AIbs, D-Arge)hGLP-1 (7-36)N-1 (Aiba, 13-Ala ArgflhGLP-1 (7-37)NH 2 (AIV, Phe 3t 13-Aat)hGLP-1 (7-36)N8 2

(AIS

3 (Ailb" (Ailb", (AibM 3', (AIM"a, (Ab'"

(AVIM",

(Aiba" 5 Phe"')hGLP-1 (7-36)NH 2 Nal 3 l )hGLP- 1(7-36)N- 2 Na1 28 )hGLP-1 (7-36)NH 2 Ah2g-34, Nal' 1 )hGLP-1 (7-36)NH 2 Phe 31)hGLP-1 (7-36)NH 2 Nallt 3 I)hGLPD-1 (7-36)NH 2 Nal1 2 31)hGLP-1 (7-36)NH2 Lys 3 (N'-decanoyl))hGLP-1(7-36) NH 2 Example 403 (Aib' 5 ".Arg't Lys'(N'-decanoyl))hGLP- 1(7-36)NH 2 Example 404 (AiM' 5 Argfl-14 Lysma(Nc-dodecanoyl))hGLP-1 (7-36)NH 2 -41- Example 405 (Aib',B-Ala5,Ser 7 (O-decanoyl))hGLP 1(7-37)-NH 2 Example 406 (Aib" 27 3-Ala 35 1 7 Arg", Lys 9 (N'-octanoyl))hGLP-1 (7-39)NH 2 Example 407 (Aib' Arg-"' 3 3-Ala 5 Lys37(N'-octanoyl))hGLP-1(7-37)NH, Example 408 (Aib', Arg"- 8-Ala 5 Lys7(N'-decanoyl))hGLP-1(7-37)NH, Example 409 (Aib', Arg

S

-Ala", Lys 3 (N'-tetradecanoyl))hGLP-1(7-37)NH, Example 410 (Aib', I-Ala 5 Lys 3 7(N'-dodecanoyl))hGLP-1(7-37)NH 2 Example 411 (Aib 8 Arg 2 3 3-Ala, Lys7(N'-dodecanoyl))hGLP-1 (8-37)NH 2 Physical data for a representative sampling of the compounds exemplified herein are given in Table 1.

Example Mol. Wt. Mol. Wt. Purity Number Expected MS(ES) (HPLC) 24 3351.8 3352.2 88% 26 3340.17 3340.9 99% 27 3353.81 3353.9 99% 29 3353.81 3353.9 99% 3352.6 3352.5 97% 51 3326.74 3326.6 99% 78 3395.81 3395.5 96% 136 3494 3494 99% 364 3523.02 3523.6 99% 365 3580.13 3580.3 369 3677.25 3677 97% 370 3692.28 3692.4 98% 371 3807.37 3807.3 98% 372 3579.11 3579.7 97.90% 373 3337.81 3338.5 94% 374 3779.3 3779.5 94% 375 3297.7 3297.5 99% 376 3327.7 3327.4 98% 377 3398.8 3398.7 97.50% 378 3311.6 3311 93% 379 3366.85 3366.5 97% 380 3309.8 3309.4 99% 381 3354.8 3354.5 97.70% 382 3350.9 3350.3 97.20% 383 3311.73 3310.7 92% 384 3481.95 3481.3 94.30% 385 3281.76 3281.6 98% 386 3509.02 3509-1 99.40% 387 3665.2 3665.1 99% 388 3365.91 3365 97% 389 3324.79 3324.2 390 3539 3539.2 93% 391 3381.74 3381.3 97% 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 3410.89 3481.95 3286.76 3300.76 3350.81 3400.87 3406.84 3356.77 3384.87 3400.87 3466.03 3522.:05 3550.11 3567.09 3763.38 3636.15 3664.21 3720.32 3692.27 3555.13 3409.8 3481.1 3286.2 3299-4 3349.4 3400.1 3406.4 3356.6 3384.43 3401.3 3466.9 3522.06 3550.2 3763.2 3635.8 3663.3 3719.5 3691.7 3554.4 99% 99.20% 93% 99% 99%.

99% 99% 94% 99% 97.40% 93% 98% 99% 99% 99% 99% 99% 99% TABLE 1 42a The words "comprising, having, including" should be interpreted in an inclusive sense meaning that additional features may also be added.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or in any other country.

Claims

1. A compound of formula (R 2 R 3 0 A 1 1 -A 1 -A' 3 A' 4 -A' 5 -A 8 -A' 9 -A0-A 2 '-A22-A 23 -A 24 -A 2

5-A2-A' 7

26-A 29_A3_A31 -A 32 -A 33 -A 34A_A A 3 -A30 A _8A39-R (I) wherein A' is L-His, Ura, Paa, Pta, Amp, Tma-His, des-amino-His, or deleted; A' is Ala, D-Ala, Aib, Aco, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A9 is Glu, N-Me-Glu, N-Me-Asp or Asp; A" is Gly, Acc, B-Ala or Aib; All is Thr or Ser, A' 2 is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, 13-Nal, Cha, T rp or X'-Phe; A'1 3 is Thr or Ser, is Ser or Aib; A' 5 is Asp or Glu; A" is Val, Acc, Aib, Leu, lIe, Tie, Nle, Abu, Ala or Cha; A17 is Ser or Thr, is Seror Thr. A' 2 is Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, I3-Nal or X'-Phe; A" is Leu, Ace, Aib, Nie, Ile, Cha, Tlie. Val, Phe or X'-Phe: A 2 is Glu or Asp; A' is Gly. Ac. B-Ala, Glu or Aib; A1 3 is GIn, Asp, Asn or Glu; A 24 is Ala, Aib, Val, Abu, Tie or Ace; A21 is Ala, Aib, Val, Abu, Tie, Ace, Lys, Arg, hArg, Orn, C(O) or HN-CH((CH-I.-X 3 A' is Lys, Arg, hArg, Gm, HN-CH((CH 2 or HN-CF((CH- 2 C(O); A 2 1 is Glu Asp, Leu, Aib or Lys: A' is Phe, Pal, 13-Nal, X'-Phe, Aic, Ace, Aib, Cha or Trp; A2 is lie. Ac,. Aib. Leu, Ne, Cha. Tie. Val, Abu. Ala or Phe: A' is Ala, Aib or Ace; A" t is Trp. 13-Nal, 3-Pal, 4-Pal, Plie, Acc. Aib or Cl-a; A 32 is Leu, Acc, Aib, Nie, Ilie, Cha, Tie, Phe, X t -Phe or Ala; A" is Val, Acc, Aib. Leu, Ilie, Tie, Nie, Cha. Ala, Phe, Abu, Lys or X'-Phe; A34 is Lys, Arg. hArg, Om, HN-CH((CH 2 0 or HN-CH((GH 2 3 C(O); A' is Gly, B3-Ala, 0-Ala, Gaba, Ave. Aib, Acc or a B-amino acid;, A-16 is L- or 0-AMg, D- or L-Lys, D- or L-hArg, D- or L-Orn, HN-CH((CH 2 0 HN-CH((CH 2 6 -X 3 or deleted; A' M is Gly, B3-Ala, Gaba, Ava, Aib, Acc. Ado, Mrg. Asp. Aun, Aec, HN-(CHZ)m,-C(O). HN-CH((CH 2 0 R' 1 a 0-amino add, or deleted; AM3 is 0- or L-Lys, D- or L-Arg, 0- or L-hArg. Dl- or L-Omn, HN-CH((CH 2 0 HN-CH((CH 2 X-X 3 Ava, Ado, Aec or deleted;, is D- or L-Lys, 0- or L-Arg, HN-CH((CH 2 t LRll))-C(O). Ava, Ado, or Aec; X 1 for each occurrence is independently selected from the group consisting of C 8 )alkyl, OH and halo; Rt is OH. NH 2 (C,-C~oakoxy. or NH-X 2 -CH-tO, wherein )X 2 is a (Cr- C,2)hydrocarbon moiety, and V is H. OH, CO 2 H or CONH 2 X3 isX 2 )A -CH 3 -NH-C(O)-CHr-N \N-(CH 2 2 -NH-C(O)-R 1 or -C(O)-NHR'1 2 wherein X0 is, independently for each occurrence, -NH- or -Cl- 2 and wherein f is, independently for each occurrence, an integer from 1 to 29 inclusive; each of R 2 and R 3 is independently selected from the group consisting of H, C 30 )alkyl, (C 2 -C, 0 )alker4'l. phenyl(C,-C,,)alkyl, naphthyl(C -C)alkyl, hydroxy(C 1 C 3 4,alkyl, hydroxy(C 2 -C3,)aikenyl. hydroxyphenyI(C 1 -C,,)akyl, and ft+ hydroxynaphthy(C-,)akyl; or one of R' and R 3 is (CH 3 2 -N-C=N(0H93 2 (Ci- C 3 ,,)acyl. -Gjalkylsulfonyl, C(O)X 5 orH2)- -C )S2 N-(CH,)q-CO- wherein Y is H, OH or NH,; ris 0 to 4; q is 0 to 4; and X 5 is (C 1 -Co 30 )alkyl, (C 2 -C0)atkenyl, phenyl(C,-C 3 )alkyl, naphthyl(C,-C,,)alkyl, hydroxy(C 1 -Co 30 )alkyl, hydroxy(C 2 -Co)akenyl, hydroxyphenyl(C,-C3)alkyl or hydroxynaphthyl(C,-C,)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 and R" is, independently for each occurrence, H, (C,-C,)alkyl, C,)acyl, (C,-C,)alkyIsulfonyl, or -C(O)-CH -N and and R' 1 3 each is, independently for each occurrence, (C,-C,)alkyl; provided that: when A' is Ura, Paa or Pta, then R 2 and R 3 are deleted; when R' 0 is (C,-C,)acyl, (C-C,)alkylsulfonyl, or -C(O)-CH-N N-(CH 2 fCHa then R" is H or (C,-C3)alkyl; at least one amino acid of.a compound of formula is not the same as the native sequence of hGLP-1(7-36, -37 or -38)NH, or hGLP-1(7-36, -37 or -38)OH; (ii) a compound of formula is not an analogue of hGLP-1(7-36, -37 or -38)NH 2 or hGLP-1(7-36, -37 or -38)OH wherein a single position has been substituted by Ala; (iii) a compound of formula is not Lysw)hGLP-1(7-38)-E, (Lys 26 (Nc- alkanoyl))hGLP-1(7-36, -37 or (Lys 4 (N,-alkanoyl))hGLP-1(7-36, -37 or 38)-E. (Lysm"-bis(Nr-lkanoyi))hGLP-1(7-36 -37 or (Arga, Lys"(N,- alkanoyl))hGLP-1(8-36, -37 or (Arg2 M Lys"(N.-alkanoyl))hGLP-1(7-36, -37 or -38)-E or Lys"(N-alkanoyl))hGLP-1(7-38)-E, wherein E is -OH or -NH 2 (iv) a compound of formula is not Z'-hGLP-1(7-36, -37 or -38)-OH, Z'-hGLP-1(7- 36, -37 or wherein Z' is selected from the group consisting of: (Arg2"). (Arg". Lys"), (Arg, Lysf), (D-Lys'6). (Arg' 5 (D-Argf). (Arg 3 Lys-) or (Arg"z.. Lys'); (0 (Asp2'); at least one of (D-Ala') and (Asp 9 and (N-acyl-His'), (N-alkyl-His'), (N-acyl-D-His') or (N-alkyl-D-His 7 a compound of formula is not a combination of any two of the substitutions listed in groups to and (vi) a compound of formula is not (N-Me-Ala')hGLP-1 (8-36 or (Glu' S )hGLP- 1(7-36 or (Asp 21 )hGLP-1(7-36 or -37) (Phe 3 hGLP- 1 7-36 or -37) or (Aib 83 )hGLP-1(7-36)NH 2 or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein A" is Thr; A' 3 is Thr; A 1 is Asp; A' 7 is Ser A" is Ser A 2 is Glu; A' is Gin or Glu; A 2 is Glu; and A 3 is Trp; or a pharmaceutically acceptable salt thereof. 3. A compound according to claim 2, wherein A 9 is Glu, N-Me-Glu or N- Me-Asp; A' is Phe, Acc or Aic; A" is Val, Acc or Aib; A" 1 is Tyr; A W is Leu, Acc or Cha; A 2 is A[a, Aib or Acc; A 25 is Ala, Aib, Ace, Lys, Arg, hArg, Om, HN-CH((CH,),- or HN-CH((CH 2 3 A" is Phe; A 29 is lie or Ace; A 3 is Ala or Aib; A" is Leu, Acc or Cha; and A" is Val or Acc; or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3. wherein A' is Ala, D-Ala, Aib. A6c. N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A'O is Gly; A 1 2 is Phe, A6c or A5c; A" is Val, A6c or A5c; A 2 is Leu, A6c, A5c or Cha; A" is Gly, /-Ala or Aib; A" is Ala or Aib; A2 is lie, A6c or A5c; A 3 is Leu, A6c, A5c or Cha; A 3 is Val, A6c or A5c; A" is Aib, 8-Ala, Ado, A6c, A5c or Gly; and A" 7 is Gly, Aib, 3-Ala. Ado, D-Ala or deleted; or a pharmaceutically acceptable salt thereof. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein X 4 for each occurrence is e for each occurrence is independently 1 or 2; and R' is OH or NHz. 6. A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Rt is H and R 3 is (C,-C0,)alkyl, (C2-C,)alkeny, (C,-C,o)acyl, (C,-C,3)alkylsulfonyl, -47- HO-(CH 2 2 -N N-(CH 2 2 S0 2 ,HO-(0H 2 2 -N /N-GH 2 -CO- or H 2 N-(CH 2 2 -N N-0H 2 -CO- 7, A compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R' 0 is (C 1 -C30)acyl, (C 1 -C3,)alkylsulfonyI or -C (O H -N /N (C H 2 C H 3 ,a d R s H 8. A compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein is (C 4 -C20)acyl, (C 4 -C2,)alkylsulfonyl or /N-(CH)-CH 2 9. A compound according to claim 1 wherein said compound is EPES.KiS) 7 Aib-')hGLP1 (7-36)NH 2 ((N.-HEPArHiS~y 1 AibO"-)hGLP-1 (T36)NH 2 (Aib t3-Aafl)hGLP-1 (7-36)NH 2 ArrM, Lys (Nrtetradecanoyl))hGLP-1 (7-36)NH 2 (AVi1M, Lys 3 (N-tetradecanoyl ))hGLP-1 (7-36)N- 2 (Aib'&-3- 7 Arg 2 Lys 3 (N-tetradecanoyl))hGLP-1 (7-38)NH 2 (Aib 8 5 Arg 20 LysX(Nrdecanoyl))hGLP 1 (7-36)NH. Arg 2 UM,3, Lys oNrdodecanesufonyl))hGLP-1 (7-36)NH 2 (AibBM." Arg-u. Lys-*(N 1 -(2-(4-tetradecyI-l1-piperazine)-acetyl)))hGLP- 1(7-36)NH 2 (Aib' 3 Arg-'3, Asp6(1 1-(4-tetradecyl-piperazine)))hG LP- 1 (7-36)N H 2 (Aib 5 -Th. Arg 2 Msp'( 1-tetradecylamino))hGLP-1 (7-36)NH 2 (Aib-t Arg". Lysa(N.-tetradecanoyl) ,13-Aa 3 7)hGLP- 1(7-37)-OH or Arg6tu Lys (Nrtetradecanoy))hGLP-1 (7-36)-OH, or a pharmaceutically acceptable salt thereof. A compound according to claim 9 wherein said compound is -48- (Aib 8 1-Ala 35 )hGLP-1 (7-36)NH 2 (Aib'- 3 5 Arg 26 Lys,'(Nc-tetradecanoyi))hGLP-1 (7-36)NH 2 (Aib' .,5 37 Arg 25M Lys" (N.-tetradecanoyl))hG LP- 1 38)N H 2 (Aib-3, Arg~'. 4 LYS ON.-decanoy))hGLP-1 (7-36)NH 2 or (Aib 6 1, Arg6-t4 Lys'(N.-tetradecanoyl ,3-Ala 3 7'hG LP- 1(7-37)-C H, or a pharmaceutically acceptable salt thereof. 11, A compound according to claim 1 wherein said compound is (Aib-u)hGLP-.1 (7-36)N H 2 (I3-AIt')hGLP-1 (7-36)NH 2 ((Na-Me-His)?. Aibfl-5hGLP-1 (7-36)NH 2 ((Nc-Me-His)?, Aibs, I3-Alt3)hGLP-1 (7-36 )NH 2 ((Na-Me-His)?. Aib 8 Arg 2 8" 4 )hGLP- 1(7-36)NH 2 ((NW-Me-His) 7 Aib ArgmM-1, B-A~aflhGLP-1 (7-36)NH 2 (Aib A6ce)hGLP-1 (7-36)N- 2 (Aib', A5czhhGLP-1 (7-36)NH 2 (Aib', D-Ala 35 )hGLP-1 (7-36)NH 2 (Ab 8 .3 5 A6C 32 )hGLP-1 (7-36)NH,; (Aib"' 15 A5C' 2 )hGLP-1 (7-36)NH 2 Glu-')hGLP-1 (7-36)NH 2 (Aib"'Th5hGLP-1 (7-36)NH 2 (Aib 8 -3T35hGLP- 1 (7-36)NH 2 (Aib 8 25 35 )hGLP-1 (7-35)N- 2 A6c 1620 )hGLP-1 (7-36)NH 2 (Aib'-35 A6c' 6 -N'3)hGLP-1 (7-36)NH 2 (Aib 8 A6e- 32 )hGLP-1 (7-36)NH 2 (Aib 83 t A6c~o)hGLP-1 (7-36)NH 2 (AMb. 3 5 Lys 25 )hGLP-1 (7-36)NH 2 (Aiba2 5 A6c 20 )hGLP-1 (7-36)NH 2 (AibBM3, A6 C". 2 )hGLP-1I(7-36)N H 2 (Aib. 2435 A6c2- 32 )hGLP-1 (7-36)NH 2 (AVi 35 A6c' 1 2 )hGLP- 1(7-36)N H 2 Cht)hGLP-1 (7-SOIN H 2 (Aib 8 5, AS&m)hGLP-1 (7-36)NH 2 (Aib 8 Th5 A69'I.12)hGLP-1 (7-36)NH 2 (Aib'. A6C"', e3-Aat)hGLP-1 (7-36)NH 2 I3-Aa2hGLP-1 (7-36)NH 2 (Aib""2z3)hGLP-1I (7-36)N H 2 (Aib 8 Th Glum, A6& 2 )hGLP-1 (7-36)NH 2 (Aiba 243 5 Glu 2 A6e)hGLP-1 (7-36)NH 2 (Aibh 24 Glum. A6c9)hGLP-1 (7-36)NH 2 (Aib'6 242 5 A6 0 1 0 zMx. Glum)hGLP-1 (7-36)NH 2 (Aib', A6C12 I-Aa3hGLP-1 (7-36)NH 2 (Aib'. A5c 32 l3-Aat)hG LP-1I (7-36)NH 2 (Aib', Glu"3, 3-Aafl)hGLP-1 (7-36)N- 2 (Aib' 24 I3-Aat)hGLP-1 (7-36)NH 2 (Aib", 3 0 I3-Aa 3 )hGLP-l (7-36)NH 2 (Aibl 2 13, i-AIt3)hGLP- 1 (7-36)NH 2 (AMb, Aftc 1 8 1 t3-Aa)hGLP- (7-36)N H; A6c"o 2 /3-AI)hGLP-1 (7-36)NH 2 (Aib'. A6& t c 2 3-AIafl)hGLP-1 (7-36)N H 2 (Aib', Lys 25 I3-AIaflhGLP-I (7-36)NH 2 (Alba- 4 A6e, i-AI& 5 3)hGLP-1 (7-,36 )NH 2 (Aib 8 A6&- 9 f3-Aat)hGLP-1(7-36)NH 2 (Aib 4 A6c29 32 13-AashhGLP- 1 (7-36)NH 2 (Aib 5 Abc 1 2 I3-Aat)hGLP-1 (7-36)NH,; (Aib 5 Cha 2 3 tl-Aat)hGLP-1 (7-36)NH 2 (AVb' A6&t /3-Aat)hGLP-1(7-36)NH 2 (Aib 5 AMc 32 13-Aia 3 )hGLP-1 (7-36)NH 2 (Aib 5 I3-Aa2f5h GLP- 1 (7-36)NH 2 (Atb" 22 l3-Alafl)hGLP-1 (7-36)NH 2 (Aib 5 Glu', A6c 32 I3-Aafl)hGLP-1 (7-36)NH 2 (Aib 1Th2 GlU 2 3 2 A6C 2 1 13-Aat)hG LP- 1 (7-36)N- 2 (Aib 8 1 24 Giu 23 A6c2, Lys m Nractanoyl), l3-Aafl5hGLP- 1(7-36)NH 2 (Aib' 2425 Glu'1, A6c32, 3-Ala-'shGLP-1 (7-36)NH 2 (Aib 5 24 25 A6c' 5 Glu23, B3-Ala3)hGLP-1 (7-36)NH,; D-ArgflhGLP-1 (7-36)NH 2 (Aib" 35 D-Lys M 6)hGLP-1 (7-36)NH2; (Aib t-a-lt D-Arg36 hGLP-1 (7-36)NH 2 (Aib (3-Alt., D-LysM)hGLP.1 (7-36)NH 2 (Aib" 5 Arg-"fl4hGLP-1 (7-36)NH 2 (Aib', Argl- 3 t a-Alt)hGLP-1 (7-36)NH 2 (Aib" 5 Argnr26-AhGLP-1 (7-36)N H 2 (Aib Arg5"1', I3-Aa5hGLP-1 (7-36)NH 2 (Aibs Arg 2 a3-Alar. LysZ(N'-tetradecanay))hGLP-1 (7-36)OH; (Aib 83 tkl Argasi.U Lys3(N'-tetradecanoyl))hGLP-1 (7-37)01-i (Abs35,3 7 Argm .4t LysM5(NI-tetradecanoy ))hGLP-1 (7-37)OH; (Aib 5 Arg2-M, Lys-'6(N'-tetradecanoy), D-Ala' 7 )hGLP-1 (7-37)OH; (Aib 5. 7 jArga",4 LysM6(Nc-tetradecanoy ))hGLP- 1(7-38 )OH; (Aib-t Arg" M R3-Aa LysN(NE-tetradecanoy ))hG LP-1I (7-38)OH: (Aib'- 35 Argo't4 Lys aN'-tetradecanoyl))hGLP- 1(7-38)OH: (Aib 5 Arg26"t, Lys"( N-tetradecanoy), l3-Ala 3T )hG LP- 1(7-37)OH; (Aib 821 Arg6-' Lys M (N'-tetradecanoyl))hGLP- 1(7-37)OH: (Aiba 35 Arg 2534 Ado 3 )hGLP- 1(7-37)0K: (Aib a 35 Arg",t AdoflhGLP- 1(7-37)NK 2 (Aib', Arg't4 Lys' 8 (N'-tetradecanoyl). D-Ala 3 )hGLP-1I(7-37)OH; (Aib' 1 .7 Argo-t4 Lys m (Nc-tetradecanoyI))hGLP- 1 (7-38)OH; (Aib 8 Arg 2 1 6 3 4 (3-Ala', Lysm(N'-tetradecanoy9))hGLP-1 (7-38)OH; (Aib" 5 Lys26N'-o cta noyl)Th G LP -1 (7-36)N H 2 1 (Aib" 5 Lys26N'-tetadecanOy)ThGLP-1 (7-36)NH 2 (Aib''t Lys26(Nt-hexadecafloyl))hGLP-1 (7-36)NH 2 (Aib', Lys'(NWoctanOyI), l3-Aat)hGLP- 1(7-36)N-1 2 (AVb, Lysz"(N'-tetradecaflOyl). t3-Aat')hGLP-1 (7-36)NH2; (Ait9. Lys-'(N'-hexadeCaly). 13-Aa")hGLP- 1(7-36)N H 2 (Aib 53 s. Lys26(N'-octanoyI). Arg'jhGLP- 1(7-36)N H 2 Lysm5(N'-tetradecalOYI), Argfl)hGLP-1 (7-36)NH 2 (AlbUM. Lys'(N'-hexadecanoyI), Argfl)hG LP0-1 (7-36) )N H,; (Aiba-M. Lys 2 (N-decanOyt). Argfl)hGLP-1 (7-36)NH 2 (Aib"ts Lys 2 s, Lysfl(Nt-0ctafly), Arg)hGLP-1 (7-36)NH 2 (Aib 8 Th' LyS 25 Lys'(N'-tetradecanoy), Arg M I)hG LP-1 (7-36)NH 2 (Aib" 35 Lys~s, Lys~e(N'-hexadeCaly), Arg 3 ')hGLP-1(7-36)NH 2 (Aib',3, ArgZ5-1t LV9I(Nc-octafl))hGLP-1 (7-36)NH 2 (AJbx Arg5't4 Lys~s(N'-tetradecalY))hGLP-1 (7-36)NH 2 (AI 8 -15 Arg5t4 Lysma(N'-hexad8cafly))hGLP-1 (7-36)N-1; (Aibt--h Arg 2 "t14 Lys26N'.decanoy))hGLP-1 (7-36)NH 2 (Aib Lys 6N-OCtanfl~y), Ar3. I3-Aafl)hGLP-1 (7-36)NH 2 (Aib 6 Lys~l(NI-tetradecaly). kg't S-Aafl)hGLP-1 (7-36)NH 2 (Aibt, Lysa-(Nc-hexadecanoYI), Arg't 13-Aat)hGLP-1 (7-36)NH 2 (Aibl, Lys 15N-decalOvl). Arg't t3-Aa')hGLP-1 (7-36)NH 2 (Aibl-M, Lys 3 (N'-octanoyl))hGLP-1 (7-36)NH 2 (Ai b'Th5 Lys M 4(N'-tetradecaloYl))hGLP- I (7-36)NH 2 (AibUM', Lys' (Nc-hexade'canoyI))hGLP-1 36 )NH 2 (Aibl-1. Arg' Lys"(N'-octanoyl))hGLP- 1(7-36)NH 2 (Ab't Arg', Lys 3 '(NMhexad6caloyi))hGLP-1 (7-36)NH,; (Aib 8 3 Arg' 6 Lys'(N'-cecanoyl))hGLP-1 (7-36 )NH (Ab 8 Arq2" 8 Lys M (N'-octanOyI))hGLP-1 (7-36)NH2; (Aib", 5 Arg2 5 Lys3' N'-tetradecanoy))hG LP-1 (7-36 )NH2; (Ai ba- 5 Arg"s2, LysM4(Nt-h0xadOcafly))hGLP 1 (7-36)NH,; (Aiba 35 Arft526 LyS14 Nc-decanoyI))hGLP- 1 (7-36)NH2g (Aib 82 t3 Lys 25 Arg"6, Lys 3 '(NI-octanoyI))hGLP-1I(7-36)NH 2 (Aib 8 T.3 Lys' 5 Arg 2 6 Lys34(N'-tetradecanoy))hGLP- 1(7-36)NH 2 (Aib 835 Lys 25 Arg 2 a, Lys 34(Nc-hexadecanoyf))hG LP- 1 (7-36)N H 2 (Aib 8 Th, Lys& 6 (N'-octanoyl))hGLP-1I(7-36)N H 2 (Aib m -3t Lys "(Ncte tradeca noyI)) hGLP- 1 36)N- 2 (Aib 5 5 Lys'( NE-hexadecanoyI))hG LP- 1(7-36 )N H 2 (Aib-'t Arg26, LysM(Nt-actanoyI))hGLP-1 (7-36)NH 2 (Aib' 2 '4 Arg26, LysM(NcetradecanoyI))hGLP 1 (7-36)N Hj (Aib 83 t Arg26, LysMa(Nc-hexadecanioyI))hGLP-1 (7-36)NH 2 (Aib 8 Th5 Arg-' M .u Lysm(N'-octanoyI ))hGLP- 1 (7-36)N H 2 (Aibt1 Arg 25 -1 4 Lys M a(N-exadecanoyl))hGLP-1 (7-36)N H 2 (Aib 5 35 Arg 2 Lys'N(N'-octanoyl))hGLP-1 (7-38)NH 2 (Aib 5 35 Arg6t Lys~a(N'-decanoyi))hGLP-1 (7-38)N H 2 (Aib" Arg26 3 t. Lysm(N'-tetradecanoyI))hGLP-1 (7-38)NH 2 (Aib 8 Arg-3t LysU(Nc-hexadecanoy))hGLP-1 (7-38)NH 2 37 Arg 2 Lys"(NI-octanoyQ)hGLP-1 (7-38)NH 2 (Aib 8 3S 37 ArgS'"'U, Lys m (N'-decanoyl))hGLP-1 (7-38)NH 2 (Aib 5 5 7 LysM(Nc-tetradecanoyI))bGLP-1 (7-38)NH 2 (AVib33 31 Arg5--3 LysS(Nc-hexadecanay))hGLP-1 (7-38)NH 2 (Aiba 3.37, Arg 2 4 Lys 3 mNN-octanoyl))hGLP-1 (7-38)NH 2 (Aib" M,37 Arg26 3 4 Lys (N-decanoyl))hGLP-1 (7-38)NH 2 (AibS-Mfl7, Arg26 3 t, Lys~g(N'-hexadecanoy))hGLP-1 (7-38)NH 2 (Aib 8 ,35 37 Arg 2 5 LysM'(Nc-octanoyI))hGLP-1 (7-38)NH 2 (Aib 8 35 37 Arg 25 1 4 Lys38(NI-decanoyI))hGLP-1 (7-38)NH 2 (Aib 2 3 5 .3 7 Arg 25 16.-U. Lys"A(N'-tetradecanoy ))hGLP- 1(7-38)N H 2 (Aibt .353 Arg 25 Lys3(N"-hexadec-anoyflhGLP-1 (7-38)NH 2 (Aib 83 t Lys 25 Arg6 4 Lyt-(N'-octanoyi))hG LP- 1(7-36)N H 2 (Ait, Lys 2 5 Arg2' 3 t, Lysm(Nt-tetradecanoyI))hGLP- 1(7-36 )NH 2 (Aib 8 B 3 1 5 Lys",. Arq't' Lys(Nt-hexadecanoyI))hGLP-1I(7-36)N H 2 (Aib 8 Th5 Arg 2 5 634 Lys~d(N'-odtafoyI))hGLP- 1(7-36)NH 2 (Aib 835 Arg 2526 Lyss( N'-tetradecanoyl ))hGLP-1 (7-36 )NH 2 (Aiba 3s, Arg2 526 1 t, Lys'(N'-hexadecanoy))hGLP-1 (7-36)NH2; (Aib' 5 Arg 25 '20- M Lys-'(NL-decanOyi))hGLP 1 (7-36)NH,; (Aib', Lys M 4(N'-OCtafOI) 13-Aa5)hGLP-1 (7-36)NH2; Lys34(N-tetradecanoyI), 3-AaflhGLP- 1(7-36)NH 2 (Aib', Lys'"(N'-hexadec-aoyl), B3-Alal)hGLP-1 (7-36)NH2: (Aib AMc 2 Lysfl(N.-octanl~y), 13-Aat)hG LP- 1(7-36)N H,; (At'O, Glu23, Lys34(N -octafloyI). B-Aafl5hGLP-1 (7-36)NH2; (Aib. G Iu2. A6c 32 Lysl(N 1 -octafloyl). B-Aafl)hGLP- 1(7-36)NH,; Arg25 Lys- (N t -octanly), I3-Aa5)hGLP-1 (7-36)NH,.; (Ai b8, Arg 2 6 Ly-(Ettrdcny) 13-Aa35)hGLP-1 (7-36)NH2; (Atb', Arg25. Lys34(N'-hexadecaly), 2-A~a35lhGLP-1 (7-36)NH2.; (Aib', Arg4, Lys-'(N -decanly). I3-Aatl)hGLP- 1(7-36)NH.; Arge', Lys34N -octafly). 13-Aa5)hGLP-1 (7-36)N H,; (Aib', Arg"".6 Lys M 4(N'-tetradecafloyl), 1-Ait')hGLP-1 (7-36 )NH2; (Aib', Arg"'-2. LysM(NchexadecanoyI), l3-Aafl)hGLP-1 (7-36)NH.; (Aib'. Lys' Ar, Ly(N-cafol)y, -AahGLP-1 (7-36)NH 2 (Aib', Lys 2 Arg~o, Lys'(N-ottaanoyI). A-AhGLP-1 (7-36)NH; (Aib'. Lys,". Arg", LyeSNW-hetadecaal), B3-Aafl5hGLP-1 (7-36)NH2; (Aib'. 13-Al3, Lys3 N-octanOyl))hGLP-1 (7-36)NH2,; (Aib', a-Al-1, Lys N-tetadecaloy))hGLP-1 (7-36)NH2, i3-Ait.15 Lys (N-hexadecanOyl))hGLP-1 (7-36)NH2; (Aib', Arg' 13-Ala-lt Lys~a(N'-octafloyl ))hGLP-1 (7-36)NH,; (Aib', Arge, &A13-M Lys 6N-tetradecalQYl))hGLP- 1 (7-36)NI-I; (Aiba. Arge, 13-Alt.5 Lys M (N-hexadecanoyl))hGLP-1 (7-36)NH 2 ArgM6 3 t, 1-Alas, Lys"(N'-octanoyl))hG LP-1 (7-36 )N H,; (Ai Arg-'t 1',3-Alt. Lys m (N-tetradecaflOyl))hGLP- 1 (7-36)NH2; (Aib', Arg'-4, 13-Alt', Lys'(N'- hexadec-anoyl))hGLP-1 (7-36)NH, (Aib', Argm--', (-Alt."s Lys 3tPN-decanoyl ))hG LP- 1(7-36 )N H,; Lys5t Argza3, 13-Ala 35 Lyst(N'-octanoyl))hGLP- 1 (7-36)NH2; (Aib', Lys-, Arg'"t3 Lysm 3 NN-tetradecanoyl). 13-Ait')hGLP- 1(7-36 )N H,; (Aib', Lys2 5 Arg6t4 13-Alt.15 Lysm(N6-hexadecal)lhGLP-l (7-36)NH2; (AibS, Arg 2526 3 t fl-AI& 5 Lys36(N'-octanoyI))hGLP-1 (7-36)NH 2 (Aib 8 Arg 11 2 6 .34 iZ-Ala 3 5 Lys m (N-tetradecanoyl))hGLP-1 (7-36)NH 2 (Aib 8 Arg 2 5,26 3 3-Ala 3 5 Lys36(Nc-hexadecanoyl ))hG LP- 1(7-36 )N H 2 (Aib, Arg 25 5 i3-Alat5 Lysm(N'-decanoy))hGLP-1 (7-36)NH 2 (Aib 8 35 Lys26(Nc-octanoyl). A6 0 Argfl)hG LP-1 (7-36 )NH 2 (Aib' 3 5 Lyso(N'-tetradecanoy), AMe. Arg 3 ')hG LP- 1(7-36)NH 2 Lys~o(NI-hexadecanoy), A6c2, flg3)hGLP-1 (7-36)NH 2 (Aib" 5 A6c 3 2 Lys 3 4(N'-ocanoyl))hGLP-1 (7-36)NH 2 A6c 3 2 Lys M 4(Nt--tetradecanoyl))hG LP-1 (7-36)NH 2 (Aib 8 AMc. LysS 4 (Nc-hexadecanoyl))hGLP- I(7-36)NH 2 (Aib'-3, Argo, AMc, Lys'(N'-octanoyI))hGLP-I (7-36)NH 2 Argo, AMe, Lys34(N'-tetradecancyl))hGLP-1 (7-36)N- 2 (Aib"1 3 A6c 5 2 Lys '6N'-octanoyl))hGLP-1 (7-36)NH 2 (Aib 8 A6C9 2 LysM6(Nt-tetradecanoy))hGLP-1 (7-36)N H 2 (Aib t 35 A6c 3 2 Lysr(Nc-hexadecanoyI))hGLP-1 (7-36)NH 2 Argm6, AMe, LysM6(Nv-actanoy))hGLP-1 (7-36)N H 2 Argo, AMel, Lys~l(N-tetradecanoy))hGLP-1 (7-36)NH 2 Are, AMe, Lys'(N'-hexadecanoy))hGLP-1 (7-36)NH 2 (Aib"-' 5 Argo-3t AMe, 2 Lys (N'-actanoy))hGLP-1 (7-36)NH 2 (Aib'-35 Arg 2 §M.4 A6& 2 LysM(Nt-decanoylhGLP-I(7-36)NH 2 (Ait' 15 Arg 263 t, AMc, LysM(Nc-tetradecanoy))hGLP-1 (7-36)NH 2 (Aib' 3 Argo- 3 t A6cl, Lysr(NE-hexadecanoy))hGLP-1 (7-36)NH 2 (Aib"'24 3 S LyS26(N'-octanoy), Arg")hGLP-1 (7-36)NH 2 (Aib'- 24 5 Lyso(N'-tetradecanoyl), Arg' 4 )hGLP-1 (7-36)NH 2 (Aib' 2 4 -1 Lys 2 (N-hexadecanoyl). ArgpjhGLP-1 (7-36)NH 2 (Aib 1 4 ,35 Arg26. Lys4(I#-*octanoyI))hGLP-i (7-36)NH 2 (Aib 8 L 243 5 Argo 2 LysM4(N(-tetradecanoyI))hGLP-I (7-36 )NH, (Aib' 24 .3 5 Arg~e. Lys'(N'-hexadecanoy))hGLP- 1(7-36)NH 2 (Aib 524 Argetu LysZ6(N(-octanoyl))hGLP-1 (7-36)NH 2 (Ai Argfl, Lys 3 N'-Letradecanoyl))hGLP- 1(7-36 )NH 2 (Aib 8 24 -ts Arg 2 6 1 3 t. Ly'( N t -hexadecanoyl) )hGLP- 1(7-36 )NH 2 (Aib 824 3. G IU 2 3t A6c 32 Lys 3 "(N.-octanoyi))hGLP-1 (7-36)NH 2 (Aib 8 G U 23 L yS 26 1(N'octanoyl), Arg-")hGLP- 1(7-36)NH 2 (Aibar3, Glu23, Lys 26N'-tetrad ecanoyI), Arg'flhGLP-1 (7-36 )NH 2 (Aib 8 '.35 GI u 23 Lysl6(N'-hexadecanoyI), ArgflhGLP- 1(7-36)NH 2 (Aib 8 3 5 G1U 23 Lys' (N-octanoyI))hGLP- 1 (7-36)NH 2 (Aib"1 Gluz3, A6c& 2 Lyt-(N,-octanoy))hGLP-1 (7-36)NH 2 (Aib 8 Th". CI u23 Arg', Lys"(N"-octanoyI ))hGLP-1 (7-36 )NH12; (Aib t 'ts GIU 23 Arg', Lys'(N'-tetradecanoy))hGLP-1 (7-36)NH,; (Aib 8 Th5 Glu 23 Arg 2 t. Lys M 4(N-hexadecanoyI))hGLP-1 (7-36)NH 2 (Aib 8 5 G IU 2 3 LysM(Nc-octanoyI ))hGLP- 1(7-36)NH 2 (Aib 8 C Iu23, Lys '4N'-tetradecaioyl))hGLP-1 (7-36 )N H 2 (Aib" 5 3, Gha2, LysM3(NL-hexadecanoyt))hGLP-1 (7-36)NH 2 (Aiba. 1 t, Glu23, Arg'- 3 t Lys (N'-octanoytlhG[ P- 1(7-36)NH 2 (Aib 8 Glul3, Argot' Lys-'(N t -tetradecanoy))hGLP-1 (7-36)NH 2 Glu23, Arg6't4 Lys eN-hexadecanoy9))hGLP-1I(7-36)NH 2 (Aib 8 3 t. Lys26(N'-octanoyI). Arg~hGLP-1 (7-36)NH 2 (Aib"g 3 t5 Lys~g(N-tetradecanoyl) ArW)hGLP-1 (7-36)NH 2 (Aib 8 -10' Lys 2 (N t -hexadecanoyl), Nrg-)hGLP-1l (7-36)NH- 2 Arg~e. Lysm(N'-octanoy))hGLP-1 (7-36)NH 2 (Aib 3t35 Arg26. Lys3(Nt-tetradecanoyI))hGLP-l (7-36)NH 2 (Aib 8 o 3. Arg 2 Ly- N-eaeaol)GL- (7-36)NH 2 (AibOX.3,35 Arg5t4 LysM6(Nt-octanoyI))hGLP-1 (7-36)NH 2 35 Afgtstu LysM(Nt-tetradecanoyflhGLP-1 (7-36)NH 2 (Aiba9.0,3, Argm-t" LysMo(Nt-hexadecanoyI))hGLP 1 (7-36)NH 2 (Aib 8 Glu23, A6C3 2 Lys aN-octanoy))hGLP- 1(7-36)NFt; (Aib.t5 Gtuz3, AMe, Lys- NII-tetradecanoy))hGLP-1 (7-36)NH 2 (Aib 8 ,-15 Glu23, A6e3, Ly9'3(N4i-exadecanoy))hGLP-1 (7-36)NH 2 Glut3 Argot4 AWe 2 Lysx(N'-octanoyQ))hGLP- 1(7-36)NH 2 (AibiM-, Gluzl, Argmt-14 Afct", Lys'(N'I-tetradecanoy))hGLP-1 (7-36 )N H 2 (Aib 8 3 5 Glut3 Arg~', A6c0 2 Lysm(N'-hexadecanoy))hGLP-1 (7-36)NH 2 (Aib 8 Glut3 Arg-'0t4 A~o 32 Lys'( N'-octanoyi))hGLP-1 (7-36 )N H 2 (Aib' 4 1 35 GIU 23 Arg6,3. A6& 2 Lys'"(N'-tetradecanoylflbGLP- 1 (7-36)NH 2 (Aib 82 4 3, Glu 21 Arg25 M .4 A6c' 2 Lys'(Nc-hexadecanoyl))hGLP-1 (7-36)NH 2 -56- (Aib 4 Giu 23 Arg~s' 3 t A6Co' 2 Lys'(NNEoctanoyI))hGLP-1 (7-36)NH 2 (Aib 8 24 30 5 Glut3 Arg 2 5t4, AMC3. LysM(NL-tetradecanoyI))hGLP.1 (7-36)NH 2 (Aib 8 11 24 -3-5 Glut Argot4 A~o 32 Lys"(N-hexadecanoyl))hGLP-1 (7-36)NH 2 -1 ((No-HEPES-His)t, Aib3 5 )hGLP-1(7-36)NH 2 ((Na-HEPES-H is) 7 13-Ala"5)hGLP-1 (7-36)NH 2 ((NHEPES-His)', Aib', 13-Aat)hGLP-1 (7-36)NH 2 ((NO-HEPA-His)', Ait9I)hGLP-1 (7-36)NH 2 ((Na-HEPA-Hisf., 13-Aat)hGLP-1 (7-36)NH 2 ((Na-HEPA-His)', Aibo, I-Aafl6hGLP-1 (7-36)N H 2 ((N 0 -tetradecanoyl-H is)T, AbflhGLP-1 (7-36)NH 2 ((N"-tetradecarioyl-His)'. B-Ait-)hGLP-1I(7-36)N H 2 ((NIG-tetradecarnoyl-Kis)L. AibO'5)hGLP-1 (7-36)NH 2 ((No-tetradecanoyl-His)l'. Aib', I3-Aa5hGLP-1 (7-36)N- 2 ((N*-tetradecanoyI-HisY. Arg5t4 Aib-')hGLP-1 (7-36)NH 2 ((No-tetradecanoy-HisY,. Arg.. I3-Aafl~hGLP-1 (7-36)N H 2 ((Na-tetradecanoyl-1His)f, Aib--, Arga-A)hGLP-1(7-36)NH 2 ((Nal-tetradecancyl- A Ar Asi-Ala35hGLP-1 (7-36)NH 2 ((Na-tetradecanoy-His)", ArgzZJ 4 I3-Aa5hGLP-1 (7-36)NH 2 ((Nol-tetradecanoyl-His) 7 Alb 8 Argl-'-)hGLP-1 (7-36)NH 2 ((NO-tetradecanoy-His) 7 AibO Argflaa I 3-Aa-l5hGLP-1 (7-36)NH 2 (AVib 8 'T Lys2(N'-actanesufonyI), ArgflhGLP-I (7-36)NH 2 (Aibe-3, Lysm(N'-dodecanesufonyl). Arg"')hGLP-1 (7-36)NH 2 (Aib" -m LysN6(Nt-hexadecanesulfonyl). Arg'jhGLP-1 (7-36)NH 2 ArgM. Lys'(N'-octanesulfonyl ))hGLP-1 (7-36)N H 2 Nrg 2 Lys34(Nr-dadecanesulfonyl))hGLP-1 (7-36)NH 2 (Abt3 Arg m LySM4(NA-exadecanesulony)l1GLP-1 (7-36 )NH 2 Argfm,. Lys'(Nt-octanesulfony))hGLP-1 (7-36)NH2; Argmt Lys'4(N'-hexadecanesulfonyl))hGLP- 1(7-36 )NH 2 (Aib" 5 Aspla(1-(4-decylpiperazine)), ArgflhGLP-1 (7-36)NH,; (Aib 8 Asp (1 -(4-dodecyipiperazine)), ArgflhGLP-1I(7-36)N H 2 (Aib' Asp6( 1 -(4-tetradecylpiperazine)), Arg"4)hGLP-1 (7-36)NH 2 (Aib 8 'Th ASPZG(l1-(4-hexadecylpiperazine)), Arg-A)hGLP- 1(7-36 )NH 2 -57- (Aibar3, Arg", Asp' 1 -(4-decylpiperazine)))hGLP-1 (7-36 )NH,; (Aib 8 5 Arg' 6 Asp M (1I-(4-dodecylpiperazine)))hGLP- 1(7-36)NH, (Aib 5 8 3 Arg', Asp 14 1-(4-tetradecylpiperazine)))hGLP-1 (7-36)NH2; (Aib 8 5 -3 Arg26, Asp M 1 -(4-hexadecylpiperazine)))hGLP-1 (7-36)NH,; (Aib 8 Th" Arg26--t Asp-(1 -(4-decylpiperazine)))hGLP-1 (7-36)NH2; (Aib 8 '35, Arg'-t Aspm( 1 -(4-clodecylpiperazine)))hGLP-1 (7-36)NH2; (Aib 8 Th5 Argm- 3 Asp'a1 -(4-hexadecylpiperazine)))hGLP- 1(7-36)N H,; (Aibtm Argn-3t Asp 1O~ -(4-decylpiperazine)))hGLP- 1 (7-38)N H2; (Aib' 2 5 Arg.tU Asp'N1 -(4-dodecylpiperazine)))hGLP- I (7-38)NH2: (Aibg-n, Argot' Asp M (1-(4-tetradecylpiperazirie)))hGLP-1 (7-38)NH2; Arg'"t-4 Asp-1(l -(4-hexadecylpiperazine)))hGLP-I (7-38)NH,; (Albe6r15 37 Arg2-Th34 Aspm(1 -(4-decylpiperazine)))hGLP-1 (7-38)NH2; (Aib6. 5 ,3T. Arg", Asp'(l1-(4-dod ecylpiperazine)l)hGLP-1I(7-38)Ntt; (Aib 8,5, 7 Argfl34t Asp'm(l -(4-tetradecylpiperazine)))hGLP-1 (7-38)NH2; (Aibs 8 .35. 7 Arg Ct Asp 1 -(4-hex'adecytpiperazine)))hGLP- 1 (7-38)NH2; ArgflM, Aspm(1-(4--decylpiperazine)))hGLP-1 (7-36)NH2; (AibM-'. ArQZ2.34, Asp m (1 -(4-dodecytpiperazine)))hGLP-1 (7-36)NH2; (AJb 8 'Th, Argrt.3 Asp m (1.(4-tetradecylpipera-zine)))hGLP-1 (7-36)NH,; (Aib TM Arge 3 Asp26(I-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH,2; Arg~' sp3'(1-(4-decypiperazie)))hGLP-1 (7-36)NH2; (Ab't. Argaa-1. Asp' 4 (1 (4-dodecylpiperazine)))hGLP-I (7-36)NI-t; (Aib 5 Argaa.26 AspM(1 -(4-tetraclecylpiperazine)))hGLP-1 (7-36)NH2; Argfl. Asp 3 -(4-hexadecylpiperazifle)))hGLP- 1 (7-36)NHz; (Aib 6 5 ArgZ-m-3, Asp3'(1-(4-decylpiperazine)))1GLP-1 (7-36)NH2; (Aibat, Arg25""- 4 Msp'N 1-(4-dodecylpiperazine)))hGLP-I (7-36)NH,; (Aiba-3h Arg232" 4 Aspr'(1-(4-tetradecylpiperazine)))hG LP- 1(7-36)N H,; (Aib8. 5 t Mrg25.5. 4 sp'~I -(4-hexadecylpiperazirie)))hG LP-1I(7-36)NH2; Args''t34 Asp'a(6 -(4-decylpiperazine)))hGLP- 1(7-38)N H,; (Aib 8 ,3s, Arg .6.4t Asp"( 1 -(4-dodecylpiperazine)))hG LP-l (7-38)NH2; (Aib 8 't Arg5-", 4 Asp"( 1 -(4-tetradecylpiperazine)))hGLP-l (7-38)NH, (Aib' 8,5, Arg25'Th4 Asp M (I -(4-hexadecylpiperazine)))hGLP- 1(7-38)NH,; (Alba8,35 37 Arg 2 Asp'(l -(4-decylpiperazi ne)))hG LP- 1 (7-38)NH2; (Aib 81 3 5 7 Arq255.t Asp'( 1 -(4-dodecyl piperazine fl)hGLP- I (7-38)N H,; (Aib"C 5 '3 7 Argr 2 Asp8( 1 -(4-tetradecylpiperszine)))hGLP- 1(7-38)NH (Aib 8 ,35 37 Arg 2 5 2 .3 Asp 1 -(4-hexadecylpiperazine)))hGLP- 1 (7-38)NH 2 (Aib 5 35 Arg' 6 tu Glu'(1-dodecylamnino))hGLP-1(7-36)NH 2 (Aib' 35 1, G Iu 2 (1-dodecylamino), ArgflhGLP-1(7-36)NH 2 (Aib' 35 Arg 26 Gtu- (1 -dodecylamino))hGLP-1 (7-36)NH 2 (Aib 8 -5 3 1 Arg6'.4 Glu M (1 -dodecylamino))hGLP-1 (7-38)NH,; (Alt 83 Argt Lys26(N'-(2-(4-decyL-1 -pipe razi ne).-a cetyl G LP- 1 (7-36)NH 2 (Aib' 3 t Arg"t Lys(N-(2-(4-dodecyl-1 -piperazine)-acetyl)))hGLP-1 (7-36)N- 2 (Aib'- 3 t Arg 34 Lys'(N'-(2-(4-tetradecy-1 -piperazine)-acetyl)))hGLP- 1(7-36)NH 2 (Aib 8 Arg 3 Lys2 N-(2-(4-hexadecy-1 -pipemazine)-acetyQ))hGLP- 1 (7-36)NH,; (Aib-lt Arg 2 o, LysU4(NE-(2-(4-decyl1 -piperazine)-acetyl)))hGLP-1 (7-36)NH 2 (Aib'-3, Arg 2 6, Lys 4N-(2-(4-dodecyl-1 -piperazine)-acetyl))hGLP- 1(7-36)N H 2 (Aibl-" Arg 3 Lys 3 (NN-(2-(4-tetradecy-1 -piperazine)-acetyl))DhGLP-1 (7-36)NH 2 Arg 2 6, Lys 3 (NN-(2-(4-hexadecyl-1 -piperazine)-acetyl)))hGLP-1 (7-36)NH 2 (Aib 8 Arg6t4 Ly4N-(-4dey--piperazine)-acetyl)))hGLP- 1(7-36)NH;'- (Aib 8 Th'3 Arg- 2M Lys'(N'-(2-(4-dodecyI- 1-piperazine)-acetyl)))hGLP-1 (7-36)N H 2 (Aib 8 3 Are'.t Lys 3 (N'-(2-(4-hexadecyl-1 -piperaz-ine)-acetyl)))hGLP-1 (7-36)NH 2 (Aib 8 3, Arg25M, Lys 3 1 -piperazine)-acetyl)))hGLP-1 (7-38)NH 2 (Aib-3, Arg 2634 Lysm(N'-(2-( 4-dodecy-1 -piperazine)-acetyl)))hGLP-1 (7-38)NH 2 (Aib Arg 2 3 tU Lys 3 '(N'-(2-(4-tetradecyl-1 -piperazine)-acetyfl)hGLP-1 (7-38)NH 2 (Aib" Arg26'3, Lysfl(Nc-(2-(4-hexadecyl1 -piperazine)-acetyl)))hGLP-1 (7-38 )NH 2 (Aib t3 5" 7 kg~flU LysM(Nt-(2-(4-decy-1 -piperazine)-acetyl}))hGLP-1 (7-38)N H 2 7 Arg5 4 Lys (N,-(2-(4-dodecy-1 -piperazine)-acety))}hG LP- I (7-38)NH 2 z; (Aib 8 5' 37 ArgL, Lys (N-(2-(4-tetradecyl-l1-piperazine)-acetyl)))hG LP-1 (7-38)N H 2 (Aib 5 -3 37 Arga$. 4 Lys (N-(2-(4-hexadecyl 1 -piperazine)-acetyl)))hG LP-1 (7-38)N H 2 (AibBM5, Arg253 -(-(-dcy--piperazine )-acetyl)))hGLP- 1(7-36)NH 2 (Aib'- 3 Arg 25 3 Lys~o(N-(2-(4--dodecyI- I -piperazine)-acetyl)hGLP-1 (7-36 )N H (AVb' 3 5 Arft34 Lys6( N'-(2-(4-tetradecyl-l1-piperazine)-acetyl))lhGLP- 1(7-36 )N H 2 Aib'11 35 Arg,34 Lys-(N'-(2-(4-hexadecyI-l1-piperazine)-acetyl)))hGLP- 1(7-36)N H 2; (Aib 83 t Argz--', Lys' N -(2-(4-decyl- 1 -piperazine)-acetYl ))lhGLP- 1(7-36 )N H 2 Arg25-2 Lys' (N'-(2-(4-dodecyI1 -piperazi ne)--etyl)))hGLP-1 36)N H 2 (Aib't Argna, Lys 3 (N-(2-(4-tetradecyl-1 -piperazine)-acetyl)))hGLP- 1(7-36)NH2I (Aib 5t Arg 25 2 B, Lys 34 (N'E-(2-(4-hexadecyl-1 -piperazine)-acetyl)))hGLP- 1 3)H. (Aib'9 35 Arg 25 2 Lys&NaN'-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP- 1(7-36 )NH 2 (Aib'- 35 Arg 25 25 3 t Lys (4-d odecyl-I1 -piperazine)-a cetyl)))hGLP- 1 (7 -36)N H 2 (Aibs- 5 Arg'2, 5 3 A Ly936NN'-(2-(4-tetradecyI 1 -pipe razine)-a cetyl))) hG LP- 1 (7-36 )N H z; (Ab~ r 25 2 3 LsN(2(hedcl1-ppazn)atl))GP1(7-36 )NH 2 (Aib',3t Arg 2 5 Lys (N'-(2-(4-hdecyl- -piperazine)-acety l)))hGLP- 1 -8NH (Aib'-35 Arg 2 5 2 ,3A Lys 38N'-(2-(4-cldecyl- 1 -pip erazi ne)-acety)G LP- 1 (7-38) N H 2 (Aib-t sArg25mhLst N (2(4do I l--piperaire-acetyl )))hGLP- 1(7-38 )N H 2; (Aiba-'s Arg 2 5 4.3t Lys (N-(2-(4-hexradecyIl-I-piperazine)-acelyl )))hGLP- 1(7-38 )N H 2 Arg Lys (N'-(2-(4-xdecy I- I -piperazine)-acetyl)))hGLP-1 (7-38)N H (Aiba 3.3 7 Argmst Lys'(N'-(2-(4-dodecy-1 -piperazine)-acetyl)))hGLP-1 (7-38)NH 2 (Aiba 35 ArgZ5---t Lys-"(N'9-(2-(4-tetradecyI- 1 -pipe razine)-acetyl)))h GLP- 1(7- 38)NH 2 (Aib 8 m,3, Args26', Lys'(N'-(2-(4-hexadecy-l1-piperazine)-acetyl )))hGLP- 1(7- 38)NH 2 (Aib' 3 5 Argot4 Lysm(N'-decanoy1))hGLP-1(7-36)OH; (AibiM3. Lys 2 5 Arg 2 Lys(N'-decanayI))hGLP-1(7-36)OH; (Aib'-15Arg25' M Avar., Adaa)hGLP-I (7-38)NH 2 (Aib" dArg 2 4 Asp 3 7 Ava38, Ado3)hGLP-1(7-39)N- (Aib 8 XArgflt4 Aun 3 T )hGLP-1 (7-37)NH 2 (Aib",1t35)hGLP-1 (7-36)NH 2 (Aib 6 ,Arg~o-M, i-Alt, D-Asp T Ava 3 AunflhGLP-1 (7-39)N H 2 (Glya. i3-AlahGLP-1 (7-36)NH 2 (Ser', j-Alt3)hGLP-1 (7-36)NH 2 (Aib'. GIu 2 .3 /3-AaflhGLP-1 (7-36)NH 2 (Gly', Ajbfl)hGLP-1(7-36)NH 2 (Aibt, Lys 18 f3-Ala3)hGLP-1 (7-36)NH 2 (Aibl, LeUV,. I3-Altl)hGLP-1 (7-36)NH 2 (Aib'. Lysm, t3-AaflhG LP- 1(7-36)NH 2 Lys*, Leu 2 T t3-AJt')hGLF-1 (7-36)NH 2 (Aib'. D-ArgflAhGLP- 1(7-36)NH 2 (AWb, I3-Alamt ID-Arg37)hGLP- 1 (7-37)NH 2 (Aibar". 13-Ala~shhGLP-1 (7-36)NH,; (Aib'*7, 3-Ala 1- 7 Arg-m)hG LP- 1 (7-38)NH 2 (Aib 5 27 /3-Ala3 35 3, Arg 3 f9hGLP- 1 (7-39)NH 2 (Aib', Lys''1. 7 /3-Alt)hGLP-1 (7-36)NH 2 (Aib 5 L YS 27 /3-AIa')hGLP-1 (7-36)NH 2 (Alt?, 13-Alt Arg')hGLP-1 (7-38)NH 2 (Alb", Arg-' 1 4 I3Aar,.1)hGLP-1 (7-36)NH 2 (Alt?, D-ArgflhGLP-1 (7-36)N-1 2 (Aib 8 13-Ala 35 Arg 37 )hG LP- 1 (7-37)N H,; (Aib 5 Phe 3T i-Aat)hGLP-1 (7-36 )NI- 2 Phe 3 )hGLP-1 (7-36)NH 2 (Aib m Nall') )hG LP- 1 (7-36)N H 2 (Aib'Th Nal28 31 )hGLP-1 (7-36)NH 2 (Aib' -5 NaI 3 )hGLP-1 (7-36)N H 2 (Aib" ArgM--t Phe 31 )hGLP-1 (7-36)NH 2 (Aib 8 Nal'"-')hGLP-1 (7-36)NH 2 (Aib'-1 Nal' 2.31 )hGLP-1 (7-36)NH 2 (Aibl' Lys"(N-decanoyl))hGLP-1 (7-36)NH 2 (Ait',-h Argmt LyS(N-decanoyl))hGLP-1 (7-36)NH 2 (AWbBM, ArgaltU Lys36N-dodecanoy))hGLP-1 (7-36)NH 2 (Alb ,B-Ala',SeONO0-decanoyl))hGLPI (7-37)-NH 2 (Aibar," a3-Alt 3.3, Arg3I, Lyst(N-otanoyl))hGLP-.1 (7-39)NH 2 (Ail, Arrt /4,3-Alt-1, Lys 3 (N-octanoyl))hGLP-1 (7-37)NH 2 (Alt?, ArgZM-4.1a-Alt.3 Lys 3 (N-decanoyl))hGLP-1 (7-37)NH 2 (Alt?. Arg'". 3-Alt.s Lys 3 7 (N-tetradecanoyl))hGLP-1 (7-37)NH 2 (Alt?, Arg-34t 1-Alt-', LysJl'(Nt-dodecanoyI))hGLp- I (7-37)NH 2 or (Alt?, Arg 2 a3-Altl, Lys 3 (N'-dodecanoyl ))hGLP-1I(8-37)N H 2 or a pharmaceutically acceptable salt thereof. 12. A compoid according to claim 11 wherein said compound is (Aib 8 't A6&I12hGLP-1 (7-36)NH 2 (Aib 8 5 GluO)hGLP-1(7-36)NH 2; (Aib t 6 2 t fl5hGLP-1 (7-36)NH 2 G Iu 2 3 1, A6c 32 )hGLP- 1 (7-36)NH 2 (Alt?, Glu",t 3-Aa")hGLP-1 (7-36)NH 2 (At'a 35 Arg 2 8 fl4 hGLP-1(7-36)NH 2 -61 (At 8 a 3 5 Arg~e 34 Lys,"(Nc-actanoyI))hGLP-1 (7-36)NH 2 (Ab9 35 Arg 2 "t4 Lys "(Nt-decalOyl))hG LP- 1(7-36)OH; (Aibs- 35 LyS 25 Arg 2 3 t Lys3 N'-decaloyl))hGLP-1 (7-36)OH; (Aib8, Arg 2 3 t B-Ala~s. Lys- N'-Aec-decanoyl))hGLP- 1(7-36)NH 2 (Aib' 3 Arg6-4 Ava&", Ado 3 6 8 )hGLP-1 (7-38)NH 2 (Aib'35Arg4-"t Asp",. Ava 3 Ado9)hGLP-1 (7-39)NH 2; (Aibal,Argfllt Aun 37 )hGLP-1-(7-37)NH 2 (AibdITh 5)hGLP-1 (7-36)NH 2 (Aib' ,Argfal.M, (3-Aau, D-Asp 3 Ava-'B AunNhGLP-1 (7-39)NH 2 (Gly', I3-Aa')hGLP-1 (7-36)NH 2 (Ser'. i3-Aa5)hGLP-1 (7-36)N H 2 (Aib'. Glunr-, i3-Aat)hGLP-1 (7-36 )NH 2 (Gly4. AibflhGLP-1(7-36)NH 2 (Aib, Lys"', 13-Alt3)hGLP-1 (7-36)NH 2 (Aibl, Leu1 27 I3-AaflhGLP-1 (7-36)N H 2 (Aib'. Lys33, l3-Aar)hGLP-1 (7-36)NH 2 (Aibl, Lys" 8 Leu", B-Ala')hGLP-1 (7-36)NH- 2 (Aib', D-Arg 3 )hGLP-1 (7-36)NH 2 (AVb, B-ANas, D-Arg 37 )hGLP-1I (7-37)NH 2 (Aib' 27 i3-Alafl3hGLP-1 (7-36)NH 2 (Aibarz, a3-Ala 3 7 Arg 3t )hGLP-1 (7-38)NH 2 (Aib6. L 1 7 .Aa3x Ae-A'hGLP-1(7-3)N H; (Aiba. Lys'", 2-Alat)hGLP-1 (7-36)NH 2 /3-Alt,5 Arg-uhGLP-1 (7-38)NH 2 (Aib', Arg-t 3Alar,)hGLP-1 (7-36)NH 2 D-ArgflhGLP-1 (7;36)NH 2 (Aibs. &A3t. Ar&3')hGLP-I (7-37)NH 2 (Aib'. Phe 31 3-Aat)bGLP-1 (7-36)N- 2 (Aib'Th Phe" t )hGLP-1(7-36)NI-b; (Aib" 5 Nal 3 )hGLP-1 (7-36)NH 2 Na1 2131 )hGLP-1 (7-36)NH 2 (Aibs-'s, Arg 2 0 4 Nal 3 )hGLP-1 (7-36)NH 2 Arg-t Phe 31 )hGLP-1 (7-36)NH- 2 62 o (Aib 8 g Nal'' 3 ')hGLP-1(7-36)NH,; Cl (Aiba s 5 Nal'l't)hGLP-1(7-36)NH 2 y (Aib- 3 5 Lys(N'-decanoyl))hGLP-1(7-36) NH,; c(Aib" 5 Arg 3 Lys(N'-decanoyl))hGLP-1(7-36)NH; (Aib 8 35 Arg 23 Lys"(N'-dodecanoy))hGLP-1(7-36)NH 2 (Aib',B-Ala", Ser3(O-decanoyl))hGLP1(7-37)-NH 2 e (Aib 8 7 -Alai 3 Arg", Lys(N'-octanoyl))hGLP-1 (7-39)NH,; V' (Aib e Arg 2 4 1 3 -Ala 3 Lys 3 "(N-octanoyl))hGLP-1 (7-37)NH 2 o 10 (Aib, Arg 2 5, 13-Ala, Lys 37 (N'-decanoyl))hGLP-1(7-37)NH 2 or c (Aib a Arg 2 (S-A l 5 Lys 3 (N'-tetradecanoyl))hGLP-1 (7-37)NH 2 o or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 12, wherein said compound is: (Aib 835 Arg26, 34 Phe 3 1)hGLP-1(7-36)NH 2 or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. A method of eliciting an agonist effect from a GLP-1 receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 16. A method for 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 and neurodegenerative disease, in a subject in need thereof which comprises administering to said subject an effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 17. A method according to claim 16 wherein said disease is Type I diabetes or Type II diabetes. 18. Use of a compound as claimed in any one of claims 1 to 13 in the preparation of a medicament for the treatment of disease. 19. Use as claimed in claim 18, in which the disease is 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 and neurodegenerative disease. H:\MaraR\Keep\Speci\P49062-claimpga62&63.doc 15/09/04 63 0 Dated this 1 5 t h day of September 2004 N SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SSCIENTIFIQUES SAS CD) By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia Cci 0i t(N H{:\NaraF\Keep\Specl\49.062-:laimpg.62s63.doc 1S/09/04