New songs agonists of the basis and methods of their introduction

 

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction. Technical result: the composition according to the invention is applicable in the treatment of diabetes and conditions that could benefit from lowering plasma glucose or delay and/or slowing gastric emptying or inhibition of food intake, and include parenteral liquid dosage form and dosage forms that are applicable in oral, nasal, transbukkalno, sublingual, intratracheal, and pulmonary delivery of Akindinov and agonists Akindinov. 2 C. and 14 C.p. f-crystals, 17 ill.

RELATED APPLICATIONS

This application claims the priority of provisional patent application U.S. 60/116380 entitled "New songs agonists of the basis and methods of their introduction, filed January 14, 1999, and provisional patent application U.S. 60/(not yet numbered), entitled "Application of Akindinov and their agonists to modulate levels trigliceridi full.

The SCOPE of the INVENTION

This invention relates to new compositions of basis and peptide agonists basis, dosages, and dosage compositions, which are biologically active and are delivered via injection or non-injection routes, for example through the respiratory tract through the mouth and through the intestine. These compositions and dosage forms and routes of administration applicable to the treatment of diabetes, including diabetes type I and II for the treatment of disorders in which could benefit agents, lowering glucose levels in plasma, and for treating disorders in which could benefit the introduction of agents applicable for delaying and/or slowing gastric emptying or reduce food intake.

PREREQUISITES

The following description includes information that may be useful for understanding the present invention. This is not a recognition that the information contained herein is the prototype of the proposed in the present invention, or is relevant, and does not mean that any of the publications cited specifically or indirectly, is the prototype.

Exendin are peptides that are found in the salivary secretions of ilate (Galskogo ID NO:1: His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2] is present in the salivary secretions of Heloderma horridum (Mexican adozona), and the basis-4 [SEQ ID NO:2: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2] is present in the salivary secretions of Heloderma suspectum (ilate, Gilsky JACOsub) (Eng, J., et al., J. Biol.Chem., 265:20259-62; ENP, et al., J. Biol.Chem., 267:7402-05, 1992). Amino acid sequence of basis 3 shown in Fig.1. Amino acid sequence of basis 4 shown in Fig.2. First thought on the basis of 4 is (potentially toxic) component of the poison. Currently, it appears that the basis-4 has no toxicity, and that he instead is produced in the salivary glands Galskogo of adotube.

Exendin have some sequence similarity to several members of the family of the glucagon-like peptides, with the highest homology, 53%, have with GLP-1[7-36]NH2[SEQ ID NO:3])Goke, et al., J. Biol. Chem., 268:19650-55, 1993). GLP-1[7-36]NH2also known as proglucagon [78-107] or simply as "GLP-1" that is used most often here. GLP-1 has insulinotropic effect, stimulating insulin secretion by beta cells of the pancreas. It was also reported that GLP-1 inhibits the secretion of glucagon by the alpha cells of the pancreas (Orsov is communicated, that GLP-1 inhibits gastric emptying (Willms, et al., J. Clin Endocrinol Metab 81 (I): 327-32, 1996; Wettergren A, et al., Dig Dis Sci 38 (4):665-73, 1993) and the secretion of gastric acid (Schjoldager W, et al., Dig Dis Sci 34 (5) 703-8, 1989; O'halloran DJ, et al., J Endocrinol 126 (I): 169-73, 1990; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73, 1993)). GLP-1[7-37], which has an additional glycine residue at its carboxy-late, also stimulates insulin secretion in humans (Orsov, et al. Diabetes, 42:658-61, 1993). It is believed that the transmembrane associated with adenylate cyclase G-protein receptor is responsible at least partially for insulinotropic effect of GLP-1 and, as reported, was cloned from the linecells (Thorens, Proc. Natl. Acad. Sci. USA 89: 8641-45, 1992).

GLP-1 has been the focus of considerable research in recent years due to reports of his actions, such as strengthening stimulated production of insulin (Vppe MM, Goke Century Lessons from human studies with glucagon-like peptide-1: Potential of the gut hormone for clinical use. In: Fehman HC, Goke B. Insulinotropic Gut Hormone Glucagon-Like Peptide 1. Basel, Switzerland: Karger, 1997:219-33), inhibition of gastric emptying (Wettergren A, et al., Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig. Dis. Sci. 1993 Apr; 38 (4):665-73), inhibition of secretion of glucagon (Creutzfeldt WOC, et al., Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide 1(7-36) amide in type I diabetic patients, Diabet. ature 1996 Jan; 379 (6560): 69-72). It was also reported that GLP-1 restores the sensitivity of islets of Langerhans to glucose in aging rats, restoring their glucose tolerance to tolerance of young rats (Egan JM, et al., Glucagon-like peptide-1 restores acute-phase insulin release to aged rats, Diabetologia 1997 June 40 (Suppi 1): A130). Short duration of biological action of GLP-1 in vivo is one sign of this peptide, which hinders its development as a therapeutic agent.

Pharmacological studies have demonstrated both similarities and differences between the basis-4 and GLP-1. On the basis of 4, as reported, may act on receptors GLP-1 secreting insulin cellsTC1, botryoidal cells of the pancreas of the Guinea pig and on the parietal cells of the stomach. It was also reported that this peptide stimulates the release of somatostatin and inhibits release of gastrin in isolated stomachs (Goke, et al., J. Biol.Chem. 268:19650-55, 1993; Schepp, et al., Eur. J. Pharmacol., 69:183-91, 1994; Eissele, et al. Life Sci., 55:629-34, 1994). It was reported that on the basis of 3 and the basis-4 stimulate the formation of camp in botryoidal cells of the pancreas and release them amylase (Malhotra, R., et al. Regulatory Peptides, 41:149-56, 1992; Raufman, et al., J. Biol.Chem. 267:GLP-1. For example, in one experiment it was reported that the decrease in glucose-basis-4 mice with diabetes persisted for several hours and, depending on the dose, up to 24 hours (Eng J. Prolonged effect of exendin-4 on hyperglycemia of db/db mice. Diabetes 1996 May; 45 (Suppl.2):152A (abstract 554)). On the basis of their insulinotropic activities, it was suggested that the use of basis-3 and basis 4 for the treatment of diabetes and prevention of hyperglycemia (Eng, U. S. Patent No.5424286).

It was reported that the shorter-end of the peptides of basis, such as on the basis of 4[9-39], carbauxilirovanny molecule, and fragments 3-39-9-39 are potent and selective antagonists of GLP-1 (Goke, et al., J. Biol.Chem. 268:19650-55; Raufman, J. P., et al., J. Biol.Chem. 266:2897-902, 1991; Schepp, W., et al., Eur. J. Pharm. 269:183-91, 1994; Montrose-Rafizadeh et al., Diabetes, 45 (Suppl. 2): 152A, 1996). Specifies that the basis 4[9-39] blocking of endogenous GLP-1 in vivo, resulting in reduced insulin secretion. Wang, et al., J. Clin.Invest., 95:417-21, 1995; D'alessio, et al., J. Clin. Invest., 97:133-38, 1996). It was reported that the receptor is, apparently, responsible for insulinotropic effect of GLP-1 in rats, was cloned from cells of rat islets of Langerhans (Thorens, B., the OEWG. Natl. Acad. Sci. USA 89:8641-8645, 1992). Specifies that exendin and on the basis of 4[9-39] contact cloned mouse receptor GLP-1 (receptor GLP-1 rat

It is also reported that on the basis of 4[9-39] acts as an antagonist full Akindinov by inhibiting the stimulation of low-temperature hydrothermal cells of the pancreas the basis 3 basis 4 (Raufman, et al., J. Biol.Chem. 266:2897-902, 1991; Raufman, et al., J. Biol.Chem. 266:21432-37, 1992). It was also reported that on the basis[9-39] inhibits the stimulation levels of plasma insulin-basis-4 and inhibits the activity of the basis-4 and GLP-1 stimulates the release of somatostatin and inhibiting the release of gastrin (Kolligs, F., et al. Diabetes, 44:16-19, 1995; Eissele, et al. Life Sciences, 55:629-34, 1994). The basis[9-39] were used for studying the physiological relations of Central GLP-1 in the regulation of food intake (Turton, M. D. et al. Nature 379:69-72, 1996). GLP-1 entered intracerebroventricularly (ICV) injection, inhibits food intake in rats. It was reported that inducing satiety effect of GLP-1 delivered ICV, inhibited ICV-injection of basis[9-39] (Turton, supra). However, it was reported that GLP-1 did not inhibit the consumption of pituitary research whether exendin species homologue of GLP-1 in mammals, it was reported by Chen and Drucker, who has cloned gene is the basis of Galskogo of adotube (J. Biol.Chem 272(7): 4108-15 (1997)). The observation that Galskogo of adotube also there are separate genes for proglucagon (of which forms the GLP-1), which are more similar to proglucagon mammals than the basis, indicates that exendin are species homologs of GLP-1.

Agents that serve to delay gastric emptying, have found application in medicine as diagnostic tools for gastrointestinal radiological tests. For example, the glucagon is a polypeptide hormone that is produced by the alpha cells of the islets of Langerhans of the pancreas. He is a hyperglycemic agent, which mobilizes glucose to activate glycogenolysis in the liver. He can do less to stimulate the secretion of pancreatic insulin. Glucagon is used in the treatment induced insulin hypoglycemia, for example, when intravenous glucose is impossible. However, since glucagon reduces the motility of the gastrointestinal tract, it can also be used as a diagnostic tool in gastrointestinal is olesnevich gastrointestinal disorders, associated with spasm. Daniel, et al., (Br. Med. J., 3:720, 1974) reported more rapid symptomatic loosening of acute diverticulitis in patients treated with glucagon, compared with patients who were treated with analgesic or antispasmodic agents. The review Glauser, et al., (J. Am.Coll. Emergency Physns, 8:228, 1979) describes the attenuation of the acute blockage of the esophagus after food glucagonomas therapy. In another study, glucagon significantly weakened the pain and soreness when durgiana in 21 patients with disease of the biliary tract, compared with 22 patients treated with placebo (M. J. Stower, et al., Br.J.Surg., 69:591-2, 1982).

Methods of regulation of the contractility of the gastrointestinal tract using Amylin agonists are described in co-owned by applicants International application number PCT/US 94/10225, published 16 March 1995.

The regulation of gastrointestinal contractility using agonists basis described in the jointly owned by the applicants patent application U.S. serial number 08/908867, filed August 8, 1997, entitled "regulation of gastrointestinal contractility", and this application is a partial continuation of patent zanitov the basis described in the jointly owned by the applicants patent application U.S. serial number 09/003869, submitted January 7, 1998, entitled "Application of the basis and its agonists to reduce food intake", which claims the benefit of the invention of the prior application U.S. with numbers 60/034905, filed January 7, 1997, 60/055404, filed August 7, 1997, 60/065442, filed November 14, 1997 and 60/066029, filed November 14, 1997.

It was reported that exendin have inotropic and diuretic actions described in the jointly owned by applicants International application number PCT/US 99/02554, filed February 5, 1999, notifying the advantage of the invention prior to application number 60/075122, filed February 13, 1998.

New connections-agonists the basis described in co-owned PCT applicants application serial number PCT/US 98/16387, filed August 6, 1998, entitled "New connection agonists of basis", which claims the benefit of an invention patent application U.S. serial number 60/055404, filed August 8, 1997.

Other new agonists of the basis described in co-owned PCT applicants-the application number PCT/US 98/24210, filed November 13, 1998, entitled "New connection agonists of basis", which claims the benefit of the invention predvaritelno owned by the applicants PCT application serial number PCT/US 98/24273, filed November 13, 1998, entitled "New connection agonists of basis", which claims the benefit of the invention of the provisional application U.S. number 60/066029, filed November 14, 1997.

With the onset of therapeutically active peptides and proteins obtained by genetic engineering, there was an increasing need to create opportunities in the delivery of these drugs in other ways than the parenteral route. However, it is hampered by the very properties of peptides and proteins that separate them from small molecule drugs, widely used at the present time. These properties include molecular size, sensitivity to proteolytic degradation, rapid plasma clearance, a kind of curves dose-response, immunogenicity, biocompatibility, and the tendency of peptides and proteins to undergo aggregation, adsorption and denaturation.

Usually it is understandable that the introduction of peptide drugs in other ways than subcutaneous or intravenous injection or intravenous infusion, is often not applicable in practice due to, for example, in the case of oral administration, as enzymatic degradation, and lack of absorption in the gastro-Kish is positive inconvenient, sometimes painful injections for administration of peptide drugs, such as exendin and peptide analogs are agonists of Akindinov, quoted above. In addition to the compositions and dosage, applicable for the introduction of Akindinov and agonists Akindinov by injection, there is described and claimed compositions, dosage compositions and methods that address these problems and which are not applicable in the delivery of therapeutically effective amounts of basis and agonists basis.

The content of the above articles, patents and patent applications and all other documents referred to or cited here included thereby by reference in their entirety. Applicants reserve the right to physical inclusion in this application and any full material and information from any such articles, patents, patent applications or other documents referred to or cited here.

The INVENTION

According to the first aspect, the invention provides new compositions of basis and compounds-agonists basis and their dosage forms, detect advantageous properties, which include the effects of delayed gastric emptying and reduce the level of glucose in plasmon, which contain the basis or agonist of basis, mixed with a buffer (preferably acetate buffer), a modifier suomalaiset (preferably mannitol) and optionally containing a preservative (preferably m-cresol), and the composition has a pH between about 3.0 and about 7.0 and preferably between about 4.0 and about 5.0 to). The term "agonist of basis" refers to a compound that mimics one or more effects of the basis, for example, by binding with the receptor, where the basis causes one or more of these effects, or the activation of a cascade of signal transmission by means of which the basis causes one or more of these effects. Agonists of basis include peptide agonists of basis, such as analogues and derivatives of the basis-3 and basis 4, which possess one or more desirable activities of the basis. A variety of analogs agonists basis of identified or cited here.

Additional compositions of Akindinov and agonists Akindinov in the scope of the present invention include parenteral liquid dosage form, lyophilized form with a uniform dose at one time, literie applicable in oral, nasal, transbukkalno, sublingual, intratracheal, and pulmonary delivery of Akindinov and agonists Akindinov.

Thus, the invention includes injecting liquid dosage forms that contain about 0.005 to about 0.4%, more specifically from about from 0.005 to about 0.02 percent or from about 0.005-about 0.05% (wt./vol.), accordingly, the active ingredient in the aqueous system along with approximately 0.02 to 0.5 percent (wt./about.) acetate, phosphate, citrate or glutamate or similar buffer, either single or in combination to obtain a pH of the final composition is approximately a 3.0 to 7.0, more specifically from about pH 4.0 to about 6.0, or from about 4.0 to a 5.0, as well as or approximately 1.0 to 10% (wt./about.) carbohydrate or which polyhydric alcohol modifier suomalaiset (preferably mannitol), or up to approximately 0.9% saline solution or a combination of both, leading to isotonic or isolationsim solution in the aqueous continuous phase. Approximately from 0.005 to 1.0% (wt./about.) antimicrobial preservative selected from the group consisting of m-cresol, benzyl alcohol, methyl-, ethyl-, propyl - and butylparaben amount of water for injection is added to obtain the desired concentration of the solution. Sodium chloride and other fillers may also be present, if desired. However, such fillers should maintain the overall stability of the active ingredient. Applicable polyhydric alcohols include compounds such as sorbitol, mannitol, glycerol and polyethylene glycol (PEG). Polyhydric alcohols and carbohydrates will also be effective in stabilizing the protein against denaturation caused by elevated temperatures and processes of freezing-thawing or freeze-drying. Suitable carbohydrates include galactose, arabinose, lactose or any other carbohydrate, which has no harmful effect on the patient with diabetes, if the composition is intended for this use, i.e., the carbohydrate is not metabolised by the formation of large concentrations of glucose in the blood. Preferably, the peptides of the present invention is mixed with a polyhydric alcohol, such as sorbitol, mannitol, Inositol, glycerol, xylitol, and a copolymer of polypropylene and ethylene glycol, as well as various polyethylene glycols (PEG) with molecular weight of 200, 400, 1450, 3350, 4000, 6000 and 8000). Mannitol is the preferred polyhydric alcohol.

Lyophilized unified disposable compositions of this invention are the active ingredient (the ingredient), filler to facilitate sludge (filter) (which may also act as agent toychest and/or modifier suomalaiset in the reconstruction of the solution or to promote stability of the active ingredient and/or to reduce pain during injection), and can also include a surfactant, which improves the properties of the sludge (filter) and/or facilitates the reconstruction of the solution. Lyophilized dose of the composition for a single injection include about 0.005 to about 0.4%, more specifically from about from 0.005 to about 0.02 percent or 0,005-0,05% (wt./about.) the active ingredient. May not be necessary to include a buffer in the composition and/or the restoration of lyophilized buffer if the contents of the container is intended for use within a period of stability limit for reconstituirea active ingredient. When using the buffer, it can be included in the freeze-dried or solvent to reconstitute the solution. Thus, the composition and/or the solvent to reconstitute the solution may contain individually or together approximately 0,02-0,5% (wt./about.) acetate, phosphate, citrate or gluconatesee from about pH 4.0 to about 6,0, or approximately 4,0-5,0. The filler may consist of either approximately 1.0 to 10% (wt./about.) carbohydrate or which polyhydric alcohol modifier suomalaiset (as described above) or 0.9% saline or a combination of both, which leads to isotonic or ISO-osmolar solution recreated in the aqueous phase. Can be enabled surfactant, preferably from approximately 0.1 to approximately 1.0% (wt./about.) Polysorbate 80 or another non-ionic detergent. As noted above, in lyophilized standard composition for a single injection may also contain sodium chloride, as well as other fillers, if desired. The liquid composition of this invention must be essentially isotonic and/or ISO-osmolar before lyophilization, or to allow the formation of isotonic and/or ISO-osmolar solutions after recreating solution.

The invention also includes lyophilized and liquid mnogorazovye composition. As in the case of parenteral liquid and lyophilised standard dose of the compositions described above, dried mnogozonovaya form must contain a filler formed to facilitate include from about 0.005-about 0.4%, more specifically from about from 0.005 to about 0.02 percent or from about 0.005 to 0.05% (wt./vol.), respectively, of the active ingredient. When using the buffer, it can be included in the freeze-dried or solvent to reconstitute the solution, and the composition and/or the solvent to reconstitute the solution may contain individually or together approximately 0,02-0,5% (wt./about.) acetate, phosphate, citrate or glutamate buffer, either single or in combination, to obtain a pH of the final composition is approximately a 3.0 to 7.0, more specifically from about pH 4.0 to about 6.0, or about 4,0-5,0.

The filler may consist of either approximately 1.0 to 10% (wt./about.) carbohydrate or which polyhydric alcohol modifier suomalaiset (preferably mannitol), or 0.9% of salt, or a combination that leads to isotonic or ISO-osmolar solution recreated in the aqueous phase. Can be enabled surfactant, preferably from approximately 0.1 to approximately 1.0% (wt./about.) Polysorbate 80 or another non-ionic detergent. Approximately from 0.005 to 1.0% (wt./about.) antimicrobial preservative selected from the group consisting of m-cresol, benzyl what song is Packed in a container for reuse. Sodium chloride and other fillers may also be present, if desired. The liquid composition of this invention should be essentially isotonic and/or ISO-osmolar or before lyophilization, or to allow the formation of isotonic and/or ISO-osmolar solutions after recreating solution.

Further, the invention includes a solid dosage form, applicable for oral, transbukkalno, sublingual, intratracheal, nasal and pulmonary delivery. Compositions, which are best suitable for pulmonary and/or intratracheal dosage forms may be or contain preservatives or preservative-free liquid compositions and/or dry powdered compositions. Or not containing preservatives liquid composition will be essentially identical to the compositions described above in the case of containing preservatives and preservative-free liquid for parenteral compositions. the pH of the solution should be approximately 3,0-7,0, more specifically from about pH 4.0 to about 6.0, or from about 4.0 to a 5.0, and pH greater than or equal to approximately 5,0 is preferable to reduce vozmojno.nazvanie the desired particle size and the appropriate distribution of particle size. Surfactant and/or salt can also improve the properties of the morphology of the particles and/or to facilitate uptake by tissues of the active ingredient. Dry powder dosage forms can be in the range from 1 to 100% (wt./wt.) respectively of the active ingredient. May be unnecessary inclusion of filler and/or salts to facilitate formation of a desired size and/or particle distribution. The filler and/or salt may consist of either approximately 0-99% (wt./wt.) carbohydrate or a polyhydric alcohol, or approximately 0-99% salt or a combination of both, leading to the preferred size and distribution of particles. Can be enabled surfactant, preferably from approximately 0.1 to approximately 1.0% (wt./about.) Polysorbate 80 or another non-ionic detergent. Sodium chloride and other fillers may also be present, if desired. However, such fillers will be to maintain the overall stability of the active ingredient and to promote proper hydration levels.

Also within the scope of the present invention is a composition containing up to 50 mg/ml basis or agonist of basis in 30 mm acetate buffer (pH approximately talinya dosage forms for Akindinov and agonists Akindinov for administration by injection and for the introduction of other ways. Thus, the composition of Akindinov and agonists Akindinov having comparable activity, provided for the introduction of injection from approximately 0.1 to approximately 0.5 μg / kg, administered one to three times per day. Usually, for a patient with diabetes, which weighs in the range of approximately 70 kg (average for patients with diabetes type I) to approximately 90 kilograms (average for patients with diabetes type II), for example, this would lead to a General introduction from approximately 10 to approximately 120 mcg per day in one dose or in divided doses. With the introduction in divided doses, these doses are preferably administered two or three times a day and preferably twice a day.

In a preferred procedure, the introduction of the basis or agonist of the basis is administered parenterally, preferably by injection, for example, peripheral injection. Preferably, from about 1-30 μg to about 1 mg of basis or agonist of the basis is administered per day. More preferably, from about 1-30 μg to about 500 μg, or from about 1-30 μg to about 50 μg of basis or agonist of the basis is administered per day. Most preferably, according to the or agonist of the basis is administered per day. The preferred dose based on the patient's weight for compounds having approximately the activity of the basis 4 are in the range from about 0,005 µg/kg per dose to about 0.2 μg/kg per dose. More preferably, the dose based on the patient's weight for compounds having approximately the activity of the basis 4 are in the range from about 0.02 μg/kg per dose to about 0.1 μg/kg per dose. Most preferably, the dose based on the patient's weight for compounds having approximately the activity of the basis 4 are in the range from about 0.05 μg/kg per dose to about 0.1 μg/kg per dose. These doses administered 1-4 times daily, preferably 1-2 times per day. Dose of Akindinov or agonists Akindinov will usually lower when providing continuous infusion. Dose of Akindinov or agonists Akindinov will usually be higher with the introduction of non-injection methods, such as oral, transbukkalno, sublingual, nasal, pulmonary delivery or delivery via skin patch.

Oral dose in accordance with this invention will include from about 50 to about 100 times large quantities of active ingah doses preferably from about 500 to about 5000 μg per day. Lung dose in accordance with this invention will include from about 10 to about 100 times large quantities of active ingredient, for example, from approximately 100 to approximately 12000 mcg per day in a single dose or in divided doses, preferably from about 500 to about 1000 μg per day. Nasal, transbukkalno and sublingual doses in accordance with this invention will include from about 10 to about 100 times large quantities of active ingredient, for example, from approximately 100 to approximately 12000 mcg per day in a single dose or in divided doses.

The preferred dose for nasal administration are from about 10-1000 to approximately 1200-12000 μg per day, for transbukkalno introduction from approximately 10-1000 to approximately 1200-12000 mcg per day for sublingual introduction from approximately 10-1000 to approximately 1200-8000 mcg per day. Sublingual doses are preferably lower than transbukkalno dose. Input dose for agonists Akindinov with activity, more or less of otnositel another place of this description.

In the scope of the present invention are also ways of introducing these new compositions and doses of compounds-agonists Akindinov using delivery vehicles, alternative subcutaneous injection or intravenous infusion, including, for example, through nasal delivery, pulmonary delivery, oral delivery, intratracheal delivery, sublingual delivery and transbukkalno delivery.

In accordance with another aspect, this invention provides new compositions and dosage forms of the compounds agonists Akindinov and methods of their administration that are applicable in the treatment of diabetes (including diabetes type I and type II), obesity, and other conditions that will benefit the purpose of therapy that can slow gastric emptying, reducing the levels of glucose in plasma, and to reduce food consumption.

The invention also includes methods of treatment of subjects to increase insulin sensitivity by introducing a basis or agonist of the basis. The composition of the basis or agonist of basis and dosages described herein may be used to increase the sensitivity of the subject to endogenous or exogenous insulin.

In one predpochtitelney-3 [SEQ ID NO:1]. In another preferred aspect, the specified basis is a basis-4 [SEQ ID NO:2]. Other preferred agonists of basis include the basis-4 (1-30) [SEQ ID NO:6: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly], amide of basis-4 (1-30) [SEQ ID NO:7: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH2], amide of basis-4 (1-28) [SEQ ID NO:40: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2],14Leu,25h-basis-4 [SEQ ID NO:9: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2], amide14Leu,25h-basis-4 (1-28) [SEQ ID NO:41: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2], and amide14Leu,22Ala,25h-basis-4 (1-28) [SEQ ID NO:8: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Ala Ile Glu Phe Leu Lys Asn-NH2].

Other characteristics and advantages of this invention will be apparent from the following description of its preferred options and from the claims.

In accordance with this invention and in the application here, the following terms have the following meanings, unless there is no other clear indications. "Pharmaceutically acceptable salt" includes salts of the compounds of this is the IR form of salt leads to the application form the base. The compounds of this invention are applicable both in the form of free base or in salt form, it means that both forms are within the scope of this invention.

BRIEF DESCRIPTION of DRAWINGS

Fig.1 depicts the amino acid sequence of basis-3 [SEQ ID NO:1].

Fig.2 depicts the amino acid sequence of basis-4 [SEQ ID NO:2].

Fig.3 depicts the amino acid sequence of GLP-1[7-36]NH2(GLP-1) [SEQ ID NO:3].

Fig.4 depicts plasma levels of basis-4 in rats after intratracheal injection.

Fig.5A depicts plasma concentration of basis 4 after intratracheal instillation of mice db/db.

Fig.5b depicts the effect of basis 4 on the plasma glucose after intratracheal injection to mice db/db.

Fig.6A and 6b depict the action of the basis 4 on the plasma glucose after intratracheal injection to mice ob/ob.

Fig.7a depicts the concentration of basis-4 in plasma after intratracheal instillation in rats.

Fig.7b depicts the bioavailability of basis 4 after intratracheal instillation in rats.

Fig.8 depicts plasma concentration of basis-4 in rats exposed aerosol basis 4.

Fig.9a depicts the effect of ten meters is sendina-4 in plasma after ten minutes of exposure of mice db/db aerosol basis 4.

Fig.10 depicts the concentration of basis-4 in the plasma of rats after intranasal administration of basis 4.

Fig.11 depicts the effect of intragastric administration of basis 4 on the plasma glucose of mice db/db.

Fig.12A depicts the concentration of basis-4 in plasma after sublingual administration mice db/db.

Fig.12b depicts the effect of sublingual administration of basis 4 on the plasma glucose of mice db/db.

Fig.12C depicts the concentration of basis-4 in plasma after sublingual rats.

Fig.12d depicts the bioavailability of basis 4 after sublingual administration.

Fig.12E depicts Cmax input of sublingual basis 4.

Fig.13 depicts the effect of basis 4 (injected intraperitoneally, twice per day) on food intake (a), change in body weight (b) (initial body weight 441±39 g) or change of hemoglobin A1c(C) (7,68±0,20% at 0 weeks). Curves dose-response (right panel) are for averages over the last 2-6 weeks of treatment.

Fig.14 depicts the concentration of glucose in plasma (a), the rate of glucose infusion required to maintain euglycemia (b) and lactate concentration in plasma (C) procedures with "fixing" euglycemia held at the ZDF rats, pre-treated for 6 newcopy and the concentration of lactate in the plasma based on the average values, received between 60 and 180 min procedure "commit".

Fig.15 depicts the amino acid sequences for some compounds-agonists basis applicable in this invention [SEQ ID NO:9-39].

Figures 16 and 17 depict the results of the reduction of glucose from the clinical study described in example 12.

DETAILED description of the INVENTION

Exendin and agonists of Akindinov

On the basis of 3 and on the basis 4 are naturally occurring peptides isolated from the salivary secretions Galskogo of adotube and Mexican adotube. The test animals of basis 4 showed that its ability to lower blood glucose is maintained within a few hours. On the basis of 4, the polypeptide of 39 amino acids, synthesized using solid-phase synthesis, as described herein, and shown that this synthetic material identical to a material native of basis 4.

Researched various aspects of non-clinical pharmacology of basis 4. In the brain on the basis of 4 has been mainly associated with area postrema and the area of the nucleus tractus solitarius in the diamond-shaped brain and subfornical body in the front brain. The binding of basis-4 was observed in brain and kidney of the rat and mouse. Patterns that basis-4 binds in the kidney, are neisvac blagopriyatny range of properties for the basis-4. A single subcutaneous dose of basis 4 reduced glucose in the plasma of mice db/db (diabetic) and ob/ob (diabetic obese) by 40%. In ZDF rats (Diabetic Fatty Zucker) (diabetes and obesity) 5 weeks of treatment with basis 4 resulted in a decrease HbAic (measure glycated hemoglobin used to assess levels of glucose in plasma) to 41%. Insulin sensitivity was also improved by 76% after 5 weeks of treatment, rats, ZDF obese. The tolerance to glucose primates also observed a dose-dependent reduction of glucose in plasma. Cm. sample 6, which describes the results of an experiment showing that the basis is more potent and/or effective than GLP-1 gain-stimulated glucose release insulin. In addition, example 8 describes a study showing that the ability of the basis 4 to reduce the glucose in vivo was 3430 times stronger than the ability of GLP-1.

In rodents observed insulinotropic action of basis 4 improving insulin response to glucose by more than 100%, have not been subjected to fasting rats Harlan Sprague-Dawley (HSD) and approximately 10-fold increase in under-fasting mice db/db. Higher concentrations of glucose in plasma before Ordina-4 reduction of glucose, apparently, is dependent on glucose and is the minimum, if the animals are already applicationscope (normoglycemic). Treatment basis 4 is also associated with better glycemic and insulin sensitivity, as described in examples 9 and 13.

On the basis of 4-dependent dose was reduced gastric emptying in rats HSD and was about 90 times more potent than GLP-1 in respect of this action. It was also shown that on the basis of 4 reduces food intake in mice NIH/Sw (Swiss) after peripheral injection, and he was at least 1000 times more potent than GLP-1 in respect of this action. On the basis of 4 reduced concentration of glucagon in plasma is approximately 40% shot at ZDF rats during hyperinsulinemic, hyperglycemic fixed state, but had no effect on the concentration of glucagon in plasma during euglycemia States in healthy rats. Cm. example 4. It was shown that the basis-4-dependent dose was reduced body weight in obese ZDF rats, whereas in lean ZDF rats observed decrease in body weight, apparently, is temporary.

As a result of actions to increase and restore insulin secretion, as well as ingibirovany mirawati insulin. Its effects on food intake, gastric emptying, other mechanisms that modulate the absorption of nutrients and secretion of glucagon also confirm the applicability of the basis 4 for the treatment of, for example, obesity, diabetes type I and diabetes type II, which have reduced insulin secretion.

Toxicology of basis 4 studied in studies with a single dose in mice, rats and monkeys, in studies with repeated doses (up to 28 consecutive daily doses) in rats and monkeys and in vitro tests for mutagenicity and chromosomal changes. To date, were not observed deaths and was not observed treatment-related changes in Hematology, clinical chemistry, or macroscopic or microscopic changes in tissues. It was demonstrated that the basis 4 is nematogens, and he did not cause chromosomal aberrations when tested concentrations (up to 5000 µg/ml).

In support of this study-clinical pharmacokinetics and metabolism of basis-4, was developed a number of immunoassays. The radioimmunoassay with limited sensitivity (~100 PM) was used in the initial pharmacokinetic studies. Dvuhsvetny quantitative Immunoradiometric the reamers 5 and 7. It was found that the bioavailability of basis 4, injected subcutaneously, was approximately 50-80% using this radioimmunoassay. It was similar with bioavailability observed after intraperitoneal administration (48-60%). Maximum plasma concentrations (Cmax) was observed between 30 and 43 minutes (Tmax). As Withmaxand AUC values were dose-dependent. Seeing the end of the half-life for the basis-4, injected subcutaneously, was approximately 90-110 minutes. This was significantly higher than 14-41 min observed after intravenous dosing. Similar results were obtained using IRMA-analysis. Studies on degradation basis 4 compared to GLP-1 show that the basis 4 is relatively resistant to degradation.

Study the relationship of activity with the structure (SAR) for evaluation of structures that can be associated with antidiabetic activity basis, in respect of its stability to metabolism, and its physical characteristics, especially when it relates to the stability of the peptide and to give to alternative delivery systems, led to the discovery of peptide compounds-agonists basis. Agonists e is inoculat removed or replaced with another amino acid (amino acids).

Preferred agonists of the basis are the analogues agonists of basis 4. Especially preferred agonists of the basis, which are described in International application number PCT/US 98/16387, filed August 6, 1988, entitled "New connection agonists of basis", which claims the benefit of the invention of the provisional application U.S. number 60/055 404, filed August 8, 1997, including compounds of formula (I) [SEQ ID NO:3]:

Xaa1Xaa2XAA3Gly Thr XAA4Xaa5Xaa6Xaa7XAA8

Ser Lys Gln XAA9Glu Glu Glu Ala Val Arg Leu

XAA10XAA11Xaa12Xaa13Leu Lys Asn Gly Gly XAA14

Ser Ser Gly Ala Xaa15Xaa16Xaa17Xaa18-Z

where Xaa1refers to His, Arg or Taut; Xaa2denotes Ser, Gly, Ala or Thr; XAA3represents Asp or Glu; Xaa4denotes Phe, Tight or nafcillin; Xaa5represents Thr or Ser; XAA6represents Ser or Thr; XAA7represents Asp or Glu; XAA8represents Leu, Ile, Val, pencillin or Met;

XAA9represents Leu, Ile, pencillin, Val or Met; XAA10denotes Phe, Tight or nafcillin; XAA11means Il, Val, Leu, pencillin, tert-butylglycol or Met; Xaa12represents Glu or Asp; Xaa13bosnain, Nor, nor, thioproline, N-allylglycine, N-ALKYLPHENOLS or N-alkilany; Xaa18denotes Ser, Thr or Taut; and Z represents-IT or-NH2; provided that the compound is not a basis 3 or basis 4.

The preferred N-alkyl groups for N-allylglycine, N-alkylpolyglycoside and N-alkylamine include lower alkyl groups preferably from 1 to about 6 carbon atoms, more preferably from 1-4 carbon atoms. Suitable compounds include compounds listed in Fig.1, having the amino acid sequence of SEQ ID NO:9-39.

The preferred connection agonists of basis include compounds where Xaa1indicates His or Tight. More preferably, Xaa1refers to His.

Preferred are compounds where Xaa2denotes Gly.

Preferred are compounds where XAA9represents Leu, pencillin or Met.

Preferred are compounds where XAA13means Thr or Phe.

Also preferred are compounds where XAA4represents Phe or nafcillin; XAA11means Il or Val and Xaa14, Xaa15, Xaa16and Xaa17independently selected from Pro, gamopolis the carbon atoms.

According to a particularly preferred aspect, Xaa15, XAA16and Xaa17are one and the same amino acid residue.

Preferred are compounds where Xaa18represents Ser or Tight, more preferably Ser.

Preferably Z represents-NH2.

In accordance with one aspect, preferred are compounds of formula (I), where Xaa1indicates His or Tight, more preferably His; Xaa2denotes Gly; XAA4represents Phe or nafcillin; XAA9represents Leu, pencillin or Met; XAA10represents Phe or nafcillin;

XAA11means Il or Val; Xaa14, Xaa15, Xaa16and Xaa17independently selected from Pro, homatropine, thioproline or N-alkylamino; and Xaa18represents Ser or Tight, more preferably Ser. More preferably Z represents-NH2.

In accordance with a particularly preferred aspect, especially preferred compounds include the compounds of formula (I), where Xaa1indicates His or Arg; Xaa2denotes Gly; XAA3represents Asp or Glu; Xaa4represents Phe or nafcillin; Xaa5represents Thr or Ser; XAA6represents Ser or Thr; XAA7represents Asp or Glu;he or nafcillin; XAA11means Il, Val or tert-butylglycol; Xaa12represents Glu or Asp; Xaa13means Thr or Phe; Xaa14, Xaa15, Xaa16and Xaa17independently represent Pro, gemopolis, thioproline or N-methylalanine; Xaa18represents Ser or Taut; and Z represents-IT or-NH2; provided that the compound does not have any formula of the sequence of SEQ ID NO:1 or 2. More preferably Z represents-NH2. Especially preferred compounds include compounds having the amino acid sequence of SEQ ID NO:9, 10, 21, 22, 23, 26, 28, 34, 35 and 39.

In accordance with a particularly preferred aspect, provided connections, where XAA9represents Leu, Ile, Val or pentillion, more preferably Leu or pentillion, and Xaa13denotes Phe, Tight or nafcillin, more preferably Phe or nafcillin. These connections will discover the most beneficial duration and will be less subject to oxidative degradation, both in vitro and in vivo, as well as during the synthesis of this compound.

Connection agonists of basis also include compounds described in International application number PCT/US 98/24210, filed November 13, 1998, entitled "New with the x States with the number 60/065442, filed November 14, 1997, including the compounds of formula (II) [SEQ ID NO:4]:

Xaa1XAA2XAA3Gly Xaa5Xaa6XAA7Xaa8XAA9XAA10

XAA11Xaa12XAA13XAA14Xaa15Xaa16Xaa17Ala Xaa19Xaa20

Xaa21XAA22XAA23XAA24Xaa25Xaa26XAA27Xaa28-Z1- where

Xaa1refers to His, Arg or Taut;

XAA2denotes Ser, Gly, Ala or Thr;

XAA3represents Asp or Glu;

Xaa5represents Ala or Thr;

Xaa6represents Ala, Phe, Tight or nafcillin;

XAA7represents Thr or Ser;

XAA8represents Ala, Ser or Thr;

XAA9represents Asp or Glu;

XAA10represents Ala, Leu, Ile, Val, pencillin or Met;

Xaa11represents Ala or Ser;

Xaa12represents Ala or Lys;

Xaa13represents Ala or Gln;

Xaa14represents Ala, Leu, Ile, pencillin, Val or Met;

Xaa15represents Ala or Glu;

Xaa16represents Ala or Glu;

Xaa17represents Ala or Glu;

Xaa19represents Ala or Val;

Xaa20represents Ala or AGD;

Xaa21represents Ala or Leu;

Xaa22represents Ala, Phe, Tight or nafcillin;

XAA23the represents Ala, Thr, Phe, Tight or nafcillin;

XAA26represents Ala or Leu;

XAA27represents Ala or Lys;

XAA28represents Ala or Asn;

Z1means-HE,

-NH2,

Gly-Z2,

Gly Gly-Z2,

Gly Gly Xaa31-Z2,

Gly Gly Xaa31Ser-Z2,

Gly Gly Xaa31Ser Ser-Z2,

Gly Gly XAA31Ser Ser Gly-Z2,

Gly Gly XAA31Ser Ser Gly Ala-Z2,

Gly Gly XAA31Ser Ser Gly Ala Xaa36-Z2,

Gly Gly XAA31Ser Ser Gly Ala XAA36Xaa37-Z2or

Gly Gly XAA31Ser Ser Gly Ala XAA36XAA37XAA38-Z2;

XAA31, XAA36, XAA37and XAA38denote independently Pro, gemopolis, nor, nor, thioproline, N-allylglycine, N-ALKYLPHENOLS or N-alkilany; or Z2means-HE or-NH2;

provided that not more than three of the Haa3, Xaa5, Xaa6, Xaa8, XAA10, XAA11, Xaa12, Xaa13, Xaa14, Xaa15, Xaa16, Xaa17, Xaa19, Xaa20, Xaa21, Xaa24, Xaa25, XAA26, XAA27and Xaa28represent Ala.

The preferred N-alkyl groups for N-allylglycine, N-alkylpolyglycoside and N-alkylamine include lower carbon.

The preferred connection agonists of basis include compounds in which Xaa1indicates His or Tight. More preferably, Xaa1represents His.

Preferred are compounds where Xaa2denotes Gly.

Preferred are compounds where Xaa14represents Leu, pencillin or Met.

Preferred are compounds where Xaa25means Thr or Phe.

Preferred are compounds where XAA6represents Phe or nafcillin; XAA22represents Phe or nafcillin, and XAA23means Il or Val.

Preferred are compounds where XAA31, XAA36, XAA37and XAA38independently selected from Pro, homatropine, thioproline and N-alkylamine.

Preferably Z1denotes-NH2.

Preferably Z2denotes-NH2.

In accordance with one aspect, preferred are compounds of formula (II), where Xaa1indicates His or Tight, more preferably His; XAA2denotes Gly; XAA6represents Phe or nafcillin; XAA14represents Leu, pencillin or Met; XAA22represents Phe or nafcillin; XAA23means Il or Val; is lalanine. More preferably Z1denotes-NH2.

In accordance with a particularly preferred aspect, especially preferred compounds include the compounds of formula (II), where Xaa1indicates His or AGD; XAA2represents Gly or l; XAA3represents Asp or Glu; Xaa5means l or Thr; Xaa6means l, Phe or nafcillin; Xaa7represents Thr or Ser; Xaa8represents Ala, Ser or Thr; Xaa9represents Asp or Glu; XAA10represents Ala, Leu or pencillin; XAA11represents Ala or Ser; Xaa12represents Ala or Lys; Xaa13represents Ala or Gln; Xaa14represents Ala, Leu or pencillin; Xaa15represents Ala or Glu; Xaa16represents Ala or Glu; Xaa17represents Ala or Glu; Xaa19represents Ala or Val; Xaa20represents Ala or Arg; Xaa21represents Ala or Leu; Xaa22represents Phe or nafcillin; XAA23means Il, Val or tert-butylglycol; XAA24represents Ala, Glu or Asp; Xaa25represents Ala, Trp or Phe; Xaa26represents Ala or Leu; Xaa27represents Ala or Lys; Xaa28represents Ala or Asn; Z1represents-OH, -NH2, Gly-Z2, Gly Gly-Zz, Gly Gly Xaa31-Z2, Gly Gly XAA31Ser-Z2, Gly Gly Xaa3136-Z2, Gly Gly Xaa31Ser Ser Gly Ala XAA36Xaa37-Z2, Gly Gly Xaa31Ser Ser Gly Ala XAA36XAA37Xaa38-Z2; and XAA31, XAA36, XAA37and XAA38denote independently Pro, gemopolis, thioproline or N-methylalanine; and Z2means-HE or-NH2; provided that no more than three of the Haa3, XAA5, Xaa6, Xaa8, XAA10, XAA11, Xaa12, XAA13, Xaa14, Xaa15, Xaa16, Xaa17, Xaa19, Xaa20, Xaa21, Xaa24, Xaa25, Xaa26, Xaa27and Xaa28represent Ala. Especially preferred compounds include compounds having amino acid sequence SEQ ID NO:40-61.

In accordance with a particularly preferred aspect, provided connections, where Xaa14represents Leu, Ile, Val or pentillion, more preferably Leu or pentillion, and Xaa25denotes Phe, Tight or nafcillin, more preferably Phe or nafcillin. These compounds are less sensitive to oxidative degradation, both in vitro and in vivo, as well as during the synthesis of this compound.

Connection agonists of basis also include compounds described in International ora says the advantage of the invention prior to the application of the United States with the number 60/066 029, filed November 14, 1997, including the compounds of formula (III) [SEQ ID NO:5]:

Xaa1XAA2XAA3XAA4Xaa5XAA6XAA7XAA8XAA9XAA10

XAA11XAA12XAA13XAA14Xaa15Xaa16XAA17Ala Xaa19Xaa20

Xaa21XAA22XAA23XAA24Xaa25Xaa26Xaa27Xaa28-Z1; where

Xaa1refers to His, Arg, Tight, Ala, Norval, Val or Norleu;

Xaa2denotes Ser, Gly, Ala or Thr;

XAA3represents Ala, Asp or Glu;

Xaa4represents Ala, Norval, Val, Norleu, or Gly;

XAA5represents Ala or Thr;

Xaa6denotes Phe, Tight or nafcillin;

XAA7represents Thr or Ser;

Xaa8represents Ala, Ser or Thr;

XAA9represents Ala, Norval, Val, Norleu, Asp or Glu;

XAA10represents Ala, Leu, Ile, Val, pencillin or Met;

XAA11represents Ala or Ser;

Xaa12represents Ala or Lys;

XAA13represents Ala or Gln;

Xaa14represents Ala, Leu, Ile, pencillin, Val or Met;

Xaa15represents Ala or Glu;

Xaa16represents Ala or Glu;

Xaa17represents Ala or Glu;

Xaa19represents Ala or Val;

Xaa20represents Ala or AGD;

Xaa21Nilgiris, tert-butylglycol or Met;

Xaa24represents Ala, Glu or Asp;

Xaa25represents Ala, Trp, Phe, Tight or nafcillin;

XAA26represents Ala or Leu;

XAA27represents Ala or Lys;

Xaa28represents Ala or Asn;

Z1means-HE,

-NH2,

Gly-Z2,

Gly Gly-Z2,

Gly Gly Xaa31-Z2,

Gly Gly XAA31Ser-Z2,

Gly Gly XAA31Ser Ser-Z2,

Gly Gly Xaa31Ser Ser Gly-Z2,

Gly Gly Xaa31Ser Ser Gly Ala-Z2,

Gly Gly XAA31Ser Ser Gly Ala XAA36-Z2,

Gly Gly XAA31Ser Ser Gly Ala XAA36Xaa37-Z2,

Gly Gly XAA31Ser Ser Gly Ala XAA36XAA37Xaa38-Z2; or

Gly Gly XAA31Ser Ser Gly Ala Huff36XAA37XAA38Xaa39-Z2;

where XAA31, XAA36, XAA37and XAA38denote independently Pro, gemopolis, nor, nor, thioproline, N-allylglycine,

N-ALKYLPHENOLS or N-alkilany; and

Z2means-HE or-NH2;

provided that not more than three of the Haa3, XAA4, Xaa5, Xaa6, Xaa8, XAA9, XAA10, XAA11, Xaa12, Xaa13, Xaa14, Xaa15, Xaa16, Xaa17, Xaa19, Xaa20, Xaa21, Xaa24represents His, Arg or Tight, then at least one of XAA3, XAA4and XAA5represents Ala.

Getting connections

Compounds which are active ingredients of the composition and doses of this invention may be obtained using standard solid-phase synthesis of peptides and preferably an automated or semiautomated peptide synthesizer. Getting basis 3 and basis 4 described in examples 1 and 2 below. Additional peptide analogues (agonists basis described in the examples 13-198 below.

Usually using automated or semi-automated synthesis of peptides-N-carbarnoyl-protected amino acid and the amino acid attached to the growing peptide chain on a resin are combined at room temperature in an inert solvent, such as dimethylformamide, N-methylpyrrolidinone or methylene chloride in the presence of binders, such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, in the presence of a base, such as diisopropylethylamine.-N-carbarnoyl-protective group is removed from the obtained complex is Oia repeat with the next desired N-protected amino acid, which should be attached to the peptide chain. Suitable N-protective groups are well known in the field, and preferred are tert-butoxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc).

Solvents, derivatives of amino acids and 4-methylbenz-gerilimin-resin used in the synthesis of the peptides, can be purchased from Applied Biosystems Inc. (Foster City, CA). The following protected amino acids side chain can be purchased from Applied Biosystems, Inc.: Boc-Arg(Mts), Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl), Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z), Fmoc-Lyc(Boc), Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt), Fmoc-Asn(Trt) and Fmoc-Gln(Trt). Boc-His(BOM) may be purchased from Applied Biosystems, Inc. or Bachem Inc. (Torrance, CA). The anisole, dimethyl sulphide, phenol, acondition and thioanisole can be obtained from Aldrich Chemical Company (Milwaukee, WI). Air Products and Chemicals (Allentown, PA) delivers HF. Ethyl ester, acetic acid and methanol can be purchased from Fisher Scientific (Pittsburgh, PA).

Solid-phase peptide synthesis can be performed using an automatic peptide synthesizer (Model A, Applied Biosystems Inc., Foster City, CA) using NMP/HOBt (Option 1) and the method using the protective groups tBoc or Fmoc (see Applied Biosystems User's Manual in relation to the ABI 430A Peptide Synthesizer, Version 1.3 B July 1, 1988, section 6, p.49-70, Applied Biosystems is to be extracted from the resin with alternating water and acetic acid and the filtrate lyophilizer. Fmoc-peptide-resin can be split in accordance with standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc., 1990, p.6-12). The peptides can also be assembled using Advanced Chem Tech Synthesizer (Model MPS 350, Louisville, Kentucky).

Peptides may be purified by means OF VIH (preparative and analytical) using Waters Delta Prep 3000. Preparative column C4, C8 or C18 (10 μm, 2,2×25 cm; Vydac, Hesperia, CA) can be used for separation of peptides, and purity may be determined using analytical column C4, C8 or 18 (5 μm, 0,46×25 cm; Vydac). Solvents (A=0.1% OF TFU/water and B=0.1% OF TFU/CH3JV) can be delivered to the analytical column with a flow rate of 1.0 ml/min, and the preparative column, 15 ml/min Amino acid analysis can be performed using the system Waters Pico Tag and processed using Maxima. The peptides may be hydrolyzed by acid hydrolysis in the vapor phase (115°C, 20-24 h). Hydrolysates can be derivativea and analyzed using standard methods (Cohen, et al., The Pico Tag Method: A Manual of Advanced Techniques for Amino Acid Analysis, p.11-52, Millipore Corporation, Milford, MA (1989)). Analysis by bombardment with accelerated atoms can be carried out using M-Scan, Incorporated (West Chester, PA). Calibration in mA is th desorption ionization detection using time-of-flight of particles can be carried out on a mass spectrometer Applied Biosystems Bio-Ion 20. Electrospray mass spectrometry can be performed on the device VG-Trio.

Peptide compounds, which are active ingredients that are applicable in the compositions and dosages of the present invention can also be obtained using recombinant DNA in accordance with the methods currently known in this area. See, for example, Sambrook et al., (Molecular Cloning. A Laboratory Manual, 2ndEd., Cold Spring Harbor Laboratory Press (1989).

Applicability

Composition and dosages described herein are applicable in connection with their pharmacological properties. In particular, composition and doses of this invention are effective as of Akindinov and agonists Akindinov and possess activity as agents to reduce blood glucose, regulation of contractility of the stomach and slowing of gastric emptying, defined by the ability to reduce glucose levels that occur after a meal, in mammals.

Composition and introduction

Compositions and dosage forms of the basis and agonists of the basis of the present invention is applicable in connection with them on the basis of such effects and can be provided in the form of compositions suitable for parenteral (including vnutrepenialnymi delivery including oral, nasal, transbukkalno, sublingual and lung.

Compounds applicable in this invention can be provided as parenteral compositions for injection or infusion. Usually, they can, for example, be suspended in an inert oil, preferably vegetable oil, such as sesame, peanut, olive oil, or other acceptable media. Preferably, they can be suspended in aqueous media, for example, in an isotonic buffer solution at a pH of from about 3.0 to about 7.0 and more specifically from about 4.0 to 6.0 and preferably from about 4.0 to about a 5.0. These compositions can be sterilized conventional sterilization methods, or they can be sterile filtered. The compositions may contain pharmaceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH-forming buffer agents. Applicable buffers include, for example, sodium acetate/acetic acid buffer. Desirable isotonicity can be achieved using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric to adicheskie soluble substances. Sodium chloride is preferred, in particular, for buffers containing sodium ions.

The basis and connection agonists of the basis can also be prepared in the form of pharmaceutically acceptable salts (e.g. acid additive salts) and/or their complexes.

Pharmaceutically acceptable salts are salts, non-toxic at concentrations at which they are introduced. The receipt of such salts can facilitate the pharmacological use by changing the physicochemical properties of the composition without the prevention of the manifestations of the composition of its physiological actions. Examples of applicable changes in physical properties include lowering the melting point to facilitate insertion through the mucous membrane and increasing the solubility to facilitate the introduction of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid additive salts such as salts include the sulfate, hydrochloride, phosphate, sulpham, acetate, citrate, lactate, tartrate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hint. Pharmaceutically acceptable salts can be obtained from acids such as chlorotoluron acid, tartaric acid, malonic acid, methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid, cyclohexylsulfamic acid and Hinn acid. Such salts can be obtained, for example, the reaction product in the form of free acid or forms the base of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is then removed by vacuum drying or lyophilization, or by replacing ions of an existing salt for another ion on a suitable ion exchange resin.

Usually, can be also used carriers or excipients to facilitate doses of this invention. Examples of carriers and excipients include calcium carbonate, calcium phosphate, various sugars, such as lactose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents.

If desired, the solutions of the above dosage compositions can be sealed with a sealing agent, such as methylcellulose. They can be cooked in emulgirovanija pharmaceutically acceptable emulsifying agents can be used, including, for example, powder Arabian gum, nonionic surfactant (such as tween) or ionic surfactant (such as alkali sulfates or sulfonates polyether alcohols, for example, Triton).

In General, compositions, and dosage of the composition of this invention is prepared by mixing the ingredients according to conventional acceptable procedures. For example, the selected components may be simply mixed in the mixer, or other standard device to produce a concentrated mixture, which can then be brought to the final concentration and viscosity by the addition of water or sealing agent and possibly a buffer to regulate the pH or an additional solute to the regulation of toychest.

Other pharmaceutically acceptable carriers and their preparation are described in standard scientific guidelines for the preparation, for example. Remington''s Pharmaceutical Sciences by E. W. Martin. Cm. also Wang, Y. J. and Hanson, M. A. "Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers", Journal of Parenteral Science and Technology, Technical Report No.10, Suppl.42:2S (1988).

For use by the doctor, these connections must be provided in dosage standard form for a single injection containing the number of agonist of basis, with dragoneye stomach agent, lowering lipids agent or inhibitor of food intake. A therapeutically effective amount of an agonist of the basis for use in the regulation of glucose in the blood or in the regulation of gastric emptying in the case of States in which benefits deceleration or regulation of gastric emptying, are those which reduce the levels of blood glucose that occurs after a meal, preferably to not more than about 8 or 9 mm, or such, which reduce the levels of glucose in the blood, as it is desirable. In the case of patients with diabetes or intolerant to glucose individuals, the levels of glucose in plasma are higher than in normal individuals. Such individuals can be obtained a useful reduction or "smoothing" of the levels of blood glucose that occurs after eating. As will be clear to experts in the field, an effective amount of therapeutic agent will vary depending on many factors, including the physical condition of the patient, the blood sugar level or the level of inhibition of gastric emptying, which must be obtained or the desired level of reduction in food intake and other factors.

Such pharmaceutical composition is as well disorders such as diabetes, where insulin sensitivity is advantageously increased.

Form "warehouse" or "depot" - the slow drug release can be used, so that therapeutically effective amounts of such drugs are delivered into the bloodstream over many hours or days after transdermal injection or other form of delivery.

Described effective daily doses of these compounds. The exact be the introduction of a dose can be determined by the attending physician and may depend on the effectiveness of specific-use basis or connection-agonist of the basis, and the age, weight and condition of the individual. The optimal scheme is the introduction of the compounds of this application to the patient depends on factors known in the field, such as a particular disease or disorder, the desired effect and the type of patient. Although in the typical case, these connections will be used for treatment of humans, they can also be used to treat similar or identical diseases in other vertebrates, such as other primates, farm animals such as pigs, cattle and domestic chickens, and sports animals and Pets such as horses, dogs, and it is the basis or agonist of basis, mixed together with a buffer (preferably acetate buffer), a modifier suomalaiset (preferably mannitol) and optionally containing a preservative (preferably m-cresol), and this composition has a pH between about 3.0 and about 7.0 and preferably between about 4.0 and about 5.0 to).

The composition, which is best suitable for parenteral liquid dosage forms, is a composition in which the active ingredient (ingredients) is stable, with adequate buffering capacity to maintain the pH of the solution during storage of this product. Dosage form must be isotonic and/or ISO-osmolar solution to improve the stability of the active ingredient or the relief of pain during injection, or both. However, devices that deliver a very small injection volumes, may not require that the composition was isotonic and/or ISO-osmolar. If the dosage form is packaged as a dose for a single injection, the preservative may be included, but is not necessary. However, if, dosage form packaged in a container for reuse, the preservative AEE specifically from about from 0.005 to about 0.02 percent or from about 0.005-about 0.05% (wt./vol.), accordingly, the active ingredient in the aqueous system along with approximately 0.02 to 0.5 percent (wt./about.) acetate, phosphate, citrate or glutamate or similar buffer, either single or in combination to obtain a pH of the final composition is approximately a 3.0 to 7.0, more specifically from about pH 4.0 to about 6.0, or from about 4.0 to a 5.0, as well as or approximately 1.0 to 10% (wt./about.) carbohydrate or which polyhydric alcohol modifier suomalaiset (preferably mannitol) or up to approximately 0.9% of salt, or a combination of both, leading to isotonic or ISO-osmolar solution in the aqueous continuous phase. Approximately from 0.005 to 1.0% (wt./about.) antimicrobial preservative selected from the group consisting of m-cresol, benzyl alcohol, methyl-, ethyl-, propyl - and butylparaben and phenol, is also present if the composition is Packed into a container for reuse. Sufficient amount of water for injection is added to obtain the desired concentration of the solution. Sodium chloride and other fillers may also be present, if desired. However, such fillers should maintain the overall stability of the active ingredient.

Megaton is their connection as sorbitol, mannitol, glycerol and polyethylene glycol (PEG). These compounds are molecules in a straight chain. Carbohydrates, such as mannose, ribose, trehalose, maltose, glycerol, Inositol, glucose and lactose, on the other hand, are cyclic molecules that contain ketogroup or aldehyde group. These two classes of compounds are also effective in stabilizing the protein against denaturation caused by elevated temperatures and processes of freezing-thawing or freeze-drying. Suitable carbohydrates include galactose, arabinose, lactose or any other carbohydrate, which has no harmful effect on the patient with diabetes, i.e., the carbohydrate is not metabolised by the formation of large concentrations of glucose in the blood. Such carbohydrates are well known in this area as suitable for patients with diabetes.

Preferably, the peptides of the present invention is mixed with a polyhydric alcohol such as sorbitol, mannitol, Inositol, glycerol, xylitol, and a copolymer of polypropylene and ethylene glycol, as well as various polyethylene glycols (PEG) with molecular weight of 200, 400, 1450, 3350, 4000, 6000 and 8000). Mannitol is the preferred polyhydric alcohol.

The liquid composition of this invention should be essentially what Tracey electrolyte or combination of electrolytes and non-electrolytes, which would be equivalent to the osmotic pressure relative to the osmotic pressure where it is introduced here, for example, in the case of parenteral injection of the composition, the tissue of the mammal. Similarly, ISO-osmolar solution can be defined as a solution which has a concentration of non-electrolytes, which would be equivalent to the osmotic pressure relative to the osmotic pressure where it is introduced. In the application here, "essentially isotonic" means within ±20% of isotonicity, preferably within ±10%. In the application here, "essentially ISO-osmolar" means within ±20% of suomalaiset, preferably within ±10%. The prepared product for injection is enclosed in a container, usually, for example, a vial, cartridge, pre-filled syringe or disposable core.

The music that is best suited for single dose parenteral lyophilized dosage form is a composition in which the active ingredient is stable, with adequate buffering capacity to maintain the pH of the solution during storage of the reconstituted product or without this ability. This dosage form should aceste agent toychest and/or modifier suomalaiset in the reconstruction of the solution is either to promote the stability of the active ingredient and/or reduce pain during injection. As noted above, devices that deliver a very small injection volumes, may not require that the composition was isotonic and/or ISO-osmolar. Surfactant may also improve the properties of the sludge (filter) and/or to facilitate the reconstruction of the solution.

These dosage forms include about 0.005 to about 0.4%, more specifically from about from 0.005 to about 0.02 percent or 0,005-0,05% (wt./about.) the active ingredient. Can be optional inclusion of a buffer in the composition and/or the restoration of lyophilized buffer if the contents of the container is intended for use within a period of stability limit for reconstituirea active ingredient. When using the buffer, it can be included in the freeze-dried or solvent to reconstitute the solution. Thus, the composition and/or the solvent to reconstitute the solution may contain individually or together approximately 0,02-0,5% (wt./about.) acetate, phosphate, nitrate or glutamate buffer, either single or in combination, to obtain a pH of the final composition is approximately a 3.0 to 7.0, more specifically from about pH 4.0 to about 6.0, or arr polyhydric alcohol modifier suomalaiset (as described above), or to 0.9% of salt, or combinations thereof, which leads to isotonic or ISO-osmolar solution recreated in the aqueous phase. Can be enabled surfactant, preferably from approximately 0.1 to approximately 1.0% (wt./about.) Polysorbate 80 or another non-ionic detergent. As noted above, in lyophilized standard composition for a single injection may also contain sodium chloride, as well as other fillers, if desired. However, such fillers should maintain the overall stability of the active ingredient. This song should be dried within the parameters of validation, identified to maintain the stability of the active ingredient.

The liquid composition of this invention must be essentially isotonic and/or ISO-osmolar to lyophilization, or to allow the formation of isotonic and/or ISO-osmolar solutions after recreating solution. This composition should be used within the period established by studies of the retention period, as in dried form, and subsequent reconstruction of the solution. Lyophilized product is enclosed in a container, usually, for example, in a bottle. PR is to be included solvent to reconstitute the solution.

As in the case of parenteral liquid and lyophilised dose of the compositions described above, the composition of which is best suited for mnogochasovoj parenteral lyophilized dosage forms, is a composition in which the active ingredient is stable enough, with adequate buffering capacity to maintain the pH of the solution during the proposed period of storage of this product. This dosage form should contain a filler to facilitate sediment (on the filter). The filler may also act as agent toychest and/or modifier suomalaiset in the reconstruction of the solution or to promote stability of the active ingredient, or to reduce pain during injection, or both. In this case, devices that deliver a very small injection volumes, may not require that the composition was isotonic and/or ISO-osmolar. However, the preservative is necessary to facilitate reuse of the patient.

These dosage forms include about 0.005 to about 0.4%, more specifically from about from 0.005 to about 0.02 percent or approximately 0,0 Yu and/or reconstruction of lyophilized buffer, if the contents of the container is intended for use within a period of stability limit for reconstituirea active ingredient. When using the buffer, it can be included in the freeze-dried or solvent to reconstitute the solution. Thus, the composition and/or the solvent to reconstitute the solution may contain individually or together approximately 0,02-0,5% (wt./about.) acetate, phosphate, citrate or glutamate buffer, either single or in combination, to obtain a pH of the final composition is approximately a 3.0 to 7.0, more specifically from about pH 4.0 to about 6.0, or from about 4.0 to a 5.0. The filler may consist of either approximately 1.0 to 10% (wt./about.) carbohydrate or which polyhydric alcohol modifier suomalaiset (preferably mannitol), or 0.9% of salt, or combinations thereof, which leads to isotonic or ISO-osmolar solution recreated in the aqueous phase. Can be enabled surfactant, preferably from approximately 0.1 to approximately 1.0% (wt./about.) Polysorbate 80 or another non-ionic detergent. Approximately from 0.005 to 1.0% (wt./about.) antimicrobial preservative selected from the group consisting of the Sabbath.), there is also, if the composition is Packed into a container for reuse. Sodium chloride and other fillers may also be present, if desired. However, again, such fillers should maintain the overall stability of the active ingredient. This song should be dried within the parameters of validation, identified to maintain the stability of the active ingredient. The liquid composition of this invention must be either essentially isotonic and/or ISO-osmolar to lyophilization, or to allow the formation of isotonic and/or ISO-osmolar solutions after recreating solution. This composition should be used within the period established by studies of the retention period, as in dried form, and subsequent reconstruction of the solution. Lyophilized product is included in the container, usually, for example, in a bottle. The application of other containers such as cartridges, pre-filled syringe or disposable rod, may also be included solvent to reconstitute the solution.

Compositions, which are best suitable for oral, nasal, pulmonary and/or intratracheal demi and/or dry powdered or for oral administration, solid compositions. Containing preservatives or preservative-free liquid composition will be essentially identical to the compositions described above, in the case of containing and preservative-free liquid for parenteral compositions. the pH of the solution should be approximately 3.0-7.0, and pH greater than or equal to approximately 5,0 is preferred to reduce the possibility of bronchostenosis. The dry powder composition may contain a filler and/or salt to facilitate formation of the desired particle size and a suitable distribution of particle size. Surfactant and/or salt can also improve the properties of the morphology of the particles and/or to facilitate uptake by tissues of the active ingredient.

Dry powder dosage forms can be in the range from 1 to 100% (wt./wt.), respectively of the active ingredient. May be unnecessary inclusion of filler and/or salts to facilitate the education of the proper size and/or particle distribution. The filler and/or salt may consist of either approximately 0-99% (wt./wt.) carbohydrate or a polyhydric alcohol, or approximately 0-99% salt or a combination of both, leading to pre is sustained fashion from approximately 0.1 to approximately 1.0% (wt./about.) Polysorbate 80 or another non-ionic detergent. Sodium chloride and other fillers may also be present, if desired. However, such fillers should maintain the overall stability of the active ingredient and to promote proper hydration levels.

Compositions, which are best suitable for nasal and/or intratracheal dosage forms can be containing preservative or not containing preservative liquid dosage compositions described previously.

Soluble gels and/or patches may be used to facilitate transbukkalno delivery. These gels can be prepared from various types of starch and/or cellulose derivatives.

Sublingual delivery can best be liquid compositions similar to those described above as a parenteral liquid or parenteral lyophilized compositions after recreating solution, without the need for this dosage form to be isotonic and/or ISO-osmolar solution. Solid dosage forms may be similar to oral solid dosage forms, except that they must be easily soluble under the tongue.

Oral delivery can best be liquid (g solution can be more concentrated and may contain additional additives to facilitate absorption of the active ingredient in the small intestine. Solid dosage forms will contain inert ingredients together with the active ingredient to facilitate the formation of tablets. These ingredients may include polyhedral alcohols (such as mannitol), carbohydrates or types of starch, cellulose derivatives, and/or other inert, physiologically compatible material. The tablet may have intersolubility floor to minimize splitting in the stomach and thus facilitate the dissolution and absorption further along the alimentary canal.

The invention also includes a preferred dose for Akindinov and agonists Akindinov with the introduction of injection and other methods. Thus, the composition of the basis and agonists basis, with comparable activity, preparing for the introduction of injection and include from about 0.1 to about 0.5 μg / kg, administered one to three times per day. Usually, for a patient with diabetes, which weighs in the range of approximately 70 kg (average for patients with diabetes type I) to approximately 90 kilograms (average for patients with diabetes type II), for example, this would lead to a General introduction from approximately 10 to approximately the injected two or three times a day and preferably twice a day.

In a preferred procedure, the introduction of the basis or agonist of the basis is administered parenterally, preferably by injection, for example, peripheral injection. Preferably, from about 1-30 μg to about 1 mg of basis or agonist of the basis is administered per day. More preferably, from about 1-30 μg to about 500 μg, or from about 1-30 μg to about 50 μg of basis or agonist of the basis is administered per day. Most preferably, depending on the weight of the subject and the activity of the introduced compound, from about 3 μg to about 50 μg of basis or agonist of the basis is administered per day. The preferred dose based on the patient's weight for compounds having approximately the activity of the basis 4 are in the range from about 0,005 µg/kg per dose to about 0.2 μg/kg per dose. More preferably, the dose based on the patient's weight for compounds having approximately the activity of the basis 4 are in the range from about 0.02 μg/kg per dose to about 0.1 μg/kg per dose. Most preferably, the dose based on the patient's weight for compounds having approximately the activity of the basis 4 are CI, preferably 1-2 times per day. Dose of Akindinov or agonists Akindinov will usually lower when providing continuous infusion. Dose of Akindinov or agonists Akindinov will usually be higher with the introduction of non-injection methods, such as oral, transbukkalno, sublingual, nasal, pulmonary delivery or delivery via skin patch.

Oral dose in accordance with this invention will include from about 50 to about 100 times larger amount of the active ingredient, i.e., from approximately 500 to approximately 12000 mcg per day in a single dose or in divided doses, preferably from about 500 to about 5000 μg per day. Lung dose in accordance with this invention will include from about 10 to about 100 times larger amount of the active ingredient, i.e., from approximately 100 to approximately 12000 mcg per day in a single dose or in divided doses, preferably from about 500 to about 1000 μg per day. Nasal, transbukkalno and sublingual doses in accordance with this invention will include from about 10 d is about 12000 mcg per day in a single dose or in divided doses.

The preferred dose for nasal administration are from about 10-1000 to approximately 1200-12000 μg per day, for transbukkalno introduction from approximately 10-1000 to approximately 1200-12000 mcg per day for sublingual introduction from approximately 10-1000 to approximately 1200-8000 mcg per day. Sublingual doses are preferably lower than transbukkalno dose. Input dose for agonists Akindinov with activity, more or less relative to the basis-4, increasing or decreasing as needed in comparison with the above or elsewhere in this description.

Clinical studies

As described in example 10 below, carried out in two ways-blind, placebo-controlled study with only increasing dose, to test the safety, tolerability and pharmacokinetics of subcutaneously injected basis of-4 in healthy volunteers. Five single subcutaneous doses of basis-4 (0,01, 0,05, 0,1, 0,2 or 0.3 μg/kg) was investigated in 40 healthy volunteers-men in a state of deliberate starvation. The maximum plasma concentration of basis 4 was achieved between one and two hours after a dose with a small difference among the tested doses. the cnyh phenomena, reported in this study.

Healthy volunteers, men who participated in this study, on the basis of 4 was well tolerated at subcutaneous doses up to 0.1 mg/kg and including 0.1 mg/kg Decrease in plasma glucose concentrations were also observed at this dose. At doses of 0.2 mg/kg and higher, the most commonly observed adverse events were headache, nausea, vomiting, dizziness and postural (due to body position) hypotension. Observed transient fall in plasma glucose concentration after administration of doses of 0.05 mg/kg and above.

Example 12 below describes additional study of the dependence of the dose-response for lowering glucose effect of basis-4 at doses of less than 0.1 µg/kg Fourteen subjects [mean age (±SE) 55±2; average BMI (30,2±1.6 kg/m2) ] with type 2 diabetes treated with diet ± oral hypoglycemic agents, investigated after discontinuation of oral agents within 10-14 days. Evaluation was done after a randomized subcutaneous injections of placebo, 0,01, 0,02, 0,05 and 0,1 mg/kg of basis 4 days after fasting overnight. Injections were made immediately before ingestion of a standardized meal Sustacal® (7 kcal/kg) after sampling plasmas the public in the form of a weighted time average (±SE) changes in the concentration of glucose in plasma during 5-hour period. The reaction was in the range of from increment +42,0±7.9 mg/DL higher glucose concentrations during fasting for placebo, compared with a decrease of 30.5±8.6 mg/DL lower glucose concentrations during fasting with 0.1 µg/kg of basis 4.

ED50to do this, lowering the glucose effect was 0,038 mg/kg Dose of basis 4 below 0.1 µg/kg, apparently, is separated lowering glucose effects gastrointestinal side effects. Example 12 shows that on the basis of 4 not only was well tolerated at doses less than 0.1 µg/kg, but these doses significantly reduced the concentration of plasma glucose that occurs after a meal (ED500,038 mg/kg) in people with type 2 diabetes.

Alternative delivery methods

The possibility of using other delivery methods for the basis-4 was investigated by measuring of basis-4 in blood flow in combination with the observation of biological response, such as the reduction of glucose in the plasma of animals with diabetes after injection. Investigated the passage of the basis 4 through multiple surfaces, the respiratory tract (nasal, tracheal and pulmonary ways) and intestine (sublingual, by means of a gastric probe and intraduodenal ways). Biological effects and the emergence of basis 4 blood th probe peptide through the gastrointestinal tract.

Intratracheal introduction As described here, intratracheal introduction of basis 4 starving rats (20 μg/50 μl/animal) was given the increase in the average concentration of basis-4 in plasma up to 2060±960 PG/ml within 5-10 minutes after injection. Elevated concentrations of basis-4 in the plasma was maintained for at least 1 hour after instillation (see Fig.4). In mice with diabetes db/db intratracheal instillation of basis-4 (1 μg/animal) reduced the concentration of glucose in plasma by 30%, while the concentration of plasma glucose in the control group with the media was increased by 41% after 1.5 h after injection. In these animals the average concentration of basis-4 in plasma was 777±365 PG/ml after 4.5 hours after injection (see Fig.5A and 5b).

In mice with diabetic ob/ob intratracheal instillation of basis-4 (1 μg/animal) resulted in a decrease in the concentration of glucose in plasma up to 43% of the level present before treatment, after 4 hours, while the concentration of glucose in the control group with the media was not changed (see Fig.6A and 6b).

Nine starving during the night male mice Sprague-Dawley (age 96-115 days, weight 365-395, average 385 g) was anestesiologi the halothane gas, had to perform a tracheotomy and mice were catheterizable through the femoral alibali into the trachea at a distance from the level of intubation. Blood samples were taken after 5, 10, 20, 30, 60, 90, 120, 150, 180, 240, 300 and 360 min, centrifuged and the plasma was stored at -20°C for subsequent Immunoradiometric (IRMA) analysis on the N-terminal and C-terminal epitopes of intact molecules of basis 4. After intratracheal injection watched 61-74% of peak plasma concentrations within 5 minutes Tmaxtook place between 20 and 30 min after injection. AUC and Cmaxwere proportional to the dose. At a dose of 2.1 mg (1.5 nmol/kg), resulting in concentrations in plasma, about 50 PM (where observed effects on lowering glucose in humans), the bioavailability was 7.3 per cent. The coefficient of variation was 44%. At higher doses, the bioavailability was slightly lower, a CV was higher (see Fig.7a and 7b). When the tracheal route of administration t1/2 (almost certain as the fall in plasma below 50% Withmax) was 30-60 min for the lowest dose and 60-90 min for the 2 higher doses. In General, biologically effective amount of basis 4 was rapidly absorbed through the trachea without induction of apparent respiratory distress. The Airways are good through the introduction of basis 4.

Pulmonary introduction - Increased plasma concentrations of basis-4 were detected in rats exposed Aero is their 10 minutes resulted in maximum concentrations of basis 4 plasma 300-1900 PG/ml after 5 minutes after treatment (see Fig.8). Such exposure of mice with diabetes db/db aerosol basis 4 leads to a 33% decrease in plasma concentrations of glucose after 1 hour, when were detected average plasma concentration of basis 4 170±67 PG/ml Mouse with diabetes db/db control group, exposed aerosol saline solution, found no changes in plasma glucose (see Fig.9a and 9b).

Nasal introduction - Introduction of basis 4 in the nasal cavity of rats led to an increase in concentratie in the plasma. The maximum value of 300 PG/ml and 6757 PG/ml were detected after 10 minutes after administration of 1 μg and 100 μg of basis 4 (dissolved in 2 μl saline), respectively (see Fig.10).

Introduction through the gut - Male mice db/db (a weight of approximately 50 g) were starved for 2 h before and after intragastric administration of saline or basis 4 (basis 4). 9% decrease in the concentration of glucose in plasma was observed with 1 μg/200 μl/animal, and 15% decrease was observed with 3 μg/200 μl/animal compared to 10% increase of plasma glucose in controls after one hour after treatment (see Fig.11).

Sublingual introduction - Sublingual introduction of basis 4 (100 μg/5 μl/animal) mice with diabetes db/db resulted in 15% increase smart is Inoi group, receiving saline. The average level of basis-4 in plasma at 60 minutes was 4520±1846 PG/ml (see Fig.12A, 12b and 12C).

Eight rats Sprague-Dawley (-300 g) was short anestesiologi metafandom, pepetua solution containing 10 μg/3 μl (n=4) or 100 μg/3 μl (n=4), under the tongue. Blood samples were subsequently collected from locally shot of the tail and analyzed on the basis of 4 with the help of IRMA. Plasma concentrations started to rise to 3 minutes after injection and were maximal after 10 and 30 min after injection (doses of 10 and 100 μg, respectively). The concentration of basis-4 in the plasma subsequently remained above the lower limit of quantitation (LLOQ) after 5 hours. The area under the curve (area-under-the-curve (AUC)) to the end of each experiment was calculated by trapezoidal method. Received two numbers, one derived from the total immunoreactivity, the other derived from the increment of above non-zero values which are available at t=0. These values were compared with historical data obtained using intravenous bolus for the same animal model, to obtain, respectively, high and low estimates of bioavailability. For a dose of 10 mcg sublingual bioavailability was 3.1-9.6% for doses of 100 µg bioavailability b 10 and 100 μg). For 5-hour integral coefficient of variation in AUC was 20 and 64%, respectively. Maximum plasma concentration (Cmax) was achieved as quickly after the sublingual administration, as after subcutaneous injection (Tmaxabout 30 min). Withmaxafter sublingual injection of 10 ág of basis 4 was 1.5% concentration after intravenous bolus, but 14,5% concentration obtained after subcutaneous bolus. Withmaxafter sublingual injection of 100 μg of basis 4 was only 0.29 per cent concentration observed after intravenous bolus, and 6.1% concentration obtained by the subcutaneous route of administration (see Fig.12d and 12E). Thus, on the basis of 4 can be delivered at bioaffecting doses through sublingually way. Bioavailability and Cmaxwere higher, Tmaxit was the shortest and the variability of availability was lowest with the lowest sublingual dose. The lowest sublingual dose resulted in concentrations in plasma, similar to the concentrations that, as predicted, should be effective in reducing glucose in humans (approximately 50-100 PM).

For a better understanding of the present invention included the following examples, which describe the results of a series expropriative the invention, and such variations of the present invention, developed now or later, which would be within the competence of the person skilled in the art, are within the scope of this invention, described herein and in the claims.

EXAMPLE 1 - GETTING BASIS 3

His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2[SEQ ID NO:1]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-leucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.). In General, the cycles of the individual binding used during synthesis and used Fast Mos method (HBTU activation). Removing the protective groups (removal of the Fmoc group) growing peptide chain was performed using piperidine. The final removal of the protective groups of the complex completed peptide-resin was achieved by using a mixture of triethylsilane (0.2 ml), identicial (0.2 ml), anisole (0.2 ml), water (0.2 ml) and triperoxonane acid (15 ml) according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc.). Peptide precipitiously in a mixture of ether/water (50 ml) and centrifuged. The precipitate was reconstituirea in glacial acetic acid and liofilizarea the Lisa of examples 1 and 2 used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN).

The solution containing the peptide was applied to a preparative column of C-18 and purified (10-40% solvent in the solvent And on for 40 minutes). The purity of the fractions was determined isocratically using analytical column C-18. Pure fractions were combined to obtain identified above peptide. Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 19.2 minutes.

EXAMPLE 2 - GETTING BASIS 4

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2[SEQ ID NO:2]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-leucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner with basis 3 as described in example 1. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 36-46% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product Peano 4186,6; found 8186,0-4186,8 (four parties).

EXAMPLE 3 - BASIS-4 IS CIRCULATING, ASSOCIATED WITH FOOD INTAKE PEPTIDE AT GALSKOGO of ADOTUBE

In this experiment investigated, is whether on the basis of 4 metabolic role in the lizard Gilsky JACOsub. For research, if the basis-4 in the blood Galskogo of adotube in response to feeding, took samples of blood from one animal, starving for 7 weeks, before and 30 minutes after the ingestion of a small rat. Plasma was analyzed on a size basis 4 using immunology-metric analysis using pairs of monoclonal antibodies directed to epitopes on the N - and C-ends of basis 4. The concentration of basis-4 in plasma during fasting was 76 PG/ml, approximately the lower limit of quantitation. After a meal of this magnitude has increased 300 times before 23120 PG/ml.

In the second experiment, consecutive samples were taken from two animals, starving five weeks before and after the ingestion of one or two small rats (47-49 g). The concentration of basis-4 in plasma increased in 23-36 times (up to 4860, 8340 PG/ml) immediately after a meal, which is consistent with the direct passage of the basis 4 of the salivary glands into the blood. After ingestion of the second rat (t=30 min) was concentrations with t1/2 5.00 and 5,33 h, respectively. We can conclude that on the basis of 4, which, as you know, comes from the salivary glands Galskogo of adotube, appears in high concentrations in the blood immediately after a meal. This may mean associated with food intake signal for additional inhibition of food intake and stimulation of Deposit of nutrients.

EXAMPLE 4 - BASIS-4 REDUCES the SECRETION of GLUCAGON DURING HYPERGLYCEMIC "COMMIT" IN RATS WITH OBESITY AND DIABETES

Absolute or relative hyperglucagonemia is often a symptom of diabetes type I and type II, and suppression of excessive secretion of glucagon can potentially benefit in the treatment glucagon-static agents. In this example, studied the effect of basis 4 on the secretion of glucagon in males shot rats with diabetes and obesity (ZDF-rats). Using the commit Protocol hyperinsulinemia and hyperglycemia factors that use a tendency to affect the secretion of glucagon, maintained constant. The plasma glucose "fixed" at the level of approximately 34 mm for 60 min before intravenous infusion of saline (n=7) or basis 4 (of 0.21 µg + 2,1 µg/ml/h; n=7). The concentration of plasma the NGOs; the distinction is false).

The average concentration of glucagon in plasma in rats, which were administered on the basis of 4 was equal to almost half of the concentration in rats, which were injected saline solution, in the last 60 minutes "fixing" (165±18 PM against 298±26 PM, respectively; P<0,002). This Protocol hyperglycemic "commit" has also made it possible to measure insulin sensitivity. The rate of infusion of glucose during the "commit" was increased by 111±7% in rats treated with basis 4, compared with the control rats (P<0,001). In other words, on the basis of 4 showed glucagonostatic action ZDF-rats in the studies with hyperglycemic "commits", an effect that will have therapeutic value in the case of people with diabetes.

EXAMPLE 5 - the PHARMACOKINETICS of BASIS-4 IN RATS AFTER INTRAVENOUS, SUBCUTANEOUS AND INTRAPERITONEAL administration

This example describes a study to determine the plasma pharmacokinetics of basis 4 rats (body weight of each rat about 350 g) after i.v. bolus (rapid intravenous), s.c. and i.p. introduction 2,1, 21, 210 μg per rat and i.v. infusion 2,1, 21, 210 µg/h/rat (3 h). Serial plasma samples (approximately 120 µl) were analyzed using the assessed Immunoradiometric with basis 4, but do not react with GLP-1 or the tested metabolites of basis-4 or GLP-1. The lower limit of quantitation was 15 PM (63 PG/ml). Specific t1/2 for the basis-4 was 18-41 min to i.v. boles, 28-49 for continuous i.v. introduction 90-216 min for C.with. and 125-174 min to i.p. the injection. Bioavailability was 65-76% s.with. and i.p. the injection. Clearance is defined from i.v. infusion was 4-8 ml/min. Value Withmaxand AUC (area-under-curve) were in every way of introducing proportional to the dose. The volume of distribution was 457-867 ml. Clearance and bioavailability were not dose dependent. Withmax(or concentration homeostasis in plasma; Cgs) shown in the table below.

EXAMPLE 6 - COMPARISON INSULINOTROPIC actions of BASIS-4 AND GLUCAGON-LIKE PEPTIDE-1 (GLP-1) DURING INTRAVENOUS GLUCOSE RATS

In this experiment compared insulinotropic action synthetic basis-4 and GLP-1 in vivo after intravenous (i.v.) glucose administration to rats. Rats Sprague-Dawley (approximately 400 g) was anestesiologi the halothane gas and Coulibaly through the femoral artery and saphenous vein of the foot. After a 90-minute period of recovery to normal saline or peptide (30 pmol/kg/min) was administered i.v. (1 ml/h for 2 is,8 ml). The treated saline-treated basis 4 and processed GLP-1 in rats glucose concentrations in plasma were similar before injection(9,3±0,3, 9,7±0,3, 10,3±0,4 mm), increased by a similar amount after injection of glucose (21,7, 21,3, 23,7 mm) and resulted in similar 60-minute glucose AUC(987±39, 907±30, 1096±68 mm·min, respectively). I.e. glycemic stimulus was similar in each group processing. The concentration of insulin in plasma treated with saline rats was increased 3.3-fold after administration of glucose (from 230±53 up to a maximum of 765±188 PM). When infusion of the basis 4 the increase in the plasma concentration of insulin was 6.8 times (363±60-2486±365 gr). With GLP-1 increase in the plasma concentration of insulin was 2.9 times (391±27-1145±169 PM), which is similar to the concentration obtained from the treated saline rats. 60-minute AUC insulin treated saline rats was 24±6 nm·min, was increased 2.8-fold in treated basis 4 rats (67±8 nm·min; P<0,003 vs. saline; P<0,02 against GLP-1) and 20% in GLP-1-treated rats (false distinction versus saline). Amplification stimulated glucose release insulin basis 4 was also experienced at speeds infusion 3 and 300 pmol/kg/min, and it is strengthening-stimulated glucose release of insulin in intact rats.

EXAMPLE 7 - DEVELOPMENT AND VALIDATION IMMUNORADIOMETRIC ASSAY (IRMA) FOR the QUANTITATIVE MEASUREMENT of BASIS-4 IN PLASMA AND ITS APPLICATION FOR estimation of PRECLINICAL TOXICITY AND KINETIC TRIALS PHASE I

Was developed sensitive and specific Immunoradiometric analysis (IRMA) sandwich-type for the quantitative determination of plasma concentrations of basis 4 using synthetic basis 4 as the immunogen. One derived from the mouse monoclonal antibody recognizes the C-terminal epitope on the basis of 4 (capture antibody), but does not cross react with GLP-1. The second antibody (detection antibody, labeled125I) recognizes the N-terminal epitope of basis-4 and GLP-1 and requires the terminal histidine to bind. Thus, this analysis will not detect GLP-1(7-36)NH2, GLP-1(7-36)COOH or basis(3-39). Analysis on the plasma of the rat, monkey, dog, rabbit and man found the correlation coefficients between tests within tests <20% <10%, ±15% with low, medium and high controls-targets upper and lower limits of quantification of 62.8 and 2512 PG/ml, respectively. Plasma samples from estimates of 28-day subcutaneous toxicity of accendi the CSOs IRMA. Value Withmaxin animal studies shown in the table below. Sample of a person with a subcutaneous injection of 0.05, 0.1, 0.2 and 0.3 mg/kg given value With themax90, 224, 370 and 587 PG/ml.

EXAMPLE 8 COMPARISON of the effects of GLP-1 AND BASIS-4 BINDING/activation of the GLP-1 RECEPTOR AND REDUCE GLUCOSE

On the basis of 4 was synthesized by means of solid-phase synthesis of peptides and compared with synthetic GLP-1 with respect to binding in vitro with receptors GLP-1 and activation of receptors GLP-1 in vivo lowering of glucose in the plasma of mice with diabetes db/db. In the preparation of plasma membrane cell lines rat insulinoma (RINm5f), expressing the GLP-1-receptor, these peptides were tested for their ability to contact and displace radioactively labeled GLP-1 and their ability to stimulate the production of camp. It was found that the relative order of binding activity was GLP-1 > on the basis of 4. The relative order of activation of cyclase activity was GLP-1 = basis-4. Affinity, as shown in the table below differ in the range of 4-5-fold differences. In contrast, the activity reduction of glucose in vivo varies over the range 3430-fold differences. On the basis of 4 was in 3430 times Bo is the culmination of all properties.

EXAMPLE 9 comparison of the GLYCEMIC INDICES AND INSULIN SENSITIVITY IN PAIRS RECEIVING FOOD AND PROCESSED the BASIS OF 4 RATS WITH DIABETES AND OBESITY

In this example investigated whether the beneficial effects of basis 4 ZDF-rats secondary to changes in food intake. This example compares the effects obtained with basis 4, with effects observed in patients treated with salt solutions of the respective animals who consumed the same amount of food that was eaten ZDF-rats, injecting subcutaneously twice daily 10 mg basis 4. Glucose and HbAlc in plasma was measured once a week for 6 weeks. Later, one day after the last treatment, animals were anestesiologi the halothane gas and subjected hyperinsulinemia (50 IU/kg/min) euglycemic (normoglycemia) "fixation". Changes in HbAlc for 6 weeks differed between treatment groups (P<0.001 in ANOVA), increasing from receiving food ad libitum (n=5) and paired ZDF-rats (n=5) receiving the same amount of food, and treated ZDF-rats, and decreasing the treated basis 4 rats (n=5). Similarly, changes in plasma glucose differed) the amount of food, that and treated ZDF-rats, and decreasing the treated basis 4 ZDF-rats. In the last hour, 3-hour Protocol fixing the glucose infusion rate in treated basis 4 rats tended to be higher than in pair-fed (+105%) and receiving food ad libitum (+20%) controls, respectively (10,14±1,43 n=5, 8,46±0,87 n=4, 4,93±2,02 mg/kg/min, n=3; the difference unreliable. P=0,09 ANOVA). Another indicator of insulin sensitivity, the concentration of lactate in plasma differed significantly between treatment groups (P<0,02 ANOVA) and was the lowest in the treated basis 4 rats. Thus, treatment basis-4 is associated with improved glycemic indices and insulin sensitivity, which is partly, but not fully consistent with the controls receiving the same amount of food, which indicates that the improvements in the metabolic regulation of the basis 4 the ZDF-rats, at least partially caused by mechanisms beyond calorie restriction.

EXAMPLE 10 CLINICAL RESEARCH AND the STIMULATION of the SECRETION of ENDOGENOUS INSULIN SUBCUTANEOUSLY INJECTED SYNTHETIC BASIS 4 HEALTHY HUNGRY during the NIGHT VOLUNTEERS

In docosia, placebo-controlled clinical trial with whom the basis 4, on the basis of 4, prepared for subcutaneous injection, has been evaluated in healthy volunteers-men, determining the effects on the concentration of glucose and insulin in plasma. Five single subcutaneous doses of basis-4 (0,01, 0,05, 0,1, 0,2 or 0.3 μg/kg) was investigated in 40 healthy volunteers-men in a state of deliberate starvation. The maximum plasma concentration of basis 4 was achieved between 1 and 2 hours after a dose with a small difference among the tested doses. Analysis of these data showed a dose-dependent increase Withmax. No serious adverse side effects reported in this study, healthy volunteers were men who participated in this study, was well tolerated on the basis of 4 at subcutaneous doses up to and including 0.1 mg/kg Decrease in plasma glucose concentrations were also observed at this dose. At doses of 0.2 mg/kg and higher, the most commonly observed adverse events were headache, nausea, vomiting, dizziness and postural (due to body position) hypotension. Observed transient fall in plasma glucose concentration after administration of doses of 0.05 mg/kg and above.

Forty healthy lean (mean BMI (±SE) 22,7±1,2) entities in which Uchali placebo (VBOs). On the basis-4 (0,01, 0,05, 0,1, 0,2 or 0.3 mg/kg) or placebo was administered after an overnight fast and the concentration of basis-4, glucose and insulin in plasma were measured together with safety and tolerability. Not seen problems in relation to security. Dose0.1 mg/kg was tolerated as well as placebo, whereas 0.2 and 0.3 ág/kg induced a dose-dependent increase in nausea and vomiting. The maximum plasma concentration of basis 4 increased dependent on the dose way and after 0.1 mg/kg immunoreactivity of basis 4 continued during 360 min Glucose in plasma was decreased after all doses, with the exception of 0.01 mcg/kg, was at its lowest level for 30 minutes and returned to background within 180 minutes of the Subjects treated with 0.3 ág/kg, took an energy drink for 30 minutes after a dose that prevented the comparison of their data. The mean change in plasma glucose (0-180 min): 0,03±0,07, -0,07±0,08, -0,38±0,14, -0,85±0,13 and -0,83±0.23 mmol/l for placebo (VBOs), of 0.01, 0.05, 0.1 and 0.2 µg/kg, respectively; P0,02 against VBOs. The lowest recorded concentration of glucose in plasma was 3.4 mmol/L. the Corresponding average changes of insulin in plasma (0-120 min) were 0,43±0,59, 2,37±0,58, 2,28±0,66 orovich, starving during the night volunteers subcutaneous injection of basis 4 (1) did not give problems in terms of safety, (2) was well tolerated at doses0.1 mg/kg, (3) led to the immunoreactivity of basis-4 in plasma for up to 6 hours, (4) increased insulin in the plasma and decreased glucose in plasma is dependent on the dose, without induction of hypoglycemia.

EXAMPLE 11 - EFFECTIVENESS of ALTERNATIVE DELIVERY BASIS 4 IN RODENTS

In this example, experienced delivery of basis 4 through alternative injection and examined its ability to cross the mucous surface in sufficient quantities for the manifestation of the biological effect. Changes in the concentration of plasma glucose and intact synthetic basis-4 in plasma (measured using 2-sitngo Immunoradiometric analysis) was observed in mice db/db, which was injected saline solution containing different doses of synthetic basis 4, through the trachea, through aerosol fog (pulmonary route), via a stomach tube through the mouth and under the tongue (sublingual). The same routes of administration, and intraduodenal and nasal, tested on rats and expected bioavailability, for example, for bodyas the l to a significant decrease glucose activity after 1-4 h after injection (mouse, db/db, vnutritrahealno, P<0,02; mouse ob/ob, vnutritrahealno, P<is 0.0002; mouse db/db, aerosol, P<0,0001; gastric tube, P<0,002; sublingual, P<0,02). Dependent on the dose increasing the concentration of basis-4 in the plasma were to 777±365 PG/ml (mouse, db/db, vnutritrahealno); 170±67 PG/ml (mouse, db/db, aerosol); 4520±1846 PG/ml (mouse, db/db, sublingual). Similarly, in rats, the concentration of basis 4 was observed to 68682±38661 PG/ml (vnutritrahealno); 1900 PG/ml (lung by); 6757 PG/ml (nasal); 3862±2844 mo/ml (sublingual); but it was not visible absorption or biological activity during intraduodenal administration. Bioavailability of basis 4 in saline solution was about 7.3% at lower doses when delivered through the trachea, where 61-74%maxobserved within 5 minutes Kinetics after that was similar to the kinetics observed after subcutaneous injection. Bioavailability of basis 4 in saline solution for sublingual delivery was 3.1 to 9.6% at lower doses. These studies confirm the suitability of the delivery of basis 4 and its peptide agonist analogues in biologically effective amounts via a convenient non-injecting route.

EXAMPLE 12 - SIDED-BLIND, PLACEBO CONTROLLED STUDY ON the METABOLIC EFFECTS of a RANGE of doses of the example describes the results of which consists of two parts, unilaterally-blind, placebo-controlled study to test the metabolic effects of a range of doses of synthetic basis 4 provided by subcutaneous subjects with diabetes mellitus type II. Subjects participating in this study were individuals diagnosed as having type II diabetes with diet and/or oral hypoglycemic agents (IT) and with the concentration of HbA1C7,0% but12,0% at visit for screening (mass survey selection experiment).

This study began with a visit for screening, after which the subjects receiving IT, was prescribed stop taking this medication and return to the clinic after approximately 14 days, when the effects IT had disappeared. The subjects participating in part 1 of the study, was admitted to the hospital for a period of time after noon before the first dose and started three or four included in the treatment regimen of the day, providing doses. Each dose was administered with an interval of 24 hours from the other dose.

After obtaining consent and screening of subjects was randomly prescribed admission synthetic basis-4 or placebo. In the first part of ntah three or four and was determined to 1 of 4 treatment sequences, if they were to take each of the following doses: placebo or synthetic basis-4 at 0.1 or 0.01, or perhaps 0,001 mg/kg Dose was injected subcutaneously after an overnight fast. Standardized liquid food provided after 15 min after injection of the investigational medicinal product. The table below illustrates the effect of doses for part 1.

In the second part of this study, approximately three days after you complete part 1, eight subjects were also placed in the Department for clinical studies inpatient patients for four days. These actors were other subjects than those who participated in part 1. Research procedures and the scheme of events during part 2 coincided with part 1. Doses were determined after analysis of the effect on glucose in part 1.

Because did not observe a significant effect of 0.01 µg/kg during part 1, subjects were given doses in accordance with the scheme in part 2.

The subjects participating in part 2, he started to take dose after reviewing the data from part 1 in the same way. All subjects returned to the clinic after 4-6 days after their release from stage research was clear, colorless, sterile solution for subcutaneous injection, prepared in sodium acetate buffer (pH 4.5) containing 4.3% of mannitol as a modifier of suomalaiset. The concentration of the injection solution synthetic basis 4 was 0.1 mg/ml One ml of solution was placed into vials of 3 ml with rubber stoppers. The placebo solution was prepared from the same sterile compositions, but without drugs, synthetic basis 4.

The results of this study are shown in Fig.16 and 17. They show the ability of numerous different doses of basis 4 (0.02 μg/kg, 0.05 mg/kg and 0.1 mg/kg) to lower blood glucose in people with type II diabetes.

EXAMPLE 13

This example describes an experiment to determine the dependence of the dose-response for the insulin-sensitizing effects of basis 4 and its agonists in rats with diabetes and obesity. On the basis of 4 used in these studies was obtained from Bachem (Torrance, CA; Cat H8730, Lot 506189), American Peptides (Sunnyvale, CA; Cat 301577, Lot K1005ITI) and by the method of solid-phase synthesis in the laboratory (lot AR1374-11; peptide content of 93.3%). Thirty-nine male rats with diabetes and obesity (ZDF) /Gmi-(fa/fa) (age 116±20 days; weight 441±39 g) otnositelino). Of these, 35 rats used in research with hyperinsulinemia euglycemia fixation (n=9, 7, 9, 5, 5 respectively). Took samples of blood from the tip of the locally shot of the tail (mark Hurricaine 20% solution of benzocaine for local anesthesia, Beutlich, Waukegan, IL) in consciousness starving during the night the rats before treatment and at weekly intervals for 5 weeks during processing for analysis of hemoglobin And1c(inhibition DCA2000 latex-immunoagglutination, Bayer Diagnostics, Tarrytown, NY). Body weight was measured once a day.

After 6 weeks of treatment, approximately 16 hours after the last dose of basis 4 (or saline) and after fasting during the night, spent hyperinsulinemia euglycemia "fixing" (DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Amer.J.Physiol 237:E214-23, 1979) shot by halothane gas rats. Rats were thermoregulatory, tracheotomies and catheterizable through the subcutaneous veins of the legs for infusion 20% D-glucose and insulin, and through the femoral artery for blood collection and measurement of blood pressure (P23XL-Converter, Spectramed, Oxnard, CA; universal amplifier, Gould, Valley View, HE; A/D (analog-to-digital conversion), DataTranslation, Wilmington, DE). Insulin (Newsasia speed to maintain euglycemia (normoglycemia), determined by sampling for glucose and analysis with 5-minute intervals (method with immobilized glucose oxidase; YSI 2300-Stat Analyzer, Yellow Springs, OH). Average plasma glucose during the "commit" was to 103.9 mg/DL (mean coefficient of variation was 5.8 percent). For analysis was taken from data on the rate of infusion of glucose at t=60-180 min, when the reaction was close to a steady state (homeostasis). Data on plasma lactate obtained from the detector to the immobilized lackadasical included in the analyzer glucose, were also collected.

Injections were performed intraperitoneally at about 8 a.m. and 4 p.m., Monday through Friday, and at approximately 10 a.m. on Saturday and Sunday.

Paired statistical analyses were performed using the established practice of using t-student test (Instat v3.0, GraphPad Software, San Diego, CA) using P<0,05 as level of significance. To analyze the dose-response used a 4-parameter logistic regression and the General effects were determined using one-way analysis of variance (ANOVA) (Prism v3.0, GraphPad. Software, San Diego, CA).

The results showed that in rats with diabetes and obesity (ZDF-rats), processed Razlog ± 0,15 log; see Fig.13A) and body weight (ED50 of 0.42 µg ±0,15 log; see Fig.13b) to 27±2 g, which is 5.6±0.5% decrease in body weight relative to injectable saline controls.

In this group of rats for diabetes, apparently, was progressing as A hemoglobin1cinitially increased in all groups. Apparently, the injection of basis 4 however, dependent on the dose way stops and reverses the increase of hemoglobin A1c(see Fig.13C). The dose dependence of the basis 4-response for effects on hemoglobin A1cmeasured during the last 2 weeks of treatment was usually significant (P=0.05 ANOVA) and specifically at doses of 1 μg and 100 μg (P<0,005; P<0,02, respectively). A similar picture was observed in the ratio of plasma triglycerides during starvation in the last 2 weeks of treatment, where plasma concentrations were significantly reduced at all doses on 51-65% (P<0,002 ANOVA).

Thirty-five of 39 rats were included in this study, developed the state hyperinsulinemia, applicationkey "commit" after approximately 16 hours after their last treatment. The initial concentration of glucose in plasma during fasting, higher in the treated saline (489±28 mg/DL) than those processed by the basis rats die 60-180 min; the average coefficient of variation of 4.6%, see Fig.14a). The glucose infusion rate required to maintain euglycemia, increased dependent on the dose of preliminary treatment basis 4 (ED50 1.0 microgram ± 0,41 log; see Fig.14b). Processing basis-4 increased the glucose infusion rate by 48% relative to the treated saline controls.

The concentration of plasma lactate before and during the procedure of "fixing" decreased dependent on the dose of preliminary treatment basis 4 (ED50 4 µg ± 0,25 log; see Fig.14C). This effect, corresponding to a 42% increase decrease average concentration of lactate in the plasma between 60 and 180 minutes "fixing", apparently caused primarily by the decrease in the concentration of lactate before fixation (i.e., the concentration of the background); the increment in the concentration of lactate in the plasma during hyperinsulinemia were similar in all treatment groups. Were not associated with treatment differences in average blood pressure measured before and during procedures "commit".

Approximately 50% increase in insulin sensitivity observed after prolonged administration of basis-4, was an important and unexpected in connection with the observation that the basis-4 does not have a strong effect in insulative labeled glucose into glycogen in the selected soleus muscle, or in a lipid selected adipocytes; Pittner et al., unpublished data). Although we cannot exclude the possibility that the increase in insulin sensitivity may be due, in some part, improved glycemic control and reduced toxicity of glucose, it was reported that the increase in insulin sensitivity from various antidiabetic therapies, including therapies that are not classified as insulin-sensitizing therapy is very variable, and it was reported that a strong treatment using GLP-1, apparently, does not change immediately insulin sensitivity in humans (Orskov L, Holst JJ, Moller J, Orscov C, Moller N, Alberti KG, Schmitz O: GLP-1 does not acutely affect insulin sensitivity in healthy man. Diabetologia 39:1227-32, 1996; Ahren B, Larsson H, Holst JJ: Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82:473-8, 1997; UK Prospective Diabetes Study Group: Intensive blood-glucose control with drug classes sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-53, 1998). Thus, the continuous introduction of basis-4, appears to be associated with increases in insulin sensitivity, which are just as large if not larger than the increase observed with the use of other therapies, including insulin-sensibiliser peptide, having SEQ ID NO:9

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.). In General, the cycles of the individual binding used during synthesis and used Fast Mos method (HBTU activation). However, the binding in some States was less effective than expected, and required a double bind. In particular, residues Asp2, hr7and Phe6all required a double bind. Removing the protective groups (removal of the Fmoc group) growing peptide chain using piperidine was always effective. Double removal of protective groups was required in the provisions Arg20, Val19and Leu14. The final removal of the protective groups of the complex completed peptide-resin was achieved by using a mixture of triethylsilane (0.2 ml), identicial (0.2 ml), anisole (0.2 ml), water (0.2 ml) and triperoxonane acid (15 ml) according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc.). Peptide precipitiously in a mixture of ether/water (50 ml) and centrifuged. The precipitate was reconstituirea in glacial acetic acid and liofilizirovanny. Lyophilized peptide of restora% TFU in water) and solvent B (0.1% OF TFU in ACN).

The solution containing the peptide was applied to a preparative column of C-18 and purified (10-40% solvent in the solvent And on for 40 minutes). The purity of the fractions was determined isocratically using analytical column C-18. Pure fractions were combined to obtain identified above peptide. Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.5 minutes Electrospray mass spectrometry (M): calculated 4131,7; found 4129,3.

EXAMPLE 15

Obtaining a peptide having SEQ ID NO:10 Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MBHA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient of 25-75% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 21.5 minutes Elec is housego SEQ ID NO:11

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 17.9 minutes Electro-spray mass spectrometry (M): calculated 4147,6; found 4150,2.

EXAMPLE 17

Obtaining a peptide having SEQ ID NO:12

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 35-65% of the solvent In the solvent And within 30 minutes) of lyophilized peptide gave ometry (M): calculated 4212,6; found 4213,2.

EXAMPLE 18

Obtaining a peptide having SEQ ID NO:13

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient of 30-50% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 16.3 minutes Electrospray mass spectrometry (M): calculated 4262,7; found 4262,4.

EXAMPLE 19

Obtaining a peptide having SEQ ID NO:14

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent in Estonia obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4172,6.

EXAMPLE 20

Obtaining a peptide having SEQ ID NO:15 Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MBHA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4224,7.

EXAMPLE 21

Obtaining a peptide having SEQ ID NO:16 Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical OF WAS the ATEM to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4172,6.

EXAMPLE 22

Obtaining a peptide having SEQ ID NO:17

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4186,6.

EXAMPLE 23

Obtaining a peptide having SEQ ID NO:18 Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analiticheskaya then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4200,7.

EXAMPLE 24

Obtaining a peptide having SEQ ID NO:19

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4200,7.

EXAMPLE 25

Obtaining a peptide having SEQ ID NO:20

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analyticalmodel then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4202,7.

EXAMPLE 26

Obtaining a peptide having SEQ ID NO:21 Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4145,6.

EXAMPLE 27

Obtaining a peptide having SEQ ID NO:22

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MBHA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACES). Analytical the Dili then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4184,6.

EXAMPLE 28

Obtaining a peptide having SEQ ID NO:23

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4145,6.

EXAMPLE 29

Obtaining a peptide having SEQ ID NO:24

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). The analysis is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4224,7.

EXAMPLE 30

Obtaining a peptide having SEQ ID NO:25

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4172,6.

EXAMPLE 31

Obtaining a peptide having SEQ ID NO:26

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analyticalmodel then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4115,5.

EXAMPLE 32

Obtaining a peptide having SEQ ID NO:27

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4188,6.

EXAMPLE 33

Obtaining a peptide having SEQ ID NO:28

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analyticalmodel then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4131,6.

EXAMPLE 34

Obtaining a peptide having SEQ ID NO:29

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MBHA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4172,6.

EXAMPLE 35

Obtaining a peptide having SEQ ID NO:30

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analyticalmodel then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4145,6.

EXAMPLE 36

Obtaining a peptide having SEQ ID NO:31

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the provisions of thioproline 38, 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4266,8.

EXAMPLE 37

Obtaining a peptide having SEQ ID NO:32

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Complement is (0,1% TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4246,8.

EXAMPLE 38

Obtaining a peptide having SEQ ID NO:33

Identified above peptide was assembled on the resin 4-(2’-4’-acid) Fm-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the provisions of homatropine 38, 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4250,8.

EXAMPLE 39

Obtaining a peptide having SEQ ID NO:34

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-AMI is ystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the provisions of homatropine 38, 37 and 36. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4234,8.

EXAMPLE 40

Obtaining a peptide having SEQ ID NO:35

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the provisions of thioproline 38, 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the times of the ANO 4209,8.

EXAMPLE 41

Obtaining a peptide having SEQ ID NO:36

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the provisions of homatropine 38, 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4193,7.

EXAMPLE 42

Obtaining a peptide having SEQ ID NO:37

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the N-meillan the RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3858,2.

EXAMPLE 43

Obtaining a peptide having SEQ ID NO:38

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. Additional double bind was required in the N-methylalanine 38, 37 and 36. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3940,3.

EXAMPLE 44

Obtaining a peptide having SEQ ID NO:39

Identified above peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, freed from the protective groups and was purified in a similar manner to example 14. More retell A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3801,1.

EXAMPLE 45

Obtaining peptides containing carboxylic acid at the C-end, corresponding to the above sequence with C-terminal amide group

The above peptides of examples 1-30 collect on the so called Wang resin (resin-based p-alkoxybenzyl alcohol (Bachem, 0.54 mmol/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.), otscheplaut from resin, freed from the protective groups and purified in a similar manner to example 14. In the analysis using solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide spend then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry provides the experimentally determined (M).

EXAMPLE 46

Obtaining a peptide having SEQ ID NO:7

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Me the mole of 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.). In General, the cycles of the individual binding used during synthesis and used Fast Mos method (HBTU activation). Removing the protective groups (removal of the Fmoc group) growing peptide chain was performed using piperidine. The final removal of the protective groups of the complex completed peptide-resin was achieved by using a mixture of three-atysian (0.2 ml), identicial (0.2 ml), anisole (0.2 ml), water (0.2 ml) and triperoxonane acid (15 ml) according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc.). Peptide precipitiously in a mixture of ether/water (50 ml) and centrifuged. The precipitate was reconstituirea in glacial acetic acid and liofilizirovanny. Lyophilized peptide was dissolved in water). Clean without cleaning was about 75%.

At the stages of purification and analysis used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). The solution containing the peptide was applied to a preparative column of C-18 and purified (10-40% solvent in the solvent And on for 40 minutes). The purity of the fractions was determined isocratically using analytical column C-18. Pure fractions were combined to obtain identified above peptide. Analiticheskie in the quality of the product peptide, having an observed retention time of 18.9 minutes Electrospray mass spectrometry (M): calculated 3408,0; found 3408,9.

EXAMPLE 47

Obtaining a peptide having SEQ ID NO:40

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:40]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30-40% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 17.9 minutes Electrospray mass spectrometry (M): calculated 3294,7; found 3294,8.

EXAMPLE 48

Obtaining a peptide having SEQ ID NO:41

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:41]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 and mi and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 29-36% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 20.7 minutes Electrospray mass spectrometry (M): calculated 3237,6; found 3240.

EXAMPLE 49

Obtaining a peptide having SEQ ID NO:42

His Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:42]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of importantindustrial A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 36-46% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 15.2 minutes Electrospray mass spectrometry (M): calculated 3251,6; found 3251,5.

EXAMPLE 50

Obtaining a peptide having SEQ ID NO:43

EXAMPLE 51

Obtaining a peptide having SEQ ID NO:44

His Gly Glu Gly Thr Ala Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:44]

Above aminirovanie peptide was assembled on the resin 4-(2'-4'-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 35-45% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product of the peptide, which is 63.

EXAMPLE 52

Obtaining a peptide having SEQ ID NO:45

His Gly Glu Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:45]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 36-46% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 15.2 minutes Electrospray mass spectrometry (M): calculated 3221,6; found 3222,7.

EXAMPLE 53

Obtaining a peptide having SEQ ID NO:46

His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:46]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide behaviour is in ACN). Analytical RP-HPLC (gradient 34-44% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.3 minutes Electrospray mass spectrometry (M): calculated 3195,5; found 3199,4.

EXAMPLE 54

Obtaining a peptide having SEQ ID NO:47

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe lie Glu Phe Leu Lys Asn-NH2[SEQ ID NO:47]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 38-48% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 15.7 minutes Electrospray mass spectrometry (M): calculated 3221,6; found 3221,6.

EXAMPLE 55

Obtaining a peptide having SEQ ID NO:48

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2

EXAMPLE 56

Obtaining a peptide having SEQ ID NO:49

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:49]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 36%-46% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product of the peptide, it is Deno 3182,8.

EXAMPLE 57

Obtaining a peptide having SEQ ID NO:50

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Ala Glu Glu Glu Ala Val Arg Leu Phe lie Glu Phe Leu Lys Asn-NH2[SEQ ID NO:50]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid) -Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 32-42% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.9 minutes Electrospray mass spectrometry (M): calculated 3195,5; found 3195,9.

EXAMPLE 58

Obtaining a peptide having SEQ ID NO:51

His Gly Glu Giy Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:51]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and PL IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 37-47% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 17.9 minutes Electrospray mass spectrometry (M): calculated 3179,6; found 3179,0.

EXAMPLE 59

Obtaining a peptide having SEQ ID NO:52

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Ala Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:52]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 37-47% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.3 minutes Electrospray mass spectrometry (M): calculated 3179,6; found 3180,0.

EXAMPLE 60

Obtaining a peptide having SEQ ID NO:53

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2

EXAMPLE 61

Obtaining a peptide having SEQ ID NO:54

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:54]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 35-45% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide, imageno 3212,8.

EXAMPLE 62

Obtaining a peptide having SEQ ID NO:55

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:55]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 38-48% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.3 minutes Electrospray mass spectrometry (M): calculated 3152,5; found 3153,5.

EXAMPLE 63

Obtaining a peptide having SEQ ID NO:56

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:56]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and PC IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 35-45% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 12.1 minutes Electrospray mass spectrometry (M): calculated 3195,5; found 3197,7.

EXAMPLE 64

Obtaining a peptide having SEQ ID NO:57

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Ala Phe Leu Lys Asn-NH2[SEQ ID NO:57]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 38-48% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 10.9 minutes Electrospray mass spectrometry (M): calculated 3179,6; found 3180,5.

EXAMPLE 65

Obtaining a peptide having SEQ ID NO:58

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys sn-NH2 is Inetinfo.exe-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 32-42% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 17.5 minutes Electrospray mass spectrometry (M): calculated 3161,5; found 3163,0.

EXAMPLE 66

Obtaining a peptide having SEQ ID NO:59

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH2[SEQ ID NO:59]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 32-42% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product of the peptide, the ima is prohibited 3199.

EXAMPLE 67

Obtaining a peptide having SEQ ID NO:60

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH2[SEQ ID NO:60]

Identified above aminirovanie peptide was assembled on the resin 4-[2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 38-48% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.5 minutes Electrospray mass spectrometry (M): calculated 3180,5; found 3183,7.

EXAMPLE 68

Obtaining a peptide having SEQ ID NO:61

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH2[SEQ ID NO:61]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and pee IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 34-44% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 22.8 minutes Electrospray mass spectrometry (M): calculated 3194,6; found 3197,6.

EXAMPLE 69

Obtaining a peptide having SEQ ID NO:62

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro-NH2[SEQ ID NO:62]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4099,6.

EXAMPLE 70

Obtaining a peptide having SEQ ID NO:63

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg L is birali resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4042,5.

EXAMPLE 71

Obtaining a peptide having SEQ ID NO:64

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro-NH2[SEQ ID NO:64]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide was performed then chromaturia (M): calculated 4002,4.

EXAMPLE 72

Obtaining a peptide having SEQ ID NO:65

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro-NH2[SEQ ID NO:65]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3945,4.

EXAMPLE 73

Obtaining a peptide having SEQ ID NO:66

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH2[SEQ ID NO:66]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala oritel A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3905,3.

EXAMPLE 74

Obtaining a peptide having SEQ ID NO:67

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH2[SEQ ID NO:67]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3848,2.

EXAMPLE 75

Obtaining a peptide having SEQ ID NO:68

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3808,2.

EXAMPLE 76

Obtaining a peptide having SEQ ID NO:69

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH2[SEQ ID NO:69]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted for about the meter (M): calculated 3751,1.

EXAMPLE 77

Obtaining a peptide having SEQ ID NO:70

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH2[SEQ ID NO:70]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3737,1.

EXAMPLE 78

Obtaining a peptide having SEQ ID NO:71

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH2[SEQ ID NO:71]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, z0,1% TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3680,1.

EXAMPLE 79

Obtaining a peptide having SEQ ID NO:72

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser-NH2[SEQ ID NO:72]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3680,1.

EXAMPLE 80

Obtaining a peptide having SEQ ID NO:73

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3623,0.

EXAMPLE 81

Obtaining a peptide having SEQ ID NO:74

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser-NH2[SEQ ID NO:74]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted in order to determine the I (M): calculated 3593,0.

EXAMPLE 82

Obtaining a peptide having SEQ ID NO:75

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser-NH2[SEQ ID NO:75]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3535,9.

EXAMPLE 83

Obtaining a peptide having SEQ ID NO:76

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro-NH2[SEQ ID NO:76]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, protective grde) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3505,94.

EXAMPLE 84

Obtaining a peptide having SEQ ID NO:77

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro-NH2[SEQ ID NO:77]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3448,8.

EXAMPLE 85

Obtaining a peptide having SEQ ID NO:78

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Le)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3351,7.

EXAMPLE 86

Obtaining a peptide having SEQ ID NO:79

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH2[SEQ ID NO:79]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3351,8.

EXAMPLE 87

Obtaining a peptide having SEQ ID NO:80

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH2[SEQ ID NO:80]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3294,7.

EXAMPLE 88

Obtaining a peptide having SEQ ID NO:81

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro Ser Ser Gly Ala tPro tPro tPro-NH2[SEQ ID NO:81]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, zeniah 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4197,1.

EXAMPLE 89

Obtaining a peptide having SEQ ID NO:82

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala tPro tPro tPro-NH2[SEQ ID NO:82]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. The double bind was required in the provisions of 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electroepilation Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeala Ser Ser Gly Ala Pro Pro-NH2[SEQ ID NO: 83]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3948,3.

EXAMPLE 91

Obtaining a peptide having SEQ ID NO:84

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeala Ser Ser Gly Ala NMeala NMeala-NH2[SEQ ID NO:84]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. The double bind was required in regulations 36 and 31. Vent 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3840,1.

EXAMPLE 92

Obtaining a peptide having SEQ ID NO:85

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hPro hPro-NH2[SEQ ID NO:85]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. The double bind was required in regulations 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4050,1.

EXAMPLE 93

Obtaining a peptide having SEQ ID NO:86

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hPro-NH2[SEQ ID NO:86]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethan shepsle from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. The double bind was required in position 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3937,1.

EXAMPLE 94

Obtaining a peptide having SEQ ID NO:87

Arg Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH2[SEQ ID NO:87]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time of polycentropodidae peptide, having SEQ ID NO:88

His Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH2[SEQ ID NO:88]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3394,8.

EXAMPLE 96

Obtaining a peptide having SEQ ID NO:89

His Gly Glu Gly Thr Naphtylala Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:89]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner and on what kind of RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3289,5.

EXAMPLE 97

Obtaining a peptide having SEQ ID NO:90

His Gly Glu Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:90]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective v was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3280,7.

EXAMPLE 98

Obtaining a peptide having SEQ ID NO:91

His Gly Glu Gly Thr Phe Ser Thr Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:91]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected aminoacetanilide used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3294,7.

EXAMPLE 99

Obtaining a peptide having SEQ ID NO:92

His Gly Glu Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln Met Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:92]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3250,7.

EXAMPLE 100

Obtaining a peptide having SEQ ID NO:93

His Gly Glu Gly Thr Phe Thr Ser Asp pentylgly Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NHFmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3253,5.

EXAMPLE 101

Obtaining a peptide having SEQ ID NO:94

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Naphtylala Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:94]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted for opredelyayuschaya 3289,5.

EXAMPLE 102

Obtaining a peptide having SEQ ID NO:95

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe tButylgly Glu Trp Leu Lys Asn-NH2[SEQ ID NO:95]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3183,4.

EXAMPLE 103

Obtaining a peptide having SEQ ID NO:96

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Phe Leu Lys Asn-NH2[SEQ ID NO:96]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed the tel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3237,6.

EXAMPLE 104

Obtaining a peptide having SEQ ID NO:97

His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser-NH2[SEQ ID NO:97]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3637,9.

EXAMPLE 105

Obtaining a peptide having SEQ ID NO:98

His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Toxigenic)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3309,7.

EXAMPLE 106

Obtaining a peptide having SEQ ID NO:99

His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hPro hPro-NH2[SEQ ID NO:99]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 46. The double bind was required in regulations 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And for which the firmness of the product peptide. Electrospray mass spectrometry (M): calculated 3711,1.

EXAMPLE 107

Obtaining peptides containing carboxylic acid at the C-end, corresponding to the above sequence with the amide group at the C-end of SEQ ID NO:7, 40-61, 68-75, 78-80 and 87-98

Peptides having the sequence SEQ ID NO:7, 40-61, 68-75, 78-80 and 87-98 collect on the so called Wang resin (resin-based p-alkoxybenzyl alcohol (Bachem, 0.54 mmol/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.), otscheplaut from resin, the protective groups are removed and the peptide purified in a similar manner to example 46. In the analysis using solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide spend then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry provides the experimentally determined (M).

EXAMPLE 108

Obtaining peptides containing carboxylic acid at the C-end, corresponding to the above sequence with the amide group at the C-end of SEQ ID NO:62-67, 76, 77, 81-86 and 99

Peptides having the sequence SEQ ID NO:62-67, 76, 77, 81-86 and amino acids (Applied Biosystems, Inc.), otscheplaut from resin, the protective groups are removed and the peptide purified in a similar manner to example 46. In the analysis using solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide spend then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry provides the experimentally determined (M).

EXAMPLE 109

Obtaining a peptide having SEQ ID NO:100

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:100]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.). In General, the cycles of the individual binding used during synthesis and used Fast Mos method (HBTU activation). Removing the protective groups (removal of the Fmoc group) growing peptide chain was performed using piperidine. The final removal of the protective groups of the complex completed peptide-resin was achieved by using a mixture of triethylsilane (0.2 ml), identicial (0.2 ml), anisole (0.2 m is plied Biosystems, Inc.). Peptide precipitiously in a mixture of ether/water (50 ml) and centrifuged. The precipitate was reconstituirea in glacial acetic acid and liofilizirovanny. Lyophilized peptide was dissolved in water). Clean without cleaning was about 75%.

At the stages of purification and analysis used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN).

The solution containing the peptide was applied to a preparative column of C-18 and purified (10-40% solvent in the solvent And on for 40 minutes). The purity of the fractions was determined isocratically using analytical column C-18. Pure fractions were combined to obtain identified above peptide. Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 19.2 minutes Electrospray mass spectrometry (M): calculated 3171,6; found 3172.

EXAMPLE 110

Obtaining a peptide having SEQ ID NO:101

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:101]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) use the and in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 36%-46% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 14.9 minutes Electrospray mass spectrometry (M): calculated 3179,6; found 3180.

EXAMPLE 111

Obtaining a peptide having SEQ ID NO:102

His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:102]

Above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 37-47% solvent b In solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 12.2 minutes Electrospray mass spectrometry (M): calculated 3251,6; found 3263,3.

EXAMPLE 112

Obtaining a peptide having SEQ I aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylenemalonate-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 35-45% of the solvent In the solvent And within 30 minutes) of lyophilized peptide was given as a product peptide having an observed retention time of 16.3 minutes Electrospray mass spectrometry (M): calculated 3193,6; found 3197.

EXAMPLE 113

Obtaining a peptide having SEQ ID NO:104

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:104]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3228,6.

EXAMPLE 114

Obtaining a peptide having SEQ ID NO:105

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:105]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3234,7.

EXAMPLE 115

Obtaining a peptide having SEQ ID NO:106

His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:106]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’'-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group deletion is varicel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3308,7.

EXAMPLE 116

Obtaining a peptide having SEQ ID NO:107

His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:107]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3250,7.

EXAMPLE 117

Obtaining a peptide having SEQ ID NO:108

His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn-NH

EXAMPLE 118

Obtaining a peptide having SEQ ID NO:109

Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:109]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine Asciano 3200,6.

EXAMPLE 119

Obtaining a peptide having SEQ ID NO:110

Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:110]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3143,5.

EXAMPLE 120

Obtaining a peptide having SEQ ID NO:111

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:111]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3214,6.

EXAMPLE 121

Obtaining a peptide having SEQ ID NO:112

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:112]

Identified above aminirovanie peptide was assembled on the resin 4-[2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3157,5.

EXAMPLE 122

Obtaining a peptide having SEQ ID NO;113

Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-N-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3184,6.

EXAMPLE 123

Obtaining a peptide having SEQ ID NO:114

Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:114]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine schiano 3127,5.

EXAMPLE 124

Obtaining a peptide having SEQ ID NO:115

Ala Gly Asp Gly Thr NaphtylAla Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:115]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3266,4.

EXAMPLE 125

Obtaining a peptide having SEQ ID NO:116

Ala Gly Asp Gly Thr NaphtylAla Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:115]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3209,4.

EXAMPLE 126

Obtaining a peptide having SEQ ID NO:117

Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:117]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3200,6.

EXAMPLE 127

Obtaining a peptide having SEQ ID NO:118

Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH

EXAMPLE 128

Obtaining a peptide having SEQ ID NO:119

Ala Gly Asp Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:119]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3198,6.

EXAMPLE 129

Obtaining a peptide having SEQ ID NO:120

Ala Gly Asp Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:120]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3141,5.

EXAMPLE 130

Obtaining a peptide having SEQ ID NO:121

Ala Gly Asp Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:121]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3170,6.

EXAMPLE 131

Obtaining a peptide having SEQ ID NO:122

Ala Gly Asp Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:122]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid) Frnoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3113,5.

EXAMPLE 132

Obtaining a peptide having SEQ ID NO:123

Ala Gly Asp Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3228,6.

EXAMPLE 133

Obtaining a peptide having SEQ ID NO:124

Ala Gly Asp Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:124]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine schiano 3171,6.

EXAMPLE 134

Obtaining a peptide having SEQ ID NO:125

Ala Gly Asp Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:125]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3172,5.

EXAMPLE 135

Obtaining a peptide having SEQ ID NO:126

Ala Gly Asp Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:126]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3115,4.

EXAMPLE 136

Obtaining a peptide having SEQ ID NO:127

Ala Gly Asp Gly Thr Phe Thr Ser Asp Pentylgly Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:127]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3230,4.

EXAMPLE 137

Obtaining a peptide having SEQ ID NO:128

Ala Gly Asp Gly Thr Phe Thr Ser Asp Pentylgly Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe L is fenil)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3198,6.

EXAMPLE 138

Obtaining a peptide having SEQ ID NO:129

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:129]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3141,5.

EXAMPLE 139

Obtaining a peptide having SEQ ID NO:130

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:130]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3157,5.

EXAMPLE 140

Obtaining a peptide having SEQ ID NO:131

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:131]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed retell IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3100,4.

EXAMPLE 141

Obtaining a peptide having SEQ ID NO:132

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:132]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3157,6.

EXAMPLE 142

Obtaining a peptide having SEQ ID NO:133

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH

EXAMPLE 143

Obtaining a peptide having SEQ ID NO:134

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:134]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine schiano 3100,5.

EXAMPLE 144

Obtaining a peptide having SEQ ID NO:135

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Ala Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:135]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3154,5.

EXAMPLE 145

Obtaining a peptide having SEQ ID NO:136

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Ala Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:136]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3115,5.

EXAMPLE 146

Obtaining a peptide having SEQ ID NO:137

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Pentylgly Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:137]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3212,4.

EXAMPLE 147

Obtaining a peptide having SEQ ID NO:138

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Pentylgly Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe L is fenil)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3173,4.

EXAMPLE 148

Obtaining a peptide having SEQ ID NO:139

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:139]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3156,6.

EXAMPLE 149

Obtaining a peptide having SEQ ID NO:140

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Ala Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:140]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3099,5.

EXAMPLE 150

Obtaining a peptide having SEQ ID NO:141

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Ala Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:141]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid) Fm-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide is IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3156,6.

EXAMPLE 151

Obtaining a peptide having SEQ ID NO:142

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Ala Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:142]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3099,5.

EXAMPLE 152

Obtaining a peptide having SEQ ID NO:143

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Ala Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH

EXAMPLE 153

Obtaining a peptide having SEQ ID NO:144

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Ala Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:144]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3099,5.

EXAMPLE 154

Obtaining a peptide having SEQ ID NO:145

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:145]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3186,6.

EXAMPLE 155

Obtaining a peptide having SEQ ID NO:146

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Ala Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:146]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3129,5.

EXAMPLE 156

Obtaining a peptide having SEQ ID NO:147

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Ala Leu Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:147]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3129,5.

EXAMPLE 157

Obtaining a peptide having SEQ ID NO:148

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH

EXAMPLE 158

Obtaining a peptide having SEQ ID NO:149

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Ala Phe Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:149]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3172,5.

EXAMPLE 159

Obtaining a peptide having SEQ ID NO:150

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:150]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3115,5.

EXAMPLE 160

Obtaining a peptide having SEQ ID NO:151

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Naphtylala Ile Glu Trp Leu Lys Asn-NH2[SEQ ID NO:151]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group UDA is the solvent (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3266,4.

EXAMPLE 161

Obtaining a peptide having SEQ ID NO:152

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Naphtylala Ile Glu Phe Leu Lys Asn-NH2[SEQ ID NO:152]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3209,4.

EXAMPLE 162

Obtaining a peptide having SEQ ID NO:153

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Ly)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3200,6.

EXAMPLE 163

Obtaining a peptide having SEQ ID NO:154

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Val Glu Phe Leu Lys Asn-NH2[SEQ ID NO:154]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine Asciano 3143,5.

EXAMPLE 164

Obtaining a peptide having SEQ ID NO:155

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe tButylgly Glu Trp Leu Lys Asn-NH2[SEQ ID NO:155]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3216,5.

EXAMPLE 165

Obtaining a peptide having SEQ ID NO:156

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe tButylgly Glu Phe Leu Lys Asn-NH2[SEQ ID NO:156]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group at actuarial IN (0,1% TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3159,4.

EXAMPLE 166

Obtaining a peptide having SEQ ID NO:157

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Trp Leu Lys Asn-NH2[SEQ ID NO:157]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3200,6.

EXAMPLE 167

Obtaining a peptide having SEQ ID NO:158

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Asp Phe Leu Lys Asn-N-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3143,5.

EXAMPLE 168

Obtaining a peptide having SEQ ID NO:159

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH2[SEQ ID NO:159]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine BP is read 3099,5.

EXAMPLE 169

Obtaining a peptide having SEQ ID NO:160

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH2[SEQ ID NO:160]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3081,4.

EXAMPLE 170

Obtaining a peptide having SEQ ID NO:161

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Ala Lys Asn-NH2[SEQ ID NO:161]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3172,5.

EXAMPLE 171

Obtaining a peptide having SEQ ID NO:162

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH2[SEQ ID NO:162]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3115,5.

EXAMPLE 172

Obtaining a peptide having SEQ ID NO:163

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Ala Asn-NH

EXAMPLE 173

Obtaining a peptide having SEQ ID NO:164

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH2[SEQ ID NO:164]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine schiano 3100,4.

EXAMPLE 174

Obtaining a peptide having SEQ ID NO:165

Ala Giy Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Ala-NH2[SEQ ID NO:165]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems,.Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3171,6.

EXAMPLE 175

Obtaining a peptide having SEQ ID NO:166

Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH2[SEQ ID NO:166]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed Itel IN (0,1% TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3114,5.

EXAMPLE 176

Obtaining a peptide having SEQ ID NO:167

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro-NH2[SEQ ID NO:167]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4033,5.

EXAMPLE 177

Obtaining a peptide having SEQ ID NO:168

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala ptid collected on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0/55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3984,4.

EXAMPLE 178

Obtaining a peptide having SEQ ID NO:169

His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro-NH2[SEQ ID NO:169]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide was performed ZAT spectrometry (M): calculated 4016,5.

EXAMPLE 179

Obtaining a peptide having SEQ ID NO:170

His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH2[SEQ ID NO:170]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3861,3.

EXAMPLE 180

Obtaining a peptide having SEQ ID NO:171

Ala Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro-NH2[SEQ ID NO:171]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), userlastinitial A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3746,1.

EXAMPLE 181

Obtaining a peptide having SEQ ID NO:172

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH2[SEQ ID NO:172]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3742,1.

EXAMPLE 182

Obtaining a peptide having SEQ ID NO:173

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Ph resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3693,1.

EXAMPLE 183

Obtaining a peptide having SEQ ID NO:174

His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly-NH2[SEQ ID NO:167]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted for ometry (M): calculated 3751,2.

EXAMPLE 184

Obtaining a peptide having SEQ ID NO:175

His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser-NH2[SEQ ID NO:175]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3634,1.

EXAMPLE 185

Obtaining a peptide having SEQ ID NO:176

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser-NH2[SEQ ID NO: 176]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, protect the TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3526,9.

EXAMPLE 186

Obtaining a peptide having SEQ ID NO:177

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser-NH2[SEQ ID NO:177]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3477,9.

EXAMPLE 187

Obtaining a peptide having SEQ ID NO:178

His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Tr is methoxyphenyl)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3519,9.

EXAMPLE 188

Obtaining a peptide having SEQ ID NO:179

His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH2[SEQ ID NO:179]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to define the (M): calculated 3307,7.

EXAMPLE 189

Obtaining a peptide having SEQ ID NO:180

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH2[SEQ ID NO:180]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3186,5.

EXAMPLE 190

Obtaining a peptide having SEQ ID NO:181

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro Ser Ser Gly Ala tPro tPro tPro-NH2[SEQ ID NO:181]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resins which were 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4121,1.

EXAMPLE 191

Obtaining a peptide having SEQ ID NO:182

His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala tPro tPro tPro-NH2[SEQ ID NO:182]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. The double bind was required in the provisions of 37, 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electronicdigital the y Thr Phe Thr Ser Ala Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeala Ser Ser Gly Ala NMeala NMeala-NH2[SEQ ID NO: 183]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. The double bind was required in regulations 36 and 31. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3796,1.

EXAMPLE 193

Obtaining a peptide having SEQ ID NO:184

Ala Giy Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro Ser Ser Gly Ala hPro-NH2[SEQ ID NO:184]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. DVO is ü IN (0,1% TFU in the TSA). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3871,1.

EXAMPLE 194

Obtaining a peptide having SEQ ID NO:185

His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala-NH2[SEQ ID NO:185]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3750,2.

EXAMPLE 195

Obtaining a peptide having SEQ ID NO:186

His Gly Asp Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Ph is the -4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmo-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 3408,8.

EXAMPLE 196

Obtaining a peptide having SEQ ID NO:187

Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2[SEQ ID NO:187]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide spent the ACC spectrometry (M): calculated 4120,6.

EXAMPLE 197

Obtaining a peptide having SEQ ID NO:188

Ala Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2[SEQ ID NO:188]

Identified above aminirovanie peptide was assembled on the resin 4-(2’-4’-acid)-Fmoc-aminomethylphenol-ndimethylacetamide-norleucine-MVNA (Novabiochem, 0.55 mmol/g) using Fmoc-protected amino acids (Applied Biosystems, Inc.), was tsalala from resin, the protective group was removed and the peptide was purified in a similar manner to example 109. In the analysis of the used solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide is then conducted to determine the retention time obtained as the product peptide. Electrospray mass spectrometry (M): calculated 4005,5.

EXAMPLE 198

Obtaining peptides containing carboxylic acid at the C-end, corresponding to the above sequence with the amide group at the C-end of SEQ ID NO:100-166, 172-177, 179-180 and 185-188

Peptides having a carboxylic acid at the C-end, corresponding emitirovannykh sequences having SEQ ID NO:100-166, 172-177, 179-180 and 185-188, collect on the so called Wang resin (Biosystems, Inc.), otscheplaut from resin, the protective groups are removed and the peptide purified in a similar manner to example 109. In the analysis using solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes) of lyophilized peptide spend then to determine the retention time obtained as the product peptide. Electrospray mass spectrometry provides the experimentally determined (M).

EXAMPLE 199

Obtaining peptides containing carboxylic acid at the C-end, corresponding to the above sequences amide group at the C-end for peptides having SEQ ID NO:167-171, 178 and 181-184

Peptides having a carboxylic acid at the C-end, corresponding emitirovannykh sequences SEQ ID NO:167-171, 178 and 181-184, collected at 2-chlorotriethylsilane resin (200-400 mesh), 2% DVB (Novabiochem, 0.4-1.0 mmol/g)) using Fmoc-protected amino acids (Applied Biosystems, Inc.), otscheplaut from resin, the protective groups are removed and the peptide purified in a similar manner to example 109. In the analysis using solvent A (0.1% OF TFU in water) and solvent B (0.1% OF TFU in ACN). Analytical RP-HPLC (gradient 30 to 60% solvent b In solvent And within 30 minutes the ukta peptide. Electrospray mass spectrometry provides the experimentally determined (M).

EXAMPLES a-E

Used reagents GLP-1[7-36]NH2(GLP-1) was purchased from Bachem (Torrance, CA). All other peptides were obtained using the methods of synthesis, such as described there. All chemicals were of the highest commercial purity. SPA-immunoassay for camp were purchased from Amersham. Radioactive ligands were purchased from New England Nuclear (Boston, MA). Cells RINmSf (American Type Tissue Collection, Rockville, MD) were grown in medium DME/F12 containing 10% fetal calf serum and 2 mm L-glutamine. Cells were grown at 37°C and 5% CO2/95% humidified air and the medium was replaced every 2-3 days. Cells were grown to confluently, then harvested and homogenized using a homogenizer transmitter station. Homogenates of cells were stored frozen at -70°C to use.

EXAMPLE A - studies ON the BINDING of GLP-1-RECEPTOR

Receptor binding was assessed by measuring the displacement of [12SI]GLP-1 or [125I]of the basis(9-39) from RINm5f membranes. Buffer for analysis contained 5 μg/ml of bestatin, 1 μg/ml of phosphoramidon, 1 mg/ml bovine serum albumin (fraction V), 1 mg/ml bacitracin, 1 mm MgCl2in 20 mm HEPES, pH 7.4. To measure the binding 30 µg meme125I]GLP-1 or [125I] of the basis (9-39) and unlabeled peptides for 120 min at 23°C in 96-well plates (Nagle Nunc, Rochester, NY). Incubation was stopped by rapid filtration using cold phosphate saline buffer, pH 7.4, and processed through polyethylenimine filters GF/B glass fibre (Wallac Inc., Gaithersburg, MD) using ardent collector Tomtec Mach II (Wallac Inc., Gaithersburg, MD). The filters were dried, combined with scintillation and radioactivity was determined in a liquid scintillation Betaplate counter (Wallac Inc.).

Samples of the peptides used in this analysis in two replications with 6 dilutions over the concentration range 10-6M-10-12M to obtain the response curves. Biological activity of the sample is expressed as the magnitude IC50calculated from raw data using an iterative program of the curve using a 4-parameter logistic equation (Prizm, GraphPAD Software).

An EXAMPLE IS the STUDY of the ACTIVATION of CYCLASE activity

Buffer for analysis contained 10 μm GTP, 0.75 mm ATP, 2.5 mm MgCl2, 0,5 mm phosphocreatine, and 12.5 u/ml of creatine kinase, 0.4 mg/ml Aprotinin, 1 μm IBMX in 50 mm HEPES, pH 7.4. Membranes and peptides were combined in 100 ml of buffer for analysis in 96-hole of planetarydata filtering in a fresh 96-well plate using a vacuum filtration setup Millipore. The content of camp in supernatant was quantified using SPA-immunoassay. In this analysis, the peptides were determined in triplicate at 7 dilutions over the concentration range 10-6M - 10-12M to obtain the response curves. The biological activity of a particular sample is expressed as the value EC50calculated as described above.

EXAMPLE - DETERMINATION of GLUCOSE LEVELS IN the BLOOD of MICE DB/DB

For this study used mice C57BLKS/J-m-db aged at least 3 months. Mice were obtained from Jackson laboratory and gave them to acclimate for at least one week before use. Mice were kept in groups of ten animals at 22°C±1°with the cycle of light:dark 12:12, lights on at 6 am. All animals were deprived of food for 2 hours before sampling blood background. Approximately 70 μl of blood was taken from each mouse by ocular puncture, after light anesthesia metafandom. After sampling the blood of the background to measure the concentration of glucose in the plasma of all animals received subcutaneous injections of vehicle (10,9% NaCl), basis 4 or the test compound (1 mg) in the media. Again took blood samples using the same procedures PEFC is the percentage change in value in the plasma, the magnitude of the background.

EXAMPLE D - DEFINE the dependence of the DOSE-RESPONSE of GLUCOSE LEVELS IN the BLOOD of MICE DB/DB

For this study used mice C57BLKS/J-m db/db aged at least 3 months. Mice were obtained from Jackson laboratory and gave them to acclimate for at least one week before use. Mice were kept in groups of ten animals at 22±1°with the cycle of light:dark 12:12, lights on at 6 am. All animals were deprived of food for 2 hours before sampling blood background. Approximately 70 μl of blood was taken from each mouse by ocular puncture, after light anesthesia metafandom. After sampling the blood of the background to measure the concentration of glucose in the plasma of all animals received subcutaneous injections of either the media or the basis of 4 or test compounds at the indicated concentrations. Again took blood samples using the same procedure after exactly one hour from injection and measured the concentration of glucose in plasma. For each animal was calculated percent change values in the plasma, the magnitude of the background, and evaluated the dependence of the response on the dose using the software Graphpad Prizm.

EXAMPLE E - EMPTIED the Dina-4 and/or connection-agonist of the basis on gastric emptying in rats. This experiment was performed according to a modification of the method Scarpignato, et al., Arch. Int. Pharmacodyn. Ther. 246:286-94, 1980. Used male rats Harlan Sprague-Dawley (HSD). All animals were kept in an increase of 22.7 ą 0.8°with the cycle of light:dark 12:12 (and the experiments were conducted during the light cycle) and feed and water were provided ad libitum (diet LM-485, Teklad, Madison, WI). On the basis of 4 was synthesized in accordance with standard methods of peptide synthesis. Getting basis 4 described in example 14. Determination of gastric emptying by the method described below was performed after fasting for about 20 hours to ensure that the stomach does not contain chyme, which would interfere with spectrophotometric measurements of absorption.

In conscious rats received via a stomach tube 1.5 ml containing no calories gel containing 1.5% methylcellulose (M-0262, Sigma Chemical Co, St Louis, MO) and 0.05% of the indicator phenol red. Twenty minutes after administration via a stomach tube to rats was anestesiologi using 5% halothane gas, the stomach was exposed and recorded at privateroom and the lower esophageal sphincter using arterial clamps were removed and opened in alkaline solution, which is brought up to a fixed volume. The content of jeludkovoe 560 nm. In separate experiments on 7 rats as the stomach and the small intestine was cut and opened in alkaline solution. The amount of phenol red, which could be extracted from the upper gastrointestinal tract within 20 min insertion through the gastric tube was 89±4%; dye, which apparently binds irreversibly to the surface, related to the intestinal canal, could be considered for balance. To account for the maximum extraction of the dye is less than 100%, the percentage of stomach contents remaining after 20 min, expressed in the form of part of stomach contents extracted from control rats, dead immediately after insertion through the gastric tube in the same experiment. The percentage of remaining stomach contents = (absorption at 20 min)/(absorption at 0 min) × 100.

Various modifications of the present invention, in addition to the shown and described herein will become apparent to experts in this field from the previous description and are within the scope of the following claims.

Claims

1. Pharmaceutical composition for treatment of diabetes, slowing of gastric emptying or reduction in food intake, which is a stable liquid dosage form, suitable for repeated use, and provides the basis or agonist of basis, buffer, modifier suomalaiset and a preservative selected from the group consisting of m-cresol, phenol, benzyl alcohol, methyl-, ethyl-, propyl - and butylparaben, and this composition has a pH between about 4.0 and 6.0.

2. The composition according to p. 1, where the basis is a basis 4.

3. Composition under item 1 or 2, where the basis or agonist of the basis is present in a concentration of 0.005 to 0.4% (wt./vol.).

4. Composition under item 1 or 2, where the basis or agonist of the basis is present in a concentration of 0.005 to 0.05% (wt./vol.).

5. Composition under item 1 or 2,tion buffer is acetate or glutamate buffer.

7. The composition according to p. 6, where the specified buffer is an acetate buffer.

8. Composition under item 1 or 2, where the concentration of the buffer is in the range of 0.02 to 0.5% (wt./vol.).

9. Composition under item 1 or 2, where the specified pH is between about 4.0 and 5.0.

10. Composition under item 1 or 2, where the specified modifier suomalaiset is mannitol or sorbitol.

11. The composition according to p. 10, where the specified modifier suomalaiset is mannitol.

12. Composition under item 1 or 2, where the concentration of the modifier suomalaiset is 1-10% (wt./vol.).

13. Composition under item 1 or 2, where the specified preservative is m-cresol.

14. Composition under item 1 or 2 for use in the method of administration to a subject in need this, and this method involves (a) injecting a specified subject one to three times daily of 0.1-0.5 μg of basis or agonist of basis per kilogram; (b) oral administration of a specified subject 500-12000 mcg per day given basis or agonist of basis in a single dose or in divided doses; c) introduction 100-12000 mcg per day given basis or agonist of the basis in the pulmonary system of the specified subject in a single dose or in divided doses; (d) nasal introduction 10-12000 mcg per day boccalino introduction 10-12000 mcg per day given basis or agonist basis of a specified subject in a single dose or in divided doses; f) sublingual introduction 10-8000 mcg per day given basis or agonist basis of a specified subject in a single dose or in divided doses; or (g) injecting a specified subject 1 μg to 1 mg of basis or agonist of the basis in the day.

15. Composition under item 1 or 2 for use in the method of administration to a subject in need this, and this method involves injecting the basis or agonist of the basis in the specified subject in the quantity equal to 0.005 mg/kg per dose up to 0.2 µg/kg per dose.

16. Composition under item 1 or 2 to use in order to increase the sensitivity of the subject to exogenous or endogenous insulin.

Priority items:

14.01.1999 - PP.1-13, 16;

10.01.2000 - PP.14 and 15.



 

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