Title of Invention	GLP-2 DERIVATIVES
Abstract	ABSTRACT 1939/MAS/97 GLP-2 DERIVATIVES Derivatives of hGLP-2 and analogues thereof and fragments thereof and analogues of such fragments having a lipophilic substituent have interesting pharmacological properties, in particular they have a more protracted profile of action than the parent peptides.

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FIELD OF THE INVENTION The present invention relates to novel derivatives of human glucagon-like peptide-2 (hGLP-2) and analogues thereof and fragments thereof and analogues of such fragments which have a protracted profile of action and to methods of making and using them. BACKGROUND OF THE INVENTION Peptides are widely used in medical practice, and since they can be produced by recombinant DNA technology it can be expected that their importance will increase also in the years to come. When native peptides or analogues thereof are used in therapy it is generally found that they have a high clearance. A high clearance of a therapeutic agent is inconvenient in cases where it is desired to maintain a high blood level thereof over a prolonged period of time since repeated administrations will then be necessary. Examples of peptides which have a high clearance are: ACTH, corticotropin-releasing factor, angiotensin, calcitonin, insulin, glucagon, glucagon-like peptide-1, glucagon-like peptide-2, insulin-like growth factor-1, insulin-like growth factor-2, gastric inhibitory peptide, growth hormone-releasing factor, pituitary adenylate cyclase activating peptide, secretin, enterogastrin, somatostatin, somatotropin, somatomedin, parathyroid hormone, thrombopoietin, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, oxytocin, opiods and analogues thereof, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminase, adenosine deaminase and ribonuclease. In some cases it is possible to influence the release profile of peptides by applying suitable pharmaceutical compositions, but this approach has various shortcomings and is not generally applicable. The amino acid sequence of GLP-2 and other preproglucagon fragments is given i.a. by Schmidt ef al. (Diabetologia 28 704-707 (1985). Little is known about the physical chemical properties of GLP-2 but GLP-2 is excpected, like GLP-1, to be a highly flexible and unstable molecule. GLP-2 and fragments thereof and analogues of GLP-2 and fragments thereof are potentially useful i.a. in regulation of appetite and in the treatment of small bowel syndrome. However, the high clearance limits the usefulness of these compounds, and thus there still is a need for improvements in this field. SUMMARY OF THE INVENTION Preproglucagon, from which GLP-2 originates, is synthesized i.a. in the L-cells in the distal illeum, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1 and GLP-2 occurs mainly in the L-cells. GLP-2 is a 34 amino acid residue peptide. A simple system is used to describe fragments, analogues and derivatives of GLP-2. Thus, for example, Lys20GLP-2(1-33) designates a fragment of GLP-2 formally derived from GLP-2 by deleting the amino acid residues No. 34 and substituting the naturally occurring amino acid residue in position 20 (Arg) by Lys. Similarly, Arg^Lys^NMetradecanoyOGLP-ICf-SS) designates a derivative of a GLP-2 analogue formally derived from GLP-2 by C-terminal addition of a Lys residue, exchange of the naturally occurring amino acid residue in position 30 (Lys) with an Arg residue and tetradecanoylation of the s-amino group of the Lys residue in position 35. In its broadest aspect, the present invention relates to derivatives of GLP-2 and analogues thereof. The derivatives according to the invention have interesting pharmacological properties, in particular they have a more protracted profile of action than the parent peptides. In the present text, unless otherwise specified, "GLP-2" designates human GLP-2. The designation "an analogue" is used to designate a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide. The term "derivative" is used in the present text to designate a peptide in which one or more of the amino acid residues have been chemically modified, e.g. by alkylation, acylation, ester formation or amide formation. The term "a GLP derivative" is used in the present text to designate a derivative of GLP-2 or an analogue thereof. In the present text, the parent peptide from which such a derivative is formally derived is in some places referred to as the "GLP moiety" of the derivative. In a preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent attached to any one amino acid residue. In another preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent attached to any one amino acid residue with the proviso that only if the substituent has an co-carboxylic acid group or is an alkyl group can it be attached to the N-terminal or C-terminal amino acid residue of the parent peptide. In another preferred embodiment, the present invention relates to a GLP-2 derivative wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferred from 8 to 25 carbon atoms. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an amino group of the amino acid residue. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to an amino acid residue in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid residue. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an unbranched alkane a, In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or a dipeptide such as Gly-Lys. In the present text, the expression "a dipeptide such as Gly-Lys" is used to designate a dipeptide wherein the C-terminal amino acid residue is Lys, His or Trp, preferably Lys, and wherein the N-terminal amino acid residue is selected from the group comprising Ala, Arg, Asp, Asn, Gly, Glu, Gin, He, Leu.Val, Phe and Pro. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of a Lys residue or a dipeptide containing a Lys residue, and the other amino group of the Lys residue or a dipeptide containing a Lys residue forms an amide bond with a carboxyl group of the lipophilic substituent. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein an amino group of the parent peptide forms an amide bond with a carboxylic group of the amino acid or dipeptide spacer, and an amino group of the amino acid or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of the amino acid or dipeptide spacer, and the carboxyl group of the amino acid or dipeptide spacer forms an amide bond with an amino group of the lipophilic substituent. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys, and wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of Asp or Glu, or a dipeptide containing an Asp or Glu residue, and a carboxyl group of the spacer forms an amide bond with an amino group of the lipophilic substituent. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which comprises a partially or completely hydrogenated cyclopentano-phenathrene skeleton. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a straight-chain or branched alkyl group. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is the acyl group of a straight-chain or branched fatty acid. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is an acyl group selected from the group comprising CH3(CH2)„CO-, wherein n is 4 to 38, preferably CH3(CH2)8CO-, CH3(CH2)8CO-, CH3(CH2)10CO-, CH3(CH2)12CO-, CH3(CH2)14CO-, CH3(CH2)1BCO-, CH3(CH2)18CO-, CH3(CH2)2oCO- and CH^CH^CO-. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is an acyl group of a straight-chain or branched alkane a,ro-dicarboxylic acid. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is an acyl group selected from the group comprising HOOC(CH2)mCO-, wherein m is 4 to 38, preferably HOOC(CH2)14CO-, HOOC(CH2)16CO-, HOOC(CH2)18CO-, HOOC(CH2)2oCO- and HOOC(CH2)22CO-. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula CH3(CH2)p((CH2)qCOOH)CHNH-CO(CH2)2CO-, wherein p and q are integers and p+q is an integer of from 8 to 40, preferably from 12 to 35. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula CH3(CH2)rCO-NHCH(COOH)(CH2)2CO-f wherein r is an integer of from 10 to 24. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula CH3(CH2)sCO-NHCH((CH2)2COOH)CO-, wherein s is an integer of from 8 to 24. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula COOH(CH2),CO- wherein t is an integer of from 8 to 24. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NH-CO(CH2)uCH3, wherein u is an integer of from 8 to 18. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NH-COCH((CH2)2COOH)NH-CO(CH2)wCH3, wherein w is an integer of from 10 to 16. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NH-CO(CH2)2CH(COOH)NH-CO(CH2)xCH3, wherein x is an integer of from 10 to 16. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NH-CO(CH2)2CH(COOH)NHCO(CH2)yCH3, wherein y is zero or an integer of from 1 to 22. In a further preferred embodiment, the present invention relates to a GLP-2 derivative which has one lipophilic substituent. In a further preferred embodiment, the present invention relates to a GLP-2 derivative which has two lipophilic substituents. In a further preferred embodiment, the present invention relates to a GLP-2 derivative in which the C-terminal amino acid residue is present in the form of the amide. In a further preferred embodiment, the present invention relates to a GLP-2 derivative having a lipophilic substituent which can be negatively charged. In a further preferred embodiment, the present invention relates to a GLP-2 derivative the parent peptide of which is selected from the group comprising GLP-2(1-35) or an analogue thereof. In a further preferred embodiment, the present invention relates to a GLP-2 derivative derived from a GLP-2 fragment selected from the group comprising GLP-2(1-30); GLP-2(1-31); GLP-2(1-32); GLP-2(1-33); GLP-2(1-34) and GLP-2(1-35). In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein the designation analogue comprises derivatives wherein a total of up to ten amino acid residues have been exchanged with any a-amino acid residue. In a further preferred embodiment, the present invention relates to a derivative of a GLP-2 analogue wherein the designation analogue implies that the parent peptide is human GLP-2 wherein a total of up to six, more preferred up to three, amino acid residues have been added, deleted or substituted with other amino acid residues which can be coded for by the genetic code. In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein the parent peptide is selected from the group comprising Lys20GLP-2(1-33) and Lys20Arg30GLP-2(1-33). In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein the parent peptide is Arg30Lys34GLP-2(1-34). In a further preferred embodiment, the present invention relates to a GLP-2 derivative wherein the parent peptide is selected from the group comprising Arg^Lys^GLP^O-SS); Arg3035Lys20GLP-2(1-35) and Arg^GLP^I-SS). In a further preferred embodiment, the present invention relates to a GLP-2 derivative which is selected from the group comprising Lys20(NE-tetradecanoyl)GLP-2(1-33); Lys20'30-bis(NMetradecanoyl)GLP-2(1-33); Lys20(N8-tetradecanoyl)Arg3QGLP-2(1-33); Arg30Lys35(NMetradecanoyl)GLP-2(1-35); Arg3o,3SLys2o(NE.tetradecanoy,)GLp.2(1.35); Arg35Lys30(NMetradecanoyl)GLP-2(1-35); Arg30Lys34(NE-tetradecanoyl)GLP-2(1-34); Lys20(Ne-(co-carboxynonadecanoyl))GLP-2(1-33); Lys^-bisfNMco-carboxynonadecanoyOJGLP^O-SS); Lys2O(Ne-((»-carboxynonadecanoyl))Arg30GLP-2(1-33); Arg30Lys35(NE-(a)-carboxynonadecanoyl))GLP-2(1-35); Arg30'35Lys20(Nc-(co-carboxynonadecanoyl))GLP-2(1-35); Arg35Lys30(NE-(co-carboxynonadecanoyl))GLP-2(1 -35); and Arg30Lys34(Ne-(co-carboxynonadecanoyl))GLP-2(1-34). In a further preferred embodiment, the present invention relates to a pharmaceutical composition comprising a GLP-2 derivative and a pharmaceutical^ acceptable vehicle or carrier. In a further preferred embodiment, the present invention relates to the use of a GLP-2 derivative according to the invention for the preparation of a medicament which has a more protracted action than the parent peptide. In a further preferred embodiment, the present invention relates to the use of a GLP-2 derivative according to the invention for the preparation of a medicament with protracted effect for the treatment of obesity. In a further preferred embodiment, the present invention relates to the use of a GLP-2 derivative according to the invention for the preparation of a medicament with protracted effect for the treatment of small bowel syndrome. DETAILED DESCRIPTION OF THE INVENTION To obtain a satisfactory protracted profile of action of the GLP-2 derivative, the lipophilic substituent attached to the GLP-2 moiety preferably comprises 4-40 carbon atoms, in particular 8-25 carbon atoms. The lipophilic substituent may be attached to an amino group of the GLP-2 moiety by means of a carboxyl group of the lipophilic substituent which forms an amide bond with an amino group of the amino acid to which it is attached. As an alternative, the lipophilic substituent may be attached to said amino acid in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid. As a further option, the lipophililic substituent may be linked to the GLP-2 moiety via an ester bond. Formally, the ester can be formed either by reaction between a carboxyl group of the GLP-2 moiety and a hydroxyl group of the substituent-to-be or by reaction between a hydroxyl group of the GLP-2 moiety and a carboxyl group of the substituent-to-be. As a further alternative, the lipophilic substituent can be an alkyl group which is introduced into a primary amino group of the GLP-2 moiety. In one preferred embodiment of the invention, the lipophilic substituent is attached to the GLP-2 moiety by means of a spacer in such a way that a carboxyl group of the spacer forms an amide bond with an amino group of the GLP-2 moiety. Examples of suitable spacers are succinic acid, Lys, Glu or Asp, or a dipeptide such as Gly-Lys. When the spacer is succinic acid, one carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the other carboxyl group thereof may form an amide bond with an amino group of the lipophilic substituent. When the spacer is Lys, Glu or Asp, the carboxyl group thereof may form an amide bond with an amino group of the amino acid residue, and the amino group thereof may form an amide bond with a carboxyl group of the lipophilic substituent. When Lys is used as the spacer, a further spacer may in some instances be inserted between the e-amino group of Lys and the lipophilic substituent. In one preferred embodiment, such a further spacer is succinic acid which forms an amide bond with the E-amino group of Lys and with an amino group present in the lipophilic substituent. In another preferred embodiment such a further spacer is Glu or Asp which forms an amide bond with the e-amino group of Lys and another amide bond with a carboxyl group present in the lipophilic substituent, that is, the lipophilic substituent is a NE-acylated lysine residue. In another preferred embodiment of the present invention, the lipophilic substituent has a group which can be negatively charged. One preferred group which can be negatively charged is a carboxylic acid group. The parent peptide can be produced by a method which comprises culturing a host cell containing a DNA sequence encoding the peptide and capable of expressing the peptide in a suitable nutrient medium under conditions permitting the expression of the peptide, after which the resulting peptide is recovered from the culture. The medium used to culture the cells may be any conventional medium suitable for growing the host cells, such as minimal or complex media containing appropriate supplements. Suit¬able media are available from commercial suppliers or may be prepared according to published recipes (e.g. in catalogues of the American Type Culture Collection). The peptide produced by the cells may then be recovered from the culture medium by conventional procedures including separating the host cells from the medium by centrifugation or filtration, precipitating the proteinaceous components of the supernatant or filtrate by means of a salt, e.g. ammonium sulphate, purification by a variety of chromatographic procedures, e.g. ion exchange chromatography, gelfiltration chromatography, affinity chromatography, or the like, dependent on the type of peptide in question. The DNA sequence encoding the parent peptide may suitably be of genomic or cDNA origin, for instance obtained by preparing a genomic or cDNA library and screening for DNA sequences coding for all or part of the peptide by hybridisation using synthetic oligonucleotide probes in accordance with standard techniques (see, for example, Sambrook, J, Fritsch, EF and Maniatis, T, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York, 1989). The DNA sequence encoding the peptide may also be prepared synthetically by established standard methods, e.g. the phosphoamidite method described by Beaucage and Caruthers, Tetrahedron Letters 22 (1981), 1859 -1869, or the method described by Matthes et a/., EMBO Journal 3 (1984), 801 - 805. The DNA sequence may also be prepared by polymerase chain reaction using specific primers, for instance as described in US 4,683,202 or Saiki et a/., Science 239 (1988), 487 -491. The DNA sequence may be inserted into any vector which may conveniently be subjected to recombinant DNA procedures, and the choice of vector will often depend on the host cell into which it is to be introduced. Thus, the vector may be an autonomously replicating vector, i.e. a vector which exists as an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g. a plasmid. Alternatively, the vector may be one which, when introduced into a host cell, is integrated into the host cell genome and replicated together with the chromosome(s) into which it has been integrated. The vector is preferably an expression vector in which the DNA sequence encoding the peptide is operably linked to additional segments required for transcription of the DNA, such as a promoter. The promoter may be any DNA sequence which shows transcriptional activity in the host cell of choice and may be derived from genes encoding proteins either homologous or heterologous to the host cell. Examples of suitable promoters for directing the transcription of the DNA encoding the peptide of the invention in a variety of host cells are well known in the art, cf. for instance Sambrook et al., supra. The DNA sequence encoding the peptide may also, if necessary, be operably connected to a suitable terminator, polyadenylation signals, transcriptional enhancer sequences, and translational enhancer sequences. The recombinant vector of the invention may further comprise a DNA sequence enabling the vector to replicate in the host cell in question. The vector may also comprise a selectable marker, e.g. a gene the product of which complements a defect in the host cell or one which confers resistance to a drug, e.g. ampicillin, kanamycin, tetracyclic chloramphenicol, neomycin, hygromycin or methotrexate. To direct a parent peptide of the present invention into the secretory pathway of the host cells, a secretory signal sequence (also known as a leader sequence, prepro sequence or pre sequence) may be provided in the recombinant vector. The secretory signal sequence is joined to the DNA sequence encoding the peptide in the correct reading frame. Secretory signal sequences are commonly positioned 5' to the DNA sequence encoding the peptide. The secretory signal sequence may be that normally associated with the peptide or may be from a gene encoding another secreted protein. The procedures used to ligate the DNA sequences coding for the present peptide, the promoter and optionally the terminator and/or secretory signal sequence, respectively, and to insert them into suitable vectors containing the information necessary for replication, are well known to persons skilled in the art (cf., for instance, Sambrook et al.., supra). The host cell into which the DNA sequence or the recombinant vector is introduced may be any cell which is capable of producing the present peptide and includes bacteria, yeast, fungi and higher eukaryotic cells. Examples of suitable host cells well known and used in the art are, without limitation, E. coli, Saccharomyces cerevisiae, or mammalian BHK or CHO cell lines. The GLP-2 derivatives of the invention can be prepared by introducing the lipophilic substituent into the parent GLP-2 or GLP-2 analogue using methods known per se, see for example WO 95/07931, the contents of which is hereby incorporated in its entirety by reference. Ne-acylation of a Lys residue can be carried out by using an activated amide of the acyl group to be introduced as the acylating agent, e.g. the amide with benzotriazole. The acylation is carried out in a polar solvent in the presence of a base. Pharmaceutical compositions Pharmaceutical compositions containing a GLP-2 derivative according to the present invention may be administered parenterally to patients in need of such a treatment. Parenteral administration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump. A further option is a composition which may be a powder or a liquid for the administration of the GLP-2 derivative in the form of a nasal or pulmonal spray. As a still further option, the GLP-2 derivatives of the invention can also be administered transdermal^, e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally. Pharmaceutical compositions containing a GLP-2 derivative of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences. 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995. Thus, the injectable compositions of the GLP-2 derivative of the invention can be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the ingredients as appropriate to give the desired end product. Thus, according to one procedure, the GLP-2 derivative is dissolved in an amount of water which is somewhat less than the final volume of the composition to be prepared. An isotonic agent, a preservative and a buffer is added as required and the pH value of the solution is adjusted - if necessary - using an acid, e.g. hydrochloric acid, or a base, e.g. aqueous sodium hydroxide as needed. Finally, the volume of the solution is adjusted with water to give the desired concentration of the ingredients. Examples of isotonic agents are sodium chloride, mannitol and glycerol. Examples of preservatives are phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol. Examples of suitable buffers are sodium acetate and sodium phosphate. Further to the above-mentioned components, solutions containing a GLP-2 derivative according to the present invention may also contain a surfactant in order to improve the solubility and/or the stability of the derivative. A composition for nasal administration of GLP-2 may, for example, be prepared as described in European Patent No. 272097 (to Novo Nordisk A/S) or in WO 93/18785. The GLP-2 derivatives of this invention can be used in the treatment of various diseases. The particular GLP-2 derivative to be used and the optimal dose level for any patient will depend on the disease to be treated and on a variety of factors including the efficacy of the specific peptide derivative employed, the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the case. It is recommended that the dosage of the GLP-2 derivative of this invention be determined for each individual patient by those skilled in the art in a similar way as for known parent peptides. The pharmacological properties of the compounds of the invention can be tested e.g. as described in our International Patent Application No. PCT/DK97/00086 the contents of which is hereby incorporated in its entirety by reference. The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and In the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. EXAMPLES The following acronyms for commercially available chemicals are used: NMP : N-Methyl-2-pyrrolidone. EDPA : N-Ethyl-N,N-diisopropylamine. TFA Trifluoroacetic acid. Myr-ONSu: Tetradecanoic acid 2,5-dioxopyrrolidin-1-yl ester. Abbreviations: PDMS: Plasma Desorption Mass Spectrometry HPLC: High Performance Liquid Chromatography amu: atomic mass units EXAMPLE 1 Synthesis of Lys30 (NMetradecanoyl) hGLP-2. A mixture of hGLP-2 (10.0 mg. 2.7 umol), EDPA (9.6 mg, 74.3 umol). NMP (210 ul) and water (100 ul) was gently shaken for 15 min. at room temperature. To the resulting mixture was added a solution of Myr-ONSu (21.5 mg, 6.6 umol) in NMP (32 u.l). The reaction mixture was gently shaken for 30 min. at room temperature, and an additional amount of a solution of Myr-ONSu (14.4 mg, 4.4 umol) in NMP (22 ul). The resulting mixture was gently shaken for 15 min. at room temperature. The reaction was quenched by the addition of a solution of glycine (4.5 mg, 4.5 umol) in 50% aqueous ethanol (451 ul). The reaction mixture was purified by column chromatography using a cyanopropyl column (Zorbax 300SB-CN) and a standard acetonitrile/TFA system. The column was heated to 65°C and the acetonitrile gradient was 0-100% in 60 minutes. The title compound ( 5.0 mg, 47 %) was isolated from the eluate. EXAMPLE 2 The following example provides evidence for the required property of compounds according to the invention, the protracted effect illustrated with the half-life in plasma from pigs, TVS. Metabolic stability of selected GLP-2 derivatives. The degradation of GLP-2 derivatives in vivo in pigs have been studied and TVS value determined for selected GLP-2 derivatives according to the present invention (TVS: Terminal plasma elimination half-life). All test substances were dissolved in 20 mM phosphate buffer pH 7.4. Female LYD crossbred pigs weighing 50-75 kg. were used. All test substances were dosed 0.5 nmol/kg. The dosing volume was approx. 1 ml per animal. Subcutaneous injections were given at the right side of the neck approximately 7 cm from the ear and 9 cm from the middle of the neck. Injections were given with a stopper on the needle, allowing 0.5 cm of the needle to be inserted. Blood samples were drawn from an ear vein catheter. The catheter was rinsed with heparin 50 IE/ml in physiological saline. During sampling the first ml blood drawn was discarded. Blood samples were kept on ice for no longer than 20 min. before centrifugation (4°C, 4000 rpm, 10 min). After centrifugation plasma was isolated and transferred to Micronic-tubes in duplo. The plasma samples were analysed by ELISA. We Claim: 1. A GLP-2 derivative comprising a lipophilic substituent attached to any one amino acid residue, wherein the parent peptide is selected from the group comprising GLP-2(l-30); GLP-2(l-31); GLP-2(l-32); GLP-2(l-33); GLP-2(l-34) and GLP-2(l-35) or an analogue thereof, wherein the designation analogue comprises derivatives wherein a total of up to ten amino acid residues have been exchanged with any a-amino acid residue, wherein the lipophilic substituent comprises from 8 to 25 carbon atoms and wherein said GLP-2 derivative has a more protracted action than the parent peptide. 2. The GLP-2 derivative according to claim 1 with the proviso that only if the substituent has an o-carboxylic acid group or is an alkyl group it can be attached to the N-terminal or C-terminal amino acid residue of the parent peptide. 3. The GLP-2 derivative according to any one of the preceding claims, wherein said lipophilic substituent is attached to said amino acid in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an amino group of the amino acid. 4. The GLP-2 derivative according to any one of the claims 1-2, wherein said lipophilic substituent is attached to said amino acid in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid. 5. The GLP-2 derivative according to any one of the preceding claims, wherein the lipophilic substituent is attached to the parent peptide by means of a spacer. 6. The GLP-2 derivative according to claim 5, wherein the spacer is an unbranched alkane a,co-dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent. 7. The GLP-2 derivative according to claim 5, wherein the spacer is an amino acid residue except Cys, or a dipeptide such as Gly-Lys. 8. The GLP-2 derivative according to claim 7, wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of Lys or a dipeptide containing a Lys residue, and the other amino group of the Lys or a dipeptide containing a Lys residue forms an amide bond with a carboxyl group of the lipophilic substituent. 9. The GLP-2 derivative according to claim 7, wherein an amino group of the parent peptide forms an amide bond with a carboxylic group of the amino acid or dipeptide spacer, and an amino group of the amino acid or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent. 10. The GLP-2 derivative according to claim 7, wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of the amino acid or dipeptide spacer, and the carboxyl group of the amino acid or dipeptide spacer forms an amide bond with an amino group of the lipophilic substituent. 11. The GLP-2 derivative according to claim 7, wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of Asp or Glu, or a dipeptide containing an Asp or Glu residue, and a carboxyl group of the spacer forms an amide bond with an amino group of the lipophilic substituent. 12. The GLP-2 derivative according to any one of the preceding claims, wherein the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton. 13. The GLP-2 derivative according to any one of claims 1-11, wherein the lipophilic substituent is an straight-chain or branched alkyl group. . 14. The GLP-2 derivative according to any one of claims 1-11, wherein the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid. 15. The GLP-2 derivative according to claim 14, wherein the acyl group is selected from the group comprising CH3(CH2)„CO-, wherein n is 4 to 38, preferably CH3(CH2)6CO-, CH3(CH2)8CO-, CH3(CH2)i0CO-, CH3(CH2)12CO-, CH3(CH2)14CO-, CH3(CH2)16CO-, CH3(CH2)i8CO-, CH3(CH2)20CO- and CH3(CH2)22CO. 16. The GLP-2 derivative according to any of claims 1-11, wherein the lipophilic substituent is an acyl group of a straight-chain or branched alkane a,co-dicarboxylic acid. 17. The GLP-2 derivative according to claim 16 wherein the acyl group is selected from the group comprising HOOC(CH2)mCO-, wherein m is 4 to 38, preferably HOOC(CH2)i4CO-, HOOC(CH2)I6CO-, HOOC(CH2)18CO-, HOOC(CH2)20CO- and HOOC(CH2)22CO. 18. The GLP-2 derivative according to any of claims 1-11, wherein the lipophilic substituent is a group of the formula CH3(CH2)p((CH2)qCOOH)CHNH-CO(CH2)2CO-, wherein p and q are integers and p+q is an integer of from 8 to 40, preferably from 12 to 35. 19. The GLP-2 derivative according to any of claims 1-11, wherein the lipophlic substituent is a group of the formula CH3(CH2)rCO-NHCH(COOH)(CH2)2CO-, wherein r is an integer of from 10 to 24. 20. The GLP-2 derivative according to any of claims 1-11, wherein the lipophilic substituent is a group of the formula CH3(CH2)sCO-NHCH((CH2)2COOH)CO-, wherein s is an integer of from 8 to 24. 21. The GLP-2 derivative according to any of claims 1-11, wherein the lipophilic substituent is a group of the formula COOH(CH2)tCO- wherein t is an integer of from 8 to 24. 22. The GLP-2 derivative according to any of claims 1-11, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH2)4NH-CO(CH2)uCH3, wherein u is an integer of from 8 to 18. 23. The GLP-2 derivative according to any one of claims 1-11, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH2)4NH-COCH((CH2)2COOH)NH-CO(CH2)wCH3, wherein w is an integer of from 10 to 16. 24. The GLP-2 derivative according to any one of claims 1-11, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH2)4NH-CO(CH2)2CH(COOH)NH-CO(CH2)xCH3, wherein x is an integer of from 10 to 16. 25. The GLP-2 derivative according to any one of claims 1-11, wherein the lipophilic substituent is a group of the formula -NHCH(COOH)(CH2)4NH-CO(CH2)2CH(COOH)NHCO(CH2)yCH3, wherein y is zero or an integer of from 1 to 22. 26. The GLP-2 derivative according to any one of the preceding claims which has one lipophilic substituent. 27. The GLP-2 derivative according to any one of claims 1-25 which has two lipophilic substituents. 28. The GLP-2 derivative according to any one of the preceding claims wherein the parent peptide is selected from the group comprising Lys20GLP-2(l-33); Lys20Arg30GLP-2(l-33); Arg30Lys35GLP-2(l-35); Arg30'35Lys20GLP-2(l-35); Arg35GLP-2(l-35); Arg30Lys34GLP-2(l-34). 29. The GLP-2 derivative according to any one of the preceding claims, which is selected from the group consisting of 30.A pharmaceutical composition comprising a GLP-2 derivative according to any one of the preceding claims and a pharmaceutically acceptable vehicle or carrier.

Documents:

1939-mas-1997 abstract duplicate.pdf

1939-mas-1997 abstract.pdf

1939-mas-1997 claims duplicate.pdf

1939-mas-1997 claims.pdf

1939-mas-1997 correspondence-others.pdf

1939-mas-1997 correspondence-po.pdf

1939-mas-1997 description (complete) duplicate.pdf

1939-mas-1997 description (complete).pdf

1939-mas-1997 form-13.pdf

1939-mas-1997 form-19.pdf

1939-mas-1997 form-2.pdf

1939-mas-1997 form-26.pdf

1939-mas-1997 form-3.pdf

1939-mas-1997 form-4.pdf

1939-mas-1997 form-6.pdf

1939-mas-1997 petition.pdf