MXPA00001419A - Novel exendin agonist compounds - Google Patents

Abstract

Novel exendin agonist compounds are provided. These compounds are useful in treating Type I and II diabetes and conditions which would be benefited by lower plasma glucose and delaying and/or slowing gastric emptying.

Description

NOVEDO COMPOUNDS OE AGENDA OF EXENDINE RELATED REQUEST This application claims the benefit of the provisional application for E.U.A. No 60 / 055,404, issued on August 8, 1997, the contents of which are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention relates to novel compounds that have activity as exendin agonists. These compounds are useful in the treatment of type I and II diabetes, in the treatment of disorders that may benefit from agents that reduce plasma glucose levels and in the treatment of disorders that would benefit from agents useful for slowing and / or slow down gastric emptying.

BACKGROUND OF THE INVENTION The following description includes information that may be useful for the understanding of the present invention. It is not admitted that any information provided therein, is the prior art to the invention claimed herein, and that none of the publications mentioned specifically or implicitly are of the prior art to this invention.

Exendin The exendins are peptides found in the venom of the Gila monster, a common lizard in Arizona and northern Mexico. Exendin-3 (SEQ ID No. 1) is present in the venom of Heloderma horridum, and exendin-4 (SEQ ID No. 2) is present in the venom of Heloderma suspectum (Eng, J ., et al., J. Biol. Chem .. 265: 20259-62, 1990; Eng., J., et al., J. Biol. Chem., 267: 7402-05, 1992). The amino acid sequence of exendin-3 is shown in Figure 2. The amino acid sequence of exendin-4 is shown in Figure 3. The exendins have some similarity in sequence, with several members of the family of glucagon-like peptides, with the highest homology, 53%, being up to GLP-1 [7-36] NH2, [SEQ. ID. DO NOT. 3] (Goke, et al., J. Biol. Chem. 268: 19650-55, 1993). GLP-1 [7-36] NH2, also known as proglucagon [78-107] or simply, "GLP-1," has an insulinotropic effect, which stimulates insulin secretion from pancreatic β-cells. The amino acid sequence of GLP-1 is shown in Figure 4. GLP-1 also inhibits the secretion of glucagon from pancreatic cells (0rsov, et al., Diabetes 42: 658-61, 1993; D'Alessio, et al., J. Clin. Invest., 97: 133-38, 1996). GLP-1 is reported because it inhibits gastric emptying (Willms B, et al., J. Clin Endocrinol Metab 81 (1): 327-32, 1996; Wettergren A, et al., Dia Dis Sci 38 (4): 665 -73, 1993), and the secretion of gastric acid. Schjoldager BT, et al., Diq Dis Sci 34 (5): 7-03-8, 1989; O'Halloran DJ, et al., J, Endocrinol 126 (1): 169-73; 1990; Wettergren A, et al., Diq Dis Sci 38 (4) 665-73, 1993). GLP-1 [7-37], which has an additional glycine residue at its carboxy terminus, also stimulates insulin secretion in humans (Orsov, et al., Diabetes 42: 658-61, 1993). A receptor coupled to transmembrane-cyclase G protein adenylate which is believed to be responsible for the insulinotropic effect of GLP-1, has been cloned from the ß-cell line (Thorens, Proc. Nati. Acad. Sci. USA 89: 8641-45 (1992)). Reportedly, exendin-4 acts on GLP-1 receptors in insulin-secreting ßTC1 cells, in acinar cells dispersed from the guinea pig pancreas, and in parietal cells from the stomach; it is also said that the peptide stimulates the release of somatostatin and inhibits the release of gastrin in isolated stomachs (Goke, et al., J. Biol. Chem. 268: 19650-55, 1993; Schepp, et al., Eur. J Pharmacol .. 69: 183-91, 1994; Eissele, et al., Life Sci., 55: 629-34, 1994). It was found that exendin-3 and exendin-4 stimulate the production of cAMP in and the release of amylase from pancreatic acinar cells (Malhotra, R., et al., Requlatory Peptides, 41: 149-56, 1992; Raufman, et al., J. Biol. Chem. 267: 21432-37, 1992; Singh, et al., Requl., Pept. 53: 47-59, 1994). Based on its insulinotropic activities, the use of exendin-3 and exendin-4 has been proposed for the treatment of diabetes mellitus and the prevention of hyperglycemia (Eng, U.S. Patent No. 5,424,286).

Agents that serve to slow gastric emptying have found a place in medicine as diagnostic aids in gastrointestinal radiological examinations. For example, glucagon is a polypeptide hormone that is produced by the a cells of the pancreatic islets of Langerhans. It is a hyperglycemic agent that mobilizes glucose by activating hepatic glycogenolysis. It can to a certain extent stimulate the secretion of pancreatic insulin. Glucagon is used in the treatment of insulin-induced hypoglycemia, for example, when intravenous administration of glucose is not pose. However, since glucagon reduces the motility of the gastrointestinal tract it is also used as a diagnostic aid in gastrointestinal radiological examinations. Glucagon has also been used in several studies to treat several painful gastrointestinal disorders related to spasm. Daniel, et al. (Br. Med. J., 3: 720, 1974) reported rapid symptomatic relief of acute diverticulitis in patients treated with glucagon compared to those who had been treated with analgesics or antispasmodics. A review by Glauser, et al., (J. Am. Coil, Emerqencv Phvsns, 8: 228, 1979) described the relief of acute esophageal obstruction by food followed by glucagon therapy. In another study glucagon significantly relieved pain and tenderness in 21 patients with biliary tract disease compared with 22 patients treated with placebo (M.J. Stower, et al., Br. J. Surq. 69: 591-2, 1982).

Methods for regulating gastrointestinal motility using amylin agonists are described in International Application No. PCT / US94 / 10225, published March 16, 1995. Methods for regulating gastrointestinal motility using exendin agonists are described in US patent application Not of series 08 / 908,867. Certain exendin agonists are described in the provisional application of E.U.A. No. 60 / 065,442 issued on November 14, 1997 and in the provisional application of E.U.A. Non-serial 60 / 066,029 issued on November 14, 1997.

BRIEF DESCRIPTION OF THE INVENTION According to one aspect, the present invention provides novel exendin agonist compounds that exhibit advantageous properties including effects for slowing gastric emptying and reducing plasma glucose levels. In accordance with the present invention, the compounds of the formula (I) [SEQ. ID. DO NOT. 40]: í * * s a A «iß £. 1 5 10 Xaaj Xaa2 Xaa, Gly Thr Xaa, Xaa5 Xaa6 Xaat Xaat 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaa,: Xaa12 Xaal3 Leu Lys Asn Gly Gly Xaa14 35 Ser Ser Gly Ala Xaa15 Xaal6 Xaa17 Xaalß- Z where Xaai is His, Arg or Tyr; Xaa2, is Ser, Gly, Ala or Thr; Xaa3, is Asp or Glu; Xaa4 is Phe, Tyr or naphthylalanine; Xaa5 is Thr or Ser; Xaa6 is Ser or Thr; Xaa7, is Asp or Glu; Xaa8 is Leu, Lie, Val, pentiglicin or Met; Xaag is Leu, Lie, Pentylglycine, Val or Met; Xaa 10 is Phe, Tyr or naphthylalanine; Xaa-n is Lie, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa-? 2 is Glu or Asp; Xaa-? 3 is Trp, Phe, Tyr, or naphthylalanine; Xaau, Xaa-? 5, Xaaiß and Xaa-? 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine, Xaa? 8 is Ser, Ther or Tyr; and Z is -OH or -NH2; with the proviso that the compound does not have the formula of SEQ. ID. US. 1 or 2. Also included within the scope of the present invention are the pharmaceutically acceptable salts of the compounds of formula (I) and the pharmaceutical compositions including said compounds and salts thereof. Also provided are the compounds of the formula (II) [SEQ. ID.

DO NOT. 36]: J * -. * - * E- 1 5 10 Xaa, Xaa2 Xaa, Gly Thr Xaa4 Xaa5 Xaat Xaa, Xaa, 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaa ?: Xaa ,, Xaa13 Leu X, Gly Gly Xaa14 35 Ser Ser Gly Ala Xaals Xaal6 Xaa17 Xaalß-Z where Xaa-i is His, Arg or Tyr; or 4-imidazopropionyl; Xaa2, is Ser, Gly, Ala or Thr; Xaa3) is Asp or Glu; Xaa4 is Phe, Tyr or naphthylalanine; Xaas is Thr or Ser; Xaa6 is Ser or Thr; Xaa7, is Asp or Glu; Xaa8 is Leu, Lie, Val, Pentylglycine or Met; Xaag is Leu, Lie, Pentylglycine, Val or Met; Xaa-io is Phe, Tyr or naphthylalanine; Xaa-n is Lie, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa-? 2 is Glu or Asp; Xaa-? 3 is Trp, Phe, Tyr, or naphthylalanine; Xi is Lys Asn, Asn Lys, Lys-NHe-R Asn, Asn Lys-NHe "R, where R is Lys, Arg, alkanoyl or cycloalkylalkanoyl straight or branched chain of CC? O; Xaa-?, Xaais, Xaa- iß and Xaa are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine, Xaa-8 is Ser, Thr or Tyr, and Z is -OH or -NH2; that the compound does not have the formula of SEQ ID NO: 1 or 2. Also included within the scope of the present invention are the pharmaceutically acceptable salts of the compounds of formula (II) and the pharmaceutical compositions including said compounds and you come out of them. . ß Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless otherwise stated. The term "amino acid" refers to natural amino acids, non-natural amino acids, and analogous amino acids, all in their stereoisomers D and L if their structure permits said stereoisomeric forms. Natural amino acids include alanine, (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His ), isoleucine (lie), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), trionine (Thr), tiptofan (Trp), tyrosine (Tyr) ) and Valina (Val). Non-natural amino acids include, but are not limited to, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2- aminoheptanoic, 2-aminoisobutyric acid, 3-aminoisbutyric acid, 2-aminopimelic acid, tertiary butyglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N- Ethyl paraffin, homoproline, hydrosilisine, alo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmokin, alo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalene, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid and thioproline. Analogous amino acids include natural and non-naphureal amino acids which are chemically blocked, reversibly or irreversibly, or modified at their N-terminal amino group or their side chain groups, for example, methionine sulfoxide, methionine sulfone, S- ( carboxymethyl) -cysteine, S- (carboxymethyl) -cysteine sulfoxide and S- (carboxymethyl) cysteine sulfone. The term "amino acid analogue" refers to an amino acid wherein the C-terminal carboxy group, the N-terminal amino group or side chain functional group has been chemically encoded to another functional group. For example, beta-methyl ester of aspartic acid is an amino acid analogue of aspartic acid; is an amino acid analogue of aspartic acid; N-ethylglycine is an amino acid analogue of glycine; or alanine carboxamide is an amino acid analogue of alanine. The term "amino acid residue" refers to radicals having the structure: (1) -C (0) -R-NH-, where R is typically -CH (R ') -, where R' is a side chain of amino acid, typically H or carbon containing a substituent; or (2) "~ C (~ 0)" - where p is 1, 2 or 3 representing the acid I azetidinecarboxylic, proline or pipecolic acid residues, respectively. The term "lower", which is referred to herein in conjunction with organic radicals such as alkyl groups, defines said groups including up to about 6, preferably up to 4 and advantageously including one or more carbon atoms. Said groups can be straight chain or branched chain. "Pharmaceutically acceptable salts" include salts of compounds of the present invention derived from the combination of said compounds and an organic or inorganic acid. In practice, the use of the salt form is equivalent to the use of the base form. The compounds of the present invention are useful in both free bases and salt forms, with both forms being considered within the scope of the present invention. In addition, the following abbreviations represent the following: "ACN" or "CH3CN" refers to acetonitrile. "Boc", "tBoc" or "Tboc" refers to t-butoxycarbonyl. "DCC" refers to N.N'-dicyclohexylcarbodiimide. "Fmoc" refers to fluorenylmethoxycarbonyl. "HBTU" refers to 2- (1 H-benzotriazol-1-yl) -1,3,3-tetramethyluronium hexafluorophosphate. "HOBt" refers to 1-hydroxybenzotriazole monohydrate. "homoP" or "hPro" refers to homoproline. "Mela" or "Nme" refers to N-methylalanine. "naph" refers to naphthylalanine. "pG" or "pGly" refers to pentylglycine. "tBuG" refers to tertiary butylglycine. "ThioP" or "tPro" refers to thioproline.

H BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents the amino acid sequence for certain compounds of the present invention [SEQ. ID. US. 5 to 35]. Figure 2 represents the amino acid sequence for exendin-3 [SEQ. ID. DO NOT. 1]. Figure 3 represents the amino acid sequence for exendin-4 [SEQ. ID. DO NOT. 2]. Figure 4 represents the amino acid sequence for GLP-1 [SEQ. ID. DO NOT. 3]. Figure 5 depicts the dose-dependent effects of exendin-4 compared to compound 1 of Figure 1 [SEQ. ID. DO NOT. 5] in plasma glucose levels in db / db mice. Figure 6 represents a comparison of the effects on gastric emptying of exendin-4, exendin-4 acid and compound 1 of Figure 1 [SEQ. ID. DO NOT. 5].

DETAILED DESCRIPTION OF THE INVENTION Preferred Compounds According to the present invention, the compounds of the formula (I) [SEQ. ID. DO NOT. 4]: UsSt. «A¿d 5 10 Xa! Xaa: Xaa, Gly Thr Xaa, Xaa5 Xaa6 Xaa-Xaa8 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaa ?: Xaa ?: Xaa13 Leu Lys Asn Gly Gly Xaa 35 Ser Ser Gly Ala Xaa15 Xaa16 Xaa17 Xaa18- Z where Xaai is His, Arg or Tyr; Xaa2 is Ser, Gly, Ala or Thr; Xaa3 is Asp or Glu; Xaa is Phe, Tyr or naphthylalanine; Xaas is Thr or Ser; Xaaß is Ser or Thr; Xaa7 is Asp or Glu; Xaa8 is Leu, Me, Val, pentylglycine or Met; Xaag is Leu, Lie, Pentylglycine, Val or Met; Xaa-io is Phe, Tyr or naphthylalanine; Xaa-n is He, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa-? 2 is Glu or Asp; Xaa 3 is Trp, Phe, Tyr, or naphthylalanine; Xaau, Xaa-? 5, Xaa-iß and Xaa? 7 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa? 8 is Ser, Thr or Tyr; and Z is -OH or -NH2; as long as the compound does not have the formula SEQ. ID. US. 1 or 2. Preferred N-alkyl groups for N-alkylglycine, N-alkylpentylglycine and N-alkylalanine include lower alkyl groups preferably from 1 to about 6 carbon atoms, most preferably from 1 to 4 carbon atoms. Suitable compounds of the formula (I) include those having amino acid sequences of SEQ. ID. US. 5 to 35. Preferred exendin agonist compounds of formula (I) include those wherein Xaa-i is His or Tyr. Xaai is most preferably "1r3 His." Preferred compounds are those wherein Xaa2 is Gly, said compounds are preferred wherein Xaag is Leu, pentylglycine or Met. Preferred compounds of formula (I) include those where Xaa13 is Trp or Phe. Also preferred are the compounds of the formula (I) wherein Xaa is Phe or naphthylalanine; Xaa-p is He or Val and Xaau, Xaa-is, Xaa-iß and Xaa-7 are independently selected from Pro, homoproline, thioproline or N-alkylalanine. Preferably N-alkylalanine has an N-alkyl group of 1 to about 6 carbon atoms. According to an especially preferred aspect, Xaa15, Xaa-6 and Xaa-7 are the same amino acid residues. Preferred compounds of formula (I) is wherein Xaa18 is Ser or Tyr, most preferably Ser. Preferably Z is -NH2. According to one aspect, the compounds of formula (I) wherein Xaa-i is His or Tyr, most preferably His; Xaa2 is Gly; Xaa4 is Phe or naphthylalanine; Xaa9 is Leu, pentylglycine or Met; Xaa-io is Phe or naphthylalanine; Xaan is He or Val; Xaa-? ) Xaa-15, Xaa-iß and Xaa-7 are independently selected from Pro, homoproline, thioproline or N-alkylalanine; and Xaa18 is Ser or Tyr, most preferably Ser. Most preferably Z is -NH2. According to an especially preferred aspect, the compounds that are especially preferred include those of the formula (I) wherein: Xaai is His or Arg; Xaa2 is Gly; Xaa3 is Asp or Glu; Xaa is Phe or naphthylalanine; Xaas is Thr or Ser; Xaaß is Ser or Thr; Xaa is Asp or Glu; Xaa8 is Leu or pentylglycine; Xaag is Leu or pentylglycine; Xaa-ioß Phe or naphthylalanine; Xaan is He, Val or t-butyltilglycine; Xaa12 is Glu or Asp; Xaa? 3 is Trp or Phe; Xaa-? , Xaa 5, Xaa 6, and Xaa 7 are independently Pro, homoproline, thioproline, or N-methylalanine; Xaa? 8 is Ser or Tyr: and Z is -OH or -NH2; as long as the compound does not have the formula SEQ. ID. US. 1 or 2. Most preferably Z is -NH2. Especially preferred compounds of the formula (I) include those having amino acid sequences of SEQ, ID. US. 5, 6, 17, 18, 19, 22, 24, 31, 32 and 35. According to an especially preferred aspect, the compounds of formula (I) are provided wherein Xaag is Leu, He, Val or pentylglycine, very preferably Leu or pentylglycine, and Xaa? 3 is Phe, Tyr or naphthylalanine, most preferably Phe or naphthylalanine. These compounds will exhibit advantageous duration of action and will be less subject to oxidative degradation, both in vitro and in vivo, as well as during the synthesis of the compound. Also provided are the compounds of the formula (II) [SEQ. ID. DO NOT. 36]: 1 5 10 Xaa > Xaa2 Xaa3 Gly Thr Xaa, Xaas Xaa Xaa Xaaß 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaan Xaal2 Xaa13 Leu Xl Gly Gly Xaa14 35 Ser Ser Gly Ala Xaa15 Xaal6 Xaa17 Xaalß-Z where Xaa -i is His, Arg, Tyr or 4-i? twdazopropionyl; Xaa2 is Ser, Gly, Ala or Thr; Xaa3 is Asp or Glu; Xaa4 is Phe, tyr or naphthylalanine; Xaa5 is Thr or Ser; Xaa6 is Ser or Thr; Xaa7 is Asp or Glu; Xaa8 is Leu, He, Val, pentylglycine or Met; Xaag is Leu, He, pentylglycine, Val or Met; Xaa-io is Phe, Tyr or naphthylalanine; Xaa-n is He, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa- | 2 is Glu or Asp; Xaa 3 is Trp, Phe, Tyr, or naphthylalanine; Xi is Lys Asn, Asn Lys, Lys-NHe-R Asn, Asn Lys-NHe-R, where R is Lys, Arg, alkanoyl or cycloalkylalkanoyl straight or branched chain of C-i-C-io; Xaau, Xaa-is, Xaa? ß and Xaa-? are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa? 8 is Ser, Thr; or Tyr; and Z is -OH or -NH2; as long as the compound does not have the SEQ formula. ID. US. 1 or 2. Also included within the scope of the present invention are the pharmaceutically acceptable salts of the compounds of the formula (II) and the pharmaceutical compositions including said compounds and salts thereof. Suitable compounds of the formula (II) include the compound having the amino acid sequences of SEQ. ID. US. 37-40. Preferred exendin agonist compounds of the formula (II) include those wherein Xaa-i is His, Tyr or 4-imidazopropionyl. Most preferably, Xaa-i is His or 4-imidazopropionyl. Preferred are compounds of formula (II) wherein Xaa2 is Gly.

Preferred are compounds of the formula (II) wherein Xaag is Leu, pentylglycine or Met. Preferred are compounds of formula (II) wherein Xaa- | 3 is Trp or Phe. Preferred are the compounds of the formula (II) wherein X-? it's Lys Asn, or Lys-NHe -R Asn, wherein R is Lys, Arg, straight or branched chain alkanoyl of C1-C10. Also preferred are compounds of the formula (II) wherein Xaa4 is Phe or naphthylalanine; Xaa-io is Phe or naphthylalanine; Xaa-n is He or Val and Xaa-15, Xaa-iß and Xaa-7 are independently selected from Pro, homoproline, thioproline or N-alkylalanine. According to an especially preferred aspect, Xaa-? 8 is Ser or Tyr. Such compounds are preferred where Xaa? 8 is Ser. Preferably, Z is -NH2. According to a preferred aspect, the compounds of the formula (II) wherein Xaa is Phe or naphthylalanine are preferred; Xaaio is Phe or naphthylalanine; Xaan is He or Val, X-i is Lys Asn, or Lys-NHe -R Asn, where R is Lys, Arg, straight or branched chain alkanoyl of C1-C10 and Xaa, Xaa-? 5, Xaai6 and Xaa-? they are independently selected from Pro, homoproline, thioproline or N-alkylalanine. The compounds mentioned above form salts and bases with various inorganic and organic acids. Said salts include salts prepared with organic and inorganic acids, for example HCl, HBr, H2S04, H3P0) trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid, toluene sulfonic acid, maleic acid, fumaric acid and camphor sulfonic acid. Salts prepared with bases include ammonium salts, alkali metal salts, for example sodium and potassium salts, and alkaline earth salts, for example, calcium and magnesium salts. Acetate, hydrochloride, and trifluoroacetate salts are preferred. The salts can be formed by conventional means, by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water that is subsequently removed by vacuum or by freeze drying or by exchanging the ions of an existing salt for another ion in a suitable ion exchange resin.

Utility The compounds described above are useful in view of their pharmacological properties. In particular, the compounds of the invention are exendin agonists, and possess activity as agents to regulate gastric motility and to slow down gastric emptying, as shown by their ability to reduce post-prandial glucose levels in mammals.

Preparation of compounds The compounds of the present invention can be prepared using standard solid phase peptide synthesis techniques and preferably an automated or semi-automated peptide synthesizer. Typically, using such techniques, an amino acid protected with aN-carbamoyl and an amino acid linked to the growing peptide chain in a resin is coupled at room temperature in an inert solvent such as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the presence of coupling agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in the presence of a base such as diisopropylethylamine. The a-N-carbamoyl protecting group is removed from the resulting peptide resin using a reagent such as trifluoroacetic acid or piperidine, and the repeated coupling reaction with the next desired N-protected amino acid to be added to the peptide chain. Suitable N-protecting groups are well known in the art, with the preferred ones being t-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc). The solvents, amino acid derivatives and 4-methylbenzydril-amine resins used in the peptide synthesizer can be purchased from Applied Biosystems Inc. (Foster City, CA). The following protected side chain amino acids can be purchased from Applied Biosystems, Inc.: Boc-Arg (Mts), Fmoc-Arg (Pmc), Boc-Thr (Bzl), Fmoc-Thr (t-Bu), Boc-Ser (Bzl). ), Fmoc-Ser (t-Bu), Boc-Tyr (BrZ), Fmoc-Tyr (t-Bu), Boc-Lys (Cl-Z), Fmoc-Lys (Boc), Boc-Glu (Bzl), Fmoc-Glu (t-Bu), Fmoc-His (Trt), Fmoc-Asn (Trt), and Fmoc-Gln (Trt). Boc-His (BOM), can be purchased from Applied Biosystems, Inc. or Bachem Inc. (Torrance, CA). Anisole, dimethylsulfide, phenol, ethanedithiol, and thionisol can be obtained from Aldrich Chemical Company (Milwaukee, Wl). Air Products and Chemicals (Allentown, PA), supplies HF. Ethyl ether, acetic acid and methanol can be purchased from Fisher Scientific (Pittsburgh, PA). Solid phase peptide synthesis can be carried out with an automatic peptide synthesizer (model 430A, Applied Biosystems Inc., Foster City, CA) using the NMP / HOBt system (option 1) and tBoc or Fmoc chemistry (see Applied Biosystems User's Manual for the ABI 430A Peptide Synthesizer, Version 1.3B July 1, 1988, section 6, pp. 49-70, Applied Biosystems, Inc., Foster City, CA) with blocking. The Boc-peptide resins can be separated with HF (-5 ° C at 0 ° C, 1 hour). The peptide can be extracted from the resin by alternating water and acetic acid, and the filtrates are lyophilized. The Fmoc-peptide resins can be separated according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc., 1990, pp. 6-12). The peptides can also be linked using an Advanced Chem Tech synthesizer (model MPS 350, Louisville, Kentucky). The peptides can be purified by RP-HPLC (preparation and analytical) using a Waters Delta Prep 3000 system. A preparation column of C4, C8 or C18 (10 μ, 2.2 x 25 cm, Vydac, Hesperia, CA) can be used to isolate peptides, and the purity can be determined using an analytical column of C4, C8 or C18 (5 μ, 0.46 x 25 cm, Vydac). Solvents (A = 0.1% TFA / water and B = 0.1% TFA / CH3CN) can be supplied to the analytical column at a flow rate of 1.0 ml / min and to the preparation column at 15 ml / min. The amino acid analyzes can be carried out in the Waters Pico Tag system and processed using the Maximum program. The peptides can be hydrolyzed by hydrolysis of the vapor phase acid (115 ° C, 20-24 hours). The hydrolyzates can be derived and analyzed by standard methods (Cohen, et al., The Pico Taq Method: A Manual of Advanced Techniques for Amino Acid Analvsis, pp. 11-52, Millipore Corporation, Milford, MA (1989)). The atom bombardment analysis can be carried out by means of M-Scan, Incorporated (West Chester, PA). The mass calibration can be performed using cesium iodide or cesium / glycerol iodide. Plasma desorption ionization analysis using path detection time can be carried out on an Applied Biosystems Bio-lon 20 mass spectrometer. Electrospray mass spectroscopy can be carried out on a VG-Trio machine. Peptide compounds useful in the invention can also be prepared using recombinant DNA techniques, using methods now known in the art. See, for example. Sambrook et al., Molecular Cloninq: A Laboratory Manual. 2nd Ed. Cold Spring Harbor (1989). The non-peptide compounds useful in the present invention can be prepared by methods known in the art. The compounds referred to above can form salts with various inorganic and organic acids and bases. Said salts include salts prepared with organic and inorganic acids, for example, HCl, Hbr, H 2 SO, H 3 P 0, trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid, toluene sulfonic acid, maleic acid, fumaric acid and camphor sulfonic acid. Salts prepared with bases include ammonium salts, alkali metal salts, for example, sodium and potassium salts, and alkaline earth salts, for example, calcium and magnesium salts. The acetate, hydrochloride and trifluoroacetate salts are preferred. The salts may be formed by conventional means, such as by reaction of the acid or base-free forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is not soluble, or in a solvent, such as water, which is then removed in vacuo or by freeze drying or exchanging the ions of an existing salt with another ion in a suitable ion exchange resin. Formulation and administration The compounds of the invention are useful in view of their effects similar to exendin and can conveniently be provided in the form of formulations suitable for parenteral administration (including intravenous, intramuscular and subcutaneous) nasal or oral. In some cases, it will be convenient to provide an exendin or exendin agonist and another gastric anti-thinning agent, such as glucagon, an amylin or an amylin agonist, in a single composition or solution to be administered as a whole. In other cases it may be more convenient to administer another agent antivacized separately from said exendin or exendin agonist. Even in other cases it may be beneficial to supply an exendin or an exendin agonist, either in co-formula or separately with other glucose-lowering agents, such as insulin. A practitioner of j_, «-H - ¿. *. j_- medicine can best determine an appropriate administration format for each patient individually. Suitable pharmaceutically acceptable carriers and their formulation are described in standard formulations, for example, Remington's Pharmaceutical Sciences by E.W. Martin. See also Wang, Y.J. and Hanson, M.A. "Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers", Journal of Parenteral Science and Technology. Technical Report No. 10, Supp. 42: 2S (1988). The compounds useful in the invention can be provided as parenteral compositions for injection or infusion. For example, a vegetable oil, such as sesame oil, peanut, olive, or other acceptable vehicle, may be suspended in an inert oil, suitably. Preferably, they are suspended in an aqueous vehicle, for example, in an isotonic pH buffer at a pH of about 5.6 to 7.4. These compositions can be sterilized by conventional sterilization techniques or can be sterilized by filter. The compositions may contain pharmaceutically acceptable auxiliary substances as required under approximate physiological conditions, such as pH regulating agents. Useful pH regulators include, for example, acetic acid / sodium acetate pH regulators. A "depot" or "depot" slow-release preparation form may be employed to release therapeutically effective amounts of the preparation into the bloodstream for many hours or days after injection or transdermal delivery. The desired isotonicity can be carried out using sodium chloride or other pharmaceutically acceptable agents, such as dextrose, boric acid, sodium tartrate, propylene glycol, polyols (such as mannitol and sorbitol), or other organic or inorganic solutes. Sodium chloride is preferred in particular for pH regulators that contain sodium ions. The claimed compounds can also be formulated as pharmaceutically acceptable salts (e.g., acid addition salts) and / or complexes thereof. The pharmaceutically acceptable salts are non-toxic salts in the concentration in which they are administered. The preparation of said salts can facilitate pharmacological use by altering the physico-chemical characteristics of the composition without preventing it from exerting its physiological effect. Examples of useful alterations in physical properties include lowering the melting point to facilitate administration through the mucosa and increase solubility to facilitate administration of higher concentrations of the drug. Pharmaceutically acceptable salts include acid addition salts, such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethansulfate, benzenesulfate, p-toluenesulfonate, cyclohexyl sulfamate and quinate. The pharmaceutically acceptable salts can be obtained from acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, acid p-toluenesulfonic acid, cyclohexylsulfamic acid and quinic acid. Said salts can be prepared by means of, for example, the reaction of forms without acid or base of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is not soluble, or in a solvent, such as water, which then it is removed in vacuo or by freeze drying or exchanging the ions of an existing salt with another ion in a suitable ion exchange resin. The vehicles or excipients can also be used to facilitate the administration of the compound. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars, such as lactose, glucose or sucrose, or types of starch derived from cellulose, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents. The compositions or pharmaceutical composition can be administered by various routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical or through the mucosa. If desired, the solutions of the above compositions can be thickened with a thickening agent, such as methylcellulose. They can be prepared in emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed, including, for example, acacia powder, a nonionic surfactant (such as Tween), or an ionic surfactant (such as alkali polyether alcohol sulphates or sulphonates). , for example, Triton). The compositions useful in the invention are prepared by mixing the ingredients following generally accepted procedures. For example, the selected components can be mixed simply in a mixer or other standard device to produce a concentrated mixture which can then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a pH regulator to control the pH, or an additional solute to control the tonicity. For use by the physician, the compounds will be provided in unit dosage forms containing an amount of an exendin agonist, with or without another antivaking agent. The therapeutically effective amounts of an exendin agonist for use in the control of gastric emptying and in conditions where gastric emptying is conveniently decreased or regulated are those that decrease postprandial blood glucose levels, preferably to no more than about 8 or 9 mM or so that the blood glucose levels are reduced as desired. In diabetic or glucose intolerant individuals, plasma glucose levels are higher than in normal individuals. In such individuals the beneficial reduction or "decrease" in post-prandial blood glucose levels can be obtained. As will be recognized by those skilled in the art, an effective amount of therapeutic agent will vary with many factors including the age and weight of the patient, the physical condition of the patient, the level of blood sugar or the level of gastric emptying inhibition that will be obtained, and other factors. Said pharmaceutical compositions are useful for causing gastric hypomotility in a subject and can also be used in other disorders in which gastric motility is conveniently reduced. The effective daily antivacification dose of the compounds will almost always be in the range of 0.01 or 0.03 to about 5 mg / day, preferably around 0.01 or 0.5 to 2 mg / day, and more preferably 0.01 or 0.1 to 1 mg / day approximately, for a patient of 70 kg., administered in a single dose or divided. The exact dose to be administered is determined by the attending physician and depends on where the particular compound lies within the scale mentioned above, as well as the individual's age, weight and condition. Administration should start at the first sign of symptoms and soon after the diagnosis of diabetes mellitus. The administration can be by injection, preferably subcutaneous or intramuscular. Orally active compounds can be taken orally, however, doses should be increased 5-10 times. In general, in the treatment or prevention of elevated, inappropriate or unwanted post-prandial blood glucose levels, the compounds of this invention can be administered to patients in need of such treatment on a dose scale similar to those determined with i? prior, however, the compounds are administered more frequently, for example, once, twice or three times a day. The optimal formulation and mode of administration of the compounds of the present application to a patient depends on factors known in the art, such as the specific disease or disorder, the desired effect, and the type of patient. Although almost always the compounds will be used to treat human patients, they can also be used to treat similar or identical diseases in other vertebrates, such as other primates, farm animals, such as pigs, cattle and poultry, and animals for sports and pets. , such as horses, dogs and cats. To assist in the understanding of the present invention, the following examples describing the results of a series of experiments are included. The experiments related to this invention, of course, should not be construed as specifically limiting the invention and such variations of the invention, now known or further developed, which would be within the scope of one skilled in the art are considered to be within the scope of the invention. of the invention, as described herein and claimed below.

EXAMPLE 1 Preparation of amidated peptide having SEQ ID. DO NOT. Í51 The previously identified peptide was assembled on MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxy from acetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.). In general, single coupling cycles were used in the synthesis and Fast Moc chemistry (activation of HBTU) was used. However, in some positions, the coupling was less efficient than expected and double couplings were required. In particular, all Aspg, Thr and Pheß residues required double coupling. Deprotection (removal of the Fmoc group) from the growth peptide chain using piperidine was not always efficient. Double deprotection was required at the Arg2o, Val-ig, and Leuu positions. The final deprotection of the completed peptide resin was achieved using a mixture of triethylsilane (0.2 ml), ethanedithiol (0.2 ml), anisole (0.2 ml), water (0.2 ml) and trifluoroacetic acid (15 ml) according to the methods standards (Introduction to Cleavage Techniques, Applied Biosystems, Inc.). The peptide was precipitated in ether / water (50 ml) and centrifuged. The precipitate was reconstituted in glacial acetic acid and lyophilized. The lyophilized peptide was dissolved in water. The crude purity was around 55%. In the steps of purification and analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used.

The peptide-containing solution was applied to a C-18 preparation column and purified (10% to 40% solvent B in solvent A for 40 minutes). The purity of the fractions was determined socratically using an analytical column of C-18. The pure fractions were collected by providing the peptide previously identified. Analytical RP-HPLC (gradient from 30% to 60% solvent B in solvent A for 30 minutes) of the lyophilized peptide gave the product peptide having an observed retention time of 14.5 minutes. Electrospray mass spectrometry (M): calculated 4131.7; found: 4129.3.

EXAMPLE 2 Preparation of peptide having SEQ. ID. DO NOT. T61 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (25% to 75% gradient of solvent A to solvent B for 30 minutes) of the lyophilized peptide gave the product peptide having an observed retention time of 21.5 minutes. Electrospray mass spectroscopy (M): calculated 4168.6; found 4171.2.

EXAMPLE 3 Preparation of peptide having SEQ. ID. DO NOT. 171 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide gave the product peptide having an observed retention time of 17.9 minutes. Electrospray mass spectroscopy (M): calculated 4147.6; found 4150.2.

EXAMPLE 4 Preparation of peptide having SEQ. ID. DO NOT. [81 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR 3 (gradient from 35% to 65% solvent A to solvent B for 30 minutes) of the lyophilized peptide gave the product peptide having an observed retention time of 19.7 minutes. Electrospray mass spectroscopy (M): calculated 4212.6; Found 4213.2.

EXAMPLE 5 Preparation of peptide having SEQ. ID. DO NOT. T91 The previously identified peptide was assembled in MBHA resin of 4- (2, 4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 50% solvent A to solvent B for 30 minutes) of the lyophilized peptide gave the product peptide having an observed retention time of 16.3 minutes. Electrospray mass spectroscopy (M): calculated 4262.7; found 4262.4.

EXAMPLE 6 Preparation of peptide having SEQ. ID. DO NOT. f101 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4172.6.

EXAMPLE 7 Preparation of peptide having SEQ. ID. DO NOT. [111 The previously identified peptide was assembled in MBHA resin of 4- (2, 4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% of solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4224.7.

EXAMPLE 8 Preparation of peptide having SEQ. ID. DO NOT. [121 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4172.6. i 'tf- - EXAMPLE 9 Preparation of peptide having SEQ. ID. DO NOT. [131 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4186.6.

EXAMPLE 10 Preparation of peptide having SEQ. ID. DO NOT. [141 The peptide previously identified was assembled in MBHA resin of 4- (2'-4'-d¡methoxyphenol) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4200.7.

EXAMPLE 11 Preparation of peptide having SEQ. ID. DO NOT. M51 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4200.7. 3ß * - EJEl? PCO 12 Preparation of peptide having SEQ. ID. DO NOT. [161 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (30% to 60% gradient of solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4202.7.

EXAMPLE 13 Preparation of peptide having SEQ. ID. DO NOT. [171 The previously identified peptide was assembled on MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4145.6.

EXAMPLE 14 Preparation of peptide having SEQ. ID. DO NOT. H81 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4184.6.

EXAMPLE 15 Preparation of peptide having SEQ. ID. DO NOT. H91 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4145.6.

EXAMPLE 16 Preparation of peptide having SEQ. ID. DO NOT. [201 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin, was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4224.7. EXAMPLE 17 Preparation of peptide having SEQ. ID. DO NOT. T2n The previously identified peptide was assembled in MBHA resin of 4- (2, 4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine.

(Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR 15 (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4172.6. < *, .. 'i &SSZ *, * ?. r-i-afc-ír 4 @ EXAMPLE 8 Preparation of peptide having SEQ. ID. DO NOT. [221 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) -and-solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4115.5.

EXAMPLE 19 Preparation of peptide having SEQ. ID. DO NOT. [231 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4188.6.

EXAMPLE 20 Preparation of peptide having SEQ. ID. DO NOT. [241 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4131.6.

EXAM & O 21 Preparation of peptide having SEQ. ID. DO NOT. [251 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), was separated from the resin, deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (TFA al 0.1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4172.6.

EXAMPLE 22 Preparation of peptide having SEQ. ID. DO NOT. [261 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4145.6.

EXAMPLE 23 Preparation of peptide having SEQ. ID. DO NOT. [271 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37 , 36 and 31 of thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4266.8.

X * .: EJEfijS: 2 Preparation of peptide having SEQ. ID. DO NOT. [281 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37 and 36 thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4246.8.

EXAMPLE 25 Preparation of peptide having SEQ. ID. DO NOT. [291 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37, 36 and 31 of thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4250.8.

EXAMPLE 26 Preparation of peptide having SEQ. ID. DO NOT. [301 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37 , 36 and 31 of thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4234.8.

Preparation of peptide having SEQ. ID. DO NOT. 1311 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37 , 36 and 31 of thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4209.8.

EXAMPLE 28 Preparation of peptide having SEQ. ID. DO NOT. T321 The previously identified peptide was assembled in MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings at positions 38 of thioproline are required. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4193.7.

EXAMPLE 29 Preparation of peptide having SEQ. ID. DO NOT. T331 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), was separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37 , 36 and 31 of thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 3858.2.

EJEJÉLd 30 Preparation of peptide having SEQ. ID. DO NOT. [341 The previously identified peptide was assembled in MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37 and 36 of thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 3940.3.

EXAMPLE 31 Preparation of peptide having SEQ. ID. DO NOT. T351 The previously identified peptide was assembled on MBHA resin of 4- (2'-4, -dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc), separated from the resin , was deprotected and purified in a manner similar to Example 1. Double couplings are required * £ additional at positions 38, 3lf¡ | t > and 31 thioproline. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 3801.1.

EXAMPLE 32 Preparation of peptide having SEQ. ID. DO NOT. [361 4-lmidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys-NHeoctanoyl Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser -? / H2 [SEQ ID. DO NOT. 36] was assembled on MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37, 36 and 31 of proline. Fmoc-Lys-NHeoctanoyl acid was used to couple in position 27. Instead of using protected His for final coupling in position 1, 4-imidazoylpropionic acid is directly coupled to the N-terminus of residues 2-39 in the resin . In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR ._. * zJ 'EÉSÍii-. (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4294.5.

EXAMPLE 33 Preparation of peptide having SEQ. ID. DO NOT. [371 4-lmidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe He Glu Phe Leu Lys- NHeoctanoyl Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 [SEQ ID.

DO NOT. 37] was assembled into MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamimodonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37, 36 and 31 of proline. Fmoc-Lys-NHeoctanoyl acid was used to couple in position 27. Instead of using protected His for final coupling in position 1, 4-imidazoylpropionic acid is directly coupled to the N-terminus of residues 2-39 in the resin . In the analysis the solvent A (TFA al 0. 1% in water) and solvent B (0.1% TFA in ACN). Analytical RP-CLAR (gradient of 30% to 60% of solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the ? - »• _ * •" product peptide. Electrospray mass spectroscopy (M): calculated 4242.7.

EXAMPLE 34 Preparation of peptide having SEQ. ID. DO NOT. [381 4-lmidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys-NHeoctanoyl Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser- / V- / 2 [ SEQ ID. DO NOT. 38] was assembled on MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37, 36 and 31 of proline. Fmoc-Lys-NHeoctanoyl acid was used to couple at position 28. Instead of using protected His for final coupling at position 1, 4-imidazoylpropionic acid is directly coupled to the N terminus of residues 2-39 protected in the resin. In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4294.5.

EXAMPLE 35 Preparation of peptide having SEQ. ID. DO NOT. T391 4-lmidazolylpropionyl-Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Árg Leu Phe He Glu Phe Leu Asn Lys-NHeoctanoyl Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser -? // - / 2 [SEQ ID. DO NOT. 36] was assembled on MBHA resin of 4- (2'-4'-dimethoxyphenyl) -Fmoc aminomethylphenoxyacetamidonorleucine (Novabiochem, 0.55 mmole / g) using amino acids protected with Fmoc (Applied Biosystems, Inc.), separated from the resin, deprotected and purified in a manner similar to Example 1. Additional double couplings are required at positions 38, 37, 36 and 31 of proline. Fmoc-Lys-NHeoctanoyl acid was used to couple at position 28. Instead of using protected His for final coupling at position 1, 4-imidazoylpropionic acid is directly coupled to the N-terminus of residues 2-39 in the resin . In the analysis, solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used. Analytical RP-CLAR (gradient from 30% to 60% solvent A to solvent B for 30 minutes) of the lyophilized peptide is carried out to determine the retention time of the product peptide. Electrospray mass spectroscopy (M): calculated 4242.7.

Preparation of C-terminal carboxylic acid peptides corresponding to the above C-terminal amide sequences.

The above peptides of examples 1 to 35 are assembled in the so-called Wang resin (p-alkoxybenzyl alcohol resin (Bachem, 0.54 mmole / g)) using amino acids protected with Fmoc (Applied Biosystems, Inc.), separated from the resin, deprotected and purified in a manner similar to that of Example 1. Solvent A (0.1% TFA in water) and solvent B (0.1% TFA in ACN) were used in the analysis. Analytical RP-HPLC (gradient from 30% to 60% solvent B in solvent A for 30 minutes) of the lyophilized peptide was then carried out to determine the retention time of the product peptide. Electrospray mass spectrometry provides an experimentally determined (M).

EXAMPLES A A D Reagents used GLP-1 was purchased from Bachem (Torrance, CA), all other peptides were prepared domestically using synthetic methods such as those described herein. All chemicals were of higher commercial grade. The AMPc SPA immunoassay was purchased from Amersham.

The radioligands were purchased from New England Nuclear (Boston, MA). RINmdf cells (American Type Tissue ^ Wectíon, Rockville, MD) were cultured in a DME / F12 medium containing 10% fetal bovine serum and 2 mM L-glutamine. The cells were cultured at 37 ° C and 5% CO 2/95% humidified air and the medium was replaced every 2 or 3 days. The cells were cultured to conflue and then harvested and homogenized using a Polytron homogenizer. The cell homogenates were frozen by storage at -70 ° C until use.

EXAMPLE A GLP-1 receptor link studies The receptor binding is evaluated by measuring displacement of human [125l] GLP-1 (7-36) or [125l] exendin (9-39) of the RINmdf membranes. The pH regulator of the assay contained 5 μg / ml of bestatin 1 μg.ml of phosphoramidon, 1 mg / ml of bovine serum albumin (fraction V), 1 mg / ml of bacitracin, and 1 mM of MgCl 2 in 20 mM of HEPES, pH 7.4. To measure the binding, 30μg of membrane proteins (Bradford protein assay) were resuspended in 200μl of the assay pH buffer and incubated with 60 pM [125l] of human GLP-1 or exendin (9-39) and the unlabeled peptides for 120 minutes at 23 ° C in 96-well plates. (Nagle Nunc, Rochester, NY). Incubations were terminated by rapid filtration with buffered saline at its pH of cold phosphate, pH 7.4, through glass fiber filters GF / B treated with polyethyleneimine (Wallac Inc., Gaithersjbu, MD) using a plate harvester Tomtec Mach II (Wallac Inc., Gaithersburg, MD). The filters were dried, combined with a scintillator, and the radioactivity was determined in a Betaplate liquid scintillator counter (Wallac Inc.). Peptide samples were run in the assay as duplicate dots in 6 dilutions at a concentration scale of 10"6M to 10" 12M to generate response curves. The biological activity of a sample is expressed as a CI5o value calculated from the empirical data using an interactive curve-setting program that uses a logistic equation of parameter 4 (Prism, GraphPAD Software).

EXAMPLE B Cyclase activation study The pH regulator of the assay contains 10 μM of GTP, 0.75 mm of ATP, 2.5 mM of MgCl2, 0.5 mM of phosphocreatine, 12.5 U / ml of creatine kinase, 0.4 mg / ml of aprotinin, 1 μM of IBMX in 50 mM of HEPES , pH 7.4. Membranes and peptides were combined in 100 ml of assay pH buffer in 96-well filter bottom plates (Millipore Corp., Bedford, MA). After 20 minutes of incubation at 37 ° C, the assay was terminated by supernatant transfer by filtration in a fresh 96-well plate using a Millipore vacuum manifold. The contents of cAMP supernatants were quantified by SPA immunoassay. Peptide samples were run in the assay as triplicate points at 7 dilutions in a concentration range of 10"6M to 10" 12M to generate response curves. The biological activity of a particular sample was expressed as an EC50 value calculated as described above. The results were tabulated in table 1.

TABLE 1 Activity in the cyclase assay RINmdf Exendina 4 [SEQ. ID. DO NOT. 2] 0.23 Compound 1 [SEQ. ID. DO NOT. 5] 0.17 Compound 2 [SEQ. ID. DO NOT. 6] 0.23 Compound 3 [SEQ. ID. DO NOT. 7] 0.42 EXAMPLE C Determination of blood glucose levels in db / db mice - 1 hour protocol The C57BL / 6J-m = / = Leprdb mice, at least 3 months old, were used for the study. The mice were obtained from The Jackson Laboratory and acclimated for at least a week in the animal house. The mice were housed in groups of 10 to 22 ° + 1 ° C with a light: dark cycle of 12:12, with light at 6:00 am. All animals were fasted for 2 hours before taking the baseline blood samples. Approximately 100μl of blood was removed from each mouse by a hole in the eye, after light anesthesia with the methophane. After collecting the baseline blood samples, to measure plasma glucose concentrations, all animals received subcutaneous injections of any vehicle, exendin-4 or test compound at the indicated concentrations. The blood samples were removed again, using the same sample procedure, after exactly one hour of the injections, and the plasma glucose concentrations were measured. For each animal, the percent change in plasma value, baseline value, and a dose-dependent ratio were evaluated using the Graphpad Prizm ™ software.

Figure 5 depicts the effects of various doses of exendin-4 and compound 1 of Figure 1 [SEQ. ID. DO NOT. 5] on plasma glucose levels.

EXAMPLE D The following study was carried out to examine the effects of exendin-4, exendin-4 acid and an exendin agonist (compound 1 of Figure 1 [SEQ ID NO: 5]) on gastric emptying and on rats This experiment was done after a modification of the method of Scarpignato, et al., Arch. Int. Pharmacodyn. Ther. 246: 286-94 (1980). Male Harlan Sprague Dawley rats (HSD) were used. The animals were housed at 22.7 ± 0.8 C in a light cycle: dark of 12:12 hours (the experiments were carried out during the light cycle) and supplied and moistened ad libitum (Diet LM-485, Tekiad, Madison .Wl). Exendin-4 and exendin-4 acid were synthesized according to standard methods of peptide synthesis. The preparation of compound 1 [SEQ. ID. DO NOT. 5] is described in example 1. The determination of gastric emptying by the method described below is carried out after a -20 hr fast to ensure that the stomach does not contain chyme that could interfere with the measurements of spectrophotometric absorbency.

Conscious rats rec: f £ > They were fed by forced feeding, 1.5 ml of an a caloric gel containing 1.5% methylcellulose (M-0262, Sigma Chemical Co., St. Louis, MO) and 0.05% phenol red indicator. Twenty minutes after the forced feeding, the rats were anesthetized using 5% alotano, the stomach was exposed and held in the pyloric and inferior esophageal sphincters using artery forceps, removed and opened in an alkaline solution that was made at a volume fixed. The content in the stomach was derived from the intensity of phenol red in the alkaline solution, measured by absorbance at a wavelength of 560 nm. In the separate experiments in 7 rats, the stomach and small intestine were removed and opened in an alkaline solution. The amount of phenol red that could be recovered from the upper gastrointestinal tract in the 20 minutes of forced feeding was 89 ± 4%; the dye that seemed to bind irremediably to the luminal surface of the intestine can explain the rest. To consider a maximum decolorizing recovery of less than 100%, the percentage of the content remaining in the stomach after 20 minutes was expressed as a fraction of the gastric content recovered from the control rats sacrificed immediately after forced feeding in the same experiment. Percent residual gastric content = (absorbance at 20 min) / (absorbance at 0 mm) x 100. In the baseline studies, without drug treatment, the gastric emptying was determined during 20 minutes. In the dose-response studies, the rats were treated with 0.01, 0.1, 0.3, 1, 10 and 100 μg of exendin-4, 0.01, 0.03, 0.1, 1, 10 and 100 μg of ISβ or exendin-4. , and 0.1, 0.3, 1, 10 and 100 μg of compound 1 [SEQ. ID. DO NOT. 5].

The results are shown in Figure 6. The results, shown in Figure 6 and Table II, show that the exendin agonists, exendia-4 acid and compound 1 are potent voiding inhibitors. gastric. The EC50 of exendin-4 was 0.27 μg. The EC50 of the acid of exendin-4 and compound 1 were comparable (0.12 μg and 0.29 μg, respectively).

TABLE II Compound EC5o- (μg) Exendin-4 0.27 Exendin-4 acid 0.12 Compound 1 0.29

Claims (40)

NOVELTY OF THE INVENTION CLAIMS

1. - A peptide compound of the formula (I) [SEQ. ID. DO NOT. 4]: 1 5 10 Xaa. Xaa2 Xaa3 Gly Thr Xaa, Xaa5 Xaa6 Xaa, Xaa, 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaa Xaa. , Xaa13 Leu Lys Asn Gly Gly Xaal4 35"Ser Ser Gly Ala Xaa: 5 Xaa1G Xaa17 Xaa18-Z where Xaa-i is His, Arg or Tyr; Xaa2, is Ser, Gly, Ala or Thr; Xaa3, is Asp or Glu; Xaa4 is Phe, Tyr or naphthylalanine; Xaa5 is Thr or Ser; Xaaß is Ser or Thr; Xaa7, is Asp or Glu; Xaa8 is Leu, Lie, Val, pentiglicin or Met; Xaag is Leu, He, pentylglycine, Val or Met; Xaa-io is Phe, Tyr or naphthylalanine; Xaan is He, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa-? 2 is Glu or Asp; Xaa 3 is Trp, Phe, Tyr, or naphthylalanine; Xaa-? , Xaa-? 5, Xaa16 and Xaa17 are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; Xaa18 is Ser, Ther or Tyr; and Z is OH or -NH2; with the proviso that the compound does not have the formula of SEQ. ID. US. 1 or 2; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, further characterized in that Xaa-i is Hys or Tyr.

3. The compound according to claim 2, further characterized in that Xaa-i is His.

4. The compound according to claim 2, further characterized in that Xaa2 is Gly.

5. The compound according to claim 4, further characterized in that Xaag is Leu, pentylglycine or Met.

6. The compound according to claim 5, further characterized in that Xaa-? 3 is Trp or Phe.

7. The compound according to claim 6, further characterized in that Xaa is Phe or naphthylalanine; Xaaio is Phe or naphthylalanine; Xaan is He or Val and Xaau, Xaa-is, Xaa-t6 and Xaa? 7 are independently selected from Pro, homoproline, thioproline or N-alkylalanine.

8. The compound according to claim 7, further characterized in that Xaa? 8 is Ser or Tyr.

9. The compound according to claim 8, further characterized in that Xaa18 is Ser.

10. The compound according to claim 9, further characterized in that Z is -NH2.

11. The compound according to claim 1, further characterized in that Xaa2 is Gly.

12. The compound according to claim 1, further characterized in that Xaag is Leu, pentylglycine or Met.

13. The compound according to claim 1, further characterized in that Xaa? 3 is Trp or Phe.

14. The compound according to claim 1, further characterized in that Xaa is Phe. or naphthylalanine; Xaaio is Phe or naphthylalanine; Xaa-n is He or Val and Xaa-, Xaa? , Xaa ^ and Xaa1 are independently selected from Pro, homoproline, thioproline, or N-alkylalanine.

15. The compound according to claim 1, further characterized in that Xaa18 is Ser or Tyr.

16. The compound according to claim 1, further characterized in that Z is -NH2.

17. The compound according to claim 1, further characterized in that it has an amino acid sequence selected from SEQ. ID. US. 5 to 35.

18. The peptide compound of the formula (I) [SEQ. ID. DO NOT. 4]: 1 5 10 Xaaj Xaa- Xaa3 Gly Thr Xaa, Xaa5 Xaa6 Xaa7 Xaa8 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaau Xaa, - Xaa.3 Leu Lys Asn Gly Gly Xaa14 35 Ser Ser Gly Ala Xaa15 Xaa10 Xaa17 Xaa18-Z wherein Xaa-i is His or Arg; Xaa2, is Gly or Ala; Xaa3 is Asp or Glu; Xaa is Phe or naphthylalanine; Xaa5 is Thr or Ser; Xaaß is Ser or Thr; Xaa, is Asp or Glu; Xaa8 is Leu, or pentiglycine; Xaag is Leu, or pentylglycine; Xaa-io is Phe or naphthylalanine; Xaan is He, Val, or tert-butylglycine; Xaa-? 2 is Glu or Asp; Xaa? 3 is Trp or Phe; Xaau, Xaa-5, Xaaiß and Xaa 7 are independently Pro, homoproline, thioproline or N-methylalanine; Xaa18 is Ser or Tyr; and Z is -OH or -NH2; with the proviso that the compound does not have the formula SEQ. ID. US. 1 or 2; and pharmaceutically acceptable salts thereof.

19. The compound according to claim 18, further characterized in that it has an amino acid sequence selected from SEQ. ID. US. 5, 6, 17, 18, 19, 22, 24, 31, 32, and 35.

20. The compound according to claim 18, further characterized in that it is exendin-3 acid.

21. The compound according to claim 18, further characterized in that it is exendin-4 acid.

22. A composition comprising a compound of any of claims 1-18, 20 or 21 in a pharmaceutically acceptable carrier.

23. The composition comprising a compound according to claim 19, in a pharmaceutically acceptable carrier.

24. A peptide compound of the formula (II) [SEQ. ID.

DO NOT. 40]. 5 10 Xaax Xaa-Xaa3 Gly Thr Xaa, Xaa5 Xaa6 Xaa7 Xaa8 15 20 Ser Lys Gln Xaa, Glu Glu Glu Ala Val Arg Leu 25 30 Xaa10 Xaan Xaa12 Xaal3 Leu 3 Gly Gly Xaa14 Ser Ser Gly Ala Xaa? Xaal6 XaaJ7 Xaa18 -Z where Xaai is His, Arg or Tyr; or 4-Midazopropionyl; Xaa2, is Ser, Gly, Ala or Thr; Xaa3, is Asp or Glu; Xaa is Phe, Tyr or naphthylalanine; Xaa5 is Thr or Ser; Xaaß is Ser or Thr; Xaa7, is Asp or Glu; Xaa8 is Leu, He, Val, pentylglycine or Met; Xaag is Leu, He, pentylglycine, Val or Met; Xaa-? 0 is Phe, Tyr or naphthylalanine; Xaan is He, Val, Leu, pentylglycine, tert-butylglycine or Met; Xaa-? 2 is Glu or Asp; Xaa-? 3 is Trp, Phe, Tyr, or naphthylalanine; Xi is Lys Asn, Asn Lys, Lys-NHe-R Asn, Asn Lys-NHe "R, where R is Lys, Arg, alkanoyl or cycloalkylalkanoyl straight or branched chain of C1-C10, Xaa, Xaa-? 5, Xaa -iß and Xaa are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine, Xaa18 is Ser, Thr or Tyr, and Z is -OH or -NH2; that the compound does not have the formula of SEQ ID NO: 1 or 2 and pharmaceutically acceptable salts thereof The compound according to claim 24, further characterized in that Xaa-i is His, Tyr or 4 imidazopropionyl

26. The compound according to claim 25, further characterized in that Xaa-i is His or 4-imidazopropionyl.

27. The compound according to claim 24, further characterized in that Xaa2 is Gly.

28. The compound according to claim 24, further characterized in that Xaag is Leu, pentylglycine or Met.

29. The compound according to claim 24, further characterized in that Xaa-? 3 is Trp or Phe.

30. The compound according to claim 24, further characterized in that X < ? is Lys, Asn, or Lys-NHe-R Asn, where R is Lys, Arg, straight or branched chain alkanoyl of C1-C10.

31. The compound according to claim 24, further characterized in that Xaa-io is Phe or naphthylalanine; Xaan is He or Val and Xaau, Xaa-ts, Xaa16 and Xaa-7 are independently selected from Pro, homoproline, thioproline, or N-alkylalanine.

32. The compound according to claim 24, further characterized in that Xaa-? 8 is Ser or Tyr.

33. The compound according to claim 32, further characterized in that Xaa? 8 is Ser.

34.- The compound according to claim 24, further characterized in that Z is -NH2.

35. The compound according to claim 24, further characterized in that Xaa is Phe or naphthylalanine; Xaa-? 0 is Phe or naphthylalanine; Xaan is lie or Val; X-? is Lys Asn, or Lys-NHe-R Asn, wherein R is Lys, Arg, straight or branched chain alkanoyl of C1-C-10 and Xaa 4, Xaa-5, Xaa-i6 and Xaa-7 are independently selected from Pro, homoproline, thioproline or N-alkylalanine.

36. The compound according to claim 35, further characterized in that Xaa-? 8 is Ser or Tyr.

37. The compound according to claim 35, further characterized in that Z is -NH2.

38. The compound according to claim 22, further characterized in that it has an amino acid sequence selected from SEQ. ID. US. 36-39. 39.- The composition comprising a compound of any of claims 24-37 in a pharmaceutically acceptable carrier. 40.- The composition comprising a compound according to claim 38 in a pharmaceutically acceptable carrier.