JP2000505105A - Analogs of peptide YY and uses thereof - Google Patents

Abstract

  (57) [Summary] The present invention provides an analog of PYY. The present invention also provides compositions and methods useful for modulating biological activities such as cell growth, nutrient transport, lipolysis, intestinal water and electrolyte secretion.

Description

DETAILED DESCRIPTION OF THE INVENTION                   Analogs of peptide YY and uses thereof                         Mention of federally supported research   This invention was made with part of government funding and, therefore, the Government Has certain rights.                                 Background of the Invention   The present invention relates to peptide derivatives useful as therapeutic agents in the treatment of gastrointestinal disorders. You.   Peptide YY (PYY) is a 36-residue peptide peptide originally isolated from porcine intestinal tract. And are localized in endocrine cells of the gastrointestinal tract and pancreas (Tatemoto, Proc. Natl Acad. Sci. 79: 2514, 1982). Peptide YY has N-terminal and C-terminal tyrosine Have an amide; therefore, these two tyrosines are given the name PYY. (Y represents the amino acid tyrosine in peptide nomenclature). Furthermore, PYY Neuropeptide Y (NPY), a homologous peptide, and many central and terminal regulatory This neuropeptide (NPY) was originally isolated from porcine brain. (Tatemoto, Proc. Natl Acad. Sci. 79: 5485, 1982). What is the cellular localization of PYY? In contrast, NPY is present in the submucosal and mesenteric nerves, which are And innervates the smooth muscle layer (Ekblad et al., Neuroscience 20: 169, 1987). PYY and Both NPY appear to inhibit intestinal motility and blood flow (Laburthe, Trends Endoc rinol. Metab. 1: 168, 1990), they are also basic (Cox et al., Br. J. Pharma. col. 101: 247, 1990; Cox et al. Physiol. 398: 65, 1988; Cox et al., Peptides 12; 32. 3, 1991; Fridl et al., Br. J. Pharmacol. 88: 425,1986) and in rats ( Lundberg et al., Proc. Natl Acad. Sci. USA 79: 4471, 1982; Playford et al., Lancet. 335: 1555, 1990) and in humans (Playford et al., Supra) to induce secretagogue induction. Attenuates intestinal secretion and stimulates net (net) absorption (MacFadyen et al., Neuropeptides 7: 219, 1986). In addition, plasma PYY Levels are reported to be elevated in several diseases causing diarrhea (Adrian et al., Gastroenterology 89: 1070, 1985). Putting these together, these Observations indicate that PYY and NPY are associated with the postprandial circulatory system (Adrian et al., Gastorenterology 89 1070, 1985; Balasubramaniam et al., Neuropeptides 14: 209, 1989) It regulates intestinal endocrine secretion and absorption and acts as a natural inhibitor of diarrhea. Suggests that it can play a role.   The high-affinity PYY receptor system, which has a slightly higher affinity for PYY than for NPY, Characteristic of the intestinal epithelium (Laburthe et al., Endocrinology 118: 1910, 1986; Labur the et al., Trends Endocrinol. Metab. Supra), negatively bound to adenylate cyclase ( negatively coupled) (Servin et al., Endocrinology 124: 692, 1989). Consistently, PYY is a voltage clamped preparation of rat small intestine. reparations) show greater antisecretory capacity than NPY (Cox et al., J. Physiol. On the other hand, the C-terminal fragment of NPY is more effective than PYY in its antisecretory ability. It was found to be ineffective (Cox et al., Br. J. Pharmacol. Supra). Some parts Structure-activity studies using segmented sequences show activity to interact with intestinal PYY receptors Led to the identification of PYY (22-36) as a site (Balsubramaniam et al., Pept. Res. . 1:32, 1988).   In addition, PYY is a nutrient intake (e.g., Bilcheik et al., Digestive Disease Week 506: 6). 23, 1993), cell proliferation (eg, Laburthe, Trends Endocrino. Meta). b. 1; 168, 1990; Voisin et al. Biol. Chem., 1993), lipolysis ( See, for example, Valet et al. Clin. Invest. 85: 291 1990) and blood vessels (See, for example, Lundberg et al., Proc. Natl Acad. Sci. USA 79: 4471, 1982). ) And many other physiologically active substances.   The amino acid sequences of porcine and human PYY are shown below:   Pig PYY YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY (SEQ.ID.NO.1)   Human PYY YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY (SEQ.ID.NO.2) The amino acid sequences of dog PYY and rat are the same as pig PYY.Summary of the Invention   In one aspect, the invention features novel analogs of peptide YY of the formula And have:  Wherein x is a chain of 0-5 amino acids, including the N-terminus, one of which is R₁ And R_TwoBound to;   Y is a 0-4 amino acid chain, including the C-terminus, one of which is R_ThreeAnd R_Four Bound to;   R₁Is H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g., formyl, acetyl and And myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈ Alkaryl (eg, p-methylphenyl):   R_TwoIs H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g., formyl, acetyl and And myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈ Alkaryl (eg, p-methylphenyl);   A^{twenty two}Is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or is deleted;   A^{twenty three}Is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N-Me-Ala or Re;   A^{twenty four}Is Leu, Ile, Val, Trp, Gly, Nle, Nva, Aib, Anb, N-Me-Leu or Deleted;   A^{twenty five}Is Arg, Lys, homo-Alg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAlkyl or aryl), Orn or Is deleted;   A²⁶Is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrazolylalanine, N-M e-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H , Branched or linear C₁-C_TenAn alkyl or aryl group), Orn or Deleted;   A²⁷Is an aromatic amino acid other than Tyr;   A²⁸Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;   A³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A³¹Is Val, Leu, Ile, Trp, Nle, Nva, Aib, Anb or N-Me-Val;   A³²Is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;   R_ThreeIs H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g., formyl, acetyl and And myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈ Alkaryl (eg, p-methylphenyl);   R_FourIs H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g., formyl, acetyl and And myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈ Alkaryl (e.g., p-methylphenyl), or pharmacologically acceptable Salts.   In a preferred embodiment, A²⁷Is Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Dip.   In a preferred embodiment, x is A¹⁷-A¹⁸-A¹⁹-A²⁰-A^{twenty one}Where:   A¹⁷Is Cys, Leu, Ile, Val, Nle, Nva, Aib, Anb or N-Me-Leu;   A¹⁸Is Cys, Ser, Thr, N-Me-Ser or N-Me-Thr;   A¹⁹Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAlkyl or C₆-C₁₈Aryl)), C ys or Orn;   A²⁰Is an aromatic amino acid or Cys; and   A^{twenty one}Is an aromatic amino acid, Cys or a pharmacologically acceptable salt thereof. You.   In another preferred embodiment, Y is A³³-A³⁴-A³⁵-A³⁶Where:   A³³Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAn alkyl or aryl group), Cys or O rn;   A³⁴Is Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb;   A³⁵Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAn alkyl or aryl group), Cys or O rn; and   A³⁶Is an aromatic amino acid, Cys or a pharmacologically acceptable salt thereof. You.   Preferably, this compound should have the formula:   N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH_Two (SEQ.ID.No.3), H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln -Arg-Tyr-NH_Two(SEQ. ID No. 4), N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Le u-Val-Thr-Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.5), N-α-Ac-Ala-Ser-Leu-Arg-H is-Thi-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.6), N-α-Ac- Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID . No. 7) or pharmacologically acceptable salts thereof.   In another aspect, the invention features novel analogs of peptide YY of the formula are doing:   Where the N-terminal amino acid is R₁And R_TwoBinds to   Y is a 0-4 amino acid chain, including the C-terminus, one of which is R_ThreeAnd R_Four Bound to;   R₁Is H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g., formyl, ace Chill, myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C_{1 8} Alkaryl (eg, p-methylphenyl);   R_TwoIs H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g. formyl, acetyl, Myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈Al Caryl (eg, p-methylphenyl);   A^{twenty five}Is Arg, Lys, homo-Alg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAlkyl or aryl), Orn or Is deleted;   A²⁶Is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrazolylalanine, N-M e-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H , Branched or linear C₁-C_TenAn alkyl or aryl group), Orn or Deleted;   A²⁷Is an aromatic amino acid;   A²⁸Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;   A³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A³¹Is Val, Ile, Trp, Nva, Aib, Anb or N-Me-Val;   A³²Is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;   R_ThreeIs H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g. formyl, acetyl, Myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈Al Caryl (eg, p-methylphenyl); and   R_FourIs H, C₁-C₁₂Alkyl (eg methyl), C₆-C₁₈Aryl (e.g. Enyl, naphthaleneacetyl), C₁-C₁₂Acyl (e.g. formyl, acetyl, Myristoyl), C₇-C₁₈Aralkyl (eg benzyl), or C₇-C₁₈Al Caryl (e.g., p-methylphenyl), or a pharmacologically acceptable salt thereof Kind.   In a preferred embodiment, A²⁷Are Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Is Dip.   In a preferred embodiment, Y is A³³-A³⁴-A³⁵-A³⁶Where:   A³³Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAlkyl or C₆-C₁₈Aryl)), C ys or Orn;   A³⁴Is Gln, Asn, Ala, Gly, N-Me-Gln, Aib, Cys or Anb;   A³⁵Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H, branched or straight chain C₁-C_TenAlkyl or C₆-C₁₈Aryl)), C ys or Orn; and   A³⁶Is an aromatic amino acid, Cys or a pharmacologically acceptable salt thereof. You.   Preferably, this compound should have the formula:   N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.N o. 8)   In another aspect, the invention features analogs of dimers of peptide YY I have. The dimer may comprise two peptides of formula I, two peptides of formula II, Is formed by either one peptide of formula I and one peptide of formula II Can be In one embodiment, the dimer is a primary or a primary located on each peptide. Formed using a dicarboxylic acid linker capable of binding to a secondary free amine. example If R. Vavrek and J.M. Stewart, Peptides: Structure and Function, 381-384 (Pierce Ch. emical Co. 1983). Examples of suitable dicarboxylic acid linkers are succinic acid, gluta Minic acid and phthalic acid. In other embodiments, the dimer of one peptide Amino acids capable of binding to free amine groups and free carboxyl groups of other peptides It is formed using a linker. The amino acid linker is preferably a non-α-amino acid. New Examples of suitable amino acid linkers are amino-caproic acid and amino-valeric Is an acid. In another embodiment, the dimer is a cysteine located on each peptide. Formed by disulfide bonds between them. For example, M. Berngtowicz and G.W. Piats ueda, peptide: structure and function, 233-244 (Pierce Chemical Co. 1983); Al See bericio et al., Peptides, 1990, 535 (ESCOM 1991).   In yet another aspect, the invention relates to at least one pseudo-pair between amino acid residues. It features an analog of Formula I or Formula II having a peptide bond. “Fake pepti Is a carbon atom that participates in the bond between two residues Methylene carbon, ie CH_TwoReduced to -NH; or less preferably However, the carbonyl carbon of CO-NH is CH_Two-S, CH_Two-CH_Two, CH_Two-O or CH_Two-CO It means that it has been replaced somewhere. As used herein, the pseudopeptide The bond is symbolized by “Ψ”. Preferably, the pseudopeptide bond is one or more Between amino acid residues, for example A²⁸ΨA²⁹, A²⁹ΨA³⁰, A³⁰ΨA³¹, A³¹ΨA³², A³² ΨA³³, A³³ΨA³⁴, A³⁴ΨA³⁵Or A³⁵ΨA³⁶Is arranged like Good. In addition, such pseudopeptide bond analogs can be used as dimers as described above. Can be used to form analogs of Pseudopeptide bond chemistry details A simple discussion is described in Coy et al., (1998), Tetrahedron, 44: 835-841. I have.   In yet another embodiment, the invention relates to a radiolabeled compound of formula I and formula II It is characterized by analogs that have been created. Preferably, the analog is a phenyl It is preferred to have tyrosine iodide at carbon position 3 or 5 of the ring. Radioactive iodine The element is I¹²⁵Or I^{one two Three}It is preferred that Tyrosine iodide residues in peptides See European Patent Application 0389180 for examples of chemistry related to This sentence Make a part of the text with your help. Therefore, PYY tags labeled with radioactive material Nalog predicts PYY receptors, e.g., predicts cells containing PYY receptors Can be used to   The symbols x, y, z, A described in the peptide sequence herein^{twenty two}, A^{twenty three}, A^{twenty four} Ser, Leu, etc. represent amino acid residues, ie, when at the N-terminus, = N-CH (R) -CO- , When at the C-terminus, -NH-CH (R) -CO-N =, or when not at the N- or C-terminus, -NH -CH (R) -CO- (wherein R is the side chain of the amino acid or its residue (or identify ng) group). For example, when R is Asp, -CH_TwoCOOH is Gly -H for Ser, -CH for Ser_TwoOH, Ala -CH_ThreeAnd for Arg -CH_TwoC H_TwoCH_TwoCH_TwoNH_TwoIt is. When amino acid residues are optically active, D- Unless otherwise stated, L-form is meant.   As indicated above, and to briefly describe the present invention, The abbreviations of various amino acids that are used or not used are used. They are Are understood by those skilled in the art, but are described below for clarity. . All peptide sequences described herein are provided in a conventional manner. Where the N-terminal amino acid is on the left and the C-terminal amino acid is on the right. Two amino acid residues Short lines between groups indicate peptide bonds. Asp = D = aspartic acid Ala = A = alanine Arg = R = arginine Asn = N = asparagine Cys = C = cysteine Gly = G = glycine Glu = E = glutamic acid Gln = Q = glutamine His = H = histidine Ile = I = isoleucine Leu = L = Leucine Lys = K = lysine Met = M = methionine Phe = F = phenylalanine Pro = P = Proline Ser = S = Serine Thr = T = Threonine Trp = W = tryptophan Tyr = Y = Tyrosine Val = V = Valine Orn = ornithine Nal = 2-naphthylalanine Nva = norvaline Nle = norleucine Thi = 2-thienylalanine Pcp = 4-chlorophenylalanine Bth = 3-benzothienylalanine Bip = 4,4'-biphenylalanine Tic = tetrahydroisoquinoline-3-carboxylic acid Aib = aminoisobutyric acid Anb = α-amino normal butyric acid Dip = 2,2-diphenylalanine Thz = 4-thiazolylalanine   The compounds of the present invention can be provided in the form of pharmacologically acceptable salts. Wear. Examples of suitable salts include therapeutically acceptable organic acids such as acetic acid , Lactic acid, maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid Acid, salicylic acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, etc. Or pamoic acid, further polymeric acids such as tannic acid, carboxy Salts with methylcellulose, and inorganic acids, such as hydrohalic acids, such as hydrochloric acid , Sulfuric acid, phosphoric acid and the like.   In another aspect, the invention can reduce excess intestinal fluid and electrolyte secretion A pharmacologically acceptable carrier for one of the above compounds in a therapeutic composition. A substance.   In a preferred embodiment, the composition is a capsule, liquid, pill for oral administration In the form of tablets; liquids that can be administered intranasally, such as droplets or sprays; Or a liquid for intravenous, subcutaneous, parenteral, intraperitoneal or rectal administration. This therapeutic composition is combined with lipophilic salts such as pamoic acid In the form of oily emulsions or dispersions, or for subcutaneous or intramuscular administration In the form of a biodegradable sustained-release composition. To maximize efficacy , Zero level emissions are desired.   In other aspects, reduces excess intestinal fluid and electrolyte secretion in mammals   Characterized in that the method comprises the steps of: Administering the above compound to the subject in a therapeutically effective amount.   Further, the invention features a method of regulating cell growth in a mammal, comprising the steps of: The method comprises administering to a mammal a therapeutically effective amount of a composition of a compound described above. including. Preferably, the method modulates intestinal cell proliferation.   The invention also relates to increased nutrient transport, regulation of lipolysis and blood flow in mammals. Characterized in that the method comprises providing a therapeutically effective amount of the composition described above. It also includes administration to mammals.   The compounds of the present invention are useful in a wide range of organisms related to their antisecretory and antimotility properties. Show activity. The compounds may be produced by direct interaction with epithelial cells, or In other words, to inhibit the secretion of hormones or neurotransmitters that stimulate intestinal secretion Therefore, it seems to suppress gastrointestinal secretion. The compounds of the present invention also provide a net water absorption Intestinal blood flow may also be controlled, which may in turn alter the intestinal hydrostatic pressure to favor yield.   The compounds of the present invention may be associated with excessive intestinal electrolytes and reduced water secretion and absorption, e.g., infection. (Eg, viral or bacterial) diarrhea, inflammatory diarrhea, short-term colon syndrome or Various related to diarrhea commonly occurring after surgical procedures such as ileal fistula formation Is particularly useful in the treatment of any gastrointestinal disorder (e.g., Harrison's Prin ciples Of Internal Medicine, McGraw-Hill Inc., New York, 12th edition. thing). Examples of infectious diarrhea include acute viral diarrhea, acute bacterial diarrhea (e.g., Lumonella, Gram-negative bacteria and Clostridium or protozoan infections ), Or traveler's diarrhea (e.g., Norwalk virus or rotavirus (rot awirus)), but is not limited thereto. Malabsorption in cases of inflammatory diarrhea Syndrome, tropical spue, chronic pancreatitis, Crohn's disease, diarrhea and Including, but not limited to, irritable bowel syndrome. Further, the peptide of the present invention Emergency or life-threatening situations related to gastrointestinal disorders, for example, after surgery or It has also been found that it can be used to treat cholera. Furthermore, the present invention Compounds suffer from acquired immunodeficiency syndrome (AIDS), especially in cachexia Can be used to treat patients.   The compounds of the present invention also inhibit small intestinal fluid and electrolyte secretion, Increased transport and increased cell proliferation, eg, regulation of lipolysis in adipose tissue, It is also useful for regulating blood flow in mammals.   The compounds of the present invention are truncated versions of natural PYY peptides Therefore, shorter peptides are useful for compound synthesis and purification. Not only is it more easily utilized, but it also improves and reduces operating procedures and costs. Furthermore, Shorter PYY compounds indicate that such peptides interact solely with the PYY receptor. Will not interact with homologous receptors such as NPY Y1 and Y3. Therefore, unwanted agonists (agonists) or antagonists (antagonists) Substances) Minimize by-products.   Other features and advantages of the present invention include the following description of the preferred embodiments of the invention, and It will be clear from the appended claims.                             Detailed description of the invention   The drawings are first described.Drawing   FIG. 1 shows N-α-Ac- [Phe obtained by HF cleavage.²⁷] PYY (22-36) (SEQ.ID.NO. 3) shows semipreparative reverse phase chromatography of (≒ 25 mg). Condition: V ydac C18 semi-preparative column (250 x 10 mm, 300 mm pore size, 10 micron particles Size); flow rate 4.7 ml / min; fractions 1, 2, 3 and 4 were collected and analyzed. Analyzed by chromatography. Combining homogeneous fractions (1-3) , Dried in a speed bag.   FIG. 2 shows PYY (SEQ. ID. NO. 1), PYY (22-36) (SEQ. ID. NO. 10), [Im-DNP-His²⁶] PY Y (SEQ. ID. NO. 9), [Ala³²] PYY (22-36) (SEQ.ID. NO.11), [Ala^23,32] PYY (22-36) ( SEQ.ID. NO.12), [Glu²⁸] PYY (22-36) (SEQ. ID. NO. 13), N-α-Ac-PYY (22-36) (SEQ. .ID. NO.14), N-α-Ac- [p.Cl-Phe²⁸] PYY (22-36) (SEQ.ID. NO.15), N-α-Ac- [Gl u²⁶] PYY (22-36) (SEQ.ID. NO.16), N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ.ID.NO.3), N-α-Ac- [N-Me-Tyr²⁶] PYY (22-36) (SEQ.ID. NO.17), N-α-myristoyl-PYY (22-36) 36) (SEQ. ID. NO. 18), N-α-naphthaleneacetyl-PYY (22-36) (SEQ. ID. NO. 19), Jejunal Membrane in Rats with Increased Concentrations of PYY and PYY (22-26) (SEQ.ID. Against¹²⁵Figure 4 shows a graph of the inhibition of I-PYY binding.   3A-B show one reference point of short-circuit current (SCC) in voltage clamp preparation of rat jejunum. (SEQ.ID.NO.1), PYY (22-36) (SEQ.ID.NO.10) and analogs Show the effect. The change in voltage in SCC is more between 3 and 7 different jejunal preparations μA / 0.6cm^Two, Mean ± SEM. The peptides shown in A and B are shown in FIG. The same symbols as in the above are shown.   FIG. 4 shows PYY, N-α-Ac-PYY (22-36) (SEQ.ID. NO.14), N-α-Ac- [Tic²⁷] PYY (22- 36) (SEQ. ID. NO. 25), N-α-Ac- [Bip²⁷] PYY (22-36) (SEQ.ID.NO.22), N-α-Ac- [N al²⁷] PYY (22-36) (SEQ.ID. NO.23), N-α-Ac- [Bth²⁷] PYY (22-36) (SEQ.ID.NO.21) , N-α-Ac [Phe²⁷] PYY (22-36) (SEQ.ID.NO.3), N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ. ID. NO.26), N-α-Ac (Tyr²⁷] PYY (22-36) (SEQ.ID. NO.5) and N-α-Ac [Thi²⁷] PY Increased concentration of Y (22-26) (SEQ.ID. NO.6) on rat jejunal membrane¹²⁵The conclusion of I-PYY 4 shows a graph of inhibition in the case of the above.   A description of the synthesis, analysis of biological efficacy and use of preferred embodiments of the present invention is set forth below. Do. To determine the structural requirements needed to eliminate antisecretory effects, PYY activity Synthesizes several analogs of the sexual site, PYY (22-36), and And antisecretory capacity were compared.   We now describe the structure, synthesis and use of preferred embodiments of the present invention.Construction   The peptides of the present invention have the general formula listed in the Summary of the Invention above. So All of these are important for both antisecretory activity and use as antidiarrheal compounds. It has an aromatic amino acid group at position 7.Synthesis   The peptides of the present invention can be prepared by any technique known to those skilled in the peptide art. Can also be synthesized. An excellent overview of many technologies that work quite well is the Solid Phase Pe ptide Synthesis Second Edition (Stewart, JM and Young, JD, Pierce Chemical Company, Rockford, IL, 1984).   The peptides listed in Tables 1 and 2 were synthesized as follows. Pe Peptide synthesis was performed on an Applied Biosystems model 430A synthesizer. Was. Amino acid and sequence analysis is performed by Waters Picotag and Applied Each was performed using a BioSystems model 470A device. Peptide, standard Water with model 481 spectrometer and U6K injector -Purified using a Model 600 solvent delivery system. The peptide mass is According to the method, University of Michigan, Protein Chemisitry Facility, Ann A rbor, Michigan. All Boc-L-amino acid derivatives, solvents, chemistry Species and resin were obtained commercially and used without further purification.   Paramethylbenzhydroxylamine (MBHA) resin (0.45 mmol, -N H_Two) Is placed in the reaction vessel of the peptide synthesizer and the protected amino acid derivative is provided to the manufacturer. Program provided by and modified to incorporate the double coupling method ( For example, using Balasubramaniam et al., Peptide Research 1:32, 1988) It was pulled. All amino acids were replaced with 2.2 equivalents of a preformed symmetrical anhydride ( Coupling was performed using symmetrical anhydrides). However, Arg, Gl n and Asn are replaced with preformed 1-hydroxybenzo to avoid side reactions. Coupled as triazole (HOBT) ester. At the end of the synthesis, The N-α-Boc group was removed and in some cases the ninhydrin test (Anal. Biochem. Acetic anhydride (2 equivalents) and diisopropylethyl until 34; 595, 1970) is negative. Free α-NH_TwoWas acetylated. Then the peptide tree Fat (~ 1.0 g), p-cresol (~ 0.8 g) at -2 to -4 ° C for 1 hour Treated with contained HF (10 ml). HF is discharged and the remainder is diethyl ether And washed repeatedly with diethyl ether and extracted with acetic acid. (2 × 15 ml) and lyophilized. The crude peptide thus obtained is shown in FIG. Purified by semi-preparative RP-HPLC as described.   Examples of synthesized analogs are: analysis Binding research   Tyr³⁶Labeled only in¹²⁵Preparation of I-PYY and rat jejunal epithelial plasma membrane (See, eg, Laburthe et al., Endocrinology, supra; Servin et al.) Viosin et al., Ann. N. Y. Acad. Sci. 611: 343, 1990). 2% binding experiment BSA, 0.1% bacitracin, 5 mM MgCl_TwoAnd 0.05 nM¹²⁵I- A total of 0.25 ml of PYY, with or without competitor peptide, is contained. Performed in 60 mM HEPES buffer, pH 7. Binding peptide and free peptide The peptide was separated from the peptide by centrifugation at 20,000 × g for 10 minutes. Non-specific¹²⁵I -PYY binding is measured in the presence of 1 μM unlabeled PYY and is 10% of total binding Indicated.   Short circuit current measurement   The antisecretory effect of this peptide was determined as described by Cox et al. (J. Physiol. Supra). Short-circuit current and auto-fixation current in rat jejunal mucosa placed in Ussing chamber It was determined by measuring the pressure. Simply put, a strip of mucous membrane, Oxygen addition (95% O_Two/ 5% CO_Two) Krebs-Henseleit solution (NaCl, 11 7 mM, KCl, 4.7 mM, CaCl_Two2.5 mM; MgSO_Four, 1.2 mM, NaHCO_Three, 24.8 mM and glucose, 11.1 mM), pH 7.4, Perspex Ussi chamber containing 37 ° C ng chambers) (window size, 0.6cm^Two) Between the two halves. In a routine manner, four preparations of jejunum were obtained each from animals. These are ratios It showed comparable potential differences and SCCs, but they were not balanced. Preparation The object is automatically voltage clamped using a W-P dual voltage clamp and the SCC is Recorded continuously on recorder. Once a stable baseline SCC is reached, the peptide is Cumulative concentration--reaction in addition to soleoleal reservoir only Configured profile.   Data analysis   All points in the binding experiments are the average of at least three experiments performed in duplicate. It is. For clarity, the SEM in the binding experiment is not shown in FIG. , Less than 10%. The value of the change in SCC is between 3 and 7 different preparations From μA / 0.6cm^TwoThe average is ± 1 SEM. EC₅₀Value is the cumulative concentration The degree-response curves were calculated using an interaction curve fitting program. Data group (S CC recordings) were compared with a disproportionate (p-value <0.5 as a statistically significant difference). unpaired) using the Student's t test.   The results of the biological activities of the compounds according to the invention are listed below (see Tables 1 and 2). That). As mentioned above, the test compound is purified and its purity in the rat jejunum. Assayed for binding and antisecretory capacity.   The purified peptide was determined to be> 96% homogeneous by analytical reverse phase chromatography. And had the expected amino acid composition and mass. For example, Table 1 shows that N-α-A c- [Phe²⁷3] shows the chromatogram of PYY (22-36) (SEQ. ID. NO. 3). Free pep The tide was further characterized by sequencing analysis (see Tables 1 and 2). The overall peptide yield was in the range of 10% to 30%.   ¹²⁵PYY substituted with I-PYY, [im-DNP-His²⁶] PYY (SEQ. ID. NO. 9) and PYY (22- 36) An analog of (SEQ.ID. NO.10) binds to rat jejunal epithelial plasma membrane in a concentration-dependent manner did. [im-DNP-His²⁶PYY (SEQ.ID.NO.9) and PYY (22-36) (SEQ.ID.NO.10) I c₅₀20 times lower performance than PYY based on It showed a maximum response equivalent to that of mon (FIG. 2, Table 1). [Ala³²] PYY (22-36) (SEQ.ID. NO.1 Thr in 1)³²Substitution with Ala reduces binding capacity, while Ser³²And Thr³²of Substitution of both with Ala further reduced the affinity of the receptor. Helicity changes [Glu²⁸] Introduction of negative charge at position 28 in PYY (22-36) (SEQ.ID. NO.13) Incorporation reduced binding, presumably by preventing ionic interactions. Hydrophobic groups are It is known to enhance the interaction with sceptors (Balasubrananiam et al., Bioche m. Biophys. Res. Comm. 137: 1041, 1986), N-α-myristoyl of PYY (22-36) And binding of N-α-naphthaleneacetyl derivatives was also determined. These analogs Both were slightly less than PYY (22-36) (SEQ. ID. NO. 10), probably due to increased steric hindrance. Showed low binding affinity. On the other hand, N-α-acetylation of PYY (22-36) (SEQ. ID. NO. 1) 4) increased the affinity of the receptor four times. Further, N-αAc-PYY (22-36) (SEQ. ID. NO. 2) 0) further structure-activity studies³⁶By N-Me-Tyr or His²⁶P.Cl Substitution with -Phe has been shown to reduce binding capacity. However, Tyr²⁷Phe Displacement increased receptor affinity by 28%. PY as control The binding of Y (22-36) (SEQ. ID. NO. 10) and some of its analogs was also tested. . However, none of these analogs even at 10 μM¹²⁵I-PYY binding Did not inhibit.   In rat jejunal mucosal preparations, the PYY (22-36) (SEQ. ID. The baseline SCC was lowered in a dependent manner (FIGS. 3A and B) and the calculated EC₅₀Table of values No. 1 The PYY (22-36) (SEQ.ID. NO.10) analog is generally an inhibitor of binding. The ability as an antisecretory enhancer is lower than before. The order of analog abilities is two notable Exceptions to be taken are: N-α-myristoyl-PYY (22-36) (SEQ. ID. NO. 18) and N-α-na Phthaleneacetyl-PYY (22-36) (SEQ.ID. NO.19) It was like. Tyr by N-α-acetylation and Phe²⁷Of the PYY (22-36) This analog, N-α-Ac- [Phe²⁷PYY (22-36) (SEQ.ID.NO.3) It was only nine times less potent than the intact hormone. Furthermore, during the maximum inhibition reaction There were no significant differences, these were PYY (440 nM, n = 6) (SEQ. ID. NO. 1) and N -α-Ac- [Phe²⁷] About PYY (22-36) (1.4 μM, n = 7) (SEQ. ID. NO. 3) -12.6 ± 2.4 and -12.0 ± 1.3 μA / 0.6cm^TwoSo Was. Table 1: Comparison of binding and antisecretory capacity of PYY, PYY fragments and their analogs a: Isocratic, 27% CH containing 0.1% TFA_ThreeCN; b: average of three individual experiments; c: isocratic, 32% CH containing 0.1 TFA_ThreeCN; d: According to reference 10 n. d .: Not measured   N-α-myristoyl-PYY (22-36) (SEQ.ID. NO18) and N-α-naphthalene acetyl Le-PYY (22-36) (SEQ.ID. NO.19) analog is in contrast to its altered binding ability. Show a slight antisecretory response with a threshold concentration of about 20 nM, 2 and 3 respectively. EC greater than 0 μM₅₀The value was shown. Then, a cumulative concentration of 7.4 μM N-α- Ristoyl-PYY (22-36) (SEQ. ID. NO. 18) was -5.2 ± 0.6 μA / 0.6 cm^Two( The baseline SCC was lowered to n = 7). Continued addition of PYY (100 nM) , -10.2 ± 0.7 μA / 0.6 cm^Two(N = 7) to further reduce the SCC Is significantly different from the control response to PYY (22-36) (SEQ.ID. NO.10)? Was. It can antagonize the PYY response, and three tissues are converted to this analog (1 μM) to construct a PYY concentration-response curve and compare it to the control. This Fragment of 0.4 ± 0.3 μA / 0.6 cm^TwoReduce the baseline current until PYY EC₅₀Values (4.4 ± 1.2 nM, n = 3) are for untreated controls (2.6 ± 1.1 nM, n = 3).   These results indicate that the active portion of PYY (SEQ. ID. NO. 1), PYY (22-36) (SEQ. ID. Modification substantially increases both the binding and antisecretory capacity of this fragment. It can indicate that addition can be caused. The key analog of this series Showed the following sequence of abilities: PYY (SEQ.ID.NO.1)> N-α-Ac- [Phe²⁷] PYY (22 -36) (SEQ.ID.NO.3)> N-α-Ac-PYY (22-36) (SEQ.ID.NO.14)> PYY (22-36) (SEQ ID . NO.10). In addition, our research shows that Ser^{twenty three}And Thr³²Hydroxyl group and His²⁶of The imidazole group is important for its interaction with intestinal PYY-preferred receptors. Indicated. There is generally a good correlation between analog binding and antisecretory capacity. But there were some notable exceptions.   N-α-myristoyl-PYY (22-36) (SEQ ID No. 18) and N-α-naphthalene acetyl Le-PYY (22-36) (SEQ.ID. NO.19) analog has moderate capacity¹²⁵Inhibits I-PYY binding However, it showed a weak antisecretory response. This observation indicates that these analogs are antagonists (A Entagonist). However, these analogs Pre-treatment of the jejunal membrane does not significantly alter the antisecretory response to PYY The reason for the contradiction remains unclear at this time.   Table 2 and FIG. 4 show additional PYY (22-36) (SEQ.ID. NO.10) and PYY (25-36) NALOG IC₅₀Indicates the value. Based on the results shown in FIG. The following analogs have demonstrated the ability in the following order: N-α-Ac- [Tic²⁷] PYY (22-36) (SEQ.ID. NO.25) <N-α-Ac- [Bip²⁷] PYY (22-36) (SEQ. ID. NO.22) <N-α-Ac- [Nal²⁷] PYY (22-36) (SEQ.ID. NO.23) <N-α-AC- [Bth²⁷] PYY (22-36) (SEQ. ID. NO. 21) <N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ.ID.NO.3) <N-α-Ac -[Phe²⁷] PYY (25-36) (SEQ.ID. NO.26) <N-α-Ac- [Trp²⁷] PYY (22-36) (SEQ.ID.NO. 5) <N-α-Ac- [Thi²⁷] PYY (22-36) (SEQ.ID.NO.6) <N-α-Ac-PYY (22-36) (SEQ.ID. NO.14) <PYY (SEQ. ID. NO. 1). Table 2: Comparison of receptor binding data for PYY and PYY analogs   To date, the NPY / PYY receptors characterized are subtypes of Y-1, Y-2 and Y-3. (Balsubramaniam et al., J. Biol. Chem. 265: 14724, 199). 0; Michel, Trends Pharmacol. Sci. 12: 389, 1991). Y-1 and Y-2 receptors Both show a preference for PYY over NPY, with the more important C-termini of NPY and PYY Fragments are only valid for the Y-2 subtype. On the other hand, Y-3 Putter shows a greater affinity for NPY than for PYY. Anti-secretory anti-jejunal mucosa in rats PYY (SEQ.ID.NO.1)> NPY (SEQ.ID.NO.24)> PYY (13-36) (SEQ.ID.NO.32)> Since NPY (13-36) (SEQ. ID. The sceptors are Y-2 like and Y-1 selective agonist [Pro³⁴] Completely insensitive to NPY (Cox et al., Peptides, supra). The results further indicate that N-α-Ac-PYY (22-36) (SEQ. ID. NO. .14) and N-α-Ac- [Phe²⁷] PYY (22-36) (SEQ.ID.NO.3) is PYY (22-36) (SEQ.ID.NO. .10) and that they are more capable than the corresponding C-terminal fragments of NPY of various lengths. (Cox et al., Br. J. Pharmacol. Supra). PYY (SEQ.ID. NO.1) and its NPY (SEQ.ID.NO.24) and its corresponding flags for the C-terminal fragment The higher affinity compared to the Laburthe, supra; Voisin et al, Ann. N. Y. Acad. Sci. joukei Viosin et al., Am. J. Physiol.).   In addition, the analogs listed in Table 3 were synthesized as described above and tested for binding activity. Have been tested. The results shown in Table 3 indicate that N-α-Ac- [Tyr^{twenty two}, Phe²⁷] PYY (22-36) (SE Q.ID. NO. 7) is similar to PYY (SEQ. ID. NO. 1) in its competitive binding. The introduction of aromatic amino acids such as Tyr at position 22 is an effective PYY analog. Which indicates that. use   The practice of the method of the invention will result in an effective amount of an analog of the invention, such as N-α-Ac- [Phe²⁷] P YY (22-36) (SEQ.ID.NO.3), N-α-Ac- [Tyr²⁷] PYY (22-36) (SEQ.ID. NO.24), N-α- AC- [Phe²⁷] PYY (25-36) (SEQ.ID.NO.3), N-α-Ac- [Thi²⁷] PYY (22-36) (SEQ.ID.NO .6) or any one or combination of its derivatives, alone or in accordance with the invention In combination with one or more other compounds of the type known and ordinary in the art. Administration is via any of the acceptable methods. These compounds or compositions are: Thus, oral (eg, oral vestibular), sublingual, parenteral (eg, intramuscular, intravenous) Intra- or subcutaneous), rectally (eg, suppository or cleanser), transdermal (eg, skin Tropolation) or inhalation (aerosol) It can also be in the form of solid, liquid or gaseous doses, including tablets and tablets. And suspensions. Administration should be in a single unit dose form and in a continuous treatment And, where appropriate, in a single administration treatment.   Therefore, the method of the present invention may be particularly susceptible to or particularly likely to relieve symptoms. Implemented when imminent. Alternatively, the method of the present invention provides continuous or prophylactic treatment. Effectively implemented as   Useful pharmacological carriers for the preparation of the compositions of the present invention are solid, liquid or It can be a gas; the composition can be a tablet, pill, capsule, suppository, powder, Enteric coated or other protected formulations (e.g., ionic Bound to exchange resin or packaged in fatty protein vesicles ), Sustained-release preparations, solutions, suspensions, elixirs, aerosols, etc. Can be Carriers are of petroleum, animal, plant or synthetic origin, e.g. You can choose from various oils including peanut oil, soybean oil, mineral oil, sesame oil, etc. You. Water, saline, aqueous dextrose, and glycols should be And especially for injectable solutions (when isotonic with blood). New For example, a formulation for intravenous administration is prepared by dissolving a solid active ingredient in water and preparing an aqueous solution. Containing a sterile aqueous solution of the active ingredient prepared by sterilizing the aqueous solution . Suitable pharmacological excipients include starch, cellulose, talc, glucose, Toast, talc, gelatin, malt, rice, flour, chalk, silica, stainless steel A Magnesium phosphate, sodium stearate, glycerol monostearate , Sodium chloride, dried skim milk, glycerol, propylene glycol, Contains water, ethanol, etc. The composition may contain preservatives, stabilizers, wetting or emulsifying agents, It can also contain conventional pharmacological additives such as salts and buffers to control pressure. Wear. Suitable pharmacological carriers and their formulations are described in E.W. Remingt by Martin It is described in on's Pharmaceutical Sciences. In any case, like this The composition comprises an effective amount of the active compound, and a suitable carrier, and is suitable for the recipient. It is prepared in an appropriate dosage form for administration.   The dose of the compound of the present invention for treating the above diseases depends on the method of administration, Will vary depending on the age and weight of the patient and the condition of the recipient. It will be determined by the operating physician or veterinarian. By your doctor or veterinarian The amount of active compound determined is referred to herein as a "therapeutically effective amount." Typical administration is oral or parenteral. Daily administration for oral administration The dose is typically 0.1 to 100 mg / kg (body weight), The total daily dose is typically 0.001 to 50 mg / kg (body weight).   Gastrointestinal disorders, especially infections (eg viruses and bacteria), inflammatory diarrhea or surgery Because of the effectiveness of preventing or treating inflammation caused by It is important to be relatively non-toxic, non-antigenic and non-irritating at the It is important.   The examples and embodiments described herein are set forth for illustrative purposes only. Various changes or changes can be expected by those skilled in the art, and They are intended to be included in the spirit and scope of the present invention and in the appended claims. is there.

[Procedure amendment] [Submission Date] May 21, 1999 (May 21, 1999) [Correction contents]                             The scope of the claims 1. A compound having the formula:   Wherein x is Cys or deleted;   Y is a 0-4 amino acid chain, including the C-terminus, one of which is R_ThreeAnd R_Four Bound to;   R₁Is H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   R_TwoIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   A^{twenty two}Is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or is deleted;   A^{twenty three}Is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N-Me-Ala or Re;   A^{twenty four}Is Leu, Gly, Ile, Val, Trp, Nle, Nva, Aib, Anb, N-Me-Leu or Deleted;   A^{twenty five}Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or aryl) or Orn Or deleted;   A²⁶Is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrazolylalanine, N-M e-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H , Branched or linear C₁-C_TenAn alkyl or aryl group), Orn or Deleted;   A²⁷Is an aromatic amino acid other than Tyr;   A²⁸Is Leu, Val, TrP, Nle, NVa, Aib, Anb or N-Me-Leu;   A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;   A³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A³¹Is Val, Leu, Ile, Trp, Nle, Nva, Aib, Anb or N-Me-Val;   A³²Is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;   R_ThreeIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl; and   R_FourIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl, or pharmacologically accepted Are its salts. 2. A²⁷Is Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Dip 2. The compound according to item 1, wherein 3. Y is A³³-A³⁴-A³⁵-A³⁶The compound according to claim 1, which is: Where:   A³³Is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (wherein , R is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group Or Orn;   A³⁴Is Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb;   A³⁵Is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (wherein , R is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group Or Orn; and   A³⁶Is an aromatic amino acid, Cys, or a pharmacologically acceptable salt thereof. is there. 4. The compound has the formula N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.3) or its pharmacologically acceptable 4. The compound according to claim 3, which is a salt. 5. The compound has the formula H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gl n-Arg-Tyr-NH_Two(SEQ.ID.No.4) or pharmacologically acceptable salts thereof A compound according to claim 3. 6. The compound has the formula N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.5) or its pharmacologically acceptable 4. The compound according to claim 3, which is a salt. 7. The compound has the formula N-α-Ac-Ala-Ser-Leu-Arg-His-Thi-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.6) or its pharmacologically acceptable 4. The compound according to claim 3, which is a salt. 8. N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Ty r-NH_Two(SEQ.ID.No.7) or a pharmacologically acceptable salt thereof. 4. The compound according to item 3, wherein 9. A compound having the formula:   Where the N-terminal amino acid is R₁And R_TwoBinds to   Y is a 0-4 amino acid chain, including the C-terminus, one of which is R_ThreeAnd R_Four Bound to;   R₁Is H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   R_TwoIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   A^{twenty five}Is Arg, Lys, homo-Alg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or aryl) or Orn Or deleted;   A²⁶Is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrazolylalanine, N-M e-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H , Branched or linear C₁-C_TenAn alkyl or aryl group), or Orn Yes;   A²⁷Is an aromatic amino acid;   A²⁸Is Leu, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;   A³⁰Is Leu, Ile, Val, TrP, Nle, Nva, Aib, Anb or N-Me-Leu;   A³¹Is Val, Leu, Trp, Nva, Aib, Anb or N-Me-Val;   A³²Is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;   R_ThreeIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl; and   R_FourIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl or pharmacologically acceptable The salts that are used. 10. A²⁷Is Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Dip. 10. The compound according to claim 9, wherein 11. Y is A³³-A³⁴-A³⁵-A³⁶A compound according to claim 9, which is: Where:   A³³Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group) , Cys or Orn;   A³⁴Is Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb;   A³⁵Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group) , Cys or Orn; and   A³⁶Is an aromatic amino acid, Cys, or a pharmacologically acceptable salt thereof. is there. 12. The compound has the formula N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Ar g-Tyr-NH_Two12. The compound according to claim 11, having (SEQ. ID. No. 26). 13. Therapeutic composition capable of reducing excess intestinal water and electrolyte secretion Wherein the composition is a composition for treating a compound according to claim 1 or 9. A composition comprising a therapeutically effective amount and a pharmacologically acceptable carrier substance.14 . Regulates cell growth in mammalsTherapeutic composition capable ofSo And saidCompositionIs a therapeutically effective amount of claim 1 or 9 Compound and a pharmacologically acceptable carrier substanceIncluding, composition.Fifteen . Promotes nutrient transport in mammalsTherapeutic composition capable ofIn The aboveCompositionIs described in claim 1 or claim 9 in a therapeutically effective amount. Listed compounds and pharmacologically acceptable carrier substancesA composition comprising.16 . Regulates lipolysis in mammalsTherapeutic composition capable ofSo And saidCompositionIs a therapeutically effective amount of claim 1 or 9 And a pharmacologically acceptable carrier substanceA composition comprising.17 . Regulate blood flow in mammalsTherapeutic composition capable ofAnd SaidCompositionIs a therapeutically effective amount of a compound according to claim 1 or claim 9. Compound and a pharmacologically acceptable carrier substanceA composition comprising.18 . Claims Two peptides according to claim 1 or claim 9, or claims Including one peptide according to claim 1 and one peptide according to claim 9 A dimer compound, wherein the dimer has an amide bond between the two peptides. Or a dimer compound formed by disulfide bond.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/00 A61P 43/00 43/00 C07K 7/06 C07K 7/06 7/08 ZNA 7/08 ZNA A61K 37/02 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF , BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, E , ES, FI, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN

Claims (1)

[Claims] 1. A compound having the formula:   Wherein x is Cys or deleted;   Y is a 0-4 amino acid chain, including the C-terminus, one of which is R_ThreeAnd R_Four Bound to;   R₁Is H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   R_TwoIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   A^{twenty two}Is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala or is deleted;   A^{twenty three}Is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N-Me-Ala or Re;   A^{twenty four}Is Leu, Gly, Ile, Val, Trp, Nle, Nva, Aib, Anb, N-Me-Leu or Deleted;   A^{twenty five}Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or aryl) or Orn Or deleted;   A²⁶Is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrazolylalanine, N-M e-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H , Branched or linear C₁-C_TenAn alkyl or aryl group), Orn or Deleted;   A²⁷Is an aromatic amino acid other than Tyr;   A²⁸Is Leu, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;   A³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A³¹Is Val, Leu, Ile, Trp, Nle, Nva, Aib, Anb or N-Me-Val;   A³²Is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;   R_ThreeIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl; and   R_FourIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl, or pharmacologically accepted Are its salts. 2. A²⁷Is Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Dip 2. The compound according to item 1, wherein 3. Y is A³³-A³⁴-A³⁵-A³⁶The compound according to claim 1, which is: Where:   A³³Is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (wherein , R is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group Or Orn;   A³⁴Is Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb;   A³⁵Is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (wherein , R is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group Or Orn; and   A³⁶Is an aromatic amino acid, Cys, or a pharmacologically acceptable salt thereof. is there. 4. The compound has the formula N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH_Two(SEQ. ID No. 3) or its pharmacologically acceptable 4. The compound according to claim 3, which is a salt. 5. The compound has the formula H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gl n-Arg-Tyr-NH_Two(SEQ.ID.No.4) or pharmacologically acceptable salts thereof A compound according to claim 3. 6. The compound has the formula N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.5) or its pharmacologically acceptable 4. The compound according to claim 3, which is a salt. 7. The compound has the formula N-α-Ac-Ala-Ser-Leu-Arg-His-Thi-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH_Two(SEQ.ID.No.6) or its pharmacologically acceptable 4. The compound according to claim 3, which is a salt. 8. N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Ty r-NH_Two(SEQ.ID.No.7) or a pharmacologically acceptable salt thereof. 4. The compound according to item 3, wherein 9. A compound having the formula:   Where the N-terminal amino acid is R₁And R_TwoBinds to   Y is a 0-4 amino acid chain, including the C-terminus, one of which is R_ThreeAnd R_Four Bound to;   R₁Is H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   R_TwoIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl;   A^{twenty five}Is Arg, Lys, homo-Alg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or aryl) or Orn Or deleted;   A²⁶Is Ala, His, Thr, 3-Me-His, 1-Me-His, β-pyrazolylalanine, N-M e-His, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R is H , Branched or linear C₁-C_TenAn alkyl or aryl group), or Orn Yes;   A²⁷Is an aromatic amino acid;   A²⁸Is Leu, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A²⁹Is Asn, Ala, Gln, Gly, Trp or N-Me-Asn;   A³⁰Is Leu, Ile, Val, Trp, Nle, Nva, Aib, Anb or N-Me-Leu;   A³¹Is Val, Leu, Trp, Nva, Aib, Anb or N-Me-Val;   A³²Is Thr, Ser, N-Me-Ser, N-Me-Thr or D-Trp;   R_ThreeIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl; and   R_FourIs H, C₁-C₁₂Alkyl, C₆-C₁₈Aryl, C₁-C₁₂Acyl, C₇ -C₁₈Aralkyl or C₇-C₁₈Alkaryl or pharmacologically acceptable The salts that are used. 10. A²⁷Is Phe, Nal, Bip, Pcp, Tic, Trp, Bth, Thi or Dip. 10. The compound according to claim 9, wherein 11. Y is A³³-A³⁴-A³⁵-A³⁶A compound according to claim 9, which is: Where:   A³³Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group) , Cys or Orn;   A³⁴Is Cys, Gln, Asn, Ala, Gly, N-Me-Gln, Aib or Anb:   A³⁵Is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-ε-NH-R (where R Is H, branched or linear C₁-C_TenAlkyl or C₆-C₁₈An aryl group) , Cys or Orn; and   A³⁶Is an aromatic amino acid, Cys, or a pharmacologically acceptable salt thereof. is there. 12. The compound has the formula N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Ar g-Tyr-NH_Two12. The compound according to claim 11, having (SEQ. ID. No. 26). 13. Therapeutic composition capable of reducing excess intestinal water and electrolyte secretion Wherein the composition is a composition for treating a compound according to claim 1 or 9. A composition comprising a therapeutically effective amount and a pharmacologically acceptable carrier substance. 14． In a way to reduce excess intestinal fluid and electrolyte secretion in mammals The method as claimed in claim 1 or claim 9, wherein the method comprises a therapeutically effective amount. The compound described above and a pharmacologically acceptable carrier substance are injected into the mammal. Providing the method. 15. A method of regulating cell proliferation in a mammal, said method comprising treating A pharmacologically effective amount of the compound of claim 1 or 9; Administering to the mammal an acceptable carrier material. Law. 16. A method of promoting nutrient transport in a mammal, said method comprising treating A pharmacologically effective amount of the compound of claim 1 or 9; And administering to the mammal a carrier substance acceptable to the mammal. Method. 17． A method of regulating lipolysis in a mammal, said method comprising treating A pharmacologically effective amount of the compound of claim 1 or 9; Administering to the mammal an acceptable carrier material. Law. 18. A method of regulating blood flow in a mammal, said method comprising: A pharmacologically effective amount of a compound according to claim 1 or 9 in an amount effective for the administration. Administering to the mammal an entrained carrier material. 19. Claims Two peptides according to claim 1 or claim 9, or claims Including one peptide according to claim 1 and one peptide according to claim 9 A dimer compound, wherein the dimer has an amide bond between the two peptides. Or a dimer compound formed by disulfide bond.