AU2005203169B2 - Analogues of GLP-1 - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, S.A.S.

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 us: 1A

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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 t' comprising said analogues.

O 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 O 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 pmol/L to a peak postprandial level of 40 pmol/L. It has been demonstrated that, for a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann, 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 Sci 1993:38:665-73) and may enhance peripheral glucose disposal (D'Alessio, D.A. et al., J. Clin Invest 1994:93:2293-6).

In 1994, the therapeutic potential of GLP-1 was suggested following the observation that a single subcutaneous dose of GLP-1 could completely normalize postprandial glucose levels in patients with non-insulin-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. 4th, et al., Nature 1993:361:362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe

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

Numerous studies have shown that when given to healthy subjects, GLP-1 l 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 O diabetes management in Glucagon III, Handbook of Experimental Pharmacology,

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Lefevbre PJ, Ed. Berlin, Springer Verlag, 1996, p. 311-326), effects which are O glucose dependent (Kreymann, et al., Lancet ii: 1300-1304, 1987; Weir, G.C., Set al., Diabetes 38:338-342, 1989). Moreover, it is also effective in patients with diabetes (Gutniak, N. Engl J Med 226:1316-1322, 1992; Nathan, et al., cDiabetes 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 (Creutzfeldt, et al., Diabetes Care 19:580-586, 1996), raising the possibility of its use as a therapeutic agent.

GLP-1 is, however, metabolically unstable, having a plasma half-life 2 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

-A-A'-A

o A -A 1

-A

1 2

A-A

13

-A

14

-A

15 1

-A

16

-A

17

-A

8 A 20

-A

21

-A

2 2

-A

23

-A

24

-A

25

-A

26

-A

2 7

A

2 -A -A-A1_A 3

-A

3 3 -A4-A 5 -A-A -A-A 39

(I)

wherein

A

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

A

8 is Ala, D-Ala, Aib, Acc, 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, /3-Ala or Aib; A" is Thr or Ser;

A

2 is Phe, Acc, Aic, Aib, 3-Pal, 4-Pal, i3-Nal, Cha, Trp or X'-Phe; A" is Thr or Ser; A" is Ser or Aib; cl Al 5 is Asp or Giu;

A"

8 is Val, Aco, Aib, Leu, lie, Tie, Nie, Abu, Ala or Cha; A A 7 is Ser or Thr;

A'

8 is Ser or Thr;

A

19 is Tyr, Cha, Phe, 3-Pal, 4-Pal, Acc, 13-Nal or X'-Phe;

A

20 is Leu, Acc, Aib, Nie, lie, Cha, Tie, Val, Phe or X'-Phe; Va

A

2 is Glu or Asp;

A

2 is Gly, Acc, B-Ala, Glu or Aib;

A

23 is Gin, Asp, Asn or Glu; o 10 A2 4 is Ala, Aib, Val, Abu, Tie or Acc;

A

2 5 is Ala, Aib, Val, Abu, Tie, Acc, Lys, Arg, hArg, Om, HN-CH((CH 2 1 0

R'

1 C(O) or HN-CH((CH 2 )e-X 3

A

2 6 is Lys, Arg, hArg, Orn, HN-CH((CH 2 or HN-CH((CH 26

-X

3

C(O);

A

27 is GIu Asp, Leu, Aib or Lys;

A

28 is Phe, Pal, 13-NaI, X'-Phe, Aic, Acc, Aib, Cha or Trp;

A"

9 is lie, Acc, Aib, Leu, Nie, Cha, Tie, Val, Abu, Ala or Phe;

A

30 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, Nle, lie, Cha, Tie, Phe, X'-Phe or Aia;

A

3 3 is Vai, Acc, Aib, Leu, lie, Tie, Nie, Cha, Ala, Phe, Abu, Lys or X'-Phe; A 3 is Lys, Arg, hArg, Orn, HN-CH((CH 2

),-N(R'OR

11 or HN-CH((CH 2

),X

3

G(O);

A

35 is Gly, 13-Ala, 0-Ala, Gaba, Ava, Aib, Acc or a 0-amino acid; A 3 is L- or D-Arg, 0- or L-Lys, 0- or L-hArg, D- or L-Orr, HN-CH((CH 2

HN-CH((CH

2 3 or deleted;

A

37 is Gly, 13-Aia, Gaba, Ava, Aib, Acc, Ado, Arg, Asp, Aun, Aec, HN-(CH 2

HN-CH((GH

2 0

R

1 a 0-amino acid, or deleted;

A

3 8 is 0- or L-Lys, D- or L-Arg, 0- or L-hArg, 0- or L-Orn, HN-CH((CH 2 )n-N(R' 0

HN-CH((CH

2 3 Ava, Ado, Aec or deleted; A' is D- or L-Lys, 0- or L-Arg, HN-CH((CH 2 Ava, Ado, or Aec; X' for each occurrence is independently selected from the group consisting of

C

6 )aikyl, OH and halo; 0 0 c R' is OH, NH 2

(C,-C

3 )alkoxy, or NH-X 2

-CH

2 -ZO, wherein X 2 is a (Ci-

C,

1 )hydrocarbon moiety, and Z 0 is H, OH, COH or CONH is X -N N-(CH2

-CH,

X is13 -NH-C(D)-CH,-N N-(CH,) 2

-NH-C(O)-R

C 5 or -C(O)-NHR' 2 wherein X 4 is, independently for each occurrence, -NHor -CH 2 and wherein f is, independently for each occurrence, an integer N from 1 to 29 inclusive; each of R 2 and R 3 is independently selected from the group consisting of H, C3o)alkyl, (C 2 -C3)alkenyl, phenyl(C-C 30 )alkyl, naphthyl(C,-C3)alkyl, hydroxy(C 1

C

3 )alkyl, hydroxy(C 2 -C,)alkenyl, hydroxyphenyl(C-C 3 0)alkyl, and 1' hydroxynaphthyl(C,-C3o)alkyl; or one of R 2 and R 3 is (CH 3 2

-N-=N(CH

3 2

(C-

Y(CH,)r-N N-(CH 2 )qSO 2

C

30 )acyl, (C-C)alkylsulfonyl, C(O)X 5 or N-(CH,)q-CO- ;wherein Y is H, OH or NH,; r is 0 to 4; q is 0 to.4; and X 5 is (C,-C)alkyl, (C 2

-C

3 ,)alkenyl, phenyl(C-C 30 )alkyl, naphthyl(C,-C)alkyl, hydroxy(Cl-C 30 )alkyl, hydroxy(C,-C 30 )alkenyl, hydroxyphenyl(C,-C,,)alkyl or hydroxynaphthyl(C,-C3)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 R 10 and R 11 is, independently for each occurrence, H, (C,-C 3 )alkyl,

C

3 ,,)acyl, (C,-C 3 )alkylsulfonyl, -C((NH)(NH 2 or -C(O)-CHi--N

N-(CH

2 )f-CH, S1; and

R

1 2 and R 15 each is, independently for each occurrence, (C,-C)alkyl;

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Cl provided that: Swhen A 7 is Ura, Paa or Pta, then R and R 3 are deleted; when R 1 0 is (Cl-C 3 0 )acyl, (C,-C,)alkylsulfonyl, -C((NH)(NH 2 or -C(O)-CH2 N N-(CH2)f-CH 3 St then R 11 is H or (C,-C3,)alkyl;

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at least one amino acid of a compound of formula is not the same as the O native sequence of hGLP-1 (7-36, -37 or -38)NH, or hGLP-1 (7-36, -37 or -38)OH; Tn (ii) a compound of formula is not an analogue of hGLP-1(7-36, -37 or -38)NH 2 or ShGLP-1(7-36, -37 or -38)OH wherein a single position has been substituted by Ala; cl (iii) a compound of formula is not (Arg 2 34 Lys 3 8 )hGLP-1(7-38)-E, (Lys2(Nsalkanoyl))hGLP-1(7-36, -37 or (Lys4(N,-alkanoyl))hGLP-1(7-36, -37 or 38)-E, (Lys 2 8 ,-bis(N,-alkanoyl))hGLP-1(7-36, -37 or (Arg 2 6 Lys3(Nralkanoyl))hGLP-1(8-36, -37 or (Arg 26 34 Lys 3 (N,-alkanoyl))hGLP-1(7-36, -37 or -38)-E or (Arg 2 3 Lys(N.-alkanoyl))hGLP-1(7-38)-E, wherein E is -OH or -NH,; (iv) a compound of formula is not Z 1 -hGLP-1(7-36, -37 or -38)-OH, Z'-hGLP-1(7- 36, -37 or -38)-NH 2 wherein Z' is selected from the group consisting of: (Arg 26 (Arg 4 (Arg 26 (Lys 3 (Arg 26 Lys36), (Arg 4 Lys 36 (D-Lys 36 (Arg 36 (D-Arg 3 6 (Arg 26 3 4 Lys 36 or (Arg 2 6 3 6 Lys); (Asp 2 1 at least one of (Aib 8 (D-Ala 8 and (Asp 9 and (Tyr 7 (N-acyl-His 7 (N-alkyl-His 7 (N-acyl-D-His 7 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')hGLP- 1(7-36 or (Asp 2 hGLP-1(7-36 or -37) or (Phe")hGLP-1(7-36 or -37) or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing compound is where A" is Thr; A' 3 is Thr; A 15 is Asp; A' 7 is Ser; A" 1 is Ser or Lys; A 2 is Glu; A 2 3 is Gin or Glu; A 27 is Glu, Leu, Aib or Lys; and A 31 is Trp, Phe or 3-Nal; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A 9 is Glu, N-Me-Glu or N-Me-Asp; A 12 is Phe, Acc, 3-Nal or Aic; A 6 is Val, Acc or Aib; A 19 is Tyr or /3-Nal; A 2 is Leu, Acc or Cha; A 2 4 is Ala, Aib

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lN or Acc; A 2 5 is Ala, Aib, Acc, Lys, Arg, hArg, Orn, HN-CH((CH,),-N(R 1 or 3 HN-CH((CH 2

A

28 is Phe or /3-Nal; A 2 9 is lie or Acc; A 30 is Ala or Aib; A 32 is Leu, Acc or Cha; and A" is Val, Lys or Acc; or a pharmaceutically acceptable salt C" thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where A 8 is Ala, D-Ala, Aib, A6c, A5c, N-Me-Ala, N-Me-D-Ala or N-

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SMe-Gly; A 1 0 is Gly; A 1 2 is Phe, /3-Nal, A6c or A5c; A 1 is Val, A6c or A5c; A 2 0 is Leu, ec O A6c, A5c or Cha; A 2 is Gly, 8-Ala, Glu or Aib; A 24 is Ala or Aib; A" is lie, A6c or tr A5c; A 32 is Leu, A6c, A5c or Cha; A 3 is Val, Lys, A6c or A5c; A 35 is Aib, 3-Ala, Ado, o 10 A6c, A5c, D-Arg or Gly; and A 37 is Gly, Aib, f-Ala, Ado, D-Ala Ava, Asp, Aun, D- 'l Asp, D-Arg, Aec, or deleted; or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the immediately foregoing group of compounds is where X 4 for each occurrence is and R 1 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 2 is H and R 3 is (C,-Co)alkyl, (C2-C, 0 )alkenyl, (C,-C3,)acyl, (C,-C3o)alkylsulfonyl, HO-(CH 2 -N N-(CH), 2 SO,- HO-(CH), 2 -N N-CH 2

-CO-

or

H

2

N-(CH

2 2 -N N-CH 2

-CO-

A preferred compound of the formula is where A 8 is Ala, D-Ala, Aib, A6c, N-Me-Ala, N-Me-D-Ala or N-Me-Gly; A' 0 is Gly; A 12 is Phe, 3-Nal A6c or

A'

6 is Val, A6c or A5c; A 20 is Leu, A6c, A5c or Cha; A 22 is Gly, B-Ala, Glu or Aib; A 2 4 is Ala or Aib; A 2 is lie, A6c or A5c; A" is Leu, A6c, A5c or Cha; A 33 is Val, Lys, A6c or A5c; A 3 5 is Aib, f-Ala, Ado, A6c, A5c D-Arg or Gly; and A 37 is Gly, Aib, f-Ala, Ado, D-Ala, Ava, Asp, Aun, D-Asp, D-Arg, Aec, HN-CH((CH2)n-N(R'R"))-C(O) or deleted; X 4 for each occurrence is e for each occurrence is independently 1 or 2; R' is OH or NH2; R' 0 is (C,-C3o)acyl, (C,-C,3)alkylsulfonyl or Z N-(GH 2 )fCH 3 and R 1 is H; or a pharmaceutically acceptable salt thereof.

More preferred of the immediately foregoing compounds is where is -C(O)-CHr-N NICH 2 )rCH 3 O C 20 )aCYl, (C 4

-C

2 0 )alkylsulfonyl or ,or a pharmaceutically acceptable salt thereof.

0 A more preferred compound of formula is where said compound is of the formula: (Aib 83 1 5 )hGLP-1I(7-36)NH 2 ((N.-HEPES-His)f, Aib 835 )hGLP-1 (7-36)NH 2 ((N.-HEPA-HiS) 7 Aib 8 35 )hGLP-1 (7-36)N- 2 (Aib 8 13-Ala 35 )hGLP-1 (7-36)N H 2 (Ai b 8 Arg 263 t Lys 3 (Nr.-tetradec-anoyl))hG LP- 1(7-36)NH 2 (Aib't Arg 26 Lys34(N,.-tetradecanoyl))hGLP-i (7-36)NH 2 (Aibsb 8 5 37 Arg 2634 Lys 3 (Nr.-tetradecanoyl hGLP-1 (7-38)NH 2 (Aib 8 35 Arg 283 t Lys3(N,.-decanoyi))hGLP- 1(7-36 )N H 2 (Aib 8 3, Arg 26 t LysM1(N.-dodecanesulfonyl))hGLP-1 (7-36)NH 2 (Ai b 835 Arg 26 Lys 3 (N-(2-(4-tetradecyl-l1-piperazi ne )-acetyl LP- 1(7-36)N H 2 (Aib 825 Arg 2 6 t34 Asp 3 8 l(l1-(4-tetradecyl-piperazine)))hGLP-1I(7-36)N H 2 (Aib 835 Arg 263 t As p 38 (1 -tetradecylamino))hGLP-l (7-36)NH 2 (Ai b 835 Arg 26 -1t Lys 3 (Nr-tetradecanoyl) ,13-Alaf7lhG LP- 1(7-37)-OH or (Aib b.

35 Arg 26 ,1 Lys~l(N,.-tetradecanoyI GLP-1 (7-36)-OH, or a pharmaceutically acceptable salt thereof More preferred of the immediately foregoing group of compounds is a compound of the formula: (Aib 835 )hGLP-1 (7-36)N H 2 (Aiba, 13-AaflhGLP-1 (7-36)N H 2 (Aib 8 35 Arg 2 e1, Lys34(N.-tetradecanoyl))hGLP-1 (7-36)NH 2 (Aib 8 3537 Arg 2 634 Lys 3 8 Nrtetradecanoyl ))hG LP-1 (7-38 )N H, (Aib 83 5 Arg 26 Lys 3 (N-decanoyl))hGLP- 1 (7-36)NH 2 or (Aib 835 Arg 283 t Lys'(N.-tetradecanoyI),B3-Aa3)hGLP-1 (7-37) -OH, or a Z pharmaceutically acceptable salt thereof.

Another mare preferred compound of formula is where said compound is of the formula: (Aiba- 35 A6c 32 )hGLP-1 (7-36)NH 2 (Aib 8 35

GIU

23 )hGLP-1 (7-36)NH 2 (Aib 8 2 4 -)hGLP-1 (7-36)NH 2 O(AVib 35 GIu 23 A6c 32 )hGLP- 1(7-36)N H 2 0(AibB, GI U 23 13-Ala 3 )hGLP-1 (7-36)NH 2 (Aibt35 Arg 2 3 )hGLP-1(7-36)NH 2 (Aib.

35 Arg 2 8 3 4 L ys 35 (N'octanoyl))hGLP-1 (7-36)NH 2 (Aib 835 Arg26' 34 Lys 36 (Nt-decanoyl))hGLP- 1(7-36)0 H; (Aib 835 L ys 25 Arg 2834 Lys 3 8 1( N t -decanoyl))hGLP- 1 (7-36)QH; (AV, Arg 2 834 B-Ala 3 5 Lys'6(Nt-Aec-decanoyl))hGLP-1 (7-36)NH 2 (Aib 83 5Arg 26 3 4 Ava 3 7L AdomlhGLP-1 (7-36)NH 2 (Aib 835 1 Arg 283 t Asp 37 Ava 3 8 AdMOM 9 )hGLP-1 (7-39)NH 2 (Aib 8 2 t5Arg 2 8 't4 Aun 37 )hGLP-i (7-37)NH 2 (Aib 817

I

3 ,)hGLP-1 (7-36)NH 2

(A

8 ,Arg 2 1.1, B3-Ala 35 D-Asp 3 7 Ava 3 1, Aun 3 )hGLP-1 (7-39)NH 2 (Gly 8 B-Ala 35 )hGLP-1 (7-36)NH 2 (Ser 8 13-Ala 3 1)hGLP-1 (7-36)NH 2 (Aib 8 0I1 22 2 3 3-Aafl)hGLP-1 (7-36)NH 2 (Gly 8 Aib 35 )hGLP-1 (7-36)NH 2 (Aib 8 Lys' 8 1-Ala 35 )hGLP-1 (7-36)NH 2 (Aib, Leu 2 7 /3-Ala 35 )hGLP-1 (7-36)NH 2 (Aib 8 Lys 33 13-Ala 35 )hGLP-1 (7-36)NH 2

(AV

8 Lys", Let? 7 f3-Ala 35 )hGLP-1 (7-36)NH 2 (Aib, D-Arg 36 )hGLP-1 (7-36)NH 2 (Aib 8 /3-Ala 3 5 D-Arg 37 )hGLP-1 (7-37)NH 2 (Aib 8 11 27 1-Alt-1)hGLP-1 (7-36)NH 2 (Aib 8 11 27 B-Ala 3 1.

3 1, Arg 38 l)hGLP-1 (7-38)NH 2 (Aib 82 7 B3-Ala 3 537 Arg 38 39 )hGLP-1 (7-39)NH 2 (Aib8, Lys 1 8 1 2 7 13-Ala 35 )hGLP-1 (7-36)NH 2 (Aib 8 Lys 2 1 7 13-Ata 35 )hGLP-1 (7-36)NH- 2 0 0 cl (Aib, B3-Ala 35 Arg-)hGLP-1(7-38)NH 2 (Aib 8 Argt", -Ala 3 ,)hGLP-1(7-36)NH 2 (AibO, D-Argf)hGLP-1(7-36)NH 2 C (Aib, 3-Ala5, Arg 37 )hGLP-1(7-37)NH,; (Aiba, Phe 31 /3-Ala5)hGLP-1 (7-36)NH 2 (Aib' 3 5 Phe 31 )hGLP-1(7-36)NH

\O

(Aib6 35 Na3l 3 )hGLP-1(7-36)NH 2 (Aib 535 Nal 2 8 3 )hGLP-1(7-36)N H 2 (Aib 8 3 Arg 34 Na 31 )hGLP-1(7-36)NH 2 o 10 (Aib 8 a 35 Arg26-34", Phe 3 1 )hGLP-1(7-36)NH,; (Aib 835 Nal 19 3 1 )hGLP-1(7-36)NH; (Aib1 35 Na' 12 3 1 )hGLP-1(7-36)NH2; (Aib1 3 5 Lys 3 (N'-decanoyl))hGLP-1 (7-36) NH 2 (Aib 835 Arg 34 Lys 2 6(Nr-decanoyl))hGLP-1 (7-36)NH 2 (Aib 8 35 Arg 2 6 34, LyS3(NE-dodecanoyl))hGLP-1(7-36)NH 2 (Aib 8 ,B-Ala 3 5 Ser 37 (0-decanoyl))hGLP1 (7-37)-NH,; (Aib, 27 /-Ala 5 3 Arg, Lys3(NE-octanoyl))hGLP-1(7-39)NH 2 (Aib 8 Arg 26 13-Ala 35 LysS(N'-octanoyl))hGLP-1 (7-37)NH,; (Aib 5 Arg26', S-Ala 35 Lys 37 (N-decanoyl))hGLP-1(7-37)NH 2 or (Aib 8 Arg 25 34 13-Ala 3 5 LyS3(NE-tetradecanoyl))hGLP-1(7-37)NH 2 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 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

in yet another aspect, the present invention provides a method of eliciting an agonist effect from a GLP-1 receptor in a subject in need thereof which comprises administering to said subject an effective amount of a compound of formula as defined hereinabove or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a method of treating a disease selected from the group consisting of Type I diabetes, Type It diabetes,

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c obesity, glucagonomas, secretory disorders of the airway, metabolic disorder, Sarthritis, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic C syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake is desired, in a subject in need thereof which comprises O administering to said subject an effective amount of a compound of formula as defined hereinabove or a pharmaceutically acceptable salt thereof. A preferred 0 method of the immediately foregoing method is where the disease being treated is tr Type I diabetes or Type II diabetes.

0 With the exception of the N-terminal amino acid, all abbreviations Ala) Cof amino acids in this disclosure stand for the structure of -NH-CH(R)-CO-, wherein R is the side chain of an amino acid CH 3 for Ala). For the N-terminal amino acid, the abbreviation stands for the structure of (R 2

R

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 2 and R 3 are not present since Ura, Paa and Pta are considered here as des-amino amino acids. Amp, /-Nal, Nle, Cha, 3-Pal, 4-Pal and Aib are the abbreviations of the following a-amino acids: 4-aminophenylalanine, 13-(2-naphthyl)alanine, norleucine, cyclohexylalanine, pyridinyl)alanine, 3-(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-glutamic acid; Tie is tert-butylglycine; Abu is a-aminobutyric acid; Tba is tert-butylalanine; Orn is ornithine; Aib is a-aminoisobutyric acid; 3-Ala is i-alanine; Gaba is y-aminobutyric acid; Ava is 5-aminovaleric acid; Ado is 12aminododecanoic acid, Aic is 2-aminoindane-2-carboxylic acid; Aun is 11aminoundecanoic acid; and Aec is 4-(2-aminoethyl)-1-carboxymethyl-piperazine,

O

HNN N -N

II

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-1-cyclohexanecarboxylic acid (A6c); 1-amino-l-cycloheptanecarboxylic acid (A7c); 1-amino-1- -11cyclooctanecarboxylic acid (A8c); and 1-amino-1 -cyclononanecarboxylic acid (A9c).

In the above formula, hydroxyalkyl, hydroxyphenylalkyl, and hydroxynaphthylalkyl may contain 1-4 hydroxy substituents. COX 5 stands for -C=O0X 5 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:

O

N H CH 3

H

N

H

SWhat is meant by Lys(Nt-alkylsulfonyl) is 00 N CH3 A N

H

H 0 %^lhk representea Dy mne loiiowing strucuri; is meant by Lys(Ne-(2-(4-alkyl-1-piperazine)-acetyl)) is represented by the following 0 OH 3 N N N 3 N

H

H 0 i. 4. sLI1ruU I l: Asp(1-(4-alkyl-piperazine)) by SWhat is meant by the following is represented structure: H O What is meant by Asp(1-alkylamino) 0

H

N

CH

3 XN II is represented by the following structure: H O What is meant by Lys(Nc-Aec-alkanoyl) is represented by the structure:

S(N

N N r N 3 H 0 The variable n sO in the foregoing structures is 1-30. What is meant by Lys (Ne-ace-alkanoyl) is c represented by the structure: NN N N CH 3 H 0

N

H O 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 diisopropylethylamine, 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 3 )hydrocarbon moiety" encompasses alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there are C 2

-C

3 o.

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 8 for Ala 8 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-

O

O

cl 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, indicates that the C-terminus of the peptide is amidated. hGLP-1(7-36) means that the C-terminus is the free acid. In Cl hGLP-1(7-38), residues in positions 37 and 38 are Gly and Arg, respectively.

Detailed Description u O The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, Stewart, et al., Solid Phase Synthesis (Pierce O Chemical Co., 2d ed. 1984). The substituents R 2 and R 3 of the above generic Sformula may be attached to the free amine of the N-terminal amino acid by S 10 standard methods known in the art. For example, alkyl groups, (C,-C 30 )alkyl, may be attached using reductive alkylation. Hydroxyalkyl groups, C3,)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 acid and diisopropylcarbodiimide in methylene chloride for one hour. If the free acid contains a free hydroxy group, p-hydroxyphenytpropionic acid, then the coupling should be performed with an additional 3 molar equivalents of HOBT.

When R' is NH-X 2

-CH

2

-CONH

2

ZO=CONH

2 the synthesis of the peptide starts with BocHN-X 2

-CH

2 -COOH which is coupled to the MBHA resin. If

R

1 is NH-X 2

-CH

2 -COOH, ZO=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)-1-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 200 ml of dioxane and 100 ml of water. To it was added 67 ml of 2N NaOH. The solution was cooled in an ice-water bath. 32.0 g (0.147 mol) of di-tert-butyl-dicarbonate was added to this solution. The reaction mixture was stirred overnight at room temperature. Dioxane was then removed under reduced pressure. 200 ml of ethyl acetate was added to the remaining aqueous solution.

The mixture was cooled in an ice-water bath. The pH of the aqueous layer was adjusted to about 3 by adding 4N HCI. The organic layer was separated. The 0

O

aqueous layer was extracted with ethyl acetate (1 x 100 ml). The two organic Z layers were combined and washed with water (2 x 150 ml), dried over anhydrous MgSOd, filtered, and concentrated to dryness under reduced pressure. The residue was recrystallized in ethyl acetate/hexanes. 9.2 g of the pure product was obtained. 29% yield.

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

'V In the synthesis of a GLP-1 analogue of this invention containing A5c, A6c O 10 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,, 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,-C 30 )alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups, (C,-C3o)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% C02/95% air.

Radioligand Binding: Membranes were prepared for radioligand binding studies by

O

O

c homogenization of the RIN cells in 20 ml of ice-cold 50 mM Tris-HCI 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 C resuspended in 50 mM Tris-HCI, containing 2.5 mM MgCI,, 0.1 mg/ml bacitracin (Sigma Chemical, St. Louis, MO), and 0.1% BSA. For assay, aliquots (0.4 ml) O were incubated with 0.05 nM 125 1)GLP-1(7-36) (-2200 Ci/mmol, New England Nuclear, Boston, MA), with and without 0.05 ml of unlabeled competing test 0 peptides. After a 100 min incubation (25 the bound 125 1)GLP-1(7-36) was in 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 125 1)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 acetic 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.

I-16-

O

O

C As is well known to those skilled in the art, the known and potential uses of 3Z 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, C1997, 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 O 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 Cdisorders wherein the reduction of food intake is desired. GLP-1 analogues of the present invention that elicit an antagonist effect from a subject can be used for treating the following: hypoglycemia and malabsorption syndrome associated with gastroectomy or small bowel resection.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula in association with a pharmaceutically acceptable carrier.

The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. In general, an effective dosage for the activities of this invention is in the range of 1x10 7 to 200 mg/kg/day, preferably lx10 4 to 100 mg/kg/day, which can be administered as a single dose or divided into multiple doses.

The compounds of this invention can be administered by oral, parenteral 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

M

O

O

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

CLiquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert Odiluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and O 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 Cnon-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.

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

Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications. U.S. Patent No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form.

U.S. Application No. 08/929,363 filed September 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S.

Application No. 08/740,778 filed November 1, 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextrin. U.S. Application No.

09/015,394 filed January 29, 1998, teaches absorbable sustained release -18-

O

O

c compositions of a bioactive agent. U.S. Application No. 09/121,653 filed July 23, 1998, teaches a process for making microparticles comprising a therapeutic agent _such as a peptide in an oil-in-water process. U.S. Application No. 09/131,472 filed August 10, 1998, teaches complexes comprising a therapeutic agent such as a peptide and a phosphorylated polymer. U.S. Application No. 09/184,413 filed O 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 O foregoing patents and applications are incorporated herein by reference.

tf Unless defined otherwise, all technical and scientific terms used herein have 0 10 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-3Ala-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 (Aib')hGLP-1(7-36)NH 2 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 (1992). 4-methylbenzhydrylamine (MBHA) resin (Peninsula, Belmont, CA) with the substitution of 0.91 mmol/g was used. The Boc amino acids (Bachem, CA, Torrance, CA; Nova Biochem., LaJolla, CA) were used with the following side chain protection: Boc-Ala-OH, Boc-Arg(Tos)-OH, Boc-Asp(OcHex)- OH, Boc-Tyr(2BrZ)-OH, Boc-His(DNP)-OH, Boc-Val-OH, Boc-Leu-OH, Boc-Gly- OH, Boc-Gln-OH, Boc-Ile-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 -19-

O

O

cl synthesis was carried out on a 0.20 mmol scale. The Boc groups were removed by Z treatment with 100% TFA for 2 x 1 min. Boc amino acids (2.5 mmol) were pre- Sactivated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF and were C 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- O 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 O solution of 20% mercaptoethanol/10% DIEA in DMF for 2 x 30 min. to remove the SDNP 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 0°C 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 mL/min (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 ((Na-HEPES-His) 7 Aib*.

3 )hGLP-1(7-36)NH2 The title compound (HEPES is (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)) can be synthesized as follows: after assembly of the peptide (Aib' 35 )hGLP-1(7-36)NH 2 on MBHA resin (0.20 mmol) according to the procedure of Example 1, the peptide-resin is treated with 100% TFA (2 x 2 min.) and washed with DMF and DCM. The resin is then neutralized with 10% DIEA in DMF for 2 min.

O

O

Cl After washing with DMF and DCM, the resin is treated with 0.23 mmol of 2-chloro- S1-ethanesulfonyl chloride and 0.7 mmol of DIEA in DMF for about 1 hour. The resin is washed with DMF and DCM and treated with 1.2 mmol of 2- Cl hydroxyethylpiperazine for about 2 hours. The resin is washed with DMF and DCM and treated with different reagents 20% mercaptoethanol 10% DIEA in DMF Oand 15% ethanolamine 15% water 70% DMF) to remove the DNP group on the His side chain and formyl group on the Trp side chain as described above Ce O before the final HF cleavage of the peptide from the resin.

Example 3 ((N.-HEPA-His) 7 Aib 3 5 )hGLP-1 (7-36)NH 2 l The title compound (HEPA is (4-(2-hydroxyethyl)-1-piperazineacetyl)) can be made substantially according to the procedure described in Example 2 for making ((No-HEPES-His) 7 Aibs,3)hGLP-1(7-36)NH 2 except that 2-bromoacetic anhydride is used in place of 2-chloro-l-ethanesulfonyl chloride.

Example 4 (Aib", 3-Ala 35 )hGLP-1(7-36)NH 2 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' 6 )hGLP-I(7-36)NH, in Example 1 above, but using the appropriate protected amino acids depending on the desired peptide.

Example (Aib 8 3 5 Arg 2 6 3 4 Lys 3 (Nc-tetradecanoyl))hGLP-1(7-36)NH 2 The Boc amino acids used were the same as those in the synthesis of (Aib' 35 )hGLP-1(7-36)NH, 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 mmot 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 I-21-

O

O

protecting group. The resin was washed with DMF. Myristic acid (2.5 mmol) was pre-activated with HBTU (2.0 mmol) and DIEA (1.0 mL) in 4 mL of DMF for 2 min _and was coupled to the Fmoc-Lys-resin. The coupling time was about 1 hr. The C 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 Stransferred 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 O synthesis of (Aib" 5 )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 acid in place of the Myristic acid used in Example Example 6: (Aib 8 35 Arg 26 Lysm(N.-tetradecanoyl))hGLP-1(7-36)NH 2 Yield 89.6 mg; MS(ES) 3577.2, Calculated MW 3578.7; Purity 96%.

Example 7: (Aib' 35 37 Arg 2 4 Lys" 3 (N,-tetradecanoyl))hGLP-1(7-38)NH 2 Yield 63.3 mg; MS(ES) 3818.7; Calculated MW 3819.5; Purity 96%.

Example 8: (Aib l 35 Arg 2 6 3 4 Lys 36 (Ne-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 8 3 Arg 2 6 4 Lys'(N-tetradecanoyl))hGLP- 1(7-36)NH 2 Fmoc-Lys(Boc)-OH amino acid 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(N-alkanoyl) 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.

'I

O

O

CA Example 9 (Aib 8 3 5 Arg 2 8 3 Lys'(N.-dodecanesulfonyl))hGLP-1(7-36)NH 2 _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 ON 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken

VO

for about 2 min. To the solution is then added 0.2 mmol of MBHA resin(substitution O 0.91 mmol/g). The mixture is shaken for about 1 hr. The resin is washed with It) DMF and treated with 100% TFA for 2x2 min to remove the Boc protecting group.

0 o 10 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(Nc-alkylsulfonyl) 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 3 5 Arg 2 63 4 Lys"(N,-(2-(4-tetradecyl-1-piperazine)-acetyl)))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 -23-

O

O

Cl 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 C with HBTU (2.0 mmol) and DIEA (1 mL) in 4 mL of DMF for about 2 min and is added to the resin. The mixture is shaken for about 10 min and washed with DMF.

O 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 O for about 4 hrs. After washing with DMF, the resin is treated with 3 mmol of acetic n 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 l washed with DMF and transferred to the reaction vessel of the peptide synthesizer to continue the synthesis. The remaining synthesis and purification procedures for the peptide are the same as the procedures described for Example 1.

The syntheses of other compounds of the present invention containing Lys(N-(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(Ne-(2-(4-alkyl- 1-piperazine)-acetyl)) during the alkylation step. If the Lys(N.-(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' 3 5 Arg 26 3 4 Asp 6 (1-(4-tetradecyl-piperazine)))hGLP-1 (7-36)NH, The Boc amino acids to be used in this example are the same as the amino acids used in synthesis of Example 5 except Fmoc-Asp(O-tBu)-OH is used at position 36. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution 0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2x15 min to remove the tBu protecting group. The resin is washed with DMF and is treated with HBTU (0.6 mmol) and DIEA (1mL) in 4 mL -24-

O

O

Cl of DMF for about 15 min. 0.6 mmol of piperazine is added to the reaction mixture 3 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 C 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 O 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 Ce 0 the synthesis. The remaining synthesis and purification procedures for the peptide iV are the same as those for the synthesis of Example 1.

The syntheses of other compounds of the present invention comprising l 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)-acetyl)) during the alkylation step. if the Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue is not at the C-terminus, the peptide fragment immediately prior to the Asp(1-(4-alkylpiperazine)) or Glu(1-(4-alkylpiperazine)) residue is assembled on the resin on the peptide synthesizer first.

Example 12 (Aib.

3 5 Arg 26 3 4 Asp 6 (1-tetradecylamino))hGLP-1 (7-36)NH 2 The Boc amino acids to be used for this example are the same as those used in Example 5. The first amino acid residue is coupled to the resin manually on a shaker. 2.5 mmol of Fmoc-Asp(O-tBu)-OH is dissolved in 4 mL of 0.5N HBTU in DMF. To the solution is added 1 mL of DIEA. The mixture is shaken for about 2 min. To the solution is then added 0.2 mmol of MBHA (substitution 0.91 mmol/g) resin. The mixture is shaken for about 1 hr. The resin is washed with DMF and treated with 100% TFA for 2x15 min to remove the t-Bu protecting group. The resin is washed with DMF and is treated with HBTU (0.6 mmol) and DIEA (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

O

O

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

l 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 o Glu(1-alkylamino), respectively, in the peptide, while Boc-Asp(OcHex)-OH or Boc- SGlu(OcHex)-OH amino acid is used for the residue of Asp or Glu, respectively. If o 10 the Asp(1-alkylamino) or Glu(1-alkylamino) residue is not at the C-terminus, the Speptide 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 835 Arg 26 34 Lys(N.-tetradecanoy),13-Ala 37 )hGLP-1 (7-37)-OH The Boc amino acids used are the same as those in the synthesis of (Aib 835 Arg 2 6 3 4 Lys 3 (Nc-tetradecanoyl))hGLP-1(7-36)NH, (Example 270 mg of Boc-f-Ala-PAM resin (Novabiochem, San Diego, California, substitution=0.74 mmol/g) was used. The Boc protecting group on Boc-13-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 835 Arg 2 63 4 Lys"(N,-tetradecanoyl))hGLP-1 (7-36)-OH The Boc amino acids to be used are the same as those in the synthesis of (Aib 8 35 Arg' 4 Lys 3 (N,-tetradecanoyl))hGLP-1(7-36)NH 2 (Example Fmoc- Lys(Boc)-OH (2.5 mmol) is pre-activated with HBTU (2.0 mmol), HOBt (2.0 mmol and DIEA (2.5 ml) in DMF (4 ml) for about 2 min. This amino acid is coupled to 235 mg of PAM resin (Chem-lmpex, Wood Dale, IL; substitution 0.85 mmol/g) manually on a shaker. The coupling time is about 8 hrs. The remainder of the synthesis and purification procedures are the same as those in Example Electro-spray mass spectrometer analysis gave the molecular weight at 3579.15 in agreement with the calculated weight 3579.5.

O

O

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

O

Example 366 O (Aib 8 i-Ala 3 5 Aec 37 )hGLP-1(7-37)NH 2 SA mixture of MBHA resin (0.2mmol, substitution=0.91mmol/g), Fmoc-Aec- S 10 OH (0.40g, 0.829 mmol), HBTU (1.5 mL 0.5M in DMF) and DIEA (0.5mL) in a C 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 f 3 -Ala 3 5 Aec')hGLP-1(7-38)NH 2 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 8 i3-Ala 35 Aec 37 3 )hGLP-1 (7-38)NH 2 A mixture of MBHA resin (0.2mmol, substitution=0.91 mmol/g), Fmoc-Aec- OH (0.289g, 0.6 mmol), HBTU (1.12 mL 0.5M in DMF) and DIEA (0.4mL) in a reaction vessel was shaken on a shaker for 2h at room temperature. The resin was then washed with DMF and treated with 30% piperidine in DMF for 2X15min. The resin was washed with DMF. To the reaction vessel were added Fmoc-Aec-OH (0.289g, 0.6 mmol), HBTU (1.12 mL 0.5M in DMF) and DIEA (0.4mL). The mixture was shaken at room temperature for 2h. The resin was washed with DMF -27-

O

O

Cl and treated with 30% piperidine in DMF for 2X15min. The resin was washed with SDMF 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 C 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 O at 3663.9 in agreement with the calculated molecular weight 3664.26. Purity 100%; Yield 75.3mg.

C(

n Example 369 (Aib 8 Arg 26 34 1-Ala 3 5 Lys36(N-Aec-decanoyl))hGLP-1 (7-36)NH 2 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 DlEA (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.

Eampe (Aib 3 5 )hGLP-1 (7-36)NH 2 Example 16: (3-Ala 35 )hGLP-1(7-36)NH 2 Example 1 7: ((N"-Me-His) 7 Aib)hGLP-1 (7-36)NH 2 Example 18: ((N'-Me-His) 7 Aib', /-Ala')hGLP-1 (7-36)NH 2 Example 19: ((N-Me-His) 7 Aib 83 Arg 2 )hGLP-1(7-36)NH, -28- ClExample 20: ((N"-Me-His) 7 Aib 8 Arg 2 6M B3-Ala35)hGLP-1 (7-36)NH 2 Example 21: (Aib', A6cflhG LP- 1 (7-36)NH 2 Example 22: (Aib 8 A5c 35 )hGLP-1 (T36)N H 2 Example 23: (Aib 8 D-Alt3)hGLP-1 (7-36)N- 2 Example 24: (Aib 83 A6c 32 )hGLP-1(7-36)NH 2 ON Example 25: (Aib 835 A5c 32 )hGLP- 1(7-36 )N H 2 Example 26: (Aib 835 Glu 23 )hGLP-1(7-36)NH 2 0Example 27: (Aib 8 2 4 35 )hGLP 1(7-36 )NH 2 Example 28: (Aib 8 30 35 )hGLP- 1 (7-36)NH 2 o 'to Example 29: (Aib 2535 )hL (3)H Example 0: (Aib 8 35

A

1 2 )hGLP-1 (7-36)NH 2 Example 31: (Aib' 3 5 A6c' 1 2 1)hGLP-1 (7-36)NH 2 Example 32: (Aib 8 35 A6c 20 32 12)hGLP-1(7-36)NH 2 Example 33: (Aib 8 35 A6 C213)hGLP-1 (7-36)NH 2 Example 34: (Aib 8 25 Lys 25 ~)hGLP-1(7-36)NH 2 Example 35: (Aib 8 2 .35 LASc5)hGLP-1(7-36)NH 2 Example 36: (Aib 8 3 A6c~ 2 )hGLP-1 (7-36)NH 2 Example 3 (Aib 3 A6c 9 32 )hGLP1 (736)NH 2 Example 3: (Aib 8 35 A6c' 2 )GLP-1 (7-36)N H 2 Example 39: (Aib 8 3 1 5 ACa 2 0 )hGLP-1(7-36)NH 2 Example 0: (Aib ch21)iGL (7-3H 2 Example 41: (Aib 8 A6c' 3 )hGLP- (7-36 )NH 2 Example 421: (Ai b 13 A6' 6 2 %l 5 )GP 1(7-36 H73N 2 Examle 43:(Aib 83 ~c 5 ,20 S-Ala 2 )hGLP-1 (7-36)NH 2 Example 4: (Aib 35 )hGL la 2 (3)H 2 Example 45: (Aib 2 5 GLu 23 AcGL-(7-36)NH 2 Example 4: (Aib 35

GIU

2 3 A6c 32 )hGLP- (7-36)NH 2 Example 47: (Ai b 8 a, 24 3 5 t G I23 A6C 32 )hG LP- 1(7-36)NH 2 Example 47: (Ai b 8 24 25 5 9 G A6 u3 2 )hGLP-1 (7-36)N H 2 Example 49: (Aib 8 A6c 10 32 GI-AUa 3 )hGLP-1(7-36)NH 2 Example 50: (Aib', A6c 3 1 2 i3-Al3 5 )hGLP-1(7-36)NH 2 Example 51: (Aib 8 Gu 2 13-Ala' 5 )hGLP-1 (7-36)NH 2 Example 52:, (Aib 824 f&Ala35)hG LP- 1 (7-36)N H 2 Example 53: (Ai b 830 I3-AlaflhG LP- 1(7-36 )N H 2 ClExnpe :(Aib 8 25 f3Alt )hGLP-1 (7-36)NH 2 3 Example 55: (Aib 8 A6c 152 I3-Alt3)hGLP-1(7-36)NH 2 __Example 56: (Aib 6 A6c 1 ,21.

32 3-A[t3)hGLP-1 (7-36)NH 2 ClExample 57: (Aib A6& 03 2 13-Ala 3 5 )hGLP-1(7-36)NH 2 Example 58: (Aib, A6c 20 I3-Aa)hGLP-1 (7-36)NH 2 ONExample 59: (Aib 8 Lys",. 13-Ala1 5 )hGLP-1 (7-36)NH 2 Example 60: (Aib 8 24 AWc 2 I3-Ala 35 )hGLP-1 (7-36)NH 2 o Example 61: (AMb, A6c 2 2 f3-Aa5hGLP-1 (7-36)NH 2 .2 C9.2 tfl Example 52. (Aib 824 A6c 9 2 13-Ala5hGLP-1 (7-36)NH 2 Eape6:0bAC2 -l 5)GP173)H o 0 Example 63: (Aib 8 A~c 2 I3-Ala 35 )hGLP-1(7-36)NH 2 ClExample 64: (Aib Ca 1 3 13-Ala 3 )hGLP-1(7-36)NH 2 Example 65(Aib 8 AWc 33 f3-Ala 35 )hGLP-1 (7-36)NH Example 6 (Aib A-A 32 ,223-Al)hGLP-1 (7-36)NH 2 Example 67: (Aib I3-Aa 2 )hGLP-1 (7-36)NH 2 Example 9: (Ab G',A 2 13-Ala 35 -)hGLP-1 (7-36)NH 2 Example 9: (Aib, GU 23

A

2 I3-Ala 35 )hGLP-1 (7-36)NH 2 Example (Aib 8 24 GILu 3

AOL?

2 13',-Ala 35 )hGLP- 1A1 (73 )H 2 Example 72: (Aib 8 24 ,2 G IU 3 A6c 32 Ly(-ctanoyhl), I-A 3 )hGL-1(73)H Example 72: (Aib 82425 G6I 2 3

O?

2 3, -Al)hGLP-1 (7-36)NH 2 Example 73: (Aib 8242 DArc 16 0 2 ,GL? i-Al 3 P (7-36)N H Example 75: (Aib 83 5 D-Arg 36 )hGLP-1 (7-36)NH 2 Example 75:(Aib 835 -Lsla5 -rhGLP (7-36)NH 2 Examnple 76 IAibe, 13-Ala 35 D-AyrhG LP-1 (7-36 )N H 2 77: (Aib 8 11Ala 3 Dh-Ly 38 hGL-1 (736 N H 79: (AVb 3 Arg 26 f 3-lhGLP-1P- (7-36)NH 2 Example 79: (Aib 8 Arg 2 6 .1 tA)hGLP-1 (7-36)NH 2 Example 51: (Ai b 83 Arg 252634 )h P-Al 1(7GL-6 )N H 2

NH

Example i: (Aib 8 Arg 25263 1-Ala 3 5 )GLP 1(-36)aecN 2 )hGP17-6 Example 82: (Aib t Arg 2 t. 1- 3 Lys 3 5 ('-traetranoyl )hG L-7-360 Example 8 (Aib Arg 2 3 Lys N3 LS36tetradecanoyl))hGLP-1 (7-37)OH Exml .4 b 35 6 3 Ar -t y-ttetradecanoyl)Aa3)hGLP 1 (7-37)OH Example 65: (Aib 8 35 Arg 26 4 LysS(N~erdcny) 3 )GL-173) Example 86: (Aib 8 7 Arg2- 34 LyS 3 6 Nctetrad ecanoyl))hG LP- 1 (7-38)OH Example 87: (Aib t 1 3 5 Arg 2 ,34 13-Ala 3 1, Lysfl(Nc-tetradecanoy))hGLP-1 (7-38)OH Cl Example 88: (Aib", 5 Arg"' 3 Lys'(N'-tetradecanoyl))hGLP-1 (7-38)0K S Example 8 9 (Aib 8 Arg Lys 3 (Nc-tetradecancyI), /3-AIa 3 )h GLP- 1 (7-37)OH Example 90: (Aib 8 37 Arg 2 Lys'(N'-etradecanoyl))hGLP- 1(7-37 )QH ClExample 191: (Aib 835 Arg 26 3 4 Ado 37 )hGLP-1 (7-37)OH Example 92: (Aib 8 Arg 2 4 31, Ado 3 )hGLP-1(7-37)NH 2 Example 93: (Ai b 8 Arg 2 3 Lys 3 (Nt-tetradecanoyI), D-Ala 37 )hGLP-1 (7-37)OH en Example 94: (Aib 8 7 Arg26 I (7-38)O 0 Example 95: (Aib 8 Arg 28 /3-Ala 37 Ly sS(NE-tetradecanoyl))bGLP-1 (7-38)OH oExample 96: (Aib 835 L ysZ(Nx-octanoyl ))hGLP-1 (7-36)N H 2 8,506N-erdcny)hL- 73)H Cl ~10 Example 97: (Aib 8 5 Lys'N~erd~ny))GL- 73)H Example 98: (Aib 83 5 Lys~e(Nr-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 99: (Aib 8 Lysfl(NE-octanoyl), I3-Ala35hGLP-1 (7-36)NH 2 Example 100: (Aib 8 Lys 2 (N'-tetradecanoyl), 13-Ala 3 1)hGLP-1 (7-36)N- 2 Example 101: (Aib, Lys26(W-hexadecanoyl), I3-Ala 35 )hGLP-1 (7-36)NH 2 Example 102: (Aib 835 Lys 2 S,(Nc-octanoyl), Arg34)hGLP-1(7-36)NH 2 Example 103: (Aib 8 35 Lys 2 (N-tetradeca noyl), Arg34)hGLP-1 (7-36)NH 2 Example 104: (Al b 835 Lys'(Nx-hexadecanoyi), Arg34)hGLP-1I(7-36)N H 2 Example 105: (Aib 1 35 Lys 2 (Ne-decanoyl), Arg')hGLP-1 (7-36)NH 2 Example 106: (Aib 8 3 5t Lys 25 L y$ 2 6(N'-octanoyl), Arg')hGLP-1(7-36)NH 2 Example 107: (Aib 8 35 L ys 25 Lys26(Nc-tetradecanoyl), Argl)hGLP-1I(7-36)N H 2 Example 108: (Aib.

35 LyS 25 L ysze(Nx--hexadecanoyl), Arg34)hGLP-1 (7-36)N H 2 Example 109: (Aib 83 Arg 25 .3 4 L ysa 6 (Nt-octanoyl))hGLP-1 (7-36)NH 2 Example 110: (Aib 835 Arg 2 5 3 4 L ys 2 (N-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 111: (Ailte, 5 Arg 25 34 Lys 2 (Nt-hexadecanoyl1)hGLR.1 (7-36)NH 2 Example 112: (Aibe 35 Arg 25 34 Lys 2 (N-decanoyl))hGLP- I (7-36)NH 2 Example 113: (Aib 8 Lys~r(Nc-octanoyl), Arg 34 13-Aa 3 )hGLP-1 (7-36)NH 2 Example 114: (Aib, Lys"(Nc-tetradec-anoyI), Arg' I3-Ala 3 )hGLP-1(7-36)NH 2 Exampie 115: (AVb, L ys 2 s1(Nx-hexadecanoyl), Arg't I3-Ala 3 1)hGLP-1I(7-36)NH 2 Example 116: (Aib 8 LySZB1(N'-decanoyl), Arg 34 /3-Ala 3 1)hGLP-I (7-36)NH 2 Example 117: (Aib 8 35 Lys'(Nz-octanoyl))hGLP-1(7-36)NH 2 Example 118: (Aib 8 35 Lys34(Nt-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 119: (Aib 8 35 Lys34(NE-hexadecanoyl))hGLP-1 (7-36)N H 2 ClExample 120: (Aib 8 Th Arg 2 6, Lys3 4 (Nt-octanoyl))hGLP 1 (7-36)NH 2 Z Example 121: (Aib' 3 Arg 2 LysI(Nchexadecanoy))hGLP-1 (7-36)NH 2 Example 122: (Aib 5 Th, Arg 2 e, Lysm(N-decanoyi))hG LP- 1(7-36)N- 2 ClExample 123: (Aib 5 35 Arg 25 26 L yS34 Nctoctanoyl))hGLP-1 (7-36)NH 2 Example 124: (Aib'.

35 Arg 25 26 Lys'(NI-etradecanoyl))hGLP-1 (7-36)NH 2 Example 125 (Aib 8 Th Ar 2 6.y~N~eaeaol)GP173)H enExample 126: (Aibt ArgArg2 Lys' (Nr-exdecanoy))hGLP-1(7-36)NH 2 0 Example 127: (Aib 8 3s 5 Arg 25 Lys 4 (NcctanoyI))hGLP1(736)NH 2 oExample 128: (Aib 8 1 35 Lys 25 Arg 2 1 Lys 34 (N-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 129: (Aib 83 Lys 2 Arg 2 8 Lys'(Nt-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 130:. (Aib 8 35 Ly3(-otny )GP1 (7-36)N H 2 Example 131: (Aib 8 35 Lys 3 S (NE-tetradecanoy ))hGLP- 1(7-36 )NH 2 Example 132: (Aib' 35 LysSS5(Nc-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 133: (Aib 535 Arg 25 Lys-6(Nt-octanoyl))hGLP-1(7-36)NH 2 Example 134: (Aib 8 t5 Arg 25 6, Ly&s-(NE-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 135: (Aib 8 ,3 5 Arg 2 L ys 3 (Nc-hexadecanoyI))hGLP-1 (7-36)NH 2 Example 136: (Aib 8 11, 5 Arg 26 3 LyS 3 (Nroctanoyl))hGLP-1 (7-36)NH 2 Example 137: (Aib 8 ,35 Arg 26 34 Ly-s 3 (NE-hexadec-anoyl))hG LP-1 (7-36)NH 2 Example 138 (Aib" 35 Arg26"t4 Lysfl(NE-ocGtanoyI))hGLP-1 (7-38) NH 2 Example 139: (Aib 8 35 Arg26-3, LysSS(Nc-deca noyl))hGLP-i(7-38)NH 2 Example 140: (Aib 635 Arg 2

U

34 Lys 3 s(NL-tetradecanoyl))hGLP-1 (7-38)NH 2 Example 141: (Aib 5 35 Arg 26 3 t LySS8(N E hexadecanoyl))hGLP-1 (7-38)NH 2 Example 142: (Aib 8 3 3 7 Arg 2 5,2,M, Lys'(Nt-octanoyl))hGLP- 1 (7-38)NH 2 Example 143: (Aib 8 5 3 5, 7 Arg 25 263 4 Lys35(N'-decanoyl GLP- I (7-38)N H 2 Example 144: (Aib 83 5 3 7, Arg25 26 3 4 Lys~a(Nc-letradecanoy))hGLP-1(7-38)NH 2 Example 145: (Aib 8 35 37 Arg 25 26 L ySB1(Nx-hexadecanoyl))hG LP-1 (7-38)NH 2 Example 145: (Aib 8 35 37 Arg 26 M 4, Lys 3 (N'--octanoyl))hGLP-1 (7-38)N H 2 Example 147: (Aib 8 35 37 Arg6t Lys'(N'-cdecanoyl))hGLP-1I(7-38)N H 2 Example 148: (Aib 8 ,35 3 7 Arg 2

M

34 Lys~a(N'-hexadecanoyl))hG LP- 1 (7-38)NH 2 Example 149: (AIb 8 35 37 Arg 25 '6 3 L y536(Nx-octanoyl))hGLP-1 (7-38 )N H 2 Exampre so:.(Aib 8 35 37 Arg 2 6,2e3 L ys 3 8(Nx-decanoyl))hG LP- 1 (7-38)NH 2 Example 151: (Aib 8 3 7 Arg" 2 63 Lys' (Ne-tetradecanoyl))hG L P-1(7-38)NH 2 -32- Examp 152 ,3Aib3 7 Ar 2 5 2634 Ly -(-hexadecanoyl))hGLP-1 (7-38)NH 2 Example 153: (Aib 8 Lys 25 Arg 26 ut Lys'( NI-octanoyI))hG LP-1 (7-36)NH 2 Example 154: (Aib,t5 Lys 25 ArgflM, Lys'(NE-tetradecanoyI))hGLP-1 (7-36)NH 2 Example 155: (Aib' 3 t Lys 25 Arg26'34 1 L ys36(Nt-hexadecanoy))hGLP-1 (7-36)NH 2 Example 156: (Aib 8 Th, Arg 2 528 3 Lys3GN-octanoyl))hGLP-1 (7-36)N- 2 Example 157: (Aib'"T Arg 25 26 Lys&(N-tetradecanoy))hGLP-1 (7-36)NH 2 Example 158a(Aib" 35 Arg 25 2 8, 3 Lys36(NI-hexadecanoyI))hGLP-1 (7-36)NH 2 Example 159: (Aib 8 Arg 25.26a Lys'(NE-decanoyl))hGLP-1(7-36)NH 2 Example 160: (Aib8, LysO(NcoctanoyI), 13-Ala 5 hGLP-1 (7-36)NH 2 Example 161: (Aib Lys'(NI-etradecanoyI), 1-Ala 3 )hGLP-1 (7-36)NH 2 Example 162:- (Aib 6 Lys34(Nt-hexadecanoyl), 13-Alt3)hGLP-1 (7-36)NH 2 Example 163: (Aib A6C 32 Lys'(N,-octanoyI), f-Ala 3 1)hG LP-1 (7-36)NH 2 Example 164: (Aib GlIU 23 Lys 34 (N.-octanoyl), I3-Ala 35 )hGLP-1(7-36)NH 2 Example 165: (Aib 6 Gl u2,A6c32, Lys'(Nr-octanoyl), 13-Alal)hGLP-1(7-36)NH 2 Example 166: (Aib 8 Arg 26 Lys 34 (N'-octanoyl), f3-Ala 3 5 )hGLP-1(7-36)NH 2 Example 167: (Aib 8 Arg 2 6 L ys 34 (NE-tetradecanoyl), I3-Ala 35 )hGLP-1 (7-36 )NH 2 Example 168: (Aib 8 Arg 26 Lys34(Nc-hexadecarioyl). 13-Alal)hGLP-1 (7-36)NH 2 example 169: (AibV, Arg 26 Lys-1(N'-decanoyl), I3-Ala5)hGLP- 1(7-36)NH 2 Example 170: Example 171: Example 172: (Aib 8 Example 173: (Aib Example 174: Example 175: Example 176: Example 177: Example 176: (Aib 8 Example 179: (Aib 6 Arg 25 26 1, Lys34(N'-octanoyl), i3-Ala 35 )h GLP- 1 (7-36)N ft (Ab 8 Arg 2 5 2 6 Lys' (N-tetradecanoyl), /3-Ala 3 1)hGLP-1 (7-36)NH 2 Arg 2526 1 LysI(Nc--hexadecanoy), i3-Ala 35 )hGLP- 1(7-36)N H 2 Arg 2 1.

2 LysM(Ns-decanoyl), I3-Alafl5hG LP-1 (7-36)NH 2 (Aib 8 Lys" 5 Arg 26 Ly9I4(N'-octanoyl), 1-Ala1 5 )hGLP-1 (7-36)NH 2 (Aib 6 Lys 2 5 Arg 2 Lys34(Nr-tetradecanoyl), I3-Ala')hG LP- 1(7-36)NH 2 (Ai b 8 Lys 25 Arg 2 Lyt3(N-hexadecanoy), B3-Ala 35 )hGLP- 1(7-36)NH 2 (Aib 8 13-Ala 35 Lys~a(NE-octanoyl))hGLP-1 (7-36)NH 2 1S-Ala 3 1, Lys3f(Nt-tetradecanoyI))h GLP-1I(7-36)N ft (Aib 13-Ala 35 LySG1(Nc-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 180: (Aib 8 Arg 2 6 13-Ala 3 Lysa 6 (Nt-octanoyl))bGLP-1(7-36)NH 2 Example 181: (Aib 8 Arg 2 2-Ala 35 Lys36e(Nr-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 182: (Aib, Arg 2 6 IS-Ala 3 5 Lys 3 (Nx-hexadecanoyI))hGLP-1 (7-36)NH 2 Example 183: (Aib 8 Arg 2 6.

34 13-Ala 3 5 Lys 3 (Nt-octanoyl))hGLP-1 (7-36)NH 2 ClExample 184: (Aib 8 Arg 2 "t B,1-Alt, Lys36(N'-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 185 (Aib 8 Arg&

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13-Ala-15 Lys 38 (NS. hexadecanoyl))hGLP-1 (7-36)NH 2 Exml 188. (Aib 8 Arg 2 B3-Alt 5, Lyst(N-decanoy))hGLP-1 (7-36)NH 2 ClExample 187: (Aib 8 Lys, Arg 28 /3-Ala 35 Lys3 N-octanoyl))hGLP-1 (7-36)NH 2 Example 188: (Aib 8 Lys 2 5 Arg28 3 t LysM'(NE-tetradecanoyI), 13-Al )hGLP-1 (7- IND 36)NH 2 enExample 189: (Aib 8 Lys 25 Arg 2 5 34 13-Alt, Lys 3 (N-hexadecanoyl ))hGLP-1I(7-36)N H, 0 xapl 10 (ibr 2 .2,34 B-Ala 35 Lys 38 (N,-octanoyl))hGLP-1 (7-36)NH 2 o ~Example 191: (Aib 8 Arg 25 8 4 1-l, Lys Ntetradecanoyl))hGLP-1 (7-36)NH 2 E-xare 192: (Aib t Arg 25 2 ,4 B3-Ala 3 L ys 3 8 1(N-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 193: (Ai Arg25Z.' 3 t 13-Ala 35 LyS 6 (Nc-decanoyl ))hGLP- I (7-36)N H 2 Example 194: (Aib 8 35 L ys 2 (Ne-octanoyI), A6&3 2 Arg34)hGLP-1 (7-36)NH 2 Example 1Q5: (Aib b 835 L ys 26 NEtetradecanoyi), A6 C32 Arg

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4)hG LP- 1(7-36 )NH 2 Example 196: (Aib 8 1 35 Lysn(Nx-hexadecanoyl), A6C12, Arg 34 )hGLP-1(7-36)N- 2 Example 197: (Aib 83 Afct", Lys34(Nc-octanoyl))hGLP-1 (7-36)N- 2 Example 198: (Aib 8 3 5, A6c 32 1 Lys34(Nr-tetradecanoyl))hGLP 1 (7-36)NH 2 Example 199: (Aib" 5 A6c32, Lys3 4 (Nz-hexadec-anoyl))hGLP-1 (7-36)NH 2 Example 200: (Aib 535 Arg 2 6, A6c 32 Lys 34 (NF-octanoyl))hGLP-1 (7-36)NH 2 Example 201: (Aib 8 35 Arg 26 A6c 32 Lys'(Nt-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 202: (Afb 835 A6C 3 2 Lys 3 (Nt.octanoyl))hGLP-1(7-36)NH 2 Example 203: (Alb 8 3 1 5 A6c 32 Lys36(N-tetradecanoyl))hGLP- 1(7-36 )NH 2 Example 204: (Aib 8 3 5 A6c 32 L ysS(NE-hexacdecanoyl))hGLP-1 (7-36)NH 2 Example 205: (Aib 8 35 Arg 2 6 A6c 32 L ys 3 (NE-octanoyI))hGLP-1 (7-36)NH 2 Example 206: (Aib 8 -:15 Arg 2 6 A6e 32 Lysae(NI-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 207: (Aib 8 11 35 Arg 2 5 A6c 32 Lys 3 6 (NE-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 208; (Aib 8 35 Arg 2 6 t1 A6Ct2, Lys'f(NE-octanoyl))hGLP 1 (7-36)NH 2 Example 209: (Ab 835 Arg 26 3 4 AGO3 2 Lys 3 rS(Nc-decanoyl))hGLP 1 (7-36)NH 2 Example 210: (Aib 8 .1 5 Arg 2 "t.34 A6c 32 Lyst(N-tetradecanoyl))hGLP 1 (7-36)NH 2 Example 211: (Aib 8 11 3 5 Arg 26 34t A6c 32 L ys 3 6(NI-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 212: (Aib 8 11 2 4 35 L ys 2 S(Nt-octanoyl), Arg')hGLP-1 (7-36)NH 2 Example 213: (Ai b 8 24 .35, L ys 2 5 QPN-tetradec-anoyl), Arg-IhGLP-1 (7-36)NH 2 Example 214: (Aib 8 11 2 435 Lys 2 (N-hexadecanoyl), Arg')hGLR-1 (7-36)NH 2 C]Example 215: (Aib 824 5 Arg 2 1 Lys$ 4 (Ns-octanoyl))hGLP-1 (7-36)NH 2 Example 216: (Aib3 2 5 Arg 2 6. Ly34 Example 217: (Aib 8 24 35 Arg26, Lys

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4(Nt-hexadecanoy))hGLP-1 (7-36)NH 2 C]Example 218: (Aib 8 24 35 Arg 263 Lys(Nc-octanoyl))hGLP-1(7-36)NH 2 Example 219: (Aib 8 24 ,35h Arg26 34 Lys 3 Q1(NE-tetradecanoyl))hG LP- 1 (7-36)N H 2 IND Example 220: (Aib 5 3 1, Arg 2 ",34 Lys 3 (NEhexadecanoyI))hG LP-1 (7-36)N H 2 Example 221: (Aib 82 t Glu 23 A6C9 2 Lys&"(N,-octanoyI))hGLP-1 (7-36)NH 2 Example 222: (Aib 6 3 5 Glu 2 3 1 Lys~g(Nr-octanoyl), Arg 3 ')hGLP-1(7-36)NH 2 U2 o Example 223: (Aib 83 Glu 3 LysZ(Nt-tetrad ecanoyl), ArgM)hGLP-1(7-36)NH 2 .302 y2 Example 224: (Aib 835 Giu 2 Lys 2 (Nt-hexadecanoyl), Arg 3 )hGLP-1(7-36)NH 2 Example 225: (Aib 8 35 GlU 2 3 Lys,"(Nr.octanoyl))bGLP-1 (7-36)NH 2 Example 226: (Aib t 3 5 GIu 23 A6 C 32 Lys34(N 1 -octanoyl))hGLP-1 (7-36)NH2 Example 227: (Aib 8 35 GlU 23 Arg 2 8 Lys'(Nt-octanoyl))hG LP-1 (7-36)NH 2 Example 228: (Aib 8 35 GlU 23 Arg 26 Lys34(NI:-tetradecanoyI))hGLP- 1 (7-36)NH 2 Example 229: (Aib 8 Glu 2 1 3 Arg 2 63 Lys34(N-hexadecanoyI))hGLP-1 (7-36)NH 2 Example 230: (Aib 835 GlIU 23 Lys 3 E'(Nx-octanoyl))hGLP-1 (7-36)NH 2 Exnmpde 231: (Aib 8 35 GlIU 23 LysS 8 6(N Etetrad ecanoyl))hGL P-1 (7-36)NH 2 Example 232: (At 83 5 GI U 23 LyS31(Nc-hexadecanoyl))hGLP-1 (7-36)NH 2 Example 233: (Aib 8 3, GlIU 23 Arg 26 34, LysS(Nr-octanoyl))hGLP-1 (7-36)NH 2 Example 234 (Aiba,3 5

GIU

23 Arg 26 34 L yS(Nc-tetradecanoyl))hGLP-1 (7-36)NH 2 Example 235: (Aib 8 Giu 23 Arg 26 '1 LyssB1(Nx-hexadecanoy1))hGLP-1 (7-36)NH 2 Examle 26: (ib.

3 5 LyZBNoctanoyl), Arg 34 )hG LP-1 (7-36 )NH 2 Example 23: (Alba Lys 26 (N'rdcny) rflGL-I(-6NH Example 238: (Aib 83 35 L s 2 B(N-et exeanoyl), Argm)hGLP-1 (-36)NH 2 Example 239: (Aib 8303 1 5 Arg 2 1 L(Nexaocanoyl)A)hGLP -1-36)NH 2 Example 240: (Aib 8 6.13 35 Arg 26 Lys34(NE-ottaanoyl))hLP1 (7-36)NH 2 Example 241: (Aib"- 0 3 5 Ar g 2 Lys'(Nthexradecanoyl))hGLP-1 (7-36)NH 2 Example 242: (Aib 'b0 3 5 Arg2, Lys 3 (Nexaocanoyl))hGLP- (7-36 )NH 2 Example 243. (A 3 0 .3rg 53 Lr2-3Lys S3(N-tetraeanoyl ))hGLP- I (7-36)N H 2 Example 244: (Aib' 35 Arg 26 34 Lys 3 5 (N'Ktexadecanoyl))hGLP1(736)NH 2 Example 245: (Aib 8 3 35 AGl 2 3 Ly1(NLxdcanoyl))hGLP1 (7-36)NH 2 Example 245: (Aibs 35 G3, A6 Lys1 6 (N-teanoyl ))hG LP-1 (7-36 )N H 2 Example 247: (Aib 82 5 Glu23, A6c 32 Lys~a(N'-hexadecanoyI ))hGLP-1 (7-36)NH 2 Example 248: (Aib 8 3 1, GI u 2 3 Arg 26 3 t A6c 32 Lys-4(Nc-octa noyl ))hG LP-1I(7-36)NH 2 Example 249: (Aib 8 35 Glu 23 Arg2.t AcMe, Lys'( N'-tetradecanoyl))hGLP-1(7-36)NH 2 Example 250:, (Aib 6 35 GlU 23 Arg-', A6c 32 LysM8(Nt-hexadecanoyl))hGLP-1(7- 36)NH 2 IDExample 251: (Aib 6 4 5 Glu 2 3 Arg2O" A6& 2 Lys-3(Nr-octanoyl))hGLP-1 (7-36)NH 2 enExample 252: (Aib'8 24 35

GJU

23 Arg 2 .4t A6c 32 Lys38(Nc-tetradecanoyQ))hGLP-1 (7-36)NH 2 0Exam pie 253: (Aib 624 3 Glu 23 Arg 26 3 4 AWc2, Lyse( N t -hexadeca noyl))hGLP-1 (7o 36)NH 2 Example 254: (Aibs- 24 '30 5 GluI Arg 2 U A6c 2 Lys 3 (Nc-octanoyI))hGLP-1(7-36)NH 2 Example 255: (Aib 8 2 4 .30,35 G I U 23 Arg 26 34 A6C 32 Lys 36 NC-tetradeca noyl ))hGLP- 1(7-36 )N H 2 Example 256: (Aib 6 8 243 035 GIu 23 Arg 2634 A6c 32 LYsS(Nx-hexadeca noyl))hGLP- 1(7- 36)NH 2 Example 257: ((N--HEPES-H isf, Aib 35 )hGLP-1 (7-36)NH 2 Example 258: ((NU-HEPESH IS) 7 13-Ala 35 )hGLP-1 (7-36)NH 2 Example 2W9 ((Nu-HEPES-H Aib 6 i3-Alt )hGLP-1 (7-36)NH 2 Example 260: ((Na-HEPA-H Aib1 5 )hGLP-1 (7-36)NH 2 Example 261: ((N"-HEPA-His) 7 (3-Ala 35 ThGLP-I (7-36)NH 2 Example 262: ((N'41EPA-HiS) 7 Aib i3-Ala 3 5 )hGLP-1 (7-36)NH 2 Example 263 -tetradecanoyl-His) Atb1 5 )hGLP-1 (7-36)N H 2 Example 264: ((N"-tetradecanoy[-His) 7 IS-Ala 3 )hGLP-1 (7-36)N H 2 Example 265: ((Nu-tetradecanoyl-His)f, Aib 6 35 )hGLP-1 (7-36)NH 2 Example 266: ((Na-tetradecanoyl-H is) 7 Aib 6 I3-Ala 35)hGLP-1 (7-36 )NH 2 Example 267: ((No-etradecanoyk-H is) 7 Arg 2634 Aib 35 )hG LP-1 (7-36)N- 2 Example 268- ((N"-tetradecanoyl-His) 7 Arg 2634 13-Ala35)hGLP-1 (7-36)NH 2 Example 269: ((NG-tetradecanoyl-His )7 Aib 1.

5 Arg 2 .4)hGLP-1 (7-36)NH 2 Example 270: ((N"-tetradecanoyl-His 7 Aib Arg 26 .34 I3-Ala, 35 )hGLP-1 (7-36)NH 2 Example 27t: ((N--Aetradecanoy[-His) 7 Arg 2 5 26 3 4 13-Ala 35 )hGLP- 1(7-36)NH 2 Example 272: ((Na-tetradecanoyl-His) 7 Aib 835 Arg 2 5 2 ,14)hGLP-1 (7-36)NH 2 Example 273: ((NaI-tetradecanoyl-His) 7 Aib 5 Arg 2 5 26 ,3 4 13 -Ala 35 )hGLP-1 (7-36)NH 2 Example 274: (Aib" 5 L ys 2 (Nx-octanesulfonyl), Arg34)hGLP-1 (7-36)N H 2 Example 275: (Aib b 8 35 L ys 2 (Ntdodecanesulfonyl), Arg')hG LP- I (7-36)N H 2 -36- 0 Example 276: (Aib 8 5 Lys 2 (Nc-hexadecanesulfonyI), Arg 34 )hGLP- 1(7-36)NH 2 3Example 277: (Aib 6, 5 Arg 2 Lys 3 NNcoctanesulfonyI))hGLP-1(7-36)NH 2 ___Example 278- (Aib 835 Arg 6 Lys34(Nr-dode canesulfonyl))hGLP-1 (7-36)NH 2 ClExample 279: (Aib 8 1 35 Arg 2 Lys 4N-hexadecanesulfonyl ))hGLP- 1 (7-36)NH 2 280: (Aiba-35 Arg 2 Lys'(Nx,-octanesulfonyl))hGLP-1(7-36)NH 2 ONExample 281: (Aib 8 35 Arg 2634 L ys 3 (Ne-hexadecanesulfonyI))hGLP-1 (7-36)NH 2 Exml 8;(Aib t35 1 Asp 2 (-(4-decylpiperaie) r'hL- 73)H 282: (i83-, s21- delp razi Arg4)hGLP-1 (7-36)NH 2 0Example 284: (Aib Asp~r 1 rdecylpiperazine)), Arg 34LP-1(7-36)NH 2 Examle 84:(Ai 8 As 26 -(-teradeylpperzine), rgfhGLP1 (-36N3H o 10 Example 285: (Aibaxa, Asp'(1-(4-hexadecylpiperazine)), Arg )hGLP-1(7-36)NH 2 Exml 8:(is.5,Ar2 sci-4dcliprzn))GP173)H Example 286: (Aib 8 35 Arg 2 6 Asp

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(1 -(4-ddecylpiperazine)))hGLP-1 (7-36)NH 2 Example 288: (Aib .1 Arg 26 Asp I rdecylpiperazine)))hGLP-1 (7-36)NH 2 Exampie 288: (Aib 8 35 Arg 26 Asp 34 (1-(4-teradecylpiperazine)))hGLP-1 (7-36)NH 2 Example 289: (Aib 8 Arg 2 6 Asp -(4-adecylpiperazine)))hGLP- 1 (7-36)NH 2 Example 291: (Aib b 83 5 Arg 263 t As p 3 6(1 -(4-do ecyl piperazine)))h GLP- 1 (7-36)NH 2 Example 2: (Aib 1, Arg 2 3, As p 36 adecylpiper ine)))hGLP-1 (7-3 2 Example 292: (Ai 3 t Arg 2 3 Asp 3 (-(4xdecylpiperazine)))hGLP-1 (7-3 6)NH 2 Example 293: (Aib 835 Arg 2 634 As p 38 (1 -(4-doecylpiperazine)))hGLP-1 (7-38)NH 2 Example 29: (Aib," 6 3 A263 sp 38 rdecylpiperazine)))hGLP-1 7-38)NH 2 295: (Aib t35 Arg 263 4 Asp35(1-(4-teradecylpiperazine)))hGLP-1 (7-38)NH 2 Example 296: (Aib 8 35 Arg 262 t34 Asp( 1 -(4-adecylpiperazine)))hGLP-1 (7-38)NH 2 Example 298: (Aib 83537 Arg 26 3 4 Aspm'( -(4-ddecylpiperazine)))hG LP-1 (7-38)N H 2 Example 299: (Aib 835 Arg 263 4 Asp 3 8 l(1 -(4-tetradecylpiperazine)))hGLP-1 (7-38)N H 2 Example 300: (Aib 8 3 537 Arg 2634 Asp 38 I -(4-hexadecylpiperazine)))hGLP-1 (7- 38)NH 2 Example 3t1; (Aib'6 35 Arg 2 534 Asp 2 8 1 -(4-decylpiperazine)))hGLP-1 (7-36)N H 2 Example 302: (Aib 8 35 Arg 253 tAs p 26 (1 odecylpipe razine)))hGLP-1 (7-36)NH 2 Example 303: (Aib 8 35 Arg 1 53 4 Asp6( 1 -(4-tetradecylpiperazine)))hG LP-1 (7-36)NH 2 Example 304: (Aib 835 Arg 25 3 4, Asp 2 6(1-(4-hexadecylpiperazine)))hGLP-1 (7-36)NH 2 Example 30 5 (Aiba .35 Arg 2 1 6 Asp 34 ecytpiperazine)))hGLP-1 (7-36)NH 2 Example 306: (Aib 835 Arg 2526 As p34(1 -(4-dodecylpiperazine)))hGLP-1 (7-36)NH 2 Example 307: (Aib 835 Arg 252 6 Asp34(1 -(4-tetradecylpiperazine)))hGLP-1 (7-36)NH 2 Example 308: (Aib 8 Th5 Arg 2526 Asp

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4( 1 -(4-hexadecyl pipe razi hG LP- 1 (7-36)NH 2

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ClExample 309: (Ab,5 rm2,,AspZ(1 -(4-decylpiperazine)))hGLP-1 (7-36)NH 2 Example 310: (Aib 8 t, Arg 5 3 AspM( 1 -(4-dodecylpiperazine)))hGLP-1' (7-36)N H 2 __Example 311: (Aib 8 35 Arg 25 26.3 Asp 38 l(1-(4-tetradecylpiperazine)))hGLP-1 (7-36)NH 2 ClExample 312: (Aib 8 -36, Arg 2526 3 4 Asp36(1I-(4-hexadecylpiperazine)))hGLP-1 (7- 36)NH 2 C>Example 313: (Aib 8,5 Arg 2 5 26 34 Asp 38 (1 -(4-decylpipe razine)))hGLP-1 (7-38)NH 2 Example 314: (Aib 8 35 Arg 252634 AspI(1 -(4-dodecylpiperazine)))hGLP-1 (7-38)NH 2 Example 316: (Aib" 5 Arg 25 2 6, 34 Asp 3 8 (l1-(4-hexadecylpiperazine)))hGLP-1 (7- 38)NH 2 ClExample 317: (Aib t 8.

537 Arg 25 25 3 4t Asp 38 (1 -(4-decylpiperazine)))hGLP-1 (7-35)N H 2 Example 318: (Ai b 8 3537 Arg 25 28 4 Asp3'(l1-(4-dodecylpiperazi-e LP- 1(7-38) NH 2 Example 319: (Aib 8 35 37 Arg 25 -26 34 Asp 31 (1-(4-tetradecylpiperazine)))hGLP- 1(7- 38)NH 2 Example 320: (Aib t 8.

3537 Arg 2526 34 Asp38(1I-(4-hexadecylpiperazine)))hG LP- 1(7-38)N IH2 Example 321: (Aib 8 Arg 263 4, Glu 38 (1 -dodecylamino))hGLP-1 (7-36)NH 2 Example 322: (Aib8.

5 GlIu 26 (1 -dodecylamirio), Arg 34 )hGLP-1 (7-36)NH 2 Example 323: (Aib 8 AS, Arg 26 GlIu 34 (1 -dodecylamino))hGLP-1 (7-36)NH 2 Example 324: (Aib 8 135 37 Arg 2 8 t Glu'(1 -dodecylamino))hGLP-1 (7-38)N- 2 Example 325: (Aib 8 35 Arg 34 L ysZ(N E_(2-(4-decyl-1 -piperazine)-acetyl )))hGLP- 1(7-36 )N H 2 Example 328: (Aib 8 35 Arg 34 L ys 2 6(N'-(2-(4-dodecyl-1 -piperazine)-acetyl )))hGLP- 1(7- 36)NH 2 Exapl 32:Ai 8 ,3 5 Ar 34

LS

2 6(Nc-(2-(4-tetradecy-1 -piperazine)-acetyl)))hGLP- 1 (7-36)NH 2 Example 328: (Aib 83 Arg", Lys 2 O1(Nt-(2-(4-hexadecy-1 -pipe razine)-acetyl)))hG LP- I (7-36)NH 2 Example 329: (Aib B.

35 Arg 28 Lys 3 4(Nc-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP-1 (7-36)NH 2 Example 330: (Aib Arg 28 L ysS(Nc-(2-(4-dodecyl-1 -piperazine)-acetyl))hGLP-1 (7- 36)NH 2 Example 331: (Aib 835 Arg 2 6 3, Lys

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(N'-(2-(4-tetradecyl-1 -piperazine)-acetyl)))hGLP- 1 (7-36)NH 2 Example 332: (Aib 8 35 Arg 2 5 Lys 34 (NE-(2-(4-hexadecyl-1 -pip erazine)-a cetyl)))h GLP- I (7-36)NH 2 Example 333: (Aib 8 35 Arg26,3, LyS 3 8 E -(2-(4-decyl-1 -piperazine)-acetyl)))bGLP-1 (7- 36)NH 2 Example 334: (Aib 35 Ar2,1,LsIN(-4ddcl1-ieaie-ctl)hL- 7 36)NH 2 Example 335: (Aib 8 35 Arg'-"t Lysxa(N;-(2-(4-hexadecyl-1 -piperazine)acetyl)))hGLP-1 (7-36)NH 2 Example 336: (Ai b 835 Arg 2 a.34, LysSB8(NE-(2-(4-decyl-1 -piperazine )-acetyl LP- 1(7- 0 38)NH 2 oExamiple 337: (Aib 8 35 Arg26 3 4 Lys3a(Nt-(2-(4-dodecy- I -pipe ra zi ne)-acetyl)))h G LP- 1 (7- O 1 38)NH 2 Example 338: (Aib 1 35 Arg 26 34 Ly'N-(-4ttrdc 1 -piperazine)acetyi)))hGLP-1 (7-38)NH 2 Example 339: (Aib 8 s, Arg 2 "t34 Ly&s(NE-(2(4-hexadecy-1 -piperazine)acetyl)))hGLP-1 (7-38)NH 2 Example 340 (Aib 835 37 Arg 26 34 Lys38(Nc-(2-(4-decy-1 -piperazine)-acetyl)))hGLP-1 (7- 38)NH 2 Example 341: (Aib 53537 Arg 263 L ys 38 (N6-(2-(4-dodecyl-1 -piperazine)-acetyl)))hGLP-1 (7- 38)NH 2 Example 342: (Aib 8 35 37 Arg634 Lysa( N t -(2-(4-tetradecyl-lI-piperazine)acetyl)))hG LP-1 (7-38)NH 2 Example 343: (Aib 835 37 Arg 26 3 4 Lys 3 8 (N-(2-(4-hexadecyI-1 -piperazine)acetyl)))hGLP-1 (7-38)NH 2 Example 344: (Ai b 825 Arg 2 Lys 2 S(Nt-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP-1 (7- 36)N H 2 Example 345 (Aib 8 35 Arg 25 34 L ys 2 6(Nt-(2-(4-dodecy-1 -piperazine)-acetyl)))hGLP-1 (7- 36)NH 2 Example 346: (Aib 83 5 Arg 25 3 t Lysfl (Nr-(2-(4-tetradecyl- 1 -piperazi ne acetyl)))hGLP-1 (7-36)NH 2 Example 347: Aib 6 35 Ar g 25 3 4t L ys 2 (Ne-(2(4hexadecy-1 -piperazine)-acetyl)))hGLP- 1 (7-36)NX 2 Example 348: (Aib 835 Ar g 2 5.

2 6 Lys 34 (Nt-(2-(4-decyl1 -piperazine)-acetyl)))hGLP-1 (7- 36)NH 2 Example 341): (Aib 8 35 Arg 2 6 Lys 34 (N(2-(4-dodecy-1 -piperazine)-acetyl)))hGLP-1 (7- 36)NH 2 Exaple350 (A b 835

A

2 5, 2 6

LS

3 4 (N-(2-(4-tetrad ecyl- I -piperazine)acetyl)))hGLP-I (7-36)NH 2 Example 351: (Aib 8 Arg -M Lys

M

(N'-(2-(4-hexadecyl-1 -piperazine)acetyl)))hGLP-1 (7-3)N 2 enExample 352: (Aib8 3, Arg 2 z Lys 3 (JP-(2-(4-decyl-1 -piperazine)-acetyl)))hGLP-I (7- 0 36)NH- 2 Example 3M3: (Aib 8 35 Arg25 h 26 34 Lysao(Nx-(2-(4-dodecyl-1 -piperazine)-acetyl )))hGLP- 1(7- 36)NH 2 Example 354: (Aib 835 Arg 25 ,26 34 Lys 3 (N-(2-(4-tetradecyl-1 -piperazine)acetyl)))hGLP-1 (7-36D)NH 2 Example 35: (Aib 5 35 Arg 252 13 34 Lys 3 5 exdecyl-1-piperazine)-l)hL- 7 act)))hGL-,73)H Example 355: (A ib8 535 Arg 252 6 34 Lys (2-(4-doecyl- 1 -pi perazine)-acey 1)))hG LP- 1 (7- 38)NH, Example 5 (Aib 3, Arg 25 2.

4 LyS38(N'-(2-(4- rdecy-1 -piperazine)-l)hL- 7 38 ae) )GL- H 2 38N Example 358: (Aib 5 8 35 Arg 2 52 34 L ys 3 s1(Nx-(2-(4-tetradecyl- 1 -piperazine 20acetyl)))hGLP-1 (7-38)NH 2 Example 39: (Ai b 53 Arg 2 5 2 34 Lys 3 (N-(4-exady-1 -piperazine)-l)hL- 7 act)))hGL-,73)H Example 3501: (Ai b 83537 Arg 252 t4 Lys 3 B(NE-(2-(4-ddecyl- -piperazine)-acety )hGLP- 7 138)NH 2 Example 3: (Aib 8 .5 37 Arg2 5 L ys 8 rdecyl- 1 -piperazine)-l )GP acetyl)))hGLP-1 (7-38)NH 2 Example 363: (AibV 835 37 Arg 2 5.6 34 Lys 3 S (Nc-(2-(4-hexadecyl- 1-piperazi ne)-acetyl)))hGLP- 1 (7-38)NH 2 Example 364: (Aib 5 Arg 2 8 3 4 Lys 3 (N -decanoyl))hGLP-1 (7-36)OH Example 365: (Aib 835 Lys 25 Arg 2 6 3 4 L ySS6(NEdecanoyl))hGLP-1l(7-36)OH Example 370 (Aib 83 ,Arg 2 4 Ava 3 7, Ado 25 )hGLP-1(7-38)NH 2 Example 371 (Aib 8 -",Arg2"34, Asp 3 7 Ava'u, Ado3 9 )hGLP-1 (7-39)N H, Example 372 (Aib"Th15Arg6"t4 Aun3 7 )hGLP- 1(7-37)NH2 Example 373 (Aib 8 17 35,)hGLP-1 (7-36)NH2 Example 374 (AibS ,Arg 25 .34, 13-Ala 3 5 0-Asp3 7 Ava 38 Au n~)hG LP- 1 (7-39)NH2 Example 375 (Gly 8 13-Ala 5 )hGLP-1 (7-36)NH2 Example 376 (Ser, /3-Aa')hGLP-1(7-36)NH2 Example 377 (Aib 8 Glu22,2, I3-Ala3 5 )hGLP-1 (7-36)NH 2 Example 378 (Gly 8 Aib35)hGLP-1 (7-36)NH2 Example 379 (Aib 8 Lys"', B-Ala3 5 )hGLP-1 (7-36)N- 2 Example 380 (Aib 8 Leu2 7 B-Ala3 5 )hGLP-1 (7-36)N-1 Example 381 (Aib 8 Lys"3, I3-Aa6)hGLP-1(7-36)NH 2 Example 382 (Aib 8 Lys', Leu2", 1-Ala')hGLP-1 (7-36)NH, Example 383 (Aib 8 D-Arg' 6 )hGLP-1 (7-36)NH 2 Example 384 (Aib 8 B3-Ala' 5 D-Arg' 7 )hGLP-1(7-37)NH 2 Example 385 (Aib 8 1 2 7 (3-Ala')hGLP-1 (7-36)NH2 Example 386 (Aib 8 "2 7 /3-Ala 1'31, Arg38)hGLP-1 (7-38)NH2 Example 387 B3-Ala3 5 .3 7 Arg3 8 .39)hGLP-1 (7-39)NH2 Example 388 (AVb, Lys' 8 7 2, 13-Aa 1 hGLP-1 (7-36)NH2 Example 389 (Aib 8 L ys2 7 A-Ala35)hGLP-1 (7-36)NH, Example 390 (Aib 8 B3-Ala"31, Arg311hGLP-1 (7-38)NH2 Example 391 (Aib', Arg26' 4 13-Ala'5 )hGLP-1 (7-36)NH2 Example 392 (Aib 8 0-Arg' 5 )hGLP-1 (7-36)N H, Example 393 (Aib 8 /3-Ala 3, Arg' 7 )hGLP-1 (7-37)NH2 Example 394 (Aib 8 Phe'3 1 i3-Ala 35)hGLP-1(7-36)NH2 Example 395 (Aib 8 Phe3 1 )hGLP-1 (7-36)NH2 Example 396 (Aib' 1, NaP 1 )hGLP-1 (7-36)NH, Example 397 (Aib 8 Na2 8 LP-1 (7-36)NH2 Example 398 (Aib 8 Arg"" Nal' )hGLP- 73)H Example 399 (Aib 8 'Th Arg2"' 4 Phe 1 )hGLP- 1(7-36)N H, Example 400 (Aib 8 Nal 1 1131)hGLP-1 (7-36)NH2 Example 401 (Aib 8 Nal 12 3')hGLP-1 (7-36)NH2 Example 402 (Ab"35, Lys 3 (Nc-decanoyl))hGLP-1(7-36) NH,1 Example 403 (AibM"3, Arg' 4 L ys2"(NL-decanoyl))hGLP-1 (7-36)NH, Example 404 (Aib Arg 26, 4 Lys 3 o(Nc-d ode canoyl))hG LP- 1 (7-36)NH,

O

O

cN Example 405 (Aib',B-Ala,Ser 7 (O-decanoyl))hGLP1(7-37)-NH, 3 Example 406 (Aib 8 2 1-Ala 353 7 Arg 3 Lys 3 "(N'-octanoyl))hGLP-1(7-39)NH 2 Example 407 (Aib 8 Arg 2 34 8-Ala 5 Lys37(Nc-octanoyl))hGLP-1 (7-37)NH 2

C

N

l Example 408 (Aib 8 Arg 26 B-Ala 3 Lys3(N'-decanoyl))hGLP-1 (7-37)NH 2 Example 409 (Aib 8 Arg 2 6, 34 f1-Ala Lys37(NE-tetradecanoyl))hGLP-1 (7-37)NH 2 Example 410 (Aib 8 Arg 26 34 3-Ala 3 Lys 3 (N-dodecanoyl))hGLP-1 (7-37)NH 2 n Example 411 (Aib', Arg 2 6 3 3 Ala 3 Lys 37 (N'-dodecanoyl))hGLP-1 (8-37)NH 2 SPhysical data for a representative sampling of the compounds exemplified n herein are given in Table 1.

C 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% 0 392 3410.89 3409.8 99% 393 3481.95 3481.1 394 3286.76 3286.2 99.20% 395 3300.76 3299.4 93% S396 3350.81 3349.4 99% 397 3400.87 3400.1 99% 398 3406.84 3406.4 99% 399 3356.77 3356.6 99% 400 3384.87 3384.43 94% 401 3400.87 3401.3 99% t 402 3466.03 3466.9 97.40% 0 403 3522.05 3522.06 93% t 404 3550.11 3550.2 98% o 405 3567.09 99% o 406 3763.38 3763.2 Cl 407 3636.15 3635.8 99% 408 3664.21 3663.3 99% 409 3720.32 3719.5 99% 410 3692.27 3691.7 99% 411 3555.13 3554.4 99% TABLE 1 42a In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, ie. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

It is to be clearly understood that although prior art publication(s) are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art in Australia or in any other country.

1 \MI 5;p: cj \I'76iH C-

Claims (2)

1. A method of treating a disease selected from the group consisting of renal failure, congestive Sheart failure, nephritic syndrome, cirrhosis, pulmonary CI 5 edema, hypertension, and disorders wherein the reduction of food intake is desired, in a subject in need thereof h which comprises administering to said subject an effective amount of a compound of the formula (Aib 8 3 5)hGLP-1(7- O 36)NH 2 or a pharmaceutically acceptable salt thereof.

2. Use of a compound of the formula C (Aib', 35 )hGLP-1(7-36)NH2, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease selected from the group consisting of renal failure, congestive heart failure, nephritic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake is desired. I \MarR\Kep\SPCCI \1'57659 dc!C 24l0,/01