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"Derivatives Of Insulinotropic Agents Conjugated With Structurally Well Defined Branched Polymers"

Abstract: Novel GLP-1 conjugated with structurally well defined polymers and their therapeutically use.

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Patent Information

Application #
Filing Date
12 July 2007
Publication Number
33/2007
Publication Type
INA
Invention Field
POLYMER TECHNOLOGY
Status
Email
Parent Application

Applicants

NOVO NORDISK A/S
NOVO ALLE, DK-2880 BAGSVAED DENMARK.

Inventors

1. BEHRENS CARSTEN
LUNDTOFTEGADE 107, 1 TH,DK-2200 KǾBENHAVN N DENMARK.
2. LAU JESPER
ROSENVAENGET 3, DK-3520 FARUM DENMARK
3. KODRA JANOS TIBOR
RYESGADE 111B, 4., DK-2100 KOBENHAVN Ǿ DENMARK.
4. KOFOD-HANSEN MIKAEL
ALDERSROGADE 45, 3.TH, DK-2200 KǾBENHAVN N DENMARK
5. HANSEN THOMAS KRUSE
TIBBEVANGEN 78, DK-2730 HERLEV DENMARK

Specification

DERIVATIVES OF INSULINOTROPIC AGENTS CONJUGATED WITH STRUCTURALLY WELL DEFINED BRANCHED POLYMERS FIELD OF THIS INVENTION This invention relates generally to methods of treating humans suffering from diabetes mellitus. More specifically, the present invention relates to insulinotropic agents conjugated with structurally well defined branched polymers. The branched polymers are composed of monomer building blocks. Furthermore, this invention relates to the use of such conjugated insulinotropic agents, for example, by pulmonary delivery for systemic absorption through the lungs to reduce or eliminate the need for administering other insulinotropic agents by injection as well as to pharmaceutical compositions comprising these compounds-and to the use of the compounds for the treatment of diseases related to diabetes. BACKGROUND OF THIS INVENTION Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. Diabetes mellitus is a disease affecting approximately 6% of the world's population. Furthermore, the population of most countries is aging and diabetes is particularly common in aging populations. Often, it is this population group which experiences difficulty or unwillingness to self-administer insulin by injection. In the United States, approximately 5% of the population has diabetes and approximately one-third of those diabetics self-administer one or more doses of insulin per day by subcutaneous injection. This type of intensive therapy is necessary to lower the levels of blood glucose. High levels of blood glucose, which are the result of low or absent levels of endogenous insulin, alter the normal body chemistry and can lead to failure of the microvascular system in many organs. Untreated diabetics often undergo amputations and experience blindness and kidney failure. Medical treatment of the side effects of diabetes and lost productivity due to inadequate treatment of diabetes is estimated to have an annual cost of about $40 billion in the United States alone. One peptide expected to become very important in the treatment of diabetes is glucagon-like peptide-1 (GLP-1). Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized La. in the L-cells in the distal ileum, in the pancreas and in the brain. GLP-1 is an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism. GLP-1 stimulates insulin secretion in a glucose-dependant manner, stimulates insulin biosynthesis, promotes beta cell rescue, decreases glucagon secretion, gastric emptying and food intake. PCT publications WO 98/08871 and WO 99/43706 disclose stable derivatives of GLP-1 analogues, which have a lipophilic substituent. These stable derivatives of GLP-1 analogues have a protracted profile of action compared to the corresponding GLP-1 analogues. In the last decade a number of peptides have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum). Exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum, and this peptide shares 52% homology with GLP-1 (7-37) in the overlapping region. Exendin-4 is a potent GLP-1 receptor agonist which has been shown to stimulate insulin release and ensuing lowering of the blood glucose level when injected into dogs. The group of exendin-4(1-39), certain fragments thereof, analogs thereof and derivatives thereof, are potent insulinotropic agents. Most importantly the group of exendin-4(1-39), insulinotropic fragments thereof, insulinotropic analogs thereof and insulinotropic derivatives thereof. Common to GLP-1 and exendins are that an extensive amouni of variants have been synthesized and studied in particular in relation the plasma half-life. Low plasma half-lifes may be due to chemical stability towards peptidases (mainly dipeptidyl aminopeptidase IV) and to renal clearance. However, these analogues and derivatives of insulionotropic peptides lack a satisfactory bioavailability when administered by the pulmonary route, i.e. when administered to the lower respiratory tract such as through the bronchioles or alveoli. WO 00/66629 discloses modified exendin agonists which have been coupled to polyethyleneglycol via a lysine residue to decrease renal clearance. WO 03/40309 discloses peptide acting as both GLP-1 receptor agonists and glucagon receptor antagonists. Among the disclosed peptides are two peptides which have been coupled to polyethyleneglycol via a C-terminal cysteine residue. WO 2004/093823 discloses polyethylene glycolated GLP-1 peptides. Pulmonary administration of GLP-1 peptides have been disclosed in WO 01/51071. and WO 00/12116. The insulinotropic peptides derived from GLP-1 and Exendin-4 stimulates insulin release only when plasma glucose levels are high, and therefore the risk of hypoglycaemic events is reduced. Thus, the peptides are particularly useful for patients with diabetes who no longer respond to OHA's (oral hyperglycaemic agents) and who should from a strict medical point of view be administered insulin. Patients and to some extent also doctors are often not keen on initiating insulin treatment before this is absolutely necessary, presumably because of the fear of hypoglycaemic events or the fear of injections/needles. Thus, there is a need for insulinotropic peptides which are sufficiently potent and which can be administered by the pulmonary route. It has been known for a number of years that some proteins can be absorbed from the lung. In fact, administration of insulin as an inhalation aerosol to the lung was first reported by Gaensslen in 1925. It is clear that not all proteins can be efficiently absorbed in the lungs. There are numerous factors which impact whether a protein can be effectively delivered through the lungs. Absorption through the lungs is dependent to a large extent on the physical characteristics of the particular therapeutic protein to be delivered. Efficient pulmonary delivery of a protein is dependent on the ability to deliver the protein to the deep lung alveolar epithelium. Proteins that are deposited in the upper airway epithelium are not absorbed to a significant extent. This is due to the overlying mucus which is approximately 30-40 urn thick and acts as a barrier to absorption. In addition, proteins deposited on this epithelium are cleared by mucociliary transport up the airways and then eliminated via the gastrointestinal tract. This mechanism also contributes substantially to the low absorption of some protein particles. The extent to which proteins are not absorbed and instead eliminated by these routes depends on their solubility, their size, as well as other less understood characteristics. It is difficult to predict whether a therapeutic protein can be rapidly transported from the lung to the blood even if the protein can be successfully delivered to the deep lung alveolar epithelium. Because of the broad spectrum of peptidases which exist in the lung, a longer absorption time increases the possibility that the protein will be significantly degraded or cleared by mucociliary transport before absorption. In addition, peptides of therapeutic interest such as hormones, soluble receptors, cytokines, enzymes etc. often have short circulation half-life in the body as a result of proteolytic degradation, clearance by the kidney or liver, or in some cases the appearance of neutralizing antibodies. This generally reduces the therapeutic utility of peptides. It is however well recognised that the properties of peptides can be enhanced by grafting organic chain-like molecules onto them. Such grafting can improve pharmaceutical properties such as half life in serum, stability against proteolytical degradation, and reduced immunogenicity. The organic chain-like molecules often used to enhance properties are polyethylene glycol-based or polyethylene based chains, i.e., chains that are based on the repeating unit -CH2CH2O-. Hereinafter, the abbreviation "PEG" is used for polyethyleneglycol. However, the techniques used to prepare PEG or PEG-based chains, even those of fairly low molecular weight, involve a poorly-controlled polymerisation step which leads to preparations having a wide spread of chain lengths about a mean value. Consequently, peptide conjugates based on PEG grafting are generally characterised by broad range molecular weight distributions. Kochendoefer et al. recently described (Science 2003, 299. 884-887) the design and synthesis of a homogeneous polymer modified erythropoiesis protein, and in WO 02/20033 (a PCT patent application) devised a general method for the synthesis of well defined polymer modified peptides. The building blocks used in this work were based on alternating water soluble linear long chain hydrophilic diamines and succinic acid, which were extended by sequential addition using standard peptide chemistry in solution or on solid support. An alternative and more attractive strategy for preparing large well defined polymers relies on the use of bi-, tri or multifurcated monomers which are oligomerized in a limited number of sequential synthesis steps. The mass growth of the polymer will in this case follow an exponential curve, with an exponent determined by the furcation number, for example, bifurcated monomers provides 2nd power growth, trifurcated monomers provides 3rd power growth, etc. The type of polymers obtained by this procedure has been well described in the literature (S.M. Grayson and J.M.J. Frechet, Chem. Rev. 2001,101, 3819) and are commonly known as dendrimers. Biodegradable 4th generation polyester dendrimers based on 2,2-bis(hydroxymethyl)-propionic acid and capped with polyethyleneoxide via a carbamate linkage has recently been reported (E.R.Gillies and J.M.J.Frechet, J. Amer. Chem. Soc, 2002,124.14137-14146). The architecture of this system bears a close resemblance to the system described by Kochendoefer et al. as described above, as the dendritic part of the structure is used to generate a polyhydroxy scaffold that function as attachment points for the polyethyleneoxide tails. However, although impressive 12 KDa structures can be made, a large degree of dispersity is introduced from each polyethyleneoxide tail, as only the core structure is chemically well defined. In light of the many potential applications for well defined polymer conjugated to biopharmaceuticals (for example, modifying pharmacokinetics and pharmacodynamics), there is a continuous need in the art for improving the technology for preparing well defined polymers and co-polymers in a precise well defined manner, from a precise number of monomer units. SUMMARY OF THIS INVENTION The present invention provides a new class of branched polymers conjugated to an insulinotropic agent. These new compounds have the general formula I mentioned below with the definitions mentioned below. The compounds of formula I contain a controlled number of monomer building blocks (designated Yb and Yt, below). This invention also provides the use of a conjugate as above as a medicament. DETAILED DESCRIPTION OF THIS INVENTION In the present specification, the following terms have the indicated meaning: The term "polypeptide" and "peptide" as used herein means a compound composed of at least five constituent amino acids connected by peptide bonds. The constituent amino acids may be from the group of the amino acids encoded by the genetic code and they may natural amino acids which are not encoded by the genetic code, as well as synthetic amino acids. Natural amino acids which are not encoded by the genetic code are for example, hydroxyproline, v-carboxyglutamate, ornithine, phosphoserine, D-alanine and D-glutamine. Synthetic amino acids comprise amino acids manufactured by chemical synthesis, i.e. D- • isomers of the amino acids encoded by the genetic code such as D-alanine and D-leucine, Aib (α-aminoisobutyric acid), Abu (α-aminobutyric acid), Tie (tert-butylglycine), β-alanine, 3-aminomethyl benzoic acid, anthranilic acid. The term "analogue" as used herein referring to a polypeptide means a modified peptide wherein one or more amino acid residues of the peptide have been substituted by other amino acid residues and/or wherein one or more amino acid residues have been deleted from the peptide and or wherein one or more amino acid residues have been added to the peptide. Such addition or deletion of amino acid residues can take place at the N-terminal of the peptide and/or at the C-terminal of the peptide. A simple system is often used to describe analogues: For example [Arg^GLP-1(7-37)Lys designates a GLP-1(7-37) analogue wherein the naturally occuring lysine at position 34 has been substituted with arginine and wherein a lysine has been added to the terminal amino acid residue, i.e. to the Gly37. All amino acids for which the optical isomer is not stated is to be understood to mean the L-isomer. Human GLP-1 is hydrolysed to GLP-1(7-37) and GLP-1(7-36)-amide which are both insulinotropic peptides. Thus, for example, [Gly8]GLP-1(7-37) designates an analogue of GLP-1 (7-37) formally derived from GLP-1 (7-37) by substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, (N-tetradecanoyl)[Lys34]GLP-1(7-37) designates GLP-1 (7-37) wherein the e-amino group of the Lys residue in position 34 has been tetradecanoylated. In aspects of the invention analogues of GLP-1 or exendin-4 has maximum of 15 amino acids has been added, deleted or exchanged compared to the native sequence, In aspects of the invention maximum of 12 amino acids has been added, deleted or exchanged. In aspects of the invention a maximum of 10 amino acids has been added, deleted or exchanged. In aspects of the invention a maximum of 8 amino acids has been added, deleted or exchanged. In aspects of the invention a maximum of 6 amino acids has been added, deleted or exchanged. In aspects of the invention a maximum of 4 amino acids has been added, deleted or exchanged. In aspects of the invention a maximum of 2 amino acids has been added, deleted or exchanged. The term "derivative" as used herein in relation to a peptide means a chemically modified peptide or an analogue thereof, wherein at least one substituent is not present in the unmodified peptide or an analogue thereof, i.e. a peptide which has been covalently modified. Typical modifications are amides, carbohydrates, alkyl groups, acyl groups, esters and the like. An example of a derivative of GLP-1(7-37) is N26-((4S)-4-(hexadecanoylamino)-butanoyl)[Arg34, Lys26]GLP-1 -(7-37). The term "insulinotropic agent" as used herein means a compound which is an agonist of the human GLP-1 receptor, i.e., a compound which stimulates the formation of cAMP in a suitable medium containing the human GLP-1 receptor (one such medium disclosed below). The potency of an insulinotropic agent is determined by calculating the EC50 value from the dose-response curve as described below. Baby hamster kidney (BHK) cells expressing the cloned human GLP-1 receptor (BHK- 467-12A) were grown in DMEM media with the addition of 100 lU/mL penicillin, 100 µg/mL streptomycin, 5% fetal calf serum and 0.5 mg/mL Geneticin G-418 (Life Technologies). The cells were washed twice in phosphate buffered saline and harvested with Versene. Plasma membranes were prepared from the cells by homogenisation with an Ultraturrax in buffer 1 (20 mM HEPES-Na, 10 mM EDTA, pH 7.4). The homogenate was centrifuged at 48,000 x g for 15 min at 4°C. The pellet was suspended by homogenization in buffer 2 (20 mM HEPES-Na, 0.1 mM EDTA, pH 7.4), then centrifuged at 48,000 x g for 15 min at 4°C. The washing procedure was repeated one more time. The final pellet was suspended in buffer 2 and used immediately for assays or stored at -80°C. The functional receptor assay was carried out by measuring cyclic AMP (cAMP) as a response to stimulation by the insulinotropic agent. cAMP formed was quantified by the AlphaScreen™ cAMP Kit (Perkin Elmer Life Sciences). Incubations were carried out in half-area 96-well microtiter plates in a total volume of 50 µL buffer 3 (50 mM Tris-HCI, 5 mM HEPES, 10 mM MgCI2, pH 7.4) and with the following addiditions: 1 mM ATP, 1 µM GTP, 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), 0.01 %Tween-20, 0.1% BSA, 6µg membrane preparation, 15µg/mL acceptor beads, 20µg/mL donor beads preincubated with 6 nM biotinyl-cAMP. Compounds to be tested for agonist activity were dissolved and diluted in buffer 3. GTP was freshly prepared for each experiment. The plate was incubated in the dark with slow agitation for three hours at room temperature followed by counting in the Fusion™ instrument (Perkin Elmer Life Sciences). Concentration-response curves were plotted for the individual compounds and EC50 values estimated using a four-parameter logistic model with Prism v. 4.0 (GraphPad, Carlsbad, CA). The term "GLP-1 peptide" as used herein means GLP-1(7-37) (SEQ ID No 1), a GLP-1(7-37) analogue, a GLP-1 (7-37) derivative or a derivative of a GLP-1 (7-37) analogue. In one embodiment the GLP-1 peptide is an insulinotropic agent. The term "exendin-4 peptide" as used herein means exendin-4(1-39) (SEQ ID No 2), an exendin-4(1-39) analogue, an exendin-4(1-39) derivative or a derivative of an exendin-4(1-39) analogue. In one embodiment the exendin-4 peptide is an insulinotropic agent. The term "DPP-IV protected" as used herein referring to a polypeptide means a polypeptide which has been chemically modified in order to render said compound resistant to the plasma peptidase dipeptidyl aminopeptidase-4 (DPP-IV). The DPP-IV enzyme in plasma is-known to be involved in the degradation of several peptide hormones, for example, GLP-1, GLP-2, Exendin-4 etc. Thus, a considerable effort is being made to develop analogues and derivatives of the polypeptides susceptible to DPP-IV mediated hydrolysis in order to reduce the rate of degradation by DPP-IV. In one embodiment a DPP-IV protected peptide is more resistant to DPP-IV than GLP-1 (7-37) or Exendin-4(1-39). Resistance of a peptide to degradation by dipeptidyl aminopeptidase IV is determined by the following degradation assay: Aliquots of the peptide (5 nmol) are incubated at 37oC with 1 µL of purified dipeptidyl aminopeptidase IV corresponding to an enzymatic activity of 5 mU for 10-180 minutes in 100 µL of 0.1 M triethylamine-HCI buffer, pH 7.4. Enzymatic reactions are terminated by the addition of 5 µL of 10% trifluoroacetic acid, and the peptide degradation products are separated and quantified using HPLC analysis. One method for performing this analysis is : The mixtures are applied onto a Vydac C18 widepore (30 nm pores, 5µm particles) 250 x 4.6 mm column and eluted at a flow rate of 1 ml/min with linear stepwise gradients of acetonitrile in 0.1% trifluoroacetic acid (0% acetonitrile for 3 min, 0-24% acetonitrile for 17 min, 24-48% acetonitrile for 1 min) according to Siegel et al., Regul. Pept. 1999;79:93-102 and Mentlein et al. Eur. J. Biochem. 1993; 214: 829-35. Peptides and their degradation products may be monitored by their absorbance at 220 nm (peptide bonds) or 280 nm (aromatic amino acids), and are quantified by integration of their peak areas related to those of standards. The rate of hydrolysis of a peptide by dipeptidyl aminopeptidase IV is estimated at incubation times which result in less than 10% of the peptide being hydrolysed. Using results from the so-called free fat cell assay, any skilled art worker, for example, a physician, knows when and which dosages to administer of the GLP-1 analogue. The term "covalent attachment" means that the polymeric molecule and the GLP-1 is either directly covalently joined to one another, or else is indirectly covalently joined to one another through an intervening moiety or moieties, such as bridge, spacer, or linkage moiety or moieties. The term "branched polymer", or "dendritic polymer" or "dendritic structure" "or dendrimer" means an organic polymer assembled from a selection of monomer building blocks of which, some contains branches. The term "conjugate", or "conjugate GLP-1", is intended to indicate a heterogeneous (in the sense of composite or chimeric) molecule formed by covalent attachment of one or more GLP-1 analogues to one or more polymer molecules. The term "polydispersity" is used to indicate the purity of a polymer. The term "polydispersity index" (PDI) is the ratio of Mw to Mn wherein Mw is ∑(Mi2Ni)/I(MiNi) and Mn is . ∑(MiNi)/ ∑(Ni), wherein MI is the molecular weight of the individual molecules present in the mixture, and Nj is the number of molecules represented by a certain molecular weight. The PDI provides a rough indication of the breadth of the distribution of the specific polymers present in a mixture. If the PDI of a certain polymer is 1, said polymer has a purity of 100%. For small generations of polymers, for example 1-3 generation, it may be more convenient to indicate the purity that to indicate a PDI. However, for longer polymers, it may be more convenient to use PDI. The term "monodisperse" is, herein, used for a polymer having a PDI of less than 1.09. In an embodiment it is less than 1.08. In an embodiment it is less than 1.07 and at leasl 1. Herein the term "structurally well defined" in connection with a product indicates that the product has a high purity of a specific, chemically well-defined compound. In an embodiment such a purity is above about 80%. In an embodiment it is above about 90%. In an embodiment it is above about 95%. In an embodiment it is above about 97.5%. "Immunogenicity" of a polymer modified GLP-1 refers to the ability of the polymer modified GLP-1, when administrated to a human, to elicit an immune response, whether humoral, cellular, or both. The term "attachment group" is intended to indicate a functional group on the GLP-1 or linker modified GLP-1 capable of attaching a polymer molecule either directly or indirectly through a linker. Useful attachment groups are, for example, amine, hydroxyl, carboxyl, aldehyde, ketone, sulfhydryl, succinimidyl, maleimide, vinylsulfone or haloacetate. The term "reactive functional group" means by way of illustration and not (imitation, any free amino, carboxyl, thiol, alkyl halide, acyl halide, chloroformiate, aryloxycarbonate, hydroxy or aldehyde group, carbonates such as the p-nitrophenyl, or succinimidyl; carbonyl imidazoles, carbonyl chlorides; carboxylic acids that are activated in situ; carbonyl halides, activated esters such as N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, esters of such as those comprising 1,2,3-benzotriazin-4(3H)-one, phosphoramidites and H-phosphonates, phosphortriesters or phosphordiesters activates in situ, isocyanates or isothiocyanates, in addition to groups such as -NH2, -OH, -N3, -NHR' or -OR' (where R' is a protection group as defined below), -O-NH2, alkynes, or any of the following: hydrazine derivatives (-NH-NH2), hydrazine carboxylate derivatives (-O-C(O)-NH-NH2), semicarbazide derivatives (-NH-C(0)-NH-NH2), thiosemicarbazide derivatives (-NH-C(S)-NH-NH2), carbonic acid dihydrazide derivatives (-NHC(O)-NH-NH-C(O)-NH-NH2), carbazide derivatives (-NH-NH-C(0)-NH-NH2), thiocarbazide derivatives (-NH-NH-C(S)-NH-NH2), aryl hydrazine derivatives (-NH-C(O)-C6H4-NH-NH2), hydrazide derivatives (-C(O)-NH-NH2), and oxylamine derivatives, such as -C(O)-O-NH2, -NH-C(O)-O-NH2 and -NH-C(S)-O-NH2. The term "protected functional group" means a functional group which has been protected in a way rendering it essential non-reactive. Examples of protection groups used for amines include but are not limited to tert-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, azides etc. For a carboxyl group, other groups become relevant such as tert-butyl, or more generally alkyl groups. Appropriate protection groups are known to the skilled person, and examples can be found in Green & Wuts "Protection groups in organic synthesis", 3rd Edition, Wiley-interscience. The term "cleavable moiety" is intended to mean a moiety that is capable of being selectively cleaved to release the branched polymer linker or branched polymer linker GLP-1 from for example, a solid support. The term "generation" refers to a single uniform layer, created by reacting one or more identical functional groups on an organic molecule with a particular monomer building block. Dendrimer synthesis demands a high level of synthetic control which is achieved through stepwise reactions, building the dendrimer up one monomer layer, or "generation," at a time. Each dendrimer consists of a multifunctional core molecule with a dendritic wedge attached to each functional site. The core molecule is referred to as "generation 0". Each successive repeat unit along all branches forms the next generation, "generation 1", "generation 2," etc. until the terminating generation. With a dendrimer made from exclusively bifurcated monomers, the number of reactive surface groups available for reaction is 2m, where m is an integer of 1, 2, 3 ... 8 representing the particular generation. For a dendrimer made of exclusively trifurcated monomers, the number of reactive groups is 3m, and for a dendrimer made exclusively from a multifurcated monomer with n branches, the number of reactive groups is nm. For branched polymers in which different monomers are used in each individual generation, the number of reactive groups in a particular layer or generation can be calculated recursively knowing the layer position and the number of branches of the individual monomers. The term "functional in vivo half-life" is used in its normal meaning, i.e., the time at which 50% of the biological activity of the GLP-1 or conjugate is still present in the body/target organ, or the time at which the activity of the GLP-1 or conjugate is 50% of its initial value. As an alternative to determining functional in vivo half-life, "serum half-life" may be determined, i.e., the time at which 50% of the GLP-1 or conjugate molecules circulate in the plasma or bloodstream prior to being cleared. Determination of serum-half-life is often more simple than determining functional half-life and the magnitude of serum-half-life is usually a good indication of the magnitude of functional in vivo half-life. Alternative terms to serum half-life include plasma half-life, circulating half-life, circulatory half-life, serum clearance, plasma clearance, and clearance half-life. The GLP-1 or conjugate is cleared by the action of one or more of the reticulo-endothelial system (RES), kidney, spleen, or liver, by tissue factor, SEC receptor, or other receptor-mediated elimination, or by specific or unspecific proteolysis. Normally, clearance depends on size (relative to the cut-off for glomerular filtration), charge, attached carbohydrate chains, and the presence of cellular receptors for the GLP-1. The functionality to be retained is normally selected from procoagulant, proteolytic, co-factor binding or receptor binding activity. The functional in vivo half-life and the serum half-life may be determined by any suitable method known in the art. The term "increased" as used about the functional in vivo half-life or plasma half-life is used to indicate that the relevant half-life of the GLP-1 or conjugate is statistically significantly increased relative to that of a reference molecule. For instance the relevant half-life may be increased by at least about 10% or at least 25%, such as by at least about 50%, for example, by at least about 100%, 150%, 200%, 250%, or 500%. The term "halogen" means fluoro, chloro, bromo or iodo. The term "heavy atom" as used herein means an atom having a molar weight equal to or larger than carbon, for example, C, N, 0 and S. The terms "alkyl", "alkylene", "alkantriyl", and "alkantetrayl" represents a saturated, branched or straight hydrocarbon group having from 1 to 18 carbon atoms. In an embodiment it is from 1 to 10 carbon atoms. In an embodiment it is from 1 to 6 carbon atoms with one, two, three, or four bonds, respectively. Typical groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. Specific alkylene, alkantriyl, and alkantetrayl groups include the corresponding divalent, trivalent, and tetravalent radicals. The terms "alkenyl" and "alkenylene" refer to a C2-6-alkenyl and C2-6-alkenylene, respectively, and represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond and having one or two bonds, respectively. Typical C2-6-alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 1-ethylprop-2-enyl, 1,1-(dimethyl)prop-2-enyl, 1-ethylbut-3-enyl, and 1,1-(dimethyl)but-2-enyl. Examples of C2-6-alkenylen groups include the corresponding divalent radicals. The terms "alkynyl" or "alkynylene" refer to a C2-6-alkynyl or C2-6-alkynylene, representing a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond and having one or two bonds, respectively. Typical C2-6-alkynyl groups include, but are not limited to, 1-propynyl, 2-propynyl, isopropynyl, 1,3-butadynyl, 1-" butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 1-ethylprop-2-ynyl, 1,1-(di-methyl)prop-2-ynyl, 1-ethylbut-3-ynyl, 1,1-(dimethyl)but-2-ynyl, and C2-6-alkynylene groups include the corresponding divalent radicals. The terms "alkyleneoxy" or "alkoxy" refer to "C1-6-alkoxy" or C1-6-alkyleneoxy representing the radical -O-d.6-alkyl or -O-Ci.6-alkylene, respectively, wherein C1-6-alkyl(ene) is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like. The terms "alkylenethio", "alkenylenethio" and "alkynylenethio" refer to the corresponding thio analogues of the oxy-radicals as defined above. Representative examples are methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, and the corresponding divalent radicals and the corresponding alkenyl and alkynyl derivatives also defined above. Herein, the terms "-diyl" and "-triyl" is used and refers to different alkyl, alkenyl, alkynyl, cycloalkyl or aromatic radicals with two and three attachment points, respectively. Herein, the term "alkantrioxy" refers to an alkantriyl moiety with one oxy (-O-) attached to each of the three alkantriyl bonds. Representative examples are propantrioxy, tert-butyltrioxy ect. The term "cycloalkyl" refers to C3-8-cycloalkyl representing a monocyclic, carbocyclic" group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The term "cycloalkenyl" refers to C3-8-cycloalkenyl representing a monocyclic, carbocyclic, non-aromatic group having from 3 to 8 carbon atoms and at least one double bond. Representative examples are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. The term "poiyalkoxy" designates alkoxy-alkoxy-alkoxy-alkoxy etc. where the number of carbon atoms in each of the alkoxy moieties is the same or different. In an embodiment they are the same. Similarly, polyalkoxyalkyl and polyalkoxyalkylcarbonyl designates (polyalkoxy)-alkyl and (polyalkoxy)-alkyl-CO-, respectively. The term polyalkoxydiyl designates alkoxy-alkoxy-alkoxy-alkoxy etc having two free bonds. The term "poly" means many. In an embodiment it is a numbering the range from 2 to 24. In an embodiment it is from 2 to 12. In an embodiment it is 3,4 or 5. The term "oxyalkyl" is -O-alkyl-, i.e. a divalent radical. The term "aryl" as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like. The terms "arenetriyi" and "arenetetrayl" are moieties identical with aryl as defined above with the proviso that in arenetriyi and arenetetrayl there are not one but three and four, respectively, free bonds. With the same proviso, examples of arenetriyi and arenetetrayl are as mentioned for aryl above. The term "heteroaryl" as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydro-benzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like. The term heteroaryl-C1-6-alkyl as used herein, denotes heteroaryl as defined above and C1-6-alkyl as defined above. The terms "aryl-C1-6-alkyl" and "aryl-C2-6alkenyl" as used herein denotes aryl as defined above and C1-6-alkyl and C2-6-alkenyl, respectively, as defined above. The term "acyl" as used herein denotes -(C=O)-C1-6-alkyl wherein C1-6-alkyl is as defined above. (Formula Removed) Fmoc is: Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other. Furthermore, when combined terms are used for divalent or trivalent moities, the interpretation of such combined terms into chemical structures is done by reading the combined terms from left to right or vice versa. Hence, a term like a divalent aminoalkyt moiety also covers an alkylamino moiety. Herein, the term moiety is preferaly used in connection with divalent and trivalent radicals. To be more specific, here follows the names of some divalent moieties consisting of a combination of different terms each divalent moiety followed by an alternative definition in square paranthesis and optionally one or more specific examples of such divalent moieties:" alkyleneaminocarbonylalkylamino [-alkylene-NH-CO-alkylene-NH-, for example, -NH--CH2CH2-CO-NH-CH2CH2CH2CH2-], alkylenecarbonylamino(polyalkoxy)alkylamino [-alkylene-CO-NH-(polyalkoxy)-alkylene-NH-], alkyleneoxyalkyl [-alkylene-O-alkylene-, for example, -CH2CH2-O-CH2CH2-], carbonylalkylamino [-CO-alkylene-NH-, for example, -NHCH2CH2C(O)-J, carbonylalkylcarbonylamino{polyalkoxy)alkylamino[-CO-alkylene-CO-NH-(polyalkoxy)-alkylene-NH-], carbonylalkoxyalkylamino [-CO-alkoxy-alkylene-NH-], carbonylalkoxyalkylcarbonylamino(polyalkoxy)alkylamino[-CO-alkoxy-alkylene-CO-NH-(polyalkoxy)-alkylene-NH-], carbonyl(polyalkoxy)alkylamino [-CO-(polyalkoxy)-alkylene-NH-], (polyalkoxy)alkyl [-(polyalkoxy)-alkylene-, for example, -CH2OCH2CH20CH2CH20-CH2- and -CH2CH2OCH2CH2OCH2CH2O-CH2-], (polyalkoxy)alkylcarbonyl [-(polyalkoxy)-alkylene-CO-]. In the formulae in the square brackets, the bonds between the different moieties are indicated by"-". The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent, the substituents may be the same or different. The term "treatment" as used herein means the prevention, management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the prevention of the disease, delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition. In an embodiment the patient to be treated is a mammal, in particular a human being. The term "excipient" as used herein means the chemical compounds which are normally added to pharmaceutical compositions, for example, buffers, tonicity agents, preservatives and the like. The term "effective amount" as used herein means a dosage which is sufficient to be effective for the treatment of the patient compared with no treatment. The term "pharmaceutical composition" as used herein means a product comprising an active compound or a salt thereof together with pharmaceutical excipients such as buffer, preservative, and optionally a tonicity modifier and/or a stabilizer. Thus a pharmaceutical composition is also known in the art as a pharmaceutical formulation. The present invention relates to branched polymers attached to GLP-1 which branched polymers are made up of a precise number of monomer building blocks. The monomer building blocks may be oligomerised either on solid support or in solution using suitable monomer protection and activation strategies. A branched polymer attached to GLP-1 is herein also designated a conjugated GLP-1 or an GLP-1 conjugate. Using the methods described below, it is possible to prepare a conjugated GLP-1 wherein the branched polymer is structural well defined. Hence, the compounds of this invention are monodisperse. Using the process described herein, it is possible to prepare compounds of the general formula I below having a purity above 50%. In an embodiment it is above 75%. In an embodiment it is above 90%. In an embodiment it is above 95%. In an embodiment it is above 99% (weight/weight). In an embodiment, this invention relates to a product containing a single, specific compound of formula I in such a high purity. An embodiment of this invention provides an GLP-1 conjugate as described above, which is represented by the general formula I: ITA-L4-(L3)m-Y1 (Y2(Y3(Y4(Y5(Y6)r)q)p)s)n (I) wherein ITA represents an insulinotropic agent from which a hydrogen has been removed from an alpha-amino group present in the insulinotropic agent, or from an epsilon amino group present in lysine at any position in the insulinotropic agent, for the 1st generation of bifurcated compounds, Y1 is Yb; Y2 is Z; r, q, p, and s are all zero; and n is 2; for the 2nd generation of bifurcated compounds, Y1 and Y2 are Yb; Y3 is Z; r, q, and p are all zero; s is 4; and n is 2; for the 3rd generation of bifurcated compounds, Y1 , Y2, and Y3 are all Yb; Y4 is Z; r and q are zero; p is 8; s is 4; and n is 2; for the 4th generation of bifurcated compounds, Y1 , Y2, Y3, and Y4 are all Yb; Y5 is Z; r is zero; q is 16; p is 8; s is 4; and n is 2; and for the 5th generation of bifurcated compounds, Y1 , Y2, Y3, Y4, and Y5 are all Yb; Y6 is Z; r is 32; q is 16, p is 8; s is 4; and n is 2; wherein (Formula Removed) for the 1st generation of trifurcated compounds, Y1 is Yt; Y2 is Z; r, q, p, and s are all zero; and n is 3; for the 2nd generation of trifurcated compounds, Y1 and Y2 are Yt; Y3 is Z; r, q, and p are all zero; s is 9; and n is 3; for the 3rd generation of trifurcated compounds, Y1 , Y2, and Y3 are all Yt; Y4 is Z; r and q are zero; p is 27; s is 9; and n is 3; and for the 4th generation of trifurcated compounds, Y1 , Y2, Y3, and Y4 are all Yt; Y5 is Z; r is zero; q is 81 ; p is 27; s is 9; and n is 3; wherein (Formula Removed) wherein A is -CO-, -C(O)O-, -P(=O)(OR)- or -P(=S)(OR)-, wherein R is hydrogen, alkyl or optionally substituted aryl; and B is -NH- or -O-; with the proviso that when B is -NH-, then A is -CO- or -C(O)O-, and when B is -0-, then A is -P(=0)(OR)- or -P(=S)(OR)-; and wherein the group B of one monomer layer (generation) (exemplified by Y1, Y2, and Y3) is connected to the group A of the adjacent, following layer where Y has the following number as suffix (exemplified by Y2; Y3, and Y4, respectively) or is connected to Z; X3 is a nitrogen atom, alkantriyl, arenetriyl, alkantrioxy, an aminocarbonyl moiety of the formula -CO-N<, an acetamido moiety of the formula -CH2CO-N< or a moiety of the formula: -CO-NH-Q-NH-CO- I wherein Q is alkantriyl; X4 is alkantetrayl or arenetetrayl; In embodiments of the invention L1 is a valence bond, oxy, alkylene, alkyleneoxyalkyl, polyalkoxydiyl, (polyalkoxy)alkylcarbonyl, oxyalkyl or (polyalkoxy)alkyl wherein the terminal alkyl moiety of the last 3 moieties is connected to A ; In embodiments of the invention L1 is connected to A in the oxy- part of the last three moieties. In embodiments of the invention L2is a valence bond, oxy, alkylene, alkyleneoxyalkyl, polyalkoxydiyl, (polyalkoxy)alkylcarbonyl, oxyalkyl or (polyalkoxy)alkyl wherein the terminal alkyl moiety of the last 3 moieties is connected to B; In embodiments of the invention L2 is connected to B in the other end of the divalent radicals. In embodiments of the invention L3 represents a valence bond, alkylene, oxy, polyalkoxydiyl, oxyalkyl, alkylamino, carbonylalkylamino, alkylaminocarbonylalkylamino, carbonylalkyl-carbonylamino(polyalkoxy)alkylamino, carbonylalkoxyalkylcarbonylamino(polyalkoxy)- alkylamino, alkylcarbonylamino(polyalkoxy)alkylamino, carbonyl(polyalkoxy)alkylamino or carbonylalkoxyalkylamino wherein the terminal carbonyl, alkyl and oxy moiety of the last 10 moieties, is connected to the ITA group, optionally via the L4 moiety; In an embodiments of the invention the moieties are connected in the other end of the divalent radical. m is zero, 1, 2 or 3; In embodiments of the invention L4 is selected among a valence bond and a moiety of the formula -CO-L5-CH=N-O-, wherein L5 is a valence bond, alkylene or arylene, and wherein the terminal carbonyl moiety in said U moiety, is connected to the ITA moiety; In embodiments of the invention the moieties are connected in the other end of the divalent radical. and Z is hydrogen, alkyl, alkoxy, hydroxyalkyl, polyaikoxy, oxyalkyl, acyl, polyalkoxyalkyl, or polyalkoxyalkylcarbonyl. As defined above, L1, L2, L3 and L4 all shall be interpreted as divalent radicals, X3 is a trivalent radical and X4 is a tetravalent radical. In the definition of formula I above and elsewhere herein, the three terms bifurcated, trifurcated and generation are used in an attempt to facilitate the understanding hereof and they should not in any way result in a restricted interpretation. Hence, the 1st generation of bifurcated compounds can be illustrated by the formula la: ITA-L4-(L3)m-Y1(Y2)2(la) which also can be illustrated by formula la' (Formula Removed) wherein ITA, Y1, Y2, L3, L4, m, Yb and Z each are as defined above. Furthermore, the 2nd generation bifurcated compounds can be illustrated by the formula Ib ITA-L4-(L3)m-Y1(Y2(Y3)4)2 (Ib) which also can be illustrated by the formula Ib' (Formula Removed) wherein ITA, Y1, Y2, Y3, L3, L4, m, Yb and Z each are as defined above. Alternatively, this invention can be illustrated by drawing the formula of, for example, the 4th generation bifurcated compounds as in the following formula Ic: (Formula Removed) wherein all the symbols are as mentioned above (and the perpendicular lines are not a part of the formula, but illustrates the different levels). Formula Ic is only given in an attempt to -illustrate this invention and is not to be used to limit the scope of protection. In an embodiment of this invention, r is zero. In another embodiment of this invention, r and q are each zero. In another embodiment of this invention, n is 2 (for bifurcated compounds) or 3 (for trifurcated compounds). In another embodiment of this invention, s is 4 (for bifurcated compounds) or 9 (for trifurcated compounds). In another embodiment of this invention, s is 4, and p is 8 (for bifurcated compounds) or s is 9, and p is 27 (for trifurcated compounds). As mentioned above, compounds of formula I contains one or more Yb moieties. If a compound of formula I contains more than one Yb moiety, those moieties may be the same or different. In an embodiment of this invention, all Yb moieties are identical. In another embodiment of this invention, the Yb moieties from the same level are identical, but the Yb moieties (or moiety) in one level are (is) different from the Yb moieties (or moiety) in another level, each level being identified by the suffixes n, s, p, q and r, respectively, in formula I. In a specific moiety Yb, the two B moieties are the same or different. In an embodiment such two B moieties are the same. Furthermore, in an embodiment the specific moiety Yb, the two L2 moieties are the same or different. In an embodiment such two L2 moieties are the same.This, similarly, applies for the Yt moieties and the B and L2 moieties present therein. In an embodiment of this invention, it relates to bifurcated compounds, in another embodiment, it relate to trifurcated compounds. The two or three L2 moieties present in any Yb or Yt moiety, respectively, may be the same or different. In an embodiment of this invention, the two or three L2 moieties present in any Yb or Yt moiety, respectively, are the same. At least for illustrative purposes but also to some extent in practice, the major part of the non insulinotropic agent of compounds of formula I can be build from compounds of formula IVb or IVc having the following formula: (Formula Removed) wherein L1, L2, X3 and X4 are as defined above, and wherein -A' and -B1 are groups which can react to form the moiety -A-B-; wherein A and B are as defined above. The nature of the covalent bond formed by reaction between the groups A' and B' depends upon the selection of A' and B', and include, as indicated above, amide bonds, carbamate bonds, phosphate ester bonds, thiophosphate ester bonds, and phosphit bonds. In an embodiment, A' is selected from the group consisting of -COOH, -COOR, -OCOOR, -OP(NR2)OR, -(O=)P(OR)2, -(S=)P(OR)(OR'), -(S=)P(SR)(OR'), -(S=)P(SR)(SR'), -COCI, -COBr, -OCOBr, -P(OR)3, p-nitrophenyl carbonate (-OC(=O)OC6H4NO2), succinimidyl carbonate (-OC(=0)-Nhs, where Nhs is N-hydroxysuccinimid), carbonylimidazole (-C(=O)-lm, where Im is imidazol), oxycarbonylimidazole (-OC(=O)-lm, where Im is imidazol), carbonylchlorides (-C(=O)CI), chloroformiate (-OC(=0)CI), isocyanate (-N=C=0) and isothiocyanates (-N=C=S), wherein R and R' represents C1-6-alkyl, aryl or substituted aryl. In another embodiment, B' is selected from the group consisting of -NH2, -OH, -N3, -NHR' and -OR'; where R' is a protection group, that facilitates stepwise monomer oligomerization as used in, for example, peptide chemistry and oligonucleotide chemistry. Non-limiting examples of protecting groups includes 9-fluorenylmethoxycarbonyl (designated Fmoc), tert-butoxycarbonyl (designated Boc), phthaloyl, triphenylmethyl, and substituted triphenylmethyl, trihaloacetyl such as trifluoroacetyl or trichloroacetyl, pixyl, trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl. Other examples of appropriate protection groups are known to the skilled person, and suggestions can be found in Green & Wuts "Protection groups in organic synthesis", 3rd edition, Wiley-interscience. X3 may be a branched, trivalent organic radical (linker). In an embodiment X3 is of hydrophilic nature. In an embodiment, it includes a multiply-functionalised alkyl group containing up to 18. In an embodiment it contains from 1 to about 10 carbon atoms. In another embodiment, X3 is a single nitrogen atom. In another embodiment, X3 is alkantriyl. In another embodiment, X3 is propan-1,2,3-triyl. In another embodiment X3 is an alkantrioxy. In another embodiment, X3 is alkantriyl, alkantrioxy or a moiety of the formula: -CO-NH-Q-NH-CO-, wherein Q is alkantriyl; and, furthermore, X3 can be an aminocarbonyl moiety of the formula -CO-N< or an acetamido moiety of the formula -CH2CO-N< and, in another embodiment X3 has one of the following formulas: (Formula Removed) the two last moieties being (R) and (S)-1,5-bis(aminocarbonyl)pentyl. In an embodiment of this invention, X4 is symmetrical. In an embodiment X4 is benzen-1,3,4,5-tetrayl. In another embodiment of this invention, X3 or X4 is symmetrically. Examples of L1 and L2 are alkylene and -((CH2)m slight heat evolution. A cream coloured suspension was formed. The mixture was stirred at ambient temperature over night. Excess sodium hydride was carefully destroyed by addition of water (20 ml) while cooling the mixture. The suspension was taken to dryness by rotary evaporation, and the residue partitioned between DCM and water. The water phase was extracted twice with DCM then acidified by addition of acetic acid (25 ml). The water phase was then extracted twice with DCM, and the combined organic phases were dried over sodium sulphate, and evaporated to dryness. The residual oil at this point contained the title material as well as bromoacetic acid. The later was removed by re-dissolving the oil in DCM (50 ml) containing piperidine (5 ml); stir for 30 min., and then wash of the organic solution trice with 1N aquoeus HCI (3x). Pure title material was then obtained after drying (Na2SO4) and evaporation of the solvent. Yield: 7.54 g (63%). 1H-NMR (CDCI3): δ = 3.48 ppm (t, 4H); 3.55-3.80 (m, 16H); 4.28 (s, 2H); 4.30 (m, 1H); 8.50 (bs, 1H). 13C-NMR (CDCIa): δ = 51.04 ppm; 69.24; 70.50; 70.72; 71.39; 71.57; 80.76; 172.68. LC-MS: m/e = 399 (M+Na) +; 349 (M-N2). R, = 2.34 min. EXAMPLE 7 lmidazole-1-carboxylic acid 1,3-bis(2-(2-azidoethoxy)ethoxy)propan-2-yl ester (Formula Removed) 1,3-Bis[2-(2-azidoethoxy)ethoxy]propan-2-ol (1.00 g; 3.3 mmol) was dissolved in DCM (5 ml) and carbonyldiimidazole (1.18 g , 6.3 mmol) was added. The mixture was stirred for 2h at room temperature. Solvent was removed and the residue was dissolved in methanol (20 ml) and stirred for 20 min. Solvent was removed and the clear oil, thus obtained was further purified by column chromatography on silica using 2 % MeOH in DCM as eluent. Yield: 372.4 mg (35%). 1H-NMR (CDCI3): δ =3.33 (t, 4H); 3,60-3,75 (m, 12H); 3,80 (d, 4H); 5.35 (m, 1H); 7.06 (s, 1H);7.43(s, 1H);8.16(s, 1H). LC-MS: m/e = 413 (M+1). Rt = 2.35 min. EXAMPLE 8 tert-Butyl2-(1,3-bis[2-(2-azidoethoxy)ethoxy]propan-2-yloxy)acetate (Formula Removed) 2-(1,3-Bis[2-(2-azidoethoxy)ethoxy]propan-2-yloxy)acetic acid (5.0 g; 13.28 mmol) was dissolved in toluene (20 ml), and the reaction mixture was heated to reflux under an inert atmosphere. N,N-dimethylformamid-di-tert-butylacetal (13 ml; 54.21 mmol) was then added dropwise over 30 min. Reflux was continued for 24h. The dark brown solution was then filtered through Celite. Solvent was removed under vacuum, and the oily residue was purified by flash chromatography on silica, using 3% methanol dichloromethane as eluent. Pure fractions were pooled and evaporated to dryness. The title material was obtained as a yellow clear oil. Yield: 5.07 g (88%). 1H-NMR (CDCI3): 6 = 1.42 ppm (s, 9H); 3.35 (t, 4H); 3.54-3.69 (m, 16H); 3.75-3.85 (m, 1H); 4.16 (s, 2H). 13C-NMR (CDCI3, selected peaks): 6 = 30.35 ppm.; 52.93; 70.65; 72.25; 73.12; 73.90; 80.44; 83.55; 172.28. TLC: Rf = 0.33 in ethyl acetate -heptane (1:1). EXAMPLE 9 te/t-Butyl2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetate (Formula Removed) tert-Butyl 2-(1,3-bis[2-(2-azidoethoxy)ethoxy]propan-2-yloxy)acetate (5.97 g, 11.7 mmol) was dissolved in ethanol-water (25 ml; 2:1), and acetic acid (5 ml) was added, followed by a aqueous suspension of Raney-Nickel (5 ml). The mixture was then hydrogenated at 3 atm., for 16 h using a Parr apparatus. The catalyst was then removed by filtration, and the reaction mixture was taken to dryness by rotary evaporation. The oily residue was dissolved in water and freeze dried to give a quantitative yield of title material. 1H-NMR (CDCI3): δ = 1.45 ppm (s, 9H); 3.15 (bs, 4H); 3.48-3.89 (broad m, 17H); 4.15 (s, 2H). 13C-NMR (CDCI3, selected peaks): δ = 28.44 ppm.; 39.81; 68.17; 70.58; 70.79; 70.99; 78.81; 82.31; 170.59. EXAMPLE 10 2-(1,3-Bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetic acid (Formula Removed) 2-(1,3-Bis[2-(2-azidoethoxy)ethoxy]propan-2-yloxy)acetic acid (1.00 g; 2.65 mmol) was dissolved in 1N aqueous hydrochloric acid (10 ml) and a 50% aqueous suspension of 5 % palladium on carbon (1 ml) was added. The mixture was hydrogenated at 3.5 atm using a Parr apparatus. After one hour the reaction was stopped, and the catalyst removed by filtration. The solvent was removed by rotary evaporation, and the residue was evaporated twice from acetonitrile. Yield: 930 mg (88 %). 1H-NMR (D20): δ = 3.11 ppm (t, 4H); 3.53-3.68 (m, 16H); 3.80 (m, 1H); 4.25 (s, 2H). 13C-NMR (D2O): 6 = 38.18 ppm.; 65.43; 66.09; 68.55: 69.13; 69.23; 77.18; 173.42. EXAMPLE 11 2-(1,3-Bis[2-(2-{9-fluorenylmethyloxycarbonylamino}ethoxy)ethoxy]propan-2-yloxy)acetic acid (Formula Removed) 2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetic acid (9.35 g; 28.8 mmol) was added DIPEA (10 ml; 57 mmol). The reaction mixture was cooled on an ice bath, and chlorotrimethylsilane (15 ml; 118 mmol) dissolved in DCM (50 ml) was added dropwise, followed by DIPEA (11 ml; 62.7 mmol). To the almost clear solution was added dropwise a solution of Fmoc-CI (15.0 g; 57 mmol) in DCM (50 ml). The reaction mixture was stirred overnight, then diluted with DCM (500 ml) and added to 0.01 N aqueous HCI solution (500 ml). The organic layer was separated; washed with water (3x 200 ml) and dried over anhydrous sodium sulfate. Solvent was removed by rotary evaporation. The crude product was purified by flash chromatography on silica using ethylacetate-heptane (1:1) as eluent. Pure fractions were collected and taken to dryness to give 9.20 g (42%) of title material. 1H-NMR (D20): δ = 3.34 ppm (t, 4H); 3.45-3.65 (m, 16H); 3.69 (bs, 1H); 4.20 (t, 2H); 4.26 (s, 2H); 4.38 (d, 4H); 5.60 (t, 2H); 7.30 (t, 4H); 3.35 (t, 4H); 7.58 (d, 4H); 7.72 (d, 4H). 13C-NMR (D2O; selected peaks): 6 = 21.20 ppm.; 30.75; 34.64; 67.66; 68.90; 70.38; 70.51; 80.02; 120.37; 125.54; 127.48; 128.09; 128.67; 136.27; 141.69; 173.63; 176.80. EXAMPLE 12 2-[2-(2-azidoethoxy)ethoxy]ethanol (Formula Removed) A slurry of 2-(2-(-2-chloroethoxy)ethoxy)ethanol (25.0g, 148 mmol) and sodiumazide (14.5g, 222mmol) in dimethylformamide (250ml) was standing at 100 °C night over. The reaction mixture was cooled on an ice bath, filtered and the organic solvent was evaporated in vacuo. The residue was dissolved in dichloromethane (200ml), washed with water (75ml), the water-phase was extracted with additional dichloromethane (75ml) and the combined organic phases were dried with magnesium sulphate (MgS04), filtered and evaporated in vacuo giving an oil which was used without further purification. Yield: 30.0 g (100%). 13C-NMR (CDCI3): 5 = 72.53; 70.66-70.05; 61.74; 50.65 EXAMPLE 13 (2-[2-(2-Azidoethoxy)ethoxy]ethoxy)acetic acid (Formula Removed) The above 2-[2-(2-azidoethoxy)ethoxy]ethanol (26g,148mmol) was dissolved in tetrahydrofuran (100rnl) and under an nitrogen atmosphere slowly added to an ice cooled slurry of sodium hydride (24 g, 593 mmol, 60% in oil)) (which in advance had been washed with heptane (2x100ml)) in tetrahydrofuran (250ml). The reaction mixture was standing for 40 min. then cooled on a ice bath followed by slowly addition of bromoacetic acid (31 g, 223mmol) dissolved in tetrahydrofuran (150ml) and then standing about 3 hours at RT. The organic solvent was evaporated in vacuo. The residue was suspended in dichloromethane (400ml). Water (100ml) was slowly added, where after the mixture was standing for 30 min. under mechanical stirring. The water phase was separated, acidified with hydrochloride (4N) and extracted with dichloromethane (2x75ml). All the combined organic phases were evaporated in vacuo giving a yellow oil. To the oil was slowly added a solution,of piperidine (37 ml, 371 mmol) in dichloromethane (250ml), the mixture was standing under mechanical stirring for 1 hour. The clear solution was diluted with dichloromethane (100ml) and washed with hydrochloride (4N, 2x100ml). The water phase was extracted with additional dichloromethane (2x75ml) and the combined organic phases were evaporated in vacuo, giving an yellow oil which was used without further purification. Yield: 27.0 g (66%). 13C-NMR (CDCI3): δ = 173.30; 71.36; 70.66-70.05; 68.65; 50.65 EXAMPLE 14 (S)-2,6-Bis-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}acetylamino)hexanoic acid methyl ester (Formula Removed) The above (2-[2-(2-azidoethoxy)ethoxy]ethoxy)acetic acid (13g, 46.9mol) was dissolved in dichloromethane (100ml). N-Hydroxysuccinimide (6.5g, 56.3mmol) and 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (10.8g, 56.3mmol) was added and the reaction mixture was standing for 1 hour. Diisopropylethylamine (39ml, 234mmol) and L-lysine methyl ester dihydrochloride (6.0g, 25.8mmol) were added and the reaction mixture was standing for 16 hours. The reaction mixture was diluted with dichloromethane (300ml), extracted with water (100ml), hydrochloride (2N, 2x100ml), water (100ml), 50% saturated sodiumhydrogencarbonate (100ml) and water (2x100ml). The organic phase was dried with magnesium sulphate, filtered and evaporated in vacuo, giving an oil, which was used without further purification. Yield: 11g (73 %). LCMS: m/z = 591.13C-NMR (CDCI3): (selected) 8 = 172.48; 169.87; 169.84; 71.093-70.02; 53.51; 52.34; 51.35; 50.64; 38.48; 36.48; 31.99; 31.40; 29.13; 22.82. EXAMPLE 15 (S)-2,6-Bis-(2-{2-[2-(2-t-butyloxycarbonylaminoethoxy)ethoxy]ethoxy}acetylamino)hexanoic acid methyl ester (Formula Removed) To a solution of the above (S)-2,6-bis-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy} acetylamino)hexanoic acid methyl ester (1.0g, 1.7mmol) in ethylacetate (15ml) was added di-tert-butyl dicarbonat (0.9g, 4.24mmol) and 10% Pd/C (0.35g). Hydrogen was then constantly bubbled through the solution for 3 hours. The reaction mixture was filtered and the organic solvent was removed in vacuo. The residue was purified by flash chromatography using ethylacetate/methanol 9:1 as the eluent. Frations containing product were pooled and the organic solvent was removed in vacuo giving an oil. Yield: 0.60g (50%). LC-MS: m/z = 739 (M+1). EXAMPLE 16 (S)-2,6-Bis-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}acetylamino)hexanoic acid methyl ester (Formula Removed) The above (S)-2,6-bis-(2-{2-[2-(2-t-butyloxycarbonylaminoethoxy)ethoxy]ethoxy}acetylamino) hexanoic acid methyl ester (0.6g, 0.81 mmol) was dissolved in dichloromethane (5ml). Trifluoroacetic acid (5ml) was added and the reaction mixture was standing about 1 hour. The reaction mixture was evaporated, in vacuo, giving an oil, which was used without further purification. Yield: 0.437 g (100%). LC-MS m/z = 539 (M+1) EXAMPLE 17 (S)-2,6-Bis-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}acetylamino)hexanoic acid (Formula Removed) To a solution of (S)-2,6-bis-(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}acetylamino) hexanoic acid methyl ester (2.0g, 3.47mmol) in methanol (10ml) was added sodium hydroxide (4N,1.8ml, 6.94mmol) and the reaction mixture was standing for 2 hours. The organic solvent was evaporated in vacuo, and the residue was dissolved in water (45ml) and acidified with hydrochloric acid (4N).The mixture was extracted with dichloromethane (150ml) which was washed with saturated aqueous sodium chloride (2x25ml). The organic phase was dried over magnesium sulphate, filtered and evaporated, in vacuo, giving an oil. LC-MS m/z = 577 (M+1). EXAMPLE 18 N-(tert-Butyloxycarbonylaminoxybutyl)phthalimide (Formula Removed) To a stirred mixture of N-(4-bromobutyl)phthalimide (18.9 g, 67.0 mmol), MeCN (14 ml), and N-Boc-hydroxylamine (12.7 g, 95.4 mmol) was added DBU (15.0 ml, 101 mmol) in portions. The resulting mixture was stirred at 50 °C for 24 h. Water (300 ml) and 12 M HCI (10 ml) were added, and the product was extracted three times with AcOEt. The combined extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The resulting oil (28 g) was purified by chromatography (140 g SiO2, gradient elution with heptane/AcOEt). 17.9 g (80%) of the title compound was obtained as an oil. 1H NMR (DMSO-d6) δ= 1.36 (s, 9H), 1.50 (m, 2H), 1.67 (m, 2H), 3.58 (t, J = 7 Hz, 2H), 3.68 (t, J = 7 Hz, 2H), 7.85 (m, 4H), 9.90 (s, 1H). EXAMPLE 19 4-(tert-Butyloxycarbonylaminoxy)butylamine (Formula Removed) To a solution of N-(tert-butyloxycarbonylaminoxybutyl)phthalimide (8.35 g, 25.0 mmol) in EtOH (10 ml) was added hydrazine hydrate (20 ml), and the mixture was stirred at 80 °C for 38 h. The mixture was concentrated and the residue co-evaporated with EtOH and PhMe. To the residue was added EtOH (50 ml), and the precipitated phthalhydrazide was filtered off and washed with EtOH (50 ml). Concentration of the combined filtrates yielded 5.08 g of an oil. This oil was mixed with a solution of K2C03 (10 g) in water (20 ml), and the product was extracted with DCM. Drying (MgSO4) and concentration yielded 2.28 g (45%) of the title compound as an oil, which was used without further purification. 1H NMR (DMSO-d6): δ = 1.38 (m, 2H), 1.39 (s, 9H), 1.51 (m, 2H), 2.51 (t, J = 7 Hz, 2H), 3.66 (t, J = 7 Hz, 2H). EXAMPLE 20 2-(1,3-Bis[2-(2-hydroxyethoxy)ethoxy]propan-2-yloxy) acetic acid tert-butyl ester (Formula Removed) 1,3-Bis[2-(2-trityloxyethoxy)ethoxy]propan-2-ol (0.3 g, 0.40 mmol) was evaporated once from dry pyridine and once from dry acetonitrile. The residual was dissolved in dry DMF (2 mL), under nitrogen, 60% NaH - oil suspension (24 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 15 minutes. tert-Butylbromoacetate (0.07 mL, 0.48 mmol) was added and the mixture was stirred for an additional 60 minutes. The reaction was quenched with ice, then partitioned between diethyl ether (100 mL) and water (100 ml). The organic phase was collected, dried (Na2SO4), and solvent removed in vacuo to afford an oil which was eluted on silical gel column with EtOAc/Heptane/Et3N (49:50:1). Fraction containing main product was collected. The solvent was removed in vacuo and the residue was dissolved in 80 % aqueous acetic acid (5 mL) and stirred at room temperature overnight. Solvent was removed in vacuo and the crude material dissolved in diethyl ether (25 mL), and washed with water (2 x 5mL). The water phases were collected and the water removed on rotorvap to yield 63 mg of the title compound. 1H NMR (CDCI3): δ = 4.19 (s, 2H), 3.78-3.55 (m, 21H), 1.49(s, 9H). EXAMPLE 21 N,N-Bis(2-(2-phthalimidoethoxy)ethyl)-O-tert-butylcarbamate (Formula Removed) N,N-Bis(2-hydroxyethyl)-O-tert-butylcarbamate is dissolved in a polar, non-protic solvent such as THF or DMF. Sodium hydride (60 % suspension in mineral oil) is added slowly to the solution. The mixture is stirred for 3 hours. N-(2-Bromoethyl)phthalimide is added. The mixture is stirred until the reaction is complete. The reaction is quenched by slow addition of methanol. Ethylacetate is added. The solution is washed with aqueous sodium hydrogencarbonate. The organic phase is dried, filtered, and subsequently concentrated under vacuum as much as possible. The crude compound is purified by standard column chromatography. EXAMPLE 22 N, N- Bis(2-(2-am inoethoxy)ethyl)-O-tert-butylcarbamate (Formula Removed) N,N-Bis(2-(2-phthalimidoethoxy)ethyl)-O-tert-butylcarbamate is dissolved in a polar solvent such as ethanol. Hydrazine (or another agent known to remove the phthaloyl protecting group) is added. The mixture is stirred at room temperature (or if necessary elevated temperature) until the reaction is complete. The mixture is concentrated under vacuum as much as possible. The crude compound is purified by standard column chromatography or if possible by vacuum destination. EXAMPLE 23 N,N-Bis(2-(2-benzyloxycarbonylaminoethoxy)ethyl)-0-tert-butylcarbamate (Formula Removed) N,N-Bis(2-(2-aminoethoxy)ethyl)-O-tert-butylcarbamate is dissolved in a mixture of aqueous sodium hydroxide and THF or in a mixture of aqueous sodium hydroxide and acetonitrile. Benzyloxychloroformate is added. The mixture is stirred at room temperature until the reaction is complete. If necessary, the volume is reduced in vacuo. Ethyl acetate is added. The organic phase is washed with brine. The organic phase is dried, filtered, and subsequently concentrated in vacuo as much as possible. The crude compound is purified by standard column chromatography. EXAMPLE 24 Bis(2-(2-phtha!imidoethoxy)ethyl)amine (Formula Removed) Bis(2-(2-phthalimidoethoxy)ethyl)-tert-butylcarbamate is dissolved in trifluoroacetic acid. The mixture is stirred at room temperature until the reaction is complete. The mixture is concentrated in vacuo as much as possible. The crude compound is purified by standard column chromatography. EXAMPLE 25 11-Oxo-17-phthalimido-12-(2-(2-phthalimidoethoxy)ethyl)-3,6,9,15-tetraoxa-12-azahepta- decanoic acid (Formula Removed) 3,6,9-Trioxaundecanoic acid is dissolved in dichloromethane. A carbodiimide (for example N,N-dicyclohexylcarbodiimide or N,N-diisopropylcarbodiimide) is added. The solution is stirred over night at room temperature. The mixture is filtered. The filtrate can be concentrated in vacuo if necessary. The acylation of amines with the formed intramolecular. anhydride is known from literature (for example Cook, R. M.; Adams, J. H.; Hudson, D. Tetrahedron Lett., 1994, 35, 6777-6780 or Stora, T.; Dienes, Z.; Vogel, H.; Duschl, C. Langmuir 2000,16, 5471-5478). The anhydride is mixed with a solution of bis(2-(2-phthalimidoethoxy)ethyl)amine in a non-protic solvent such as dichloromethane or N,N-dimethylformamide. The mixture is stirred until the reaction is complete. The crude compound is purified by extraction and subsequently standard column chromatography. EXAMPLE 26 5-Oxo-11 -phthalimido-6-(2-(2-phthalimidoethoxy)ethyl)-3,9-dioxa-6-azaundecanoic acid (Formula Removed) A solution of diglycolic anhydride in a non-protic solvent such as dichloromethane or N,N-dimethylformamide is added dropwise to a solution of bis(2-(2-phthalimidoethoxy)ethyl)amine in a non-protic solvent such as dichloromethane or N,N-dimethylformamide. The mixture is stirred until the reaction is complete. The crude compound is purified by extraction and subsequently standard column chromatography. EXAMPLE 27 Bis-[2-{1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]ammonium acetate (Formula Removed) Diethylenetriamine (15.8 ml, 145.4 mmol) was added slowly to glacial acetic acid (175 ml) while it was cooled on icebath. Phthalic anhydride (43.1g, 290.8 mmol) was added. The resulting mixture was refluxed for 20 h. The solution was cooled. The mixture was concentrated in vacua. The resulting viscous oil was co-evaporated from acetonitrile 3 times. The oil was mixed with acetonitrile (250 ml) and the mixture was heated to reflux briefly. The solution was kept in fridge over night. The formed crystals were isolated by filtration. The isolated bright yellow crystals were dried in vacuum oven. Yield: 33.5 g, 63 % Additional material could be obtained by crystallisation of the filtrate after concentration (in vacua). 1H-NMR (d6-DMSO) δ: 7.81-7.74 (m, 8H), 3.60 (t, J= 6.32 Hz, 4H), 3.70-3.20 (b, 15H), 2.76 (t, J= 6.32 Hz, 4H), 1.91 (s, 5H presumably residual acetic acid is present). 13C-NMR (d6-DMSO) δ: 168.3,146.0, 134.5,132.0, 123.2, 46.5, 37.5 - minor peaks from acetonitrile and acetic acid also observed. LC-MS (ES-positive mode), m/z: 364 EXAMPLE 28 2-[2-({Bis-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]carbamoyl}methoxy)ethoxy]-ethoxy}acetic acid (Formula Removed) 3,6,9-Trioxaununcandioic acid (2.67 g, 12 mmol) and A/,A/-dicyclohexylcarbodiimide (2.48 g, 12 mmol) were mixed in dichloromethane (90 ml). The resulting mixture was stirred for 30 -minutes. The mixture was filtered and subsequently concentrated in vacua. The formed compound was dissolved in dichloromethane (250 ml). Bis-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-ammonium acetate (4.0 g, 9.45 mmol) and N,NN',N'-tetramethylguanidine (1.15 g, 10.0 mmol) were added to solution. The resulting mixture was stirred for at least 20 h. The mixture was concentrated in vacuo. Ethyl acetate (150 ml) and aqueous sodium hydrogencarbonate (5 % w/w, 150 ml) were added. The phases were separated. Concentrated hydrochloric acid was added to the aqueous phase until pH was 1 -2. The solution was extracted with dichloromethane (4 x100 ml). The combined organic extracts were dried over magnesium sulphate, filtered, and concentrated in vacuoio yield bright yellow syrup. Yield: 2.55 g, 48 % 1H-NMR (CDCI3) δ: 7.86-7.69 (m, 8H), 4.17 (s, 2H), 4.09 (s, 2H), 3.94-3.51 (several multisets, 16H). 13C- NMR (CDCI3) δ: 172.2, 170.4, 168.3, 168.0, 134.4, 134.0, 132.0, 131.7, 123.6, 123.4, . 71.3, 70.5, 70.4, 70.3, 69.2, 69.0, 44.6, 44.0, 35.7, 35.4 LC-MS (ES-positive mode), m/z: 568 [M+H]+and 591 [M+Na]+ EXAMPLE 29 ({Bis-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]carbamoyl}methoxy)acetic acid (Formula Removed) Bis-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]ammonium acetate (25.8 g, 60.9 mmol) was suspended in DCM (100 ml). N,N,N',N'-Tetramethylguanidine (7.00 g, 60.9 mmol) was added upon which massive precipitation occurred. Additional dichloromethane (50 ml) was added. Diglycolic anhydride (8.48 g, 73.0 mmol) was added in 1 portion. The mixture was stirred for at least 20 h. The mixture was concentrated in vacuo. The resulting syrup was dissolved in a mixture of ethyl acetate (750 ml) and saturated aqueous sodium hydrogencarbonate (750 • ml). The organic phase was extracted with saturated aqueous sodium hydrogencarbonate (2x200 ml). The combined aqueous phases were acidified with concentrated hydrochloric acid (pH 1-2) - massive precipitation of white solid. The combined aqueous phases were extracted with dichloromethane (400 and 2 x 200 ml). The organic phase was dried over magnesium sulphate and filtered. The organic phase was concentrated in vacuo to about 200 ml after which it was filtered again. Further precipitation occurred during filtration and concentration. The filtrate was evaporated to yield a white solid. Yield: 6.04 g 1H-NMR (d6-DMSO) δ: 12.65 (b, 1H), 7.89-7.80 (m, 8H), 4.08 (s, 2H), 3.81-3.75 (m, 6H), 3.59-3.50 (m, 4H) 13C- NMR (CDCI3) δ: 171.4, 169.4, 168.3, 168.1, 134.9, 134.7, 131.9, 131.8, 123.5, 123.3, 68.4, 67.4, 44.3, 43.5, 35.9, 35.5 LC-MS (ES-positive mode), m/z: 480 [M+H]+ EXAMPLE 30 Benzyl phenyl carbonate (Formula Removed) According to: Pittelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15,2195- 2202. Phenyl chloroformate (54.1 g, 500 mmol) was added dropwise to a mixture of benzyl alcohol (78.3 g, 500 mmol), dichloromethane (90 ml) and pyridine (50 ml) in a 1 l-flask with condenser and addition funnel. The mixture was stirred for 1 h. Water (125 ml) was added. The phases were separated. The organic phase was washed with dilute sulfuric acid (2 M, 2x125 ml). Brine had to be added in the final wash in order to obtain good separation. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude compound was vacuum destined to yield a colourless liquid. Yield:104.3g, 91 % 1H-NMR (CDCI3) δ: 7.46-7.17 (2 multisets, 10H), 5.27 (s, 2H) 13C- NMR (CDCl3) δ: 152.5, 149.9, 133.5, 128.3, 127.6, 127.5, 127.3, 124.8, 119.8, 69.1 EXAMPLE 31 Bis-(2-benzyloxycarbonylaminoethyl)ammonium chloride (Formula Removed) According to: Pittelkow, M.; Lewinsky, R.; and Christensen, J. B. Synthesis 2002, 15, 2195- 2202. Benzyl phenylcarbonate (25,1 g, 110 mmol) was added dropwise to a solution of diethylenetriamine (5,16 g, 50 mmol) in dichloromethane (100 ml). The mixture was stirred for at least 20 h. The organic phase was washed with phosphate buffer (0.025 M K2HPO4, 0.025 M NaH2PO4, 2000 ml, pH adjusted to 3 with 2 M sulfuric acid). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Yield: 25.2 g A portion (5 g) of the crude oil was mixed with hydrochloric acid (2 M, 15 ml). The mixture was stirred for 15 minutes. The mixture was filtered. The isolated solid was mixed with abs. ethanol (600 ml). The mixture was brought to reflux. The boiling mixture was decanted in order to remove insoluble impurities. The compound crystallized over night at 5 °C. Yield: 2.84 g (white crystals) 1H-NMR (d6-DMSO) δ: 8.96 (b, 2H), 7.51 (t, J= 5.56 Hz, 2H), 7.40-7.30 (b, 10H), 5,04 (s, 4H), 3.33 (q, J= 6.06 Hz, 4H), 3.00 (b, 4H) 13C- NMR (d6-DMSO) δ: 156.6, 137.2, 128.7, 128.3, 128.2, 66.0, 46.8, 37.1 LC-MS (ES-positive mode), m/z: 372.5 [M+H]+ EXAMPLE 32 [2-(2-{[Bis-(2-benzyloxycarbonylaminoethyl)carbamoyl]methoxy}ethoxy)ethoxy]acetic acid (Formula Removed) 3,6,9-Trioxaundecandioic acid (1.83 g, 8.3 mmol) and N,/V'-dicyclohexylcarbodiimide (1.70 g, 8.3 mmol) were mixed in dichloromethane (10 ml). The resulting mixture was stirred for 30 minutes. The mixture was filtered and subsequently concentrated in vacua. The formed compound was mixed with bis-(2-benzyloxycarbonylaminoethyl)ammonium chloride (2.8 g, 6.87 mmol) and /V,/V,/V',/V-tetramethylguanidine (791 mg, 6.87mmol)(250 ml) in N,N-di-methylformamide (27 ml). The resulting mixture was stirred for 20 h. The mixture was concentrated in vacuo. Ethyl acetate (150 ml) and aqueous sodium hydrogencarbonate (5 % w/w, 150 ml) were added. The phases were separated. The organic phase was extracted with aqueous sodium hydrogencarbonate (5 % w/w, 2 x 100 ml). The combined aqueous extracts were mixed with ethyl acetate (200 ml). Concentrated hydrochloric acid was added to the mixture until pH was 2-3. The phases were separated immidiately. The aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were dried with magnesium sulphate, filtered, and concentrated in vacuo to yield colourless syrup. Yield: 2.17 g, 55% 1H-NMR (CDCI3) δ: 10.2 (b, 1H), 7.31 (b, 10H), 6.10 (b, 1H), 5.84 (b, 1H), 5.06 (s, 2H), 5.04 (s, 2H), 4.17-4.09 (m, 4H), 3.72-3.22 (several multisets, 16H) 13C- NMR (CDCI3) δ: 172.9, 171.2, 157.3, 137.0, 128.9-128.4 (several signals), 71.3, 70.8, 70.7, 70.3, 68.9, 67.1, 67.0, 47.5, 46.0, 39.6 LC-MS (ES-positive mode), m/z: 576 [M+H]+ EXAMPLE 33 [2-(2-{[Bis-(2-aminoethyl)carbamoyl]methoxy}ethoxy)ethoxy]aceticacid (Formula Removed) [2-(2-{[Bis-(2-benzyloxycarbonylaminoethyl)carbamoyl]methoxy}ethoxy)ethoxy]acetic acid (725 mg, 1.26 mmol) is dissolved in methanol (50 ml). Palladium on activated carbon (150 mg, 5 % Pd, wet, Degussa catalyst type E101 NO/W) was added. The mixture was stirred in an atmosphere of hydrogen gas for 20 h. The mixture was filtered. The filtrate was concentrated in vacuo. LC-MS (ES-positive mode), m/z: 309 [M+H]+, 291 [M-H20]+ EXAMPLE 34 [2-(2-{[Bis-(2-benzyloxycarbonylaminoethyl)carbamoyl]methoxy}ethoxy)ethoxy]aceticacid 2,5-dioxopyrrolidin-1-yl ester (Formula Removed) [2-(2-{[Bis-(2-benzyloxycarbonylaminoethyl)carbamoyl]methoxy}ethoxy)ethoxy]aceticacid (1.45 g, 2.52 rnmol) was mixed with N-hydroxysuccinic imide (291 mg, 2.53 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (485 mg, 2.53 mmol), and N,N,N',N'-tetramethylguanidine (291 mg, 2.53 mmol). The mixture was stirred for 20 h. Aqueous sodium hydrogensulfate (5 % w/w, 150 ml) and dichloromethane (100 ml) were added. The phases were separated. The aqueous phase was extracted with dichloromethane (2 x 100 and 2 x 50 ml). The combined organic phases were dried over solid sodium sulfate, filtered, and concentrated in vacuo. LC-MS (ES-positive mode), m/z: 674 [M+H]f, 577 (unreacted starting material). EXAMPLE 35 1,2,3-Benzotriazin-4(3H)-one-3-yl 2-[2-(2-methoxyethoxy)ethoxy]acetate (Formula Removed) 3-Hydroxy-1 ,2,3-benzotriazin-4(3H)-one (10.0 g; 61 .3 mmol) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (10.9 g; 61.3 mmol) was suspended in DCM (125 ml) and DIC (7,7 g; 61.3 mmol) was added. The mixture was stirred under a dry atmosphere at ambient temperature over night. A precipitate of diisopropyl urea was formed, which was filtered off. The organic solution was washed extensively with aqueous saturated sodium hydrogen carbonate solution, then dried (Na2SO4) and evaporated in vacuo, to give the title product as a clear yellow oil. Yield was 16.15 g (81%). 1H-NMR (CDCI3): δ = 3.39 ppm (s, 3H); 3.58 (t, 2H); 3.68 (t, 2H); 3.76 (t, 2H); 3.89 (t, 2H); 4.70 (s, 2H); 7.87 (t, 1H); 8.03 (t, 1H); 8.23 (d, 1H); 8.37 (d, 1H). 13C-NMR (CDCI3, selected peaks): δ = 57.16 ppm; 64.96; 68.71; 68.79; 69.59; 69.99; 120.32; 123.87; 127.17; 130.96; 133.63; 142.40; 148.22; 164.97. OLIGOMERIC PRODUCTS: Solid Phase Oligomerisation: The reactions described below are all performed on polystyrene functionalised with the Wang linker. The reactions will in general also work on other types of solid supports, as well as with other types of functionalised linkers. Solid phase azide reduction: The reaction is known (Schneider, S.E. et al. Tetrahedron, 1998, 54(50) 15063-15086) and can be performed by treating the support bound azide with excess of triphenyl phosphine in a mixture of THF and water for 12-24 hours at room temperature. Alternatively, trimethylphosphine in aqueous THF as described by Chan, T.Y. et al Tetrahedron Lett. 1997, 38(16), 2821-2824 can be used. Reduction of azides can also be performed on solid phase using sulfides such as dithiothreitol (Meldal, M. et al. Tetrahedron Lett. 1997, 38(14), 2531-2534) 1,2-dimercaptoethan and 1,3-dimercaptopropan (Meinjohanns, E. et al. J. Chem. Soc, Perkin Trans 1,1997,6, 871-884) ortin(ll) salts such as tin(ll)chloride (Kim, J.M. et al. Tetrahedron Lett, 1996, 37(30), 5305-5308). Solid phase carbamate formation: The reaction is known and is usually performed by reacting an activated carbonate, or a halo forrniate derivative with an amine, preferable in the presence of a base. EXAMPLE 36 3-(1,3-Bis{2-[2-([benzoylamino]ethoxy)ethoxy}propan-2-yloxycarbonyl)amino)propanoicacid (Formula Removed) This example uses the 1,3-bis[2-(2-azidoethoxy)ethoxy]propan-2-yl-p-nitrophenylcarbonate monomer building block prepared in example 4 in the synthesis of a second generation carbamate based branched polymer capped with 2-[2-(2-methoxyethoxy)ethoxy]acetic acid. The coupling chemistry is based on standard solid phase carbamate chemistry, and the protection methodology is based on a solid phase azide reduction step as described above. Step 1: Fmoc-p-Ala-Wang resin (100 mg; loading 0.31 mmol/g BACHEM) was suspended in dichloromethane for 30 min, and then washed twice with DMF. A solution of 20% piperidine in DMF was added, and the mixture was shaken for 15 min at ambient temperature. This step was repeated, and the resin was washed with DMF (3x) and DCM (3x). Step 2: Coupling of monomer building blocks: A solution of 1,3-bis[azidoethoxyethyl]propan-2-yl-p-nitrophenylcarbamate (527 mg; 1,4 mmol, 4x) was added to the resin together with DIPEA (240 jil; 1,4 mmol, 4x). The resin was shaken for 90 min, then drained and washed with DMF (3x) and DCM (3x). Step 3: Capping with acetic anhydride: The resin was then treated with a solution of acetic anhydride, DIPEA, DMF (12:4:48) for 10 min. at ambient temperature. Solvent was removed and the resin was washed with DMF (3x) and DCM (3x). Step 4: Deprotection (reduction of azido groups): The resin was treated with a solution of DTT (2M) and DIPEA (1M) in DMF at 50 oC for 1 hour. The resin was then washed with DMF (3x) and DCM (3x). A small amount of resin was withdrawn and treated with a solution of benzoylchloride (0.5 M) and DIPEA (1 M) in DMF for 1h. The resin was cleaved with 50% TFA/DCM and the dibenzoylated product analysed with NMR and LC-MS. 1H-NMR (CDCI3): 6 = 3.50-3.75 (m, 20H); 3.85 (s, 1H); 4.25 (d, 2H); 6.95 (t, 1H); 7.40-7.50 (m, 6H); 7.75 (m, 4H). LC-MS: m/z = 576 (M+1); R, = 2.63 min. EXAMPLE 37 3-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}ethoxy)ethoxy]propan-2-yl- oxy)acetylamino]propanoic acid (Formula Removed) Step 1: Fmoc-β-Ala linked Wang resin (A22608, Nova Biochem, 3.00 g; with loading 0.83 mmol/g) was swelled in DCM for 20 min. then washed with DCM (2x20 ml) and NMP (2x20 ml). The resin was then treated twice with 20% piperidine in NMP (2x15 min). The resin was washed with NMP (3x20 ml) and DCM (3x20 ml). Step 2: 2-(1,3-Bis[2-(2-azidoethoxy)ethoxy]propan-2-yloxy)acetic acid (3.70 g; 10 mmol) was dissolved in NMP (30 ml) and DhbtOH (1.60 g; 10 mmol) and DIG (1.55 ml; 10 mmol) was added. The mixture was stirred at ambient temperature for 30 min, and then added to the resin obtained in step 1 together with DIPEA (1.71 ml; 10 mmol). The reaction mixture was shaken for 1.5 h, then drained and washed with NMP (5x20 ml) and DCM (3x20 ml). Step 3: A solution of SnCI2.2H2O (11.2 g; 49.8 mmol) in NMP (15 ml) and DCM (15 ml) was then added. The reaction mixture was shaken for 1h. The resin was drained and washed with NMP:MeOH (5x20 ml; 1:1). The resin was then dried in vacuo. Step 4: A solution of 2-[2-(2-methoxyethyl)ethoxy]acetic acid (1.20 g; 6.64 mmol), DhbtOH (1.06g; 6.60 mmol) and DIG (1.05 ml; 6.60 mmol) in NMP (10 ml) was mixed for 10min, at room temperature, and then added to the 3-[2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetylamino]propanoic acid tethered wang resin (1.0 g; 0.83 mmol/g) obtained in step 3. DIPEA (1.15 ml, 6.60 mmol) was added, and the reaction mixture was shaken for 2.5 h. Solvent was removed, and the resin was washed with NMP (5x20 ml) and DCM (10x20 ml). Step 5: The resin product of step 4 was treated with TFA:DCM (10 ml, 1:1) for 1 hour. The resin was filtered and washed once with TFA:DCM (10 ml, 1:1). The combined filtrate and washing was then taken dryness, to give a yellow oil (711 mg). The oil was dissolved in 10% acetonitril-water (20 ml), and purified over two runs on a preparative HPLC apparatus using a C18 column, and a gradient of 15-40% acetonitril-water. Fractions were subsequently analysed by LC-MS. Fractions containing product were pooled and taken to dryness. Yield: 222 mg (37%). LC-MS: m/z = 716 (M+1), Rt = 1.97 min. 1H-NMR (CDCI3): δ = 2.56 ppm (t, 2H); 3.36 (s, 6H); 3.46-3.66 (m, 39H); 4.03 (s, 4H); 4.16 (s, 2H); 7.55 (t, 2H); 8.05 (t, 1H). 13C-NMR (CDCI3, selected peaks): 6 = 33.71 ppm; 34.90; 58.89; 68.94; 69.40; 69.98; 70.09; 70.33; 70.74; 70.91; 71.07; 71.74; 79.07; 171.62; 171.97; 173.63. EXAMPLE 38 3-(1,3-Bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}ethoxy)ethoxy]- propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetylamino)propanoicacid (Formula Removed) This material was prepared from 3-[2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)-acetylamino]propanoic acid tethered wang resin (1.0 g; 0.83 mmol/g), obtained in step 3 of example by repeating step 2-5, doubling the amount of reagents used. Yield: 460 mg (33%). MALDI-MS (a-cyano-4-hydroxycinnamic acid): m/z = 1670 (M+Na). 1H-NMR (CDCI3): δ = 2.57 ppm (t, 2H); 3.38 (s, 12H); 3.50-3.73 (m, 85 H); 4.05 (s, 8H); 4.17 (s, 2H); 4.19 (s, 4H); 7.48 (m, 4H); 7.97 (m, 3H). 13C-NMR (CDCI3, selected peaks): 6 = 38.81 ppm; 58.92; 69.46; 69.92; 70.05; 70.05; 70.13; 70.40; 70.73; 70.97; 71.11; 71.88; 76.74; 77.06; 77.38; 171.33; 172.02. Alternative mode of preparation: This example uses the 2-(1,3-bis[azidoethoxyethyl]propan-2-yloxy)acetic acid monomer building block prepared in example 6 in the synthesis of a second generation amide based branched polymer capped with 2-[2-(2-methoxyethoxy)ethoxy]acetic acid. The coupling chemistry is based on standard solid phase peptide chemistry, and the protection methodology is based on a solid phase azide reduction step as described above. Step 1: Fmoc-p-Ala-Wang resin (100 mg; loading 0.31 mmol/g BACHEM) was suspended irr dichloromethane for 30 min, and then washed twice with DMF. A solution of 20% piperidine in DMF was added, and the mixture was shaken for 15 min at ambient temperature. This step was repeated, and the resin was washed with DMF (3x) and DCM (3x). Step 2: Coupling of monomer building blocks: A solution of 2-(1,3-bis[azidoethoxyethyl]-propan-2-yloxy)acetic acid (527 mg; 1,4 mmol, 4x) and DhbtOH (225 mg; 1,4 mmol, 4x) were dissolved in DMF (5 ml) and DIG (216 µ1,1,4 mmol, 4x) was added. The mixture was left for 10 min (pre-activation) then added to the resin together with DIPEA (240 ul; 1,4 mmol, 4x). The resin was shaken for 90 min, then drained and washed with DMF (3x) and DCM (3x). Step 3: Capping with acetic anhydride: The resin was then treated with a solution of acetic anhydride, DIPEA, DMF (12:4:48) for 10 min. at ambient temperature. Solvent was removed and the resin was washed with DMF (3x) and DCM (3x). Step 4: Deprotection (reduction of azido groups): The resin was treated with a solution of DTT (2M) and DIPEA (1M) in DMF at 50 SC for 1 hour. The resin was then washed with DMF (3x) and DCM (3x). A small amount of resin was withdrawn and treated with a solution of benzoylchloride (0.5 M) and DIPEA (1 M) in DMF for 1h. The resin was cleaved with 50% TFA/DCM and the dibenzoylated product analysed with NMR and LC-MS. 1H-NMR (CDCI3): δ = 3.50-3.75 (m, 20H); 3.85 (s, 1H); 4.25 (d, 2H); 6.95 (t, 1H); 7.40-7.50 (m, 6H); 7.75 (m, 4H). LC-MS: m/e = 576 (M+1); Ft, = 2.63 min. Step 5-7 was performed as step 2-4 using a double molar amount of reagents but same amount of solvent. Step 8: Capping with 2-[2-(2-methoxyethoxy)ethoxy]acetic acid: A solution of 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (997 mg; 5.6 mmol, 16x with respect to resin loading) and DhbtOH (900 mg; 5.6 mmol, 16x) were dissolved in DMF (5 ml) and DIG (864 ul, 5.6 mmol, 16x) was added. The mixture was left for 10 min (pre-activation) then added to the resin together with DIPEA (960 ul; 5.6 mmol, 16x). The resin was shaken for 90 min, then drained and washed with DMF (3x) and DCM (3x). Step 9: Cleavage from resin: The resin was treated with a 50% TFA - DCM solution at ambient temperature for 30 min. The solvent was collected and the resin was washed an additional time with 50% TFA - DCM. The combined filtrates were evaporated to dryness, and the residue was purified by chromatography. EXAMPLE 39 3-(1,3-Bis{2-(2-[2-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}- ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetylamino)-ethoxy)ethoxy}propan-2-yloxy)acetylamino)propanoic acid (Formula Removed) This material was prepared from 3-[2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)-acetylaminojpropanoic acid tethered wang resin (1.0 g; 0.83 mmol/g), obtained in step 3 of example by repeating step 2-3 with 2x the amount of reagents used, then repeating step 2-5 with 4x the amount of reagent used. Yield: 84 mg (4%). LC-MS: (m/2)+1 = 1758; (m/3)+1 = 1172; (m/4)+1 = 879; (m/5)+1 = 704. R, = 2.72 min. 1H-NMR (CDCI3): 6 = 2.51 ppm (t, 2H); 3.33 (s, 24H); 3.44-3.70 (m, 213H); 3.93 (s, 16H); 4.08 (s, 14H); 7.25 (m, 8H); 7.69 (m, 7H). 13C-NMR (CDCI3, selected peaks): δ = 38.94 ppm; 59.33; 69.78; 70.08; 70.37; 70.44; 70.56; 70.82; 71.10; 71.26; 71.51; 72.17; 79.24; 170.60; 171.22. EXAMPLE 40 N-Hydroxysuccinimidyl 3-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}- ethoxy)ethoxy]propan-2-yloxy)acetylamino]propanoate (Formula Removed) 3-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}ethoxy)ethoxy]propan-2-yl-oxy)acetylamino]propanoic acid (67 mg; 82 µmol) was dissolved in THF (5 ml). The reaction-mixture was cooled on an ice bath. DIPEA (20 µl; 120 µmol) and TSTU (34 mg; 120 µmol) was added. The mixture was stirred at ambient temperature overnight at which time, the reaction was complete according to LC-MS. LC-MS: m/z = 813 (M+H); Rt = 2.22 min. EXAMPLE 41 N-Hydroxysuccinimidyl 3-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acet- amino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetyl-amino)propanoate (Formula Removed) Prepared from 3-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}-ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)-acetylamino)propanoic acid and TSTU similarly as as described in example 40. LC-MS: (m/2)+1 = 873, R, = 2.55 min. EXAMPLE 42 N-Hydroxysuccimidyl 3-(1,3-bis{2-(2-[2-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)- ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)-acetylamino)ethoxy)ethoxy}propan-2-yloxy)acetylamino)propanoate (Formula Removed) Prepared from N-hydroxysuccinimidyl 3-(1,3-bis{2-(2-[2-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}-propan-2-yloxy)acetylamino)ethoxy)ethoxy}propan-2-yloxy)acetylamino)propanoic acid and TSTU as described in example 40. LC-MS: (m/4)+1 = 903, Rt = 2.69 min. EXAMPLE 43 N-(4-tert-Butoxycarbonylaminoxybutyl) 3-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxy- ethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetylamino)propanamide (Formula Removed) N-Hydroxysuccinimidyl 3-(1 ,3-bis{2-(2-[2-(1 ,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acet-amino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetyl-amino)propanoate (105 mg; 0.06 mmol) was dissolved in DCM (2 ml). Then a solution of 4-(tert-butyloxycarbonylaminoxy)butylamine (49 mg; 0.24 mmol) was added followed by DIPEA (13 µl 0.07 mmol). The mixture was stirred at ambient temperature for one hour, then concentrated under reduced pressure. The residue was dissolved in 20% acetonitril-water (4 ml), and purified on a preparative HPLC apparatus using a C18 column, and a step gradient of 0, 10, 20, 30, and 40% (10 ml elutions each) of acetonitril-water. Fractions containing pure product was concentrated and dried for 16 hours in a vacuum oven to give a yellow oil. Yield: 57 mg (51%). LC-MS: (m/2)+1 = 918, Rt = 2.75 min. 1H-NMR (CDCI3): δ = 1.42 ppm (s, 9H); 2.40 (t, 2H); 3.21 (dd, 2H); 3.33 (s, 12H); 3.38-3.72 (m, 99H); 3.80 (m, 2H); 3.95 (s, 8H); 4.08 (s, 6H); 6.99 (m, 1H); 7.23 (m, 4H); 7.69 (m, 2H); 7.85 (m, 1H); 8.00 (m, 1H). 13C-NMR (CDCI3, selected peaks): 6 = 28.27 ppm; 38.58; 58.97; 69.42; 69.72; 70.01; 70.08; 70.20; 70.41; 70.46; 70.73; 70.91; 71.16; 71.22; 71.81; 78.89; 81.33; 170.27; 170.89. EXAMPLE 44 N-(4-Aminoxybutyl) 3-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acet- amino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetyl-amino)propanamide (Formula Removed) N-(4-tert-Butoxycarbonylaminoxybutyl) 3-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxy-ethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetylamino)propanamide (19 mg; 10 µmol) was dissolved in 50% TFA/DCM (10 ml), and the clear solution was stirred at ambient temperature for 30 min. The solvent was removed by rotary evaporation, and the residue was stripped twice from DCM, to give a quantitative yield (19 mg) of the title product. LC-MS: (m/2)+1 = 868, (m/3)+1 = 579, R, = 2,35 min. EXAMPLE 45 tert-Butyl2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2- yloxy)acetate (Formula Removed) tert-Butyl 2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetate (1.74 g; 4.5 mmol, example 9) and 1,2,3-benzotriazin-4(3H)-one-3-yl 2-[2-(2-methoxyethoxy)ethoxy]acetate (2.94 g; 9 mmol, example 35) were dissolved in DCM (100 ml). DIPEA (3.85 ml; 22.3 mmol) was added and the clear mixture was stirred for 90 min at room temperature. Solvent was removed in vacuo, and the residue was purified by chromatography on silica, using MeOH -DCM (1:16) as eluent. Pure fractions were pooled and taken to dryness to give the title material as a clear oil. Yield was 1.13 g (36 %). 1H-NMR (CDCI3): δ = 1.46 ppm (s, 9H); 3.38 (s, 6H); 3.49-3.69 (m, 37H); 4.01 (s, 4H); 4.18 (s, 2H); 7.20 (bs, 2H). EXAMPLE 46 2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)- acetic acid: (Formula Removed) tert-Butyl 2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetate (470 mg; 0.73 mmol) was dissolved in DCM-TFA (25 ml, 1:1) and the mixture was stirred for 30 min at ambient temperature. The solvent was removed, in vacuo, and the residue was stripped twice from DCM. LC-MS: (M+1) = 645, R, = 2,26 min. 1H-NMR (CDCI3): δ = 3.45 ppm (s, 6H); 3.54-3.72 (m, 37H); 4.15 (s, 4H); 4.36 (s, 2H). EXAMPLE 47 N-Hydroxysuccimidyl 2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}ethoxy)- ethoxy] propan-2-y loxy)acetate (Formula Removed) 2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)-acetic acid (115 mg; 0.18 mmol) was dissolved in THF (5 ml). The reaction mixture was placed on an ice bath. TSTU (65 mg, 0.21 mmol) and DIPEA (37 jal; 0.21 mmol) was added and the reaction mixture was stirred at 0 SC for 30 min, then at room temperature overnight. The reaction was then taken to dryness, to give 130 mg of the title material as an clear oil. LC-MS: (m+1) = 743, (m/2)+1 = 372, R, = 2,27 min. EXAMPLE 48 t-Butyl 3-(1,3-bis{2-(2-[2-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acet- amino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)acetyl-amino)ethoxy)ethoxy}propan-2-yloxy)acetate (Formula Removed) The material was prepared from two equivalents of N-hydroxysuccimidyl 2-(1,3-bis[2-(2-{2-[2- (2-methoxyethoxy)ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)acetate and one equivalent of tert-butyl 2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetate, using the protocol and purification method described in example 45. Further dendritic growth may be acchieved by removing the te/t-butyl group as described in example 46 and subsequent N-hydroxysuccimidyl ester formation as described in example 47 followed by coupling to tert-butyl 2-(1,3-bis[2-(2-aminoethoxy)ethoxy]propan-2-yloxy)acetate as described in this example. EXAMPLE 49 (S)-2,6-Bis(2-[2-(2-[2-(2,6-bis-[2-(2-[2-(2-azidoethoxy)ethoxy]ethoxy)acetylamino]hexanoyl- -amino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoic acid methyl ester (Formula Removed) (S)-2,6-Bis(2-{2-[2-(2-azidoethoxy)ethoxy]ethoxy}acetylamino)hexanoic acid (1.8g, 3.10mmol)) was dissolved in a mixture of dimethylformamide/dichloromethane 1:3 (10ml), pH was adjusted to basic reaction using diisopropylethylamine, N-hydroxybenzotriazole and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and the reaction mixture was standing for 30 min. Then this reaction mixture was added to a solution of (S)-2,6-bis-(2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}acetylamino)hexanoic acid methyl ester (0.37g, 0.70mmol in dichloromethane) and the reaction mixture was standing the night over. The reaction mixture was diluted with dichloromethane (150ml), washed with water (2x40ml), 50% saturated sodium hydrogen carbonate (2x30ml) and water (3x40ml). The organic phase was dried over magnesium sulphate, filtered and evaporated in vacuo giving an oil. Yield: 1.6g (89%). LC-MS: m/z = 1656 (M+1), 828.8 (M/2)+1 and 553 (M/3)+1. EXAMPLE 50 (S)-2,6-Bis(2-[2-(2-[2-((S)-2,6-bis[2-(2-[2-(2-tert-butoxycarbonylaminoethoxy)ethoxy]ethoxy)- acetylamino]hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoic acid methyl ester (Formula Removed) To a solution of the above (S)-2,6-Bis(2-[2-(2-[2-((S)-2,6-bis[2-(2-[2-(2-azidoethoxy)ethoxy]-ethoxy)acetylamino]hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoicacid methyl ester (1.6g, 0.97mmol) in ethylacetate (60ml), was added di-tert-butyl dicarbonate (1.0g, 4.8mmol) and Pd/C (10%, 1.1g). Hydrogen was constantly bubbled through the reaction mixture for 2 hours. The reaction mixture was filtered and the organic solvent was removed in vacuo giving an oil which was used without further purification. Yield: 1.8 g (98%). LC-MS: m/z = 1953 (M+1), 977 (M/2)+1. EXAMPLE 51 (S)-2,6-Bis(2-[2-(2-[2-((S)-2,6-bis[2-(2-[2(2aminoethoxy)ethoxy]ethoxy)acetylamino]- hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoic acid methyl ester (Formula Removed) butoxycarbonylaminoethoxy)- ethoxy]ethoxy)acetylamino]hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoicacid methyl ester was dissolved in dichloromethane (20ml) and trif luoroacetic acid (20ml) was added. The reaction mixture was standing for 2 hours. The organic solvent was evaporated in vacuo, giving an oil. Yield: 1.4g (100%). LC-MS: m/z = 1552 (M+1); 777.3 (M/2)+1; 518.5 (M/3)+1 and 389.1 EXAMPLE 52 (S)-2,6-Bis-(2-[2-(2-[2-((S)-2,6-bis-[2-(2-[2-(2-(2-(2-(2-methoxyethoxy)ethoxy)acetylamino)-ethoxy)ethoxy]ethoxy)acetylamino]hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)-hexanoic acid methyl ester (Formula Removed) To a solution of 2-(2-(methoxyethoxy)ethoxy)acetic acid (1.3 g, 7.32 mmol) in a mixture of dichloromethane and dimethylformamide 3:1 (20 ml) was added N-hydroxysuccinimide (0.8g, 7.32 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4g, 7.32mmol). The reaction mixture was standing for 1 hour, where after the mixture was added to a solution of (S)-2,6-bis(2-[2-(2-[2-((S)-2,6-bis[2-(2-[2(2aminoethoxy)ethoxy]ethoxy)acetyl-amino]hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoic acid methyl ester (1.42g,-0.92mmol) and diisopropylethylamine (2.4ml, 14.64 mmol) in dichloromethane (10ml). The reaction mixture was standing night over. The reaction mixture was diluted with dichloromethane (100ml) and extracted with water (3x25 ml). The combine water-phases were extracted with additional dichloromethane (2x75 ml). The combined organic phases were dried over magnesium sulphate, filtered and evaporated in vacuo. The residue was purified by flash chromatography using 500 ml ethyl acetate, followed by 500ml ethyl acetate / methanol 9:1 and finally methanol as the eluent. Fractions containing product were evaporated in vacuo giving an oil. Yield: 0.75 g (38%). LC-MS: m/z = 1097 (M/2)+1; 732 (M/3)+1 and549(M/4)+1. The(S)-2,6-Bis-(2-[2-(2-[2-((S)-2,6-bis-[2-(2-[2-(2-(2-(2-(2-methoxyethoxy)ethoxy)acetyl-amino)ethoxy)ethoxy]ethoxy)acetylamino]hexanoylamino)ethoxy]ethoxy)ethoxy]acetyl-amino)hexanoic acid methyl ester can be saponified to the free acid and attached to a free amino group of ITA for example, on either E amino lysin residues or on the terminal a-amino group using an activated ester. The activated ester may be produced and coupled to the amino group of the ITA peptide by standard coupling methods known in the art such as diisopropylethylamine and N-hydroxybenzotriazole or other activating conditions. Alternatively, the tertbutyl protected carboxylic acids intermediate above, may be deprotected and subsequemtly activated as OSu esters (for example, as described in example 40) for attachment to the ITA peptide. EXAMPLE 53 [2-(2-([Bis-(2-(2-[2-(2-frbis-(2-benzvloxvcarbonvlaminoethvl)carbamovl1methoxy}ethoxy)- ethoxyacetvlamino)ethyl)carbamovl1methoxy}ethoxy)ethoxy]acetic acid A solution of [2-(2-{[bis-(2-benzyloxycarbonylaminoethyl)carbamoyl]methoxy}ethoxy)ethoxy]- acetic acid 2,5-dioxopyrrolidin-1-yl ester (2.53 mmol - from previous experiment, mass not determined) in tetrahydrofuran (50 ml) and a solution of [2-(2-{[bis-(2-aminoethyl)carbamoyl]- methoxy}ethoxy)ethoxy]acetic acid (1.26 mmol -from previous experiment, mass not determined) in aqueous sodium hydrogencarbonate (5 % w/w, 50 ml) were mixed. The mixture was stirred for at least 20 h. Solid sodium hydrogensulfate was added until pH was 2-3. The phases were separated. The aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined organic phases were washed with aqueous sodium hydrogensulfate (5 % w/w, 50 ml). The aqueous phase was extracted with dichloromethane (2 x 50 ml). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacua. Yield: 989 mg LC-MS (ES-positive mode), m/z: 1423 [M+H]+ General procedure for synthesis of dendrimers with charged phosphate backbones. (Formula Removed) Alternatively, the tertbutyl protected carboxylic acids intermediate above, may be deprotected and subsequently activated as OSu esters (for example as described in example 47) for attachment to insulin. EXAMPLE 54 (Formula Removed) 2-(2-Trityloxyethoxy)ethanol: (Formula Removed) Triphenyl chloromethane (10g, 35.8 mmol) was dissolved in dry pyridine, diethyleneglycol (3.43 ml, 35.8 mmol) was added and the mixture was stirred under nitrogen overnight. Solvent removed in vacuo. Dissolved in dichloromethane (100 mL) and washed with water. Organic phase dried over Na2SO4 and solvent removed in vacuo. Crude product was purified by recrystallization from heptane/toluene (3:2) to yield the title compound. 1H NMR (CDCI3): δ = 7.46 (m, 6H), 7.28, (m, 9H), 3.75 (t, 2H), 3.68 (t, 2H), 3.62 (t, 2H), 3.28 (t, 2H). LC-MS: m/z = 371 (M+Na); R, = 2.13 min. 2-[2-(2-Trityloxyethoxy)ethoxymethyl]oxirane: (Formula Removed) 2-(2-Trityloxyethoxy)ethanol (6.65 g, 19 mmol) was dissolved in dry THF (100 mL). 60 % NaH (0.764 mg, 19 mmol) was added slowly. The suspension was stirred for 15 min. Epibromohydrin (1.58 mL, 19 mmol) was added and the mixture was stirred under nitrogen at room temperature overnight. The reaction was quenched with ice, separated between diethyl ether (300 mL) and water (300 mL). The water fase was extracted with dichloromethane. The organic phases were collected, dried (Na2SO4) and solvent removed in vacou.to afford an oil which was purified on silical gel column eluted with DCM/MeOH/Et3N (98:1:1) to yield the title compound. 1H NMR (CDCIa): δ = 7.45 (m, 6H), 7.25, (m, 9H), 3.82 (dd, 1H), 3.68 (m, 6H), 3.45 (dd, 1H), 3.25 (t, 2H), 3.15 (m, 1H ), 2.78 (t, 1H), 2.59 (m, 1H). LC-MS: m/z = 427 (M+Na); R, = 2.44 min. 1,3-Bis[2-(2-trityloxyethoxy)ethoxy]propan-2-ol: (Formula Removed) 2-(2-Trityloxyethoxy)ethanol (1.14 g, 3.28 mmol) was dissolved in dry DMF (5 mL). 60 % NaH (144 mg, 3.61 mmol) was added slowly and the mixture was stirred under nitrogen at room temperature for 30 min. The mixture is heated to 40°C. 2-[2-(2-Trityloxyethoxy)ethoxymethyl]oxirane (1.4 g, 3.28 mmol) was dissolved in dry DMF (5 mL) and added drop wise to the solution under nitrogen while stirring was maintained. After ended addition the mixture is stirred under nitrogen at 40°C overnight. The heating is removed and after cooling to room temperature the reaction is quenched with ice and poured into saturated aqueous NaHCO3(100 mL), extracted with diethyl ether (3 x75 mL). The organic phases are collected, dried (Na2SO4), and solvent removed in vacuo to afford an oil which was purified on silical gel column eluted with EtOAc/Heptane/Et3N (49:50:1) to yield -the title compound. 1H NMR (CDCI3): 6 = 7.45 (m, 12H), 7.25, (m, 18H), 3.95 (m, 1H), 3.78-3.45 (m, 16H), 3.22 (t, 4H), LC-MS: m/z = 775 (M+Na); R, = 2.94 min. 1 ,3-Bis[2-(2-trityloxyethoxy)ethoxy]propan-2-ol (2-cyanoethyl diisopropylphosphoramidite): (Formula Removed) 1,3-Bis[2-(2-trityloxyethoxy)ethoxy]propan-2-ol (0.95 g, 1.26 mmol) was aveporated twice from dry pyridine and once from dry acetonitrile. Dissolved in dry THF (15 mL), while stirring under nitrogen, diisopropylethylamin (1.2 mL, 6.95 mmol) was added. The mixture was coold to 0°C with an icebath 2-cyanoethyl diisopropylchlorophosphoramidite (0.39 mL, 1.77 mmol) was added under nitrogen. The mixture was stirred for 10 minutes at 0°C followed by 30 minutes at room temperature. Aqueous NaHCO3(50 mL) was added and the mixture extracted with DCM/Et3N (98:2) (3x30 mL). Organic phases were collected, dried (Na2SO4), and solvent removed in vacuo to afford an oil which was purified on silical gel column eluted with EtOAc/Heptane/Et3N (35:60:5) to yield the 703 mg of title compound. 31P-NMR (CDCI3): δ149.6ppm {2-[2-(2-Hydroxyethoxy)ethoxy]-1 -[2-(2-hydroxyethoxy)ethoxymethyl]ethoxy}acetic acid tert-butyl ester: (Formula Removed) 1,3-Bis[2-(2-trityloxyethoxy)ethoxy]propan-2-ol (0.3 g, 0.40 mmol) was evaporated once from dry pyridine and once from dry acetonitrile. Dissolved under nitrogen in dry DMF (2 ml), 60% NaH (24 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 15 minutes, tert-butylbromoacetate (0.07 mL, 0.48 mmol) was added and the mixture was stirred for additional 60 minutes. The reaction was quenched with ice. Separated between diethyl ether (2 x50 mL) and water (2 x 50 mL), the organic phases were collected, dried (Na2SO4), and solvent removed in vacuo to afford an oil which was eluted on silical gel column with EtOAc/Heptane/Et3N (49:50:1). Fraction containing main product was collected, solvent removed in vacuo and dissolved in 80 % aqueous acetic acid (5 mL) and stirred at room temperature overnight. Solvent was solvent removed in vacuo. And crude material dissolved in diethyl ether (25 mL), washed with water (2 x 5mL). The water phases were collected and the water removed on rotorvap to yield 63 mg of the title compound. 1H NMR (CDCI3): δ = 4.19 (s, 2H), 3.78-3.55 (m, 21H), 1.49 (s, 9H). 2-(1,3-Bis[2-(2-hydroxyethoxy)ethoxy]propan-2-oxy) acetic acid tert-butyl ester (63 mg, 0.16 mmol) was evaporated twice from dry acetonitrile. 1,3-Bis[2-(2-trityloxyethoxy)ethoxy]propan-2-oxy p-cyanoethyl N,N-diisopropylphosphoramidite (353 mg, 0.37 mmol) was evaporated twice from dry acetonotrite, dissolved on dry acetonitrile (2 mL) and added. A solution of tetrazole in dry acetonitrile (0.25 M, 2.64 mL) was added under nitrogen and the mixture was stirred at room temperature for 1 hour. 5.5 mL of an I2 -solution (0.1 M in THF/lutidine/H2O 7:2:1) was added and the mixture was stirred an additional 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 2% aqueous sodium sulfite until the iodine colour disappeared. The organic phase was dried (Na2S04), and solvent removed in vacuo. The residue was dissolved in 80 % aqueous acetic acid (5 mL) and stirred at room -temperature overnight. Solvent was removed in vacuo and the crude material was added diethyl ether (25 mL) and water (10 mL). The water phase was collected and water removed in vacuo. Product was purified on reverse phase preparative HPLC C-18 colum, gradient 0-40 % acetonitrile containing 0.1 % TFA to give the title tert-butyl-protected 2nd generation branched polymer product. LC-MS: m/z =1171 (M+Na); 1149 (M+), 1093 (toss of tert-butyl in the MS); Rt = 2.76 min. Deprotection of β-cyanoethyl groups and removal of tert-butyl ester group, is subsequently done using conventional base and acid treatments as known to the person skilled in the art.. ATTACHMENT OF DENDRIMERS TO ITA: EXAMPLE 55 N-epsilon26,3-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}ethoxy)ethoxy]- propan-2-yloxy)acetyiamino]propanoyl[Arg34]GLP-1-(7-37)-OH (Formula Removed) R34-GLP-1(7-37) (LB. Knudsen era/., J. Med. Chem. 2000, 43, 1664-1669. )(110 mg; 33 umol) was suspended in water (30 ml). To the unclear suspension was added DIPEA (156 ul; 1.6 mmol), and the mixture was stirred for 10 min, during which time the solution turned clear. The pH was measured to 10. A solution of N-hydroxysuccinimidyl 3-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)-ethoxy]acetylamino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]-propanoate (80.4 mg; 99 umol, example 32) in water (6.0 ml) was then added. The reaction mixture became yellow and turned slightly unclear. The mixture was stirred at room temperature for 45 min. Then a solution of glycine (5.3 ml, cone. = 10 mg/ml) was added. The mixture was stirred for 5 min at room temperature. The reaction mixture was then purified over 2 run by preparative HPLC with direct injection (20 ml and 16 ml respectively), using a C18 column (20x2 cm) with a linear gradient of 25-55% water - acetonitri! and a flow of 10 ml/min, collecting 10 ml fractions. The individual fractions containing product were analyzed using LC-MS (electorspray) and HPLC (metode A). Samples containing pure compound were pooled to give a total volume of 80 ml of sample with a final concentration of 1.05 mg/ml as determined from relative absorption measurement at  = 276 nm. Samples were frozen and stored at -18 °C, until use. Yield: 84.6 mg (67%). MALDI-TOF-MS (a-cyano-4-hydroxycinnamic acid): m/z = 4080. LC-MS (electrospray): (m/3)+1 = 1261; (m/4)+1 = 1021; Rt = 3.54 min. HPLC (Method A): Rt = 36.46 min. EXAMPLE 56 N-epsilon26-3-(1,3-Bis{2-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetamino}-ethoxy)- ethoxy]propan-2-yloxy)acetylamino]ethoxy])ethoxy}propan-2-yloxy)acetylamino)-propanoyl- [Arg34]GLP-1-(7-37)-OH (Formula Removed) R34-GLP-1(7-37) (15.6 mg; 4.5 umol) was suspended in water (10 ml). To the unclear suspension was added DIPEA (86 ul; 0.88 mmol), and the mixture was stirred for 10 min, during which time the solution turned clear. The pH was measured to 10. A solution of N- . hydroxysuccinimidyl 3-(1,3-bis{2-(2-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)-ethoxy]acetamino}ethoxy)ethoxy]propan-2-yloxy)acetylamino]ethoxy)ethoxy}propan-2-yloxy)-acetylamino)propanoate (93.0 mg; 53 umol, example 33) in water (2.0 ml) was then added. The reaction mixture remained clear. The mixture was stirred at room temperature for 40 min. Then a solution of glycine (3.0 ml, cone. = 10 mg/ml) was added. The mixture was stirred for 5 min at room temperature. The mixture was purified by preparative RP-HPLC as follows: The total sample volumne (15 ml) was injected on to a C18 column (20x2 cm), and eluted using a linear gradient from 25% -55% water-acetonitril with a flow of 10 ml/min. collecting 10 ml fractions. The individual fractions containing product were analyzed using LC-MS (electorspray) and HPLC (metode A). Samples containing pure compound were pooled to give a total volume of 24 ml of sample with a final concentration of 0.25 mg/ml as determined from relative absorption measurement at . = 276 nm. Samples were frozen and stored at -18 °C, until use. Yield: 5.8 mg (24%). LC-MS (electrospray): (m/3)+1 = 1672; (m/4)+1 = 1254; (m/5)+1 = 1004; Rt = 3.25 min. HPLC (Method A): Rt = 35.64 min. Example 57 Preparation of A-((S)-2,6-Bis-(2-[2-(2-[2-((S)-2,6-bis-[2-(2-[2-(2-(2-(2-(2-methoxyethoxy)- ethoxy)acetyiamino)ethoxy)ethoxy]ethoxy)acetylamino]hexanoylamino)ethoxy]ethoxy)- ethoxy]acetylamino)hexanoyl)[Aib8'22i35,Lys37]GLP-1 (7-37) amide (Formula Removed) 1 .a Synthesis of the protected peptidyl resin. Boc-His(Boc)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Aib-Gln(Trt)-Ala-Ala-Lys(Boc)-Glu(OtBu)-Phe-lle-Ala-Trp(Boc)-Leu-Val-Lys(Boc)-Aib-Arg(Pmc)-Lys(Dde)-Rink amide resin was prepared according to the Fmoc strategy on an Applied Biosystems 433A peptide synthesizer in 0.25 mmot scale using the manufacturer supplied FastMoc UV protocols which employ HBTU mediated couplings in NMP, and UV monitoring of the deprotection of the Fmoc protection group. To improve the coupling efficiency, Aib residues and residues following Aib, these residues were coupled using HATU instead of HBTU as the coupling reagent. The starting resin (438 mg) used for the synthesis was 4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)- phenoxy resin (Rink amide resin) (Merck Biosciences GmbH, Germany, cat. #: 01-12-0013) with a substitution capacity of 0.57 mmol /g. The protected amino acid derivatives used were (2S)-6-[1-(4,4-Dimethyl-2,6-dioxo-cyclohexylidene)-ethylamino]-2-(9H-fluoren-9-ylmethoxy-carbonylamino)hexanoic acid (Fmoc-Lys(Dde)-OH), Fmoc-Arg(Pmc)-OH, Fmoc-Aib-OH, Fmoc-Lys(Boc)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-lle-OH , Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH and Boc-His(Boc)-OH The yield was 1.37 g of dry peptidyl resin. 1.b Characterisation of the peptidyl resin The resin was characterized by cleaving off the crude peptide from 50 mg of this resin by treating it for 2 hours with a mixture of 14 µl TIS, 14 µl H20 and 0.5 ml TFA. The resin was removed by filtration and the crude peptide was isolated by precipitation and wash with Et2O. HPLC and LC-MS analysis was performed on the dry precipitate. Analytical results: (Table Removed) 1 .c Deprotection of Dde The protected peptidyl resin resulting from (1.a) (1.35 g, 250//mol) was washed in NMP:DCM 1:1 (15 ml) twice. A freshly prepared solution of hydrazine hydrate 2% in NMP (20ml) was added. The reaction mixture was shaken for 12 min at room temperature, and then filtered. The hydrazine treatment was repeated twice. After this the resin was washed extensively with NMP, DCM and NMP. 1 .d attachment of branched polymer The Dde deprotected resin is suspended in NMP (20ml). (S)-2,6-Bis-(2-[2-(2-[2-((S)-2,6-bis-[2-(2-[2-(2-(2-(2-(2-methoxyethoxy)ethoxy)acetylamino)ethoxy)ethoxy]ethoxy)acetylamino]-hexanoylamino)ethoxy]ethoxy)ethoxy]acetylamino)hexanoic acid preactivated with TSTU as described in example 39 is added together with DIPEA and the suspension is shaken overnight. Then the resin is isolated by filtration and washed extensively with NMP, DCM, 2-propanol, methanol and Et2O and dried in vacuo. 1 .e Cleavage of the product The resin from 1 .d is stirred for 3 h at room temperature with a mixture of 350 µl TIS, 350 µl H2O and 14 ml TFA. The resin is removed by filtration and washed with 3 ml TFA. The collected filtrates are concentrated in vacuo. to 5 ml and the crude product is precipitated by addition of 40 ml Et2O followed by centrifugation. The pellet is washed with 40 ml Et2O two times and then air dried. 1 .f Purification of product. The crude peptide is dissolved in H2O/AcOH (40:4) (40ml) and purified by semipreparative HPLC in 2 runs on a 25 mm x 250 mm column packed with 7µ C-18 silica. The column is eluted with a gradient of CH3CN from 40 to 62% against 0.1% TFA / H2O at 10 ml/min at a temperature of 40 °C for 47min. The peptide containing fractions are collected, diluted with 3 volumes of H2O and lyophilized. The final product obtained is characterized by HPLC. Compounds of this invention includes: (Formula Removed) Example 58 N-epsilon26,3-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-propan-2-yloxy)acetylamino]propanoyl [Aib8,22,35]GLP-1 (7-37) amide (Formula Removed) Dde-Lys(Fmoc)-Glu(OtBu)-Phe-lle-Ala-Trp(Boc)-Leu-Val-Arg(Pmc)-Aib-Arg(Pmc)-Gly-Rink amide resin was prepared according to the Fmoc strategy on an Applied Biosystems 433A peptide synthesizer in 0.25 mmol scale using the manufacturer supplied FastMoc UV protocols which employ HBTU mediated couplings in NMP, and UV monitoring of the deprotection of the Fmoc protection group. The terminal Fmoc group was removed by treatment with 2% DBU in DMF (3x3 min), and acylated on the lysine side chain, first with Fmoc-AEEAc-OH and after Fmoc deprotection with 3-[2-(1,3-bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}ethoxy)ethoxy]propan-2-yloxy)acetic acid. The terminal Dde-group was then removed with 10% hydrazin in NMP. The N-terminal of the peptide was then elongated with the Boc-His(Boc)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Aib-Gln(Trt)-Ala-Ala-sequence using the manufacturer supplied FastMoc UV protocols which employ HBTU mediated couplings in NMP, and UV monitoring of the deprotection of the Fmoc protection group. The peptide was cleaved form the resin using 5% triisopropylsilane and 5% water inTFA. The resin was filtered off, and washed with TFA. The combined filtrates were reduced to a minimal volume, and the peptide was precipitated by addition of cold diethyl ether, and isolated by centrifugation. The precipitate was washed trice with cold diethylether. The crude peptide was purified by RP18-HPLC. The column was eluted with a gradient of CH3CN from 36 to 60% against 0.1% TFA / H2O at 10 ml/min. The peptide containing fractions were collected, diluted with H2O and lyophilized. LC-MS (electrospray): (m/3)+1 = 1409.8; (m/4)+1 = 1057.0; (m/5)+1 = 846.2; Rt = 3.28 min. HPLC (Method A): Rt = 29.08 min. Example 59 N-alfa7-formyl,N-epsilon26,3-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]acetylamino}- ethoxy)ethoxy]propan-2-yloxy)acetylamino]propanoyl[Arg34]GLP-1-(7-37)-OH (Formula Removed) N-epsilon26,3-[2-(1,3-Bis[2-(2-{2-[2-(2-methoxyethoxy)ethoxy3acetylamino}ethoxy)ethoxy3-propan-2-yloxy)acetylamino]propanoyl[Arg34]GLP-1-(7-37)-OH (Example 55) was dissolved in water (20 ml) and pH was adjusted to 9 with triethylamine. A 1:1 mixture of acetic anhydride and formic acid was prepared, and 5 ul of this solution (3 eq.) were added while keeping pH at 9 with triethylamine addition. The reaction mixture was stirred for 1 h, then another 5 ul of the 1:1 mixture of acetic anhydride / formic acid was added. The last step was repeated for one more time, then the mixture was stirred at room temperature for 3h. The product was then purified as described in example 58, to give 9 mg of title material. LC-MS (electrospray): (m/3)+1 = 1370.7; (m/4)+1 = 1028.7; Rt = 3.25 min. HPLC (Method A): Rt = 37.75 min. Method for measuring pulmonary bioavailability. The present protocol describes the methods and materials used in the development of an anaesthetized rat model for pulmonal delivery of aerosols. The aerosols are generated by use of a nebulizer catheter with a well defined droplet/particle size (mean mass aerodynamic diameter, MMAD). The nebulizer catheter is an extruded multi-lumen catheter that provides fine-particle, baffle-free, aerosols. It incorporates multiple (typically 4-6) gas-lumens around one liquid lumen. Each lumen extends the length of the catheter which tapers to a fine (-0.5 mm diameter) nozzle with tiny orifices at the distal tip. The intimate contact between the gas and liquid at the tip produces a fine aerosol without baffling. The nebulizer catheter is guided through an endotracheal tube and is placed just above the main bronchial branch. The aerosol is deposited in pulses managed from a control unit. EQUIPMENT The equipment for pulmonary delivery is obtained from Trudell Medical International (London, Ontario, Canada). Nebulizer catheters Nebulizer catheters (Aeroprobe®) are supplied from the manufacturer in a number of different configurations and lengths. These different designs will accommodate a variety of different fluid and flow-rates, as well as provide aerosol particle-sizes that may be as low as 5 µm MMAD (mean mass aerodynamic diameter). In the present experiments a catheter with the following dimensions is used: Outer lumens gas flow of 1.4 L/min, inner lumen liquid flow of 0.7 ml/min, and MMAD of about 7-8 µm (PN 104504-050) with a length of 50 cm (1). Control unit LABNeb® Catheter control system (CCS). The Aeroprobe catheter is connected to the control system according to (2). Air with a pressure of 100 psi is used as supporting gas and maximal fluid pressure, usually 98 psi. A 100 µl syringe is used as reservoir. The LABNeb CCS used a pulse time of 80 msec and a gas delay of 20 msec. Thus, 2.3 ml air and 0.93µI test solution are delivered in each pulse. ANIMALS Sprague Dawley S rats weighing between 250 and 350 g. The animals are housed under standardised conditions with free access to food (Altromine 1324) and drinking water. On the experimental day the animals are used in their fed state. SOLUTION FOR ANAESTHESIA Hypnorm® (fentanyl 0.2 mg/ml, fluansol 10 mg/ml) is diluted with sterile water 1 +1. Dormicum® (midazolam 5 mg/ml) is diluted with sterile water 1 + 1. The two solutions are mixed 1 + 1. Surgical procedures and intratracheal administration Anaesthesia is induced by injecting subcutaneously the prepared Hyponorm/Dormicum solution 0.25 ml/100 g BW.An endotracheal tube (PE 240, Becton Dickinson) is inserted and guided to a position about ½ cm above the branch of the two main bronchii. Any heat loss is" minimised by wrapping a plastic shield round the rat. Before applying the test solution into the lungs, it is secured that the syringe and catheter system is free of air bubbles. Before applying the test solution endotracheally, it is sprayed into a vial to test subsequently the amount of substance administered by the catheter. Then, the catheter is guide through the endotracheal tube leaving 1-2 mm of the catheter tip free of the tube end and the test solution is aerosolised into the lungs of the anaesthetised rat. Protraction of GLP-1 derivatives after i.v. or s.c. administration The protraction of a number GLP-1 derivatives of the invention was determined by monitoring the concentration thereof in plasma after sc administration to healthy pigs, using the methods described below. For comparison also the concentration in plasma of GLP-1 (7-37) after sc. administration was followed. The protraction of other GLP-1 derivatives of the invention can be determined in the same way. Pharmacokinetic testing of GLP-1 analogues in minipias The test substances were dissolved in a vehicle suitable for subcutaneous or intravenous administration. The concentration was adjusted so the dosing volume was approximately 1 ml. The study was performed in 12 male Gottingen minipigs from Ellegaard Gottingen Minipigs ApS. An acclimatisation period of approximately 10 days was allowed before the animals entered the study. At start of the acclimatisation period the minipigs were about 5 months old and in the weight range of 8-10 kg. The study was conducted in a suitable animal room with a room temperature set at 21-23°C and the relative humidity to > 50%. The room was illuminated to give a cycle of 12 hours light and 12 hours darkness. Light was from 06.00 to 18.00 h. The animals were housed in pens with straw as bedding, six together in each pen. The animals had free access to domestic quality drinking water during the study, but were fasted from approximately 4 pm the day before dosing until approximately 12 hours after dosing. The animals were weighed on arrival and on the days of dosing. The animals received a single intravenous or subcutaneous injection. The subcutaneous injection was given on the right side of the neck, approximately 5-7 cm from the ear and 7-9 cm from the middle of the neck. The injections were given with a stopper on the needle, allowing 0.5 cm of the needle to be introduced. Each test substance was given to three animals. Each animal received a dose of 2 -nmol/kg body weight. Six animals were dosed per week while the remaining six were rested. A full plasma concentration-time profile was obtained from each animal. Blood samples were collected according to the following schedule: After intravenous administration: Predose (0), 0.17 (10 minutes), 0.5,1,2, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours after injection. After subcutaneous administration: Predose (0), 0.5,1,2, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours after injection. At each sampling time, 2 ml of blood was drawn from each animal. The blood samples were taken from a jugular vein. The blood samples were collected into test tubes containing a buffer for stabilisation in order to prevent enzymatic degradation of the GLP-1 analogues. Plasma was immediately transferred to Micronic-tubes. Approximately 200 µl plasma was transferred to each Micronic-tube. The plasma was stored at -20°C until assayed. The plasma samples were assayed for the content of GLP-1 analogues using a immunoassay. The plasma concentration-time profiles were analysed by a non-compartmental pharmacokinetic analysis. The following pharmacokinetic parameters were calculated at each occasion: AUC, AUC/Dose, AUC%Extrap, Cmas, tmax, z t½, CL, CL/f, Vz, Vz/f and MRT. Selected compounds of the invention were tested in Danish Landrace pigs. Pharmacokinetic testing of GLP-1 analogues in pigs Pigs (50% Duroc, 25% Yorkshire, 25% Danish Landrace, app 40 kg) were fasted from the beginning of the experiment. To each pig 0.5 nmol of test compound per kg body weight was administered in a 50 µM isotonic solution (5 mM phosphate, pH 7.4, 0.02% Tween®-20 (Merck), 45 mg/ml mannitol (pyrogen free, Novo Nordisk). Blood samples were drawn from a catheter in vena jugularis. 5 ml of the blood samples were poured into chilled glasses containing 175µI of the following solution: 0.18 M EDTA, 15000 KIE/ml aprotinin (Novo Nordisk) and 0.30 mM Valine-Pyrrolidide (Novo Nordisk), pH 7.4. Within 30 min, the samples were centrifuged for 10 min at 5-6000*g. Temperature was kept at 4°C. The supernatant was pipetted into different glasses and kept at minus 20°C until use. The plasma concentrations of the peptides were determined in a sandwich ELISA or by RIA using different mono- or polyclonal antibodies. Choice of antibodies depends of the GLP-1 derivatives. The time at which the peak concentration in plasma is achieved varies within wide limits, depending on the particular GLP-1 derivative selected. General assay protocol for sandwich ELISA in 96-wells microtiterplate Coating buffer (PBS): Phosphate buffered saline, pH7.2 Wash-buffer (PBS-wash): Phosphate buffered saline, 0.05 % v/v Tween 20, pH 7.2 Assay-buffer (BSA-buffer): Phosphate buffered saline, 10 g/l Bovin Serum Albumin (Fluka 05477),0.05 % v/v Tween 20, pH 7.2 Streptavidin-buffer: Phosphate buffered saline, 0.5 M NaCI, 0.05 % v/v Tween 20, pH7.2 Standard: Individual compounds in a plasma-matrix A-TNP: Nonsens antibody AMDEX: Streptavin-horseradish-peroxodase (Amersham RPN4401V) " TMB-substrate: 3,3',5,5'tetramethylbenzidine (<0.02 %), hydrogen peroxide The assay was carried out as follows (volumen/well): 1.) coat with 100 µl catching antibody 5 µg/ml in PBS-buffer incubate o/n , 4 °C  5x PBS-wash  blocked with last wash in minimum 30 minutes then empty the plate 2.) 20 µl sample + 100 µI biotinylated detecting antibody 1 µg/ml in BSA-buffer with 10µg/ml A- TNP incubate 2 h, room temperature, on a shaker 5x PBS-wash, then empty the plate 3.) 100µIAMDEX 1:8000 in Streptavidin-buffer incubate 45-60 minute, room temperature, on a shaker 5x PBS-wash, then empty the plate 4.)100 µl TMB-substrate  incubate x minute at room temperature on a shaker  stop the reaction with 100µl 4 M H3PO4 Read the absorbance at 450 nm with 620 nm as reference The concentration in the samples was calculated from standard curves. General assay protocol for RIA DB-buffer: 80 mM phosphate buffer, 0.1 % Human serum albumin, 10 mM EDTA, 0.6 mM thiomersal, pH 7.5 FAM-buffer: 40 mM phosphate buffer, 0.1 % Human Serum Albumin, 0.6 mM thiomersal, pH 7.5 Charcoal: 40 mM phosphate buffer, 0.6 mM thiomersal, 16.7 % bovine plasma, 15 g/l activated carbon , pH 7.5 (mix the suspension minimum 1 h before use at 4 °C) Standard: Individual compounds in a plasma-matrix The assay was carried out in minisorp tubes 12x75 mm (volumen/tube) as follows: (Table Removed) Mix - incubate 30 min at 4 °C - centrifuge at 3000 rpm, 30 min - immediately after transfer supernatants to new tubes, close with stopper and count on gamma-counter for 1 minute. The concentration in the samples was calculated from individual standard curves. GLP-1 RADIO RECEPTOR ASSAY (RRA): The method is a radiometric-ligand binding assay using LEADseeker imaging particles. The assay is composed of membrane fragments containing the GLP-1 receptor, unlabeled GLP-1 analogues, human GLP-1 labelled with 125I and PS LEADsee/cer particles coated with wheat germ agglutinin (WGA). Cold and 125l-labelled GLP-1 will compete for the binding to the receptor. When the LEADsee/cer particles are added they will bind to carbohydrates residues on the membrane fragments via the WGA-residues. The proximity between the 125l-molecules and the LEADsee/cer particles causes light emission from the particles. The LEADseeker will image the emitted light and it will be reversibly correlated to the amount of GLP-1 analogue present in the sample. REAGENTS & MATERIALS: Pre treatment of animal plasma: Animal plasma was heat treated for 4 hrs at 56°C arid centrifuged at 10.000 rpm for 10 minutes. Afterwards, Val-Pyr (10 //M) and aprotenin (500 KIE/mL) was added and stored at <-18°C until use. GLP-1 analogues calibrators: GLP-1 analogues were spiked into heat-treated plasma to produce dilution lines ranging from approximately 1 µM to 1 pM. GLP-1 RRA assay buffer: 25 mM Na-HEPES (pH=7.5), 2.5 mM CaCI2, 1 mM MgCI2, 50 mM NaCI, 0.1 % ovalbumin, 0.003% tween 20, 0.005% bacitracin, 0.05% NaN3. GLP-1 receptor suspension: GLP-1 receptor membrane fragments were purified from baby hamster kidney (BHK) cells expressing the human pancreatic GLP-1 receptor. Stored <-80°C until use. WGA-coupled polystyrene LEADseeker imaging beads (RPNQ0260, Amersham): The beads were reconstituted with GLP-1 RRA assay buffer to a concentration of 13.3 mg/mL. The GLP-1 receptor membrane suspension was then added and incubated cold (2-8°C) at end-over-end for at least 1 hr prior to use. [125l]-GLP-1(7-36)amide (Novo Nordisk A/S). Stored <-18°C until use. Elhanol 99.9% vol (De Dansk Spritfabrikker A/S): Stored <-18°C until use. Multiscreen® Solvinert 0.45 µm hydrophobic PTFE plates (MSRPN0450, Millipore Corp.) Poly propylene plates (cat. no. 650201, Greiner Bio-One) White polystyrene 384-well plates (cat. no. 781075, Greiner Bio-One) APPARATUS: Horizontal plate mixer Centrifuge with a standard swinging-bucket microtitre plate rotor assembly UltraVap - Drydown Sample Concentrator (Porvair) LEADseeker™ Multimodality Imaging System (Amersham) ASSAY PROCEDURE: Sample preparation: Mount the Multiscreen® Solvinert filter plate on a chemical-comparable receiver plate (i.e. poly propylene plates) to collect the filtrate. Add 150 µL ice-cold ethanol 99.9% into the empty wells of the Multiscreen® Solvinert filter plate followed by 50 µL calibrator or plasma sample. Place the storage lid on the filter plate. Incubate 15 minutes at 18-22°C on a horizontal plate mixer. Place the assembled filter and receiver plate, with the lid, into a standard swinging-bucket microtitre plate rotor assembly. The filtrate is then collected in the empty wells of the receiver plate at 1500 rpm for 2 minutes. Dry down the filtrate by using the UltraVap with heated (40°C) N2 for duration of 15 miuntes. Reconstitute the dry material by adding 100 µL GLP-1 RRA assay buffer into each well. Incubate for 5 minutes on a horizontal mixer. GLP-1 radio receptor assay: Use the following pipetting scheme and white polystyrene 384-well plates: • 35µL GLP-1 RRA assay buffer • 5 µL reconstituted filtrate. • 10 µL [125l]-GLP-1(7-36)amide. The stock solution was diluted in GLP-1 RRA assay buffer to 20.000 cpm/well prior to use. • 15 µL GLP-1 receptor membrane fragments (≈0.5 µg/well) pre-coated to WGA-polystyrene LEADseeker imaging beads (0.2 mg/well) Seal the plates and incubate over night at 18-22°C The light emission from each wells are detected by using the LEADseeker™ Multimodality Imaging System for duration of 10 minutes. Stimulation of cAMP formation in a cell line expressing the cloned human GLP-1 receptor. Purified plasma membranes from a stable transfected cell line, BHK467-12A (tk-ts13), expressing the human GLP-1 receptor was stimulated with GLP-1 and peptide analogues, and the potency of cAMP production was measured using the AlphaScreen™ cAMP Assay Kit from Perkin Elmer Life Sciences. A stable transfected cell line has been prepared at NN and a high expressing clone was selected for screening. The cells were grown at 5% CO2 in DMEM, 5% FCS, 1% Pen/Strep and 0.5 mg/ml G418. Cells at approximate 80% confluence were washed 2X with PBS and harvested with Versene, centrifuged 5 min at 1000 rpm and the supernatant removed. The additional steps were all made on ice. The cell pellet was homogenized by the Ultrathurax for 20-30 sec. in 10 ml of Buffer 1 (20 mM Na-HEPES, 10 mM EDTA, pH=7.4), centrifuged 15 min at 20.000 rpm and the pellet resuspended in 10 ml of Buffer 2 (20 mM Na-HEPES, 0.1 mM EDTA, pH=7.4). The suspension was homogenized for 20-30 sec and centrifuged 15 min at 20.000 rpm. Suspension in Buffer 2, homogenization and centrifugation was repeated once and the membranes were resuspended in Buffer 2 and ready for further analysis or stored at -80°C. The functional receptor assay was carried out by measurering the peptide induced cAMP production by The AlphaScreen Technology. The basic principle of The AlphaScreen Technology is a competition between endogenous cAMP and exogenously added biotin-cAMP. The capture of cAMP is achieved by using a specific antibody conjugated to acceptor beads. Formed cAMP was counted and measured at a AlphaFusion Microplate Analyzer. The EC50 values was calculated using the Graph-Pad Prisme software. CLAIMS 1. A conjugate comprising a structurally well-defined branched polymer covalently attached to an insulinotropic agent. 2. A conjugate according to claim 1 represented by the general formula I (Formula Removed) wherein ITA represents an insulinotropic agent from which a hydrogen has been removed from an alpha-amino group present in the insolinotropic agent, or from an epsilon amino group present on a lysine at any position in the insolinotropic agent, for the 1st generation of bifurcated compounds, Y1 is Yb; Y2 is Z; r, q, p, and s are all zero; and n is 2; for the 2nd generation of bifurcated compounds, Y1 and Y2 are Yb; Y3 is Z; r, q, and p are all zero; s is 4; and n is 2; for the 3rd generation of bifurcated compounds, Y1, Y2, and Y3 are all Yb; Y4 is Z; r and q are zero; p is 8; s is 4; and n is 2; for the 4th generation of bifurcated compounds, Y1, Y2, Y3, and Y4 are all Yb; Y5 is Z; r is zero; q is 16; p is 8; s is 4; and n is 2; and for the 5th generation of bifurcated compounds, Y1, Y2, Y3, Y4, and Y5 are all Yb; Y6 is Z; r is 32; q is 16, p is 8; s is 4; and n is 2; wherein (Formula Removed) for the 1st generation of trifurcated compounds, Y1 is Yt; Y2 is Z; r, q, p, and s are all zero; and n is 3; for the 2nd generation of trifurcated compounds, Y1 and Y2 are Yt; Y3 is Z; r, q, and p are all zero; s is 9; and n is 3; for the 3rd generation of trifurcated compounds, Y1, Y2, and Y3 are all Yt; Y4 is Z; r and q are zero; p is 27; s is 9; and n is 3; and for the 4th generation of trifurcated compounds, Y1, Y2, Y3, and Y4 are all Yt; Y5 is Z; r is zero; q is 81; p is 27; s is 9; and n is 3; wherein (Formula Removed) wherein A is -CO-, -C(O)O-, -P(=O)(OR)- or -P(=S)(OR)-, wherein R is hydrogen, alkyl or optionally substituted aryl; and B is -NH- or -O-; with the proviso that when B is -NH-, then A is -CO- or -C(O)O-, and when B is -0-, then A is -P(=O)(OR)- or -P(=S)(OR)-; and wherein the group B of one monomer layer (generation) (exemplified by Y1, Y2, and Y3) is connected to the group A of the adjacent, following layer where Y has the following number as suffix (exemplified by Y2; Y3, and Y4, respectively) or is connected to Z; X3 is a nitrogen atom, alkantriyl, arenetriyl, alkantrioxy, an aminocarbonyl moiety of the formula -CO-N<, an acetamido moiety of the formula -CH2CO-N< or a moiety of the formula: -CO-NH-Q-NH-CO- I wherein Q is alkantriyl; X4 is alkantetrayl or arenetetrayl; L1 is a valence bond, oxy, alkylene, alkyleneoxyalkyl, polyalkoxydiyl, (polyalkoxy)alkyl-carbonyl, oxyalkyl or (polyalkoxy)alkyl; L2is a valence bond, oxy, alkylene, alkyleneoxyalkyl, polyalkoxydiyl, (polyalkoxy)alkyl-carbonyl, oxyalkyl or (polyalkoxy); L3 represents a valence bond, alkylene, oxy, polyalkoxydiyl, oxyalkyl, alkylamino, carbonyl-alkylamino, alkylaminocarbonylalkylamino, carbonylalkylcarbonylamino(polyalkoxy)alkyl-amino, carbonylalkoxyalkylcarbonylamino(polyalkoxy)alkylamino, alkylcarbonylamino(poly-alkoxy)alkylamino, carbonyl(polyalkoxy)alkylamino or carbonylalkoxyalkylamino; m is zero, 1, 2 or 3; L4 is selected among a valence bond and a moiety of the formula -CO-L5-CH=N-O-, wherein L5 is a valence bond, alkylene or arylene, Z is hydrogen, alkyl, alkoxy, hydroxyalkyl, polyalkoxy, oxyalkyl, acyl, polyalkoxyalkyl or polyalkoxyalkylcarbonyl. 3. A conjugate according to claim 2, wherein Y1 is Yb (i.e. bifurcated compounds). 4. A conjugate according to claim 2 or 3, wherein X3 is a branched, trivalent organic radical of one of the following six formulae: (Formula Removed) 5. A conjugate according to claims 2-4, wherein Y1 is Yt (i.e. trifurcated compounds). 6. A conjugate according to the any of the claims 2-5, wherein X4 is benzen-1,3,4,5-tetrayl. 7. A conjugate according to any of the claims 2-6, wherein L1 a valence bond, oxy (-O-), oxymethyl (-OCH2-) or a moiety of the general formula -CH2(OCH2CH2)n"-OCH2C(O)-, where n" is an integer from 0 to 10. 8. A conjugate according to any of the claims 2-7, wherein L2 is a moiety of the formula (- CH2CH2O-)2, also having the formula: (Formula Removed), -CH2CH2OCH2CH2O-, - CH2CH2OCH2CH2OCH2CH2OCH2-, -CH2CH2OCH2CH2- or -CH2CH2-. 9. A conjugate according to any of the claims 2-8, wherein L3 is a valence bond or a divalent linker radical such as those illustrated by the following six formulae: (Formula Removed) wherein each end of the divalent radicals can be attached to the ITA group. 10. A conjugate according to any of the claims 2-9, wherein L4 and the adjacent L3 is a divalent linker radical such as those illustrated by the following eight formulae: (Formula Removed) wherein each ends of the divlent radicals can be connected to the ITA group 11. A conjugate according to any of the claims 2-10, wherein U is an oxyiminoalkylcarbonyl moiety in both isomeric (syn and anti) forms, an oxyiminoalkylarylcarbonyl moiety in both isomeric (syn and anti) forms, or a valence bond. 12. A conjugate according to any of the claims 2-11, wherein Z is a capping agent that can react with a terminal amino group or hydroxy group, preferably a group having one of the following three formulae: (Formula Removed) where Me is methyl. 13. A conjugate according to any of the claims 2-12, wherein A is one of the three moieties: - CO-, -P(O)O- and -P(S)O-. 14. A conjugate according to any of the claims 2-13, wherein B is oxy or the moiety -NH-. 15. A conjugate according to any of the preceding claims, wherein the insulinotropic agent is GLP-1 peptide or an exendin-4 peptide. 16. A conjugate according to any of the preceding claims, wherein said insulinotropic agent (ITA) is a DPPIV protected peptide. 17. A conjugate according to any of the preceding claims, wherein said insulinotropic agent (ITA) has an EC50 of less than 1 nM as determined by the functional receptor assay disclosed herein. 18. A conjugate according to any of the preceding claims, wherein said insulinotropic agent (ITA) has an EC50 of less than 300 pM, less than 200 pM or less than 100 pM as determined by the functional receptor assay disclosed herein. 19. A conjugate according to any one of the preceding claims, wherein said insulinotropic agent (ITA) is selected from a peptide comprising the amino acid sequence of the formula (II): Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Ala- Xaa25-Xaa26-Xaa27-Phe-lle-Xaa30-Trp-Leu-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38-Xaa39-Xaa40- Xaa41-Xaa42-Xaa43-Xaa44-Xaa45-Xaa46 Formula (II) (SEQ ID No: 3) wherein Xaa7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, p-hydroxy- histidine, homohistidine, Nα-acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3- pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; Xaa8 is Ala, D-Ala, Gly, Val, Leu, lle, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1- aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid; Xaa16 is Val or Leu; Xaa18 is Ser, Lys or Arg; Xaa19 is Tyr or Gin; Xaa20 is Leu or Met; Xaa22 is Gly, Glu or Aib; Xaa23 is Gin, Glu, Lys or Arg; Xaa25 is Ala or Val; Xaa26 is Lys, Glu or Arg; Xaa27 is Glu or Leu; Xaa28 is Ala, Glu or Arg; Xaa33 is Val or Lys; Xaa34 is Lys, Glu, Asn or Arg; Xaa35 is Gly or Aib; Xaa36 is Arg, Gly or Lys; Xaa37 is Gly, Ala, Glu, Pro, Lys, amide or is absent; Xaa38 is Lys, Ser, amide or is absent. Xaa39 is Ser, Lys, amide or is absent; Xaa40 is Gly, amide or is absent; Xaa41 is Ala, amide or is absent; Xaa42 is Pro, amide or is absent; Xaa43 is Pro, amide or is absent; Xaa44 is Pro, amide or is absent; Xaa45 is Ser, amide or is absent; Xaa46 is amide or is absent; provided that if Xaa38, Xaa39, Xaa40, Xaa41, Xaa42, Xaa43, Xaa44, Xaa45 or Xaa46 is absent then each amino acid residue downstream is also absent. 20. A conjugate according to claim 19, wherein said insulinotropic agent (ITA) is a peptide comprising the amino acid sequence of formula (III): Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa18-Tyr-Leu-Glu-Xaa22-Xaa23-Ala-Ala-Xaa26-Glu-Phe-lle-Xaa30-Trp-Leu-Val-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38 Formula (III) (SEQ ID No: 4) wherein Xaa7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, (3-hydroxy-histidine, homohistidine, Nα-acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; Xaa8 is Ala, D-Ala, Gly, Val, Leu, lle, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid; Xaa18 is Ser, Lys or Arg; Xaa22 is Gly, Glu or Aib; Xaa23 is Gin, Glu, Lys or Arg; Xaa26 is Lys, Glu or Arg; Xaa30 is Ala, Glu or Arg; Xaa34 is Lys, Glu or Arg; Xaa35 is Gly or Aib; Xaa36 is Arg or Lys; Xaa37 is Gly, Ala, Glu or Lys; Xaa38 is Lys, amide or is absent. 21. A conjugate according to any one of the proceeding claims, wherein said insulinotropic agent (ITA) is selected from GLP-1(7-35), GLP-1(7-36), GLP-1(7-36)-amide, GLP-1(7-37), GLP-1(7-38), GLP-1(7-39), GLP-1(7-40), GLP-1(7-41) or an analogue thereof. 22. A conjugate according to any one of the preceding claims, wherein said insulinotropic agent (ITA) comprises no more than fifteen amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1), or no more than ten amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1). 23. A conjugate according to the proceeding claim, wherein said insulinotropic agent (ITA) comprises no more than six amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1). 24. A conjugate according to any one of the preceding claims, wherein said insulinotropic (ITA) agent comprises no more than 4 amino acid residues which are not encoded by the genetic code. 25. A conjugate according to any one of the preceding claims, wherein said insulinotropic agent (ITA) comprises an Aib residue as the second amino acid residue from the N-terminal. 26. A conjugate according to any one of the preceding claims, wherein the N-terminal amino acid residue (position 7 in formulae II and III) of said insulinotropic agent (ITA) is selected from the group consisting of D-histidine, desamino-histidine, 2-amino-histidine, p-hydroxy- histidine, homohistidine, Nα-acetyl-histidine , α-fluoromethyl-histidine, α-methyl-histidine, 3- pyridylalanine, 2-pyridylalanine and 4-pyridylalanine. 27. A conjugate according to any one of the preceding claims, wherein said insulinotropic agent (ITA) is selected from the group consisting of [Arg34]GLP-1(7-37), [Arg26,34]GLP-1(7- 37)Lys, [Lys36Arg26,34]GLP-1(7-36), [Aib8'22,35]GLP-1(7-37), [Aib8'35]GLP-1(7-37), [Aib8'22]GLP- 1 (7-37), [Aib8'22'35 Arg26,34]GLP-1 (7-37)Lys, [Aib8'35 Arg26,34]GLP-1(7-37)Lys, [Aib8'22 Arg26,34]GLP-1(7-37)Lys, [Aib8'22'35 Arg26,34]GLP-1 (7-37)Lys, [Aib8'35 Arg26,34GLP-1(7-37)Lys, [Aib8'22,35 Arg26]GLP-1 (7-37)Lys, [Aib8'35Arg26]GLP-1(7-37)Lys, [Aib8'22Arg26]GLP-1(7-37)Lys,[Aib8'22,35Arg34]GLP-1(7-37)Lys, [Aib8'35Arg34]GLP-1 (7-37)Lys, [Aib8,22Arg34]GLP-1 (7-37)Lys, [Aib8,22,35Ala37]GLP-1 (7-37)Lys, [Aib8,35Ala37]GLP-1 (7-37)Lys, [Aib8,22Ala37]GLP-1 (7-37)Lys, [Aib8,22,35Lys37]GLP-1(7-37), [Aib8,35Lys37]GLP-1(7-37), [Aib8,22Lys37]GLP-1(7-37) or derivatives thereof which has been amidated on the C-terminal, exendin-4(1-39), ZP-10, i.e. [Ser38L.ys39]Exendin-4(1-39)LysLysLysLysLys-amide (SEQ ID No. 5). 28. A conjugate according to any one of the preceding claims, wherein said insulinotropic agent (ITA) is attached to a branched polymer according to any one of the preceding claims via a carboxyl group, an amino group, a keto group, a hydroxyl group, a thiol group or a hydrazide group. 29. A conjugate according to any of the preceding claims, wherein said compound has an EC50 of less than 1000 pM, less than 500 pM, less than 300 pM, less than 200 pM, less than 100 pM, less than 50 pM or less than 10 pM as determined by the functional receptor assay disclosed herein. 30. A pharmaceutical composition comprising a compound according to any one of the proceding claims, and a pharmaceutically acceptable excipient. 31. Use of a compound according to any one of the claims 1-29 for the preparation of a medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers. 32. Use of a compound according to claim 31 for the preparation of a medicament for delaying or preventing disease progression in type 2 diabetes. 33. A method for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers by administering an effective amount of a compound accordiing to any fo the claims 1-29.

Documents

Application Documents

# Name Date
1 5400-delnp-2007-Form-18-(16-02-2009).pdf 2009-02-16
2 5400-delnp-2007-pct-308.pdf 2011-08-21
3 5400-delnp-2007-pct-304.pdf 2011-08-21
4 5400-delnp-2007-pct-237.pdf 2011-08-21
5 5400-delnp-2007-pct-220.pdf 2011-08-21
6 5400-delnp-2007-pct-210.pdf 2011-08-21
7 5400-delnp-2007-pct-101.pdf 2011-08-21
8 5400-delnp-2007-form-5.pdf 2011-08-21
9 5400-delnp-2007-form-3.pdf 2011-08-21
10 5400-delnp-2007-form-2.pdf 2011-08-21
11 5400-delnp-2007-form-1.pdf 2011-08-21
12 5400-delnp-2007-description (complete).pdf 2011-08-21
13 5400-delnp-2007-correspondence-others.pdf 2011-08-21
14 5400-delnp-2007-claims.pdf 2011-08-21
15 5400-delnp-2007-abstract.pdf 2011-08-21
16 5400-DELNP-2007_EXAMREPORT.pdf 2016-06-30