Synthetic peptide amides and their dimers

FIELD: biotechnologies.

SUBSTANCE: invention refers to ligands in the form of synthetic peptide amides of a kappa-opiate receptor, and namely to agonists of the kappa-opiate receptor, which show a low inhibition degree of P450 CYP and a low degree of penetration into brain. According to the invention, synthetic peptide amide is described by the following formula:

EFFECT: pharmaceutical compositions containing the above compounds are suitable for prophylaxis and curing of pain and inflammation, which are related to different diseases and states.

19 cl, 11 dwg, 53 ex

 

RELATED APPLICATIONS

[0001] This application claims the priority of provisional applications U.S. serial number 60/858,120; 60/858,121; and 60/858,123, filed November 10, 2006, and provisional application U.S. serial number 60/928,527; 60/928,551 60/928,557, filed may 10, 2007, each of which is explicitly incorporated in this description by reference in its entirety.

The SCOPE of the INVENTION

[0002] the Invention relates to synthetic peptide Amida in the peptide chain which is incorporated D-amino acids and, more specifically, to such synthetic peptide Amida, which are agonists of the Kappa-opioid receptors, and to methods of their use as prophylactic and therapeutic agents.

BACKGROUND of the INVENTION

[0003] the Kappa-opiate receptors proposed as targets for intervention to treat or prevent a wide range of diseases and conditions introduction agonists of the Kappa opioid receptor. See, for example Jolivalt et al., Diabetologia, 49 (11): 2775-85; Epub Aug.19, 2006), which describes the efficiency asimadoline, agonist of the Kappa receptor in diabetic neuropathy in rodents; and Bileviciute-Ljungar et al., Eur. J. Pharm. 494: 139-46 (2004), which describes the efficiency of the Kappa agonist U-50,488 on the model of neuropathic pain in chronic restrictions in rats (CCI) and block the effects of opiate antagonist naloxone. These observations support the t application of agonists of the Kappa-opioid receptor for the treatment of diabetic, viral and chemotherapy-induced neuropathic pain. Also considered the use of agonists of the Kappa receptors for the treatment or prevention of visceral pain, including gynecological disorders such as spasms in connection with dysmenorrhea and endometriosis. See, for example, Riviere, Br. J. Pharmacol. 141: 1331-4 (2004).

[0004] Agonists of the Kappa opioid receptor is also proposed for the treatment of pain, including hyperalgesia. It is believed that the hyperalgesia cause changes in the environment of the peripheral sensory endings, secondary to local tissue damage. Tissue damage (e.g., abrasions, burns and inflammation can significantly increase the excitability of polymodal nociceptors (fiber) and mechanical receptors with a high threshold (Handworker et al. (1991) Proceeding of the VIthWorld Congress on Pain, Bond et al., eds., Elsevier Science Publishers BV, pp.59-70; Schaible et al. (1993) Pain 55: 5-54). It is believed that this increase in excitability and over-reinforced reaction-sensitive afferent endings underlies hyperalgesia, where the reaction to pain is a result of excessively enhanced reaction to the stimulus. Is hyperalgesia status in the state of pain after injury repeated and, apparently, responsible for the main part of the state of pain after injury/inflammation. Woold et al. (1993) Anesthesia and Analgesia 77: 362-79; Dubner et al. (1994) Textbook of Pain, Melzack et al, eds., Churchill-Livingstone, London, pp.225-242.

[0005] the Kappa-opiate receptors proposed as targets for the prevention and treatment of cardiovascular diseases. See, for example, Wu et al. "Cardioprotection of Preconditioning by Metabolic Inhibition in the Rat Ventricular Myocyte - Involvement of kappa Opioid Receptor" (1999) Circulation Res vol.84: pp.1388-1395. Cm. also Yu et al. "Anti-Arrythmic Effect of kappa Opioid Receptor Stimulation in the Perfused Rat Heart: Involvement of cAMP-Dependent Pathway" (1999) J Mol Cell Cardiol. vol.31(10): pp.1809-1819.

[0006] it is Also been found that the development or progression of such diseases and conditions are involved in the neurodegeneration or cell death of neurons, can be prevented or at least slowed by treatment with agonists of the Kappa opioid receptor. It is believed that the improved result is a consequence of treatment with agonists of the Kappa opioid receptor. See, for example, Kaushik et al. "Neuroprotection in Glaucoma" (2003) J. Postgraduate Medicine vol.49 (1): pp.90-95.

[0007] the Presence of Kappa-opioid receptors on immune cells (Bidlak et al., (2000) Clin. Diag. Lab. Immunol. 1(5):719-723) involved in the inhibitory effects of agonist and a Kappa-opioid receptors, which are known to suppress the expression of HIV-1. Cm. Peterson RK et al., Biochem Pharmacol. 2001, 61(19):1145-51.

[0008] Walker, Adv. Exp. Med. Biol. 521:148-60 (2003) evaluated the anti-inflammatory properties of Kappa agonists for the treatment of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease and eczema. Bileviciute-Ljungar et al., Rheumatology 45:295 to 302 (2006) described the Ute decrease pain and degeneration when induced by adjuvant-blockers using the Kappa agonist U-50, 488.

[0009] Wikstrom et al., J. Am. Soc. Nephrol. 16:3742-7 (2005) describe the use of the Kappa agonist, TRK-820 for the treatment of uremic and induced by opioids itching and Ko et al., J. Pharmacol. Exp. Ther. 305:173-9 (2003) describe the effectiveness of U-50,488 when induced by morphine itch in monkeys.

[0010] Also carefully considered the use of opioids peripheral actions, including the use of Kappa agonists, for the treatment of gastrointestinal diseases. See, for example, Lembo, Diges. Dis. 24:91-8 (2006) for discussions on the use of opioids in the treatment of disorders of the gastrointestinal tract, including irritable bowel syndrome (IBS), bowel obstruction, functional dyspepsia.

[0011] Also shown the possibility of using the Kappa-opioid disorders of the eye, including inflammation of the eye and glaucoma. Cm. Potter et al., J. Pharmacol. Exp. Ther. 309:548-53 (2004), which describes the role of highly active agonist of the Kappa-opiate receptor, bremazocine in reducing intraocular pressure and blocking this effect by norbinaltorphimine (norBNI), the components of the prototype antagonist of Kappa-opioid receptors; and Dortch-Carnes et al., CNS Drug Rev. 11(2):195-212 (2005). In U.S. patent 6,191,126 issued Gamache, disclosed the use of Kappa-opioid agonists for the treatment of eye pain. Also it is shown that the pain in the ears cure for the introduction of the Kappa-opiate agonists. Cm. U.S. patent 6,174,878, also issued Gamache.

[0012] the Kappa-opiate agonists increase the excretion of water by the kidneys and reduce sodium excretion with urine (i.e., cause a selective water diuresis, also known as Alvarez). Many, but not all researchers attribute this effect at the expense of suppression of secretion of vasopressin by the pituitary gland. Studies that compared the opioids act centrally and presumably perifericheskie selective Kappa-opioids, led to the conclusion that the Kappa-opiate receptors within the blood-brain barrier responsible for mediating this effect. Other researchers have proposed to treat hyponatremia nociceptive peptides or charged conjugates of peptides that act perifericheskie on receptors nociceptin that is a related but different from the Kappa-opiate receptor mechanism. See: D.R.Kapusta, Life Sci., 60:15-21, 1997; U.S. patent 5,840,696 and patent application U.S. 20060052284.

BRIEF description of the INVENTION

[0013] In the present invention proposed a synthetic peptide amides of the formula I:

and their stereoisomers, mixtures of stereoisomers, prodrugs, pharmaceutically acceptable salt, hydrate, solvate, N-oxides, hydrates of the salts of acids and isomorphic crystalline forms.

[0014] In formula I, each Xaa1independently selected from the following D-amino acids: (A)(the'D-phenylalanine, (A)(A')α-methyl-D-phenylalanine, D-tyrosine, D-1,2,3,4-Tetra-hydroisoquinoline-3-carboxylic acid, D-tert-leucine, D-neopentylglycol, D-phenylglycine, D-Homo-phenylalanine and β-(E)D-alanine, where each (A) and each (A') represent the substituents in the phenyl ring, independently selected from-H, -F, -Cl, -NO2, -CH3, -CF3, -CN, -CONH2and where everyone (E) independently selected from cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, tanila and thiazolyl. Each XAA2independently selected from (A)(A') D-phenylalanine, 3,4-phenylalanine, (A)(A')(α-Me)D-phenylalanine, D-1-naphthylamine, D-2-naphthylamine, D-tyrosine, (E)D-alanine and D-tryptophan. Each XAA3independently selected from D-norleucine, D-phenylalanine, (E)-D-alanine, D-leucine, α-MeD-leucine, D-hemolysin, D-valine and D-methionine. Each XAA4independently selected from (B)2D-arginine, (B)2D-norashikin ()2D-homoarginine, ζ-(B)D-hemolysin, D-2,3-diaminopropionic acid, ε-(D-lysine, ε-(B)2-lysine, D-aminomethylpyrrolidine, amidino-D-aminomethyl-phenylalanine, γ-()2D-α,γ-diaminoalkanes acid, δ-(V)2α-(') D-ornithine, D-2-amino-3(4-piperidyl)-propionic acid, D-2-amino-3(2-aminopyrrolidine)propionic acid, D-α-amino-β-amidino-propionic acid, α-amino-4-piperidineacetic acid, CIS-α,4-Duminica-hexane acetic acid, TRANS-α,4-diaminocyclohexane sour is you, CIS-α-amino-4-methyl-aminocyclo-hexadecanoic acid, TRANS-α-amino-4-methylenecycloartanol acid, α-amino-1-amidino-4-piperidineacetic acid, CIS-α-amino-4-guanidino-cyclohexadecane acid and TRANS-α-amino-4-guanidinopentanoic acid, where each (B) is independently selected from-H and C1-C4alkyl and (B') represents-H or (α-Me); and p is 0 or 1.

[0015] the Fragment G is selected as one of the following fragments : (i)to(iv):

(i) G is a

where each of p, q, r, s and t are independently 0 or 1, provided that at least one of s and t is 1. Fragment L is a linker selected from ε-D-Lys, ε-Lys, δ-D-Orn, δ-Orn, γ-aminobutyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctyl acid, 4-amino-4-carboxypeptidase (D-Lys-Gly covenants)2,

(ii) G is a

where p is 1 and XAA3-Haa4is selected from D-norleucine- (In)2D-arginine, D-leucine-δ-(V)2α-(') D-ornithine - α-methyl-D-leucine-δ ()2-α (') D-ornithine-; and fragment

represents an optionally substituted fragment in the form of a 4-8-membered heterocyclic ring, where the ring heteroatoms in the specified cyclic fragment are nitrogen atoms; where each Y Z independently represents a carbon atom or nitrogen; provided that when such ring fragment is a 6, 7 or 8-membered ring, Y and Z are separated by at least two ring atoms and provided that when such ring fragment contains one heteroatom which is nitrogen, that ring fragment is not aromatic.

(iii) G is a

where p is 1; and a fragment

represents an optionally substituted fragment in the form of a 4-8-membered heterocyclic ring, where Y represents a carbon atom or a nitrogen atom and Z represents carbon, nitrogen, oxygen, sulfur, sulfoxide or sulfonyl; provided that when such ring fragment is a 6, 7 or 8-membered ring, Y and Z are separated by at least two ring atoms, provided that when such ring fragment is not aromatic and Z is a carbon atom or a nitrogen atom, then this ring fragment includes at least one heteroatom sulfur or oxygen in the ring; and provided that when such ring fragment is aromatic, then Y is a carbon atom.

(iv) G is a

where J represents a 5-, 6 - or 7-membered heterocyclic ring fragment, containing 1, 2 or 3 heteroatoms in the ring, decay of R 3and R4independently selected from C1-C3of alkyl, halogen, -OH, -CF3, -NH2, -COOH and amidino; and each of R5and R6independently selected from C1-C3of alkyl, oxo, halogen, -OH, -CF3, -NH2, -COOH and amidino.

[0016] the Fragment W' is selected as one of the following three options: nil; -NH-(CH2)b-where b is 0, 1, 2, 3, 4, 5 or 6; and-NH-(CH2)c-O-, where c is 2 or 3.

[0017] the Fragment V is C1-C6alkyl and the operator e is 0 or 1, where if e is 0, then V 0 and R1and R2directly attached to one or different atoms of the ring. Group R1and R2can be any of (a), (b), (c) or (d)as follows:

(a) R1represents H, OH, halogen, CF3, -NH2, -COOH, C1-C6alkyl, amidino, C1-C6alkyl substituted amidino, aryl, optionally substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, CN, CONH2, COR', SO2R', CONR'R', NHCOR', OR' or SO2NR'r R"; where specified optionally substituted heterocyclyl optionally substituted by 1 or 2 substituents, independently selected from the group consisting of C1-C6of alkyl, -C1-C6alkoxy, oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino; where each of R' and R" independently represents H, C1-C8alkyl, aryl, heterocyclyl R' and R" together form a 4-8-membered ring, which is optionally substituted by 1 or 2 substituents, independently selected from the group consisting of C1-C6of alkyl, alkoxy, C1-C6, -OH, -Cl, -F, -NH2, -NO2, -CN and-COOH, amidino; and R2represents H, amidino, once or twice C1-C6substituted alkylamino, -CN, -CONH2, -CONR'R", -NHCOR', SO2NR'r R", or-COOH; or

(b) R1and R2together may form optionally substituted fragment in the form of a 4-9-membered heterocyclic monocyclic or bicyclic ring that is attached to the same atom of ring Y - and Z-containing ring fragment; or

(c) R1and R2together with one atom of ring Y - and Z-containing ring fragment can form an optionally substituted 4-8 membered heterocyclic ring fragment with the formation of spirotrichous; or

(d) R1and R2together with two or more neighbouring ring atoms of the Y and Z-containing ring fragment can form an optionally substituted fragment in the form of a 4-9-membered heterocyclic monocyclic or bicyclic ring fused with the Y - and Z-containing ring fragment.

[0018] Each of the above optional replaced 4-9-membered heterocyclic ring fragments, which include R1and R2not necessarily Zam is on 1 or 2 substituents, independently selected from C1-C6of alkyl, -C1-C6alkoxy, optionally substituted phenyl (as defined above), oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino.

[0019] the above definition of formula I are subject to the following three conditions:

(1) If Y and Z-containing ring fragment is a 6 - or 7-membered ring containing one heteroatom in the ring, and if one of Y and Z represents C, and the other of Y and Z represents N, and e is 0, R1is not HE, and R1and R2both are not H;

(2) If Y and Z-containing ring fragment represents a 6-membered ring containing two heteroatoms in the ring as Y, and Z represent nitrogen atoms, W is equal to 0 and the fragment-Ve(R1)(R2) is attached to Z, then Ve(R1)(R2selected from amidino, C1-C6alkyl substituted amidino, dihydroimidazole, -CH2COOH and-CH2C(O)NH2; and

(3) If Y and Z-containing ring fragment represents a 6-membered ring containing a heteroatom sulfur or oxygen in the ring, or if the Y and Z-containing ring fragment is a non-aromatic 6-membered ring which contains two heteroatoms in the ring, where Y and Z represent nitrogen atoms, and W is equal to 0, or if the Y and Z-containing ring fragment is provided which allows a 6-membered aromatic ring, which contains one heteroatom in the ring, which is a nitrogen atom, then, if e is 0, R1and R2both are not hydrogen.

[0020] the Invention also provides selective agonist of the Kappa-opiate receptor (herein also referred to as agonist or just agonist Kappa), which is a synthetic peptide amidon according to the invention, as described above.

[0021] the Invention also provides a pharmaceutical composition, which contains the synthetic peptide amides of the invention and a pharmaceutically acceptable diluent, excipient or carrier.

[0022] Also proposed a method of treating or preventing associated with the Kappa-opiate receptors of the disease or condition in a mammal. The method comprises the administration to a mammal of a composition which contains an effective amount of a synthetic peptide amide according to the invention. The invention also provides the use of synthetic peptide amides of the invention for the preparation of medicaments and pharmaceutical compositions suitable for the treatment associated with the Kappa-opiate receptors of the disease or condition in a mammal.

[0023] the Invention also provides a method of treating or preventing associated with the Kappa-opiate receptors of the disease or the status is I have a mammal, where the synthetic peptide amides of the invention is administered in conjunction with a reduced dose of analgesic mu-opioid agonist, to achieve therapeutic analgesic effect and analgesic compound mu-opioid agonist causes associated side effect (especially respiratory depression, sedation, euphoria, antidiuretic effect, nausea, vomiting, constipation and physical addiction, dependence and addiction). Reduced dose of analgesic mu-opioid agonist that is administered in accordance with this method, causes less severe related side effects than the side effects associated with the dose of compound required to achieve the same therapeutic analgesic effect with monotherapy.

[0024] the Invention also provides a method of treating or preventing peripheral hyperalgesia, where the method comprises local application or administration to a mammal in need of treatment an effective amount of a composition that contains an effective anti hyperalgesia number of synthetic peptide amides of the invention in a carrier designed for local application or administration.

[0025] the Invention also provides a method of treating or preventing hyponatremia or hypokalemia and, thus treating or preventing the disease or with the standing, associated with hyponatremia or hypokalemia, such as congestive heart failure, liver cirrhosis, nephrotic syndrome, hypertension or edema and, preferably, where the increased secretion of vasopressin is associated with the specified disease or disorder, the method comprises administration to a mammal aquarelease effective amount of the synthetic peptide amides of the invention in a pharmaceutically acceptable diluent, auxiliary substance or medium.

BRIEF DESCRIPTION of FIGURES

[0026] Figure 1: Shows the General scheme used for the synthesis of compounds (1). D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethylation]-(SEQ ID NO: 1): Phase a-g carried out with the following reactants or conditions: a) Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine, DIEA, DHM; b) 25% piperidine/DMF; c) Fmoc-D-Orn(Boc)-HE, DIC, HOBt, DMF; d) Fmoc-D-Leu-OH, DIC, HOBt, DMF; e) Fmoc-D-Phe-OH, DIC, HOBt, DMF; (f) Boc-D-Phe-OH, DIC, HOBt, DMF; (g) TFU/TIS/H2O(95:2,5:2,5).

[0027] Figure 2: Shows the General scheme used for the synthesis of compound (13): D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethylation]-NH2(SEQ ID NO: 1). Stage a-h carried out with the following reactants or conditions: a) 25% piperidine, DMF; (b) Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine, HBTU, DIEA, DMF; c) 25% piperidine, DMF; (d) Fmoc-D-Orn(Boc)-OH, DIC, HOBt, DMF; e) Fmoc-D-Leu-OH, DIC, HOBt, DMF; (f) Fmoc-D-Phe-OH, DIC, HOt, DMF; (g) Boc-D-Phe-OH, DIC, HOBt, DMF; (h) TFU/TIS/H2O(95:2,5:2,5).

[0028] Figure 3: Shows the General scheme used for the synthesis of derivatives of tetrapeptide homopiperazine, such as compound (11). Stage a-s carried out with the following reactants or conditions: a) homopiperazin, DHM; b) Fmoc-D-Dap(ivDde)-HE or Fmoc-D-Dap(ivDde)-HE or Fmoc-D-Orn(Aloe)-HE or Fmoc-D-Orn(Z)-OH or Fmoc-D-Lys(Dde)-HE or Fmoc-D-Arg(Pbf)-HE, DIC, HOBt, DMF; c) 25% piperidine in DMF; d) Fmoc-D-Leu-OH or Fmoc-D-Nle-OH, DIC, HOBt, DMF; e) Fmoc-D-Phe-OH, DIC, HOBt, DMF; f) Z-D-Phe-OH, DIC, HOBt, DMF; n=0-3; R3=iPr, nPr; PG4 = ivDde, Dde, Aloc, Z, Pbf in the case of D-Arg; (g) 4% hydrazine in DMF; (h) Pd(PPh3)4, CHCl3/Asón/NMM; i) O-NBS-Cl, kollidon, NMP; (j) dimethylsulfate, DBU, NMR; (k) mercaptoethanol, DBU, NMP; 1) Z-OSu, DMF; (m) acetone, Asón, NaBH(OAc)3, TMOF; n) 1H-pyrazole-1-carboxamidine, DIEA, DMF; n=0-3; R3=iPr, nPr; R4=H, Me, iPr, amidino; PG4 = Z, H, if R4represents amidino; o) 50% TFU/DHM; p) hydroiodic S-methyl-N-methylisothiazolone, DIEA, DMF; (q) hydroiodic 2-methylthio-2-imidazolin, DIEA, DMF; d) Iodate, DIEA, DMF; s) TMSOTf/TFU/m-cresol (2:7:1); n=0-3; R3=iPr, nPr; R4=H, Me, iPr, amidino; R5=H, Et, amidino, 4,5-dihydro-1H-imidazol-2-yl, N-methylcarbamoylmethyl.

[0029] Figure 4: Shows the General scheme used for the synthesis of compounds (25)to(38). Stage a-h carried out with the following reactants or conditions: a) EDC, HOBt, DIEA, THF; b) TFU, DHM; (c) BOC-D-Phe-OH, EDC, HOBt, DIEA; d) H2, Pd/C; (e) H-D-Lys)-OAll, TBTU, DIEA, DMF; (f) Pd(PPh3)4pyrrolidin; (g) amine HNR1R2, HBTU, DMF; (h) HCl, dioxane.

[0030] Figure 5: Shows the General scheme used for the synthesis of compound (40): D-Phe-D-Phe-D-Leu-D-Orn-[ε-Lys(D-Orn-D-Leu-H)]-H (SEQ ID NO: 1). Stage a-i carried out with the following reactants or conditions: a) Fmoc-L-Lys(Dde)-OH, DIEA, DHM; b) 25% piperidine/DMF; c) Fmoc-D-Orn(Boc)-HE, PyBOP, DIEA, DMF; (d) Boc-D-Leu-OH, PyBOP, DIEA, DMF; e) 4% hydrazine, DMF; (f) Fmoc-D-Leu-OH, PyBOP, DIEA, DMF; (g) Fmoc-D-Phe-OH, PyBOP, DIEA, DMF; (h) Boc-D-Phe-OH, PyBOP, DIEA, DMF; (i) TFU/TIS/H2O(95:2,5:2,5).

[0031] Figure 6: Shows the General scheme used for the synthesis of compounds (51): 1N,4N-bis-(D-Phe-D-Phe-D-Leu-D-Nar)-4-amino-4-carboxyl piperidine (SEQ ID NO: 6). Stage a-k carried out with the following reactants or conditions: a) 35% piperidine, DMF; (b) N-BOC-(4-Fmoc-amino)piperidine-4-carboxylic acid, PyBOP, DIEA, DMF; c) 30% TFU/DHM; (d) Boc-D-Dab(Fmoc)-HE, PyBOP, DIEA, DMF; (e) Boc-D-Leu-OH, PyBOP, DIEA, DMF; (f) Boc-D-Phe-OH, PyBOP DIEA, DMF; (g) Boc-D-Phe-HE, PyBOP, DIEA, DMF; (h) 2% DBU/DMF; (i) 1H-pyrazole-1-carboxamidine, DIEA, DMF; (j) copper acetate, pyridine, DBU, DMF/water; (k) 95% TFU/water.

[0032] Figure 7: Shows the General scheme used for the synthesis of compound (52): D-Phe-D-Phe-D-Leu-D-Lys-Gly covenants)2-D-Leu-D-Phe-D-Phe. Stage a-h carried out with the following reactants or conditions: a) Fmoc-glycine, DIEA, DHM; b) 25% piperidine/DMF; c) Fmoc-D-Lys(Boc)-OH, PyBOP, DIEA, DMF; (d) Fmoc-D-Leu-HE, PyBOP, DIEA, DMF; e) Fmoc-D-Phe-H, PyBOP, DIEA, DMF; (f) Boc-D-Phe-OH, PyBOP, DIEA, DMF; (g) TFU/TIS/H2O; h) PyBOP, DIEA, DMF;

[0033] Figure 8: Shows the General scheme used for the synthesis of compound (53): D-Phe-D-Phe-D-Leu-D-Orn-[R/S-2-carboxymethyl]-(SEQ ID NO: 1). Stage a-g carried out with the following reactants or conditions: a) GCOS-morpholine-2-carboxylic acid, DIEA, DHM; b) 25% piperidine/DMF; c) Fmoc-D-Orn(Boc)-HE, DIC, HOBt, DMF; (d) Fmoc-D-Leu-OH, DIC, HOBt, DMF; e) Fmoc-D-Phe-OH, DIC, HOBt, DMF; (f) Boc-D-Phe-OH, DIC, HOBt, DMF; (g) TFU/TIS/H2O(95:2,5:2,5).

[0034] Figure 9: Shows the General scheme used for the synthesis of compound (55): D-Phe-D-Phe-D-Leu-D-Orn-N (homomorpholine) (SEQ ID NO: 1). Stage a-d carried out using the following reactants or conditions: a) homomorpholine, EDC, HOBt, THF; (b) H2Pd/C, MeOH; (c) BOC-D-Phe-D-Phe-D-Leu-OH, EDC, HOBt, THF; d) TFU, THM.

[0035] Figure 10: Curves dose-response for compound (17) in ICR mice in the test model induced by acetic acid cramps (unfilled circles) and average (solid circles), and rectangles errors; and test models of movement (empty squares), mean (solid squares and rectangles errors.

[0036] Figure 11: Concentration in plasma after intravenous administration of a single bolus of compound (19) Javanese makkam. Plasma samples were collected via 2, 5, 10, 15, 30, 60, 120 and 240 minutes after injection.

DETAILED DESCRIPTION

[0037] Yes the Mr. the description of the term "synthetic peptide amides" denotes the connection according to the invention, corresponding to the formula I or a stereoisomer, mixture of stereoisomers, prodrug, pharmaceutically acceptable salt, hydrate, MES, hydrate acid salt, N-oxide or isomorphic crystalline form. Denote Xaa1, Xaa2, Xaa3and Xaa4represent D-amino acid synthetic peptide Amidah according to the invention. The stereoisomers of the synthetic peptide amides of the invention corresponding to formula I are limited to compounds containing amino acids in the D-configuration, where it is indicated in the Formula I. the Stereoisomers of the synthetic peptide amides of the invention include compounds with D - or L-configuration of the chiral centers, in addition to the alpha-carbon atoms of four amino acids at positions Xaa1, XAA2, XAA3and XAA4. The term "mixture of stereoisomers" refers to mixtures of such stereoisomers according to the invention. In this description, the term "racemate" refers to a mixture of stereoisomers containing equal proportions of compounds with D - and L-configuration of one or more chiral centers, in addition to the alpha-carbon atoms Xaa1, Xaa2, Xaa3and Xaa4without changing the chirality of the alpha carbon atoms Xaa1, Xaa2, Xaa3and Xaa4.

[0038] the Nomenclature used to define the peptides herein described Schroder &Lubke, The Peptides, Academic Press, 1965, where, in accordance with the tvii with the conventional view, N-end is on the left and C-right end. If the amino acid residue is present in isomeric forms, L-isomeric form, and D-isomeric form amino acids are included, unless otherwise noted. Amino acids in this description are usually identified by the standard three letter code. D-isomer amino acids specified by the prefix "D-", for example, in "D-Phe"that denotes a D-phenylalanine, D-isomer of phenylalanine. Also, the L-isomer is indicated by the prefix "L-", for example, in "L-Phe". The peptides in this description are presented according to the traditional arrangement, as the amino acid sequence from left to right: from N-Terminus to the C-end, unless otherwise indicated.

[0039] In this description, D-Arg is D-arginine, D-Har is D-homoarginine, which contains a side chain by one methylene group is longer than D-Arg and D-Nar is D-norashikin, which contains a side chain by one methylene group is shorter than D-Arg. Similarly, D-Leu denotes a D-leucine, D-Nle D denotes norleucine, and D-Hle is D-hemolysin. D-Ala denotes a D-alanine, D-Tyr denotes a D-tyrosine, D-Trp represents D-tryptophan, and D-Tic denotes a D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. D-Val acid, D-valine, and D-Met acid D-methionine. D-Pro denotes a D-Proline, Pro-amide denotes a D - or L-form Proline amide. D-Pro-amide is D-Proline with the amide group formed at the carboxyl the fragment, where the amide nitrogen can be a substituted alkyl, as in the case of-NRaRbwhere each of Raand Rbindependently represents a C1-C3alkyl group, or one of Raand Rbrepresents a-N. Gly represents glycine, D-Ile denotes a D-isoleucine, D-Ser denotes a D-serine, and D-Thr denotes a D-threonine. (E)D-Ala denotes a D-isomer of alanine containing the substituent (S) at the β-carbon. Examples of such groups as substituent (S) include cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl. Thus, cyclopentyl-D-Ala denotes a D-isomer of alanine substituted by cyclopentyl at the β-carbon atom. Similarly, D-Ala(2-thienyl) and (2-thienyl)D-Ala interchangeable, and both denote the D-isomer of alanine substituted at the β-carbon atom by tanila, which is attached in position 2 of the ring.

[0040] In this description of D-Nal denotes a D-isomer of alanine, substituted naphthyl at the β-carbon atom. D-2Nal denotes a substituted naphthyl-D-alanine, where naftalin attached in position 2 of the ring structure, and D-1Nal denotes a substituted naphthyl-D-alanine, where naftalin attached in position 1 of the ring structure. (A)(A')D-Phe denotes a D-phenylalanine, is substituted on the phenyl ring with 1 or 2 substituents, independently selected from halogen, nitro, methyl, halogenmethyl (such as trifluoromethyl), p is halogenmethyl, cyano and carboxamide. D-(4-F)Phe denotes a D-phenylalanine, is substituted by fluorine in position 4 of the phenyl ring. D-(2-F)Phe denotes a D-phenylalanine, is substituted by fluorine in position 2 of the phenyl ring. D-(4-Cl)Phe denotes a D-phenylalanine, is substituted with chlorine at position 4 of the phenyl ring. (α-Me)D-Phe denotes a D-phenylalanine, substituted stands at the alpha carbon atom. (αMe)D-Leu denotes a D-leucine, substituted stands at the alpha carbon atom.

[0041] the Notation (B)2D-Arg, (B)2D-Nar and (B)2D-Har represent D-arginine, D-norashikin and D-homoarginine, respectively, each of which contains two groups of substituent (B) in the side chain. D-Lys denotes a D-lysine, and D-Hlys denotes a D-hemolysin. ζ-(B)D-Hlys, ε-(B)D-Lys, and ε is the(In)2-D-Lys represent D-hemolysin and D-lysine, each containing in the side chain of the amino group, substituted by 1 or 2 substituent groups (I), as shown. D-Orn denotes a D-ornithine, and δ-(V)α (') D-Orn denotes a D-ornithine, substituted (In') at the alpha-carbon atom, and substituted (B) in the side chain of δ-amino group.

[0042] D-Dap denotes a D-2,3-diaminopropionic acid. D-Dbu represents the D-isomer of alpha, gamma-diaminoalkanes acid, and (B)2D-Dbu is alpha, gamma diaminobutane acid, substituted by two groups of the substituent (B) in gamma-amino group. Unless otherwise stated, each of (B) groups of such double-substituted residues is ezavisimo selected from N and C 1-C4-alkyl. In this description, D-Amf denotes a D-(NH2CH2)Phe, i.e, D-isomer of phenylalanine, substituted aminomethyl phenyl ring, and D-4Amf represents a specific D-Amf, in which aminomethyl attached in position 4 of the ring. D-Gmf denotes a D-Amf(amidino), which represents D-Phe, where the phenyl ring is substituted by-CH2NHC(NH)NH2. Amd is amidino, C(NH)NH2symbols and conventions (Amd) D-Amf and D-Amf (Amd) is also equivalent to apply for D-Gmf. Denote i.l.y bit and Ior, respectively, are used to denote Lys of isopropyl and Orn of isopropyl, where the amino group of the side chain alkylated isopropyl group.

[0043] Alkyl means an alkane radical, which may be a branched, unbranched and cyclic alkyl group, such as, without limitation, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, tert-butyl, sec-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, cyclohexylethyl. C1-C8alkyl refers to alkyl groups containing from 1 to 8 carbon atoms. Similarly, C1-C6alkyl refers to alkyl groups containing from 1 to 6 carbon atoms. Also, C1-C4alkyl refers to alkyl groups containing from 1 to 4 carbon atoms. Lower alkyl refers to C1-C6alkyl. Me, Et, Pr, Ipr, Bu, and Pn are equivalent for presents is I common alkyl groups: methyl, ethyl, propyl, isopropyl, butyl and pentyl, respectively. Although the connection for the alkyl group is usually at one end of the alkyl chain, the connection can be located anywhere elsewhere chain, such as 3-pentyl, which may also be designated as ethylpropyl or 1-aterproof-1-yl. Alkyl substituted, for example, C1-C6alkyl substituted amidino, shows that the corresponding fragment is substituted by 1 or more alkyl groups.

[0044] If the specified portion is equal to 0, such a fragment is missing, and if it is indicated that this fragment is attached to two other fragments, such two other fragment are connected by a single covalent bond. If the connecting fragment shown in this description as attached to the ring in any position of the ring and attached to the other two fragments, such as R1and R2in the case when it is noted that the connecting fragment is equal to 0, each of the fragments of R1and R2can be independently attached to any position on the ring.

[0045] the Terms "heterocycle", "heterocyclic ring" and "heterocyclyl apply equally in the present description and refer to a ring or ring fragment that contains at least one non-carbon atom in the ring, which is also referred to as the heteroatom, and which may represent a nitrogen atom, a sulfur sludge is oxygen. If you specify that the ring is a certain number of members, number determines the number of atoms in the ring without designation of any substituents or hydrogen atoms attached to the ring atoms. Heterocycles, heterocyclic rings and heterocyclyl fragments can contain one or more heteroatoms independently selected from nitrogen atom, sulfur or oxygen within the ring. Ring may contain substituents at any available position. For example, without limitation, 6 - and 7-membered rings often contain substituents in position 4 of the ring, and 5-membered rings usually contain substituents in position 3, where the ring is attached to the peptide chain amide at position 1 of the ring.

[0046] the Term "saturated" refers to the absence of double or triple links, and the use of the term in connection with rings denotes a ring contains no double or triple bonds in the outside ring, but does not denote the absence of double or triple bonds in the substituents attached to the ring. The term "non-aromatic" is used in the context of a specific ring to indicate the absence of aromaticity in this ring, but does not denote the absence of double bonds within the ring, including double bonds, which are part of the aromatic ring condensed with the specified ring. Not forbidden is ricotta double bond between an atom of ring a saturated heterocyclic ring fragment and the atom outside the ring, for example, the sulfur atom in the ring is connected by a double bond with oxygen atom of the substituent. In this description, heterocycles, heterocyclic rings and heterocyclyl fragments also include saturated, partially unsaturated and heteroaromatic ring, a condensed bicyclic structure of the rings, if not otherwise specified. A heterocycle, heterocyclic ring or heterocyclyl fragment can be condensed with a second ring which may be saturated, partially unsaturated or aromatic ring, which may represent a heterocycle or the carbon cycle. If specified, two Deputy may not necessarily together to form an additional ring. Rings can be substituted in any available position. A heterocycle, heterocyclic ring and heterocyclyl fragment may, if specified, can be optionally substituted in one or more of the provisions of the ring by one or more independently selected substituents, such as, for example, C1-C6alkyl, C3-C8cycloalkyl, C1-C6alkoxy, halogen, C1-C6alkyl, optionally substituted phenyl, aryl, heterocyclyl, oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino. Suitable optional substituents include phenyl, for example, without limitation, one or more groups, is selected from C 1-C3of alkyl, C1-C3alkoxy, halogen, C1-C3of alkyl, oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino.

[0047] D-Phe and substituted D-Phe are examples of suitable amino acids for residue Xaa1in Formula I. the Phenyl ring can be substituted at any of positions 2, 3 and/or 4. Specific examples of allowed substitutions include, for example, chlorine or fluorine in position 2 or 4. Also the alpha carbon atom can be methylated. Other equivalent balances that are conservative substitutions for D-Phe, may also be used. They include D-Ala(cyclopentyl), D-Ala(thienyl), D-Tyr, D-Tic. The residue in position 2, Xaa2may also be a D-Phe or substituted D-Phe with such replacements, including substituents at the carbon atom in position 4 of the phenyl ring or as position 3 and position 4. Alternatively, XAA2can be a D-Trp, D-Tyr or D-alanine, substituted naphthyl. The residue in position 3, Xaa3can represent any non-polar amino acid residue, such as D-Nle, D-Leu, (α-Me)D-Leu, D-Hle, D-Met or D-Val. However, D-Ala(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or D-Phe may also be used as XAA3. The residue in position 4, Xaa4can represent any positively charged amino acid residue is, for example, D-Arg, D-Har, which may be optionally substituted lower alkyl groups, such as one or two ethyl groups. Alternatively, it may be D-Nar, and any other equivalent residues such as D-Lys or D-Orn (any of which may be alkylated ω-amino group, for example, methyl or ISO-propyl groups, or methylated at α-carbon atom). In addition, D-Dbu, D-4-Amf (which may be optionally substituted amidino) and D-Hlys are also suitable amino acids for a given position.

[0048] the Compounds according to the invention contain one or more chiral centers, each of which has two possible three-dimensional spatial arrangement (configuration) of the four substituents around a Central carbon atom. They are known as stereoisomers and, more specific, as enantiomers (all chiral centers in the reverse configuration) or diastereoisomer (two or more chiral centers, at least one chiral center in the same configuration). In a specific embodiment of the invention, indicates that amino acids, which form the basis of tetrapeptide, Xaa1Xaa2Xaa3Xaa4represent D-aminonicotinate, ie, their configuration, the opposite is usually present in mammals. The link to the stereoisomers of the synthetic peptide amides of the invention is asaeda chiral centers, in addition to the alpha-carbon atoms of D-amino acids that make up Xaa1-Xaa4. Thus, the stereoisomers of the synthetic peptide amides that are variants of the invention, which States that each of Xaa1-Xaa4is a D-amino acid, do not include L-amino acids or racemic mixtures of amino acids in these positions. Similarly, the reference to the racemate in this description refers centers, in addition to the alpha-carbon atoms of D-amino acids that make up Xaa1-Xaa4. Chiral centers in synthetic peptide Amidah according to the invention, for which stereoisomer may be in the R or S configuration, include chiral centers in the fragment attached to the C-end Xaa4and chiral centers in any of the substituents on the side chain of the amino acid Xaa1-Xaa4.

[0049] the Synthetic peptide amides of the invention described in this description (equally referred to as compounds of synthetic peptide amides, compounds according to the invention, the connection (number) or simply "connection"), can be applied or can be obtained in alternative ways. For example, many amino compounds compounds can be used or can be obtained in the form of a salt with the acid. Often these salts improve the selection and connection properties in the process of handling. For example, the dependence on reagents, the reaction conditions and the like, compounds, for example, the synthetic peptide amides described in this description can be applied or to be received, for example, as cleaners containing hydrochloride or tosylate salt. Isomorphic crystalline forms, all of chiral and racemic forms, N-oxides, hydrates, solvate and hydrate salts of the acids are also within the context of the present invention.

[0050] Certain acidic or basic synthetic peptide amides of the present invention may exist as zwitter-ions. All forms of such synthetic compounds of peptide amides, including the free acid, free base and zwitter ions are within the context of the present invention. In this field it is well known that compounds containing both amino and carboxyl groups often exist in equilibrium with their sitter-ionic forms. Thus, it should be clear that for any compound described herein, which includes, for example, as the amino-and carboxyl group included the appropriate zwitter-ion.

[0051] In one embodiment, the present invention proposes a synthetic peptide amides of the formula:

and their stereoisomers, mixtures of stereoisomers, prodrugs, pharmaceutically acceptable salt, hydrate, solvate, hydrate with the lei acids, N-oxides and isomorphic crystalline forms, where each Xaa1independently selected from (A)(A')D-phenylalanine, (A)(A')(α-Me)D-phenylalanine, D-tyrosine, D-1,2,3,4-tetrahydroisoquinoline-Karbonovoi acid, D-phenylglycine, D-neopentylglycol, D-phenylglycine, D-homophenylalanine and β-(E)D-Ala, where each of (a) and (A') represents the substituent in the phenyl ring, independently selected from-H, -F, -Cl, -NO2, -CH3, -CF3, -CN, -CONH2and where each (S) independently selected from cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, tanila and thiazolyl. Each Haag independently selected from (A)(A')D-phenylalanine, (A)(A')(α-Me)D-phenylalanine, naphthyl-1-D-alanine, naphthyl-2-D-alanine, D-tyrosine, (E)D-alanine and D-tryptophan. Each Xaa3independently selected from D-norleucine, D-phenylalanine, (E)D-alanine, D-leucine, (α-Me)D-leucine, D-hemolysin, D-valine and D-methionine. Each XAA4independently selected from (I)2D-arginine, (B)2D-norashikin ()2D-homoarginine, ζ-(B)D-hemolysin, D-2,3-diaminopropionic acid, ε-(B)D-lysine, ε-(B)2-Lisino D-(NH2CH2-)phenylalanine, amidino-D-(NH2CH2-)phenylalanine, γ-()2D-diaminoalkanes acid, δ-(V)2α-(') D-ornithine, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidine)propionic acid, D-α-amino-β-propionic acid, α-amino-4-piperidineacetic acid, CIS-α,4-diaminocyclohexane acid, TRANS-α,4-diaminocyclohexane acid, CIS-α-amino-4-methyl-aminocyclo-hexadecanoic acid, TRANS-α-amino-4-methylenecycloartanol acid, α-amino-1-amidino-4-piperidineacetic acid, CIS-α-amino-4-guanidino-cyclohexadecane acid and TRANS-α-amino-4-guanidinopentanoic acid, where each (I) independently selected from the group consisting of-H and C1-C4of alkyl, and (B') represents-H or (α-Me); and p is 0 or 1.

[0052] In another embodiment, G is selected as one of the following four fragments:

(i) G is a

where each of p, q, r, s and t are independently 0 or 1, provided that at least one of s and t is 1; and L represents a linker selected from ε-D-lysine, ε-lysine, δ-D-ornithine, δ-ornithine, γ-aminomaslyanoi acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctyl acid, 4-amino-4-carboxyl of piperidine and (D-Lys-Gly lactam)2. Synthetic peptide amides of this option in this description are equally referred to as "dimer structure", "dimers"or "dimers synthetic peptide amides", because they include two synthetic component peptide amides, United linker fragment L.

(ii) G is a

where p is 1; XAA3 4is selected from D-Nle-(B)2D-arginine, D-leucine-δ-(V)2α-(') D-ornithine, and (α-Me)D-leucine-δ ()2-α (') D-ornithine-; and Y and Z-containing ring fragment

represents an optionally substituted fragment in the form of a 4-8-membered heterocyclic ring, where the ring heteroatoms in the specified ring fragment are nitrogen atoms; where each Y and Z independently represents a carbon atom or a nitrogen atom; provided that when such ring fragment is a 6-, 7 - or 8-membered ring, Y and Z are separated by at least two ring atoms; and provided that when such ring fragment contains one heteroatom which is a nitrogen atom, then this ring fragment is not aromatic.

(iii) G is a

where p is 1;

and fragment

represents an optionally substituted fragment in the form of a 4-8-membered heterocyclic ring, where Y is C or N and Z represents a carbon atom, a nitrogen atom, an oxygen atom, a sulfur atom, sulfoxide group or sulfonyloxy group; provided that when such ring fragment is a 6-, 7 - or 8-membered ring, Y and Z are separated by at least two ring atoms; provided that if such it is litsevoy fragment is not aromatic, and Z represents a carbon atom or a nitrogen atom such ring fragment includes at least one heteroatom sulfur or oxygen within the ring; and provided that when such ring fragment is aromatic, then Y is a carbon atom; and (iv) G is a

where J represents a 5-, 6 - or 7-membered heterocyclic ring fragment, containing 1, 2 or 3 heteroatoms in the ring, where each of R3and R4independently selected from C1-C3of alkyl, halogen, -OH, -CF3, -NH2, -COOH and amidino; and each of R5and R6independently selected from C1-C3of alkyl, oxo, halogen, -OH, -CF3, -NH2, -COOH and amidino; where W' is selected from: null;

-NH-(CH2)b-where b is 0, 1, 2, 3, 4, 5 or 6; and

-NH-(CH2)c-O-, where c is 2 or 3.

[0053] In another embodiment, V represents C1-C6alkyl, and e is 0 or 1, where if e is 0, then V is equal to 0, and R1and R2directly attached to the same or different ring atoms; where

(a) R1represents-H, -OH, halogen, CF3, -NH2, -COOH, C1-C6alkyl, amidino, C1-C6alkyl substituted amidino, aryl, optionally substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, CN, CONH2, COR', SO2R', CONR'R', NHCOR', OR' what if SO 2NR'r R"; where specified optionally substituted heterocyclyl optionally contains 1 or 2 substituent, independently selected from the group consisting of C1-C6of alkyl, -C1-C6alkoxy, oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino; where each of R' and R" independently represents-H, C1-C8alkyl, aryl, heterocyclyl, or R' and R" form a 4-8-membered ring, which optionally is substituted by 1 or 2 substituents, independently selected from the group consisting of C1-C6of alkyl, -C1-C6alkoxy, -OH, -Cl, -F, -NH2, -NO2, -CN and-COOH, amidino; and R2represents H, amidino, amidino substituted by one or two C1-C6-alkyl, -CN, -CONH2, -CONR'R", -NHCOR', -SO2NR'r R", or-COOH; or

(b) R1and R2together may form optionally substituted fragment in the form of a 4-9-membered heterocyclic monocyclic or bicyclic ring that is attached to the same atom of ring Y - and Z-containing ring fragment; or

(c) R1and R2together with one atom of ring Y - and Z-containing ring ring can form an optionally substituted 4-8 membered heterocyclic ring fragment with the formation of spirotrichous; or

(d) R1and R2together with two or more neighbouring ring atoms of the Y and Z-the content is the future of ring fragment can form an optionally substituted fragment in the form of a 4-9-membered heterocyclic monocyclic or bicyclic ring, condensed with the Y - and Z-containing ring segment; and where each of the specified optionally substituted 4-9-membered heterocyclic ring fragments containing R1and R2optional single or double-substituted by substituents independently selected from the group consisting of C1-C6of alkyl, -C1-C6alkoxy, optionally substituted phenyl, oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino;

provided that if Y and Z-containing ring fragment is a 6 - or 7-membered ring containing one heteroatom in the ring, and if one of Y and Z represents C, and the other of Y and Z represents N, and e is 0, R1is not-OH, and R1and R2both are not-H; provided that when Y and Z-containing ring fragment is a non-aromatic 6-membered ring containing two heteroatoms in the ring, as Y and Z represents N, W 0, and-Ve(R1)(R2) is attached to Z, then Ve(R1)(R2selected from the group consisting of amidino, C1-C6alkyl substituted amidino, dihydroimidazole, -CH2COOH and-CH2C(O)NH2; and, finally, provided that if Y and Z-containing ring fragment represents a 6-membered ring containing a heteroatom S, or O in the ring, or if the Y and Z-containing calcev the second fragment is a 6-membered ring, containing two heteroatoms in the ring, where both Y and Z represents N, and W is equal to 0, or if the Y and Z-containing ring fragment represents a 6-membered aromatic ring containing one heteroatom in the ring, and the heteroatom represents N, then, if e is 0, R1and R2both are not-H.

[0054] in another embodiment, the proposed synthetic peptide amides of the formula:

and their stereoisomers, mixtures of stereoisomers, racemates, prodrugs, pharmaceutically acceptable salt, hydrate, solvate, N-oxides, hydrates, salts of acids and isomorphic crystalline forms; where

Xaa1selected from (A)(A')D-Phe, (α-Me)D-Phe, D-Tyr, D-Tic, D-phenylglycine, D-homophenylalanine and β-(E)D-Ala, where each of (a) and (A') represent the substituents in the phenyl ring, independently selected from-H, -F, -Cl, -NO2, -CH3, -CF3, -CONH CN and2and (E) selected from cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, tanila and thiazolyl. Xaa2selected from (A)(A')D-Phe, (α-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala and D-Trp; XAA3-Haa4is selected from D-Nle-(B)2D-Arg-D-Leu-δ-(V)2α(B')D-Orn - and (α-Me)D-Leu-δ ()2-α (') D-Orn-; where each of (I) independently selected from-H and C1-C4of alkyl, and (') represents-H or (α-Me). W in the formula above is selected as one of the following three options:

(i) zero, provided that if W is 0, Y is predstavljaet a N; or

(ii) -N-(CH2)bwhere b is 0, 1, 2, 3, 4, 5 or 6;

or

(iii) -N-(CH2)c-O-, where c is 2 or 3, provided that Y represents a carbon atom.

[0055] In one embodiment, Y -, and Z-containing fragment in the above formula represents an optionally substituted 4-8 membered saturated heterocyclic ring fragment, containing 1 or 2 nitrogen atom, in which none of the atoms of the ring, except for Y and Z, is not a heteroatom, Y represents C or N, Z represents C or N, and at least one of Y and Z represents N, and provided that in the case of a 4 - or 5-membered heterocyclic ring, or Y, or Z is a C, and in the case of heterocycle containing 2 nitrogen atom, Y and Z are separated by two or more carbon atoms of the ring.

[0056] In another embodiment, if the Y - and Z-soderjali ring fragment represents a saturated 6-membered ring, which contains only two heteroatoms in the ring, which both represents N, and W is O, Z is n

[0057] In another embodiment, the fragment V is a C1-C6alkyl, and e is 0 or 1, where if e is 0, then V is equal to 0, and R1and R2directly attached to the same or different atoms of the ring. R1represents H, OH, -NH2, -COOH, C1-C6alkyl, amidino, C1-C6Ala is lemesany amidino, dihydroimidazole, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, CN, CONH2, CONR'R', NHCOR' or SO2NR'r R"where each R' and R" independently represents N or C1-C6alkyl, or R' and R" form a 4-8-membered ring, where the ring is optionally substituted by 1 or 2 substituents, independently selected from C1-C6of alkyl, -OH, -Cl, -F, -NH2, -NO2, -CN and-COOH, amidino; and R2represents H, amidino, amidino substituted by one or two C1-C6-alkyl, -CN, -CONH2, -CONR'R", -NHCOR', -SO2NR'r R", or-COOH.

[0058] In one embodiment, formula I is subject to two conditions: (i) if Y and Z-containing ring fragment is a 6 - or 7-membered ring, and if one of Y and Z represents C, and e is 0, R1is not HE, and R1and R2both are not H; and (ii) if Y and Z-containing ring fragment represents a 6-membered ring, as Y and Z represents N, and W is equal to 0 then -(V)eR1R2attached to the atom of the ring, in addition to Z; and if e is 0, R1and R2both are not-H.

[0059] In certain embodiments, the synthetic peptide amides of the invention are described by the formula:

where Xaa1selected from (A)(A')D-Phe, (α-Me)D-Phe, D-Tyr, D-Tic, and (E)D-Ala, where each of A and A' represents a substituent in the phenyl ring, independently selected from-H, -F, - Cl, NO 2, -CH3, -CF3, -CN, -CONH3and where E is selected from the group consisting of cyclopentyl, pyridyl, tanila and thiazolyl. XAA2selected from (A) (A')D-Phe, (α-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala and D-Trp. Xaa3selected from D-Nle, D-Phe, cyclopentyl-D-Ala, D-Leu, (α-Me)D-Leu, D-Hle, D-Val and D-Met. Xaa4selected from (B)2D-Arg, (B)2D-nArg, (B)2D-Har, ζ-(B)D-Hlys, D-Dap, ε-(B)D-Lys, ε-(B)2-D-Lys, D-Amf, amidino-D-Amf, γ-(B)2D-Dbu, δ-(B)2α(B')D-Orn, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidine)propionic acid, D-α-amino-β-amidinopropane acid, (R)-α-amino-4-piperidineacetic acid, CIS-α,4-diaminocyclohexane acid, TRANS-α,4-diaminocyclohexane acid, CIS-α-amino-4-methylenecycloartanol acid, TRANS-α-amino-4-methylamino-cyclohexadecane acid, α-amino-1-amidino-4-piperidineacetic acid, CIS-α-amino-4-guanidinosuccinic acid and TRANS-α-amino-4-guanidinopentanoic acid, where each (I) independently selected from the group consisting of N and C1-C4of alkyl, and (') represents H or (α-Me). Fragment W selected as one of the following three options:

(i) zero; (ii) -N-(CH2)bwhere b is 0, 1 2, 3, 4, 5 or 6; and

(iii) -N-(CH2)c-O-, where c is 2 or 3, provided that Y represents a carbon atom.

[0060] Y -, and Z-containing ring fragment

represents an optionally substituted 6-8-membered saturated heterocyclic ring fragment, where none of the atoms of the ring, except for Y and Z, is not a heteroatom, Y and Z are separated by at least two carbon atoms of the ring, Y represents C or N and Z represents S, O or N.

[0061] the Fragment V is a C1-C6alkyl, and e is 0 or 1, where if e is 0, then V is equal to 0, and R1and R2directly attached to the same or different ring atoms; R1represents H, OH, -NH2, -COOH, C1-C6alkyl, amidino, C1-C6alkyl substituted amidino, dihydroimidazole, D-Pro, Gly, D-Ala, D-Val, D-Leu, D-Ile, D-Lys, D-Arg, D-Orn, D-Ser, D-Thr, -CN, -CONH2, -CONR'R", -NHCOR' or-SO2NR'r R"where each R' and R" independently represents-H or C1-C8alkyl, or R' and R" form a 4-8-membered ring, which optionally is substituted by 1 or 2 substituents, independently selected from C1-C6of alkyl, -OH, -Cl, -F, -NH2, -NO2, -CN and-COOH, amidino; and R2represents-H, amidino, C1-C6alkyl substituted amidino, -CN, -CONH2, -CONR'R", -NHCOR', -SO2NR'r R", or-COOH.

[0062] In certain embodiments employ one of the following three conditions: if e is 0, R1and R2both are not H; when W represents-N-(CH2)with-O-Y performance, which defaults to a C, and c is 2 or 3; or (iii) when Z represents N, Y represents N, W 0, Y - and Z-containing ring fragment is a non-aromatic 6-membered ring, and-Ve(R1)(R2) is attached to Z, and Ve(R1) (R2selected from amidino, C1-C6alkyl substituted amidino, dihydroimidazole, -CH2COOH and-CH2C(O)NH2.

[0063] In certain embodiments, the synthetic peptide amides of the invention is a dimer, which include two component synthetic peptide amides, United linker fragment L.

[0064] In one aspect, the synthetic peptide amides are described by the formula:

[0065] In the above formula, each Xaa1independently selected from (A)(A')D-Phe, (α-Me)D-Phe, D-Tyr, D-Tic, and (E)D-Ala, where each of (a) and (A') represents the substituent in the phenyl ring, independently selected from-H, -F, -Cl, -NO2, -CH3, -CF3, -CN, -CONH2and where (E) is selected from tanila, cyclopentyl, pyridyl and thiazolyl. Each Xaa2independently selected from (A)(A')D-Phe, (α-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr and D-Trp; and r is 0 or 1. Each XAA3independently selected from D-Nle, D-Phe, cyclopentyl-D-Ala, D-Leu, (α-Me)D-Leu, D-Hle, D-Val and D-Met; and s is 0 or 1. Each XAA4independently selected from (B)2D-Arg, (B)2D-nArg, (B)2D-Har, ε-(B)D-Hlys, D-2,3-diaminopropionic KIS is the notes, ε-(B)D-Lys, ε-(B)2-D-Lys, D-Amf, amidino-D-Amf, (B)2D-Dbu, δ-(B)2α(B')D-Orn, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidine)propionic acid, D-α-amino-β-amidinopropane acid, where each (I) independently selected from the group consisting of H and C1-C4of alkyl, and (') represents H or (α-Me); and each of p, q, r, s and t are independently 0 or 1, provided that at least one of q, r, s and t is 1. In some aspects of the invention, at least one of s and t is 1.

[0066] the Fragment of L is the failure of a linker selected from ε-D-Lys, ε-Lys, δ-D-Orn, δ-Orn, γ-aminobutyric acid, 8-aminooctanoic acid, 11-aminoundecanoic acid, 8-amino-3,6-dioxaoctyl acid, amidino-4-amino-4-carboxyl of piperidine and (D-Lys-Gly covenants)2.

[0067] the Stereoisomers, mixtures of stereoisomers, prodrugs, pharmaceutically acceptable salt, hydrate, solvate, hydrates, salts of acids, N-oxides and isomorphic crystalline forms of such synthetic peptide amides are also within the context of the present invention.

[0068] In another aspect of the present invention offers a synthetic peptide amides of the formula:

where G represents

and where q is 0 or 1; r is 0 or 1; s is 0 or 1; each of p and t independently represents 0 or 1,provided that at least one of q, r, s and t is 1; and L represents a linker selected from ε-D-Lys, ε-Lys, δ-D-Orn, δ-Orn, γ-aminobutyric acid, 8-aminooctanoic acid, 11-aminoundecanoic acid, 8-amino-3,6-dioxaoctyl acid, 4-amino-4-carboxyl of piperidine and (D-Lys-Gly covenants)2.

[0069] In another embodiment of the invention proposes a synthetic peptide amides of the formula:

where G represents

where J represents a 5-, 6 - or 7-membered heterocyclic ring fragment, containing 1, 2 or 3 heteroatoms in the ring, where each of R3and R4independently selected from C1-C6of alkyl, halogen, -OH, -CF3, -NH2, -COOH and amidino; and each of R5and R6independently selected from C1-C3of alkyl, oxo, halogen, -OH, -CF3, -NH2, -COOH and amidino.

[0070] In another embodiment of the invention proposes a synthetic peptide amides of the formula:

where G represents

and W is 0, Y represents N, Z represents S. In one aspect, Y -, and Z-containing ring fragment represents a 6-membered saturated ring containing one heteroatom in the ring.

[0071] In another embodiment, G is a

The Y and Z both represent N and are the only heteroatoms in the ring in Y - and Z-containing ring fragment. In another embodiment, e is 0, and the substituents R1and R2together with 0, 1 or 2 ring atoms of the Y and Z-containing ring fragment are monocyclic or bicyclic 4-9-membered heterocyclic ring fragment. In one aspect of this variant, R1and R2together with one atom of ring Y - and Z-containing ring fragment are 4-8-membered heterocyclic ring fragment, which, together with the Y - and Z-containing ring fragment forms spirotrichous, and W is equal to 0.

[0072] In one embodiment, G is a

and e is 0, and R1and R2attached directly to the same atom of the ring. Alternatively, in another embodiment R1represents H, HE, -NH2, -COOH, -CH2COOH, C1-C3alkyl, amidino, C1-C3alkyl substituted amidino, dihydroimidazole, D-Pro, D-Pro amide, or CONH2and where R2represents H, -COOH or C1-C3alkyl.

[0073] In another embodiment, G is selected from:

and.

[0074] In one embodiment, the invention proposes a synthetic peptide amides, where each Xaa2represents D-Phe, each XAA3represents the D-Nle, and each XAA4represents the D-Arg. In another embodiment, each Xaa1represents the D-Ala(2-thienyl).

[0075] In one embodiment, G is a

and dipeptide Xaa3-Xaa4selected from D-Leu-D-Orn and D-Nle-D-Arg. In another embodiment, Xaa1-Xaa2represents D-Phe-D-Phe. In another embodiment, Xaa1represents the D-(4-F)Phe, Xaa2represents the D-(4-Cl)Phe.

[0076] In another embodiment, each Xaa1represents D-Phe or D-Ala(2-thienyl), and each Xaa2represents the D-(4-Cl)Phe. In another embodiment, each XAA3represents the D-Leu or D-Nle. In another embodiment, G is a

and Xaa1selected from D-Phe, D-(4-F)Phe, D-(2-F)Phe, cyclopentyl D-Ala, D-Ala 2-tanila, Xaa2selected from D-(4-F)Phe, D-(4-Cl)Phe, D-1Nal, D-2Nal or D-Trp, and Xaa3-Xaa4selected from D-Nle-D-Arg and D-Leu-D-Orn.

[0077] In one embodiment, Xaa1can be a (A)(A')D-Phe, and in one aspect, each Xaa1represents D-Phe. In another embodiment, each Xaasub> 2represents D-Phe. In another embodiment, each XAA3selected from D-Nle, D-Leu. In another embodiment, each XAA4selected from a δ(B)2D-Orn, D-Arg. In one aspect, each XAA4is a δ(B)2D-Orn, and each (C) is selected from-H, methyl and isopropyl. In another aspect, each XAA4is a (B)2D-Orn, where one of the (In) represents H and the other (B) selected from the group consisting of methyl and isopropyl. In another aspect, each XAA4represents the D-Orn.

[0078] In another embodiment, each XAA4selected from (B)2D-Arg and δ-(B)2D-Orn. In one aspect, each XAA4selected from D-Arg (Et)2D-Arg and δ-(V)D-Orn, and (C) represents H, Me, iPr, or Bu.

[0079] In another embodiment, G is a

,

and W is equal to 0.

[0080] In another embodiment, G is a

,

and W represents-N-(CH2)bwhere b is 0, 1, 2, 3 or 4. In one aspect, b is 0, and Y represents a carbon atom. In another aspect, b is 1 or 2, and Y represents a nitrogen atom. In another embodiment, W represents-N-(CH2)with-O-. In one aspect, C is 1 or 2. In another aspect, Y -, and Z-containing ring fragment is a 4 - or 5-membered ring, and Y represents a nitrogen atom. In another embodiment, Y -, and Z-containing collabouration is a 4-or 5-membered ring, and Y represents a carbon atom.

[0081] In another embodiment, Y -, and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a nitrogen atom, and Z represents a carbon atom. In another alternative embodiment, Y -, and Z-containing ring fragment represents a 6-membered ring. In one aspect, Y -, and Z - containing ring fragment is a 7-membered ring. In another aspect, Y -, and Z-containing ring fragment is a 6 - or 7-membered ring, and both Y and Z represent nitrogen atoms.

[0082] In another embodiment, e is 0, and R1and R2attached directly to the same atom of the ring. In one aspect, e is 0, R2represents-H, and R1attached directly to a carbon atom of the ring adjacent to Z. In another aspect, R1represents H, amidino, C1-C3alkyl substituted amidino, C1-C3alkyl, dihydroimidazole, D-Pro, D-Pro-amide or-CONH2and where e is 0, and R2is a-H. In another aspect, R1represents-H, amidino or methylamino. In one aspect, Y -, and Z-containing ring fragment represents a 5-membered ring, e is 0, and R1represents-COOH.

[0083] In another embodiment, G is a

and Xaa represents D-Phe, XAA2represents D-Phe, XAA3represents the D-Leu, Xaa4is a δ-(B)2D-Orn, where (B) represents-H, methyl or isopropyl; further, where W is equal to 0, Y - and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a nitrogen atom, e is 0, R1represents-NH2, amidino, C1-C3alkyl, C1-C3alkyl substituted amidino, dihydroimidazole, D-Pro or D-Pro amide, and R2represents H or-COOH.

[0084] In certain embodiments, the synthetic peptide amides of the invention, there are two independent residue Xaa1, Xaa2, Xaa3and Xaa4. For example, in embodiments that are described by the formula:

where G is:

and one or more of q, r and s is 1, or both p and t are equal to 1, there are two residue Xaa1, Xaa2, Xaa3and Xaa4, respectively. In such embodiments, each residue of the Xaa1, Xaa2, Xaa3and Xaa4may be identical. Thus, both residue Xaa1may be identical, for example, D-phenylalanine. Also, each residue XAA2, XAA3and Xaa4may be identical. Thus, for example, each XAA2can be a D-(4-F)Penilaian is h, each XAA3may be D-leucine, and each XAA2may be D-arginine.

[0085] an Alternative, and in other embodiments, each residue of one or more pairs of residues Xaa1, Xaa2, Xaa3or Xaa4may be different. For example, one residue Xaa1may be D-phenylalanine, while the second residue Xaa1in the same molecule may be another residue Xaa1for example, D-(4-F) - phenylalanine. Similarly, one residue XAA2may be D-phenylalanine, while the second residue XAA2in the same molecule may represent the failure of D-Ala(2-thienyl). Similarly, one residue Xaa3can be a D-norleucine, while the second residue Xaa3in the same molecule may be a D-leucine. In the same form, one residue Xaa4can be a D-ornithine, while the second residue Xaa4in the same molecule may be a D-arginine, etc.

[0086] In one embodiment, the invention proposes a synthetic peptide amides, where Xaa1represents the D-Ala(2-thienyl). In another embodiment, Xaa1represents the D-(4-F) phenylalanine, and Xaa2represents the D-(4-Cl)phenylalanine. In another embodiment, each Xaa1is a D-phenylalanine or D-Ala(2-thienyl), and each Xaa2represents the D-(4-Cl)phenylal the NIN. In another embodiment, Xaa1-Xaa2represents the D-fenilalanina-D-phenylalanine.

[0087] In one embodiment, each Xaa3selected from D-norleucine and D-leucine. In another embodiment, each Xaa2is a D-phenylalanine, each Xaa3represents the D-norleucine, and each XAA4represents the D-arginine. In another embodiment, each XAA3may be D-leucine or D-norleucine.

[0088] In another embodiment, XAA4selected from a δ ()2D-ornithine, D-arginine. Alternatively, each Xaa4is a δ ()2D-ornithine and each (C) is selected from-H, methyl and isopropyl. In another embodiment, each Xaa4represents (I)2D-ornithine, where one (I) represents-H and the other (B) is selected from methyl and isopropyl. In one aspect, each XAA4is a (B)2D-arginine or δ-(B)2D-ornithine. In another embodiment, each XAA4may represent a residue selected from D-arginine (Et)2D-arginine and δ-(V)D-ornithine, and where (C) represents-H, methyl, isopropyl or butyl. In one embodiment, the dipeptide Xaa3-Xaa4selected from D-leucine-D-ornithine and D-norleucine-D-arginine.

[0089] In one particular embodiment, the synthetic peptide amides of the invention are described by the formula

where G is:

and b is 0, and Y represents a carbon atom. In another embodiment, b is 1 or 2, and Y represents a nitrogen atom. In a particular aspect of the invention, b is 2.

[0090] In another embodiment, G is a

and Y - and Z-containing fragment is a [ω(4-aminopiperidine-4-carboxylic acid)]-OH.

[0091] In one specific embodiment, Xaa1selected from D-Phe, D-(4-F)Phe, D-(2-F)Phe, cyclopentyl D-Ala, 2-thienyl D-Ala, XAA2selected from D-(4-F)Phe, D-(4-Cl)Phe, D-1Nal, D-2Nal or D-Trp and XAA3-Haa4selected from D-Nle-D-Arg and D-Leu-D-Orn.

[0092] In another embodiment, W is an N-CNS linker of the formula-N-(CH2)with-O-. In one aspect, C is 1 or 2. In an alternative embodiment, W is equal to 0, and XAA1XAA2XAA3XAA4directly attached to y In the second alternative embodiment, W represents N-alkyl linker of the formula-NH-(CH2)2-.

[0093] In another specific embodiment, Y -, and Z-containing ring fragment is a 4 - or 5-membered ring, and Y represents a nitrogen atom. Alternatively, Y -, and Z-containing ring fragment may represent a 4 - or 5-membered ring, where Y represents a carbon atom. In another embodiment, Y -, and Z-containing ring fragment is a 6-or 7-membered ring, Y represents a nitrogen atom, and Z, not only is em a carbon atom. In one aspect of this variant, Y -, and Z-containing ring fragment represents a 6-membered ring. Alternatively, Y -, and Z-containing ring fragment can be a 7-membered ring. In one aspect of this variant, Y -, and Z-containing ring fragment is a 6 - or 7-membered ring, and both Y and Z represent nitrogen atoms. Alternatively, Y -, and Z-containing ring fragment may represent a 6-membered ring. In another alternative embodiment, Y -, and Z-containing ring fragment is a 7-membered ring.

[0094] In another specific embodiment, Y -, and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a carbon atom, and Z represents a nitrogen atom. In one aspect of this variant, Y -, and Z-containing ring fragment represents a 6-membered ring. Alternatively, Y -, and Z-containing ring fragment can be a 7 - or 8-membered ring. In one aspect, Y is a nitrogen atom, and Z represents a carbon atom. In one alternative embodiment, each of Y and Z represents a nitrogen atom.

[0095] In another particular embodiment, Y -, and Z-containing ring fragment is an optionally substituted 4-8 membered heterocyclic ring fragment, where Y is an atom ug is erode or nitrogen atom, and Z represents carbon, nitrogen, oxygen, sulfur, sulfoxide or sulfonyl; and 4-8-membered heterocyclic ring fragment optionally contains 1 or 2 substituent, independently selected from C1-C6of alkyl, -C1-C6alkoxy, oxo, -OH, -Cl, -F, -NH2, -NO2, -CN, -COOH and amidino. In one aspect, if the Y - and Z-containing ring fragment is a 6, 7 or 8-membered ring, Y and Z are separated by at least two atoms of the ring. In another aspect, if the Y - and Z-containing ring fragment is not aromatic, and Z represents a carbon atom or a nitrogen atom, then this ring fragment contains at least one heteroatom sulfur or oxygen within the ring. In a particular aspect, if the Y - and Z-containing ring fragment is aromatic, then Y is a carbon atom.

[0096] In one embodiment, the synthetic peptide amides of the invention, R1represents-H, -OH, -NH2, -COOH, C1-C3alkyl, amidino, C1-C3alkyl substituted amidino, dihydroimidazole, D-Pro, D-Pro-amide or-CONH2. In another specific embodiment, R2represents an alkyl-H, -COOH or C1-C3. In one aspect, only one of R1and R2represents a hydrogen atom. In a specific embodiment, R1represents-H, D-Pro, D-Pro-amide or-NH2and R represents H or-COOH. In one aspect of this variant, R1represents-NH2and R2represents-COOH.

[0097] In one embodiment, e is 0, and R1and R2attached directly to the same atom of the ring. In a specific embodiment, e is 0, R2represents-H, and R1attached directly to a carbon atom of the ring adjacent to Z. In another specific embodiment, R1represents-H, amidino, C1-C3alkyl, substituted amidino, C1-C3alkyl, dihydroimidazole, D-Pro, D-Pro-amide or-CONH2and e is O, and R2represents-N.

[0098] In one embodiment, the synthetic peptide amides of the invention, Xaa1represents D-Phe, XAA2represents D-Phe, XAA3represents the D-Leu, XAA4is a δ-(B)2D-Orn, where () represents-H, methyl or isopropyl; so that if W is equal to 0, Y - and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a nitrogen atom, e is 0, R1represents-NH2, amidino, C1-C3alkyl, C1-C3alkyl substituted amidino, dihydroimidazole, D-Pro or D-Pro-amides, and R2represents H or-COOH.

[0099] In one specific embodiment, G is one of the following:

and.

[00100] a Variety of assays can be used to validate the presence of the synthetic peptide amides of the invention have high affinity and selectivity in relation to the Kappa-opiate receptor, the duration of biological activity in vivo and the absence of side effects on the Central nervous system. Analyses using receptor well known in the prior art, and cloned Kappa-opiate receptors in several species, for example, mu - and Delta-opiate receptors. Kappa-opiate receptors, as well as mu - and Delta-opiate receptors are classic, seven transmembrane-covering associated with G protein receptors. Although these cloned receptors make it easy to host a screening connection-specific candidate, for example, peptide or derivative peptide, natural sources of opiate recuperability also suitable for screening, as is well known from the prior art (Dooley CT et al. Selective ligands for the mu, delta, and kappa opioid receptors identified from a single mixture based tetrapeptide positional scanning combinatorial library. J. Biol. Chem. 273:18848-56, 1998). Thus, screening both in terms of Kappa-and mu-opioid receptors, recombinant or natural origin, can be performed to determine the selectivity of the synthetic peptide amides of the invention in relation to the Kappa-opiate receptors compared to mu.

[00101] In a particular embodiment, the synthetic peptide amides of the invention are selective agonists of the Kappa opioid receptor. The activity of the synthetic peptide amides of the invention as agonists of specific receptor can be measured as the concentration which achieves a half-maximal effect, expressed as the value EC50. The activity of the synthetic peptide amides of the invention as agonists of the Kappa-opiate receptor, expressed as a percentage of the maximum effect that can be monitored can be determined in a variety of ways well known in the prior art. See, for example, Endoh T, et al., 1999, Potent Antinociceptive Effects of TRK-820, a Novel K-Opioid Receptor Agonist, Life Sci. 65 (16) 1685-94; and Kumar V et al., Synthesis and Evaluation of Novel Peripherally Restricted K-Opioid Receptor Agonists, 2005 Bioorg Med. Chem Letts 15:1091-1095.

[00102] Examples of such methods of analysis to determine the values of the deposits of Esau below. Many standard methods of analysis for characteristics of opiate ligands are well known to the person skilled in the art. See, for example, Waldhoer et al., (2004) Ann. Rev. Biochem. 73: 953-990, and Satoh & Minami (1995) Pharmac. Ther. 68(3):343-364 and cited in this description of the link.

[00103] In certain specific embodiments, the synthetic peptide amides of the invention are agonists of the Kappa-opioid receptor with EC50less than about 500 nm. In other embodiments, the synthetic peptide amides as agonists of the Kappa-opioid receptors exhibit EC50less than approximately 100 nm. In other embodiments, the synthetic peptide amides as agonists of the Kappa-opioid receptors exhibit EC50less than approximately 10 nm. In particular embodiments, the synthetic peptide amides of the invention as agonists of the Kappa-opioid receptors exhibit EC50less than about 1.0 nm, less than about 0.1 nm or less than about 0.1 nm or even less than about 0.01 nm. Compounds in accordance with the above option may exhibit EC50at least 10 times more for mu - and Delta-opiate receptor than for the Kappa-opiate receptor, preferably at least 100 times greater, and most preferably at least 1000 times greater, for example, EC50less than approximately 1 nm on the I Kappa-opiate receptor, and EC50more about 1000 nm for the mu-opiate receptor and Delta-opioid receptors.

[00104] In specific embodiments, the synthetic peptide amides of the invention vysokoselektivnye against Kappa compared to mu-opioid receptors. In certain embodiments, the synthetic peptide amides of the invention demonstrate the value EC50for mu-opioid receptor of at least 100 times higher than the corresponding values EC50for the Kappa-opiate receptor. In particular embodiments, the synthetic peptide amides of the invention demonstrate the value EC50for the mu-opiate receptor at least 1000 times higher than the corresponding values EC50for the Kappa-opiate receptor. Alternatively, the selectivity of the synthetic peptide amides of the invention can be expressed as a higher value EC50for mu-opioid receptor compared to the Kappa-opiate receptor. Thus, in specific embodiments, the synthetic peptide amides of the invention demonstrate the value EC50more than approximately 10 microns for the mu-opiate receptor, and values of the EU50less than approximately 10 nm, and in other embodiments less than about 1.0 nm or even less than about 0.01 nm for the Kappa-opiate receptor. In another embodiment, a specific synthetic peptide is haunted amides may exhibit EC 50less than about 1 nm for the Kappa-opiate receptor, and EC50more about 1000 nm for the mu-opiate receptor, or Delta-opioid receptors.

[00105] Another property of the synthetic peptide amides of the invention is their characteristic property is a low degree of inhibition of isozymes of cytochrome P450. Isoenzymes of cytochrome P450constitute a large superfamily of heme-tiletnij proteins responsible for metabolic oxidative inactivation of many therapeutic and other biologically active compounds. Usually, they act as a terminal oxidase in multi-component circuits of electron transfer, which are also known as cytochrome P450-containing monooxygenase systems.

[00106] Over 50 different isoenzymes of cytochrome P450identified and classified into families, grouped according to genetic relatedness, which is estimated by the homology of the sequences of nucleic acids. Of the isoenzymes of the cytochrome P450in human cells, the most common isoenzymes 1A2 and 3A4, although isoenzymes V, 2S9, 2C19, 2D6 and 2E1 also contribute to oxidative inactivation entered therapeutics. Although inhibition of isozymes of cytochrome P450it may be useful from the viewpoint of elongation lie is no after administration in vivo, in the course of which supported the effective concentration of the synthetic peptide amides of the invention, this effect also extends the presence of any simultaneously introduced therapeutic compound that undergoes oxidation under the action of the cytochrome P450. This increase of the period of presence may cause the presence of simultaneously introduced a therapeutic agent after the optimal treatment period or may exceed desirable levels or safe concentration levels in vivo. This lengthening of the presence and/or concentration increase is difficult to accurately quantify and preferably avoid them. Therapeutic agents, which show little or no inhibition of the activity of the isoenzymes of the cytochrome P450do not carry the potential for this problem and can safely be administered concomitantly with other therapies without the risk of impact on the rate of inactivation of therapeutic compound that is introduced at the same time, under the influence of isoenzymes of cytochrome P450.

[00107] Particular variants of the synthetic peptide amides of the invention exhibit a low degree of inhibition of isozymes of cytochrome P450at therapeutic concentrations of the synthetic peptide amides, while the AK other largely not demonstrate inhibition of isozymes of cytochrome P 450at therapeutic concentrations. In some embodiments, the synthetic peptide amides at a concentration of 10 µm demonstrate inhibition of isozymes of cytochrome P450CYP1A2, CYP2C9, CYP2C19 or CYP2D6 less than approximately 50%. In particular embodiments, the synthetic peptide amides at a concentration of 10 µm demonstrate any inhibition of these isoenzymes of cytochrome P450less than approximately 20%. In some embodiments, the synthetic peptide amides at a concentration of 10 µm demonstrate any inhibition of these isoenzymes of cytochrome P450less than approximately 10%.

[00108] In another embodiment, the synthetic peptide amides of the invention in an effective concentration show no more than about 50% inhibition of any of the P450 CYP1A2, CYP2C9, CYP2C19 or CYP2D6 synthetic inorganic salts in a concentration of 10 μm after incubation for 60 minutes with human liver microsomes.

[00109] the Synthetic peptide amides of the invention in the introduction, the mammal or patient person in a therapeutically effective concentration demonstrate low or essentially no penetration through the blood-brain barrier. Kappa-opiate receptors (hereinafter equivalent called Kappa receptors) are distributed in peripheral tissues, including the skin and catfish is critical tissues, as well as in the internal organs of humans and other mammals. The Kappa receptors are also found in the brain. Activation of Kappa receptors in peripheral tissues causes pain suppression and inflammatory reactions, whereas activation of Kappa receptors in the brain causes a sedative effect, and possibly also leads to severe dysphoria and hallucinations. In certain embodiments, the synthetic peptide amides of the invention, with the introduction of therapeutically effective concentrations demonstrate low or essentially no penetration through the blood-brain barrier and, thus, minimize or even completely free of sedative, hallucinogenic effect many other Kappa agonists that exhibit some degree of penetration through the blood-brain barrier.

[00110] One suitable indicators of the extent to which the synthetic peptide amides of the invention penetrate the blood-brain barrier, represents the ratio of peak plasma concentration and the concentration in the brain tissue. In particular embodiments, the synthetic peptide amides of the invention, when introduced in a dose of approximately 3 mg/kg, demonstrate at least 5-fold lower concentration of synthetic peptide amides in the brain compared with the plasma at the time when the and achieves peak plasma concentration.

[00111] Another suitable indicator of the extent to which the synthetic peptide amides of the invention penetrate the blood-brain barrier, represents the ratio of the dose required to achieve a sedative effect, and the dose needed to achieve an analgesic effect. Analgesic and sedative effects of stimulation of Kappa receptor agonists of the Kappa receptor can be measured using standard assays, well known specialist in this field.

[00112] In specific embodiments, the synthetic peptide amides of the invention demonstrate the ED50for sedative effect at least about 10 times the ED50for analgesic effect. In particular embodiments, the synthetic peptide amides of the invention demonstrate the ED50for sedative effect at least about 30 times the ED50for analgesic effect. In other embodiments, the synthetic peptide amides of the invention demonstrate the ED50for sedative effect at least about 50 times the ED50for analgesic effect.

[00113] In another embodiment, the synthetic peptide amides of the invention demonstrate the ED50for sedative effect on the model reduction of movements in mice at least approximately 10 times more EDsub> 50synthetic peptide amides for analgesic effect on the models of writhing in mice.

[00114] Other suitable prognostic factor expected degree of penetration of the synthetic peptide amides of the invention through the blood-brain barrier, is provided by the values of the membrane permeability of the synthetic peptide amides in the cell or another cell of a mammal, with the introduction of therapeutically adequate concentration. In certain embodiments, the synthetic peptide amides of the invention demonstrate in therapeutically adequate concentrations of low or essentially no ability to penetrate the monolayer appropriately cultured cells of human or other mammals. This parameter permeability can be expressed as apparent permeability, Pappthat is the specific permeability of the monolayer of cells for the target compounds. Any suitable for the cultivation of a monolayer of mammalian cells can be used to determine the permeability for specific target compounds, although for this purpose are often used certain cell lines. For example, the cell line Caco-2 is an adenocarcinoma of the colon and rectum of the person, which can be used as a model system is we culture monolayer to determine the membrane permeability for compounds according to the invention. In certain embodiments, the synthetic peptide amides of the invention exhibit Pappless than approximately 10-6cm/sec. In some other embodiments, the synthetic peptide amides of the invention exhibit Pappless than approximately 10-7cm/sec.

[00115] In one embodiment, the synthetic peptide amides of the invention at a dose of approximately 3 mg/kg in rats reach peak plasma concentrations of the synthetic peptide amide, and shows at least 5 times lower concentrations in the brain than the peak concentration in plasma.

[00116] In another embodiment, the synthetic peptide amides of the invention exhibit at least about 50% of maximum effectiveness after approximately 3 hours after a dose of approximately 3 mg/kg of the synthetic peptide amide in rats.

[00117] In one embodiment, the synthetic peptide amides of the invention demonstrate a lasting effect in a mammal, e.g. humans. In one aspect, the synthetic peptide amides demonstrate the duration of action at the level of at least approximately 50% of maximum effectiveness after 3 hours after administration of 0.1 mg/kg of the synthetic peptide amide. In another aspect, the synthetic peptide amides demonstrate the duration of action is and the level of at least about 75% of maximum effectiveness after 3 hours after administration of 0.1 mg/kg of the synthetic peptide amide. In a particular aspect, the synthetic peptide amides demonstrate the duration of action at the level of at least approximately 90% maximum efficiency through 3 hours after administration of 0.1 mg/kg of the synthetic peptide amide. In a particular aspect, the synthetic peptide amides show a duration of at least approximately 95% maximum efficiency through 3 hours after administration of 0.1 mg/kg of the synthetic peptide amide.

[00118] In another embodiment, the invention features a pharmaceutical composition that contains synthetic peptide amides in accordance with any of the above options and a pharmaceutically acceptable excipient or carrier. The invention provides methods, compositions or dosage forms which are used and/or contain synthetic peptide amides of the invention are selective in relation to the Kappa-opiate receptors. In particular embodiments, the synthetic peptide amides of the invention show a pronounced affinity to the Kappa-opiate receptors and have a high activity as agonists of the Kappa opioid receptor.

[00119] the Prodrug compounds, such as synthetic peptide amides of the invention includes pharmaceutically acceptable derivatives, which, if can pre order to romatsa, through metabolism or other process in a biologically active form of connection. Prodrugs especially desirable if the Prodrug has more favorable properties than the active connection, from the point of view of bioavailability, stability or fitness for a particular recipe.

[00120] In this description, associated with the Kappa-opiate receptor disease, condition or disorder is any disease, condition or disorder that is preventable or treatable by the activation of Kappa-opioid receptors. In one aspect, the synthetic peptide amides of the invention are agonists of the Kappa-opioid receptors that activate the Kappa-opiate receptor. In some embodiments, the specific dose and route of administration of the synthetic peptide amides of the invention can be selected by the Clinician, therefore, in order to completely prevent or cure a disease, condition or disorder. In other embodiments, the specific dose and route of administration of the synthetic peptide amides of the invention, selected by the Clinician, alleviate or reduce the severity of one or more symptoms of the disease, condition or disorder.

[00121] In this description, an "effective amount" or "sufficient amount" of the synthetic peptide amides of p the invention indicates the number of connections, as described herein, which may be therapeutically effective from the viewpoint of suppression to prevent or treat symptoms of a particular disease, disorder, condition, or side effect. In this description of "reduced dose" of analgesic mu-opioid agonist refers to a dose that, when introduced in combination with the Kappa-opioid agonist, such as the synthetic peptide amides of the invention, will be lower than usually offer a specific patient, in order to reduce the severity of one or more side effects connection. Dose reduction may be selected so that the reduction of the analgesic or other therapeutic effect of the compound represented an acceptable compromise given to reduce the side effect(s), where the reduction of degree of analgesic or other therapeutic effect of analgesic mu-opioid agonist fully or at least partially compensated analgesic or other therapeutic effect of the synthetic peptide amide according to the invention. Co-administration of analgesic mu-opioid agonist with a synthetic peptide amidon according to the invention, which acts as a Kappa-opioid agonist, also allows the introduction of a reduced dose of the synthetic peptide amide and/or analgesic mu-opiate the agonist to achieve the same therapeutic effect, as with the introduction of higher doses of the synthetic peptide amide or analgesic mu-opioid agonist, in monotherapy.

[00122] In this description, "pharmaceutically acceptable" refers to compounds, materials, compositions and/or dosage forms which are, within the medical judgment, suitable for contact with the tissues of human beings and animals without the expressed, irritation, allergic reactions or other complications is proportional to the ratio of benefit/risk, which is reasonable for a medical condition to be treated.

[00123] In this description, a "unit dosage forms" refers to physically discrete unit suitable as a single dose for a particular individual or condition to be treated. Each unit may contain a predetermined quantity of compound(s) active synthetic peptide amide, designed to provide the desired therapeutic effect(s), optionally in combination with a pharmaceutical carrier. The specification for the dosage forms may be based upon (a) the unique characteristics of the active compound or compounds and the particular therapeutic effect to be achieved, and (b) the limitations inherent in this obliterator such active compound or compounds. Unit dose is often expressed as the mass of compound per unit of body weight, for example, in milligrams of compound per kilogram of body weight of the subject or patient (mg/kg). Alternatively, the dose can be expressed as the number of connections per unit body weight per unit time (mg/kg/day) in a particular treatment regimen. As another alternative, the dose can be expressed as the number of connections per unit area of a body surface (mg/m2) or per unit area of body surface per unit time (mg/m2/day). For local products, doses may be expressed in a manner customary for such preparations, for example, tape, ointments length of ½ inch, is introduced into the eye, where the concentration of compounds in the drug is expressed as a percentage of the recipe.

[00124] In this description, "pharmaceutically acceptable salts" refer to derivatives of compounds, where the original connection change through education of its salts with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of basic residues such as amines with mineral or organic acids; salts of acidic residues such as carboxylic acids and the like, alkali or organic compounds. Pharmaceutically acceptable salts include conventional non-toxic salts or the Quaternary ammonium salts and the parent compound, is broken off, for example, non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric acid, nitric acid and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, Panova, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova acid, etc. Such physiologically acceptable salts receiving means, known from the prior art, for example, by dissolving the free amine bases with excess acid in aqueous alcohol or neutralization of the free carboxylic acid by a base of an alkali metal, such as hydroxide, or an amine. Thus, the pharmaceutically acceptable salt of the synthetic peptide amides may be formed by any such peptide amidon containing acidic, basic, or both functional groups. For example, peptide amides containing a carboxylic acid group, can in the presence of a pharmaceutically suitable base to form the carboxylate anion, Conn is nausica with a cation, such as the cation is sodium or potassium. Similarly, peptide amides containing functional amino group, can in the presence of a pharmaceutically suitable acid, such as HCl, to form a salt.

[00125] One example of a pharmaceutically acceptable MES synthetic peptide amides is a combination of peptide amides with solvent molecules, which gives a range of solvent molecules in combination with peptide inorganic salts. Especially suitable hydrates of such compounds are the hydrates, which have comparable activity, or hydrates, which are converted back to the active compound after administration. Pharmaceutically acceptable N-oxide synthetic peptide amide that contains amine represents a connection, where the amine nitrogen atom attached to the oxygen atom.

[00126] the Pharmaceutically acceptable crystalline isomorphic crystalline or amorphous form of a synthetic peptide amide according to the invention may be any crystalline or non-crystalline form pharmaceutically acceptable acid, basic, zitter-ionic, salt, hydrate or any other suitably resistant, physiologically compatible form of synthetic peptide amide according to the invention.

[00127] the Synthetic peptide amides of the briteney can be entered in the pharmaceutical composition. The composition can contain an effective amount of a synthetic peptide amide in a pharmaceutically acceptable diluent, auxiliary substance or medium. Conventional excipients, carriers and/or diluents for use in the pharmaceutical compositions generally inert and constitute a large part of the drug.

[00128] In a particular embodiment, the synthetic peptide amide is an agonist at the Kappa-opiate receptor. In another embodiment, the synthetic peptide amide is a selective agonist of the Kappa-opiate receptor. Website-the target can be a Kappa receptor in a patient or subject in need of such treatment or prevention. Certain agonists of the Kappa-opiate receptor synthetic peptide amides of the invention are perifericheskie and demonstrate low-grade or no effect on the Central nervous system in therapeutically effective doses.

[00129] a Pharmaceutical excipient or carrier may be any suitable compatible, non-toxic substance, such as a carrier for the delivery of the synthetic peptide amide according to the invention. Suitable excipients or carriers include, but are not limited to, sterile water (preferably pyrogen-free), saline, phosphate buffered saline (FOSFA the private buffer solution), water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone (PVP), citric acid, tartaric acid, oil, lipid substances, waxes, or any suitable mixture of the above components.

[00130] the Pharmaceutical preparation according to the invention can be a liquid, semisolid or solid dosage form. For example, the pharmaceutical preparation can be in the form of solution for injection, drops, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointment, cream, lotion, gel, emulsion, spray or granular form, for example, pills or granules, optionally, compressed into tablets or lozenges that are placed in capsules or suspended in a liquid. Tablets may also contain binders, lubricants, diluents, colorants, flavoring agents, moisturizing agents, and can be coated with the enteric-soluble shell to pass intact through the acidic environment of the stomach and dissolve in the more alkaline conditions of the intestinal lumen. Alternatively, tablets can be coated by the sugar-coated or film-coated water soluble film. Pharmaceutically who ielemia adjuvants, buffer agents, dispersing agents, etc. may also be included in pharmaceutical compositions.

[00131] Binders include, for example, starch, mucilage, gelatin and sucrose. Lubricants include talc, Likopodija, magnesium and calcium stearate/stearic acid. Diluents include lactose, sucrose, mannitol, salt, starch and kaolin. Moisturizing agents include propylene glycol and sorbitan.

[00132] In this description, the application or introduction means introducing a pharmaceutical preparation according to the invention in the area, such inflamed joint, which demonstrates painful and/or inflamed condition. Such local introduction includes intra-articular, for example, intra-articular application, by injection, introduction through the catheter or delivery in the composition of the biocompatible device. Thus, the local introduction means introducing discrete internal region of the body, such as the joint, the area of soft tissue (e.g. muscle, tendon, ligament, intraocular or other interior area of soft tissue or other internal part of the body. In particular, in this description of the local introduction refers to the introduction, which does not lead to a significant extent to the system introduction and/or systemic delivery of active agents in the present compositions. Also, in this described the local introduction is intended to outline introduction to discrete areas of the body, in addition to various major body cavities (e.g., abdominal and/or chest cavity).

[00133] In this description, the drawing means drawing on the surface of the body, such as skin, eye, mucous membrane and lips, which can be located in or on any part of the body, including, but not limited to, epidermis, or any other layer of the skin or any other tissue of the body. Local introduction or application involves direct contact of the pharmaceutical preparation according to the invention with the tissue, such as skin or membrane, especially the cornea, or mucous membrane of the mouth, vagina or rectal area. Thus, for the purposes of this description local application refers to the application of tissue accessible surface of the body, such as skin (outer shell or surface) and the mucosa (producing, allocating and/or containing mucus surface). In particular, local application means the application, which does not imply or substantially does not involve systemic delivery of active compounds in these compositions. Examples of mucosal surfaces include the surface of the mucous membranes of the eyes, the mouth (e.g., lips, tongue, gums, cheeks, sublingual area and sky), larynx, esophagus, bronchi, trachea, nasal passages, vagina and rectum/anus.

[00134] In SL the tea oral administration, the active ingredient can be administered in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. Active ingredient(s) can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharinate, talc, magnesium carbonate, etc. are Examples of additional inactive ingredients, which can be added to provide desirable color, flavor, stability, buffering capacity, dispersion or other known desirable characteristics - red ferric oxide, silica gel, sodium lauryl sulphate, titanium dioxide, edible white ink, etc. Such fillers may be used to obtain CT. As tablets and capsules can be manufactured in the form of products with slow release, to ensure a continuous release of a therapeutic agent for hours. Molded tablets may be coated with sugar or film-coated to mask the unpleasant taste and protect the tablet from exposure to the atmosphere, or enteric-soluble envelope DL the selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring agents to improve the tolerability of the patient. To improve the stability and absorption of drugs, peptides according to the invention can be released from the capsules after passing through hard proteolytic environment of the stomach. Ways to improve the stability and absorption of peptides after oral administration are well known in the prior art (for example, Mahato RI. Emerging trends in oral delivery of peptide and protein drugs. Critical Reviews in Therapeutic Drug Carrier Systems. 20: 153-214, 2003).

[00135] Such dosage forms as tablets, chewable tablets and chewing gum to provide a rapid therapeutic effect in comparison with the dosage forms of the compounds of the synthetic peptide amides of the invention for oral administration, demonstrating significant buccal absorption. Preparations in the form of chewing gum are solid, single-dose preparations with a basis consisting mainly of rubber, which are designed for chewing, but not intended for swallowing, and contain one or more compounds according to the invention, which are released during chewing and are intended for local treatment of pain and inflammation in the mouth or systemic delivery after absorption through the buccal were slit the out shell. See, for example, U.S. patent 6,322,828 issued Athanikar and after Gubler, entitled "method for the production of pharmaceutical chewing gum".

[00136] For nasal administration, selective agonists of the Kappa-opiate receptor peripheral actions can be introduced into the aerosol. The term "aerosol" includes any suspended in gas phase compounds of the present invention, which can be inhaled into the bronchioles or nasal passages. Specifically, aerosol includes a suspension in a gaseous phase droplets of the compounds of the present invention, which can be produced dosing inhaler or nebulizer or atomized spray. Aerosol also includes a dry powder composition of the compounds of the present invention, suspended in air or another gas-carrier, which may be introduced by injection of the inhalator device, for example, see Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6: 273-313; and Raeburn et al. (1992) J. Pharmacol. Toxicol. Methods 27:143-159.

[00137] the Pharmaceutical compositions of the invention can be prepared in a form suitable for systemic administration, for example, intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, transdermal, intravaginal, rectal, intra-lungs, or oral administration. Al is ernative, the pharmaceutical compositions according to the invention can be suitable for local administration, for example, for local or informationstore injection or transdermal injection with the assistance of plaster, coated or impregnated with a drug, and local injection in the joint, for example, intra-articular injection.

[00138] Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, ready for dilution with solvent immediately before use, including tablets for subcutaneous injection, sterile suspensions ready for injection, sterile dry insoluble products ready for dilution with solvent immediately before use, and sterile emulsion. The solutions may be aqueous or nonaqueous, and, thus, are intended to be introduced by injection, infusion or with the use of implantable pumps. For intravenous, subcutaneous and intramuscular injection of suitable preparations according to the invention include drugs of microcapsules with properties controlled release (R.Pwar et al. Protein and peptide parenteral controlled delivery. Expert Opin Biol Ther. 4(8): 1203-12, 2004) or by encapsulation in liposomes, for example, polyethylene coated liposomes, which are known from the prior art as providing an elongated period of stay in the AOC is the Otok (for example, Koppal, T. "Drug delivery technologies are right on target". Drug Discov. Dev.6, 49-50, 2003).

[00139] For introduction into the eye, the present invention provides a method of treating glaucoma or pain and inflammation of the eye, including an introduction to the eyes of the patient in need of such treatment, a therapeutically effective amount of the synthetic peptide amides of the invention. Synthetic peptide amides can be applied topically acceptable to the eye a pharmaceutical carrier or in the form of a non-system application in the form of contact lenses or intraocular implant, which may optionally contain polymers, which provide a prolonged release of synthetic peptide amides. Such acceptable to the eye pharmaceutical carriers can include adjuvants, antimicrobial preservatives, surfactants, agents for increasing the viscosity, etc. Of the prior art it is known that high concentrations of many compounds can irritate the eyes, and low concentrations have less irritant effect; therefore, the drug is often designed in such a way as to enable the lowest effective concentration of active compounds, preservative, surface-active substance and/or agent for increasing the viscosity of the specified agent for increasing the viscosity of preferably has a high surface tension, that is to reduce eye irritation with increasing retention of ophthalmic solutions on the surface of the eye. Such controlled release of the synthetic peptide amides of the invention may continue for implants from 6 months to a year, or for shorter periods (3-14 days) for contact lenses. Such implants can be an osmotic pumps, biodegradable matrix or intraocular device extended release. Such compositions for topical application may include a buffered salt solution containing or not containing liposomes.

[00140] the Aqueous polymer solutions, aqueous suspensions, ointments and gels can be used for preparations of synthetic peptide amides of the invention intended for topical use in the eye. Aqueous preparations can also contain liposomes to create a reservoir of synthetic peptide amides. Some of these local products are gels that increase the retention of the cornea without discomfort and vision problems associated with ointments. Compatible with eye pharmaceutical carrier may also include biodegradable synthetic polymer. Biodegradable compositions of microspheres that are registered for use in humans include polylactide: poly (lactic acid), poly(glycolic acid) and poly(Molo is s-coglycolide) acid. Additional biodegradable drugs include, but are not limited to: poly (anhydride-co-imide), poly(lactic glycolic acid), polyethylene-2-cyanoacrylate, polycaprolacton, polyhydroxybutyrate valerate, polychaetes and polyethylene oxide/polybutylene terephthalate. The intraocular implant or injection compositions with slow release, which contain synthetic peptide amides of the invention can provide long-term control (varies from months to years) intraocular pressure and, thus, to eliminate or reduce the need for topical drugs. Suitable methods of introducing drugs and dispensing of ophthalmic dosage forms are disclosed in U.S. Patent 7,122,579 issued by Schwartz and others, and in U.S. patent 7,105,512 issued Morizono and other routes of administration ophthalmic dosage forms in the contact lenses are disclosed in Gulsen and Chauhan, Ophthalmic drug delivery through contact lenses. Investigative Ophthalmology and Visual Science, (2004) 45: 2342-2347.

[00141] Drugs for transdermal injection is injected into the device suitable for such an introduction, where the specified device is used, for example, iontophoresis (Kalia YN et al. lontophoretic Drug Delivery. Adv Drug Deliv Rev. 56:619-58, 2004) or surface that penetrate the dermis (Prausnitz MR. The microneedles for Transdermal Drug Delivery. Adv Drug Deliv Rev. 56:581-7, 2004), such as known from the prior art, which are suitable for improving transdermal the second drug delivery. The device elektroprenos and methods of its use are disclosed in U.S. patent 6,718,201. Applications of iontophoresis to facilitate transdermal delivery of peptides disclosed in U.S. patent 6,313,092 and U.S. patent 6,743,432.

[00142] In this description, the terms "elektroprenos", "iontophoresis" and "ionophoretically" refers to the introduction (shipping) through the surface of the body (e.g. skin or mucosa) one or more pharmaceutically active compounds by the application of electromotive force to the reservoir containing the agent. The connection can be delivered by electromigration, by electroporation, electroosmosis, or any combination thereof. Electroosmosis is called electrohydrogenesis, electroconvective and electrically induced osmosis. In General, the electroosmosis compounds in the tissue is the result of migration of the solvent, which contains the connection in the application of electromotive force to the reservoir of therapeutic compounds, for example, the flow of solvent-induced electromigration of other ions. In the process of elektroprenos may occur with certain modifications or changes in the skin, such as the formation of transient pores in the skin, which is also known as "electroporation". Any carrier substances using electricity, reinforced modifications, or change surface the human body (for example, the formation of pores in the skin), also covered by the term "elektroprenos" in this description. Thus, in this description, with reference to the compounds of the present invention, the terms "elektroprenos", "iontophoresis" and "ionophoretically" refers to (1) the delivery of charged agents by electromigration, (2) the delivery of uncharged agents in the process of electroosmosis, (3) the delivery of charged or uncharged agents by electroporation, (4) the delivery of charged agents combined processes of electromigration and electroosmosis, and/or (5) delivery of a mixture of charged and uncharged agents combined processes of electromigration and electroosmosis. In devices of elektroprenos in General, there are two electrodes, both of which are placed in close electrical contact with some part of the skin. One electrode, called the active or donor electrode, is the electrode from which therapeutic agent is delivered into the body. The other electrode, which is called the counter or return electrode, serves to close the electrical circuit through the body. In connection with the patient's skin, the loop is closed by connecting the electrodes to a source of electrical energy such as a battery, and usually to the circuit is able to control the current passing through the device.

[00143] depending on e is tricesimo charge connection for transdermal delivery, the anode or the cathode can be an active or donor electrode. Thus, if the connection that is subject to migration is positively charged, for example, the connection is shown as an example in Example 1 of this specification, the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the return electrode, completing the circuit. However, if the connection for the delivery of negatively charged, the cathode electrode is the active electrode and the anode electrode is a return electrode. Device elektroprenos additionally require a reservoir or source of therapeutic agent to be delivered into the body. These reservoirs medicines connected with the anode or cathode of the device elektroprenos to provide a fixed or renewable source of one or more desired substances or agents. Each electrode unit consists of an electrically conductive electrode associated with the ion conducting with conductive ions of the liquid reservoir in the application placed in such a way as to contact the skin of the patient. Tanks gel, such as described by Webster (U.S. patent 4,383,529) represent one of the shape of the tank, because the hydrated gels are easier to handle and manufacture, than anannya liquid containers. Water is one of liquid solvents that can be used in such tanks, partly because salt of the peptide compounds according to the invention is water soluble, and partly because the water does not irritate the skin, thus allowing prolonged contact between the hydrogel reservoir and the skin. For elektroprenos, synthetic peptides according to the invention can be introduced into the product to enhance the fluidity of substances, such as ionic surfactants or co-solvents other than water (see, for example, U.S. patent 4,722,726 and European patent application 278,473, respectively). Alternatively, the outer layer of skin (i.e., stratum corneum) can be mechanically destroyed before the introduction of elektroprenos through the skin, for example as described in U.S. patent 5,250,023.

[00144] the Synthetic peptide amides of the peripheral actions, which are well suited for elektroprenos, can be selected by measuring their current process elektroprenos through the surface of the body (e.g. skin or mucosa), for example, compared with a standardized test peptide with known characteristics current elektroprenos, for example, tireotropin-releasing hormone (R. Burnette et al. J. Pharm. Sci. (1986) 75:738) or vasopressin (Nair et al. Pharmacol Res. 48: 175-82, 2003). Transdermal current elektroprenos can be determined with the use of the eat a number of ways in vivo or in vitro, well known from the prior art. In vitro methods include clamping the piece of leather of suitable mammal (e.g. human cadaver skin) between the donor and receptor compartment of the cell flow elektroprenos, where the side of the stratum corneum slice of the skin facing the donor compartment. A liquid solution or gel containing the drug to be delivered, placed in contact with the stratum corneum, and the electric current fed to the electrodes, one electrode in each compartment. Transdermal current is calculated by taking the samples for the quantitative determination of the drug in the receptor compartment. Two successful models used to optimize transdermal delivery of drugs by elektroprenos, the model of the isolated sample of pig skin (Heit MC et al. The Transdermal iontophoretic peptide delivery: in vitro and in vivo studies with luteinizing hormone releasing hormone. J. Pharm. Sci. 82: 240-243, 1993), and the use of isolated hairless skin hairless rodents or Guinea pigs, for example, see Hadzija BW et al. Effect of freezing on iontophoretic transport through hairless rat skin. J. Pharm. Pharmacol. 44, 387-390, 1992. Compounds according to the invention for transdermal ionophoretically delivery can contain one or usually two charged nitrogen atom, to facilitate shipping.

[00145] In other suitable transdermal delivery devices use delivery with high speed under pressure is m, in order to achieve penetration of the skin without the use of needles. Transdermal delivery can be improved, as is known from the prior art, the use of chemical enhancers, which in this area is sometimes referred to as "penetration enhancers", i.e, compounds that are administered along with the drug (or in some cases used to pre-treat the skin, before the introduction of the drug) to increase the permeability of the stratum corneum and thus provide increased penetration of drugs through the skin. Chemical penetration enhancers represents compounds that are non-toxic and serve only to facilitate diffusion of the drug through the stratum corneum, by passive diffusion or energy-driven process, such as elektroprenos., for example, Meidan VM et al. Enhanced iontophoretic delivery of buspirone hydrochloride across human skin using chemical enhancers. Int. J. Pharm. 264: 73-83, 2003.

[00146] the Pharmaceutical dosage forms for rectal injection include rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories in this description represent a rigid body for insertion into the rectum, which melt or soften at body temperature, releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically when mimie substance, used in rectal suppositories include bases or carriers and agents that increase the melting point of suppositories. Examples of bases include cocoa butter, glycerin-gelatin, karbowski (polyoxyethyleneglycol) and appropriate mixtures of mono-, di - and triglycerides of fatty acids. A combination of different bases may also be used. Agents that increase the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by extrusion or molding. Mass rectal suppositories is usually from about 2 g to about 3 g Tablets and capsules for rectal injection is manufactured by using the same pharmaceutically acceptable substance(s) and the same methods, as in the case of preparations for oral administration.

[00147] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous media, non-aqueous media, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspendresume and dispersing agents, emulsifiers, airing or chelating agents and other pharmaceutically acceptable substances.

[00148] Examples of the aqueous media include sodium chloride injection, ringer's solution for injection, isotonic dissolve the glucose for injection, sterile water for injection, glucose solution and ringer's solution with lactate for injection. Nonaqueous parenteral carrier includes a non-volatile vegetable oils, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in mnogorazovye containers that include phenols or Cresols, mercury compounds, benzyl alcohol, chlorobutanol, methyl and propyl esters of p-hydroxybenzoic acid, thimerosal, benzalkonium chloride and benzathine chloride. Isotonic agents include sodium chloride and glucose. Buffering agents include phosphate and citrate. Antioxidants include sodium bisulfite. Mestnoanesteziruyuschie tools include procaine hydrochloride. Suspendresume and dispersing agents include sodium carboxymethylcellulose, hypromellose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (tween 80). Airing or chelating agents for metal ions, such as EDTA, may also be introduced. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol to mix with water media, and the pH may be raised to a physiologically compatible values added on the m sodium hydroxide, of hydrochloric acid, citric acid or lactic acid.

[00149] the Active ingredient may be administered in a single dose or can be divided into a number of smaller doses, which are administered at intervals of time or in the form of a drug controlled release. The term "controlled drug release" includes preparations that enable continuous delivery of the synthetic peptide amides of the invention to the subject over a period of time, for example, from a few days to weeks. Such drugs can be administered subcutaneously or intramuscularly and allow continuous continuous continuous release of a predefined number of connections in the body of the subject over a period of time. The preparation of synthetic peptide amide controlled release may constitute, for example, the preparation of a medicinal product containing polymer microcapsules, such as described in U.S. patent No. 4,677,191 and 4,728,721 included in this description by reference. Carry out the correction of the concentration of pharmaceutically active compounds in such a way that the introduction provides an effective amount to provide the desired effect. The exact dose depends on age, weight and condition of the patient or animal as is known in the prior art. For any to whom Kratovo subject, specific regimens can be adjusted after some time according to the individual need and the professional judgment of the person who enters or oversees the administration of drugs. Thus, the intervals of concentration, as defined in the description given for example only and are not intended to limit the scope or practice of the claimed invention.

[00150] the Unit dose of parenteral drug include packaging in vials or filling the syringe with needle or without it, for the introduction. All preparations for parenteral administration are usually sterile, as practiced in this area. For illustration, intravenous infusion of a sterile aqueous buffered solution containing the active compound, is an effective way of introduction. In another embodiment, a sterile aqueous or oily solution or suspension containing the active material, can be introduced by injection, as needed, to provide the desired pharmacological effect.

[00151] the Pharmaceutical compositions according to the invention can be delivered or injected, transdermal, through the mucous membrane, intranasally, subcutaneously, intramuscularly, orally, or topically (e.g., eyes). The composition can be entered for prophylactic treatment of individuals suffering from and at risk of the disease or disorder. For therapeutic applications, the pharmaceutical composition is typically administered to a subject suffering from a disease or disorder, in an amount sufficient to inhibit, prevent or alleviate diseases or disorders. Quantity adequate to ensure such impacts are defined as "therapeutically effective dose."

[00152] the Pharmaceutical compositions according to the invention can be introduced mammal for preventive or therapeutic purposes in the form of any of the above drugs and routes of administration. The mammal can be any mammal, such as a home or an agricultural mammal or even a wild mammal. The mammal can be any Primate, ungulate animal from the family dog or cat. For example, without limitation, a mammal can be a pet such as a dog or cat; valuable mammal, such as a thoroughbred horse or animal exhibit; farm animals such as cow, goat, sheep or pig, or a Primate such as a monkey, gorilla, orangutan, lemur, monkey or chimpanzee. Suitable mammal for the prevention or treatment using the pharmaceutical compositions according to the invention, is the man.

[00153] the Pharmaceutical compositions of p the invention can be introduced mammal, which is the disease or condition treatable by the activation of Kappa-opioid receptors. Alternatively, the pharmaceutical compositions can be entered in the prevention ways to a mammal at risk of acquiring or developing the disease or condition amenable to prevention of the activation of Kappa-opioid receptors. Disease or condition that is amenable to treatment or prevention of the introduction of the pharmaceutical compositions according to the invention, include, but are not limited to, any condition that may be alleviated by activation of Kappa-opioid receptors, including such conditions as pain, inflammation, itching, hyponatremia, hypokalemia, congestive heart failure, liver cirrhosis, nephrotic syndrome, hypertension, edema, intestinal obstruction, cough, and glaucoma.

[00154] In a particular embodiment, the pharmaceutical compositions according to the invention can be administered together or can include one or more other therapeutic compounds or adjuvants, such as, without limitation, other opioids, cannabinoids, antidepressants, anticonvulsants, antipsychotics, antihistamines, acetaminophen, corticosteroids, antagonists of ion channels, non-steroidal anti-inflammatory drugs (N is EAP) and diuretics, many of which act synergistically with synthetic inorganic salts according to the invention.

[00155] Suitable opiates include, but are not limited to, Alfentanil, Alpharadin, Anileridine, bremazocine, buprenorphine, butorphanol, codeine, canarvon, dextromoramide, dextropropoxyphene, dezocine, diamorphine, Dihydrocodeine, dihydromorphine, Diphenoxylate, Dipipanone, doxicillin, ethoheptazine, Etiketten, Ethylmorphine, Etorphine, fentanyl, hydrocodone, hydromorphone, Ketobemidone, levomethadyl, Levorphanol, lofentanil, loperamide, meperidine (pethidine), meptazinol, methadone, morphine, morphine-6-glucuronide, nalbuphine, nalorfin, Nicomorphine, oxycodone, Oxymorphone, pentazocine, phenazocine, Phenoperidine, piritramid, propiram, propoksifen, Remifentanil, Sufentanil, teledat, tonatzin and tramadol.

[00156] in One variant of the invention is a combined drug and/or co-administration with severe opiate agonist activity with respect to the mu-opiate receptor, such as morphine, fentanyl, hydromorphone, or oxycodone, together with a synthetic peptide inorganic salts according to the invention, to reduce the doses of mu-opioid, where the dose of mu-opioid reduce to minimize common side effects of mu-opioids, especially in patients not previously treated opioids. These side effects include constipation, nausea, vomiting, sedation, ENT is the buy of breath, itching, confusion of thoughts, disorientation and impaired cognitive function, urinary retention, biliary spasm ways, delirium, myoclonic jerks and seizures. The choice of reduced doses of mu-opioid requires clinical judgment of expert and depends on the unique characteristics of different mu-opioids, but also on patient characteristics, such as intensity of pain, the patient's age, concomitant disease, current treatment and potential bezmedikamentoznoy interaction, the results of previous treatment, and patient preference (McCaffery, M. and Pasero, C., Pain Clinical Manual, Second Edition, Mosby, 1999).

[00157] the Cannabinoids that are appropriate for the joint implementation or introduction in the pharmaceutical composition according to the invention include any natural cannabinoid, for example, tetrahydrocannabinol (THC) or a derivative of THC, or synthetic cannabinoid, for example, levonantradol, Marinol, nabilone, rimonabant or salitex.

[00158] Antidepressants suitable for joint injection or introduction into the pharmaceutical composition according to the invention include, for example, tricyclic antidepressants such as imipramine, desipramine, trimipramine, protriptyline, nortriptyline, amitriptyline, doxepin, and clomipramine; atypical antidepressants, such as amoxapine, maprotiline, trazodone, bupropion, and venlafaxine; specific inhibitors of ortogonality serotonin, such as fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine; specific reuptake inhibitors of norepinephrine, such as reboxetine; or dual action antidepressants such as nefazodone and mirtazapine.

[00159] the Neuroleptics, suitable for joint injection or administration of the pharmaceutical compositions according to the invention include any neuroleptic for example, the connection with the activity of the receptor antagonist of dopamine D2, such as domperidone, metoclopramide, levosulpiride, sulpiride, triterpenoid, ziprasidone, zotepine, clozapine, chlorpromazine acetophenazine, terfenadine chlorprothixene, fluphenazine, loxapine, mesoridazine, molindone perphenazine, pimozida piperacetazine, perchlorinated, thioridazine, thiothixene, trifluoperazine triflupromazine, pipamperone, amperozide, quetiapine, melperone, remoxipride, haloperidol, risperidone, olanzapine, sertindole, ziprasidone, amisulpride, prochlorperazine and thiothixene.

[00160] Anticonvulsants, such as phenobarbital, phenytoin, primidone, carbamazepine, tosucceed, lamotrigine, valproic acid, vigabatrin, felbamate, gabapentin, levetiracetam, oxcarbazepine, remacemide, tiagabine and topiramate may also appropriately be introduced in the pharmaceutical compositions according to the invention.

[00161] muscle Relaxants, such as Methocarbamol, orfina is Rin, carisoprodol, meprobamate, chlorphenesin carbamate, diazepam, chlordiazepoxide and chlorzoxazone; protivomigrenoznae agents such as sumatriptan, analeptics such as caffeine, methylphenidate, amphetamine, and modafinil; antihistamines such as chlorpheniramine, cyproheptadine at, promethazine and pyrilamine, corticosteroids, such as methylprednisolone, betamethasone, hydrocortisone, prednisolone, cortisone, dexamethasone, prednisone, alclometasone, clobetasol, clocortolone, desonide, desoximetasone, diflorasone, fluotsinolon, fluocinonide, flurandrenolide, fluticasone, formation, halcinonide, halobetasol, loteprednol, mometazon, prednicarbate and triamcinolone, also can be entered in the pharmaceutical compositions according to the invention.

[00162] the Blockers of ion channels, such as, a blocker of sodium channels, carbamazepine, which are usually used to treat ringing in the ears, arrhythmia, ischemic stroke and epilepsy, you can enter together or to enter into pharmaceutical compositions according to the invention. Alternative or additionally, calcium channel blockers, such as ziconotide, can also be used as antagonists of ion channels associated with the NMDA receptor, such as ketamine. There is evidence that at least some of these blockers of ion channels may contribute to analgetics is th effect of the Kappa agonist and thus, to reduce the dose required for effective relief of pain. See, for example, Wang et al., 2000, Pain 84:271-81.

[00163] Suitable NSAIDs, or other neopatria compounds with anti-inflammatory and/or pain-soothing activity that you can enter together or to enter into pharmaceutical compositions according to the invention, include, but are not limited to, one or more of the following list: derived aminoalkanoic acid, such as etofenamate, meclofenamic acid, mefenamovaya acid, niflumova acid; derivatives of akriluksusnoy acid, such as acemetacin, amfenac, cinmetacin, clairac, diclofenac, fenclofenac, vinklarek, fenclozic, fentiazac, glucometry, isoxepac, lonazolac, medicinova acid, naproxen, oxiplatin, proglumetacin, sulindac tiaramide, tolmetin; derivatives Arellano acid, such as butibufen, fenbufen; arylcarbamoyl acid, such as clidanac, Ketorolac, and tinoridine. derivatives arylpropionic acid, such as, carprofen, fenoprofen, flunoxaprofen ibuprofen, ibuproxam, oxaprozin derived phenylalkanoic acid, such as flurbiprofen, Pittodrie, pirprofen, pranoprofen, Protazanov acid and tiaprofenic acid; pyrocarbonic acid, such as etodolac; pyrazole derivatives, such as Marisol; pyrazolones such as cloth the zones, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone, phenylpyrrolidine, skibotn and thiazolidinedione; salicylic acid derivatives such as aspirin, Brasilien, diflunisal, fendosal, glycolicglycolic, mesalamine, 1 afterselect, magnesium salicylate, olsalazine and salicylamide, salsalate and sulfasalazin; casinoroxy, such as droxicam, isoxicam and piroxicam, others, such as ε-acetamidomalonate acid, acetaminophen, s-adenosylmethionine, 3-amino-4-hydroxipropionic acid, amixetrine, bendazac, bukola, carbazone, kromolin, divinename, diazol, hydroxychloroquine, indomethacin, Ketoprofen and its active metabolite 6-methoxy-2-naphthyloxy acid; guaiazulene, heterocyclic aminoalkyl esters mycophenolate acid and its derivatives, nabumetone, nimesulide, orgotein, oxaceprol, derived oxazole, phrenilin, pivoxil, 2-substituted 4,6-di-tert-butyl-s-hydroxy-1,3-pyrimidines, proquazone and tenidap, as well as inhibitors of COX-2 (cyclooxygenase II)such as celecoxib or rofecoksib.

[00164] Suitable diuretics, which can be introduced together or to enter into the pharmaceutical preparations according to the invention, include, for example, carbonic anhydrase inhibitors such as acetazolamide, dichlorphenamide and methazolamide; osmotic diuretics, such as glycerin, isosorbide, mannitol, and urea; inhibitory Na +-K+-2Cl--symptoms (loop diuretics or diuretics acting at the top departments), such as furosemide, bumetanide, ethacrynic acid, torsemide, axonemal, piretanide and tripled; inhibitors of the Na+-Cl--symport (thiazide and designatable diuretics), such as bendroflumethiazide, chlorthiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone and chinease; and, in addition, inhibitors of renal epithelial Na channels+such as amiloride and triamterene, and antagonists mineralocorticoid receptors (aldosterone antagonists such as spironolactone, canrenone, potassium, canrenoate and eplerenone, which together are also classified as diuretics K+-saving. One option is a combined drug and/or joint introduction of loop and thiazide diuretic together with a synthetic peptide inorganic salts according to the invention to reduce the dose of loop or thiazide diuretic where the dose of loop or thiazide diuretic is reduced to minimize unwanted water retention and prevent or reduce the severity of hyponatremia, especially in contact congestive heart failure and other medical conditions in which the reduction of fluid retention in organizme normalization of sodium balance could be useful to the patient, in need of such treatment. Cm. R M Reynolds et al. Disorders of sodium balance Brit. Med. J. 2006; 332: 702-705.

[001165] Related to the Kappa-opiate receptor, hyponatriemia can represent any disease or condition in which there is hyponatremia (low sodium), for example, cavalca, if the concentration of sodium in the plasma falls below 135 mmol/l, a disorder that can develop separately, or as a complication of other medical conditions or as a consequence of therapy, which can cause a depletion of sodium.

[00166] Another option is a combined drug and/or joint introduction potassium-conservation of diuretic, for example, antagonist receptor mineralocorticoid, such as spironolactone or eplerenone, together with a synthetic peptide inorganic salts according to the invention, to reduce the dose specified potassium-conservation of diuretic where the specified dose of diuretic is reduced to minimize hyperkaliemia or metabolic acidosis, for example, in patients with cirrhosis of the liver.

[00167] In specific embodiments, the synthetic peptide amides of the invention exhibit a prolonged duration of action when injected into therapeutically adequate doses in vivo. For example, in some embodiments, the synthetic peptide amides of the invention with the introduction of mlekopitayushchie is the dose of 3 mg/kg of the synthetic peptide amide retain at least about 50% of the maximum efficiency in the analysis, dependent on the Kappa-opiate receptor 3 hours after injection. In some other embodiments, the synthetic peptide amides of the invention when administered to a mammal at a dose of 0.1 mg/kg of the synthetic peptide amide retain at least about 50% of the maximum efficiency in the analysis are dependent on the Kappa-opiate receptor 3 hours after injection. Maximum operational efficiency is defined as the highest level of performance, specific for a particular analysis, dependent on the Kappa-opioid receptor for all three agonists.

[00168] In certain embodiments, the synthetic peptide amides of the invention when administered to a mammal at a dose of 0.1 mg/kg retain at least about 75% of maximum effectiveness after 3 hours after injection. In other embodiments, the synthetic peptide amides of the invention when administered to a mammal at a dose of 0.1 mg/kg retain at least about 90% of maximum effectiveness after 3 hours after injection. In other embodiments, the synthetic peptide amides of the invention when administered to a mammal at a dose of 0.1 mg/kg retain at least about 95% maximum efficiency in postal administration three hours.

[00169] the invention further provides a method of treating or preventing associated the Kappa-opiate receptors of the disease or condition in a mammal, where the method comprises the administration to a mammal a composition containing an effective amount of a synthetic peptide amide according to the invention. The mammal can be any mammal, such as a home or an agricultural mammal, or even a wild mammal. Alternatively, the mammal may be a Primate, ungulate animal, dog or cat. For example, without limitation, a mammal can be a pet, a valuable mammal, such as a purebred animal or exhibit an animal; farm animals such as cow, goat, sheep or pig, or a Primate such as a monkey or monkey. In one particular aspect, the mammal is a human.

[00170] the Effective amount may be determined by the average person skilled in the art according to routine methods. For example, the effective amount may be defined as a unit dose sufficient to prevent or treat associated with receptor Kappa disease or condition in a mammal. Alternatively, the effective amount may be determined as a quantity sufficient to approach the concentration of EC50or amount, sufficient to approach the value 2 or 3, or about 5 or even up to about 10 times p is ebisawa concentration EC 50in therapeutically adequate fluids of biological origin mammal, for example, if the liquid biological origin is in direct contact with the target-tissue, for example, the synovial fluid of inflamed joints in patients suffering from rheumatoid arthritis.

[00171] In one embodiment, the synthetic peptide amide according to the invention is a pharmaceutical composition that contains an effective amount of a synthetic peptide amide according to the invention and a pharmaceutically acceptable excipient or carrier. In one aspect, the pharmaceutical composition contains a synthetic peptide amides of the invention in an amount effective for treating or preventing associated with the Kappa-opioid receptor in a mammal, such as man. In another aspect associated with the Kappa-opiate receptor status is a pain, inflammation, itching, swelling, bowel obstruction, cough or glaucoma.

[00172] In one embodiment, the pharmaceutical composition according to the invention further comprises one or more of the following compounds: opioid, cannabinoid, antidepressant, anticonvulsant, adjunct corticosteroid, an ion channel blocker, or non-steroidal anti-inflammatory drug (NSAID).

[00173] Pharm is septicemia composition, which contain synthetic peptide amides of the invention and a pharmaceutically acceptable solvent or carrier can be used for treating or preventing one or more of a variety associated with Kappa-opiate receptor diseases, disorders or conditions.

[00174] Associated with the Kappa-opiate receptor disease, disorder or condition that is preventable or curable synthetic inorganic salts according to the invention, can be anything related to the Kappa-opiate receptor status, including, without limitation, acute or chronic pain, inflammation, itching, hyponatremia, edema, intestinal obstruction, cough and glaucoma. For example, related to the Kappa-opiate receptor pain may be neuropathic pain, somatic pain, visceral pain or skin pain. Some of the disease, disorder or condition associated with more than one form of pain, such as postoperative pain may include any or all of neuropathic, somatic, visceral and cutaneous components of pain, depending on the type and length of the surgical procedure.

[00175] Associated with the Kappa-opiate receptor inflammation can be any inflammatory disease or condition, including, without limitation, sinusitis, rheumatoi the hydrated arthritis, tenosynovitis, bursitis, Andonic, lateral epicondylitis, adhesive capsulitis, osteomyelitis, osteoarthritis inflammation, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), inflammation of the eyes, ear infection or inflammation of autoimmune origin.

[00176] Associated with the Kappa-opiate receptor itching can represent any disease or condition associated with itching, for example, itchy eyes, for example, is associated with conjunctivitis, itchy ears, itchy: associated with end-stage renal disease, in which many patients receive kidney dialysis, and other forms of cholestasis, including primary biliary cirrhosis, intrahepatic cholestasis of pregnancy, chronic cholestatic liver disease, uremia, malignancy cholestasis, jaundice, and dermatological condition, such as eczema (dermatitis), including atopic or contact dermatitis, psoriasis, polycythemia Vera, red flat zoster, simple chronic zoster, pediculosis (lice), thyrotoxicosis, dermovate foot, hives, itching, vaginitis, anal itching associated with hemorrhoids, itching as a result of insect bites and induced drugs itching, and also induced mu-opioid itching.

[00177] Associated with the Kappa-opiate receptor swelling can represent any related is Noah with edema disease or condition, such as, swelling as the result of congestive heart failure or syndrome of inappropriate secretion of antidiuretic hormone (ADH).

[00178] Related to the Kappa-opiate receptor obstruction of the bowel may be any associated with intestinal obstruction disease or condition, including, without limitation, post-operative ileus or induced opioid bowel dysfunction.

[00179] Related to the Kappa-opiate receptor neuropathic pain can represent any neuropathic pain, such as trigeminal neuralgia, the pain of diabetic origin, the pain of viral origin, for example, pain associated with shingles induced by chemotherapy pain, pain caused by cancer that is associated with invasion and metastasis in nervous tissue, neuropathic pain associated with traumatic injury and surgical procedures, as well as the types of headaches, for which it is assumed neuropathic component, such as migraine.

[00180] Related to the Kappa-opiate receptor pain includes pain in the eyes, for example, after a photo-refractive keratectomy (PRK), break eye orbital fracture bottom, chemical burns, scratches or irritation of the cornea, or associated with conjunctivitis, corneal ulcers, with what larita due to herpes zoster, the episcleritis, sclerotization, ophthalmic herpes, interstitial keratitis, acute Ericom (inflammation of the iris), dry keratoconjunctivitis, orbital cellulitis, orbital pseudoophonus, hand, foot, trachoma or uveitis.

[00181] Related to the Kappa-opiate receptor pain also includes a sore throat, especially associated with inflammatory conditions, such as allergic rhinitis, acute bronchitis, the common cold, contact ulcers, viruses, herpes simplex, infectious mononucleosis, influenza, cancer of the larynx, acute laryngitis, acute necrotizing ulcerative gingivitis, peritonsillar abscess, burns the throat, pharyngitis, influenza, laryngopharyngitis, acute sinusitis and tonsillitis.

[00182] in Addition, related to the Kappa-opiate receptor pain may be the pain of arthritis, kidney stones, stones in the urinary tract, stones in the bile ducts and pain when passing stones in the gall paths, pain in the spasms of the uterus, dysmenorrhea, endometritis, mastitis, neuralgia, postoperative pain (for example, after appendectomy, open surgical intervention in the area of the colon, rectum, treatment of hernia prostatectomy, resection of the colon, gastrectomy, splenectomy, colectomy, stoma, pelvic laparoscopy, tubal ligation, hysterectomy, vasectomy is or cholecystectomy), pain after a medical procedure (for example, after a colonoscopy, cystoscopy, hysteroscopy or occipital or biopsy of the cervix or endometrium), ear pain, breakthrough pain in cancer and pain associated with disorder of the gastrointestinal tract, such as inflammatory bowel disease or irritable bowel syndrome or other inflammatory condition, especially of internal organs (e.g., gastroesophageal reflux disease, pancreatitis, acute polymeric, ulcerative colitis, acute pyelonephritis, cholecystitis, cirrhosis, liver abscess, liver inflammation, duodenal ulcer or gastric ulcer, esophagitis, gastritis, gastroenteritis, colitis, diverticulitis, intestinal obstruction, ovarian cysts, inflammatory disease of the pelvis, perforated ulcer, peritonitis, prostatitis, interstitial cystitis) or contact with toxic agents such as insect toxins, or drugs, such as salicylates or NSAIDs.

[00183] In the present invention proposes a method of treating or preventing associated with the Kappa-opiate receptors of the disease or condition in a mammal, such as human, where the method comprises the administration to a mammal a composition containing an effective amount of the synthetic peptide amides of the invention. In another embodiment associated with the Kappa-op is atnam receptor status is a pain, inflammation (such as inflammation in rheumatoid arthritis, inflammation in osteoarthritis, inflammation in inflammatory bowel disease, inflammation in irritable bowel syndrome, inflammation of the eyes, ear infection or inflammation of autoimmune Genesis), itch (such as atopic dermatitis, is associated with renal dialysis itching, itchy eyes, itchy ears, itching as a result of insect bites or induced by opioids itching of the skin), swelling, bowel obstruction, cough, or glaucoma. In one aspect, the pain is a neuropathic pain such as trigeminal neuralgia, migraine, pain diabetic origin, pain, viral induced by chemotherapy pain or pain in patients with metastatic cancer), somatic pain, visceral pain or skin pain. In another aspect of the pain is the pain of arthritis, pain, kidney stone disease, pain in the spasms of the uterus, dysmenorrhea, endometriosis, neuralgia, postoperative pain, pain after medical procedures, pain in the eyes, pain in the ears, proryvnuju pain for cancer or the pain associated with disorder of the gastrointestinal tract, such as inflammatory bowel disease or irritable bowel syndrome. In another aspect of the pain is the pain associated with surgery, where surgical the e intervention is a laparoscopy pelvic area, tubal ligation, hysterectomy, and cholecystectomy. Alternatively, the pain may be pain associated with medical procedures such as colonoscopy, cystoscopy, hysteroscopy or endometrial biopsy. In a particular aspect, atopic dermatitis can be psoriasis, eczema or contact dermatitis. In another specific aspect, bowel obstruction is a postoperative bowel obstruction or induced opioid bowel dysfunction.

[00184] Related to the Kappa-opiate receptor pain includes hyperalgesia, which is supposedly caused by changes in the micro on the whirling peripheral sensory endings and develops secondary to local tissue damage. Damage (e.g., abrasions, burns and inflammation of the tissue can significantly increase the excitability of polymodal nociceptors (fiber) and mechanical receptors high threshold (Handworker et al. (1991) Proceeding of the VIthWorld. Congress on Pain, Bond et al., eds., Elsevier Science Publishers BV, pp.59-70; Schaible et al. (1993) Pain 55: 5-54). It is believed that this increase in excitability and over-reinforced reaction-sensitive afferent endings underlies hyperalgesia, where the reaction to pain is a result of excessively enhanced reaction to the stimulus. Is hyperalgesia status in the state of pain after injury re-sell monsterbone and apparently, responsible for the main part of the state of pain after injury/inflammation. Woold et al. (1993) Anesthesia and Analgesia 77: 362-79; Dubner et al. (1994) Textbook of Pain, Melzack et al., eds., Churchill-Livingstone, London, pp.225-242.

[00185] In another embodiment related to the Kappa-opiate receptor status is a pain, inflammation (such as inflammation in rheumatoid arthritis, inflammation in osteoarthritis, inflammation in inflammatory bowel disease, inflammation in irritable bowel syndrome, inflammation of the eyes, ear infection or inflammation of autoimmune Genesis), itch (such as atopic dermatitis, is associated with renal dialysis itching, itchy eyes, itchy ears, itchy insect bite result or induced by opioids itching of the skin), swelling, bowel obstruction, cough, or glaucoma. In one aspect, the pain is a neuropathic pain such as trigeminal neuralgia, migraine, pain diabetic origin, pain, viral induced by chemotherapy pain or pain in patients with metastatic cancer), somatic pain, visceral pain or skin pain. In another aspect of the pain is the pain of arthritis, pain, kidney stone disease, pain in the spasms of the uterus, dysmenorrhea, endometriosis, neuralgia, postoperative pain, pain after medical procedures, pain in the eyes, pain is in my ears, proryvnuju pain for cancer or the pain associated with disorder of the gastrointestinal tract, such as inflammatory bowel disease or irritable bowel syndrome. In another aspect of the pain is the pain associated with surgery, where surgical intervention is a laparoscopy pelvic area, tubal ligation, hysterectomy, and cholecystectomy. Alternatively, the pain may be pain associated with medical procedures such as colonoscopy, cystoscopy, hysteroscopy or endometrial biopsy. In a particular aspect, atopic dermatitis can be psoriasis, eczema or contact dermatitis. In another specific aspect, bowel obstruction is a postoperative bowel obstruction or induced opiate dysfunction of the intestine.

[00186] In another embodiment related to the Kappa-opiate receptor status is associated with a Kappa-opiate receptor status, preventable or treatable sodium - and potassium-sberegayuschim by diuresis, also known as Alvarez. An example of such related to the Kappa-opiate receptor States, preventable or treatable by the introduction of the synthetic peptide amides of the invention, includes swelling. Swelling can be a result of any of the many who olenych diseases or conditions, such as congestive heart failure or the syndrome of inappropriate secretion of antidiuretic hormone.

[00187] In another embodiment related to the Kappa-opiate receptor status is a hyponatremia or another associated with edema disease. Related to the Kappa-opiate receptor hyponatremia or swelling may be any disease or condition associated with hyponatremia or swelling, such as hyponatremia and edema associated with congestive heart failure or with syndrome of inappropriate secretion of antidiuretic hormone (ADH), or hyponatremia associated with intensive therapy with a diuretic with the use of thiazide and/or loop diuretics. Synthetic peptide amides of the invention show a pronounced sodium - and potassium-saving aquarelease effect, which is favourable in the treatment of pathological conditions of the puffiness that is associated with hyponatremia and/or hypokalemia. Accordingly, the synthetic peptide amides of the invention are also suitable for methods of treating or preventing associated with hyponatremia States, some of which are listed below. Associated with hyponatremia status can be categorized in accordance with the volemic status as giperwolemicescoy, euvolemia or hypovolemia the ical.

[00188] Giperwolemicescoy hyponatremia is usually caused by an increase in the total water content in the body, as can be observed in cases of congestive heart failure, nephrotic syndrome, and cirrhosis of the liver.

[00189] Euvolemic hyponatremia is often detected when the syndrome of inappropriate secretion of antidiuretic hormone (ADH) and may also be associated with pneumonia, small cell lung cancer, polydipsia, cases, head injuries and organic causes (e.g., use of certain drugs, such as haloperidol) or psychogenic cause.

[00190] Hypovolemic hyponatremia is the result of the relative decrease of the total content of sodium in the body, and may be associated with the use of diuretics, cases of interstitial nephritis or excessive sweating.

[00191] Such forms of hyponatremia can also be additionally classified in accordance with the concentration of sodium in the urine (i.e., the concentration is greater than or less than 30 mmol/L. See: R M Reynolds et al. Disorders of sodium balance, Brit. Med. J. 2006; 332:702-705.

[00192] Related to the Kappa-opiate receptor hyponatremia may be any disease or condition where there is hyponatremia (low sodium), for example, if the sodium concentration in the plasma falls below 135 moll, the anomaly, which may occur separately or, more often, as a complication of other medical conditions or as a consequence of therapy, which can cause a depletion of sodium.

[00193] In addition to the listed conditions, and various other conditions associated with hyponatremia, including, without limitation: neoplastic causes excessive secretion of ADH, including malignant neoplasms of the lung, duodenum, pancreas, ovary, bladder and ureter, thymoma, mesothelioma, bronchial adenoma, carcinoid, gangliocytoma and Ewing sarcoma; infections, such as pneumonia (bacterial or viral), abscesses (lung or brain), caving (aspergillosis), tuberculosis (lung or brain), meningitis (bacterial or virus, encephalitis and AIDS; vascular causes, such as cerebrovascular occlusion or hemorrhage and thrombosis of the cavernous sinus; neurological causes, such as Guillain-Barre syndrome, multiple sclerosis, delirium tremens, amyotrophy lateral sclerosis, hydrocephalus, psychosis, peripheral nervous exhaustion, head injury (closed and open), tumor, or infection of the Central nervous system and stroke Central nervous system, affecting hypothalamic osmoreceptor; congenital malformations, including: agent corpus callosum, cleft palate/cleft g the BA and other defects of the middle line; metabolic causes, such as acute intermittent porphyria, asthma, pneumothorax and breathing with positive pressure; use of drugs, such as thiazide diuretics, acetaminophen, barbiturates, cholinergic agents, estrogens, oral hypoglycemic agents, vasopressin or desmopressin, a high dose of oxytocin, hlorpropamid, vincristine, carbamazepine, nicotine, phenothiazines, cyclophosphamide, tricyclic antidepressants, monoamine oxidase inhibitors and serotonin reuptake inhibitors serotonin; additional administration of hypotonic fluids, for example, during hospitalization, surgery, or during or after athletic work (i.e. associated with physical activity hyponatremia), and the use of food additives with low sodium elderly. See, for example, Harrison''s Principles of Internal Medicine, 16th Ed. (2005), p.2102.

[00194] Other conditions associated with renal insufficiency, include hyponatremia, nephrotic syndrome (membranous nephropathy and minimal disease changes), cachexia, malnutrition, rhabdomyolysis, surgical procedures, routine cardiac catheterization, blood loss, as well as hypercalcemia, hypokalemia and hyperglycemia followed by glycosuria, leading to osmotic diuresis.

[00195] the invention also p is alagaesia method of treating or preventing a neurodegenerative disease or condition in a mammal, such as a person, where the method comprises the administration to a mammal of a composition which contains an effective amount of the synthetic peptide amides, as described above. Neurodegenerative disease or condition can be any Neurodegenerative disease or condition such as ischemia, anoxia, stroke, brain injury, spinal cord injury or reperfusion injury. Alternatively, a neurodegenerative disease or condition may be a neurodegenerative disease of the eye. Specific neurodegenerative eye diseases treatable or preventable by the method according to the invention include glaucoma, macular degeneration, ischemic disease of the retina and diabetic neurasthenia.

[00196] In certain embodiments the invention provides methods of preventing or treating certain diseases and conditions, neurons such as diseases and conditions, including neurodegenerative component. Synthetic peptide amides of the invention can be entered in a quantity effective to protect neuronal cells against the effects of pathology or injury that would lead to neurodegeneration and/or cell death of the neuron in the absence of treatment. For example, several diseases or condition of the eye, which include neurodegen the operational component, can be prevented or treated by the introduction of an effective amount of the synthetic peptide amides of the invention. Such diseases and conditions of the eye include glaucoma, macular degeneration, ischemic disease of the retina and diabetic neurasthenia. It is believed that in the progress of these diseases and conditions involving neurodegeneration or cell death of neurons, for example, programmed cell death (apoptosis), in which cells are neurons are routed on a path that in the absence of intervention will lead to cell death. It was found that the development or progression of such diseases and conditions can be prevented or at least slowed down, the agonist of the Kappa-opiate receptor. It is believed that this improved result is due to treatment with agonists of the Kappa opioid receptor. See, for example, Kaushik et al. "Neuroprotection in Glaucoma" (2003) J. Postgraduate Medicine vol.49 (1): pp.90-95.

[00197] In the case of glaucoma is that prevention and treatment introduction agonists of the Kappa-opiate receptor mediated at least two different types of activity, induced by the activation of Kappa-opioid receptor: neuroprotective and reduction of intraocular pressure (IOP). Not being tied to a theory, it is believed that neuroprotection, at least partially, is the result of induction at the territorial natriuretic peptide (ANP) in the eye, that leads to protection against oxidative damage and other types of damage.

[00198] it is Also considered that an abnormally high intraocular pressure is a factor leading to the development of glaucoma. Increased intraocular pressure can also be prevented or treated by administration of agonists of the Kappa-opioid receptor with three different types of activity that are triggered by activation of the receptor: decreases the secretion of aqueous humor, the increase in the expiration of the aqueous humor and Alvarez (sodium-and potassium-saving diuresis, leading to the excretion of water).

[00199] the invention also features a method of treating or preventing associated with the receptor Kappa disease or condition of the eye of a mammal, such as increased intraocular pressure (IOP). The method comprises the administration to a mammal of a composition which contains an effective amount of the synthetic peptide amides, as described above. In one aspect of the invention, the synthetic peptide amides of applied locally. In another aspect, the synthetic peptide amides is injected in the form of the implant.

[00200] In other embodiments, the invention provides methods of preventing or treating certain cardiovascular diseases and conditions, including a component of cell degeneration. Synthetic peptide amides of the invention can enter the number of the operation, effective for the protection of myocardial cells against the effects of pathology or injury that would lead to degeneration and/or cell death in the absence of treatment. For example, several cardiovascular diseases or conditions can be prevented or treated by the introduction of an effective amount of the synthetic peptide amides of the invention. Such cardiovascular diseases and conditions include, but are not limited to, coronary artery disease, heart ischemia, myocardial infarction, reperfusion injury and arrhythmias. See, for example, Wu et al. "Cardioprotection of Preconditioning by Metabolic Inhibition in the Rat Ventricular Myocyte - Involvement of kappa Opioid Receptor" (1999) Circulation Res vol.84: pp.1388-1395. Cm. also Yu et al. "Anti-Arrythmic Effect of kappa Opioid Receptor Stimulation in the Perfused Rat Heart: Involvement of a cAMP-Dependent Pathway" (1999) J Mol Cell Cardiol. vol.31 (10): pp.1809-1819.

[00201] Diseases and conditions other tissues and organs, which can be prevented or treated by the introduction of an effective amount of the synthetic peptide amides of the invention include, but are not limited to, ischemia, anoxia, stroke, brain injury or spinal cord injury and reperfusion injury.

[00202] in Another form related to the Kappa-opiate receptor pain treatable or preventable synthetic inorganic salts according to the invention, is a hyperalgesia. In one embodiment, the method includes the introduction is the development of an effective amount of a synthetic peptide amide according to the invention to a mammal, suffering from or at risk for the development of hyperalgesia to prevent, alleviate or completely eliminate hyperalgesia.

[00203] the Synthetic peptide amides of the invention can be entered by the methods disclosed herein, for the treatment or prevention of any hyperalgesic state, for example, without limitation, hyperalgesic condition associated with allergic dermatitis, contact dermatitis, skin ulcers, inflammation, rash, irritation fungal nature, and hyperalgesia conditions associated with infectious agents, burns, scratches, bruises, bruises, frostbite, rash, acne, bites/sting of an insect, skin ulcers, mucositis, gingivitis, bronchitis, laryngitis, sore throat, shingles irritation fungal nature, fever blisters, boils, plantar warts, surgical procedures or lesions of the vagina. For example, the synthetic peptide amides of the invention can be applied topically on the surface of the mucous membrane such as the mouth, esophagus, or larynx, or bronchial or nasal passages. Alternatively, the synthetic peptide amides of the invention can be applied topically on the vagina or the rectum/anus.

[00204] in Addition, the synthetic peptide amides by izopet is of possible ways to enter, disclosed herein, for the treatment or prevention of any hyperalgesic condition associated with burns, abrasions, bruises, scratches (for example, scratching of the cornea), bruises, frostbite, rash, acne, bites/sting of an insect, skin ulcers (such as diabetic ulcers or bedsores), mucositis, inflammation, gingivitis, bronchitis, laryngitis, sore throat, shingles, fungal irritation of nature (such as athlete's foot or Jock itch), fever blisters, boils, plantar warts or lesions of the vagina (for example, the defeat of the vagina associated with infections or sexually transmitted diseases). The methods provided for the introduction of the synthetic peptide amides of the invention for the treatment or prevention of hyperalgesia, include the ways in which the compound is applied topically on the surface of the eye, oral cavity, larynx, esophagus, bronchial passages, nasal passages, vagina, or rectum/anus.

[00205] Hyperlysinemia States associated with recovery after surgery, you can also control the introduction of the synthetic peptide amides of the invention. Hyperalgesia conditions associated with recovery after surgery, can be any Hyperalgesic the States, associated with recovery after surgery, for example, radial keratectomy, tooth extraction, lumpectomy, episiotomy, laparoscopy and arthroscopy.

[00206] Hyperlysinemia conditions associated with inflammation, you can also control the introduction of the synthetic peptide amides of the invention. Inflammation of the periodontium, inflammation orthodontist, inflammatory conjunctivitis, hemorrhoids and inflammation associated with diseases, sexually transmitted diseases, can be treated or prevented by the local introduction or application of the synthetic peptide amides of the invention.

[00207] the invention also features a method of inducing diuresis in a mammal, in need thereof. The method comprises the administration to a mammal a composition containing an effective amount of the synthetic peptide amides of the invention, as described above.

[00208] the invention also proposes a method of induction of prolactin secretion in a mammal. The method comprises the administration to a mammal a composition containing an effective amount of the synthetic peptide amides of the invention, as described above. Method of induction of prolactin secretion is suitable for treatment of a mammal, such as man, suffering from insufficient lactation, inadequate lactation, suboptimal lactation, decreased concentration in the spine of sperm age-related disorders, type I diabetes, insomnia or poor sleep with rapid eye movement (REM sleep). In a particular aspect, the method includes the combined introduction of the synthetic peptide amides with reduced dose of analgesic mu-opioid agonist to achieve therapeutic analgesic effect, where the connection causes the associated side effects, and reduced the dose of a compound causes a less pronounced accompanying side effect than a side effect caused by the dose of analgesic mu-opioid agonist necessary to achieve a therapeutic analgesic effect with monotherapy.

[00209] the present invention also proposes a method of binding the Kappa-opioid receptor in a mammal, where the method includes a step of introducing to a mammal a composition containing an effective amount of a synthetic peptide amide of the present invention. An effective amount can be determined by the average person skilled in the art in accordance with routine methods. For example, the effective amount may be determined as a unit dosage sufficient to connect with Kappa-opioid receptor in a mammal and to induce antinociceptive effect, antiinflammatory effect, aquarelease effect or increased levels prolac the ina in serum or any other associated with the Kappa-opioid receptor effect. Alternatively, the effective amount may be determined as a quantity sufficient to reach levels close to EC50in a biological body fluid of the mammal, or an amount sufficient to achieve levels 2 or 3 or up to approximately 5 times or even up to about 10 times higher than EU50suitable for the treatment of a biological fluid of a mammal.

SYNTHESIS of PEPTIDE AMIDES AND DIMER PEPTIDE AMIDES of the INVENTION

[00210] the Compound (1): D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethyl-piperazine]-(SEQ ID NO: 1):

[00211] Connection (2) D-Phe-D-Phe-D-Leu-D-Orn-[4-carboxymethyl-piperidine]-(SEQ ID NO: 1):

[00212] the Compound (3) D-Phe-D-Phe-D-Nle-D-Arg-D-Pro-OH (SEQ ID NO: 2):

[00213] the Compound (4) D-Phe-D-Phe-D-Leu-D-Orn-[(2S,4R)-4-amino-pyrrolidin-2-carboxylic acid]-(SEQ ID NO: 1):

[00214] the Compound (5) D-Phe-D-Phe-D-Leu-D-Orn-[(2S,45)-4-amino-pyrrolidin-2-carboxylic acid]-(SEQ ID NO: 1):

[00215] the Compound (6) D-Phe-D-Phe-D-Leu-D-Orn-[omega - (4-aminopiperidin-4-carboxylic acid)]-(SEQ ID NO: 1):

[00216] the Compound (7) D-Phe-D-Phe-D-Leu-D-Orn-[omega (D/L-2-amino-3-(4-N-piperidinyl)propionic acid)]-(SEQ ID NO: 1):

[00217] the Connection is s (8) D-Phe-D-Phe-D-Leu-D-Orn-[omega(D/L-4-piperazin-2-carboxylic acid)]-(SEQ ID NO: 1):

[00218] the Compound (9) D-Phe-D-Phe-D-Leu-D-Orn-[isonicotinoyl acid]-(SEQ ID NO: 1):

[00219] the Compound (10) D-Phe-D-Phe-D-Leu-D-Orn-[N-(4-piperidinyl)-L-Proline]-(SEQ ID NO: 1):

[00220] the Compound (11) D-Phe-D-Phe-D-Leu-D-Orn-[homopiperazine amide] (SEQ ID NO: 1):

[00221] the Compound (12) D-Phe-D-Phe-D-Leu-D-Orn-[4-(4-piperidinyl)-butane acid]-(SEQ ID NO: 1):

[00222] the Compound (13) D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethyl-piperazine]-NH2(SEQ ID NO: I):

[00223] the Compound (14) D-Phe-D-Phe-D-Leu-D-Orn-[N-(4-piperidinyl)-L-Proline]-NH2(SEQ ID NO: 1):

[00224] the Compound (15) D-Phe-D-Phe-D-Leu-D-Orn-[4-amino-1-carboxymethyl-piperidine]-NH2(SEQ ID NO: 1):

[00225] the Compound (16) D-Phe-D-Phe-D-Leu-D-Orn-[4-amidinopropane amide] (SEQ ID NO: 1):

[00226] the Compound (17) D-Phe-D-Phe-D-Leu-D-Orn-[4-(4,5-dihydro-1H-imidazol-2-yl)homopiperazine amide] (SEQ ID NO: 1):

[00227] the Compound (18) D-Phe-D-Phe-D-Leu-D-Orn-[4-acylhomoserine amide] (SEQ ID NO: 1):

[00228] the Compound (19) D-Phe-D-Phe-D-Leu-D-Orn-[4-(N-methyl)amidino-homopiperazine amide] (SEQ ID NO: 1):

[00229] the Compound (20) D-Phe-D-Phe-D-Leu-(5-iPr)D-Orn-[the mega(4-aminopiperidin-4-carboxylic acid)]-(SEQ ID NO: 3):

[00230] the Compound (21) D-Phe-D-Phe-D-Leu-(5-Me)D-Orn-[4-amidinopropane amide] (SEQ ID NO: 4):

[00231] the Compound (22) D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[4-amidinopropane amide] (SEQ ID NO: 3):

[00232] the Compound (23) D-Phe-D-Phe-D-Leu-(δ-Me)D-Orn-[homopiperazine amide] (SEQ ID NO: 4):

[00233] the Compound (24) D-Phe-D-Phe-D-Leu-(6-iPr)D-Orn-[homopiperazine amide] (SEQ ID NO: 3):

[00234] the Compound (25): D-Phe-D-Phe-D-Leu-D-Lys-[1,3-dioxolane-2-yl)mechanisn amide] (SEQ ID NO: 5):

[00235] the Compound (26): D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazine-1-yl)pyrimidine amide] (SEQ ID NO: 5):

[00236] the Compound (27): D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazine-1-yl)pyrazine amide] (SEQ ID NO: 5):

[00237] the Compound (28): D-Phe-D-Phe-D-Leu-D-Lys-[1-(pyridine-2-yl)piperazine amide] (SEQ ID NO: 5):

[00238] the Compound (29): D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazine-1-yl)thiazole amide] (SEQ ID NO: 5):

[00239] the Compound (30): D-Phe-D-Phe-D-Leu-D-Lys-[N,N-dimethylpiperazine-1-sulfonamide amide] (SEQ ID NO: 5):

[00240] the Compound (31): D-Phe-D-Phe-D-Leu-D-Lys-[1-(methylsulphonyl)piperazine amide] (SEQ ID NO: 5):

[00241] the Compound (32): D-Phe-D-Phe-D-Leu-D-Lys-[1-(phenylsulfonyl)piperazine amide] (SEQ ID O: 5):

[00242] the Compound (33): D-Phe-D-Phe-D-Leu-D-Lys-[phenyl(piperazine-1-yl)methanone amide] (SEQ ID NO: 5):

[00243] the Compound (34): D-Phe-D-Phe-D-Leu-D-Lys-[thiomorpholine-1,1-dioxide amide] (SEQ ID NO: 5):

[00244] the Compound (35): D-Phe-D-Phe-D-Leu-D-Lys-[6-trifluoromethyl-3-aminomethyl pyridine amide] (SEQ ID NO: 5):

[00245] the Compound (36): D-Phe-D-Phe-D-Leu-D-Lys-N-methyl-1-(tetrahydro-2H-Piran-4-yl)methanamine amide (SEQ ID NO: 5):

[00246] the Compound (37): H-D-Phe-D-Phe-D-Leu-D-Lys-[5-(aminomethyl)-1H-benzo[d]imidazol-2(3H)-she amide] (SEQ ID NO: 5):

[00247] the Compound (38); D-Phe-D-Phe-D-Leu-D-Lys-N-methyl-1-(5-methylpyrazine-2-yl)-methanamine amide) (SEQ ID NO: 5):

[00248] the Compound (39):

[00249] the Compound (40):

[00250] the Compound (41):

[00251] the Compound (42):

[00252] the Compound (43):

[00253]

Compound (44):

[00254] the Compound (45):

[00255] the Compound (46):

[00256] the Compound (47):

[00257] the Compound (48):

[00258] the Compound (49): 1N,4N-bis-[D-Phe-D-Phe-D-Leu-(iPr)D-Orn]-4-amino-4-carboxyl piperidine

[00259] the Compound (50): 1N,4N-bis-[D-Phe-D-Phe-D-Leu-D-Dap(amidino)]-4-amino-4-carboxyl piperidine

[00260] the Compound (51): 1N,4N-bis-(D-Phe-D-Phe-D-Leu-D-Nar)-4-amino-4-carboxyl piperidine

[00261] the Compound (52):

[00262] the Compound (53) D-Phe-D-Phe-D-Leu-D-Orn-[R/S-2-carboxymethyl]-(SEQ ID NO: 1):

[00263] the Compound (54) D-Phe-D-Phe-D-Leu-D-Orn-[R/S-2-carboxymyoglobin]-(SEQ ID NO: 1):

[00264] the Compound (55) D-Phe-D-Phe-D-Leu-D-Orn-N(homomorpholine) (SEQ ID NO: 1):

[00265] the Compound (56)D-Phe-D-Phe-D-Leu-D-Orn-N(sometimesvalid) (SEQ ID NO: 1):

[00266] the Compound (57) D-Phe-D-Phe-D-Leu-D-Dap(amidino)-[homomorpholine amide] (SEQ ID NO: 6):

[00267] the Compound (58) D-Phe-D-Phe-D-Leu-D-Dap(amidino)-[homotaurine amide] (SEQ ID NO: 6):

[00268] the Compound (59) D-Phe-D-Phe-D-Nle-D-ap(amidino)-[homomorpholine amide] (SEQ ID NO: 6):

[00269] the Compound (60) D-Phe-D-Phe-D-Nle-D-Dap(amidino)-[homotaurine amide] (SEQ ID NO: 6):

[00270] the Compound (61) D-Phe-D-Phe-D-Leu-D-Arg-[homomorpholine amide] (SEQ ID NO: 7):

[00271] the Compound (62) D-Phe-D-Phe-D-Leu-D-Arg-[genotypephenotype amide] (SEQ ID NO: 7):

[00272] the Compound (63) D-Phe-D-Phe-D-Leu-D-Orn(Me)-[homomorpholine amide] (SEQ ID NO: 4):

[00273] the Compound (64) D-Phe-D-Phe-D-Leu-D-Orn(Me)-[homotaurine amide] (SEQ ID NO: 4):

[00274] the Compound (65) D-Phe-D-Phe-D-Leu-D-Orn(iPr)-[homomorpholine amide] (SEQ ID NO: 3):

[00275] the Compound (66) D-Phe-D-Phe-D-Leu-D-Orn(iPr)-[homotaurine amide] (SEQ ID NO: 3):

EXAMPLES

[00276] General experimental methods synthesis:

[00277] the Derivatives of amino acids and resins were purchased from commercial suppliers (Novabiochem, Bachem, Peptide International and PepTech Corporation). Other reagents and solvents were purchased from Sigma-Aldrich, Fisher Scientific and VWR. Connections this description was synthesized by standard methods of solid-phase chemistry of peptides using Fmoc, and the New methodology. Unless otherwise noted, all reactions are conducted at room temperature.

[00278] In the following standard references contains General experimental guidance and epiandrosterone necessary starting materials and reagents: Kates, S.A., Albericio, F., Eds., Solid Phase Synthesis, A Practical Guide, Marcel Dekker, New York, Basel, (2000); Bodanszky, M.; Bodanszky, A., Eds., The Practice of Peptide Synthesis, Second Edition, Springer-Verlag, (1994); Atherton, E., Sheppard, R.C., Eds., Solid Phase Peptide Synthesis, A Practical Approach, IRL Press at Oxford University Press, (1989); Stewart, J.M., Young, J.D., Solid Phase Synthesis, Pierce Chemical Company, (1984); Bisello, et al., J. Biol. Chem. 273, 22498-22505 (1998); and Merrifield, R.., J. Am. Chem. Soc.85, 2149-2154 (1963).

[00279] Additional abbreviations used in this specification:

[00280] ACN: acetonitrile

[00281] Aloc: allyloxycarbonyl

[00282] Boc: tert-butoxycarbonyl

[00283] THIEF: benzotriazol-1-yl-oxy-Tris(dimethylamino)-phosphonium hexaflurophosphate

[00284] Cbz: benzyloxycarbonyl

[00285] Cbz-OSu: Nα-(benzyloxycarbonyloxy)succinimide

[00286] DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene

[00287] DHM: dichloromethane

[00288] Dde: 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ilidene)ethyl

[00289] DIC: N,N'-diisopropylcarbodiimide

[00290] DIEA: N,N-diisopropylethylamine

[00291] DMF: N,N-dimethylformamide

[00292] Fmoc: 9-fertilitycare

[00293] HATU: 2-(1H-9-asobancaria-1-yl)-1,1,3,3-tetramethylene hexaphosphate

[00294] HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylene hexaphosphate

[00295] HOBt: 1-hydroxybenzotriazole

[00296] HPLC: high performance liquid chromatography

[00297] i: every

[00298] ivDde: 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ilidene)-3-methylbutyl

[00299] NMM: 4 methylmorpholine

[00300] NMP: N-methylpyrrolidinone

[00301] All: allyl

[00302] o-NBS-C: o-nitrobenzenesulfonamide

[00303] Pbf: 2,2,4,6,7-pentamethylene-benzofuran-5-sulfonyl

[00304] PyBOP: benzotriazol-1 yloxy-Tris-pyrrolidino-Fastnet hexaphosphate

[00305] RP: reversed-phase

[00306] TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

[00307] TEAR: triethylamine phosphate

[00308] TFU: trifurcata acid

[00309] TIS: triisopropylsilane

[00310] TMOF: the trimethyl orthoformiate

[00311] TMSOTf: trimethylsilyl triftorbyenzola

[00312] Trt: trail

[00313] the Peptides synthesized on Fmoc methodology, split mixture TFU/TIS/H2O (./about./about.=95:2,5:2,5). Phase splitting in the methodology Boc carried out using the mixture of HF/anisole (about./about.=9:1) or a mixture of TMSOTf/TFU/m-cresol (about./about./about. 2:7:1).

[00314] the Reaction was combined with a lengthening chain of the peptide is carried out manually on the peptide synthesizer, reactions mediated by reagents in combination with a 2-4-fold excess of amino acid derivatives. The combination of reagents used in the synthesis of various compounds according to the invention are selected from the following combination: DIC/HOBt, HATU/DIEA, HBTU/DIEA, TBTU/DIEA, Rover/DIEA and BOP/DIEA.

[00315] removing protection from a side chain of the amino acid in position 4 (denoted by Xaa4in the final product is a synthetic peptide amide) associated with resin peptides provide as follows: peptides are collected, using as starting materials XAA4and postponeable Xaa 3then Xaa2and, in the end, Xaa1. Protective groups of the side chain of diaminoanisole entered in the Xaa position4selectively remove as follows: (i) N-Dde or N-ivDde removed by 2-4% hydrazine in DMF. Cm. Chabra, S.R., et al., Tetrahedron Lett. 39:1603-1606 (1998) and Rohwedder, B., et al., Tetrahedron Lett., 39: 1175 (1998); (ii) N-Aloc: remove using 3 EQ. (Ph3P)4Pd in CHCl3/AcOH/NMM (about./about./about.=37:2:1). Cm. Kates, S.A., et al. in "Peptides Chemistry, Structure and Biology, Proc. 13thAmerican Peptide Symposium", Hodges, R.S. and Smith, J.A. (Eds), ESCOM, Leiden, 113-115 (1994).

[00316] When the peptides are collected according to the methodology of protection with Boc protective group of the side chain of diaminoanisole entered in the Xaa position4i.e. N-Fmoc, removed by 20-30% piperidine in DMF.

[00317] Isopropylamine leaf nitrogen in the side chain of the amino acid Xaa at position4associated with resin peptides is as follows: After removing the protectors reaction associated with the resin peptide with a free ω-amino group in position XAA4with a mixture of acetone and NaBH(SLA)3in TMOF with the formation associated with resin Nω-isopropylated.

[00318] Monomethylamine leaf nitrogen in the side chain of the amino acid Xaa at position4associated with resin peptides: synthesis, associated with resin Nω-methylpiperidin free ω-amino group of a first derivatizing using on-nitrobenzenesulfonyl lorida (o-NBS-Cl; Biron, E.; Chatterjee, J.; Kessler, H. Optimized selective N-methylation of peptides on solid support. J. Pep. Sci. 12: 213-219 (2006). The resulting sulfonamide next, was identified in a mixture of dimethylsulfate and 1,8-diaza-bicyclo[5,4,0]undec-7-ene in NMP. The protective group of the o-NBS then removed using a mixture of mercaptoethanol and 1,8-diazabicyclo[5,4,0]undec-7-ene in NMP.

[00319] Guanylurea leaf nitrogen in the side chain of the amino acid Xaa at position4associated with resin peptides: After removing the protection, carry out the reaction associated with the resin peptide with a free ω-amino group in position 4 with a mixture of 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S., et al., J. Org. Chem. 57, 2497-2502 (1992) and DIEA in DMF with the formation associated with resin Nco-guanidinate.

[00320] the Peptides purified preparative HPLC in buffer solutions of triethylamine phosphate (TEAR) or triperoxonane acid (TFU). If necessary, the connection at the end of the turn in trifenatate or acetate salt using traditional methodology HPLC. Fractions with purity exceeding 97% unite and lyophilizers. The purity of the synthesized peptides define analytical reversed-phase HPLC.

[00321] Analytical reversed-phase HPLC was carried out on the delivery system several solvents Waters 600 adaptable detector optical density in the UV region Waters 486 and a Waters data module 746. Analysis of peptides by HPLC on usestyle using column Vydac C 18ones (0.46×25 cm, particle size 5 µm, pore size 300 Å) with a flow rate of 2.0 ml/min Solvent a and b: 0.1% OF TFU in H2O and 0.1% TFU in a mixture of 80% ACN/20% H2O, respectively. The values of the retention time (tR) are given in minutes. Preparative RP-HPLC was performed using preparative cartridge Vydac C18(5×30 cm, a particle size of 15-20 μm, pore size 300 Å) with a flow rate of 100 ml/min, the system for preparative chromatography Waters Prep LC 2000 with adaptable detector optical density in the UV region Waters 486 and tape plotter Servogor 120. Buffer solutions a and b: 0.1% OF TFU in H2O and 0.1% TFU in 60% ACN/40% H2O, respectively. Analysis by HPLC of the final compounds was performed on a liquid chromatograph Hewlett Packard 1090 using column Phenomenex Synergi MAX-RP Cis (2,0×150 mm, particle size 4 μm, the pore size of 80 Å) with a flow rate of 0.3 ml/min at 40°C. Buffer solutions a and b: 0.01% OF TFU in H2O and 0.01% TFU in 70% ACN/30% H2O, respectively. The identity of the synthetic peptide amides confirmed by mass spectrometry with elektrorazpredelenie. Mass spectra were recorded on a mass spectrometer Finnigan LCQ source ionization elektrorazpredelenie (ESI).

EXAMPLE 1 Synthesis of compound (1): D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethyl-piperazine]-(SEQ ID NO: 1):

[00322] figure 1 shows the General scheme used on the I-synthesis of compound (1). Used the following derivatives of amino acids: Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-Orn(Boc)-HE and Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine of the dihydrochloride. Fully protected, associated with the resin peptide synthesized in the synthesizer SYMPHONY Multiple Synthesizer (Protein technologies Inc.), using as starting materials 2-horticulturally resin (0.4 mmol; Novabiochem). Attaching the first amino acid to the resin to provide treatment with a mixture of Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine dihydrochloride (0.24 g, 0.5 mmol; Chem-Impex International Inc.) and DIEA (0.35 ml, 2 mmol) in DMF (7 ml) at room temperature for 4 hours. The resin is washed 3×DHM/MeOH/DIEA (about./about./about.=17:2:1) and 3×DHM. Subsequent elongation of the peptide chain provide indirect HBTU/DIEA single combinations with 3-times excess of amino acid derivatives. The Fmoc group is removed by treatment with 25% piperidine in DMF. For splitting, the final peptide resin is treated with a mixture of TFU/TIS/H2O (15 ml, about./about./about.=95:2,5:2,5) at room temperature for 90 minutes the Resin is filtered off and washed with TFU. The filtrate is evaporated under vacuum and the crude peptide (0.2 g, D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethyl-piperazine]-OH) (SEQ ID NO: 1) and precipitated from diethyl ether.

[00323] For purification, the above-described crude peptide (0.2 g) dissolved in 0.1% TFU in H2O (50 ml), the solution was loaded on the HPLC column and purified using overnoy system TFU (buffer solutions: A=0.1% OF TFU in H 2O and B=0.1% OF TFU in 60% ACN/40% H2O). Connection elute with a linear gradient from buffer B, 25% to 75% for 30 min, tR=35% Century Fractions with purity exceeding 97% unite, frozen and dried liofilizadora obtaining purified peptide in the form of a white amorphous powder (101 mg). Analysis by HPLC: tR=16,24, purity 100%, gradient from 5% to 25% for 20 min; MS (M+H+): the expected mass of the molecular ion 709,4, registered 709,4.

EXAMPLE 2 Synthesis of compound (2):

D-Phe-D-Phe-D-Leu-D-Orn-[4-Carboxymethyl-piperidine]-(SEQ ID NO: 1).

[00324] the Connection receive in accordance with the procedure described in the synthesis of compounds (1). The difference is the substitution of Fmoc-4-carboxymethyl-piperidine (Chem-Impex International Inc.) on Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, yield 123 mg scale synthesis of 0.4 mmol. Analysis by HPLC: tR=15,36 min, purity 100%, gradient 15% to 35% for 20 min; MS (M+H+): the expected mass of the molecular ion 665,4 registered 665,3.

EXAMPLE 3 Synthesis of compound (3):

D-Phe-D-Phe-D-Nle-D-Arg-D-Pro-OH (SEQ ID NO: 2):

[00325] get Connection in accordance with the procedure described in the synthesis of compounds (1). Used the following derivatives of amino acids: Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Nle-OH, Fmoc-D-Arg(Pbf)-HE and Fmoc-D-Pro-OH. End of ewenny peptide: amorphous powder, the output 140 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=on 20, 23 min, purity of 99.7%, gradient from 10% B to 30% for 20 min; MS (M+H+): the expected mass of the molecular ion 679,4 registered 679,5.

EXAMPLE 4 Synthesis of compound (4): D-Phe-D-Phe-D-Leu-D-Orn-[(2S,4R)-4-Amino-pyrrolidin-2-carboxylic acid]-(SEQ ID NO: 1):

[00326] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is the substitution of Fmoc-(2S, 4R)-4-amino-1-BOC-pyrrolidin-2-carboxylic acid (Chem-Impex International Inc.) on Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, exit 294 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=16,65 min, purity of 99.4%, gradient from 5% to 25% for 20 min; MS (M+H+): the expected mass of the molecular ion 652,4 registered 652,4.

EXAMPLE 5 Synthesis of compound (5): D-Phe-D-Phe-D-Leu-D-Orn-[(25,45)-4-amino-pyrrolidin-2-carboxylic acid]-(SEQ ID NO: 1):

[00327] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is the substitution of Fmoc-(25,45)-4-amino-1-BOC-pyrrolidin-2-carboxylic acid (Chem-Impex International Inc.) on Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, yield 285 mg scale Sint is for 0.3 mmol. Analysis by HPLC: tR=17,42 min, 99.5%purity, gradient from 5% B to 25% B over 20 min; MS (M+N+): the expected mass of the molecular ion 652,4 registered 652,4.

EXAMPLE 6 Synthesis of compound (6): D-Phe-D-Phe-D-Leu-D-Orn-[omega - (4-aminopiperidin-4-carboxylic acid)]-(SEQ ID NO: 1):

[00328] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is the substitution of N-Boc-amino-(4-N-Fmoc-piperidinyl)carboxylic acid (PharmaCore) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, exit 343 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=16,82 min, purity of 99.7%, gradient from 5% to 25% for 20 min; MS (M+N+): the expected mass of the molecular ion 664,4 registered 664,3.

EXAMPLE 7 Synthesis of compound (7): D-Phe-D-Phe-D-Leu-D-Orn-[ω(D/L-2-amino-3-(4-N-piperidinyl)propionic acid)]-(SEQ ID NO: 1):

[00329] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is in the replacement of 2-N-BOC-amino-3-(N-Fmoc-4-piperidyl)propionic acid (PharmaCore) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, exit 343 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=16,82 min, purity of 99.7%,gradient from 5% to 25% for 20 min; MS (M+H+): the expected mass of the molecular ion 664,4 registered 664,3.

EXAMPLE 8 Synthesis of compound (8): D-Phe-D-Phe-D-Leu-D-Orn-[omega(D/L-piperazine-2-carboxylic acid)]-(SEQ ID NO: 1):

[00330] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is in the replacement of N1-Vos-N4-Fmoc-piperazine-2-carboxylic acid (Chem-Impex International Inc.) on Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, yield 200 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=17,78 min, purity of 99.9%, gradient from 5% to 25% for 20 min; MS (M+H+): the expected mass of the molecular ion 652,4 registered 652,4.

EXAMPLE 9 Synthesis of compound (9): D-Phe-D-Phe-D-Leu-D-Orn-[isonicotinoyl acid]-(SEQ ID NO: 1):

[00331] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is the substitution of Fmoc-isonipecotic acid (NeoMPS) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, yield 125 mg in scale synthesis of 0.4 mmol. Analysis by HPLC: tR=18,74 min, purity of 99.3%, gradient from 10% to 30% for 20 min; MS (M+H+): the expected mass of the molecular ion 651,4 registered 651,3.

EXAMPLE 10 Synthesis of compound (10): D-Phe-D-Phe-D-Leu-D-Orn-[N-(4-piperidinyl)-L-Proline]-(SEQ ID NO: 1):

[00332] get Connection in accordance with the procedure described in the synthesis of compounds (1). The difference is in the replacement of N-(1-Fmoc-piperidine-4-yl)-L-Proline (NeoMPS) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, yield 18 mg scale synthesis of 0.4 mmol. Analysis by HPLC: tr=14,59 min, purity 100%, gradient from 10% to 30% for 20 min; MS (M+N+): the expected mass of the molecular ion 720,4 registered 720,3.

EXAMPLE 11 Synthesis of compound (11): D-Phe-D-Phe-D-Leu-D-Orn-[homopiperazine amide] (SEQ ID NO: 1):

[00333] the Synthesis initiated from 0.3 mmol of the peptide intermediate, Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[homopiperazine amide], which is obtained during the synthesis of compounds (19). Peptide hydrolyzing a mixture of TMSOTf/TFU/m-cresol (10 ml, about./about./about.=2:7:1), and the crude product is purified preparative HPLC according to the procedure described in the synthesis of compounds (19). The final purified peptide: amorphous powder, yield 225 mg Analysis by HPLC: tR=16,43 min, purity 100%, gradient from 2% to 22% for 20 min; MS (M+N+): the expected mass of the molecular ion 622,4 registered 622,4.

EXAMPLE 12 Synthesis of compound (12): D-Phe-D-Phe-D-Leu-D-Orn-[4-(4-piperidinyl)-butane acid]-(SEQ ID NO: 1):

[00334] get Connection in accordance with the methodology described in cinesexuality (1). The difference is in the replacement of 4-(1-GTOS-piperidine-4-yl)-butane acid (NeoMPS) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin 2-Cl-Trt. The final purified peptide: amorphous powder, exit 474 mg scale synthesis of 0.4 mmol. Analysis by HPLC: tR=17,91 min, purity 100%, gradient 15% to 35% for 20 min; MS (M+N+): the expected mass of the molecular ion 693,4 registered of 693, 3.

EXAMPLE 13 Synthesis of compound (13): D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethyl-piperazine]-NH2 (SEQ ID NO: 1):

[00335] the Synthesis is carried out, as shown in figure 2. Used the following derivatives of amino acids: Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-Orn(Boc) -HE and Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine of the dihydrochloride. Fully protected, associated with the resin peptide synthesized in the synthesizer SYMPHONY Multiple Synthesizer (Protein technologies Inc.), using as starting materials the resin Rink Amide AM (0.3 mmol; Novabiochem). Attaching the first amino acid to the resin to provide treatment with a mixture of Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride (of 0.48 g, 1 mmol; Chem-Impex International Inc.), HBTU (0,38 g, 1 mmol) and DIEA (of 0.53 ml, 3 mmol) in DMF (7 ml) at room temperature for 3 hours. The resin is washed 3×DMF.

[00336] the Subsequent elongation of the peptide chain provide indirect HBTU/DIEA single combinations with 3-times the excess production is adnych amino acids. The Fmoc group is removed by treatment with 25% piperidine in DMF. For splitting, the final peptide resin is treated with a mixture of TFU/TIS/H2O (15 ml, about./about./about.=95:2,5:2,5) at room temperature for 90 minutes. The resin is filtered off and washed with TFU. The filtrate is evaporated under vacuum and the crude peptide (0.1 g, D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-amino-ethyl)-1-carboxymethyl-piperazine]-NH2) precipitated from diethyl ether.

[00337] For purification, the above-described crude peptide (0.1 g) dissolved in 0.1% TFU in H2O (50 ml), the solution was loaded on the HPLC column and purified using a buffer system TFU (buffer solutions: A=0.1% OF TFU in H2O and B=0.1% OF TFU in 60% ACN/40% H2O). Connection elute with a linear gradient from buffer B, 25% to 75% for 30 min, tR=38% Century Fractions with purity exceeding 97% unite, frozen and dried liofilizadora obtaining purified peptide in the form of a white amorphous powder (36 mg). Analysis by HPLC: tR=16,59, purity of 99.5%, gradient from 2% to 22% for 20 min; MS (M+H+): the expected mass of the molecular ion 708,5 registered USD 708.3.

EXAMPLE 14 Synthesis of compound (14): D-Phe-D-Phe-D-Leu-D-Orn-[N-(4-piperidinyl)-L-Proline]-NH2(SEQ ID NO: 1):

[00338] the Connection receive in accordance with the procedure described in the synthesis of compound (13). The difference is in the replacement of N-(1-Fmoc-piperidine-4-yl)-L-Proline (NeoMPS) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin Rink Amide AM. The final purified peptide: amorphous powder, yield 14 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=18,13 min, purity 91.7%, gradient from 10% to 30% for 20 min; MS (M+H+): the expected mass of the molecular ion 719,5 registered 719,3.

EXAMPLE 15 Synthesis of compound (15): D-Phe-D-Phe-D-Leu-D-Orn-[4-amino-1-carboxymethyl-piperidine]-NH2(SEQ ID NO: 1):

[00339] get Connection in accordance with the procedure described in the synthesis of compound (13). The difference is the substitution of Fmoc-4-amino-1-carboxymethyl-piperidine (NeoMPS) for Fmoc-4-(2-amino-ethyl)-1-carboxymethyl-piperazine the dihydrochloride in the process of accession to the resin Rink Amide AM. The final purified peptide: amorphous powder, yield 65 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=16,74 min, purity of 99.7%, gradient from 2% to 22% for 20 min; MS (M+H+): the expected mass of the molecular ion 679,4 registered 679,3.

EXAMPLE 16 Synthesis of compound (16): D-Phe-D-Phe-D-Leu-D-Orn-[4-amidinopropane amide] (SEQ ID NO: 1):

[00340] the initiate Synthesis of 0.2 mmol of the peptide intermediate, Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[homopiperazine amide], which is obtained during the synthesis of compounds (19). For guanylurea homopiperazine to-end, the peptide is treated with a solution of 1H-pyrazole-1-carboxamidine hydrochloride (0.4 g, 3.0 mmol) and DIEA (0.5 ml, 6 mmol) in DMF (3 ml) overnight at room themes is the temperature value. Acetic acid and N2About add for quenching the reaction, the solution is freeze-dried liofilizadora to obtain the desired protected peptide Cbz-DPhe-DPhe-DLeu-DOrn(Cbz)-[4-amidinopropane amide] (0.2 mmol). Subsequent removal of the protection/hydrolysis and purification by HPLC is carried out in accordance with the procedure described in the synthesis of compounds (19). The final purified peptide: amorphous powder, yield 74 mg Analysis by HPLC: tR=10,10 min, purity 98.7 per cent, gradient from 10% to 30% for 20 min; MS (M+N+): the expected mass of the molecular ion 664,4 registered 664,5.

EXAMPLE 17 Synthesis of compound (17): D-Phe-D-Phe-D-Leu-D-Orn-[4-(4,5-dihydro-1H-imidazol-2-yl)homopiperazine amide] (SEQ ID NO: 1):

[00341] the initiate Synthesis of 0.2 mmol of the peptide intermediate, Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[homopiperazine amide], which is obtained during the synthesis of compounds (19). For guanylurea homopiperazine to-end, the peptide is treated with a solution of 2-methylthio-2-imidazoline hydroiodide (730 mg, 3.0 mmol; Aldrich) and DIEA (0.5 ml, 6 mmol) in DMF (3 ml) for 4 days at room temperature. Acetic acid and H2O add to extinguish the reaction: a solution of freeze-dried liofilizadora to obtain the desired protected peptide Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[4-(4,5-dihydro-1H-imidazol-2-yl)homopiperazine amide] (0.2 mmol). Subsequent removal of the protection/hydroly and purification by HPLC is carried out in accordance with the methodology described in the synthesis of compounds (19). The final purified peptide: amorphous powder, yield 46 mg Analysis by HPLC: tR=10,89 min, purity 100%, gradient from 10% to 30% for 20 min; MS (M+H+): the expected mass of the molecular ion 690,4 registered 690,5.

EXAMPLE 18 Synthesis of compound (18): D-Phe-D-Phe-D-Leu-D-Orn-[4-acylhomoserine amide] (SEQ ID NO: 1):

[00342] the Synthesis initiated from 0.3 mmol of the peptide intermediate, Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[homopiperazine amide], which is obtained during the synthesis of compounds (19). For atilirovanie homopiperazine to-end, the peptide is treated with a solution of iodata (0.4 mmol; Aldrich) and DIEA (0.5 ml, 6 mmol) in DMF (3 ml) for 1 day at room temperature. Subsequent removal of the protection/hydrolysis and purification by HPLC is carried out in accordance with the procedure described in the synthesis of compounds (19). The final purified peptide: amorphous powder, yield 75 mg Analysis by HPLC: tR=10,43 min, purity 98.4%of the gradient from 10% to 30% for 20 min; MS (M+H+): the expected mass of the molecular ion 650,4 registered 650,3.

EXAMPLE 19 Synthesis of compound (19): D-Phe-D-Phe-D-Leu-D-Orn-[4-(N-methyl)amidinopropane amide] (SEQ ID NO: 1):

[00343] Cm. figure 3 a General scheme of synthesis used to obtain the compounds (19). The connection is produced by guanidinium homopiperazine-the end of Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[homepipe the azina amide], which is synthesized in accordance with methods described below.

[00344] the Reagent for guanylurea S-methyl-N-methylisothiazolone hydroiodic obtained by reaction of 1,3-dimethyl-2-thiourea with methyliodide in anhydrous methanol. Cm. McKay, A.F.; Hat-ton, W.G. Synthesis of Cyclic Guanidino Acids. J. Am. Chem. Soc. (1955), 75, 1618-1620 and Kennedy, K.J., et al. A Facile Route to Cyclic and Acyclic Alkyl-Arginines. Synthetic Communications, (1998), 28, 741-746.

[00345] For the synthesis of Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[homopiperazine amide] use the following derivatives of amino acids: Z-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH and Fmoc-D-Orn(Cbz)-HE. Fully protected, associated with the resin peptide synthesized manually, using as starting materials n-nitrophenylarsonic Wang resin (5.0 g, 4.4 mmol; Novabiochem). Join homopiperazine to provide a resin by stirring the solution homopiperazine (8.7 g, 87 mmol; Acros Organics) in DHM (100 ml) overnight at room temperature. The resin is washed 3×DMF and 3×DHM. Subsequent elongation of the peptide chain ensure, through indirect HBTU/DIEA single combinations with 3-times excess of amino acid derivatives. The Fmoc group is removed by treatment with 25% piperidine in DMF. For splitting, the final peptide resin is treated with a mixture of TFU/DHM (100 ml).about.=1:1) at room temperature for 2 hours. The resin is filtered and washed DHM. The filtrate is evaporated under vacuum, and the residue is dissolved in 0.1% TFU in 60% ACN/40% H2 O. the Solution is freeze-dried liofilizadora with obtaining the crude peptide intermediate Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-homopiperazine (4.4 g). For purification, the crude peptide (4.4 g) divided into 2 portions, and each portion was dissolved in 0.1% TFU in 30% ACN (100 ml). Each solution was loaded on the HPLC column and purified using a buffer system TFU (buffer solutions: A=0.1% OF TFU in H2O and B=0.1% OF TFU in 60% ACN/40% H2O). Connection elute with a linear gradient from buffer, 40% to 100% for 25 min, tR=87% Century Fractions with purity exceeding 97% unite, frozen and dried liofilizadora obtaining purified peptide intermediate compound as a white amorphous powder (3.0 g).

[00346] For guanylurea homopiperazine to-end, the above-described peptide of the intermediate compound (210 mg, 0.3 mmol) is treated with a mixture of S-methyl-N-methylisothiazolone hydroiodide (1.4 g, 6 mmol) and DIEA (1.0 ml, 12 mmol) in DMF (4 ml) at room temperature for 18 days. The mixture is evaporated under vacuum, the residue is dissolved in 0.1% TFU in 30% ACN/70% H2O, the solution was loaded on the HPLC column and purified using a buffer system TFU (buffer solutions: A=0.1% OF TFU in H2O and B=0.1% OF TFU in 60% ACN/40% H2O). Connection elute with a linear gradient from buffer B, 70% to 100% over 30 min, tR=85% Century Fractions with a purity of more than 97% of the volume of inaut, freeze-dried liofilizadora obtaining purified peptide intermediate, Cbz-D-Phe-D-Phe-D-Leu-D-Orn(Cbz)-[N-methylhomopiperazine-1-carboximidic amide]as a white amorphous powder (100 mg).

[00347] For the final unprotect/hydrolysis described above purified peptide (100 mg) is treated with a mixture of TMSOTf/TFU/m-cresol (10 ml, about./about./about.=2:7:1) at room temperature for 2 hours. The mixture is evaporated under vacuum and the crude peptide (100 mg) precipitated from diethyl ether.

[00348] For purification, the above-described crude peptide (100 mg) dissolved in 0.1% TFU in H2O (50 ml), the solution was loaded on the HPLC column and purified using a buffer system TFU (buffer solutions: A=0.1% OF TFU in H2O and B=0.1% OF TFU in 60% ACN/40% H2O). Connection elute with a linear gradient from buffer B, 25% to 75% over 25 min, tR=43% Century Fractions with purity exceeding 97% unite, frozen and dried liofilizadora with obtaining the pure product as a white amorphous powder (53 mg). Analysis by HPLC: tR=17,99 min, purity of 99.4%, gradient from 2% to 22% for 20 min; MS (M+H+): the expected mass of the molecular ion to 678.4 registered 678,5.

EXAMPLE 20 Synthesis of compound (20):

D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[omega - (4-Aminopiperidin-4-carboxylic acid)]-HE

[00349] Used the following derivatives of amino acids: Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-rn(Aloc)-OH and N-Boc-amino-(4-N-Fmoc-piperidinyl) carboxylic acid. Fully protected, associated with the resin peptide synthesized manually, using as starting materials 2-horticulturally resin (0.8 mmol). Attaching N-Boc-amino-(4-N-Fmoc-piperidinyl)carboxylic acid to the resin and the subsequent combination is carried out in accordance with the procedure described in the synthesis of compounds (1). The collected peptide resin, Boc-D-Phe-D-Phe-D-Leu-D-Orn-oMera(4-aminopiperidin-4-carboxylic acid)-[2-Cl-Trt resin], treated with Pd(PPh3)4(4.5 mmol; Aldrich) in a mixture of CHCl3/AcOH/NMM (80 ml, about./about./about.=37:2:1) in an argon atmosphere at room temperature for 3 hours to remove the Aloc. Subsequent N-Isopropylamine carried out in accordance with the procedure described in the synthesis of compounds (22). Final cleavage and preparative purification by HPLC is carried out in accordance with the procedure described in the synthesis of compounds (1). The final purified peptide: amorphous powder, exit 336 mg. Analysis by HPLC: tR=18,88 min, purity 98.9 per cent, gradient from 5% to 25% for 20 min; MS (M+N+): the expected mass of the molecular ion 708,4 registered 708,4.

EXAMPLE 21 Synthesis of compound (21): D-Phe-D-Phe-D-Leu-(δ-Me)D-Orn-[4-amidinopropane amide] (SEQ ID NO: 1):

[00350] Cm. the diagram shown in figure 3. Used the following derivatives of amino acids: Z-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH and Fmoc-D-Orn(Aloc)-HE. Fully protected associated with cosmology peptide synthesized manually using as starting materials n-nitrophenylarsonic Wang resin (5.0 g, 4.4 mmol; Novabiochem). Join homopiperazine to provide a resin, mixing it with a solution homopiperazin (8.7 g, 87 mmol; Acros Organics) in DHM (100 ml) overnight at room temperature. The resin was washed with DMF and DHM and dried under vacuum. Received homopiperazin-urethane resin Wang (5,1 g; homopiperazin-[urethane resin Wang]) is divided into several portions, and a portion of 1.1 g (1 mmol) is used for the further synthesis of the peptide. Mediated by DIC/HOBt single combination is carried out with 3-times excess of derivatives aminokislotnaya Fmoc removed with 25% piperidine in DMF. At the end of the elongation of the peptide chain of the resin is treated with Pd(PPh3)4(3.5 g, 3.0 mmol; Aldrich) in a mixture of CHCl3/Asón/NMM (60 ml.about./about.=37:2:1) in an atmosphere of argon at room temperature for 3 hours to remove the Aloc. The resin was washed with DMF and DHM and dried under vacuum. The resulting peptide resin (1.8 g; Z-D-Phe-D-Phe-D-Leu-D-Orn-homopiperazin-[urethane resin Wang]) again divided, and a portion of 0.9 g (0.5 mmol) is used for further derivatization (N-methylation).

[00351] Methylation of omega-amino group of D-Orn in position XAA4carried out in 3 stages: (i) [protection of the o-NBS]: Associated with resin peptide (0.5 mmol) are initially treated with a solution of o-NBS-Cl (0.4 g, 2 mmol) and collidine (0.7 ml, 5 mmol) in NMP (7 ml) at room temperature for 30 minutes the Resin is then washed with NMP. (ii) [N-Met the regulation]: Further carry out the reaction associated with the resin o-NBS-protected peptide with a solution of 1,8-diazabicyclo[5,4,0]undec-7-ene (0.5 ml, 3 mmol) and dimethylsulfate (1.0 ml, 10 mmol; Aldrich) in NMP (7 ml) at room temperature for 5 minutes the Resin is then washed with NMP, and the process N-methylation repeat one more time. (iii) [unprotect o-NBS]: the Peptide resin is treated with a solution of mercaptoethanol (0.7 ml, 10 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-Yong (0.8 ml, 5 mmol) in NMP (7 ml) at room temperature for 5 minutes the Resin is then washed with NMP and the process of removing the protection, repeat one more time.

[00352] To protect the N-methyltaurine amine D-Orn in position XAA4carry out the reaction associated with the resin methylated peptide with a solution of Z-OSu (6 mmol) in DMF (7 ml). The resin was washed with DMF and DHM and dried under vacuum. The peptide then otscheplaut from the resin by treatment with a solution TFU/DHM (15 ml, about./about.=1:1) at room temperature for 2 chessmore then filtered and washed with TFU. The filtrate is evaporated under vacuum and the crude peptide (0.5 mmol; Z-D-Phe-D-Phe-D-Leu-D-Orn(Me,Z)-[homopiperazine amide]) are obtained in the form of oil.

[00353] For guanylurea homopiperazine-end portion of the above-described peptide (0.3 mmol) is treated with a solution of 1H-pyrazole-1-carboxamidine hydrochloride (0.4 g, 3.0 mmol) and DIEA (0.5 ml, 6 mmol) in DMF (3 ml) overnight at room temperature. Acetic acid and H2O added for quenching the reaction, the solution is freeze-dried liofilizadora with the floor is the group of target protected peptide, Z-D-Phe-D-Phe-D-Leu-D-Orn(Me,Z)-[4-amidinopropane amide] (0.3 mmol).

[00354] For the final unprotect/hydrolysis described above peptide (0.3 mmol) is treated with a mixture of TMSOTf/TFU/m-cresol (10 ml, about./about./about.=2:7:1) at room temperature for 2 hours. The mixture is evaporated to obtain the crude peptide (0.3 mmol) in the form of oil. Preparative purification of the crude peptide by HPLC is carried out in accordance with the procedure described in the synthesis of compounds (1). The final purified peptide: amorphous powder, yield 183 mg Analysis by HPLC: tR=17,12 min, purity 98.9 per cent, gradient from 2% to 22% for 20 min; MS (M+N+): the expected mass of the molecular ion to 678.4 registered 678,5.

EXAMPLE 22 Synthesis of compound (22): D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[4-amidinopropane amide] (SEQ ID NO: 3):

[00355] the initiate Synthesis of 0.9 g (0.5 mmol) of the peptide-resin: Z-D-Phe-D-Phe-D-Leu-D-Orn-homopiperazin-[urethane resin Wang], which is obtained during the synthesis of compound (21)described above.

[00356] For Isopropylamine omega-amino group of D-Orn in position XAA4, the peptide resin is treated with a mixture of sodium triacetoxyborohydride (3 mmol) and acetone (6 mmol) in TMOF (10 ml) overnight at room temperature. The peptide resin is then treated with a solution of Z-OSu (6 mmol) in DMF (7 ml) to protect Z. the Resin was washed with DMF and DHM and dried under vacuum. The peptide then otscheplaut from resins of the processing solution TFU/DHM (15 ml, about./about.=1:1) at room temperature for 2 hours. The resin is filtered off and washed with TFU. The filtrate is evaporated under vacuum and the crude peptide (0.5 mmol; Z-D-Phe-D-Phe-D-Leu-D-Orn(iPr,Z)-[homopiperazine amide]) was isolated in the form of oil.

[00357] the Portion of the above-described peptide (0.3 mmol) is subjected to subsequent stages of guanylurea, removal and cleaning, which is carried out in accordance with the procedure described in the synthesis of compound (21). The final purified peptide: amorphous powder, yield 166 mg Analysis by HPLC: tR=18,71 min, purity of 99.4%, gradient from 2% to 22% for 20 min; MS (M+N+): the expected mass of the molecular ion 706,5 registered 706,5.

EXAMPLE 23 Synthesis of compound (23): D-Phe-D-Phe-D-Leu-(5-Me)D-Orn-[homopiperazine amide] (SEQ ID NO: 4):

[00358] the initiate Synthesis of 0.2 mmol of the peptide intermediate compounds, Z-D-Phe-D-Phe-D-Leu-D-Orn(Me,Z)-[homopiperazine amide], which is obtained during the synthesis of compound (21). Peptide hydrolyzing a mixture of TMSOTf/TFU/m-cresol (10 ml, about./about./about.=2:7:1), and the crude product is purified preparative HPLC according to the procedure described in the synthesis of compounds (19). The final purified peptide: amorphous powder, yield 98 hanalis by HPLC: tr=16,38 min, purity 99.6%and a gradient from 2% to 22% for 20 min; MS (M+N+): the expected mass of the molecular ion 636,4 registered 636,5.

EXAMPLE 24 synthesis of the joint is (24): D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[homopiperazine amide] (SEQ ID NO: 3):

[00359] the initiate Synthesis of 0.2 mmol of the peptide intermediate compounds, Z-D-Phe-D-Phe-D-Leu-D-Orn(iPr,Z)-[homopiperazine amide], which is obtained during the synthesis of the compound (22). Peptide hydrolyzing a mixture of TMSOTf/TFU/m-cresol (10 ml, about./about./about.=2:7:1), and the crude product is purified preparative HPLC according to the procedure described in the synthesis of compounds (19). The final purified peptide: amorphous powder, yield 87 mg Analysis by HPLC: tR=18,41 min, purity 100%, gradient from 2% to 22% for 20 min; MS (M+N+): the expected mass of the molecular ion 664,5 registered 664,5.

[00360] the Confirmation of the structure of the synthetic peptide amides:

[00361] In table the calculated molecular mass of the molecular ion, MN+for each connection, and the actual molecular weight registered by the method of mass spectrometry. Also shown type phase synthesis, used in the synthesis of each compound: solid phase or mixed; and the type of resin used in the synthesis, where the resin is a 2-chlorotrityl "2-Cl-Trt" resin, hydrazinophenyl "hydrazine powered" resin. Rink AM or p-nitrophenyl-carbonate (Wang) "carbonate" resin. The number of a figure, which shows the corresponding synthesis scheme for the synthesis of each compound shown in the last column.

Table I
Synthesis and proof of structure of connections
ConnectionThe calculated molecular massRegistered private molecular weightPhase synthesisResinFirure
1709,4709,4solid2-Cl-Trt1
2665,4665,3solid2-Cl-Trt1
3679,4679,5solid2-Cl-Trt1
4652,4652,4solid2-Cl-Trt1
5652,4652,4solid2-Cl-Trt1
6666,4666,3solid2-Cl-Trt1
7694,4694,4solid2-Cl-Trt1
8652,4652,4solid2-Cl-Trt1
9651,4651,3solid2-Cl-Trt1
10720,4720,6solid2-Cl-Trt1
11622,4622,4solidCarbonate2
12693,4of 693, 3solid2-Cl-Trt1
1370,3 USD 708.3solidRink AM2
14719,5719,3solidRink AM2
15679,4679,3solidRink AM2
16664,4664,5mixedCarbonate3
17690,4690,5mixedCarbonate3
18650,4650,3mixedCarbonate3
19to 678.4678,5mixedCarbonate3
207084 708,4solid2-Cl-Trt1
21to 678.4678,5mixedCarbonate3
22706,5706,5mixedCarbonate3
23636,4636,5solidCarbonate3
24664,5664,5solidCarbonate3

EXAMPLE 25 Synthesis of compound (25): D-Phe-D-Phe-D-Leu-D-Lys-[1,3-dioxolane-2-yl)methanamine amide] (SEQ ID NO: 5):

[00362] the Specified synthesis is carried out in accordance with the scheme shown in figure 4. The following intermediates correspond shown in figure 4. To a suspension of Boc-D-Phe-OH intermediate compound I-1 (of 7.96 g, 30.0 mmol), D-Leu-OBn n-TsOH intermediate 1-2 (11,80 g, 30.0 mmol), HOBt monohydrate (4,46 g, 33.0 mmol) and DIEA (8.53 g, 66,0 mmol) in betwedn the m THF (250 ml), chilled in a bath containing ice water, added EDCI (6,33 g, 33.0 mmol) in 3 portions over 20 minutes with an interval of 5 minutes between servings. The suspension is stirred over night from the initial temperature 0°C to room temperature. After evaporation of THF, the residue is dissolved in ethyl acetate and sequentially washed with 10% citric acid solution, a saturated solution of NaHCO3and water. The organic fraction is dried over sodium sulfate and evaporated under reduced pressure. The residue is dissolved in DHM, passed through a layer of silica gel and elute with 20% ethyl acetate in hexane. Eluate evaporated to obtain the pure product, Boc-D-Phe-D-Leu-OBn, intermediate compounds 1-3 (12,40 g, 88%) as a clear oil. LC-MS: the ratio of mass-to-charge = 469 (M+H).

[00363] the Intermediate compound 1-3 (12,40 g of 26.5 mmol) is dissolved in DHM (50 ml). Add TFU (25 ml)and the solution stirred at room temperature for 2 caspase evaporation DHM and TFU, double-carry out azeotropic distillation of the residue with toluene to obtain salt TFU D-Phe-Leu-OBn, intermediate compounds 1-4. The resulting crude dipeptide suspended in THF, and added Boc-D-Phe-OH (6,36 g, 24 mmol), HOBt monohydrate (Android 4.04 g of 26.4 mmol) and DIEA (8.7 ml, 50.0 mmol) at 0°C. Added EDCI (6,33 g, 6.4 mmol) in 4 portions over 20 minutes with an interval of 5 minutes between servings. Suspension var who're asked at a temperature of from 0°C. to room temperature over night. After evaporation of THF, the residue is dissolved in ethyl acetate and washed sequentially with 10% citric acid solution, a saturated solution of NaHCO3and water. The organic fraction is dried over sodium sulfate and evaporated under reduced pressure. The remainder will recrystallized from 400 ml of a mixture of acetone/hexane (1:3) to give 9.1 g of the pure product. The mother liquor evaporated and then recrystallized from a mixture of acetone/hexane (1:3) to give 2.0 g of product. The total yield is 11.1 g (68% for 2 stages). LC-MS: the ratio of mass-to-charge = 616 (M+H). [00364] In a flask, purged with nitrogen, moist palladium on coal (1.8 g) and a solution of Boc-D-Phe-D-Phe-D-Leu-OBn, intermediate compounds 1-5 (11.1 g, 18,05 mmol) in methanol (50 ml). The mixture is stirred in hydrogen atmosphere (balloon) overnight. After filtration through brownmillerite, the methanol is evaporated under reduced pressure. The residue is dissolved in acetone (20 ml) and added slowly to 500 ml of water with 25 ml 1 n HCl under vigorous stirring. Pure product Boc-D-Phe-D-Phe-D-Leu-OH, the intermediate connection 1-6, receive filtering 9.4 g (99%). LC-MS: the ratio of mass-to-charge = 526 (M+H).

[00365] To a solution of intermediate compound 1-6 (of 2.06 g, 3.90 mmol), D-Lys(New)-OH hydrochloride (1.26 g, 3.90 mmol) and DIEA (1.7 ml, 9.8 mmol) in DMF added TBTU (1.56 g, 4,88 mmol) in 3 portions over 15 min at 0°C. After stirring over night at tempera what ur from 0°C to room temperature, DMF is evaporated under a deep vacuum. The crude reaction mixture was precipitated in 400 ml of a mixture of ice water and filtered to separate the precipitate, Boc-D-Phe-D-Phe-D-Leu-D-Lys(Boc)-OAll, the intermediate compound 1-7 (2,60 g)which was used without further purification in the next stage.

[00366] To a solution of intermediate compounds 1-7 (2,60 g, 3.3 mmol) in MeCN (75 ml) add pyrrolidine (1.1 ml, 13.3 mmol) and tetrakis(triphenylphosphine)palladium (400 mg, 0.35 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 3 hours and evaporated to the dry state. The residue is purified by reversed-phase column chromatography using a mixture of 30% MeCN/water to 90% MeCN/water to obtain the pure acid, intermediate compounds 1-8 (2.0 g, 80%) after evaporation of a mixture of acetonitrile/water. LC-MS: the ratio of mass-to-charge = 754 (M+H).

[00367] To a solution of acid, an intermediate compound I-8 (150 mg, 0.20 mmol), amine HNRaRb, (1,3-dioxolane-2-yl)methanamine (31 mg, 0.30 mmol) and DIEA (175 μl, 1.0 mmol) in DMF (5 ml) is added HBTU (113 mg, 3.0 mmol) at 0°C. After stirring overnight at a temperature from 0°C to room temperature, the DMF is evaporated under reduced pressure. The residue is stirred with 4 n HCl in 1,4-dioxane (2.0 ml) at room temperature for 1 hour. After removal of the dioxane, the residue is dissolved in water and purified by reversed-phase column is cromatografia with a gradient from a mixture of 10% MeCN/water mixture to 60% MeCN/water for 30 minutes to obtain a pure product the compound (25)

(44 mg, yield 44% for 2 stages) after evaporation of the solvent. LC-MS: the ratio of mass-to-charge = 639 (M+H).

EXAMPLE 26 Synthesis of compound (26): D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazine-1-yl)pyrimidine amide] (SEQ ID NO: 5):

[00368] the Compound (26) are obtained in substantially the same manner as described in Example 25, except that 2-(piperazine-1-yl)pyrimidine use on stage combination with Amida. LC-MS: the ratio of mass-to-charge = 700 (M+H).

EXAMPLE 27 Synthesis of compound (27): D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazine-1-yl)pyrazin amide] (SEQ ID NO: 5):

Connection 27 get in substantially the same manner as described in Example 25, except that 2-(piperazine-1-yl)pyrazin use on stage combination with Amida. LC-MS: the ratio of mass-to-charge = 700 (M+H).

EXAMPLE 28 Synthesis of compound (28): D-Phe-D-Phe-D-Leu-D-Lys-[1-(pyridine-2-yl)piperazine amide] (SEQ ID NO: 5):

[00369] the Compound (28) are obtained in substantially the same manner as described in Example 25, except that 1-(pyridine-2-yl)piperazine used at the stage of combining with Amida. LC-MS: the ratio of mass-to-charge = 699 (M+H).

EXAMPLE 29 Synthesis of compound (29): D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazine-1-yl)thiazole amide] (SEQ ID NO: 5):

[00370] the Connection 29 get in substantially the same manner as described in Example 25, except that 2-(piperazine-1-yl) thiazole use on stage with Etania with Amida. LC-MS: the ratio of mass-to-charge = 705 (M+H).

EXAMPLE 30 Synthesis of compound (30): D-Phe-D-Phe-D-Leu-D-Lys-[N,N-dimethylpiperazine-1-sulfonamide amide] (SEQ ID NO: 5):

[00371] the Connection 30 get in substantially the same manner as described in Example 25, except that N,N-dimethyl-piperazine-1-sulfonamide use on stage combination with Amida. LC-MS: the ratio of mass-to-charge = 729 (M+H).

EXAMPLE 31 Synthesis of compound (31): D-Phe-D-Phe-D-Leu-D-Lys-[1-(methylsulphonyl)piperazine amide] (SEQ ID NO: 5):

[00372] the Connection 31 get in substantially the same manner as described in Example 25, except that 1-(methylsulphonyl)piperazine is used at the stage of combining with Amida. LC-MS: the ratio of mass-to-charge = 700 (M+H).

EXAMPLE 32 Synthesis of compound (32): D-Phe-D-Phe-D-Leu-D-Lys-[1-(phenylsulfonyl)piperazine amide] (SEQ ID NO: 5):

[00373] the Connection 32 get in substantially the same manner as described in Example 25, except that 1-(phenylsulfonyl) piperazine is used at the stage of combining with Amida. LC-MS: the ratio of mass-to-charge = 762 (M+H).

EXAMPLE 33 Synthesis of compound (33); D-Phe-D-Phe-D-Leu-D-Lys-[phenyl(piperazine-1-yl)methanone amide] (SEQ ID NO: 5):

[00374] the Connection 33 get in substantially the same manner as described in Example 25, except that phenyl(piperazine-1-yl)methanon use on stage combination with Amida. LC-MS: the ratio is their mass-to-charge = 726 (M+H).

EXAMPLE 34 Synthesis of compound (34); D-Phe-D-Phe-D-Leu-D-Lys-[thiomorpholine-1,1-dioxide amide] (SEQ ID NO: 5):

[00375] the Connection 34 get in substantially the same manner as described in Example 25, except that thiomorpholine-1,1-dioxide is used at the stage of combining with Amida. LC-MS: the ratio of mass-to-charge = 671 (M+H).

EXAMPLE 35 Synthesis of compound (35): D-Phe-D-Phe-D-Leu-D-Lys-[6-trifluoromethyl-3-aminomethylpyridine amide] (SEQ ID NO: 5):

[00376] the Connection 35 get in substantially the same manner as described in Example 25, except that 6-trifluoromethyl-3-aminomethylpyridine use on stage combination with Amida. LC-MS: the ratio of mass-to-charge = 712 (M+H).

EXAMPLE 36 Synthesis of compound (36): D-Phe-D-Phe-D-Leu-D-Lys-N-methyl-1-(tetrahydro-2-Piran-4-yl)methanamine amide (SEQ ID NO: 5):

[00377] the Connection 36 get in substantially the same manner as described in Example 25, except that (tetrahydro-2H-Piran-4-yl)methanamine use on stage combination with Amida. LC-MS: the ratio of mass-to-charge = 651 (M+H).

EXAMPLE 37 Synthesis of compound (37): D-Phe-D-Phe-D-Leu-D-Lys-[5-(aminomethyl)-1H-benzo[d]imidazol-2(3H)-she amide] (SEQ ID NO: 5):

[00378] the Compound (37) are obtained in substantially the same manner as described in Example 25, except that 5-(aminomethyl)-1H-benzo[a]imidazol-2(3H)-he used on stage combination with Amida. LC-MS: the ratio of the mass of the charge = 699 (M+H).

EXAMPLE 38 Synthesis of compound (38): D-Phe-D-Phe-D-Leu-D-Lys-N-methyl-1-(5-methylpyrazine-2-yl)-methanamine amide) (SEQ ID NO: 5):

[00379] Compound 38 get in substantially the same manner as described in Example 25, except that (5-methyl-pyrazin-2-yl)-methanamine use on stage combination with Amida. LC-MS: the ratio of mass-to-charge = 659 (M+H).

EXAMPLE 39 Synthesis of compound (39):

[00380] figure 5 shows a General scheme for the synthesis of compound (40). Used the following derivatives of amino acids: Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-HE, Boc-D-Leu-OH, Fmoc-D-Orn(Boc)-HE and Fmoc-Lys(Dde)-HE. Fully protected, associated with the resin peptide synthesized manually, using as starting materials 2-horticulturally resin (0.3 mmol; Peptide International). Attaching the first amino acid to the resin to provide treatment with a mixture of Fmoc-Lys(Dde)-HE (to 0.29 g, 0.5 mmol; Novabiochem) and DIEA (0.35 ml, 2 mmol) in DHM (7 ml) at room temperature for 4 chessmore washed 3 × DHM/MeOH/DIEA (about./about./about.=17:2:1), and then treated with 25% piperidine in DMF to remove the Fmoc. Subsequent elongation of the peptide chain provide indirect Rover/DIEA single combinations with 3-times excess of amino acid derivatives, Fmoc-D-Orn(Boc)-OH and Boc-D-Leu-OH. The resulting peptide resin, Boc-D-Leu-D-Orn(Boc)-Lys(Dde)-[2-Cl-Trt resin], treated with 4% hydrazine in DMF three times for 3 min to remove the Dde. Follow the linnie peptide chain provide indirect Rover/DIEA single combinations with 3-times excess of amino acid derivatives, Fmoc-D-Orn(Boc) -, Fmoc-D-Leu-OH, Fmoc-D-Phe-OH and Boc-D-Phe-OH. The Fmoc group is removed with 25% piperidine in DMF. Fully assembled peptide otscheplaut from the resin by treatment with a mixture of TFU/TIS/N2About (15 ml, about./about./about.=95:2,5:2,5) at room temperature for 90 minutes the Resin is filtered off and washed with TFU. The filtrate is evaporated under vacuum and the crude peptide (0.3 mmol; D-Phe-D-Phe-D-Leu-D-Orn-[eLys(D-Orn-D-Leu-H)]-HE) precipitated from diethyl ether.

[00381] For purification, the crude peptide (0.3 mmol) dissolved in 2% acetic acid in H2O (50 ml), the solution was loaded on the HPLC column and purified using a buffer system TEAR with a pH of 5.2 (buffer solutions: A=TEAR 5,2 and=20% TEAR 5.2 in 80% ACN). Connection elute with a linear gradient of buffer solution In 10% to 40% In for 60 minutes of Fractions with a purity of over 95%, unite, and the resulting solution was diluted with 2 volumes of water. The diluted solution is further loaded on the HPLC column for salt exchange and additionally cleaned using buffer systems TFU (buffer solutions: A=0.1% OF TFU in H2O, and B=0.1% OF TFU in 80% ACN/20% H2O) and a linear gradient from buffer, 2% to 75% for 25 min Fractions with purity exceeding 97%are pooled, frozen and dried liofilizadora obtaining purified peptide in the form of a white amorphous powder (396 mg). Analysis by HPLC: tR=13,63 min, purity of 99.7%, gradient from 10% to 30% should the 20 min; MS (M+N+): the expected mass of the molecular ion 895,5 registered 895,6.

EXAMPLE 40: Synthesis of compound (40):

[00382] get Connection in accordance with the procedure described in the synthesis of compound (39) above. The difference is in the additional amino acid residue D-Phe in the intermediate compound, the peptide resin, Boc-D-Phe-D-Leu-D-Orn(Boc)-Lys(Dde)-[2-Cl-Trt resin]. Intermediate compound resin obtained by joining Fmoc-Lys(Dde)-2-chlorotriethylsilane the resin, followed by removal of the Fmoc and receipt of amino acid derivatives Fmoc-D-Orn(Boc) -, Fmoc-D-Leu-OH and Boc-D-Phe-OH. The final purified peptide: amorphous powder, exit 508 mg scale synthesis of 0.3 mmol. Analysis by HPLC: tR=18,90 min, purity 100%, gradient from 10% to 30% for 20 min; MS (M+N+): the expected mass of the molecular ion 1042,4 registered 1042,7.

EXAMPLE 41: Synthesis of compounds(41)-(52):

Compound (41):

Compound (42):

Compound (43):

Compound (44):

The compound (45):

Compound (46):

The compound (47):

Compound (48):

Compound (49): 1N,4N-bis-[D-Phe-D-Phe-D-Leu-(iPr)D-Orn]-4-amino-4 - carboxyl piperidine

<> Connection (50): 1N,4N-bis-[D-Phe-D-Phe-D-Leu-D-Dap(amidino)]-4-amino-4-carboxyl piperidine

The compound (51): 1N,4N-bis-(D-Phe-D-Phe-D-Leu-D-Nar)-4-amino-4-carboxyl piperidine

Compound (52):

[00383] the Above compounds (41)-(52)above can be synthesized according to the General schemes shown in figure 5, 6 and 7, by methods similar to those used in the synthesis of compounds (39) and (40), described in detail above.

EXAMPLE 42 Synthesis of compound (53) D-Phe-D-Phe-D-Leu-D-Orn-[R/S-2-carboxymethyl]-(SEQ ID NO: 1):

[00384] Scheme is shown in Fig. Used the following derivatives of amino acids: Boc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Leu-OH, Fmoc-D-Orn(Boc)-and (R,S)-Fmoc-2-carboxymaltose. Fully protected, associated with the resin peptide synthesized in the synthesizer SYMPHONY Multiple Synthesizer (Protein technologies Inc.), using as starting materials 2-horticulturally resin (0.4 mmol; Novabiochem). Attaching the first amino acid to the resin to provide treatment with a mixture of (R,S)-Fmoc-2-carboxymaltose (0.18 g, 0.5 mmol; NeoMPS) and DIEA (0.35 ml, 2 mmol) in DHM (7 ml) at room temperature for 4 chessmore washed 3×DHM/MeOH/DIEA (about./about./about.=17:2:1) and 3×DHM. Subsequent elongation of the peptide chain provide indirect HBTU/DIEA single combinations with 3-times excess of amino acid derivatives. The Fmoc group is removed by treatment with 25% piperidine in DMF. For splitting, the final pepti the ing the resin is treated with a mixture of TOY/TIS/H 2O (15 ml, about./about./about.=95:2,5:2,5) at room temperature for 90 minutes the Resin is filtered off and washed with TFU. The filtrate is evaporated under vacuum and the crude peptide (0.15 g, DPhe-DPhe-DLeu-DOrn-[R/S-2-carboxymethyl]-HE) precipitated from diethyl ether. [00385] For purification, the above-described crude peptide (0.15 g) dissolved in 0.1% TFU in H2O (50 ml), the solution was loaded on the HPLC column and purified using a buffer system TFU (buffer solutions: A=0.1% OF TFU in H2O and B=0.1% OF TFU in 60% ACN/40% H2O). Connection elute with a linear gradient from buffer B, 25% to 75% for 30 min, tR=45% Century Fractions with purity exceeding 97% unite, frozen and dried liofilizadora obtaining purified peptide in the form of a white amorphous powder (84 mg). The compound is a mixture of diastereoisomers, because no attempt has been made to separate the two isomers, DPhe-DPhe-DLeu-DOrn-[R-2-carboxymethyl]-HE and DPhe-DPhe-DLeu-DOrn-[S-2-carboxymethyl]-HE. Analysis by HPLC: tp=16,93 min (49,6%) and 17,34 min (50,4%), the overall purity of 100%, gradient from 10% to 30% for 20 minutes.

[00386] figure 9 shows the General chemical scheme used in the synthesis of compound (53) the Compound (53): D-Phe-D-Phe-D-Leu-D-Orn-[R/S-2-carboxymethyl]-(SEQ ID NO: 1):

EXAMPLE 43 Synthesis of compounds (54)-(66)

[00387] the Compound (54)-(66) can be obtained by a well-known ways si is thesis. For example, compound (40), see below, can be obtained in accordance with the scheme of chemical synthesis in Fig.9.

Connection (54): D-Phe-D-Phe-D-Leu-D-Orn-[R/S-2-carboxymyoglobin]-(SEQ ID NO: 1):

[00388] figure 9 shows the General chemical scheme used in the synthesis of compound (55).

Compound (55) D-Phe-D-Phe-D-Leu-D-Orn-N(homomorpholine) (SEQ ID NO: 1):

Connection (56): D-Phe-D-Phe-D-Leu-D-Orn-N(sometimesvalid) (SEQ ID NO: 1):

Compound (57): D-Phe-D-Phe-D-Leu-D-Dap(amidino)-[homomorpholine amide] (SEQ ID NO: 8):

Connection (58); D-Phe-D-Phe-D-Leu-D-Dap(amidino)-[homotaurine amide] (SEQ ID NO: 8):

Compound (59): D-Phe-D-Phe-D-Nle-D-Dap(amidino)-[homomorpholine amide] (SEQ ID NO: 8):

Connection (60): D-Phe-D-Phe-D-Nle-D-Dap(amidino)-[homotaurine amide] (SEQ ID NO: 8):

Connection (61): D-Phe-D-Phe-D-Leu-D-Arg-[homomorpholine amide] (SEQ ID NO: 7):

Connection (62): D-Phe-D-Phe-D-Leu-D-Arg-[genotypephenotype amide] (SEQ ID NO: 7):

Connection (63): D-Phe-D-Phe-D-Leu-D-Orn(Me)-[homomorpholine amide] (SEQ ID NO: 4):

Connection (64): D-Phe-D-Phe-D-Leu-D-Orn(Me)-[homotaurine amide] (SEQ ID NO: 4):

Connection (65): D-Phe-D-Phe-D-Leu-DOrn(iPr)-[homomorpholine amide] (SEQ ID NO: 3):

Connection (66) D-Phe-D-Phe-D-Leu-D-Orn(iPr)-[homotaurine amide] (SEQ ID N0: 3):

EXAMPLE 44: the Inhibition of the production of camp stimulation of endogenous Kappa-opioid receptors in mice R1.G1 cells.

[00389] the activity of the synthetic peptide amides as agonists of the Kappa opioid receptor is determined by measuring the inhibition of stimulated Forskolin adenylate cyclase activity. Cells R1.G1 (a cell line of mouse thymoma, which expresses only the Kappa-opiate receptor and expresses not other subtypes of opiate receptor) is first processed by Forskolin (for induction of camp) plus synthetic peptide amidon in the studied concentration. After incubation, the level of camp in the treated cells R1.G1 determined using the immunoassay of camp-based energy transfer fluorescence resonance with time resolution (TR-FRET, LANCE™, Perkin Elmer). Below method is described in detail.

[00390] Mouse cells R1.G1 ADS, Manassas, VA) were cultured in suspension in DMEM with high glucose (modified Dulbecco Wednesday Needle, Cellgro, Herndon, VA)containing 10% horse serum and 2% glutaMax (Invitrogen, Carlsbad. CA) without addition of antibiotics. On the day of experiment, cells are centrifuged at a speed of 1000 rpm./min for 5 minutes at room temperature, and then prom is live 1 time in HBSS (buffered salt solution HEPES, Invitrogen, Carlsbad, CA). Next, the cells are again centrifuged and resuspended in buffer solution for stimulation (HBSS with addition of 0.05% albumin calf serum-FAF [free fatty acid albumin calf serum, Roche Applied Science, Indianapolis, IN], 5 mm HEPES) at a concentration of 2 million cells/ml Antibody supplied in the kit for immunoassay of camp LANCE™, then added to the cells according to the manufacturer's instructions, and 12,000 cells/well placed in wells containing Forskolin in a pre-defined final concentration (usually about 2.5 μm), and a predetermined number of the investigated synthetic peptide amide.

[00391] the Synthetic peptide amides were studied range of concentrations to determine their activity. Cells were incubated with synthetic peptide inorganic salts plus Forskolin for about 20 minutes at room temperature. After incubation, was carried out by lysis of the cells by adding 12 μl of manifesting mixture, supplied in the kit LANCE™, followed by incubation for 1 hour at room temperature. Fluorescence with time resolution was measured using excitation filter 330-380 nm, the filter emission 665 nm, dichroism mirror 380, and Z=1 mm Standard curve the concentration of camp in this test helps to determine the amount of camp present in each l is the NCA. The curve constructed by plotting a graph of concentration of synthetic peptide amide against the level of camp in the cells under study, and handle non-linear regression using the algorithm of approximation of a 4-parameter curve to calculate EU50concentrations of synthetic peptide amide required to achieve 50% maximal inhibiting the production of camp synthetic inorganic salts.

EXAMPLE 45: Confirmation of activity of synthetic compounds on the human Kappa-opioid receptors.

[00392] Embryonic kidney cells (cells SOME 293, ATSS, Manassas, VA) in the cups with a diameter of 100 mm transferout reagent for transfection, Fugene6 (Roche Molecular Biochemicals) and constructs the DNA at a ratio of 3.3:1. The DNA constructs used for transfection, were as follows: (i) the expression vector for the human Kappa-opioid receptor, (ii) an expression vector for human chimeric G-protein, and (iii) the construct of luciferase reporter in which the expression of luciferase induce sensitive to calcium transcription factor NFAT.

[00393] the expression Vector containing the human Kappa-opioid receptor, design, as listed below: Human OPRK1 gene clone from total RNA dorsal root ganglion person by PCR, and gene inserted into the expression vector pcDNA3 (Initrogen, Carlsbad, CA)to construct the expression vector pcDNA3 mammalian-hOPRK1 human OPRK1.

[00394] To construct a vector expression of a chimeric G-protein man, first constructing chimeric G-protein Gαqi5 by replacing the last 5 amino acids of human Gaq sequence of the last 5 amino acids of Gαi by PCR. The second mutation is introduced into this human gene Gαqi5 at amino acid position 66 for replacement of glycine (G), aspartic acid (D) method of site-directed mutagenesis. The obtained gene next subcloning in the expression vector mammalian pcDNA5/FRT (Invitrogen) to obtain the vector expression of human chimeric G-protein, pcDNA5/FRT-hGNAq-G66D-i5.

[00395] For construct reporter gene luciferase, synthetic response elements, including 3 copies of the TRE (elements 12-0-tetradecanoylphorbol-13-acetate-responsive) and 3 copies of the NFAT (nuclear factor of activated T cells) incorporate in the direction of 3'-5' in relation to the minimal promoter of c-fos. This reactive element and the promoter cassette is then inserted into pCL3-the main vector of the reporter gene luciferase (Promega)to construct the construct plasmid reporter gene luciferase pGL3b-3TRE-3NFAT-cfos-Luc.

[00396] the Mixture for transfection for each plate of cells consisted of 6 μm pcDNA3-hOPRKl, 6 µg pcDNA5/FRT-hGNAq-G66D-i5 and 0.6 µg pGL3b-3TRE-3NFAT-cfos-Luc. Cells inquire the t for one day at 37°C in a humid atmosphere, containing 5% CO2with subsequent transfection and applied to an opaque 96-well plates in a concentration of 45,000 cells per well in 100 μl of funds. The next day, the investigated compounds and compounds compare add to the cells in the individual wells. The range of concentrations of the studied compounds added to one set of holes, and a similar range of concentrations of the compounds compare add to the set of control wells. Cells are then incubated for 5 hours at 37°C. At the end of the incubation perform lysis of the cells by adding 100 μl of manifesting a mixture containing the luciferase substrate (AMP [22 µg/ml], ATP [1.1 mg/ml], dithiothreitol [of 3.85 mg/ml], HEPES [final concentration 50 mm], EDTA [0.2 mg/ml]. Triton N-101 [4 ál/ml], phenylacetic acid [45 µg/ml], oxalic acid [8,5 mg/ml], enzyme [28 µg/ml], 7,8). Tablets sealed and measure the fluorescence within 30 minutes. Data is put on a graph of the concentration of each of the compounds against fluorescence pulses per second (cps) and the resulting curves "dose-response" approximate nonlinear regression using algorithm 4 parametric curve to calculate EU50(the concentration of compound required to achieve 50% maximal increase in luciferase activity) and efficacy (maximal activation in percent compared to the full what nuccia any of the known agonists of the Kappa-opiate receptor, such as asimadoline (EMD-61753: see Joshi et al., 2000, J. Neurosci. 20(15): 5874-9), or U-69593: cm. Heidbreder et al., 1999, Brain Res. 616(1-2): 335-8).

[00397] In table II shows the values of the EU50resulting from analysis of the inhibition of camp with examples of the compounds synthesized in accordance with the present invention and studied on the model of the Kappa-opiate receptor (mKOR) mice with confirmation of the results on the model of the human Kappa opioid receptor (hKOR) the above-described method.

[00398] the Synthetic peptide amides of the invention have been investigated in such activity analysis model of the human mu-opioid receptor. Each of the investigated compounds showed EU50for the human mu-opioid receptor ≥ 1 ám.

Table II
The activity values for the Kappa-opiate agonist
Connection # mKORhKOR
EC50(nm)Efficiency (%)EC50(nm)Efficiency (%)
10,40398 0,49102
20,08970,1399
39,0588n/an/a
450,5687n/an/a
53,0196n/an/a
60,0411000,17107
70,0281020,14104
80,1971020,1693
90,088920,39134
100,08599 0,1292
110,081000,1290
120,0921000,3099
130,115960,2496
140,022960,21105
151,96693n/an/a
160,030990,1290
170,056990,1290
180,049990,1499
190,035101 0,2193
200,193920,1597
210,07897n/an/a
22of 0.08197n/an/a
230,04595n/an/a
240,03396n/an/a
250,1472850,02198
260,12 (average)780,007398
270,0005850,0293100
280,0471 0,0059100
290,084850,03192
n/d - not determined

Table II
The activity values for the Kappa-opiate agonist (continued)
Connection # mKORhKOR
EC50(nm)Efficiency (%)EC50(nm)Efficiency (%)
300,1931860,0194101
310,2456820,0073100
320,530870,011101
330,3476 920,01294
340,1916890,0306103
350,4849850,066795
360,6327890,003499
370,072870,006399
380,1894870,0165100
3967,335n/an/a
401,07960,2683
410,051000,289
420,24 970,2795
430,081010,1394
441,30910,2593
450,05960,2896
460,1295n/an/a
470,0591n/an/a
480,3485n/an/a
491,8350n/an/a
5056,6677n/an/a
5195,78 60n/an/a
5213,8176n/an/a
530,1781000,16100
n/d - not determined

[00399] Synthetic peptide amide (53) investigated in this analysis activity on the model of the human mu-opioid receptor. The compound showed EC50for the human mu-opioid receptor ≥1 ám.

EXAMPLE 46 the influence of the synthetic peptide amides on the permeability of the membrane

[00400] the cell Line of SASO-2 is a cell line of adenocarcinoma of the colon and rectum of a person, which is differentiated in culture and used to simulate the epithelial lining of the small intestine of man. Compounds of the present invention can be tested in the test membrane permeability using subclone TS SASO-2 in the standard analysis (Cerep, Seattle, WA). In short, the ratio of the apparent permeability (Papp) can be determined in the apical-basolateral direction (a-b) across monolayers of cells, kultivirovanie 96-LUN is cnyh polycarbonate membrane filters.

[00401] for Example, the compounds according to the invention can be tested in a concentration of 10 μm at pH 6.5 in 1% DMSO, with the recipient party, held at a pH of 7.4. Analysis tablet incubated for 60 minutes at 37°C with careful shaking. Samples taken at the zero point of time from the donor side and at the end of the incubation period, with both donor and recipient sides. The samples are preferably analyzed by HPLC-MS/MS. Value (expressed as 10-6cm/sec.) Papp then calculated based on the speed of the connection is on the recipient side. Connections, comparisons, such as labetalol, propranolol, ranitidine and vinblastine, can be investigated in parallel to ensure the validity of the test.

EXAMPLE 47 Inhibition of oxidase cytochrome P450[00402] the Inhibition of oxidase isoenzymes of cytochrome P450 CYP1A, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 synthetic connecting peptide amidon (17) of the invention was determined in accordance with the following methods, performed Seger (Seattle, WA):

[00403] In the analysis of the cytochrome P450CYP1A, liver microsomes human (0.2 mg/ml protein) are incubated for 15 minutes at 37°C With 10 μm of the compounds, 1 μm ethoxyresorufin, 1.3 mm NDF, 3.3 mm glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase. In the absence of the tested compound, dextromethorphan is, added as the substrate is oxidized to resorufin, and in the presence of an inhibitor of CYP isoenzyme, the number of the resulting resorufin reduced. Furafylline used as an inhibitor of comparison. The reaction mixture analysis of cytochrome P450CYP2C9 containing liver microsomes human (0.2 mg protein/ml), incubated for 15 minutes at 37°C With 10 μm of the compounds, 10 μm tolbutamide, 1.3 mm NADP, 3.3 mm glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase. In the absence of the tested compound, tolbutamide is oxidized to 4-hydroxytryptamine, and in the presence of an inhibitor of CYP isoenzyme, the number of the resulting 4-hydroxytryptamine reduced. Sulfaphenazole (IC50: 0,35 µm) serves as an inhibitor of comparison. For analysis of cytochrome P450CYP2C19, liver microsomes human (0.2 mg/ml protein) are incubated for 15 minutes at 37°C With 10 μm of the compounds, 10 μm omeprazole, 1.3 mm NADP, 3.3 mm glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase. In the absence of the tested compound, omeprazole is oxidized to 5-omeprazole, and in the presence of an inhibitor of CYP isoenzyme, the number of the resulting 4-tolbutamide is reduced. Oxybutynin (IC50; of 7.1 μm) as an inhibitor of comparison.

[00404] the Reaction mixture of the analysis of the cytochrome P450CYP2D6 containing liver microsomes human (0.2 mg/ml protein) Inc is berout for 15 minutes at 37°C with 10 μm of the compounds, 5 μm of dextromethorphan, 1.3 mm NADP, 3.3 mm glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase. In the absence of the tested compound, dextromethorphan is oxidized, and in the presence of an inhibitor of CYP isoenzyme, the amount of oxidation product is reduced. Quinidine (IC50: 0,093 μm) as an inhibitor of comparison. Recombinant human cytochrome P450CYP3A4 (20 pmol/ml) incubated for 20 minutes at 37°C with 10 μm of the compounds, 5 μm midazolam, 1.3 mm is NECESSARY, 3.3 mm glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate dehydrogenase. In the absence of the tested compound, midazolam is oxidized, and in the presence of an inhibitor of recombinant isoenzyme, the amount of oxidation product is reduced. The content of the oxidation product is determined on the basis of area under the curve after separation by HPLC-MS/Scatological (IC50: 0.55 m) is an inhibitor of comparison. In each trial, the percentage inhibition of the isoenzyme of cytochrome P450CYP P450was defined as 100 times the ratio of (1 - the amount of product in the sample in the presence of the tested compound)divided by the number of product in the sample containing the raw isoperimetrical analyses in double repetition (expressed as a percentage saved CYP activity) is shown in table III.

Table III
The percentage activity of the isoenzymes of the cytochrome P450CYP
Connection(17)
Isoenzyme P450Expt 1Expt 2
CYP1Ato 97.195,8
CYP2C999,2of 98.2
CYP2C1994,1of 97.8
CYP2D698,4of 98.2
CYP3A494,795,9

EXAMPLE 48 Pharmacokinetics in cynomolgus macaques

[00405] Single bolus connections synthetic peptide amide is administered by intravenous infusion Javanese makaka (n=4 males, body weight 3-5 kg, SNBL USA, Ltd., Everett, WA), and selected plasma samples through 5, 10, 15, 20, 30 60, 90, 120 and 180 minutes after injection. The half-life is defined as the time required to reduce the plasma concentration by 50% after reaching the maximum concentration in plasma. Cynomolgus macaques received intravenous injection ADNOC atnow the dose of a compound of the synthetic peptide amide (19) in accordance with the Protocol, described in detail in Example 19, and determined the half-life in plasma concentrations. The results are shown in .V.

Table V
The half-life connections synthetic peptide amide in vivo (19)*
Cynomolgus macaques
Route of administration half-life (minutes)intravenous 69
* Connection (19): D-Phe-D-Phe-D-Leu-D-Orn-[4-(N-methyl)amide amidino-homopiperazine] (SEQ ID NO: 1).

EXAMPLE 49 Analysis on the model induced by acetic acid of writhing in mice

[00406] In this analysis identify compounds that demonstrate analiticheskoy activity against visceral pain or pain-related activation are sensitive to low pH values of nociceptors [see Barber and Gottschlich (1986) Med. Res. Rev. 12: 525-562; Ramabadran and Bansinath (1986) Pharm. Res.3: 263-270]. Intraperitoneal injection of a dilute solution of acetic acid causes the behavior of writhing in mice. Cramps are defined as the contraction of the muscles of the abdomen, followed by pulling the front legs and lengthening of the body. The number of writhing observed in the presence and absence of the investigated connection of the clusters count to determine the analgesic activity of the compounds.

[00407] In each day of testing models of writhing included a control group of mice (n=6-8), treated with the solvent, which was treated as studied group (except that the test connection was not available in injectable dose), and the average total number of writhing in this group was used as the absolute reference point that defines the 0% reduction in pain perception for all other mice receiving the analyzed connection on the specified day. Specifically, the total number of writhing for each mouse received an investigational compound, translated in % reduction in pain perception in accordance with the following equation:

where Wvrepresent the average number of writhing in receiving solvent group, and Wcrepresent the number of writhing in mice treated with the investigational compound. Data were analyzed using a 2-parameter hill equation (also called the model Emax, where Emax is 100% anticipatable (i.e., no cramps for 15 minutes after injection of acetic acid).

[00408] of male Mice ICR mass 23-37 g was weighed and placed in individual chambers (usually glass beaker with a volume of 4000 ml) is La surveillance with a thin layer of bedding for rodents SANI-CHIPS on the bottom of the camera. To determine the activity and capacity of the compounds under study, different doses of a solution of the compound or solvent was administered by subcutaneous injection in the back of the neck after 15 or 180 minutes prior to the introduction of a solution of acetic acid. After the introduction of the compound or the control solvent, the mice were returned to individual cameras for surveillance to expect intraperitoneal administration of acetic acid solution. After 15 minutes or 3 hours, in accordance with the time interval specified in each experiment from the introduction of the connection before the injection of acetic acid, the dose corresponding to 10 ml/kg of 0.6% (vol./about.) solution of acetic acid was injected injected in the lower right quadrant of the abdomen. Immediately after injection, the mouse was returned to the camera to monitor and immediately began to record the number of writhing. The number of writhing was counted for a period of 15 minutes starting from the moment of injection of acetic acid, and data were recorded for 3 separate time periods lasting 5 minutes each (0-5 minutes 5-10 minutes 10-15 minutes).

[00409] Data were recorded as ED50and the hill coefficient. ED50 expressed as mean ± standard error of the mean (sem) (ED50+/- sem) or as the geometric mean value with 95% confidence intervals (95% CI) using the t-scale. The hill coefficient is expressed as arithmetic the conglomerate, mean ± sem, calculated on the basis of the values obtained by observation of the animals. The results are shown in figure 10.

EXAMPLE 50: Inhibition move in mice to measure the sedative effect of the compounds after subcutaneous injection

[00410] Compounds that demonstrate sedative activity, inhibit inadvertent movement of mice in the chamber studies. To determine the potential sedative effect of the studied compounds, the degree of movement after the introduction of a test compound or control solvent can be determined and compared with the help of special device designed for this purpose (measuring activity Opto-Varimex). At the beginning of each experiment, each mouse was weighed and considered to determine the proper state of health. To determine the activity and power connections, different doses of a solution of the compound or solvent injected by the subcutaneous injection of 15 or 180 minutes before logging data. Subcutaneous injection is performed in the back of the neck of the mouse, sumipntg in "tent"to allow access of the needle of the syringe. After injection, each animal is placed in individual Plexiglas box (43×43 cm) inside the unit for measuring the activity of Opto-Varimex. Before the animal is placed in the device, a thin layer of bedding for rodents SAI-CHIPS are placed on the bottom of the Plexiglas box, to create a comfortable environment. Each device for measuring the activity of Opto-Varimex then include in the registration mode data, which starts the system autolite of ATMS. The data is processed, and the results expressed in the same way as described for the data analysis on the model of writhing above.

EXAMPLE 51 Analgesic effect against the sedative effect of the synthetic peptide amide (17): D-Phe-D-Phe-D-Leu-D-Orn-[4-(4,5-dihydro-1H-imidazol-2-yl)amide homopiperazine] (SEQ ID NO: 1).

[00411] Inhibition induced by acetic acid cramps is an indicator of analgesic effect (also called the antinociceptive effect). Similarly, the reduction of movement can be used as an indicator of overall sedative effect. The value of the ED50defined in the model induced by acetic acid of writhing in mice IRC, amounted to 74 µg/kg [95% confidence interval 49-99 µg/kg] after subcutaneous administration of a synthetic peptide amide (17). The value of the ED50defined on the model of the suppression of the movement, was 3172 µg/kg [95% confidence interval 1810-4534 µg/kg] for the same synthetic peptide amide with a subcutaneous injection (see figure 10). therapeutic ratio of analgesic effect and sedative effect represents the ratio of the values of the ED50required to access the supply sedative effect, compared with the value of the ED50necessary to achieve an analgesic effect. Thus, compound (17) shows the ratio (3172/74) times, i.e. 42,86 time. Thus, therapeutic ratio for compound (17) is approximately 43 times.

EXAMPLE 52: Pharmacokinetics of compounds of synthetic peptide amides in monkeys

[00412] the Samples injected to male monkeys of Massa fascicularis (SNBL USA, Ltd., Everett, WA, specially bred cynomolgus macaques. Closely related person, as phylogenetically and physiologically) aged 3-7 years weighing 3-5 kg of Sample is injected into a superficial vein of the arm or leg [e.g., shoulder or saphenous vein of the leg) in 0.9% sodium chloride for injection, Pharm. USA (Baxter Healthcare, Deerfield, 111.), as follows: the Cartridge with the sample containing 0.4 mg of compound (19) of the present invention and 0.4 mg of each of the 9 other compounds (up to a total dose 4 mg), prepared in 2 ml of 0.9% sodium chloride for injection, with a concentration of 0.2 mg/ml each of 10 connections. An aliquot of 2 ml is administered as an intravenous bolus experimental animal that makes a total dose level of 0.8-1.3 mg/kg, depending on the body weight of each animal. Intravenous injection complete 1 ml of 0.9% sodium chloride for injection. Blood samples with a volume of 0.6 ml is taken by venipuncture peripheral vein through 2.5, 10, 15 and 30 minutes after administration of the dose, and then after 1, 2 and 4 hours. Each sample is placed in a pre-cooled glass tube containing lithium heparin, and immediately cooled on ice. Plasma taken after centrifugation with a speed of 2000 l for 15 minutes at 2-8°C. the Layers of each plasma sample is moved to a polypropylene tube and stored in a frozen state at a temperature of -60°C or below until analysis. Aliquot 100 ál of thawed plasma fixed 5 μl of a solution of a suitable internal standard 400 ng/ml (in this case, the known compounds of the synthetic peptide amides) in 0.1% TFU, and proteins precipitated with 100 μl of 0.1% TFU in acetonitrile. The samples are centrifuged at 1000×g for 5 minutes, and the supernatant analyzed by LC-MS. Analysis by LC-MS performed on a mass spectrometer Finnigan LCQ Deca connected to the system HPLC Surveyor (Thermo Electron Corporation, Waltham, Massachusetts, USA). Analysis by HPLC performed on a reversed-phase C18 columns of 2.1×150 mm, gradient from 0.01% TFU in acetonitrile to 0.01% TFU in the water. Mass determination was performed using selective reaction monitoring (SRM). Quantification was performed against a calibration curve of the analyte in blank plasma cynomolgus macaques using this internal standard. Data analysis and calculation of pharmacokinetic PA is Ametov was performed using the software RK Solutions 2.0 (Summit Research Services, Ashland, Ohio, USA). The results for compound (19): D-Phe-D-Phe-D-Leu-D-Orn-[4-(N-methyl)amide amidino-homopiperazine] (SEQ ID NO: 1) shown in figure 11.

EXAMPLE 53: Ophthalmic analgesia induced by a synthetic peptide inorganic salts according to the invention

[00413] Ocular analgesia induced by a synthetic peptide inorganic salts according to the invention, can be estimated in the analysis of in vivo on rabbits, as indicated below: 5 aliquot of the investigated compounds, 50 μl of a physiological solution of sodium chloride, in the studied concentration, introducing drip into the right eye of new Zealand rabbits, albino, not previously participated in the experiments for 20 minutes 15 minutes after the last instillation of the compounds, each animal performed a single instillation of 30 μl of a solution of 10 mg/ml capsaicin (33 mm) in the treated eye. It is known that capsaicin causes pain in the cornea. Pain in the cornea estimate the dimension of the opening of the century in millimeters using a transparent ruler in the treated and untreated eyes. In this animal model, reducing the size of the opening century after installation capsaicin is the exponent induced pain. Thus, any registered restoring the size of the opening century after treatment with investigational compound is considered as a measure clothe treatment capsaicin-induced eye pain.

[00414] Such assessments performed before treatment with investigational compound (before the test), immediately before instillation of capsaicin, and then through 1, 5, 10, 15, 20, 25, 30, 40, 50 and 60 minutes after instillation of capsaicin. The average value of the opening of the century can be expressed as a percentage of the control values over a period of 10-30 minutes after installation of capsaicin in rabbits, which was conducted prior instillation Kappa-opiate agonist according to the invention, and after the installation of control joints in standard concentrations, such as diltiazem, benzodiazepinovyj blocker calcium channel. Cm. Gonzalez et al., (1993) Invest. Ophthalmol. Vis. Sci.34: 3329-3335.

EXAMPLE 54: Dependence "dose-response" for the synthetic peptide amides of the invention in capsaicin-induced eye pain

[00415] Ocular analgesia induced investigated synthetic inorganic salts, examine when installing in several concentrations in the right eye of new Zealand rabbits, albino, previously did not participate in experiments, and evaluated as described in Example 31 above. The results are compared with the analgesia induced by 10 mg/ml morphine (non-selective opioid agonist) and 10 mm of diltiazem as the control connection in the same experiment under the same conditions.

[00416] description of each of the U.S. patents and the op is slikovnih patent applications as well as the texts of literary references cited herein, incorporated by reference in their entirety. If any definition or description, found in one or more of these links, comes into contradiction with the appropriate definition or description in this specification, it applies to the definition or description, disclosed in this specification.

[00417] the Examples given in this description are only intended in this description and should not be interpreted as limiting the invention, the full context of which will be understood by a person skilled in this field.

1. Synthetic peptide amide of the formula:

or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, or hydrate acid salt,
where each Xaa1independently selected from the group comprising D-Phe, (α-Me)D-Phe, D-Tyr, D-Tic, D-tert-leucine, D-neopentylglycol, D-phenylglycine, D-homophenylalanine and β-(E)D-Ala, where each (E) is independently selected from the group comprising cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl;
each XAA2independently selected from the group comprising D-Phe, (α-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala and D-Trp;
each Xaa3independently selected from the group comprising D-Nle, D-Phe, cyclopentyl-D-Ala, D-Leu, (α-Me)D-Leu, D-Hle, D-Val and D-Met;
each Xaa4independently selected from the group comprising (B) 2D-Arg, (B)2D-nArg, (B)2D-Har, ζ-(B)D-Hlys, D-Dap, ε-(B)D-Lys, ε-(B)2-D-Lys, D-Amf, amidino-D-Amf, γ-(B)2D-Dbu, δ-(B)2α(B')D-Orn, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidine)propionic acid, D-α-amino-β-amidinopropane acid, α-amino-4-piperidinyloxy acid, CIS-α,4-diaminocyclohexane acid, TRANS-α,4-diaminocyclohexane acid, CIS-α-amino-4-methylenecycloartanol acid, TRANS-α-amino-4-methylenecycloartanol acid, α-amino-1-amidino-4-piperidinyloxy acid, CIS-α-amino-4-guanidinosuccinic acid and TRANS-α-amino-4-guanidinosuccinic acid, where each (B) independently selected from the group comprising-H, and C1-C4alkyl, and (B') represents-H or (α-Me), and p is 0 or 1;
G is selected from one of the following fragments:
(i) G is a

where q is 0 or 1;
r is 0 or 1;
s is 0 or 1;
each of p and t are independently 0 or 1, provided that at least one of s and t is 1;
L represents a linker selected from the group comprising ε-D-Lys, ε-Lys, 4-amino-4-carboxypeptidase and (D-Lys-Gly lactam)2;
(ii) G is a

where p is 1;
Xaa3-Xaa4is selected from the group comprising D-Nle-(B)2D-Arg-D-Leu-δ-(B)2α(B')D-Orn - and (α-Me)D-Leu-δ(B 2-α(B')D-Orn-; and
fragment

represents an optionally substituted 4-8 membered heterocyclic ring fragment, where all the ring heteroatoms in the specified ring fragment represent N; where each of Y and Z independently represents C or N, and Y and Z are not adjacent atoms of the ring; provided that when such ring fragment is a 6-, 7 - or 8-membered ring, Y and Z are separated by at least 2 atoms in the ring; and provided that when such ring fragment contains one heteroatom represents N, this ring the fragment is non-aromatic;
(iii) G is a

where p is 1; and
fragment

represents an optionally substituted 4-8 membered heterocyclic ring fragment, where Y is C or N and Z represents C, N, O, S, SO or SO2; provided that, if such a ring fragment is a 6-, 7 - or 8-membered ring, Y and Z are separated by at least two ring atoms; provided that when such ring fragment is non-aromatic, and Z represents C or N, this ring fragment includes at least one heteroatom S or O in the ring; and provided that when such ring fragment is the flavor of the economic, then Y is C;
(iv) G is aminomethyl-1H-benzo[d]imidazol-2(2H)-he;
where W is absent, provided that when W is absent, Y is N;
or selected from the group including:
-NH-(CH2)b-where b is 0, 1, 2, 3, 4, 5 or 6; and
-NH-(CH2)c-O-, where c is 2 or 3;
where V represents a C1-C6alkyl, and e is 0 or 1, where if e is 0, V is absent, and R1and R2directly attached to the same or different ring atoms;
where (a) R1represents-H, -OH, CF3, -NH2, -COOH, C1-C6alkyl, amidino, C1-C6-alkyl substituted amidino, heterocyclyl, Pro-amide, Pro, CONH2, COR', SO2R', CONR'R" or SO2NR'r R"; where each of R' and R" independently represents-H, C1-C8alkyl, aryl or heterocyclyl; and R2represents H, amidino, amidino substituted by one or two C1-C6alkilani, -CONH2, -CONR'R", -SO2NR'r R", or-COOH; or
(b) R1and R2together may form a 4 to 9-membered heterocyclic monocyclic or bicyclic ring fragment attached to the same atom of ring Y - and Z-containing ring fragment, with the specified 4-9-membered heterocyclic monocyclic or bicyclic ring fragment optionally contains one or two for whom estates, independently selected from phenyl, C1-C6of alkyl, carbonyl group and(or) Cl; or
(c) R1and R2together with one atom of ring Y - and Z-containing ring fragment can form a 4-8-membered heterocyclic ring fragment, which optionally contains one or two substituent independently selected from phenyl and / or carbonyl group, with the formation of spirotrichous; or
(d) R1and R2together with two or more adjacent ring atoms of the Y and Z-containing ring fragment can form optional oxazolidinyl 4-9-membered heterocyclic monocyclic or bicyclic ring fragment fused with the Y - and Z-containing ring fragment;
provided that if Y and Z-containing ring fragment is a 6 - or 7-membered ring containing one heteroatom in the ring, and if one of Y and Z represents C, and the other of Y and Z represents N, and e is 0, R1is not-OH, and R1and R2both are not-H;
provided that if Y and Z-containing ring fragment represents a 6-membered ring containing two heteroatoms in the ring, Y and Z are N, W is absent and-Ve(R1)(R2) is attached to Z, then Ve(R1)(R2) selected from the group comprising amidino, C1-C6and killamey amidino, dihydroimidazole, -CH2COOH and-CH2C(O)NH2;
provided that if Y and Z-containing ring fragment represents a 6-membered ring containing a heteroatom S, or O in the ring, or if the Y and Z-containing ring fragment represents a 6-membered ring containing two heteroatoms in the ring, where Y and Z are N and W is absent, or if the Y and Z-containing ring fragment represents a 6-membered aromatic ring containing one heteroatom in the ring, where the heteroatom represents N, then, if e is 0, R1and R2both are not-H.

2. Synthetic peptide amide according to claim 1, where G is a

and R1and R2with 0, 1 or 2 ring atoms of the Y and Z-containing ring fragment form a monocyclic or bicyclic 4-9-membered heterocyclic ring fragment.

3. Synthetic peptide amide according to claim 2, where R1and R2together with one atom of ring Y - and Z-containing ring fragment form a 4-8-membered heterocyclic ring fragment, which, together with the Y - and Z-containing ring fragment forms spirotrichous.

4. Synthetic peptide amide according to any one of claims 1 to 3, where Xaa1-Xaa2represents D-Phe-D-Phe.

5. Synthetic peptide amide according to any one of claims 1 to 4, where each is th XAA 3selected from the group comprising D-Nle, D-Leu.

6. Synthetic peptide amide according to any one of claims 1 to 5, where each Xaa4selected from the group comprising (B)2D-Arg and δ-(B)2D-Orn.

7. Synthetic peptide amide according to any one of claims 1 to 6, where G is a

and W is absent.

8. Synthetic peptide amide according to claims 1 to 7, where G is a

and Y - and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a nitrogen atom, and Z represents a carbon atom or a nitrogen atom.

9. Synthetic peptide amide according to any one of claims 1 to 7, where G is a

and Y - and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a carbon atom, and Z represents a nitrogen atom.

10. Synthetic peptide amide of claim 8 where Y - and Z-containing ring contains one or more sulfur atoms or oxygen.

11. Synthetic peptide amide according to any one of claims 1 to 10, where R1represents-H, -OH, -NH2, -COOH, C1-C3alkyl, amidino, C1-C3-alkyl substituted amidino, dihydroimidazole, D-Pro, D-Pro amide, or CONH2and where R2represents H or-COOH.

12. Synthetic peptide amide according to claim 1, where G is a

and Xaa1represents D-Phe, Xaa2represents D-Phe, Xaa3represents the D-Leu, Xaa4is a δ-(B)2D-Orn, where (B) represents-H, methyl or isopropyl; in addition, where W is absent, Y -, and Z-containing ring fragment is a 6 - or 7-membered ring, Y represents a nitrogen atom, e is 0, R1represents-NH2, amidino, C1-C3alkyl, C1-C3-alkyl substituted amidino, dihydroimidazole, D-Pro or D-Pro amide, and R2represents H or-COOH.

13. Synthetic peptide amide according to any one of claims 1 to 6, where

selected from the group including:









and

14. Pharmaceutical composition comprising an effective amount of a synthetic peptide amide according to any one of claims 1 to 13 as an agonist of the Kappa-opiate receptor and a pharmaceutically acceptable excipient or carrier.

15. The use of synthetic peptide amide according to any one of claims 1 to 13 for the manufacture of a medicinal product for treating or preventing associated with the Kappa-opioid receptor disease or condition in a mammal, characterized in that the indicator EC50synthetic peptide amide is less than about 100 nm for the Kappa-opioid receptor.

16. The application of clause 15, which is associated with the Kappa-opioid receptor status selected from the group comprising pain, inflammation, itching, edema, hyponatremia, hypokalemia, bowel obstruction, cough, and glaucoma.

17. The application of article 16, in which the pain is selected from the group including neuropathic pain, somatic pain, visceral pain and skin pain.

18. The application of article 16, in which the pain is selected from the group including arthritic pain, pain with kidney stones, the pain due to match what's spasms, dysmenorrhoea, endometriosis, dyspepsia, pain after surgery, pain after medical procedures, pain in the eyes, pain in the ears, breakthrough pain in cancer disease and the pain associated with disorder of the gastrointestinal tract.

19. Use p in which surgery is a laparoscopic pelvic, tubal ligation, hysterectomy, and cholecystectomy.



 

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