Ligands for melanocortin receptors

FIELD: organic chemistry, medicine.

SUBSTANCE: invention represents ligands MC-4 and/or MC-3 of the formula (I): , wherein X means hydrogen atom, -OR1, -NR1R1' and -CHR1R1' wherein R1 and R1' are taken among the group: hydrogen atom, (C1-C6)-alkyl and acyl; (1) each R2 is taken independently among the group: hydrogen atom, (C1-C6)-alkyl; or (2) (a) R2 bound with carbon atom that is bound with X and Z1 and substitute R5 can be optionally bound to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; or (b) R2 bound with carbon atom that is bound with ring Ar can be bound with R7 to form ring condensed with ring Ar; each among Z1, Z2 and Z3 is taken independently from the following groups: -N(R3e)C(R3)(R3a)-, -C(R3)(R3a)N(R3e)-, -C(O)N(R3d)-, -N(R3d)C(O)-, -C(R3)(R3a)C(R3b)(R3c)-, -SO2N(R3d)- and -N(R3d)SO2- wherein each among R3, R3a, R3b and R3c, R3d, R3e when presents is taken independently among hydrogen atom and (C1-C6)-alkyl; p is a whole number from 0 to 5 wherein when p above 0 then R4 and R4' are taken among hydrogen atom, (C1-C6)-alkyl and aryl; R5 represents 5 substitutes in phenyl ring J wherein each R5 is taken among hydrogen atom, hydroxy-, halogen atom, thiol, -OR12, -N(R12)(R12'), (C1-C6)-alkyl, nitro-, aryl wherein R12 and R12' are taken among hydrogen atom and (C1-C6)-alkyl; or two substitutes R5 can be bound optionally to form carbocyclic or heterocyclic ring that is condensed with phenyl ring J; q = 0, 1, 2, 3, 4 or 5 wherein when q above 0 then R6 and R6' are taken among hydrogen atom and (C1-C6)-alkyl; Ar is taken among the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine; R7 are substitutes at ring Ar wherein each R7 is taken among hydrogen, halogen atom, -NR13R13', (C1-C6)-alkyl and nitro- wherein R13 and R13' are taken among hydrogen atom and (C1-C6)-alkyl; r is a whole number from 0 to 7 wherein when r is above 0 then R8 and R8' are taken among hydrogen atom and (C1-C6)-alkyl; B is taken among -N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring and heterocycloalkyl ring wherein R14-R17, R20 and R21 are taken independently among hydrogen atom and (C1-C6)-alkyl; s = 0, 1, 2, 3, 4 or 5 wherein when s is above 0 then R and R9' are taken among hydrogen atom and (C1-C6)-alkyl; R10 is taken among the group consisting of optionally substituted bicyclic aryl ring and optionally substituted bicyclic heteroaryl ring; D is taken among hydrogen atom, amino- and -C(O)R11 wherein R11 is taken among the following group: hydroxy-, alkoxy-, amino-, alkylamino-, -N(R19)CH2C(O)NH2 wherein R19 represents (C1-C6)-alkyl, -NHCH2CH2OH and -N(CH3)CH2CH2OH, or its isomers, salts, hydrates or biohydrolysable ester, amide or imide.

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

 

The technical field

The present invention relates to novel ligands of melanocortin (MC) receptors. These ligands preferably demonstrate the selectivity to the receptor MC-4 and/or MC-3 compared to other melanocortin receptors (in particular, the receptor MC-1).

Prior art

Melanocortin peptides (melanocortin) are peptide hormones in animals and humans that are associated with the MC receptors and stimulate them. Examples of melanocortins are α -MSH (melanocyte-stimulating hormone), β -MSH, γ -MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH mainly known for its ability to regulate peripheral pigmentation (Eberle 1988), whereas ACTH is known as inducing steroidogenic (Simpson and Waterman, 1988). In addition, melanocortin peptides are mediators of a number of other physiological actions. It is reported that they affect motivation, learning, memory, behavior, inflammation, fever, pain, blood pressure, heart rate, vascular tone, natriuresis, the blood supply to the brain, growth and regeneration of nerves, the development of the placenta, the synthesis and release of aldosterone, the release of thyroxine, spermatogenesis, ovarian mass, the secretion of prolactin and FSH follicle-stimulating hormone), uterine bleeding in women,

the secretions of the sebaceous glands and pheromone, sexual activity, the erection of the penis, the levels of glucose in the blood, intrauterine development of the fetus; the behavior associated with the regulation of appetite and other physiological manifestations associated with childbirth.

Peptide sequence ACTH and various MSH have a common tetrapeptides the skeleton of His-Phe-Arg-Trp. All these peptides obtained by proteolytic processing of propeptide of proopiomelanocortin (POMC). Over the past few years have identified five different subtypes melanocortin receptor. These MC receptors belong to the class of 7 transmembrane receptors, associated with the domain G-protein. Five MC receptors, called MC-1, MC-2, MC-3, MC-4 and MC-5, all associated stimulus in relation to the cAMP. Of the above receptors, receptor MC-2 is the receptor for ACTH, whereas others represent the MSH receptor subtypes. Receptor MC-1 is present on melanocytes and melanoma. Receptor MC-2 is present predominantly in the adrenal gland. mRNA (mRNA) for receptor MC-3 was detected in the brain, as well as in placental and intestinal tissues (Gantz et al. 1993a, Desarnaud et al. 1994, Roselli Rehfuss et al. 1993). Receptor MC-4 was initially detected in the brain (Gantz et al. 1993b; Mountjoy et al 1994). Receptor MC-5 is expressed in the brain, as well as in the Department who were peripheral tissues (Chhajlani et al 1993; Gantz et al 1994; Griffon et al 1994; Labbu et al. 1994; Barrett et al. 1994; Fathi et al. 1995). More modern data received from people indicate that all cloned MC-receptors have a more wide

tissue distribution (Chhajlani, 1996)than originally thought.

As discussed above, members of the family of melanocortin receptors can be differentiated on the basis of their distribution in tissues. Receptors MC-4, as well as receptors MC-3, were found in the hypothalamus region of the brain, which is believed to be involved in the modulation of feeding behavior. It has been shown that compounds that demonstrate selectivity for receptors MC-4/MC-3, the change in the attitude towards the needs of eating after intracerebroventricular and peripheral injection in rodents. In particular, it was shown that agonists regulate the power in the direction of reducing appetite, while antagonists have been shown to regulate the power in the direction of increase appetite. See, Fan, W. et al., “Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome”, Nature, 385(6612), pp. 165-8 (Jan. 9,1997).

The role of subtype receptor MC-4 in the regulation of the needs of food intake and the regulation of body weight was clearly confirmed in mammals. See, for example, Huszer, D. et al., “Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice”, Cell, Vol. 88, pp. 131-141 (1997); Klebig, M.L. et al., “Making emergency ectopic Expression of the Agouti Gene in Transgenic Mice Cause Obesity, Features of Type II Diabetes, and Yellow Fur”, Proc. Natl Acad Sci., Vol. 92, pp. 4728-32 (1995); Karbon, W. et al., “Expression and Function of Argt, a Novel Gene Related to Agouti”, Abstract from the Nineteenth Annual Winter Neuropeptide

Conference (1998); Fan, W. et al., “Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome”, Nature, Vol. 385, pp. 165-168 (1997); Seely, R.J., “Melanocortin Receptors in Leptin Effects”, Nature, Vol. 390, p. 349 (1997); Comuzzie, A.G., “A Major Quantitative Trait Locus Determining Serum Leptin Levels and Fat Mass is Located on Human Chromosome 2”, Nat. Gen., Vol. 15, pp. 273-276 (1997); Chagnon, Y.C. et al., Linkage and Association Studies Between the Melanocortin Receptors 4 and 5 Genes and Obesity-Related Phenotypes in the Quebec Family Study”, Mol. Med., Vol. 3(10), pp. 663-673 (1997); Lee, F. and Huszar, D, “Screening Methods for Compounds Useful in the Regulation of Body Weight”, World Patent Publication WO 97/47316 (1997); and Shutter, J.R. et al., “Hypothalamic Expression of ART, a Novel Gene Related to Agouti, is Up-Regulated in Obese and Diabetic Mutant Mice”, Gen. & Dev. Vol. 11, pp. 593-602 (1997). Stimulation of the receptor MC-4 its endogenous ligand, α MSH, produces a signal saturation and may be a mediator in the reduction of signal saturation, which is regulated by leptin. I believe that, providing potent agonists of the receptor MC-4, it is possible to suppress appetite and to achieve useful results in the loss of body mass.

Was recently identified role of subtype receptor MC-3 in the regulation of body weight and energy distribution. See, for example, Chen, A.S. et al., “Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass”, Nature Genetics, Vol. 26, pp. 97-102 (2000); Butler, A.A. et al., “A Unique Metabolic Syndrome Causes Obesity in the

Melanocortin-3 Receptor-Deficient Mouse”, Endocrinology, Vol 141, pp 3518-3521 (2000). I suppose that is honesty receptor MC-3 can modulate the distribution of energy and can provide useful results in the loss of body mass.

The above studies imply a non-redundant role of receptor MC-3, in comparison with receptor MC-4, in energy homeostasis. Therefore, compounds that stimulate both receptors MC-3 and MC receptors-4, may have a stronger effect on the body weight loss compared with compounds that are selective for either subtype receptor MC-3 or subtype of receptor MC-4.

Applicants have discovered a class of compounds, which suddenly had a high affinity in relation to subtypes of the receptor MC-4 and/or MC-3, and which are usually selective to these subtypes of MC receptors relative to other subtypes of melanocortin receptors, in particular, the subtype of the MC-1. In accordance with the purpose of the present invention to provide compounds which have an affinity for the receptor subtypes MC-4 and/or MC-3. Another aim of the invention is a method of introducing the above mentioned compounds to animals or man. Further aims of the invention will be apparent from the following disclosure of the invention.

The invention

The invention relates to a class of compounds that are ligands for receptors MC-4 and/or subtype MC-3. In particular, the invention relates to a compound having the structure

corresponding to the formula (I):

DG is:

(A) X is selected from hydrogen, fluorine, aryloxy, acyloxy, OR1, SR1, -NR1R1’and-CHR1R1’where R1and R1’independently selected from the group consisting of hydrogen, alkyl and acyl;

(B) (1) each R2independently selected from the group consisting of hydrogen, alkyl, halogen and heteroalkyl; or

(2)(a) two neighboring substituent R2or adjacent substituents R2and R3can connect with education (3-8)-membered carbocyclic or heterocyclic ring; or

(b) R2associated with the carbon atom that is associated with X and Z1and the substituent R5may not necessarily be connected, forming a carbocyclic or heterocyclic ring, which is condensed with a phenyl ring J; or;

(c) R2associated with the carbon atom, which is connected with the ring Ar, can connect with R7with the formation of a ring condensed with the ring of Ar; or

(d) R2associated with the carbon atom that is linked to the Z2and Z3may not necessarily be connected with R8forming a carbocyclic or heterocyclic

ring; or

(e) R2associated with the carbon atom that is linked to the Z3and D may not necessarily be connected with R10forming a carbocyclic or heterocyclic ring;

(C) each of the Z1, Z2and Z 3independently selected from-OC(R3)(R3a)-; -C(R3)(R3a)O-; -S(O)aC(R3)(R3a)-, where a is 0, 1 or 2; -C(R3)(R3a)S(O)b-where b is 0, 1 or 2; -N(R3e)C(R3)(R3a)-; -C(R3)(R3a)N(R3e)-; -C(O)N(R3d)-; -N(R3d)C(O)-; -C(O)C(R3)(R3a)-; -C(R3)(R3a)C(O)-; -C(R3)(R3a)C(R3b)(R3c)-; -C(R3)=C(R3a)- ;- ≡ C-; -SO2N(R3d)-; -N(R3d)SO2-; -C(R3)(R3a)P(=O)(OR3f)-; -P(=O)(OR3f)C(R3)(R3a)-; -N(R3d)P(=O)(OR3f)-; -P(=O)(or SIG3f)N(R3d)-; -P(=O)(OR3f)O-; -O-P(=O)(OR3f)-; cycloalkyl having from 3 to 8 ring atoms, and geterotsiklicheskie having from 4 to 8 ring atoms; where

(1) each of R3, R3a, R3band R3swhen present, independently selected from hydrogen, hydroxy, alkoxy, aryloxy, acyloxy, thiol, alkylthio, atillio, aaltio, amino, alkylamino, acylamino and alkyl;

(2) R3dwhen present, is selected from hydrogen, alkyl and aryl;

(3) R3ewhen present, is selected from hydrogen, alkyl, aryl and acyl; and

(4) R3fwhen present, is selected from hydrogen and alkyl;

(D) p is 0, 1, 2, 3, 4 or 5; where

(1) when p is greater than 0, each R4and R4’independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, and

acylamino

(2) when p is greater than 1, two Deputy R4together with the carbon atoms to which they are linked, can connect, forming geteroseksualnoe, cycloalkyl or aryl ring; and

(3) when p is greater than 1, the substituents R4when two adjacent carbon atoms can be both equal to zero, so that the formed double bond between two adjacent carbon atoms, or as substituents R4and the substituents R4’when two adjacent carbon atoms are all zero, so that a triple bond between two adjacent carbon atoms;

(E) R5is 5 substituents (i.e. position 2-6) in the phenyl ring J, where each R5independently selected from hydrogen, hydroxy, halogen, thiol, -OR12, -SR12, -SO2N(R1Z)(R12’), -N(R12)(R12’), alkyl, acyl, alkene, alkyne, cyano, nitro, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie; where each R12and R12’independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie; or two substituent R5may not necessarily be connected, forming a carbocyclic or heterocyclic ring, which is condensed with a phenyl ring J;

(F) q is 0, 1, 2, 3, 4 or 5; where

(1) when q is greater than 0, each R6and R6’independently selected from Fodor is Yes, of alkyl, aryl, halogen, hydroxy, alkoxy, amino, acylamino;

(2) when q is greater than 1, two Deputy R6together with the carbon atoms to which they are linked, can connect with

education geteroseksualbnogo, cycloalkyl or aryl ring; and

(3) when q is greater than 1, the substituents R6when two adjacent carbon atoms may be equal to zero, so that the formed double bond between two adjacent carbon atoms, or both substituents R6and R6’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms;

(G) Ar represents aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine;

(H) R7represents all substituents in the ring Ar, where each R7selected from hydrogen, halogen, -NR13R13’, alkyl, acyl, alkene, alkyne, cyano, nitro, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie; where each R13and R13’independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie; or two substituent R7may not necessarily be connected with the formation of a carbocyclic or heterocyclic ring condensed with the ring of Ar;

(I) r is 0, 1, 2, 3, 4, 5, 6 or 7; where

(1) each R8and R8’independently selected from hydrogen, alkyl, halogen, hydroxy, alkoxy and amino;

(2) when r is greater than 1, two Deputy R8together with the carbon atoms to which they are linked, can connect, forming geteroseksualnoe, cycloalkyl or aryl ring; and

(3) when r is greater than 1, the substituents R8when two adjacent

the carbon atoms can be equal to zero, so that the formed double bond between two adjacent carbon atoms, or both substituents R8and both substituents R8’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms;

(J) B is selected from-N(R14)C(=NR15That is =O or =S)NR16R17, -NR20R21, cyano (-CN), heteroaryl ring, such as thiophene, alkyl - or dialkylamino, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualbnogo ring containing at least one nitrogen atom in the ring, where R14, R15R16, R17, R20and R21independently selected from hydrogen, alkyl, alkene and alkyne; where, in addition, a combination of two or more R14, R15, R16and R17can optionally be combined with the atoms to which they are linked, coord is m monocyclic or bicyclic ring; preferred are-N(R14)C(=NR15)NR16R17, cyano, N(R14)C(=O)NR16R17, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualnoe ring containing at least one nitrogen atom in the ring. More preferred are-N(R14)C(=NR15)NR16R17N(R14)C(=O)NR16R17, cyano and triazole and imidazole;

(K) s is 0, 1, 2, 3, 4 or 5; where

(1) when s is greater than 0, each R9and R9’independently selected from hydrogen, alkyl, aryl, halogen, hydroxy, alkoxy, amino, acylamino;

(2) when s is greater than 1, two Deputy R9together with the carbon atoms to which they are linked, can connect,

forming geteroseksualnoe, cycloalkyl or aryl ring; and

(3) when s is greater than 1, the substituents R9when two adjacent carbon atoms may be equal to zero, so that the formed double bond between two adjacent carbon atoms, or both substituents R9and both substituents R9’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms;

(L) R10selected from the group consisting of optionally substituted bicyclic aryl ring, and optionally substituted bicyclic Goethe is Karelenergo ring; and

(M) D is independently selected from hydrogen, fluorine, hydroxy, thiol, atillio, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, -C(O)R11and-C(S)R11; where R11selected from the group consisting of hydroxy; alkoxy; amino; alkylamino; -NHOR18where R18selected from hydrogen and alkyl; -N(R19)CH2C(O)NH2where R19is alkyl; -NHCH2CH2OH; -N(CH3)CH2CH2OH; and -- NHNHC(=Y)NH2where Y is selected from O, S and NH; and

(N) where, if at least one of the Z1, Z2or Z3is other than-C(O)N(R3d)- or-N(R3d)C(O)-, then X and D may optionally be connected together through a bridging group (linker), L, which contains all of the covalent bond or a covalent bond and an ionic bond to form a cyclic analogue peptide;

or its optical isomer, diastereoisomer or enantiomer; its pharmaceutically acceptable salt, hydrate or biogerontology complex ether, amide or imide.

In addition, the invention relates to pharmaceutical compositions containing the above compounds, and to methods for treating disorders mediated by receptor MC-3 or MC-4, by introducing these compounds.

Detailed description of the invention

I. definition:

“Amino acid” refers to alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), and paraginomai acid (Asp; D), cysteine (Cys; C), glutamic acid (Glu; Q), glutamine (Gln; E), glycine (Gly; G), histidine (His; H), isoleucine (Ile; I), Latino (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), Proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y) and valine (Val; V). Common 3-letter and 1-letter abbreviations are shown in parentheses. The following are used in this description of the modified amino acids (3-letter abbreviation for each of the substituents indicated in parentheses): p-benzylpenicillin (Bpa); β -(1-naphthyl)alanine (1-Nal); β -(2-naphthyl)alanine (2-Nal); β -cyclohexylamine (Cha), 3,4-dichlorophenylamino (3,4-Dcp); 4-forfinally (4-Fpa); 4-nitrovanillin (4-Npa); 2-titillans (Tha); 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); 3-benzothiadiazin (3-Bal); 4-cyanoaniline (4-Ypa); 4-itfinally (4-Ipa); 4-brompheniramine (4-Rpa); 4,4’-biphenylene (Bip); ornithine (Orn); sarcosine (Sar); pentacarbonyliron (Pfp) and β ,β -diphenylalanine (Dip). As for the substituents represented by structural formulae (I) and (A), the substituents mentioned in them using

single-letter designations are as defined, and do not apply to single-letter amino acids corresponding to the same letter designations.

The symbol “D”preceding the above three letter abbreviations, such as “D-Nal or DPhe”, denotes a D-form amino acids. The symbol “L”preceding a three-letter abbreviation of the amino acids refers to the natural L-form amino acids. In the present description, unless otherwise noted, the lack of “D” or “L” designation indicates that the acronym refers to both the D-and L-forms. When using the conventional one-letter abbreviation, designation letter, a capital letter refers to the L-form and the designation of a small (lower case) letter belongs to the D-form, unless otherwise agreed.

“Ac” refers to acetyl (i.e. CH3C(=O)-).

“Acylamino” refers to R-C(=O)N-.

“Acyloxy” refers to R-C(=O)O-.

“Atillio” refers to R-C(=O)S-.

“Alkoxy” represents an oxygen Deputy having a hydrocarbon chain, where the hydrocarbon chain is an alkyl or alkene (i.e.,- O-alkyl or-O-alkene). Preferred alkoxygroup include (for example), methoxy (MeO), ethoxy, propoxy, allyloxy.

“Alkyl” is a saturated hydrocarbon chain having 1-15 carbon atoms, preferably 1-10, more preferably 1-4 carbon atoms. “Alkene” is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and

having 2-15 carbon atoms, preferably 2-10, more preferably 2-4 carbon atoms. “The kin” is a hydrocarbon chain, having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2-10, more preferably 2-4 carbon atoms. Alkyl, alkenone and askinosie chain (United General title of “the hydrocarbon chain may be straight or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkenone and askinosie chains have one or two branching, preferably one branch. The preferred circuits are alkyl. Alkyl, alkenone and askinosie hydrocarbon chains, each may be unsubstituted or substituted from 1 to 4 substituents; in the case of replacement, the preferred circuits are mono-, di - or tizamidine. Alkyl, alkenone and askinosie hydrocarbon chains, each may be substituted with halogen, hydroxy, aryloxy (for example, phenoxy), heteroaromatic, acyloxy (for example, acetoxy), carboxy, aryl (e.g. phenyl), heteroaryl, cycloalkyl, heterocyclization, spirocycles, amino, amido, acylamino, keto, taketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl (Me), ethyl, propyl, isopropyl, butyl, vinyl, allyl and butenyl.

In addition, specified in this specification, “lower” alkyl, alkene or alkyne (for example, “n is SSI alkyl”) is a chain, consisting of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and 2-6, preferably 2-4, carbon atoms in the

the case of alkene and alkyne.

“Alkylthio” is structurai Deputy, having a hydrocarbon chain, where the hydrocarbon chain is an alkyl or alkene (i.e.- S-alkyl or-S-alkene). Preferred ancilliary include (for example) methylthio (MeS), atillio.

“Aryl” represents an aromatic hydrocarbon ring. Aryl rings are monocyclic or condensed bicyclic ring systems. Monocyclic aryl ring containing 6 carbon atoms in the ring. Monocyclic aryl ring is also called phenyl rings. Bicyclic aryl rings contain from about 8 to about 17 carbon atoms, preferably from about 9 to about 12 carbon atoms in the ring. Bicyclic aryl ring include ring system where one ring is aryl and the other ring is aryl, cycloalkyl or heteroseksualci. Preferred bicyclic aryl ring include 5-, 6 - or 7-membered ring condensed with a 5-, 6 - or 7-membered rings. Aryl ring may be unsubstituted or substituted from 1 to 4 substituents in the ring. The aryl may be substituted with halogen, cyano, nitro, hydroxy, carboxy, and the Ino, acylamino, alkyl, heteroalkyl, halogenation, phenyl, aryloxy, heteroaromatic or any combination. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The most preferred aryl ring radical is phenyl.

“Aryloxy” is an oxygen-containing aryl

Deputy (ie,- O-aryl). Preferred alloctype include (for example) phenoxy, naphthyloxy, methoxyphenoxy, methylenedioxyphenoxy.

Used in this description, the term “basic amino acid” refers to His, Lys and Arg.

“Su” refers to butanol (i.e. CH3CH2CH2C(=O)-).

“Cycloalkyl” represents a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are non-aromatic rings. Cycloalkyl rings are monocyclic or condensed, Spiro or the United bridging communication bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from about 7 to about 12 carbon atoms in the ring. Preferred bicyclic cycloalkyl ring include 4-, 5-, 6 - or 7-membered rings, condens rowanne 5, 6 - or 7-membered rings. Cycloalkyl rings can be unsubstituted or substituted from 1 to 4 substituents in the ring. Cycloalkyl may be substituted with halogen, cyano, alkyl, heteroalkyl, halogenation, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaromatic or any combination. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl.

The term “condensed” refers to cyclic fragments having at least two common ring atom

preferably, the number of condensed cycles is three.

“Halogen” represents (F), chlorine (Cl), bromine (Br) or iodine (I).

“Heteroatom” is the atom of nitrogen, sulfur or oxygen, which in accordance with the valence of the heteroatom may be associated one or more parts; in the case of nitrogen, one oxygen atom may be optionally associated with covalent coordination communication, such as forming a N-oxide. Groups containing more than one heteroatom can contain different heteroatoms.

“Heteroalkyl” represents a saturated or unsaturated chain containing carbon and at least one heteroatom, where no two adjacent heteroatoms. Heteroalkyl chains contain from 2 to about 15 member atoms (carbon and heteroatoms) in the chain, before occhialino from 2 to about 10, more preferably from 2 to about 5. For example, alkoxy (i.e.- O-alkyl or-O-heteroalkyl) radicals included in heteroalkyl. Heteroalkyl chain can be straight or branched. Preferred branched heteroalkyl have one or two branching, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more double bonds (also referred to as “heteroalkyl”) and/or one or more triple bonds (also known as “heteroalkyl”). Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond, preferably one double bond.

Heteroalkyl chain can be unsubstituted or substituted from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di - or tizamidine. Heteroalkyl may be substituted by lower alkyl, halogen, hydroxy, aryloxy, heteroaromatic, acyloxy, carboxy, monocyclic-aryl, heteroaryl, cycloalkyl, heterocyclization, spirocycles, amino, acylamino, amido, keto, taketo, cyano, or any combination of them.

“Heteroseksualci” represents a saturated or unsaturated, non-aromatic ring containing carbon and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring, where the ring not the positioning next two heteroatoms and no carbon which, having associated with him heteroatom, would also be associated with a hydroxyl, amino or tylny radical. Heterocytolysine rings are monocyclic or condensed, connected in bridge connection or Spiro bicyclic ring systems. Monocyclic heterocytolysine rings contain from about 4 to about 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms in the ring. Bicyclic heterocytolysine rings contain from about 7 to about 17 atoms, preferably from 7 to 12 atoms. Bicyclic heterocytolysine ring may be condensed, Spiro or the United bridge connection ring systems. Preferred bicyclic heterocytolysine rings include 5-, 6 - or 7-membered ring condensed with a 5-, 6 - or 7-membered rings. Heterocytolysine rings can be unsubstituted or

substituted from 1 to 4 substituents in the ring. Heteroseksualci may be substituted with halogen, cyano, hydroxy, carboxy, keto, taketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, halogenation, phenyl, phenoxy or any combination. Preferred substituents in heteroseksualci include fluorine and alkyl.

“Heteroaryl” represents an aromatic ring containing carbon and from 1 to about 4 hetaeras the atoms in the ring. Heteroaryl rings are monocyclic or condensed bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms in the ring. Bicyclic heteroaryl rings contain from about 8 to about 17 member atoms, preferably about 8 to about 12 member atoms in the ring. Bicyclic heteroaryl rings include ring system where one ring is heteroaryl, and the other ring is aryl, heteroaryl, cycloalkyl or heteroseksualci. Preferred bicyclic heteroaryl ring systems include 5-, 6 - or 7-membered ring condensed with a 5-, 6 - or 7-membered rings. Heteroaryl rings may be unsubstituted or substituted from 1 to 4 substituents in the ring. Heteroaryl may be substituted with halogen, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, halogenation, phenyl, aryloxy, heteroaromatic or any combination. Preferred heteroaryl rings include thienyl, thiazolo, imidazol, purinol, pyrimidyl, pyridyl and furanyl.

Used in this description, the term “agonist of MC-4 and agonist MC-3” refers to compounds having affinity to the receptor MC-4 or MC receptor-3, according to the respectively, the impact of which can lead to the appearance of measurable biological activity in cells, tissues or organisms that contain receptor MC-4 or MC-3. Used in this description, the term “agonist of MC-4/MC-3” refers to a compound that is an agonist of MC-4, and an agonist of MC-3, in accordance with defined above terminology. Tests that can detect agonistic activity of compounds in relation to the MC-4 and/or MC-3, well known in this field. One such commonly used test is an enzyme immunoassay (EIA) system BioTrak™, produced by Amersham Pharmacia Biotech (Piscataway, NJ), for the direct determination of cAMP, which allows the quantification of cAMP response of cells to the ligands MC. Other used test is the screening cAMP, Tropix cAMP Screen™ produced by Tropix. Such systems allow to quantify the total cellular cAMP in cells exposed to ligands. In brief: HEK cells stably transfected receptors MC-1, MC-3 or MC-4, placed in 96-well microtiter plates and cultured overnight. In cells dosed corresponding ligand MC for 1 hour and then are lysed. The fraction of an extract of lysed cells is transferred into the analytical tablet. ELISA analysis is carried out in accordance with the instructions, prilog is a subject to the set. Each tablet contains a number of standards cAMP

construct the calibration curve, as well as a full range of agonists MC as a positive control for each receptor MC. Activity cAMP count as% of maximal activity cAMP full range of agonists MC control.

Used in this description, the terms “antagonist of MC-4” and “antagonist of MC-3” refers to compounds having affinity to the receptor MC-4 or MC receptor-3, respectively, and which blocks the stimulation of a known agonist of MC. Used in this description, the term “antagonist of MC-4/MC-3” refers to a compound that is an antagonist of MC-4, and an antagonist of MC-3, in accordance with defined above terminology. Tests that can detect connection antagonism to the MC-4 and/or MC-3, well known in this field. One of the most used test is a competitive binding using NDP-MSH, labeled with europium. In brief: HEK cells stably transfected receptors MC-1, MC-3, MC-4 or MC-5, placed in a 96-well microtiter plates and cultured overnight. Cells dosed appropriate ligand MC in the presence of euromillionen NDP-MSH for 60 min, the cells are washed several times, add a solution to enhance and measure the fluorescence. Mn is ing IC 50and Ki with each receptor for each ligand MC can be calculated using standard graphics program such as GraphPad Prism (GraphPad Software Inc., San Diego, CA).

Used in this description, the terms “receptor MC-3 and MC receptor-4” refers to known receptors MC-3 and MC-4 and their

options, induced splicing, and undescribed receptors. Receptors MC-3 described Gantz et at, above (MC-3); Desarnaud et al., above (murine MC-3) and L. Reyfuss et al., “Identification of a Receptor for Gamma Melanotropin and Other Proopiomelanocortin Peptides in the Hypothalamus and Limbic System.”, Proc. Natl. Acad. Sci USA, vol. 90, pp. 8856-8860 (1993) (rat MC-3). Receptors MC-4 described by Gantz et al., above (MC-4 people), J.D. Alvaro et al., “Morphine Down-Regulates Melanocortin-4 Receptor Expression in Brain Regions that Mediate Opiate Addiction”, Mol Pharmacol Sep, vol. 50(3), pp. 583-91 (1996) (rat MC-4) and Takeuchi, S. and Takahashi, S., “Melanocortin Receptor Genes in the Chicken-Tissue Distributions”, Gen Comp Endocrinol, vol. 112(2), pp 220-31 (Nov. 1998) (chicken MC-4).

Used in this description, the term “measurable” means that the biological effect is reproducible and significantly different from the base data scatter analysis.

The term “pharmaceutically acceptable salt” means a cationic counterion formed with any acid (carboxylic acid) group, or an anionic counterion formed with any basic (e.g., amino) group. Many such salts are known in this area, as described in international Pat is nteu publication 87/05297, Johnston et al., published September 11, 1987, included in this description by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium), salts of alkaline earth metals (such as magnesium and calcium) and organic salts. Preferred anionic salt

include halides (such as chloride salts, sulfonates, carboxylates, phosphates, triptorelin (TFA), etc. it is Obvious that among such salts are contemplated additive salts, which can provide optical center in those cases where it was not. For example, compounds of the invention can be obtained chiral tartrate salt, and this definition includes such chiral salt.

The existence of such salts is obvious to the person skilled in the art, and such specialist is capable of receiving any number of salts, provided that they are known in this field. Moreover, it is clear that staff in this area may prefer one of the salts on the basis of its solubility, stability, ease of preparation, etc. the Definition and optimization of such salts is within the practical competence of the specialist in this field.

Used in this description, the term “selective” means having preferences in the activation of a specific receptor in comparison with other receptors, which may be the number is n defined based on the testing of integrated cells, tissue, or organism that can detect the activity of the receptor, such as enzyme immunoassay (EIA) system for the direct determination of cAMP, which was discussed above. The selectivity of the compounds is determined from the comparison of the values of EC50for the receptors to be compared. Unless otherwise stated, the term “selective compared to other MC receptors” means selectivity relative to other melanocortin receptors, including

receptors MC-1, MC-2 and MC-5. For example, the connection with EC508 nm for receptor MC-4 and EC5O≥ 80 nm for receptors MC-1, MC-2 and MC-5, has selectivity for receptor MC-4 compared to other MC receptors, at least 1:10. Moreover, it is clear that the selectivity can be attributed to one of the receptors MC-1, MC-2 or MC-5, individually. For example, the connection with EC508 nm for receptor MC-4 and EC5080 nm for receptor MC-1, has selectivity for receptor MC-4 compared with the MC receptor-1 1:10. This compound is selective in comparison with receptor MC-1, regardless of its value EC50for MC-2 or MC-5. Selectivity is described in more detail below and may be determined using, for example, the software Prism v 2.0 which access is from GraphPad, Inc.

“MES” is a complex formed by the combination of the solute (for example, the claimed receptor ligand MC-4/MC-3) and a solvent (e.g. water). Cm. J. Honig et al., The Van Nostrand Chemist''s Dictionary, p. 650 (1953). Pharmaceutically acceptable solvents used in accordance with this invention include solvents that do not interfere with the manifestation of biological activity of compounds (for example, water, ethanol, ethers, acetic acid, N,N-dimethylformamide and other known or easily determined by the expert in this field.

“Spirits” represents alkyl or heteroalkyl biradially Deputy alkyl or heteroalkyl where specified biradially Deputy has a total carbon and where specified

biradially Deputy forms a ring, with the specified ring contains from about 4 to about 8 member atoms (carbon or heteroatoms), preferably 5 or 6 member atoms.

II. Connection

Compounds of the present invention are ligands of the receptor MC-4 and/or MC-3, having a structure corresponding to formula (I):

where R2, R4, R4’, R5, R6, R6’, R7, R8, R8’, R9, R9’, R10, Ar, Z1, Z2, Z3, X, B, D, p, q, r and s such as described in the section “SunOS the ü invention”, above.

In addition to the compounds described by formula (I), it is assumed that the peptide remains of the skeleton can be modified with PEG in order to increase therapeutic value of, for example, to increase the effectiveness of actions by prolongation of the half-period of the existence of drugs in vivo. Methods of modifying peptides PEG is well known in the literature. For example, it is described in the following sources, a description of each of which are included in this description by reference: Lu, Y.A. et al., “Pegylated peptides. II. Solid-phase synthesis of amino-, carboxy - and side-chain pegylated peptides”, Int. J. Pept. Protein Res., Vol. 43(2), pp. 127-38 (1994); Lu, Y.A. et al., “Pegylated peptides. I. Solid-

phase synthesis of N alpha-pegylated peptides using Fmoc strategy”, Pept. Res., Vol. 6(3), pp. 140-6 (1993); Felix, A.M. et al., “Pegylated peptides. IV. Enhanced biological activity of site-directed pegylated GRF analogs.”, Int. J. Pept. Protein Res., Vol. 46(3-4), pp. 253-64 (1995); Gaertner, H.F. et al., “Site-specific attachment of functionalized poly(ethylene glycol) to the amino terminus of proteins”, Bioconjug Chem., Vol. 7(1), pp. 38-44 (1996); Tsutsumi, Y. et al., “PEGylation of interleukin-6 effectively increases its thrombopoietic potency”, Thromb Haemost, Vol. 77(1), pp. 168-73 (1997); Francis, G.E. et al., “PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimisation of coupling techniques”, Int. J. Hematol., Vol. 68(1), pp. 1-18 (1998); Roberts, M.J. et al., “Attachment of degradable poly(ethylene glycol) to proteins has the potential to increase therapeutic efficacy”, J. Pharm. Sci, Vol 87(11), pp. 1440-45 (1998); and Tan, Y. et al., “Polyethylene glycol conjugation of recombinant methioninase for cancer therapy”, Protein Expr. Purif, Vol. 12(1), pp. 45-52 (1998). The compounds of formula (I) is t to be modified PEG directly or in connection to facilitate the operation of the PEG modification can be introduced linker (branch link)”.

With regard to formula (I)below presents a non-limiting list of preferred substituents:

X is selected from hydrogen, fluorine, aryloxy, acyloxy, OR1, SR1, -NR1R1’and-CHR1R1’. The preferred hydrogen (when D is not hydrogen), -NR1R1’and-CHR1R1’. Preferred-NR1R1’

and-CHR1R1’. Even more preferred-NR1R1’.

R1and R1’independently selected from the group consisting of hydrogen, alkyl and acyl. The preferred case when R1represents hydrogen or alkyl and R1’represents acyl.

R2independently selected from the group consisting of hydrogen, alkylhalogenide and heteroalkyl. The preferred hydrogen. Alternatively, two consecutive Deputy R2or following one after the other substituents R2and R3can connect with education (3-8)-membered carbocyclic or heterocyclic ring. In another alternative, R2associated with the carbon atom that is associated with X and Z1and the substituent R5may not necessarily be connected, forming a carbocyclic or heterocyclic ring, which condenser the Vano with the phenyl ring J. In another alternative, R2associated with the carbon atom, which is connected with the ring Ar, can connect with R7with the formation of a ring condensed with the ring of Ar. In another alternative, R2associated with the carbon atom that is linked to the Z2and Z3may not necessarily be connected with R8with the formation of carbocyclic or heterocyclic rings. In the next alternative, R2associated with the carbon atom that is linked to the Z3and D may not necessarily be connected with R10forming a carbocyclic or heterocyclic ring. With regard to the above, preferably, when R2does not form a ring with another R2and when R2does not form a ring with R3, R7or R8. More preferably, when R2does not form a ring with R10. Preferably, when the ring formed between R2and another Deputy, have 5-8 ring atoms.

Each of the Z1, Z2and Z3independently selected from-OC(R3)(R3a)-; -C(R3)(R3a)O-; -S(O)aC(R3)(R3a)-, where a is 0, 1 or 2; -C(R3)(R3a)S(O)b-where b is 0, 1 or 2; -N(R3e)C(R3)(R3a)-; -C(R3)(R3a)N(R3e); -C(O)N(R3d)-; -N(R3d)C(O)-; -C(O)C(R3)(R3a)-; -C(R3)(R3a)C(O)-; -C(R3)(R3a)C(R3b )(R3c)-; -C(R3)=C(R3a)-; -C≡ C-; -SO2N(R3d)-; -N(R3d)SO2-; -C(R3)(R3a)P(=O)(OR3f)-; -P(=O)(OR3f)C(R3)(R3a)-; -N(R3d)P(=O)(OR3f)-; -P(=O)(OR3f)N(R3d)-; -P(=O)(OR3f)O-; -O-P(=O)(OR3f)-; cycloalkyl having from 3 to 8 ring atoms, and geterotsiklicheskie having from 4 to 8 ring atoms. Preferred-OC(R3)(R3a)-; -C(R3)(R3a)O-; -S(O)aC(R3)(R3a)-, where a is equal to 2; -C(R3)(R3a)S(O)b-where b is equal to 2; -N(R3e)C(R3)(R3a)-; -C(R3)(R3a)N(R3e)-; -C(O)N(R3d)-; -N(R3d)C(O)-; -C(R3)(R3a)C(R3b)(R3c)-; -C(R3)=C(R3a)-; -C≡ C-; -SO2N(R3d)-; -N(R3d)SO2-; -C(R3)(R3a)P(=O)(OR3f)-; and-P(=O)(OR3f)C(R3)(R3a)-. Preferred-OC(R3)(R3a)-; -C(R3)(R3a)O-; -C(R3)(R3a)N(R3e)-; -C(O)N(R3d)-; -C(R3)(R3a)C(R3b)(R3c)-; -C(R3)=C(R3a)-; -SO2N(R3d)- , and-P(=O)(OR3f)C(R3)(R3a)-. Most preferred are-C(R3)(R3a)O-; -C(O)N(R3d)- and-C(R3)(R3a)C(R3b)(R3c)-. In another aspect, preferred compounds are compounds where at least one of the Z1, Z2or Z3is other than-C(O)N(R3d)-. More prepact the positive connection, where at least two of the Z1, Z2or Z3is other than-C(O)N(R3d)-. In addition, preferred compounds where (i)at least one of the Z1, Z2or Z3other than-C(O)N(R3d)-, and (ii)(a) X is other than-NR1R1’where R1’is acyl, and/or (b) D is other than-C(O)R11.

Each of R3, R3aR3band R3cif present, independently selected from hydrogen, hydroxy, alkoxy, aryloxy, acyloxy, thiol, alkylthio, atillio, aaltio, amino, alkylamino, acylamino and alkyl. Preferred are hydrogen, hydroxy, alkoxy, aryloxy and alkyl. Most preferably, when each of R3, R3a,R3band R3crepresents hydrogen.

R3dif you have selected from hydrogen, alkyl and aryl. Preferably, when R3dselected from hydrogen and alkyl.

R3eif you have selected from hydrogen, alkyl, aryl, and acyl. Preferably, when R3eselected from hydrogen and alkyl.

R3fselected from hydrogen and alkyl. When R3fis alkyl, preferred is a branched alkyl, preferably isopropyl.

p is 0, 1, 2, 3, 4 or 5. Preferably p is 1 or 2, more preferably 1.

When p is greater than 0, each R4and R4’independently selected from hydrogen alkyl, aryl, halogen (preferably fluorine), hydroxy, alkoxy, amino, acylamino. When p is greater than 1, two Deputy R4together with the carbon atoms to which they are linked, can connect, forming geteroseksualnoe, cycloalkyl or aryl ring. When p is greater than 1, the substituents R4when two adjacent carbon atoms may both be equal to zero, so that the formed double bond between two adjacent carbon atoms, or both substituents R4and R4’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms. Preferably each R4if present, hydrogen

and each R4’if present, represents hydrogen or alkyl. Most preferably, when there is no unsaturation in the chain connecting the ring J with X-containing carbon atom of formula (I).

R5is 5 substituents (i.e. position 2-6) in the phenyl ring J, where each R5independently selected from hydrogen, hydroxy, halogen, thiol, -OR12, -SR12, -SO2N(R12)(R12’), -N(R12)(R12’), alkyl, acyl, alkene, alkyne, cyano, nitro, aryl, heteroaryl, cycloalkyl and geterotsiklicheskie. Each R12and R12’independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, hetero the Rila, cycloalkyl and geterotsiklicheskie; or two substituent R5may not necessarily be connected with the formation of a carbocyclic or heterocyclic ring, which is condensed with a phenyl ring J.

Preferred substituents R5are hydrogen, hydroxy, halogen, thiol, -OR12where R12represents lower alkyl or acyl, -SR12where R12represents lower alkyl or acyl, -SO2N(R12)(R12’), -N(R12)(R12’), alkyl, cyano, nitro, aryl, heteroaryl, cycloalkyl and heteroseksualci. More preferred substituents R5are hydrogen, hydroxy, halogen, thiol, -SO2N(R12)(R12’), where R12and R12’both represent hydrogen, -N(R12)(R12’), where R12and R12’each represent hydrogen or alkyl. Even more preferred substituents R5are hydrogen, hydroxy, chlorine, fluorine, -N(R12)(R12’), where R12and R12’each represent hydrogen or alkyl. The most preferred substituents R5are hydrogen, hydroxy, chlorine, fluorine and nitro.

Regarding the ring J, preferably, when four of the

substituents R5represent hydrogen. In addition, preferably, when in position 4 is not hydrogen. Most preferably, when in the position nahoditsya not hydrogen, and the remaining 4 Deputy represent hydrogen.

q is 0, 1, 2, 3, 4 or 5, preferably, q is 0, 1 or 2, more preferably q is 1.

When q is greater than 0, each R6and R6’independently selected from hydrogen, alkyl, aryl, halogen (preferably fluorine), hydroxy, alkoxy, amino, acylamino. When q is greater than 1, two Deputy R6together with the carbon atoms to which they are linked, can connect, forming geteroseksualnoe, cycloalkyl or aryl ring. When q is greater than 1, the substituents R6when two adjacent carbon atoms may be equal to zero, so that the formed double bond between two adjacent carbon atoms, or as substituents R6and the substituents R6’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms. Preferably each R6if present, is hydrogen and each R6’if present, represents hydrogen or alkyl. Most preferably, when there is no unsaturation in the chain connecting the ring with Ar carbon atom of formula (I), which is associated with Z1and Z2.

Ar represents aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine. Ar represents FAV is preferably phenyl, the thiophene or furan. Most preferably Ar is phenyl.

R7represents the substituents in the ring Ar, where each R7independently selected from hydrogen; halogen; -NR13R13’where R13and R13’each represents hydrogen or alkyl; alkyl; acyl; alkene; alkyne; cyano; nitro; aryl; heteroaryl; cycloalkyl and geterotsiklicheskie. Optional, two Deputy R7can be connected, forming a carbocyclic or heterocyclic ring condensed with the ring of Ar. When Ar represents phenyl, preferably, when four of the five substituents R7represent hydrogen or all five substituents R7represent hydrogen. Also preferably, when two substituent R7selected from fluorine, chlorine, cyano, bromine, iodine, nitro, alkoxy and alkyl; or two substituent R7connected with the formation of a carbocyclic or heterocyclic ring fused with the phenyl ring. More preferably, when in the position 4 of the phenyl ring is hydrogen, fluorine, chlorine, cyano, bromine, iodine, nitro and alkyl, and the other four Deputy represent hydrogen. Most preferably, when in the position 4 of the phenyl ring is hydrogen or fluorine, and the other four Deputy represent hydrogen.

When Z1and Z2both represent-CO)N(R 3d)-, preferred are compounds where the carbon atom that is linked to the Z1and Z2is in the R configuration in accordance with the rules of nomenclature of Cahn-Ingold-Prelog.

r is 0, 1, 2, 3, 4, 5, 6 or 7. Preferably r is 2, 3, 4 or 5. More preferably r is 2, 3 or 5. Most preferably r is equal to 3.

Each R8and R8’independently selected from hydrogen, alkyl,

halogen (preferably fluorine), hydroxy, alkoxy and amino. Optionally, when r is greater than 1, two Deputy R8together with the carbon atoms to which they are linked, connected with the formation of geteroseksualbnogo, cycloalkyl or aryl ring. Preferably, each R8and R8’independently selected from hydrogen and alkyl. Most preferably, each R8and R8’represents hydrogen. Optionally, when r is greater than 1, the substituents R8when two adjacent carbon atoms may be equal to zero, so that the formed double bond between two adjacent carbon atoms, or as substituents R8and the substituents R8’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms.

B is selected from-N(R14)C(=NR15That is =O or =S)NR16R17, -NR20R21, cyano (-CN), heteroaryl is Aliza, for example, thiophene; alkyl - or dialkylamino, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualbnogo ring containing at least one nitrogen atom in the ring. Preferred are-N(R14)C(=NR15)NR16R17, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualnoe ring containing at least one nitrogen atom in the ring. More preferred are-N(R14)C(=NR15R16R17, cyano, N(R14)C(=O)NR16R17, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualnoe ring containing at least one nitrogen atom in the ring. More preferred is N(R14)C(=NR15)NR16R17N(R14)C(=O)NR16R17, cyano, triazole and imidazole.

R14and R15independently selected from hydrogen, alkyl, alkene and alkyne. Preferred are hydrogen and alkyl. R16and R17independently selected from hydrogen, alkyl, alkene and alkyne. The preferred hydrogen and alkyl. R20and R21independently selected from hydrogen, alkyl, alkene and alkyne. The preferred hydrogen and alkyl.

Alternatively, a combination of two or more of R14, R15, R16and R17combined with the formation of the monocyclic or bicyclic ring. For example, R14and R15together with the atoms to which they are linked, can connect, forming heteroseksualci or heteroaryl. In addition, R14and R16together with the atoms to which they are linked, can connect with the formation of geterotsiklicheskie or heteroaryl. In addition, R15and R16together with the atoms to which they are linked, can connect, forming heteroseksualci or heteroaryl. In addition, R16and R17may not necessarily be connected with the formation or heteroaryl geteroseksualbnogo rings. Preferably, when R15and R16connected with the formation of rings.

s is 0, 1, 2, 3, 4 or 5. Preferably s is 1 or 2, more preferably 1.

When s is greater than 0, each R9and R9’independently selected from hydrogen, alkyl, aryl, halogen (preferably fluorine), hydroxy, alkoxy, amino, acylamino. Preferably each R9if present, is hydrogen and each R9’if present, is hydrogen or alkyl. Optional, when s is greater than 1, two Deputy R9together with the carbon atoms to which they are linked, connected, forming

geteroseksualnoe, cycloalkyl or aryl ring. In addition, when s is greater than 1, the substituents R9when two adjacent carbon atoms can both be p is wny zero, so that a double bond between two adjacent carbon atoms. In addition, when s is greater than 1, both substituents R9and both substituents R9’when two adjacent carbon atoms may be all zero, so that a triple bond between two adjacent carbon atoms. Most preferably, when there is no unsaturation in the chain linking R10c D-containing carbon atom of formula (I).

R10selected from the group consisting of optionally substituted bicyclic aryl ring, and optionally substituted bicyclic heteroaryl ring. Preferred bicyclic aryl rings include 1-naphthyl, 2-naphthyl, indan, 1H-inden, benzocyclobutene and benzocyclobutene. Preferred bicyclic heteroaryl rings include indole, indoline, pyridine, dihydropyridines, octagenerian, benzothiophen, benzofuran, benzimidazole, benzopyran, quinoline, hinolan and isoquinoline. More preferably, when R10represents 1-naphthyl, 2-naphthyl, indole, indan, 1H-inden, benzothiophen, benzofuran and benzopyran. Most preferably, when R10represents 1-naphthyl, 2-naphthyl or indole (in particular, 3-indole).

D is selected from hydrogen, fluorine, hydroxy, thiol, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, -C(O)R11and-C(S)R11. The preferred means is Auda fluorine, hydroxy, thiol, alkoxy, aryloxy, alkylthio, acyloxy, cyano, amino, acylamino, -C(O)R11and-C(S)R11. More preferred are alkoxy,

cyano, amino, acylamino, -C(O)R11and-C(S)R11. Even more preferred are-C(O)R11and-C(S)R11. Most preferred is C(O)R11.

R11selected from the group consisting of amino; alkylamino; -NHOR18where R18selected from hydrogen and alkyl; -N(R19)CH2C(O)NH2where R19represents alkyl (preferably lower alkyl); -NHCH2CH2OH; -N(CH3)CH2CH2OH; and -- NHNHC(=Y)NH2where Y is selected from O, S and NH. Preferred R11are amino; alkylamino; -NHOR18where R18selected from hydrogen and alkyl (preferably hydrogen); -N(R19)CH2C(O)NH2where R19represents alkyl (preferably lower alkyl); -NHCH2CH2OH; and-N(CH3)CH2CH2OH. More preferred R11are amino; alkylamino; -NHOR18where R18selected from hydrogen and alkyl (preferably hydrogen); and-N(R19)CH2C(O)NH2where R19represents alkyl. The most preferred amino, alkylamino.

As indicated in relation to formula (I), if at least one of the Z1, Z2or Z3is other than-C(O)N(R3d)- or-N(R3d)C(O)-, then X and D m which may be optionally linked via a linker L, which contains all of the covalent bond or covalent bond and ionic bond, thus forming a cyclic analogue of the peptide. Such cyclic peptides have the structure corresponding to the following formula (II):

As for the cyclic compounds containing linker L, the bridge that connects X and D can be in the form covalent linkages of nature or, alternatively, may include a salt bridge, which is the result of the formation of ionic bonds. The linker may be wholly peptide in nature (i.e. containing only amino acids), non-peptide in nature (i.e. do not contain amino acids) or it can include both deputies peptide and non-peptide entered using well known methods of chemical synthesis. The linker may include aliphatic residues, aromatic residues or heteroaromatic residues, or any combination. In one embodiment, the linker may include long-chain omega-amino acids in which the amino and carboxyl groups separated by a chain of land, consisting of from about 4 to about 24 methylene groups, or a combination of these omega-amino acids and benzoic acids.

In another variant embodiment, which is the preferred embodiment, the linker can in order to contain all of the covalent bond, such as amide linkages. For example, the linker may include amide formed by the chemical combination of the amino side chains of amino acids such as Lys or Orn, and

the carboxyl group of the side chain of amino acid residue such as Asp or Glu. Alternatively, the linker may include amide formed between the amino and carboxylate groups associated with the α -carbon of the amino acids forming the bridging group (hereinafter referred to asα -amino” group of amino acids or “α -carboxyl” group of amino acids). In another alternative, the linker may include amide formed between any combination of amino side chain or carboxyl group of the side chain (amino acids) and α -amino α -carboxyl groups. Linking residues may be present amine - or carboxyl-containing structures other than natural amino acids, including, for example, 6-aminohexanoic acid as aminobenzamide residue and succinic acid as the carboxyl-containing residue. In addition, the invention takes into account the binding of using other types of chemical functional groups. In this case, such binding residues can contain various groups and substituents, including aliphatic, heteroalkyl, aromatic and heterocyclic. When covalent linking, the linker which may include, but not limited to, amide, ester, simple ether, thioether, aminoalkyl, aminoaryl, alkyl, another heteroalkyl, alkene, alkyne, heteroseksualci, aryl and heteroaryl. Preferably, the linker can include a simple ether, aminoalkyl, aminoaryl, alkyl, another heteroalkyl, alkene, alkyne, heteroseksualci, aryl and heteroaryl. More preferably, the linker can include a simple ether, aminoalkyl, alkyl, alkene and alkyne. When L contains only

covalent bonds, preferred are compounds having from about 12 to about 32 ring atoms, more preferred are compounds having from about 22 to about 28 ring of atoms.

The linker may alternatively include ion binding/Association, which favors the formation of cyclic structures. Such “ion” bridge includes a salt-forming basic or acidic functionality. For example, the communication may include an ionic bond formed between the amino group of the side chain of amino acids such as Lys or Orn, and a carboxyl group of the side chain of amino acid residue such as Asp or Glu. Alternatively, the linker may include an ionic bond formed between the amino and carboxylate groups associated with the α -carbon of the amino acids that form the linker. In another alternative, the linker may include amide formed between any to what minutia amino side chain or carboxyla side chain (amino acids) and α -amino α -carboxyl groups. When L contains an ionic bond formed ring may preferably contain from about 22 to about 28 ring of atoms.

It should be borne in mind that any free peptide α -carboxy and α -amino group (i.e. α -carboxy and α -amino group of amino acids), not involved in the formation of the ring may optionally be in the form of carboxyamides or alluminare, respectively. The most preferred L-containing compounds are analogues, where X and D form a covalently

related cyclic structure.

In relation to the compounds of the present invention, in General, although alkyl, heteroalkyl, cycloalkyl and heterocytolysine group may be substituted by hydroxy, amino and aminopropane, as stated above, the invention provides for the presence of the following:

1. Enols (OH, is attached to the carbon bearing the double bond).

2. The amino group attached to the carbon bearing the double bond (except vynalogica amides).

3. More than one hydroxy, amino or aminogroups attached to the same carbon (except when two nitrogen atom are linked to one atom of carbon and three atoms are atoms members geteroseksualbnogo ring).

4. Hydroxy, amino or aminogroups attached the sp 3-hybridized carbon, which also has an associated heteroatom.

5. Hydroxy, amino or aminogroups attached to the carbon, which also has an associated halogen.

A preferred subclass of the compounds of formula (I)where there is no linker L, required for formation of the macrocyclic ring is a subclass of compounds having the structure of formula (A), as follows:

In the above preferred subgenus of compounds, the substituents R1, R1’, Z1, R4, R4’, R5, R6, R6’, R7, B, R10and R11are as defined in relation to formula (I). Referring to formula (I), the compounds of formula (A) are compounds in which the ring J formula is a phenyl ring, where all of the positions 2, 3, 5, and 6 represent hydrogen, so that the ring is substituted only in position 4 Deputy R5that is the same as defined with respect to formula (I). Similar to the description of formula (I), the substituent R5ring and the substituent R2can optionally be connected to form a ring condensed with the depicted phenyl ring. In such a variant embodiment of the condensed ring may connect the phenyl ring in a different position than position 4. In the formula (A) ring Ar fo the formula (I) is a phenyl ring, where all positions 2’, 3’, 5’ and 6’ represent hydrogen, and the position 4’ is R7that is the same as defined above. In this regard, preferably, when R7selected from hydrogen and fluorine.

In relation to formula (A), p and q is independently 1 or 2, preferably q is 1. In addition, preferably, when R4, R4’, R6and R6’are all hydrogen. In addition, the preferred connection, where is

-N(R14)C(=NR15)NR16R17or-NR20R21.

A preferred subclass of the compounds of the formula (II) are compounds having a structure corresponding to the formula (B), as follows:

where X, Z1, Z2, Z3, D, R4, R4’, R5, R6, R6’, R7, R8, R8’, B, R9, R9’and R10are as defined above, and p is 1 or 2. Preferred compounds where R6and R6’are both hydrogen. Also preferred compounds where B represents-N(R14)C(=NR15)NR16R17or-NR20R21. Also preferably, when R8, R8’, R9and R9’are all hydrogen. Preferably, when R7selected from hydrogen and fluorine. Preferred are-N(R14)C(=NR15NR 16R17, cyano, N(R14)C(=O)NR16R17, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualnoe ring containing at least one nitrogen atom in the ring. More preferred are N(R14)C(=NR15)NR16R17N(R14)C(=O)NR16R17, cyano and triazole and imidazole.

Below is a non-limiting list of preferred compounds of formula (I). In relation to the compounds depicted above chemical structures, the scope of the invention is included as a “linear” connection (i.e. connection, where

there is no linker L, which provides a macrocyclic molecule), and macrocyclic compounds of formula (II).

The following list of uses of single and/or three-letter abbreviations of the amino acids discussed above.

YfRW-NH2Ac-YfRW-NH2
Y(2-Nal)RW-NH2Ac-YfRW
Y(1-Nal)RW-NH2Ac-Y(D-1-Nal)RW-NH2
Ac-a[DYfRWK]-NH2Ac-a[DY(D-Phe(4-Cl))RWK]-NH2
Ac-Y(2-Nal)RW-NH2Ac-[EYfRWGK]-NH2
Ac-Y(D-2-Nal)RW-NH2Ac-YFRW-NH2
Ac-Y(2-Nal)RWAc-Y(D-Phe(4-))RW-NH 2
Ac-(Phe(4-F))fRW-NHCH3Ac-(Phe(4-Cl))fRW-NH2
Ac-(Phe(4-Cl))fRW-NHCH3Ac-YfKW-NH2
Ac-YfK(2-Nal)-NH2Ac-YfK(2-Nal)-NHCH3
Ac-YfR(2-Nal)-NHCH3Ac-YfR(2-Nal)-NH2
Ac-YfR(1-Nal)-NH2(des-NH2Tyr)YfR(2-Nal)-NHCH3
Ac-TICfRW-NHCH3Ac-a[EYfRWGK]-NH2
Ac-(Phe(4-NO2))fRW-NH2Ac-(Phe(4-Cl))(D-Phe(4-F))RW-NH2
Ac-(Phe(4-Cl)(D-Phe(4-F))RW-NHCH3Bc-YfRW(Sar)-NH2
Ac-(Phe(4-Cl))fR(2-Nal)-NHCH3Bc-(Phe(4-Cl)(fRW(Sar)-NH2
Ac-YfHW-NH2Ac-Yf(Homo-His)W-NH2
Ac-(Phe(4-Cl))(Phe(4-F)R(2-Nal)-NHCH3Ac-Y(Phe(4-F)R(2-Nal)-NHCH3
Ac-FfRW-NH2Ac-FfR(2-Nal)-NHCH3

Ac-yfRW-NH2yfRW-NH2
Ac-YyRW-NH2Ac-Y(D-Phe(4-I))KW-NH2
Ac-Y(D-Phe(4-I))HW-NH2Ac-Y(D-Phe(4-I))RW-NH2
Ac-WfRW-NH2Ac-YfR(Trp(5-F)-NH2,
Ac-Y(D-Phe(4Br))RW-NH2Ac-(D-Phe(3-OH))fRW-NH2
Ac-F(D-Phe(4-I))KW]-NH2 Ac-YfR(Trp(5-OMe)-NH2
Ac-YfR(Trp(5-Br)-NH2Ac-YfR(Trp(5-Me)-NH2
Ac-a[DYfR(Trp(6-F)GK]-NH2Ac-YfR(Trp(1-Me)-NH2
Ac-a[DYfR(Trp(4-F)GK]-NH2Ac-YfR(Trp(6-Br)-NH2
Ac-a[DYfR(Trp(7-Me), GK]-NH2Ac-YfR(Trp(5-OH))-NH2
Ac-YfR(Trp(6-OH))-NH2Ac-YfR(Trp(6-Cl))-NH2
Ac-(Tyr(Me))fRWG-NH2Ac-(Tyr(CH2Ph))fRW-NH2
Ac-(Tyr(3-NH2))fRW-NH2Ac(Tyr(3-Cl))fRW-NH2
Ac-(Tyr(3-MeO))fR-NH2Ac-Y(D-Phe(5-F))RW-NH2

III. The synthesis of compounds

Compounds of the present invention can be obtained using several methods, including the method of solid-phase synthesis and a method of liquid-phase synthesis in solution. Below is a General description of the methods as solid-phase and liquid-phase synthesis in solution. In section VII we give a few typical examples for each of the above methods of synthesis (peptide).

A. Solid phase synthesis

Synthesis of linear peptides: Connection manually synthesize a brief description is presented in section VII-C below), or automatically, or by an automated synthesizer Perkin-Elmer Applied Biosystem Division (PE-ABD) Model 433, or SyntraPrep reaction setup (produced SyntraChem, Charlottesville, VA). All reagents used for peptide synthesis, can be supplied PE-ABD. In the case of PE-ABD automatic synthesizer using standard chemical

the program FastMoc 0.25 mmol control of each stage of accession by conductivity measurements. In the General case (step) synthesis of peptide using Fmoc-protective group in the case of equipment PPPS (solid phase peptide synthesis) includes the following stages: 1) removal of Fmoc-protective group by piperidine; 2) activation of the carboxyl group of amino acids; and 3) the interaction of activated amino acids with aminocom.com peptide chain bound to the polymer, with the formation of peptide bonds. FastMoc-cycles, in which amino acids activate hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU). 1.0 mmol of dry protected amino acids in the cartridge dissolved in the solution of HBTU, N,N-diisopropylethylamine (DIEA) and add 1-hydroxybenzotriazole (HOBt) in N,N-dimethylformamide (DMF) with an additional N-organic (NMP). Activated Fmoc amino acid is formed almost instantly, and the solution is transferred directly into the reaction vessel. Stage removal of the Fmoc protection (stage removal of the protective Fmoc group) supervise and regulate the conductivity measurements. The peptide chain is built on Rink Amide resin is, as required C-terminal amide. Acetyl or boutelou group to introduce N-end of the peptide chain, after getting the full length of the chain peptide. This is carried out by reaction with acetic anhydride or butyric anhydride, and 4.75% vol.:about. acetic anhydride or butyric anhydride, and 0.2% HOBt mass.:about., 2,25% DIEA in NMP with α -amino group of N-terminal amino acid residue. The final product of the synthesis in sufficient time washed with NMP and dichloromethane (DCM). When peptide synthesis is used

SyntraChem reactionary installation, as a reagent for activation, which replaces HBTU, use hexaphosphate O-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium (HATU).

Unlocks: Polymers containing synthesized peptides, is unloaded from the synthesizer was short-lived and air-dried. Using 4,0-10,0 ml of the cleavage cocktail for (91% triperoxonane acid (TFA), 2.3% of ethanedithiol, 2.3% of thioanisole and 2.3% phenol (wt.:about.) in water) for 1.5 to 3.0 hours at room temperature, otscheplaut peptides from the resin and at the same time remove the protective groups of the side chains [O-tert-butyl (OtBu) for Asp, Glu, Tyr and Ser, pentamethylcyclopentadiene-5-sulfonyl (Pbf) for Arg, tert-butoxycarbonyl (Boc) for Trp, Orn, Lys] in terms of removing the protection. The solution containing the fission products, is separated from the resin by filtration. Then precipitated peptide in Phil the waste, adding 40 ml of chilled ether. The precipitated peptide is filtered off and washed with cold ether (4 x 40 ml). For peptides that do not precipitate in ether solution due to their high hydrophobicity, the ether is evaporated in a stream of nitrogen. Then the peptides freeze and lyophilized for more than 24 hours. Peptides recovered in the solution by the addition of acetic acid.

Purification and characterization: Powder peptide together with other by-products re-dissolved in 50% acetic acid solution and purified, inhazinue in column Vydac C-8, size: VD 1.0 cm, length 25 cm, particle size 5 μm and pore size of 300 A. Use HPLC Beckman System Gold with a UV detector with detection at two wavelengths. For

Department of the peptide product from other substances install programmable elution with a linear gradient of acetonitrile and injected into the column. The eluate is collected in Pharmacia collector for collecting fractions and individual fractions after separation is subjected to analysis by the method of analytical HPLC, and the method of electrospray mass spectrometry (MS) c identify the products to ensure their identity and purity.

B. Method of liquid-phase synthesis of peptides in solution

Commercially available solvents and reagents used without purification. The reaction mixture paramesh who live with the help of magnetic stirrer and their composition control or analytical high performance liquid chromatography (HPLC), either thin-layer chromatography (TLC). The fluid is concentrated conventional manner using a rotary evaporator Buchi at 15-25 mm RT. Art. TLC carried out using plates precoated with silica gel 60 F254 with fluorescent indicator. The visualization is carried out in a standard way using UV radiation (254 nm). Flash chromatography is carried out on E. Merck silica gel 60 (230-400 mesh mesh), using the required eluent; chromatographic separation was controlled by TLC analysis. Analytical HPLC was carried out either on columns MetaChem Kromasil C4a 4.6 x 250 mm, or Polaris C18with reversed phase (particle size of 3.5 microns or 3.0 MK for C4or18, respectively), using a gradient mixture of 0.1% phosphoric acid in water (A)/acetonitrile (B) (5% B for C4or 20% B for C18to 100% over 20 min, hold 5 min) with a volumetric flow

1.0 ml/min; detection UV radiation as at 214 nm and 254 nm. Preparative HPLC was carried out either on a column of Polaris C18with reversed phase, size 50 x 250 mm (particle size of 10 microns, pore size 100 S)or column (Rainin Dynamax C4with reversed phase, size 41,4 x 250 mm (particle size of 8 microns, pore size 300 (E)using a gradient mixture of 0.1% triperoxonane acid in water (A)/acetonitrile (B) (5%→ 100% B over 55 min, hold 10 min; detection at the same time UV radiation at 214 nm.

C. General remarks

It is recognized that it is preferable to use a protective group for any reactive functional groups, such as carboxyl, hydroxyl, etc. It is the usual practice, the use of which is within the experimental experience of the specialist in this field.

These stages may be varied to increase the yield of the desired product. For professionals it is obvious that a reasonable selection of reactants, solvents, and temperature is an important factor for the successful implementation of any synthesis. Determination of optimal conditions, etc. is common. In line with this, the specialist may receive a number of compounds, guided by the above General descriptions, along with the recommendations of the examples Section VII.

It is obvious that the person skilled in the art of organic chemistry can easily perform normal manipulation of organic compounds without further manual; i.e. the implementation of such manipulation is within

qualification and practical experience of specialist in this field. The above manipulations include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidation of hydroxyl groups and the like, acylation, aromatic substitution, as e is strofilia, and nucleophilic, esterification to obtain the esters and ethers and saponification and the like, Examples of the above manipulations discussed in regular publications, such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other publications that are well-known specialist in this field.

For professionals it is obvious that some of the reactions are best carried out when a potentially reactive functional group in the molecule masked or protected, which prevents any undesirable side reactions and/or to increase the yield of the desired reaction. Often a specialist in this field are used protective groups in order to increase the yield of the desired reaction or to avoid adverse reactions. Such reactions are present in the literature, and they are also well known to specialists in this field. Examples of many of these manipulations can be found, for example, in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids with reactive side chains are used as starting substances, preferably block to prevent the occurrence of unwanted side reactions.

IV. Functional activity and selectivity for melanocortin receptors

Functional activity can be assessed using various methods known in this the area. Examples of such methods are the measurement of the responses of the second messenger, in particular cAMP, using modified cellular systems, which can give a color reaction after accumulation of the elements of the second messenger, such as cAMP, for example, as Chen et al. 1995 (Anal Biochem. 1995, 226, 349-54), Cytosensor Microphysiometer techniques (see Boyfield et al. 1996), or you can use the study of the physiological effects caused by the compounds of the invention using compounds of the invention, as such or in combination with natural or synthetic MSH peptides.

Compounds of the present invention can preferably interact (i.e. selective) with MC-4 and/or MC-3, compared with other melanocortin receptors. Selectivity is particularly important when the compound is administered to humans or other animals, to minimize the number of side effects associated with their introduction. The selectivity of the compounds in relation to the MC 3/MC-4 is defined as the ratio EU50connection to the MC-1 receptor (“EC50-MC-1”) to EC50compounds for receptor MC-3 (EC50-MC-3)/MC-4 (EC50-MC-4), with EC50determine as described above. The formula is as follows:

MC-3-selectivity = [EC50-MC-1]/[EC50-MC-3]

MC-4-selectivity = [EC50-MC-1]/[EC50-MC-4]

Consider that the connection about what things like “selectivity in relation to the MC-3 receptor” in that case, when the above

the attitude of “MC-3-selectivity equal to at least about 10, preferably at least about 100 and more preferably at least about 500.

Connection define as having “selectivity in relation to the MC-4 receptor” in that case, when the above ratio “MC-4-selectivity equal to at least about 10, preferably at least about 100 and more preferably at least about 500.

V. Methods of application and composition:

Based on the ability of the inventive compounds to be agonism or antagonism against receptor MC-4 and/or MC-3, the present invention also relates to the use described in this description of the ligands in the treatment of obesity and other disorders associated with abnormalities in body composition, including, for example, anorexia and cachexia. In addition, the compounds may be used in methods of treatment of disorders that are the result of disorders associated with body weight, including but not limited to, insulin resistance, intolerance to glucose, diabetes Type II, coronary heart disease, high blood pressure, hypertension, dyslipidemia, cancer (such as endometrial cancer, brain cancer, ovarian cancer, breast cancer, cancer of the simple is you, gallbladder cancer, colon cancer), menstrual abnormalities, hirsutism, infertility, gall bladder disease, limited pulmonary lesions, seizures, sleep apnea, gout, osteoarthritis, and thromboembolic disease. In addition,

the invention relates to the treatment of disorders related to the physiological behavior, memory (including training), cardio-vascular function, inflammation, sepsis, cardiogenic and hypovolemic shock, sexual dysfunction, penile erection, muscle atrophy, growth and nerve regeneration, intrauterine development of the fetus, etc.

Used in this description, the term “treatment” means that, at least, the introduction of the compounds of the present invention reduces the violation, acting through the receptor MC-3 or MC-4. Thus, the terms include: prevention of the development status of the disease in a mammal, in particular, in the case when it has a predisposition to the acquisition of such disease, but yet he is not diagnosed; the inhibition of the development of the specified state of the disease; and/or relief or reversal of this state of the disease.

Compounds of the present invention can be prepared in pharmaceutical compositions intended for use in the treatment or prevention of the above disease States. For this is about using standard techniques of preparation of medicines, such as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition and Peptide and Protein Drug Delivery, Marcel Dekker, NY, 1991.

Compositions of the present invention include:

a. safe and effective amount of the compounds of formula (I); and

b. pharmaceutically acceptable filler.

“Safe and effective amount” of the compounds of formula (I) represents an amount which is effective to interact with the receptor MC-4 and/or MC-3, for an animal, preferably a mammal, more preferably to humans, without excessive undesirable side effects (such as toxicity, irritation or allergic response), commensurate with an acceptable ratio of benefit/risk, when using the method of the present invention. It is obvious that the specific “safe and effective amount” can vary depending on such factors as the particular condition to be treated, the physical condition of the patient, duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used; used excipient, the solubility of the compounds of formula (I) and necessary for the composition scheme of administration of the medicine.

In addition to the proposed connection of the composition of the present invention contain one or bore the only pharmaceutically acceptable excipients. Used in this description, the term “pharmaceutically acceptable excipient” means one or more compatible solid or liquid components, which are suitable for administration to an animal, preferably a mammal, more preferably human. Used in this description, the term “compatible” means that the components of the composition can be mixed with the proposed connection and with each other to some extent, so there will not be interaction, which could reduce

the pharmaceutical efficacy of the composition under ordinary circumstances of its application. Pharmaceutically acceptable excipients should, of course, have a sufficiently high purity and sufficiently low toxicity to be suitable for administration to an animal, preferably a mammal, more preferably human, subject to treatment.

Some examples of substances that may be useful as pharmaceutically acceptable excipients or components of the composition are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and methyl cellulose; powdered tragakant; malt; gelatin; talc; solid blur the surrounding agents, such as stearic acid and magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobromine; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid, moisturizing and lubricating agents, such as sodium lauryl sulfate; colorants; fragrances; to contribute to a pelletizing; stabilizers; antioxidants; preservatives; water, free from pyrogen; isotonic saline; and buffers such as phosphate, citrate and acetate.

The choice of pharmaceutically acceptable excipients to be used in conjunction with the proposed connection is determined primarily by, by means of which the connection shall be

introduction. If the connection is subject to the introduction injected, the preferred pharmaceutically acceptable excipients is sterile water, saline (salt) solution or their mixture whose pH is preferably adjusted to about 4-10 using pharmaceutical buffer; it is also possible to use a compatible suspending means.

In particular, pharmaceutically acceptable excipients for systemic injections include sugars, starches, cellulose and its derivatives, malt, gelatin, t is lik, calcium sulfate, lactose, vegetable oils, synthetic oils, polyols, alginic acid, phosphate, acetate and citrate buffer solutions, emulsifiers, isotonic saline and free from pyrogen water. Preferred pharmaceutically acceptable excipients for parenteral administration include propylene glycol, etiloleat, pyrrolidone, ethanol and sesame oil. Preferably, pharmaceutically acceptable excipient, in compositions for parenteral administration, was, at least about 90% of the mass. of the total weight of the composition.

Compositions of the present invention is preferably formulated into a single dosage form. Used in this description, the term “unit dosage form” is a composition of the present invention, containing a number of compounds of formula (I), which is suitable for administration to an animal, preferably a mammal, more preferably human, in a single dose, according to established medical practice. The above composition

preferably contain from about 1 mg to about 750 mg, more preferably from about 3 mg to about 500 mg, more preferably from about 5 mg to about 300 mg of the compounds of formula (I).

Compositions of the present invention can be presented in any of the many forms suitable for oral, rectal, local, nasal, ocular, transdermal, pulmonary or parenteral administration. Depending on the desired specific route of administration may be used a number known in the field of pharmaceutically acceptable excipients. Such excipients include solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating substances. Can be enabled with optional pharmaceutically active substance which does not substantially inhibit the inhibitory activity of the compounds of formula (I). The number of excipient used in combination with the compound of the formula (I), should be sufficient to provide for the introduction into practice of a number of substances that meet a unit dose of a compound. Techniques and compositions for making dosage forms used in the methods of the present invention, described in the following publications, which are incorporated in this description by reference: Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

Can be used in a variety of oral dosage forms, including such solid forms as tablets, capsules,

granules, and bulk powders. These oral forms include safety is Noah and effective amount, typically, at least about 5%, and preferably from about 25% to about 50%, of compounds of formula (I). Tablets can be compressed, designed to produce powder coated intersolubility coated sugar coated film-forming substance or pressed from multiple layers may contain suitable binders, lubricating agents, diluents, disintegrators, colors, flavors, stimulating fluidity and contributing to the melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions recovered from nishiuchi granules and effervescent preparations recovered from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspendresume agents, diluents, sweeteners, contributing to the melting agents, dyes and fragrances.

Pharmaceutically acceptable excipients suitable for the preparation of dosage forms for oral administration are well known in this field. Tablets typically comprise conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin, polyvinylpyrrolidone and sucrose; disintegrators, t is such as starch, alginic acid and crosscarmellose; lubricating agents such as magnesium stearate, stearic acid and talc. To improve the flow characteristics of the powdery mixture can be used

glidant, such as silicon dioxide. To give the appearance can be used colorants, such as dyes, FD&C Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint and fruit fragrances are useful adjuvants for razzhevyvaya tablets. Capsules typically include one or more solid diluents described above. Feature selection of excipients depends on the envisaged secondary characteristics, such as taste, cost, and stability during storage, which are not significant for the purposes of the present invention, selection of appropriate excipients can be easily done by a specialist in this field.

Oral compositions can also include liquid solutions, emulsions, suspensions and other Pharmaceutically acceptable excipients suitable for the preparation of such compositions is well known in this field. Typical components of excipients for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For typical suspension suspender the s agents include methylcellulose, the sodium carboxymethyl cellulose, Avicel® RC-591, tragakant and sodium alginate; a typical humectants include lecithin and Polysorbate 80; and typical preservatives include methylparaben, propylparaben, and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, flavorings, and dyes described above.

In addition, such compositions can be coated

film-forming coating by conventional means, typically, the solubility of such coatings is pH-dependent or time-dependent manner, so that the claimed compound is released in the gastrointestinal tract near the desired location, or at different times, prolonging the desired action. Such dosage forms typically include one or more film-forming, but are not limited to, acetate-phthalate cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose, ethylcellulose, coatings Eudragit® , waxes and shellac.

Since the compounds of the present invention are peptide nature, the preferred route of administration is parenteral (preferably intravenous injection or nasal introduction, in the form of unit dosage forms. Preferred unit dosage forms include suspensions and solutions containing without the safe and effective amount of the compounds of formula (I). With the introduction of parenteral unit dosage form typically comprises from about 1 mg to about 3 g, more preferably from about 10 mg to about 1 g, the compounds of formula (I), although the number of input connections can vary, for example, from its relative affinity for the receptor subtypes MC-4/MC-3, its selectivity in comparison with other receptors, including other melanocortin receptors, etc.

Compositions of the present invention optionally may include other active medicinal substance.

Other compositions used to achieve system

delivery of the inventive compounds include sublingual and transbukkalno dosage forms. Such compositions typically include one or more soluble substances, fillers, such as sucrose, sorbitol and mannitol; binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hypromellose. May also be included above glidant, lubricating agents, sweeteners, colorants, antioxidants and fragrances.

VI. Methods of administration:

As noted, the compositions of the present invention can be entered locally or systemically. Systemic application includes any method of introducing the compounds of formula (I) in the tissues of the body, for example, intra-articular, vnutriobolochechnoe,epidermal, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, nasal, pulmonary and oral administration. The compounds of formula (I) of the present invention is preferably administered systemically, preferably parenterally, and most preferably by intravenous injection.

An individual dose of a compound, be inserted, as well as the duration of treatment, regardless of whether the treatment of local or systemic, are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound of formula (I), the indication for treatment, personal distinctive features of the subject (such as weight), compliance with the treatment regimen and the presence and severity of any side effects of treatment.

Typically, for an adult, weighing approximately 70 kg, injected the day with the systemic administration from about 1 mg to about 6 g, more typically from about 100 mg to about 3 g, the compounds of formula (I). Obviously, these boundaries doses are presented only as examples, and that the daily introduction can be adjusted depending on the factors listed above.

As is known and is carried out in practice in this area, all the compositions for parenteral administration must be sterile. For melicope the surrounding, especially people (assuming an approximate body weight of a subject of 70 kg) is preferred individual dose from about 0.001 mg to about 100 mg

The preferred method of system of injection is intravenous delivery. When using the specified shipping method preferred individual dose from about 0.01 mg to about 100 mg, preferably from about 0.1 mg to about 100 mg

In all the above ways introduction undoubtedly, the compounds of the present invention can be introduced as such or as mixtures, and, in addition, the composition can contain additional drugs or excipients, if appropriate as indicated.

The compound of the present invention can be delivered in your preferred place in the organism (person or animal)using a suitable delivery system for the drug. System drug delivery are well known in this field. For example, the technique of drug delivery,

used for compounds of the present invention is to conjugation connection with an active molecule capable of passing through a biological barrier (see, for example, Zlokovic, B.V., Pharmaceutical Research, Vol. 12, pp. 1395-1406 (1995). A specific example is the binding of the compounds of the present invention with fragments of insul is to ensure the transport of drugs through the blood-brain barrier (Fukuta, M., et al. Pharmaceutical Res., Vol. 11, pp. 1681-1688 (1994)). As a General review of technologies for drug delivery, suitable for compounds of the invention, see Zlokovic, B.V., Pharmaceutical Research, Vol. 12, pp. 1395-1406 (1995) and Pardridge WM, Pharmacol. Toxicol, Vol. 71, pp. 3-10 (1992).

VII. Typical examples of synthesis

In the following examples, the invention is described in more detail with reference to several preferred variants of its implementation, which are given only for purposes of illustration, and it should be borne in mind that these examples in no way limit the invention.

The examples use the following abbreviations:

Ac: acetyl[-C(O)CH3]

Atc: (D,L)-2-aminotetralin-2-carboxylic acid

Aun: aminoundecanoic

Bc: butanol [-C(O)(CH2)2CH3]

Boc: tert-butyloxycarbonyl

DCM: dichloromethane

DEA: diethylamine

DMF: N,N-dimethylformamide

DMAP: 4-dimethylaminopyridine

DME: 1,2-dimethoxyethane

DIEA: diisopropylethylamine

DPPA: diphenylphosphoryl

EtOAc: ethyl acetate

EDCI: hydrochloride of 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide

Fmoc: 9-fluorenylmethoxycarbonyl

HOBt, N-hydroxybenzotriazole, monohydrate

HOAt: 1-hydroxy-7-asobancaria

i-D: 2-propanol

MeOH: methanol

NMM: N-methylmorpholine

OtBu: tert-butoxy [-O-C(CH3)3]

Pbf: 2,2,4,6,7-pentamethylcyclopentadiene-5-sulfonium: 2,2,5,7,8-pentamethyl-6-x is manselton-TSA: p-toluensulfonate

PyBOP: hexaphosphate benzotriazol-1 yloxy-Tris-pyrrolidinone

PyBroP: hexaphosphate bromo-Tris-pyrrolidinone

tBu: tert-butyl [-C(CH3)3]

TEA: triethylamine

TFA: triperoxonane acid

THF: tetrahydrofuran

A. Automatic solid-phase synthesis of peptides

Example 1

Synthesis of Ac-YfRW-NH2

On the basis of the degree of substitution Rink Amide resin 0.55 mmol/g, weighed 0.45 g of resin for 0,25 Smolnogo scale synthesis. The functioning of the peptide synthesizer PE-ABD 433 check before use various flow tests to ensure accurate flow of reagent. Fmoc amino acids: Tyr-OtBu, Arg-Pmc and Trp-Boc supplied commercially in 1 mmol cartridges. Fmoc-phe (387 mg, 1 mmol) define and add in cartridges for synthesis. A freshly prepared solution of acetic anhydride is loaded into flask #4 installation. Other reagents and solvents for the synthesis of commercially supplied and loaded in the installation according to the instructions provided. For peptide synthesis using chemical program, called NAc-0,mol MonPrePk. Removal of the Fmoc protection supervise and regulate the conductivity measurements, while the statutory criteria for conductivity is 5% or less, compared with the previous cycle unprotect.

The resin is dried in air and transferred into a glass vessel and add sugary the prepared reagent for cleavage (10 ml). The reaction of removing the protection is carried out for 2 hours at room temperature with constant stirring. Then the supernatant is separated from the resin by filtration. Then the synthesized peptide precipitated in ether layer by adding 40 ml of chilled ether. Precipitation of the peptide centrifuged (Heraeus Labofuge 400, Rotor #8179) at 3500 rpm for four

minutes. The ether is poured and add 40 ml of fresh chilled ether to rinse residue peptide. Stage washing is repeated three times to remove the reaction by-products unprotect. Precipitation of the final peptide is dried by freezing during the night. The identity and purity of the peptide is defined as a method of MS, and HPLC. Determine the expected molecular mass of the peptide.

Peptide re-dissolved in 50% acetic acid and purified HPLC with reversed-phase (C8)using a linear gradient of 0-70% of a solvent In a solvent And in the course of 70 minutes at a volumetric flow of 3 ml/min, the Composition of the solvents a and b the following: A: 0,1% TFA, 2% acetonitrile in water; B: 0.1% of TFA in 95% acetonitrile. Fractions collected every 0.25 min Aliquots of each fraction analyzed as the MS method and by HPLC with reversed phase (RP-HPLC). Fractions that contain one peak absorption at 220 nm with the expected mass of the peptide, unite and lyophilized. The final purity of the peptide define analytical IWASH United factions.

The peptides described in the examples 2-54 below, easily synthesized according to the method of example 1, but with modifications which are particularly specified.

Example 2

Synthesis of Ac-YFRW-NH2

Receive according to example 1, except that the use of Fmoc-L-Phe instead of Fmoc-D-Phe.

Example 3

Synthesis of Ac-FfRW-NH2

Receive according to example 1, except that the use of Fmoc-L-Phe instead of Fmoc-L-Tyr(OtBu).

Example 4

Synthesis of Ac-PFRW-NH2

Receive according to example 1, except that the use of Fmoc-L-Pro instead of Fmoc-L-Tyr(OtBu).

Example 5

Synthesis of Ac-AfRW-NH2

Receive according to example 1, except that the use of Fmoc-L-Ala instead of Fmoc-L-Tyr(OtBu).

Example 6

Synthesis of Ac-(2-Nal)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-(2-Nal) instead of Fmoc-L-Tyr(OtBu).

Example 7

Synthesis of Ac-YfR(2-Nal)-NH2

Receive according to example 1, except that the use of Fmoc-L-(2-Nal) instead of Fmoc-L-Trp(Boc).

Example 8

Synthesis of Ac-YfR(1-Nal)-NH2

Receive according to example 1, except that the use of Fmoc-L-(1-Nal) instead of Fmoc-L-Trp(Boc).

Example 9

Synthesis of Ac-YfHW-NH2

Receive according to example 1, except that the use of Fmoc-L-His(Trt) instead of Fmoc-L-Arg(Pmc).

Example 10

Synthesis of Ac-Y(D-2-Nal)RW-NH2

Receive according to example 1, except for the receiving, using Fmoc-D-(2-Nal) instead of Fmoc-D-Phe.

Example 11

Synthesis of Ac-Y(L-N-Me-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-L-N-Me-Phe instead of Fmoc-D-Phe.

Example 12

Synthesis of Ac-A(D-N-Me-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-N-Me-Phe instead of Fmoc-L-Phe and Fmoc-L-Ala is used instead Fmoc-L-Tyr(OtBu).

Example 13

Synthesis of Ac-YF(L-N-Me-Arg)W-NH

Receive according to example 1, except that the use of Fmoc-L-N-Me-Arg(Mtr) instead of Fmoc-L-Arg(Pmc), Fmoc-L-Phe is used instead Fmoc-D-Phe.

Example 14

Synthesis of Ac-Yf(L-N-Me-Arg)W-NH2

Receive according to example 1, except that the use of Fmoc-L-N-Me-Arg(Mtr) instead of Fmoc-L-Arg(Pmc).

Example 15

Synthesis of Ac-(L-N-Me-Tyr)FRW-NH2

Receive according to example 1, except that the use of Fmoc-L-N-Me-Tyr(Bzl) instead of Fmoc-L-Tyr(OtBu) and Fmoc-L-Phe is used instead Fmoc-D-Phe.

Example 16

Synthesis of Ac-(L-N-Me-Tyr)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-N-Me-Tyr(Bzl) instead of Fmoc-L-Tyr(OtBu).

Example 17

Synthesis of Ac-Y(D-4-chloro-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-4-chloro-Phe instead of Fmoc-D-Phe.

Example 18

Synthesis of Ac-Y(D-4-fluoro-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-4-fluoro-Phe instead of Fmoc-D-Phe.

Example 19

Synthesis of Ac-Y(D-3,4-dichloro-Phe)RW-NH2

Recip is jut according to example 1, except that using Fmoc-D-3,4-dichloro-Phe instead of Fmoc-D-Phe.

Example 20

Synthesis of Ac-Y(D-4-Me-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-4-Me-Phe instead of Fmoc-D-Phe.

Example 21

Synthesis of Ac-Y(D-4-nitro-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-4-nitro-Phe instead of Fmoc-D-Phe.

Example 22

Synthesis of Ac-Y(D-phenylglycine)RW-NH2

Receive according to example 1, except that the

using Fmoc-D-phenylglycine instead of Fmoc-D-Phe.

Example 23

Synthesis of Ac-Y(D-4-Homo-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-4-Homo-Phe instead of Fmoc-D-Phe.

Example 24

Synthesis of Ac-Y(D-stellaland)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-stellaland instead of Fmoc-D-Phe.

Example 25

Synthesis of Ac-Y(D-4-titillans)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-4-titillans instead of Fmoc-D-Phe.

Example 26

Synthesis of Ac-Y(D-3-fluoro-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-3-fluoro-Phe instead of Fmoc-D-Phe.

Example 27

Synthesis of Ac-(L-4-fluoro-Phe)(D-4-fluoro-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-fluoro-Phe instead of Fmoc-L-Tyr(OtBu) and Fmoc-D-4-fluoro-Phe is used instead Fmoc-D-Phe.

Example 28

Synthesis of Ac-(D-2-fluoro-Phe)RW-NH 2

Receive according to example 1, except that the use of Fmoc-D-2-fluoro-Phe instead of Fmoc-D-Phe.

Example 29

Synthesis of Ac-(L-4-chloro-Phe)(D-4-fluoro-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-chloro-Phe instead of Fmoc-L-Tyr(OtBu) and Fmoc-D-4-fluoro-Phe is used instead Fmoc-D-Phe.

Example 30

Synthesis of Ac-(L-4-chloro-Phe)(D-4-fluoro-Phe)RW(N-Me-Gly)NH2

Receive according to example 1, except that the use of Fmoc-L-4-chloro-Phe instead of Fmoc-L-Tyr(OtBu), Fmoc-D-4-fluoro-Phe is used instead Fmoc-D-Phe and use advanced Fmoc-N-Me-Gly.

Example 31

Synthesis of Ac-(L-4-chloro-Phe)fRW(N-Me-Gly)-NH2

Receive according to example 1, except that the use of Fmoc-L-4-chloro-Phe instead of Fmoc-L-Tyr(OtBu) and use additional Fmoc-N-Me-Gly.

Example 32

Synthesis of Ac-(L-4-chloro-Phe)(D-4-fluoro-Phe)R-NH2

Receive according to example 1, except that the use of Fmoc-L-4-chloro-Phe instead of Fmoc-L-Tyr(OtBu), Fmoc-D-4-fluoro-Phe is used instead Fmoc-D-Phe and not using Fmoc-L-Trp(Boc).

Example 33

Synthesis of Ac-(L-4-chloro-Phe)(D-4-fluoro-Phe)RG-NH2

Receive according to example 1, except that the use of Fmoc-L-4-chloro-Phe instead of Fmoc-L-Tyr(OtBu), Fmoc-D-4-fluoro-Phe is used instead Fmoc-D-Phe and Fmoc-L-Gly use

instead of Fmoc-L-Trp(Boc).

Example 34

Synthesis of Ac-(L-3,4-debtor-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-3,4-debtor-Phe instead of Fmoc-L-Tyr(OtBu).

Example 35

Synthesis of Ac-Y(D-2-Me-Phe)RW-NH2

Receive according to example 1, except that the use of Fmoc-D-2-Me-Phe instead of Fmoc-D-Phe.

Example 36

Synthesis of Ac-(L-4-bromo-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-bromo-Phe instead of Fmoc-L-Tyr(OtBu).

Example 37

Synthesis of Ac-(L-4-iodine-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-iodine-Phe instead of Fmoc-L-Tyr(OtBu).

Example 38

Synthesis of Ac-(L-pendaftar-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-pendaftar-Phe instead of Fmoc-L-Tyr(OtBu).

Example 39

Synthesis of Ac-(L-4-nitro-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-nitro-Phe instead of Fmoc-L-Tyr(OtBu).

Example 40

Synthesis of Ac-(L-aminomethyl-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-aminomethyl-Phe(Boc) instead of Fmoc-L-Tyr(OtBu).

Example 41

Synthesis of Ac-(L-tetraethylene-3-carboxylic acid)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-tetraethylene-3-carboxylic acid instead of Fmoc-L-Tyr(OtBu).

Example 42

Synthesis of Ac-(L-Homo-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-Homo-Phe instead of Fmoc-L-Tyr(OtBu).

Example 43

Synthesis of Ac-(L-biphenylene)fRW-NH2

Receive according to the use of the 1, except that the use of Fmoc-L-biphenylene instead of Fmoc-L-Tyr(OtBu).

Example 44

Synthesis of Ac-(L-4-SO3-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-SO3-Phe instead of Fmoc-L-Tyr(OtBu).

Example 45

Synthesis of Ac-(L-2,6-dimethyl-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-2,6-dimethyl-Phe instead of Fmoc-L-Tyr(OtBu).

Example 46

Synthesis of Ac-(L-4-methyl-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-methyl-Phe instead of Fmoc-L-Tyr(OtBu).

Example 47

Synthesis of Ac-(L-4-NH-Phe)fRW-NH2

Receive according to example 1, except that the use of Fmoc-L-4-NH-Phe(Boc) instead of Fmoc-L-Tyr(OtBu).

Example 48

Synthesis of Ac-YfKW-NH2

Receive according to example 1, except that the use of Fmoc-L-Lys(Boc) instead of Fmoc-L-Arg(Pmc).

Example 49

Synthesis of Ac-Yf(Orn)W-NH2

Receive according to example 1, except that the use of Fmoc-L-Orn(Boc) instead of Fmoc-L-Arg(Pmc).

Example 50

Synthesis Bc-HFRW(N-Me-Gly)-NH2

Receive according to example 1, except that the use of Fmoc-L-His(Trt) instead of Fmoc-L-Tyr(OtBu), Fmoc-L-Phe is used instead Fmoc-D-Phe, butyric anhydride is used instead of acetic anhydride, and use advanced Fmoc-L-N-Me-Gly.

Example 51

Synthesis Bc-HfRW(N-Me-Gly)-NH2

Receive according to example 1, except that using the Fmoc-L-His(Trt) instead of Fmoc-L-Tyr(OtBu), butyric anhydride is used instead of acetic anhydride, and use advanced Fmoc-L-N-Me-Gly.

Example 52

Synthesis Bc-YfRW(N-Me-Gly)-NH2

Receive according to example 1, except that butyric anhydride is used instead of acetic anhydride, and use advanced Fmoc-L-N-Me-Gly.

Example 53

Synthesis Bc-YFRW(N-Me-Gly)-NH2

Receive according to example 1, except that the use of Fmoc-L-Phe instead of Fmoc-D-Phe, butyric anhydride is used instead of acetic anhydride, and use advanced Fmoc-L-N-Me-Gly.

Example 54

Synthesis Bc-FfRW(N-Me-Gly)-NH2

Receive according to example 1, except that the use of Fmoc-L-Phe instead of Fmoc-L-Tyr(OtBu), butyric anhydride is used instead of acetic anhydride, and use advanced Fmoc-L-N-Me-Gly.

B. Liquid-phase synthesis in solution

Example 55

Synthesis of (naphthalene-1-ylmethyl)amide 5-guanidino-2-[3-phenyl-2-(3-phenylpropylamine)propionamido]pentanol acid

Methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid

To a solution of 2-(R)-(2-tert-butoxycarbonylamino-3-phenylpropionic acid (2.0 g, rate of 7.54 mmol) and methyl ether

2-(S)-amino-5-nitroguanidine acid (2.0 g, 1.1 EQ.) in 100 ml of anhydrous DMF add the hydrochloride of 1-[3-(dimethylamino)propyl)-3-etiketi the MFA (1.5 g, 1.5 equiv.) 1-hydroxybenzotriazole (2.16 g, 1.4 EQ.) and triethylamine (3.0 ml, 3 EQ.). The resulting solution was stirred at room temperature for 20 hours and then the solvents are removed under reduced pressure. The resulting residue partitioned between 10% sodium carbonate (100 ml) and methylene chloride (100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

2-(S)-(2-(R)-tert-Butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid

To a solution of methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid (3.6 g, 7.5 mmol) in tetrahydrofuran (100 ml) add monohydrate of lithium hydroxide (387 mg, 1.2 EQ.) and water (10 ml). After stirring at room temperature for one hour, the reaction mixture is neutralized triperoxonane acid (0.7 ml) and the solvents removed under reduced pressure. The resulting residue partitioned between water (200 ml) and ethyl acetate (200 ml). The aqueous layer was extracted with ethyl acetate (3× 250 ml), the organic phase are combined and dried over anhydrous magnesium sulfate, filtered and the solvent is removed the ri reduced pressure. Untreated

the substance is used without further purification.

tert-Butyl methyl ether (1-(S)-{4-nitroguanidine-1-[naphthalene-1-ylmethyl)carbarnoyl]butylcarbamoyl}-2-(R)-phenylethyl)carbamino acid

To a solution of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-guanidinopentanoic acid (1.0 g, of 2.15 mmol) and C-naphthalene-1-ylmethylamino (0,377 ml, 1.2 EQ.) in 50 ml of anhydrous DMF add the hydrochloride of 1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide (532 mg, 1.5 EQ.), 1-hydroxybenzotriazole (376, 1.4 EQ.) and triethylamine (0.9 ml, 3 EQ.). The resulting solution was stirred at room temperature for 20 hours and then the solvents are removed under reduced pressure. The resulting residue partitioned between 10% sodium carbonate (75 ml) and chloroform (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide, getting listed at the beginning of the connection.

Salt triperoxonane acid (naphthalene-1-ylmethyl)amide 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine acid

To a solution of tert-butyl methyl ether (1-(S)-{4-nitroguanidine-[1-naphthalene-1-letiltasaval]butylcarbamoyl}-2-(R)-phenylethyl)carbamino acid (1.1 EQ., 1.82 mmol) in methylene chloride 100 ml) add triperoxonane acid (50 ml). The resulting solution was stirred at room temperature

for three hours and then the solvents are removed under reduced pressure. The crude substance is purified preparative HPLC with reversed phase, receiving specified in the header of the connection.

(Naphthalene-1-ylmethyl)amide 5-nitroguanidine-2-[3-phenyl-2-(3-phenylpropylamine)propionamido]pentanol acid

To a suspension of (naphthalene-1-ylmethyl)amide 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-guanidinopentanoic acid (750 mg, to 1.21 mmol), 3-phenylpropionaldehyde (strength of 0.159 ml, 1.0 EQ.) and activated molecular sieves (4 angstroms, chopped) add triethylamine (0,247 ml, 1.5 EQ.). The resulting suspension is stirred at room temperature for 24 hours and then adjusted pH to 5 with acetic acid. Then added a 1.0m solution of cyanoborohydride sodium in tetrahydrofuran (of 1.44 ml, 1.2 EQ.) at a rate of 0.2 ml/min using a syringe pump. The resulting suspension is stirred at room temperature for 24 hours, filtered through celite and the solvents removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

(Naphthalene-1-ylmethyl)amide 5-guanidino-2-[3-phenyl-2-(3-phenylpropylamine)propionamido]pentanol acid

To a solution of (naphthalene-1-ylmethyl)amide 5-nitroguanidine-2-[3-phenyl-2-(3-FeNi is propylamino)propionamido]pentanol acid (140 mg, 0,165 mmol) in methanol (30 ml) is added acetic acid (3 ml) and 5% palladium on barium sulphate (100 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours and then filtered through celite. The solvents are removed under reduced pressure and the crude

the product was then purified HPLC with reversed phase.

Example 56

Synthesis of (2-naphthalene-2-retil)amide 5-guanidino-2-(S)-[3-phenyl-2-(R)-propylamino)propionamido]pentanol acid

2-Naphthalene-2-jatiluwih ester toluene-4-sulfonic

To a solution of 2-naphthalene-2-retinol (3.0 g, to 17.4 mmol) in tetrahydrofuran (50 ml) is added anhydride para-toluenesulfonic acid (6.8 g, 1.2 EQ.) and triethylamine (7,1 ml, 3 EQ.). The resulting solution was stirred at room temperature for one hour and then the solvent is removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (20% ethyl acetate/hexane)to give specified in the header of the connection.

2-(2-Azidoethyl)naphthalene

To a solution of 2-naphthalene-2-jetelova ether, toluene-4-sulfonic acids (5.0 g, of 15.3 mmol) in DMF (100 ml) is added sodium azide (1.3 g, 1.3 EQ.). The resulting suspension is heated to 80° within twenty-four hours and then cooled to room temperature. The solvent is removed under reduced pressure and the residue is distributed is between ethyl acetate (200 ml) and water (200 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure,

receiving specified in the header connection. The crude substance is used without additional purification.

2-Naphthalene-2-ylethylamine

To a solution of 2-(2-azidoethyl)naphthalene (3.0 g, of 15.2 mmol) in tetrahydrofuran (100 ml) is added triphenylphosphine (6.0 g, 1.5 EQ.) and water (5 ml). The resulting solution is refluxed for three hours and then cooled to room temperature. The solvents are removed under reduced pressure and the crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide). Then the purified substance is turned into salt triperoxonane acid, adding an excess of triperoxonane acid, and subsequent removal of excess acid by evaporation under reduced pressure gives specified in the header of the connection.

tert-Butyl ether {1-(S)-[4-nitroguanidine-1-(2-naphthalene-2-iletileri)butylcarbamoyl]-2-(R)-phenylethyl}carbamino acid

To a solution of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid (1.0 EQ, 2.14 mmol) and 2-(2-azidoethyl)naphthalene (733 mg, 1.2 EQ.) in DMF (50 ml) was added the hydrochloride of 1-[3-(dimethylamino)propyl)-3-ethylcarbodiimide (614 mg, 1.5 EQ), 1-hydroxybenzotriazole (434 mg, 1.5 EQ.) and triethyl is min (0,877 ml, 3 EQ.). The resulting suspension is stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is partitioned between 10% sodium carbonate (75 ml) and methylene chloride (75 ml).

The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

(2-Naphthalene-2-retil)amide and 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitrosoguanidine acid

To a solution of tert-butyl methyl ether {1-(S)-[4-nitroguanidine-1-(2-naphthalene-2-iletileri)butylcarbamoyl]-2-(R)-phenylethyl}carbamino acid (1.5 g, 2.04 mmol) in methylene chloride (100 ml) add triperoxonane acid (50 ml). The resulting solution was stirred at room temperature for twenty-four hours and the solvents removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

(2-Naphthalene-2-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-propylamino)propionamido]pentanol acid

To a solution of (2-naphthalene-2-retil)amide 2-(S)-(2-(R)-amino-3-phenylpropylamine is about)-5-nitroguanidine acid (600 mg, 1.15 mmol) in tetrahydrofuran (50 ml) is added 3-phenylpropionaldehyde (0,121 ml, 0.8 EQ.) and molecular sieves (4 angstroms, crushed). The resulting suspension is stirred at room temperature for twenty-four hours and then adjusted pH to 5 with acetic acid. To the solution add cyanoborohydride sodium (1,38 ml, 1.2 EQ., 1,0M solution in tetrahydrofuran) at a speed of 0.2 ml/h using a syringe-

a pump. The resulting suspension is stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance was filtered and then purified HPLC with reversed phase, receiving specified in the header of the connection.

(2-Naphthalene-2-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-propylamino)propionamido]pentanol acid

To a solution of (2-naphthalene-2-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-propylamino)propionamido]pentanol acid (294 mg, 0.46 mmol) in 50 ml of methanol, add acetic acid (5 ml) and 5% palladium on barium sulphate (294 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and the solvents removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 57

Synthesis of (2-naphthalene-1-retil)amide 5-g is amidino-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid

2-Naphthalene-1-jatiluwih ester toluene-4-sulfonic

To a solution of 2-naphthalene-1-retinol (3.0 g, to 17.4 mmol) in tetrahydrofuran (50 ml) is added anhydride para-toluenesulfonic acid (6.8 g, 1.2 EQ.) and triethylamine (7,1 ml, 3

EQ.). The resulting solution was stirred at room temperature for one hour and then the solvent is removed under reduced pressure. The crude product is purified flash chromatography on silica gel (20% ethyl acetate/hexane), receiving specified in the header of the connection.

1-(2-Azidoethyl)naphthalene

To a solution of 2-naphthalene-1-Eletropaulo ester toluene-4-sulfonic acids (5,2 g, 15.9 mmol) in DMF (100 ml) is added sodium azide (1.3 g, 1.3 EQ). The resulting solution was heated to 80° within twenty-four hours, then cooled to room temperature and the solvents removed under reduced pressure. The residue is distributed between ethyl acetate and water, the organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure, obtaining specified in the header connection. The crude product is used without further purification.

2-Naphthalene-1-ylethylamine

To a solution of 1-(2-azidoethyl)naphthalene (3.0 g, 15,23 mmol) in tetrahydrofuran (10 ml) is added triphenylphosphine (6.0 g, 1.5 EQ.) and water (5 ml). The resulting solution is boiled with reverse you can see what these lamps for three hours and then cooled to room temperature. The solvents are removed under reduced pressure and the crude product purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header connection. Adding excessive amounts triperoxonane acid, followed by evaporation gives salt triperoxonane acid.

tert-Butyl ether {1-(S)-[4-nitroguanidine-1-(2-naphthalene-1-iletileri)butylcarbamoyl]-2-(R)-phenylethyl]carbamino acid

To a solution of methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid (1.0 g, 2.1 mmol) and 2-naphthalene-1-ylethylamine (733 mg, 1.2 EQ.) in DMF (50 ml) was added 1-hydroxybenzotriazole (434 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (614 mg, 1.5 EQ.) and triethylamine (0,877 ml, 3 EQ.). The resulting suspension is stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between methylene chloride and 10% sodium carbonate, the organic phase is dried over magnesium sulfate, filtered and the solvents removed under reduced pressure, obtaining the crude product. The product was then purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

(2-Naphthalene-1-retil)amide and 2-(S)-(2-(R)-amine is 3-phenylpropionylamino)-5-nitroguanidine acid

To a solution of tert-butyl methyl ether {1-(S)-[4-nitroguanidine-1-(2-naphthalene-1-iletileri)butylcarbamoyl]-2-(R)-phenylethyl]carbamino acid (1.3 g, 1.77 mmol) in methylene chloride (100 ml) add triperoxonane acid (50 ml). After stirring at room temperature for twenty-four hours, the solvents are removed under reduced pressure and the residue partitioned between 10% sodium carbonate (100

ml) and ethyl acetate (100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

(2-Naphthalene-1-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid

To a solution of (2-naphthalene-1-retil)amide 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine acid (690 mg, of 1.33 mmol) in tetrahydrofuran (50 ml) is added 3-phenylpropionaldehyde (0,14 ml, 0.3 EQ.) and molecular sieves (500 mg, 4 E powder). The resulting suspension is stirred at room temperature for twenty-four hours and then the pH adjusted to 5 with acetic acid. Then slowly (0.2 ml/h) syringe pump add cyanoborohydride sodium (1.6 ml, 1.2 EQ., 1.0m solution in tetrahydrofuran is). Twenty-four hours, the solvents are removed under reduced pressure and the crude product purified HPLC with reversed phase, receiving specified in the header of the connection.

(2-Naphthalene-1-retil)amide 5-guanidino-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid

To a solution of (2-naphthalene-1-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid (280 mg, 0.44 mol) in 50 ml of methanol, add acetic acid (5 ml) and 5% palladium on barium sulphate (280 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and

the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 58

Synthesis of [2-(1H-indol-3-yl)ethyl]amide 5-guanidino-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid

Methyl ester of 2-(S)-[2-(S)-(tert-butoxycarbonylmethylene)-3-phenylpropionylamino]-5-nitroguanidine acid

To a solution of 2-(S)-(tert-butoxycarbonylmethylene)-3-phenylpropionic acid (2.0 g, 7,17 mmol) and methyl ester of 2-(S)-amino-5-nitroguanidine acid (1,83 g, 1.1 EQ.) add 1-hydroxybenzotriazole (1.45 g, 1.5 EQ.), hydrochloride 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide (2,05 g, 1.5 EQ.) and triethylamine (3.0 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is partitioned between 10% sodium carbonate (150 ml) and methylene chloride (150 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude substance clean flash-

chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

Methyl ester 5-nitroguanidine-2-(S)-(2-(S)-methylamino-3-phenylpropionylamino)pentanol acid

To a solution of methyl ester of 2-(S)-[2-(S)-(tert-butoxycarbonylmethylene)-3-phenylpropionylamino]-5-nitroguanidine acid (3,3 g of 6.68 mmol) in methylene chloride (200 ml) add triperoxonane acid (100 ml). The resulting solution was stirred at room temperature and then the solvents are removed under reduced pressure. The residue is distributed between methylene chloride (150 ml) and 10% sodium carbonate (150 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

Meth is lovy ether 5-nitroguanidine-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid

To a solution of methyl ester 5-guanidino-2-(S)-(2-(S)-methylamino-3-phenylpropionylamino)pentanol acid (1.0 g, 2.54 mmol) and 3-(4-hydroxyphenyl)propanoic acid (506 mg, 1.2 EQ.) add 1-hydroxybenzotriazole (513 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (727 mg, 1.5 EQ.) and triethylamine (1.0 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced

pressure. The residue is partitioned between 10% sodium carbonate (100 ml) and methylene chloride (100 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

5-Nitroguanidine-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentane acid

To a solution of methyl ester 5-nitroguanidine-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid (534 mg, 0.98 mmol) in tetrahydrofuran (50 ml) is added monohydrate of lithium hydroxide (49 mg, 1.1 EQ.) and water (3 ml). The resulting solution was stirred at room temperature for twenty-four hours and then acidified with triperoxonane acid (1 EQ.. The solvents are removed under reduced pressure and the crude substance is distributed between ethyl acetate (75 ml) and water (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure, obtaining specified in the header of the connection.

[2-(1H-Indol-3-yl)ethyl]amide 5-nitroguanidine-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid

To a solution of 5-nitroguanidine-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid (460 mg, 0.87 mmol) and

[2-(1H-indol-3-yl)ethyl]amine (168 mg, 1.2 EQ.) add 1-hydroxybenzotriazole (176 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (250 mg, 1.5 EQ.) and triethylamine (0,36 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate (75 ml) and water (75 ml), the organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

[2-(1H-Indol-3-yl)ethyl]amide 5-guanidino-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid

To a solution of [2-(1 ሺ-indol-3-yl)ethyl]amide 5-nitroguanidine-2-(S)-(2-(S)-{[3-(4-hydroxyphenyl)propionyl]methylamino}-3-phenylpropionylamino)pentanol acid (250 mg, of 0.37 mol) in 50 ml of methanol, add acetic acid (5 ml) and 5% palladium on barium sulphate (250 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and the solvents removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 59

Synthesis of benzylamine 5-guanidino-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid

tert-Butyl ether [1-(S)-(1-benzylcarbamoyl-4-nitrogengeneratorer)-2-(R)-phenylethyl]carbamino acid

To a solution of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid (500 mg, 1,29 mmol), benzylamine (0,155 ml, 1.1 EQ.) in DMF (50 ml) was added 1-hydroxybenzotriazole (261 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (371 mg, 1.5 EQ.) and triethylamine (of 0.53 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide)to give 526 mg specified in the connection header.

Benzylated 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine is sloty

To a solution of tert-butyl methyl ether [1-(S)-(1-benzylcarbamoyl-4-nitrogengeneratorer)-2-(R)-phenylethyl]carbamino acid (512 mg, 1.12 mmol) in methylene chloride (50 ml) is added triperoxonane acid (25 ml). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the

the title compound.

Benzylated 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid

To a suspension of benzylamine 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine acid (370 mg, of 0.65 mmol), 3-phenylpropionaldehyde (0,077 ml, 0.9 EQ.) and molecular sieves (370 mg, 4 E powder) is added triethylamine (0,177 ml, 2 EQ.). The resulting suspension is stirred at room temperature for twenty-four hours and then the pH adjusted to 5 with acetic acid. Then slowly (0.2 ml/hour) add cyanoborohydride sodium (0,70 ml, 1.0m solution in tetrahydrofuran, 1 EQ.) using a syringe pump. Twenty-four hours, the suspension is filtered through celite and the solvents removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Benzylated 5-guanidino-2-(S)-[3-phenyl-2(R)-(3-phenylpropylamine)propionamido]pentanol acid

To a solution of benzylamine 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-(3-phenylpropylamine)propionamido]pentanol acid (80 mg, 0.14 mmol) in methanol (50 ml) is added acetic acid (5 ml) and 5% palladium on barium sulphate (80 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and the solvents removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 60

Synthesis of [1-carbarnoyl-2-(1H-indol-3-yl)ethyl]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-nitroguanidine acid

tert-Butyl methyl ether (1-(S)-{1-[1-carbarnoyl-2-(1H-indol-3-yl)ethylcarbamate]-4-nitrogengeneratorer}-2-(R)-phenylethyl)carbamino acid

To a solution of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid (800 mg, 1.7 mmol) and 2-(S)-amino-3-(1H-indol-3-yl)propionamide (500 mg, 1.2 EQ.) in DMF (50 ml) was added 1-hydroxybenzotriazole (350 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (491 mg, 1.5 EQ.) and triethylamine (1,17 ml, 5 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue RA is predelay between ethyl acetate (75 ml) and 10% sodium carbonate (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

[1-Carbarnoyl-2-(1H-indol-3-yl)ethyl]amide of 2-(S)-(2-(R)-amino-

3 phenylpropionylamino)-5-nitroguanidine acid

To a solution of tert-butyl methyl ether (1-(S)-{1-[1-carbarnoyl-2-(1H-indol-3-yl)ethylcarbamate]-4-nitrogengeneratorer}-2-(R)-phenylethyl)carbamino acid (1,16 g, 1.78 mmol) in methylene chloride (100 ml) add triperoxonane acid (50 ml). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

[1-Carbarnoyl-2-(1H-indol-3-yl)ethyl]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-nitroguanidine acid

To a solution of [1-carbarnoyl-2-(1H-indol-3-yl)ethyl]amide of 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine acid (250 mg, 0,378 mmol) and 2-(S)-acetylamino-3-(4-hydroxyphenyl)propionic acid (100 mg, 1.2 EQ.) in DMF (50 ml) was added 1-hydroxybenzotriazole (76 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)PR who drank]-3-ethylcarbodiimide (107 mg, 1.5 EQ.) and triethylamine (0,20 ml, 4 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

[1-Carbarnoyl-2-(1H-indol-3-yl)ethyl]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-nitroguanidine acid

To a solution of [1-carbarnoyl-2-(1H-indol-3-yl)ethyl]amide of 2-(S)-

{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-nitroguanidine acid (100 mg, 0.13 mmol) in methanol (50 ml) is added acetic acid (5 ml) and 5% palladium on barium sulphate (70 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and the solvents removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 61

Synthesis of [2-(S)-(1H-indol-3-yl)-1-methylcarbamoylmethyl]amide of 2-(2-(R)-amino-3-phenylpropionylamino)-5-(1-trityl-1H-imidazol-4-yl)pentanol acid

Methyl ester 2-amino-5-(3H-imidazol-4-yl)pentanol acid

To a suspension of 2-tert-butoxycarbonylamino-5-(3H-imidazol-4-yl)pentanol acid (2.0 g, to 11.8 mmol) is methanol (60 ml) is added anhydrous hydrogen chloride until saturation of the solution. Then the solution is refluxed for twenty-four hours and then cooled to room temperature. The solvents are removed under reduced pressure, obtaining specified in the header of the connection.

Methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-

phenylpropionylamino)-5-(3H-imidazol-4-yl)pentanol acid

To a solution of 2-(R)-2-tert-butoxycarbonylamino-3-phenylpropionic acid (500 mg, 1.88 mmol) and methyl ester 2-amino-5-(3H-imidazol-4-yl)pentanol acid (500 mg, 1.1 EQ.) add hydroxybenzotriazole (381 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (540 mg, 1.5 EQ.) and triethylamine (1,28 ml, 5 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate (75 ml) and 10% sodium carbonate (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

Methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-(1-trityl-1H-imidazol-4-yl)pentanol acid

To a solution of methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonyl is a melamine-3-phenylpropionylamino)-5-(3H-imidazol-4-yl)pentanol acid (500 mg, to 0.72 mmol) in tetrahydrofuran (50 ml) add triphenylmethylchloride (220 mg, 1.1 EQ.) and triethylamine (0.2 ml, 2 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified flash chromatography on silica gel (5% methanol/chloroform)to give specified in the header of the connection.

2-(S)-2-(R)-tert-Butoxycarbonylamino-3-phenylpropionylamino)-5-(1-trityl-1H-imidazol-4-yl)pentane acid

To a solution of methyl ester of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-(1-trityl-1H-imidazol-4-yl)pentanol acid (300 mg, 0.45 mmol) in tetrahydrofuran (30 ml) is added monohydrate of lithium hydroxide (32 mg, 1.2 EQ.) and water (3 ml), the resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. Untreated substance use directly in the next stage.

tert-Butyl ether {1-(R)-[1-(2-(S)-(1H-indol-3-yl)-1-methylcarbamoylmethyl]-4-(1-trityl-1H-imidazol-4-yl)butylcarbamoyl]-2-phenylethyl}carbamino acid

To a solution of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-(1-trityl-1H-imidazol-4-yl)pentanol acid (293 mg, 0.45 mmol) and 2-(S)-amino-3-(1H-indol-3-yl)propionamide (117 mg, 1.3 EQ.) added PyBOP (301 mg, 1.3 EQ.) triethylamine (of 0.18 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate (75 ml) and 19% sodium carbonate (75 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (5% methanol/chloroform)to give specified in the header of the connection.

[2-(S)-(1H-Indol-3-yl)-1-methylcarbamoylmethyl]amide of 2-(2-(R)-amino-3-phenylpropionylamino)-5-(1-trityl-1H-imidazol-4-yl)pentanol acid

To a solution of tert-butyl methyl ether {1-(R)-[1-[2-(S)-(1H-indol-3-yl)-1-methylcarbamoylmethyl]-4-(1-trityl-1H-imidazol-4-yl)butylcarbamoyl]-2-phenylethyl}carbamino acid (468 mg, 0.55 mmol) in methylene chloride (32 ml) is added triperoxonane acid (16 ml). Then added dropwise triethylsilane until then, until there is no longer a bright yellow color. The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 62

Synthesis of methyl ester of 2-(R)-[2-(S)-(2-benzyl-6-phenylhexanoic)-5-guanidinopentanoic]-3-naphthalene-2-ylpropionic the second acid

Methyl ester of 6-phenylhexanoic acid

A solution of 6-phenylhexanoic acid (1.9 grams, of 9.89 mmol) in methanol (50 ml) saturated with anhydrous hydrogen chloride and then refluxed for twenty-four hours. After cooling to room temperature, the solvents are removed under reduced pressure and the residue partitioned between

chloroform and 10% sodium carbonate. The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure, obtaining specified in the header of the connection.

Methyl ester of 2-benzyl-6-phenylhexanoic acid

To a cooled (-78° (C) to a solution of methyl ether 6-phenylhexanoic acid (2.8 g, 13.5 mmol) in anhydrous tetrahydrofuran (50 ml) is added slowly 2,0M solution diisopropylamide lithium in a mixture of hexane/tetrahydrofuran (7.5 ml, 1.1 EQ.). The resulting solution was stirred at -78° for fifty minutes and then slowly add benzylbromide (1,92 ml, 1.2 EQ.). The resulting solution was warmed to room temperature overnight and then the solvents are removed under reduced pressure. Then the residue is distributed between ethyl acetate and water. The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude p is oduct clean HPLC with reversed phase, getting listed at the beginning of the connection.

2-Benzyl-6-phenylhexanoic acid

To a solution of methyl ester of 2-benzyl-6-phenylhexanoic acid (2.17 g, 7,33 mmol) in tetrahydrofuran (100 ml) add monohydrate of lithium hydroxide (880 mg, 2 EQ.) and water (15 ml). The resulting solution was refluxed for forty-eight hours and then cooled to room temperature. The solvents are removed under reduced pressure and the residue distributed between ethyl acetate and 1M citric acid. The organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure.

The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Methyl ester of 2-(S)-(2-benzyl-6-phenylhexanoic)-5-nitroguanidine acid

To a solution of methyl ester of 2-benzyl-6-phenylhexanoic acid (513 mg, 1.82 mmol) and methyl ester of 2-(S)-amino-5-nitroguanidine acid (480 mg, 1.1 EQ.) in DMF (50 ml) was added 1-hydroxybenzotriazole (319 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (451 mg, 1.3 EQ.) and triethylamine (0.74-ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed f is zoé, getting listed at the beginning of the connection.

2-(S)-(2-Benzyl-6-phenylhexanoic)-5-nitroguanidine acid

To a solution of methyl ester of 2-(S)-(2-benzyl-6-phenylhexanoic)-5-nitroguanidine acid (700 mg, 1.5 mmol) in tetrahydrofuran (40 ml) add monohydrate of lithium hydroxide (180 mg, 2 EQ.) and water (3 ml). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Methyl ester 2-amino-3-naphthalene-2-ylpropionic acid

To a suspension of 2-amino-3-naphthalene-2-ylpropionic acid (300 mg, of 1.39 mmol) in methanol (40 ml) is added anhydrous chloride

hydrogen to saturate the solution. The resulting solution was refluxed for two hours and then cooled to room temperature and the solvents removed under reduced pressure, obtaining specified in the header of the connection.

Methyl ester of 2-(R)-[2-(S)-(2-benzyl-6-phenylhexanoic)-5-nitrosalicylanilide]-3-naphthalene-2-ylpropionic acid

To a solution of 2-(S)-(2-benzyl-6-phenylhexanoic)-5-nitroguanidine acid (100 mg, 0.22 mmol) and methyl ester 2-amino-3-naphthalene-2-ylpropionic acid (65 mg, 1.1 EQ.) in DMF (30 ml) added is 1-hydroxybenzotriazole (44 mg, 1 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (63 mg, 1.5 EQ.) and triethylamine (0,09 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

Methyl ester of 2-(R)-[2-(S)-(2-benzyl-6-phenylhexanoic)-5-guanidinopentanoic]-3-naphthalene-2-ylpropionic acid

To a solution of methyl ester of 2-(R)-[2-(S)-(2-benzyl-6-phenylhexanoic)-5-nitrosalicylanilide]-3-naphthalene-2-ylpropionic acid (80 mg, 0.11 mmol) in methanol (30 ml) is added acetic acid (3 ml) and 5% palladium on barium sulfate (75 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and the solvents removed under reduced pressure. Untreated

the product was then purified HPLC with reversed phase, getting mentioned in the title compound as a mixture of four diastereomers.

Example 63

Synthesis of [1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide 5-(1H-imidazol-4-yl)-2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]pentanol acid

Methyl ester of 3-phenyl-2-(R)-(3-phenylpropionylamino)propionic acid

To a solution of 3-phenylpropionate KIS is the notes (1.0 g, of 6.66 mmol) and methyl ester of 2-(R)-amino-3-phenylpropionic acid (1.19 g, 1 EQ.) in DMF (60 ml) was added 1-hydroxybenzotriazole (1.35 g, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.90 g, 1.5 EQ.) and triethylamine (2.7 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between water and ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure, obtaining specified in the header of the connection.

3-Phenyl-2-(R)-(3-phenylpropionylamino)propionic acid

To a solution of methyl ester of 3-phenyl-2-(R)-(3-phenylpropionylamino)propionic acid (1.5 g, 4,82 mmol) in tetrahydrofuran (70 ml) is added monohydrate of lithium hydroxide

(434 mg, 1.5 EQ.) and water (5 ml). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

Methyl ester 5-(3H-imidazol-4-yl)-2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]pentanol acid

To a solution of 3-phenyl-2-(R)-(3-phenylpropionylamino)propionic acid (376 mg, of 1.26 mmol) and methyl ester 2-amino-5-(3H-imidazol-4-yl)pentanol is islote (355 mg, 1.1 EQ.) in DMF (50 ml) was added 1-hydroxybenzotriazole (256 mg, 1.5 EQ.), hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (362 mg, 1.5 EQ.) and triethylamine (0,863 ml, 5 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Methyl ester 2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]-5-(1-trityl-1H-imidazol-4-yl)pentanol acid

To a solution of methyl ester 5-(3H-imidazol-4-yl)-2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]pentanol acid (473 mg, of 1.02 mmol) in tetrahydrofuran (50 ml) add triphenylmethylchloride (341 mg, 1.2 EQ.) and triethylamine (of 0.42 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. Untreated

the product was then purified flash chromatography on silica gel (5% methanol/chloroform)to give specified in the header of the connection.

2-[3-Phenyl-2-(R)-(3-phenylpropionylamino)propionamido]-5-(1-trityl-1H-imidazol-4-yl)pentane acid

To a solution of methyl ester 2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]-5-(1-trityl-1H-imidazol-4-yl)pentanol acid (380 mg, 0.54 mmol) in tetrahydrofuran (80 ml) add Aut monohydrate of lithium hydroxide (48 mg, 1.5 EQ.) and water (10 ml). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. Untreated substance use directly in the next stage.

tert-Butyl methyl ether (1-(S)-methylcarbamoyl-2-naphthalene-2-retil)carbamino acid

To a solution of 2-(S)-tert-butoxycarbonylamino-3-naphthalene-2-ylpropionic acid (1.5 g, 4.76 mmol) in DMF (50 ml) is added methylamine (3.0 ml 2,0M solution in tetrahydrofuran), PyBOP (3.7 g, 1.5 EQ.) and triethylamine (1,95 ml, 3 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate and 10% sodium carbonate, the organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (5% methanol/chloroform)to give specified in the header of the connection.

2-(S)-Amino-N-methyl-3-naphthalene-2-ylpropionic

To a solution of tert-butyl methyl ether (1-(S)-methylcarbamoyl-2-naphthalene-2-retil)carbamino acid (1.3 g, of 3.96 mmol) in methylene chloride (100 ml) add triperoxonane acid (50 ml). The resulting solution was stirred at room temperature for twenty-four hours and then actuarialy removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]-5-(1-trityl-1H-imidazol-4-yl)pentanol acid

To a solution of 2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]-5-(1-trityl-1H-imidazol-4-yl)pentanol acid (383 mg, of 0.53 mmol) in DMF (50 ml) is added 2-(S)-amino-N-methyl-3-naphthalene-2-ylpropionic (147 mg, 0.8 equiv.) PyBOP (420 mg, 1.5 EQ.) and triethylamine (0,220 ml, 3 EQ.). The resulting solution was stirred at room temperature for forty eight hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate and 10% sodium carbonate, the organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (5% methanol/chloroform)to give specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-ileti]amide 5-(1H-imidazol-4-yl)-2-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]pentanol acid

To a solution of triperoxonane acid (20 ml) in methylene chloride (40 ml) is added (1-methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-[3-phenyl-2-(R)-(3-phenylpropionylamino)propionamido]-5-(1-trityl-1H-imidazol-4-yl)pentanol acid (441 mg, 0,489 mmol who). Then add dropwise triethylsilane to the disappearance of a bright yellow color. The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), getting mentioned in the title compound as a mixture of diastereoisomers. The diastereomers share HPLC with reversed phase, receiving a diastereoisomer, eluting earlier, and the diastereoisomer, eluting later.

Example 64

Synthesis of (1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-guanidinopentanoic acid

tert-Butyl ether {1-(R)-[4-nitroguanidine-1-(S)-(1-(S)-methylcarbamoyl-2-naphthalene-2-iletileri)butylcarbamoyl]-2-phenylethyl}carbamino acid

To a solution of 2-(S)-(2-(R)-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitroguanidine acid (500 mg, 1.07 mmol) and 2-(S)-amino-N-methyl-3-naphthalene-2-ylpropionic

(440 mg, 1.2 EQ.) added PyBOP (836 mg, 1.5 EQ.) and triethylamine (of 0.58 ml, 4 EQ.). The resulting solution was stirred at room temperature overnight and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate and 10 with sodium carbonate, dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine acid

To a solution of tert-butyl methyl ether {1-(R)-[4-nitroguanidine-1-(S)-(1-(S)-methylcarbamoyl-2-naphthalene-2-iletileri)butylcarbamoyl]-2-phenylethyl}carbamino acid (500 mg, of 0.74 mmol) in methylene chloride (60 ml) is added triperoxonane acid (30 ml). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido-3-phenylpropionylamino}-5-nitroguanidine acid

To a solution of (1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-(2-(R)-amino-3-phenylpropionylamino)-5-nitroguanidine acid (400 mg, of 0.58 mmol) in DMF (60

ml) is added 2-(S)-acetylamino-3-(4-hydroxyphenyl)propionic acid (155 mg, 1.2 EQ.), PyBOP (410 mg, 1.2 EQ.) and triethylamine (of 0.32 ml, 4 EQ.). Obtained races the thief was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate and 10% sodium carbonate, the organic phase is dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure. The crude product is purified flash chromatography on silica gel (90:9:1 chloroform:methanol:ammonium hydroxide), receiving specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-guanidinopentanoic acid

To a solution of (1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-{2-(R)-[2-(S)-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}-5-nitroguanidine acid (330 mg, 0.42 mmol) in methanol (50 ml) is added acetic acid (5 ml) and 5% palladium on barium sulfate (325 mg). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours and then filtered through celite. The solvents are removed under reduced pressure and the crude product purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 65

Synthesis of (1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide 5-guanidino-2-(S)-{2-(R)-[3-(4-hydroxyphenyl)propionamido]-3-

phenylpropionylamino}pentanol acid

To a solution of (1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide of 2-(S)-(2-(R)-amino-3-f is dipropylamino)-5-nitroguanidine acid (268 mg, 3.88 mmol) and 3-(4-hydroxyphenyl)propionic acid (77 mg, 1.2 EQ.) add the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (111 mg, 1.5 EQ.), 1-hydroxybenzotriazole (78 mg, 1.5 EQ.) and triethylamine (of 0.21 ml, 4 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude substance is purified HPLC with reversed phase, receiving specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-ileti]amide 5-guanidino-2-(S)-{2-(R)-[3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}pentanol acid

To a suspension of (1-(S)-methylcarbamoyl-2-naphthalene-2-retil)amide 5-nitroguanidine-2-(S)-{2-(R)-[3-(4-hydroxyphenyl)propionamido]-3-phenylpropionylamino}pentanol acid (141 mg, 0,19 mmol) and 5% palladium on barium sulphate (100 mg) in methanol (45 ml) is added acetic acid (5 ml). The resulting suspension hydronaut at atmospheric pressure for twenty-four hours, filtered through celite and

the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

Example 66

Synthesis of (1-(S)-methylcarbamoyl-2-naphthalene-2-ileti]amide 5-guanidino-2-(S)-[3-phenyl-2-(R)-(2-phenylethanolamine)propionamido]pentanol acid

2-Phenylethanolamine

To a biphasic solution of 2-phenylethanol (10.0 g, 72,5 mmol) in 100 ml of a mixture of water with ice add acetic acid (20 ml). Then the solution is saturated with gaseous chlorine for five minutes. Then the aqueous solution is extracted with ethyl ether, dried over anhydrous magnesium sulfate, filtered and the solvents removed under reduced pressure, obtaining specified in the header of the connection.

Methyl ester of 3-phenyl-2-(R)-(2-phenylethanolamine)propionic acid

To a solution of methyl ester 2-amino-3-phenylpropionic acid (700 mg, 3.9 mmol) in tetrahydrofuran (30 ml) is added dropwise 2-phenylethanolamine (1.2 g, 5,88 mmol). To the solution add triethylamine (of 1.55 ml, 3 EQ.). Received

the solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

3-Phenyl-2-(R)-(2-phenylethanolamine)propionic acid

To a solution of methyl ester of 3-phenyl-2-(R)-(2-phenylethanolamine)propionic acid (890 mg, 2.56 mmol) in tetrahydrofuran (50 ml) is added monohydrate of lithium hydroxide (260 mg, 1.5 EQ.) and water (5 ml). The resulting solution was stirred at room temperature for twenty-four hours and then actuarialy removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

tert-Butyl ester [4-nitroguanidine-1-(R)-(1-(S)-methylcarbamoyl-2-naphthalene-2-iletileri)butyl]carbamino acid

To a solution of 2-amino-N-methyl-3-naphthalene-2-ylpropionic (1.0 g, of 2.92 mmol) and 2-(R)-tert-butoxycarbonylamino-5-nitroguanidine acid (1.12 g, 1.2 EQ.) add the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (837 mg, 1.5 EQ.), 1-hydroxybenzotriazole (592 mg, 1.5 EQ.) and triethylamine (1.2 ml, 3 EQ.). The resulting suspension is stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The residue is distributed between ethyl acetate and 10% sodium carbonate, the organic phase is dried over anhydrous magnesium sulfate,

filtered and the solvents removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the header of the connection.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-retil)amide and 2-(R)-amino-5-guanidinopentanoic acid

To a solution of tert-butyl ester [4-nitroguanidine-1-(R)-(1-(S)-methylcarbamoyl-2-naphthalene-2-iletileri)butyl]carbamino acid (800 mg, of 1.52 mmol) in methylene chloride (40 ml) add triperoxonane acid (20 ml). The resulting solution was stirred at room temperature for whom the twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, getting mentioned in the title compound as a salt triperoxonane acid.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-(2-phenylethanolamine)propionamido]pentanol acid

To a solution of 3-phenyl-2-(R)-(2-phenylethanolamine)propionic acid (150 mg, 0.45 mmol) and (1-(S)-methylcarbamoyl-2-naphthalene-2-retil)amide 2-(R)-amino-5-guanidinopentanoic acid (270 mg, 1.1 EQ.) add the hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (130 mg, 1.5 EQ.), 1-hydroxybenzotriazole (91 mg, 1.5 EQ.) and triethylamine (0.25 ml, 4 EQ.). The resulting solution was stirred at room temperature for twenty-four hours and then the solvents are removed under reduced pressure. The crude product is purified HPLC with reversed phase, receiving specified in the

the title compound.

(1-(S)-Methylcarbamoyl-2-naphthalene-2-retil)amide 5-guanidino-2-(S)-[3-phenyl-2-(R)-(2-phenylethanolamine)propionamido]pentanol acid

To a solution of (1-(S)-methylcarbamoyl-2-naphthalene-2-retil)amide 5-nitroguanidine-2-(S)-[3-phenyl-2-(R)-(2-phenylethanolamine)propionamido]pentanol acid (230 mg, 0.31 mmol) in methanol (45 ml) is added acetic acid (5 ml) and 5% palladium on barium sulphate (200 mg). The resulting suspension hydronaut at atmospheric pressure during the course the e twenty-four hours and then filtered through celite. The solvents are removed under reduced pressure and the crude product purified HPLC with reversed phase, getting mentioned in the title compound as a salt triperoxonane acid.

Example 67

Synthesis of Ac-(carb-Ff-RW-NH2(11)

The specified connection receive in accordance with the schemes IA and B:

tert-Butyl ether [1-(4-Chlorobenzyl)-3-(2,2-dimethyl-4,6-dioxo[1,3]dioxane-5-yl)-3-oxopropyl]carbamino acid (1)

To a stirring mixture of Boc-(S)-3-amino-4-(4-chlorophenyl)butyric acid (5.0 g, 16 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (2,54 g, 17.6 mmol) and DMAP (24 mmol) in DCM (160 ml) at 0° one portion added EDCI (24 mmol). The resulting mixture was stirred at 0° C for 1 h, then at room temperature for 18 hours Add DCM (100 ml) and the mixture washed with water (2× 50 ml), 5% aqueous potassium hydrosulfate (3× 50 ml), 5% aqueous sodium bicarbonate (1× 50 ml) and saturated salt solution (1× 50 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated, obtaining 1.

tert-Butyl ether [1-(4-Chlorobenzyl)-3-(2,2-dimethyl-4,6-dioxo[1,3]dioxane-5-yl)propyl]carbamino acid (2)

Sodium borohydride (63,8 mmol, 4.0 EQ.) add portions over 1 h to a stirring solution of 1 (15,96 mmol) in a mixture of DCM (180 ml) and acetic acid (10 ml, 175 IMO the e l e C 11,0 EQ.) when 0° C. the Reaction mixture was stirred at 0° C for 1 h and then at room temperature for 64 hours, the Reaction mixture was diluted with DCM (150 ml) and washed with water (1× 50 ml) and saturated salt solution (2× 50 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator, getting 2.

6-(4-Chlorobenzyl)piperidine-2-he (3a) and tert-butyl ester 2-(4-Chlorobenzyl)-6-oxopiperidin-1-carboxylic acid (3b)

Stir the mixture 2 (15,32 mmol) and xylene (140 ml)

refluxed for 6 hours the Solvent is removed by evaporation at 37° in vacuum, obtaining the crude 3a. This substance is mixed with di-tert-BUTYLCARBAMATE (5.0 equiv.) and DMAP (0.3 EQ.) in DCM (100 ml) and the mixture is stirred at room temperature for 40 hours, the Solvent is removed on a rotary evaporator and the residue purified flash chromatography on silica gel using a mixture of EtOAc-hexane (1:19, 500 ml and 1:9, 1300 ml) as eluent, receiving 3b.

tert-Butyl ether 3-benzyl-6-(4-Chlorobenzyl)-2-oxopiperidin-1-carboxylic acid (4)

Bis(trimethylsilyl)amide, sodium (5,16 ml of 1,0M solution in THF, 1.0 equiv.) added dropwise to a stirring solution of 3b (1,67 g, 5,16 mmol) in a mixture of THF-DME (1:1, 100 ml) at -78° in argon atmosphere and the mixture was stirred for 0.5 h at -78° C. To paramashiva the Oh cooled mixture is added a solution of benzylbromide (0,882 g, 5,16 mmol, 1.0 EQ.) in THF (5 ml) and continue stirring at -78° C in argon atmosphere for 2 hours, the Reaction mixture was quenched with saturated aqueous ammonium chloride (20 ml) and continue stirring for 10 minutes the mixture is Then partitioned between DCM (80 ml) and water (40 ml) and the aqueous phase extracted with DCM (2× 40 ml). The combined organic phase washed with water (1× 40 ml), dried over anhydrous magnesium sulfate and concentrated, obtaining the crude compound 4, which was purified flash chromatography on a column of silica gel using a mixture of EtOAc-hexane (1:39, 1000 ml and 1:19, 1300 ml) as eluent, obtaining 4 (only

the diastereoisomer).

2-(R)-Benzyl-5-(R)-tert-butoxycarbonylamino-6-(4-chlorophenyl)hexanoic acid (’Boc-(carb-4-Cl-Ff)-OH’, 5)

To a stirring solution of 4 (1,152 g 2,783 mmol) in a mixture of THF-water (4:1) add the monohydrate of lithium hydroxide (0,467 g, 11,132 mmol, 4 equiv.) one of these portions and added dropwise 35% hydrogen peroxide (1,95 ml, 8.0 EQ.). The resulting mixture was stirred at 0° C for 1 h and then at room temperature for 16 hours, the Reaction mixture was acidified with aqueous hydrochloric acid (11.5 ml, 1N) at 0° and extracted With DCM (4× 40 ml). The organic layer is dried over anhydrous magnesium sulfate, concentrated and the residue triturated, receiving 5 (single diastereoisomer).

Boc-R(NO2)-W-NH2(6)

HOBt (1.0 EQ.) add to mix thoroughly

to a solution of Boc-R(NO2)-OH (0,639 g, 2.0 mmol) and H-W-NH2Hl· (0,479 g, 2.0 mmol) in DMF (10 ml) at 0° C, followed by addition of EDCI (1.1 EQ.) and NMM (0,484 ml, 2.2 EQ.). The resulting mixture was stirred at 0° C for 1 h and then at room temperature for 4-18 hours, the Reaction mixture was diluted with EtOAc (100 ml) and washed with water (1× 20 ml), 1N aqueous hydrochloric acid (2× 10 ml), saturated aqueous sodium bicarbonate (2× 10 ml) and saturated salt solution (1 × 10 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated, gaining 6.

p-TSA• H-R(NO2)-W-NH2(7)

A solution of 6 (0,697 g 1,381 mmol) in a mixture of TFA-DCM-water (10:40:0,5; 15 ml) was stirred at room temperature for 2-4 h To the reaction mixture add monohydrate p-toluenesulfonic acid (1.0 EQ.). After stirring for 10 minutes the mixture is concentrated by evaporation in vacuo and the residue triturated with a mixture of ether-hexane (1:1)to give 2.

Boc-(carb-4-Cl-Ff)-R(NO2)-W-NH2(8)

Follow the method for obtaining compounds 6 and subjected to 7 (0.5 mmol) interaction with Boc-(carb-4-Cl-Ff)-OH (5, 0.5 mmol, 1.0 EQ.), getting 8.

p-TSA• H-(carb-4-Cl-Ff)-R(NO2)-W-NH2(9)

Follow the method for obtaining compounds 7 and get 9 from 8.

Ac-(carb-4-Cl-Ff)-R(NO2 )-W-NH2(10)

Follow the method for obtaining compounds 6 and subjected to 9 (0,472 mmol) interaction with acetic acid to obtain crude compound 10, which was purified preparative HPLC

(C18)and gets 10.

Ac-(carb-Ff)-R-W-NH2(11)

A mixture of 10 (200 mg, to 0.263 mmol) and 300 mg of 5% Pd-BaSO4(unrestored) in a mixture of MeOH-HOAc (10:1, 22 ml) hydronaut when the hydrogen pressure 42 lb/in2(250 kPa) at room temperature for 17 hours, the Catalyst was removed by filtration through a pillow celite, which was washed with MeOH. The filtrate is concentrated, obtaining the crude compound 11, which was purified preparative HPLC (C18), and the product is then triturated with ether, receiving 11 in the form of the TFA salt.

Examples 68 and 69

Synthesis of 3-(4-hydroxyphenyl)propanol-Atc-R-tryptamide (17) and 3-phenylpropanol-Atc-R-tryptamide (19)

The compounds of these examples receive in accordance with the submitted scheme II:

Boc-R(NO2-tryptamide (12)

HOBt (1.0 EQ.) and EDCI (0,949 g of 4.95 mmol, 1.1 EQ.) add sequentially to the thoroughly mixed mixture of Boc-R(NO2)-OH (1,437 g, 4.5 mmol) and tryptamine (0,721 g, 4.5 mmol) in DMF (20 ml) at 0° C. the resulting mixture was stirred for 30 min at 0° and then at room temperature for ~20h. The mixture is diluted with EtOAc (100 ml) and then washed successively with water (2×20 ml), 5% aqueous citric acid (3× 10 ml), 5% aqueous sodium bicarbonate (2× 10 ml) and saturated salt solution (2× 20 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated on a rotary evaporator, receiving the connection 12, which are used directly in the next stage.

H-R(NO2-tryptamide (13)

A solution of 12 (1,985 g, 4.3 mmol) in a mixture triperoxonane acid-dichloromethane-water (10:40:0,5; 50 ml) stirred at 0° C for 15 minutes and then at room temperature for 16 hours the Solvent is removed on a rotary evaporator and the residue is evaporated together with methanol (3× 40 ml). Then the crude product is purified preparative HPLC, receiving 13.

Fmoc-Atc-R(NO2-tryptamide (14)

HOAt (0,409 g 3,005 mmol), EDCI (0,632 g 3,306 mmol, 1.1 EQ.) and TEA (1.1 EQ.) add sequentially to a stirring solution of 13 (1,086 g 3,005 mmol) and Fmoc-Atc-OH (1,242 g 3,005 mmol) in DMF (15 ml) at 0° C. the resulting mixture was stirred for 30 min at 0° and then at room

temperature for 21 hours Processing as described above for 12 gives the crude 14. The resulting substance use in the next stage without further purification.

H-Atc-R(NO2-tryptamide (15)

A solution of 14 (2,27 g, 3.0 mmol) in a mixture of DEA-DMF (1:9, 30 ml) was stirred at room temperature for 3 hours the Solvent is removed by evaporation when eigendom pressure and the residue triturated with a mixture of ether-hexane (1:1, 100 ml)to give 15.

3-(4-Hydroxyphenyl)propanol-Atc-R(NO2-tryptamide (16)

Follow the method of obtaining 12 and get 0,603 g of the crude 16 15 (0,535 g, 1.0 mmol) and 3-(4-hydroxyphenyl)propanoic acid (0,166 g, 1.0 mmol). The crude product was then purified preparative HPLC, receiving 16.

3-(4-Hydroxyphenyl)propanol-Atc-R-tryptamide (17)

A mixture of 16 (0,270 g, 0,405 mmol) and 5% Pd-BaSO4(unrestored, 0,270 g) in a mixture of MeOH-HOAc (10:1, 22 ml) hydronaut at room temperature under atmospheric pressure for 17 hours, the Catalyst was removed by filtration through a pillow celite and the filtrate concentrated on a rotary evaporator. The residue is purified preparative HPLC and triturated with ether, receiving 17.

3-Phenylpropanol-Atc-R(NO2-tryptamide (18)

Follow the methodology of 16 and receive 18 of 0,535 g (1.0 mmol) of 15 and 3-phenylpropane acid (0,150 g, 1.0 mmol).

3-Phenylpropanol-Atc-R-tryptamide (19)

Follow the method get 17 and receive 19

hydrated TFA salt of 0,270 mg 18.

Example 70

Synthesis of 3-phenylpropanol-f-N(Me)R-tryptamide (25)

The compound of this example receive in accordance with the submitted scheme III:

Boc-N(Me)-R(Tos)-tryptamide (20)

Follow the technique to obtain 12 (Scheme I) and receive crude from 20 1,991 g (4.5 mmol) of Boc-N(Me)-R(Tos)-OH and 0,721 g (4.5 mmol) of tryptamine. Received neocidin the second substance use in the next stage without additional purification.

p-TSA•H-N(Me)-R(Tos)-tryptamide (21)

Follow the technique to obtain 7 (Scheme 0) and get 21 in the form of a salt of p-TSA from 2,631 g (4.5 mmol) of 20.

Boc-f-N(Me)-R(Tos)-tryptamide (22)

DIEA (0,310 ml, 1,772 mmol, 2.0 EQ.) add to the thoroughly mixed mixture of 21 (0,4293 g, 0,886 mmol), Boc-f-OH (0,2351 g, 0,886 mmol) and PyBrop (0,3795 g, 0,886 mmol) in

DCM (10 ml) at 0° C. the resulting reaction mixture was stirred at room temperature for 16 h and then diluted with EtOAc (50 ml). The organic layer is washed successively with water (1 × 10 ml), 5% aqueous sodium bicarbonate (2 × 10 ml) and saturated salt solution (2 × 10 ml) and dried over anhydrous sodium sulfate. Remove desiccant moisture and evaporation of volatiles under reduced pressure gives the crude 22.

H-f-N(Me)-R(Tos)-tryptamide (23)

A solution of 22 (0,609 g 0,833 mmol), dissolved in a mixture of TFA-DCM-water (10:40:0,5; 10 ml), stirred at 0° C for 1 h and then kept in the refrigerator at 4° within 72 hours the Solvent is removed by evaporation in vacuo and then the residue together twice evaporated with DCM (each time 10 ml). Thus obtained crude substance purified preparative HPLC and triturated with ether, receiving 23.

3-Phenylpropanol-f-N(Me)-R(Tos)-tryptamide (24)

TEA (0,209 mmol, 1.1 EQ.) add to the thoroughly mixed mixture of 23 (0,120 g 0,19 mmol), 3-phenylpropane acid (0,19 mmol) and EDCI (0,209 mmol, 1,1. EQ) in MF (3 ml) at 0° C. the resulting mixture was stirred at 0° C for 0.5 h and then at room temperature for 16 hours, the Reaction mixture was diluted with EtOAc (30 ml) and washed successively with water (2× 5 ml), 5% aqueous citric acid (3× 3 ml), 5% aqueous sodium bicarbonate (2× 3 ml) and a saturated solution of salt (2× 5 ml). The organic layer is dried over anhydrous sodium sulfate, concentrated and then triturated with ether, receiving 24.

3-Phenylpropanol-f-N(Me)-R-tryptamide (25)

Compound 24 (100 mg, 0.13 mmol) dissolved in liquid ammonia (25 ml) at -78° and to the solution with vigorous stirring with a magnetic stirrer, add small pieces of metallic sodium until then, until there is no longer a blue color, for 2 hours, the Excess reagent is destroyed by ammonium acetate and ammonia is removed by evaporation at room temperature. The residue is dissolved in methanol and the solution is filtered through a bed of silica gel, which was then washed with additional methanol. The combined methanol filtrates are concentrated on a rotary evaporator, obtaining the crude substance purified preparative HPLC, getting 25 in the form of a hydrated salt TFA.

Examples 71-75

Synthesis of H-YfRW-NH2(32), Bc-YfRW-NH2(34), CH3(CH2)8CO-YfRW-NH2(36), Bc-YfRW-tryptamide (40) and CH3(CH2)8CO-YfRW-tryptamide (42)

Connection of the criminal code of the related examples receive in accordance with the submitted scheme IV:

Boc-fR(NO2)-OMe (26)

Boc-f-OH (of 7.64 g, 28.8 mmol), H-W(NO2)-OMe· l (6,72 g, 28.8 mmol), HOBt (3.94 g, 29.2 mmol), TEA (8 ml, 57.6 mmol), and

DMF (110 ml, anhydrous) are mixed, the mixture is cooled at 0° and it was added with stirring EDCI (of 5.89 g, 30,8 mmol). After stirring at room temperature for 18 h the mixture was concentrated on a rotary evaporator, diluted with water (350 ml) and extracted with EtOAc (4× 80 ml). The combined organic extract was washed with 1N aqueous HCl (3× 60 ml), saturated aqueous NaHCO3(2× 50 ml), saturated salt solution (45 ml) and then dried with anhydrous Na2SO4. After filtration, the filtrate concentrated on a rotary evaporator, together evaporated with ether (50 ml) and dried in vacuum, obtaining 3.

p-TSA• H-fR(NO2)-OMe (27)

TFA (6 ml) was added to a solution of Boc-fR(NO2)-OMe (26) (1,49 g, 3.1 mmol) in DCM (20 ml) at 0° C. After stirring at 0° C for 30 min the reaction mixture was stirred at room temperature for 5 hours the Solvent is removed in vacuum, the residue is evaporated together with ether (25 ml) and the resulting residue is dissolved in methanol (25 ml). Add monohydrate p-toluenesulfonic acid (0.6 g, 3.1 mmol), the mixture is stirred for 5 minutes at room temperature, volatiles removed in vacuum and the residue is evaporated together with ether (2�D7; 25 ml), receiving 27.

Boc-YfR(NO2)-OMe (28)

p-TSA• H-fR(NO2)-OMe (27, of 3.46 g, 6 mmol), Boc-Y-OH (1,72 g, 6.12 mmol), HOBt (0,83 g, 6,18 mmol), TEA (1.6 ml, 12 mmol) and DMF (25 ml, anhydrous) are mixed and cooled at 0° and with stirring, add EDCI (1.1 g, 6.3 mmol). After

stirring at room temperature for 16 h the mixture was concentrated on a rotary evaporator, diluted with water (110 ml) and extracted with EtOAc (4× 23 ml). The combined organic extract was washed with 1N aqueous HCl (3× 20 ml), saturated aqueous NaHCO3(2× 25 ml), saturated salt solution (25 ml) and then dried with anhydrous Na2SO4. After filtration, the filtrate concentrated on a rotary evaporator, receiving 28.

Boc-YfR(NO2)-OH (29)

A mixture of Boc-YfR(NO2)-OCH3(28, 2.64 g, 4.1 mmol), LiOH (0,113 g, 4,72 mmol), water (0.4 ml) and MeOH (10 ml) was stirred at room temperature for 6 hours After removal of the solvent the residue is dissolved in a minimum amount of water. Add 1N HCl (approximately 4.7 ml)to neutralize the mixture to pH 5-6. Filtered the solid and dried in vacuum, obtaining 29.

Boc-YfR(NO2)W-NH2(30)

Boc-YfR(NO2)-OH (29, 0,99 g, 1.56 mmol), H-W-NH2·HCl (0,43 g, 1.8 mmol), HOBt (0.25 g, of 1.84 mmol), TEA (with 0.55 ml, 3.9 mmol) and DMF (20 ml, anhydrous) are mixed and cooled at 0° and with stirring, add EDCI (0.36 g, of 1.87 mmol). After paramasivan is at room temperature for 16 h the mixture was concentrated on a rotary evaporator, diluted with water (120 ml) and extracted with EtOAc (4× 25 ml). The combined organic extract was washed with 1N aqueous HCl (3× 20 ml), saturated aqueous NaHCO3(2× 25 ml), saturated salt solution (20 ml) and then dried with anhydrous Na2SO4. After filtration, the filtrate concentrated on a rotary evaporator, together evaporated with ether (20 ml), and

dried in vacuum, obtaining 30.

H-YfR(NO2)-Trp-NH2(31)

TFA (2 ml) are added to a solution of the peptide 30 (0.95 g, of 1.16 mmol) in DCM (6 ml) at 0° C. After stirring at 0° C for 30 min the reaction mixture was stirred at room temperature for 5 hours the Solvent is removed on a rotary evaporator and the resulting residue purified preparative HPLC, receiving 31.

H-YfRW-NH2(32)

Peptide 31 (0.25 g, 0.35 mmol), 5% Pd/BaSO4(0.25 g, unrestored) and MeOH (15 ml) are mixed and hydronaut when the hydrogen pressure of 40 pounds/inch2(276 kPa) at room temperature for 48 hours After filtration, the filtrate concentrated on a rotary evaporator and the residue purified preparative HPLC, obtaining H-YfRW-NH2(32).

Bc-YfR(NO2)W-NH2(33)

Using the technique of 28, followed by purification preparative HPLC receive 33 of the H-YfR(NO2)W-NH2(31, 0.26 g, and 0.37 mmol), butyric acid (0.037 g, 0.42 mmol), HOBt (0,059 g, 0.43 mmol), TEA (0.1 ml, of 0.74 mmol), EDCI (0,084 g, 0.44 mmol) and DMF (12 ml

Bc-YfRW-NH2(34)

Following the method of obtaining 32 receive 34 33 (0.16 g, 0.2 mmol), 5% Pd/BaSO4(0.15 g, unrestored), MeOH (12 ml) and TFA (0.1 ml).

CH3(CH2)8CO-YfR(NO2)W-NH2(35)

Using the technique of 28, followed by purification

preparative HPLC receive 35 of the H-YfR(NO2)W-NH2(31, 0.26 g, 0.36 mmol), decanoas acid (0,071 g, 0.41 mmol), HOBt (0,057 g, 0.42 mmol), TEA (0.1 ml, 0.73 mmol), EDCI (0.083 g, 0.43 mmol) and DMF (12 ml).

CH3(CH2)8CO-YfRW-NH2(36)

Follow the technique of 31 and receive 35 36 (0.2 g, 0.23 mmol), 5% Pd/BaSO4(0.18 g, unrestored), MeOH (12 ml) and TFA (0.1 ml).

Boc-YfR(NO2-tryptamide (37)

Use the technique to obtain 30 and receive 37 of Boc-YfR(NO2)-OH (29, 0.95 g, 1.5 mmol), tryptamine (0,276 g of 1.73 mmol), HOBt (0,239 g, 1.77 mmol), TEA (0.5 ml, 3.6 mmol), EDCI (0.34 g, 1.8 mmol) and DMF (18 ml).

H-YfR(NO2-tryptamide (38)

Peptide 30 (0,98 g of 1.27 mmol) in DCM (6 ml) and a solution of anisole-TFA-DCM (1:8:9, 6 ml) is mixed at 0° C and stirred under ice cooling for 20 minutes and Then the mixture is stirred at room temperature over night. The solvent is removed and the resulting residue is evaporated together with ether (2 × 25 ml)to give crude 38.

Bc-YfR(NO2-tryptamide (39)

Using the technique of 28, followed by purification preparative HPLC, get 39 from 38 (0.28 g, 0.41 mmol), oil is Noah acid (0,042 g, 0.47 mmol), HOBt (of 0.066 g, 0.49 mmol), TEA (of 0.12 ml, 0.83 mmol), EDCI (0,094 g, 0.49 mmol) and DMF (10 ml).

Bc-YfR(NO2-tryptamide (40)

Follow the technique to obtain 32 and receive 40 39 (0,19 g, 0.25 mmol), 5% Pd/BaSO4(0.18 g, unrestored), MeOH (12 ml) and TFA (0.1 ml).

CH3(CH2)8CO-YfR(NO2-tryptamide (41)

Using the technique of 28, followed by purification preparative HPLC, get 41 38 (0.27 g, 0.4 mmol), decanoas acid (of 0.081 g, 0.47 mmol), HOBt (0,065 g, 0.48 mmol), TEA (of 0.11 ml, 0.81 mmol), EDCI (0,093 g, 0.49 mmol) and DMF (12 ml).

CH3(CH2)8CO-YfRW-tryptamide (42)

Follow the technique to obtain 32 and receive 42 41 (0.21 g, 0.25 mmol), 5% Pd/BaSO4(0.18 g, unrestored), MeOH (12 ml) and TFA (0.1 ml).

Examples 76-81

Synthesis of Ac-YfRW-OMe (47), Ac-YfRW-NHCH3(49), AcYfRWSar-NH2(50), 3-(4-OH-Ph)propanol-fRW-NHCH3(53), 3-(4-OH-Ph)propanol-fRW-NH(CH2)2OH (54) and 3-(4-OH-Ph)propanol-fRW-NH(CH2)2OH (55)

The compounds of these examples receive in accordance with the scheme V:

Boc-fR(NO2)-OH (43)

Follow the technique of 29 and receive 43 of Boc-fR(NO2)-OMe (26, 2.8 g, 5.8 mmol), LiOH (0.27 g, 11 mmol) and MeOH (15 ml).

Boc-fR(NO2)W-OMe (44)

Follow the technique of 26 and receive 44 of Boc-fR(NO2)-OH (43, 4,22 g, 9,06 mmol), H-W-OMe· l (2.65 g, 10.4 mmol), HOBt (1.44 g, is 10.7 mmol), TEA (3.15 ml, and 22.6 mmol), EDCI (2,08 g, 10.9 mmol) and DMF (55 ml).

H-fR(NO 2)W-OMe (45)

TFA (12 ml) was added to a solution of 44 (5 g, 7.5 mmol) in DCM (30 ml) at 0° C. After stirring at 0° C for 1 h, the reaction mixture was stirred at room temperature for 16 hours the Solvent is removed in vacuum, the residue is evaporated together with ether (2 × 35 ml) and the product is dried in vacuum, obtaining the crude 45.

Ac-YfR(NO2)W-OMe (46)

Follow the technique of 28 and receive untreated 46 of the H-fR(NO2)W-OMe (45, 3,3 g, 5.8 mmol), Ac-Y-OH (1.5 g, 6.7 mmol), HOBt (0,93 g, 6,9 mmol), TEA (1.7 ml, 12.2 mmol), EDCI (of 1.34 g, 7 mmol) and DMF (25 ml).

Ac-YfRW-OMe (47)

Follow the technique to obtain 32 and receive 47 46 (0.2 g, 0.26 mmol), 5% Pd/BaSO4(0,19 g, unrestored), MeOH (15 ml) and TFA (0.1 ml).

Ac-YfR(NO2)W-OH (48)

Use the technique of 29, followed by purification preparative HPLC and get 48 of Ac-YfR(NO2)W-OMe (46, 0.96 g, 1.25 mmol), LiOH (0,063 g, 2.6 mmol), water (0.4 ml) and MeOH (6 ml).

Ac-YfRW-NHCH3(49)

Follow the method of obtaining 30, except stage joint evaporation, and get the product of the interaction of Ac-YfR(NO2)W-OH (48, 0.3 g of 0.39 mmol), methylamine (0,014 g, 0.45 mmol), HOBt (0,058 g, 0.43 mmol), TEA (0,092 ml of 0.91 mmol), EDCI (0,089 g, 0.47 mmol) and DMF (12 ml). The specified product was then purified preparative HPLC and then hydronaut using the technique of 32 in the presence of 5% Pd/BaSO4(0.17 g, unrestored) in MeOH (12 ml), with 49.

Ac-YfRWSar-NH2 (50)

Follow the method of obtaining 30, except stage joint evaporation, and get the product of the interaction of Ac-YfR(NO2)W-OH (19, 0.3 g of 0.39 mmol), sarcosinate·HCl (0.05 g, 0.4 mmol), HOBt (0,058 g, 0.43 mmol), TEA (0,092 ml of 0.91 mmol), EDCI (0,089 g, 0.47 mmol) and DMF (12 ml). The product was then purified preparative HPLC and then hydronaut using the technique of 32 in the presence of 5% Pd/BaSO4(0.18 g, unrestored) in MeOH (12 ml), with 50.

3-(4-OH-Ph)propanol-fRW-OCH3(51)

Using the technique of 26, followed by purification preparative HPLC receive 51 of the H-fR(NO2)W-OCH345 (2.1 g, 3.7 mmol), 3-(4-hydroxyphenyl)propanoic acid (0.71 g, 4.3 mmol), HOBt (0,59 g, 4.4 mmol), TEA (1.1 ml, of 0.91 mmol), EDCI (of 0.85 g, 4.5 mmol) and DMF (25 ml).

3-(4-OH-Ph)propanol-fRW-HE (52)

Following the method of obtaining compounds 29, receive 52 out of 51 (1,15 g of 1.61 mmol), LiOH (of 0.081 g, to 3.38 mmol), water (0.4 ml)

and MeOH (8 ml).

3-(4-OH-Ph)propanol-fRW-NHCH3(53)

Following the method of obtaining compounds 30, get the product of the interaction of 52 (0.3 g, 0.42 mmol), methylamine (0.015 g, 0.49 mmol), HOBt (0,064 g, 0.47 mmol), TEA (of 0.14 ml, 0.98 mmol), EDCI (0,098 g, 0.51 mmol) and DMF (12 ml). The specified product was then purified preparative HPLC and hydronaut by the method used to obtain 32 in the presence of 5% Pd/BaSO4(0.16 g) and MeOH (12 ml), receiving 53.

3-(4-OH-Ph)propanol-fRW-NHCH2CH2OH (54)

Following the method of obtaining compounds the Oia 30, get the product of the interaction of 52 (0.3 g, 0.42 mmol), ethanolamine (0,031 g, 0.51 mmol), HOBt (of 0.066 g, 0.49 mmol), TEA (of 0.14 ml, 1 mmol), EDCI (0.1 g, 0.52 mmol) and DMF (12 ml). The specified product was then purified preparative HPLC and hydronaut by the method used to obtain compound 32 in the presence of 5% Pd/BaSO4(0.18 g) and MeOH (12 ml), receiving 54.

3-(4-OH-Ph)propanol-fRWSar-NH2(55)

Following the method of obtaining compounds 30, get the product of the interaction of 52 (0.3 g, 0.42 mmol), sarcosinate· l (0,061 g, 0.49 mmol), HOBt (0,068 g, 0.5 mmol), TEA (0.15 ml, 1.1 mmol), EDCI (0,098 g, 0.51 mmol) and DMF (12 ml). The specified product was then purified preparative HPLC and hydronaut by the method used to obtain compound 32 in the presence of 5% Pd/BaSO4(0.18 g) and MeOH (12 ml), receiving 55.

Examples 82-84

Synthesis Bc-YfRW-NHCH3(63), Bc-YfRW-NH(CH2)2OH (64) and BcYfRW-N(CH3)(CH2)2OH (65)

The compounds of these examples receive in accordance with the submitted scheme VI:

Boc-YfRW-OCH3(56)

Follow the method for obtaining compounds 28 and obtain 2.1 g (95%) 56 of Boc-YfR(NO2)-OH (29, 1.7 g, 2.6 mmol), H-W-OCH3·l (0.68 g, 2.7 mmol), HOBt (0,42 g, 3.1 mmol), TEA (0.8 ml, 5.8 mmol), EDCI (to 0.63 g, 3.3 mmol) and DMF (25 ml).

H-YfRW-OCH3(57)

Follow the method for obtaining compounds 38 and receive 57 56 (2.1 g, 2.5 mmol) and anisole solution-TFA-DCM (1:8:9, 18 ml).

Bc-YfRW-och3(58

Following the method of obtaining compounds 28, obtain the crude product of the interaction of H-YfR(NO2)W-OCH3(57, 1,21 g of 1.65 mmol), butyric acid (0.18 g, 2 mmol), HOBt (0.26 g, of 1.95 mmol), TEA (or 0.57 ml, 4.1 mmol), EDCI (0,394 g of 2.06 mmol) and DMF (25 ml). The specified product was then purified preparative HPLC, receiving 58.

Bc-YfRW-OH (59)

Following the method of obtaining compounds of 29, 59 get out of 58 (0.1 g, 0.13 mmol), LiOH (0.004 g, 0.15 mmol), water (0.2 ml) and MeOH (2 ml).

Bc-YfRW-NHCH3(63)

Following the method of obtaining compounds of 28 receive the product of the interaction 60 59 (0.1 g, 0.125 mmol), methylamine (0,006 ml, 0.15 mmol), HOBt (0.02 g, 0.15 mmol), TEA (0.04 ml, 0.3 mmol), EDCI (0.03 g, 0.16 mmol) and DMF (3 ml). Specified product hydronaut by the method used to obtain compound 32, in the presence of 5% Pd/BaSO4(0.1 g, unrestored) in MeOH (6 ml), receiving 63.

Bc-YfR(NO2)W - NH(CH2)2OH (61)

Using the method of obtaining compounds of 28, followed by HPLC purification, get 61 59 (1.3 g, of 1.65 mmol), ethanolamine (0,12 ml, 1.9 mmol), HOBt (to 0.263 g of 1.95 mmol), TEA (with 0.55 ml, 4 mmol), EDCI (or 0.38 g, 2 mmol) and DMF (20 ml).

Bc-YfRW - NH(CH2)2OH (64)

Follow the method for obtaining compounds 32 and receive 64 in the form of solids 61 (0,22 g, 0.26 mmol), 5% Pd/BaSO4

(0.2 g, unrestored), MeOH (12 ml) and TFA (0.1 ml).

Bc-YfR(NO2)W-N(CH3)(CH2)2OH (62)

Using the method of obtaining connection 28 is followed by HPLC purification, get 62 59 (0.26 g, 0.33 mmol), N-methylethanolamine (to 0.032 ml, 0.4 mmol), HOBt (0,053 g 0,39 mmol), TEA (of 0.11 ml, 0.83 mmol), EDCI (0,076 g, 0.4 mmol) and DMF (10 ml).

Bc-YfRW-N(CH3)(CH2)2OH (65)

Follow the method for obtaining compounds 32 and receive 65 62 (0.16 g, 0,19 mmol), 5% Pd/BaSO4(0,19 g, unrestored), MeOH (10 ml) and TFA (0.1 ml).

Example 85

Synthesis of 3-(4-OHPh)propanol-YfRW-NH2(69)

The compound of this example receive in accordance with the submitted scheme VII:

3-(4-OHPh)propanol-fR(NO2)-OCH3(66)

Using the method of obtaining compounds of 28, followed by purification preparative HPLC receive 66 27 (1.5 g, 2,6

mmol), 3-(4-hydroxyphenyl)propanoic acid (0,48 g, 2.9 mmol), HOBt (of 0.43 g, 3.2 mmol), TEA (of 0.91 ml, 6.6 mmol), EDCI (to 0.63 g, 3.3 mmol) and DMF (28 ml).

3-(4-OHPh)propanol-fR(NO2)-OH (67)

Following the method of obtaining compounds 29, receive 67 66 (0.33 g, was 0.63 mmol), LiOH (0,029 g, 1.2 mmol), water (0.4 ml) and MeOH (5 ml).

3-(4-OHPh)propanol-fR(NO2)W-NH2(68)

Using the method of obtaining compounds of 28, followed by purification preparative HPLC, receive 68 67 (0.32 g, of 0.62 mmol), H-W-NH2·l (0.16 g, of 0.68 mmol), HOBt (0.1 g, 0.73 mmol), TEA (0.2 ml, 1.6 mmol), EDCI (0.14 g, 0.75 mmol) and DMF (13 ml).

3-(4-OHPh)propanol-fRW-NH2(69)

Follow the method for obtaining compounds 32 and receive 69 of 68 (0.14 g, 0.2 mmol), 5% Pd/BaSO4(0.1 g, unrestored), MeOH (9 ml) and TFA (0.1 ml).

Example 86

Synthesis of Ac-YfR-tryptamide (73)

The compound of this example receive in accordance with the submitted scheme VIII:

Ac-YfR(NO2)-OCH3(70)

Using the method of obtaining compounds of 28, followed by purification preparative HPLC, get 70 out of 27 (0.36 g, to 0.63 mmol), Ac-Y-OH (0.14 g, to 0.63 mmol), HOBt (0.1 g, of 0.74 mmol), TEA (0.17 ml, 1.2 mmol), EDCI (0.14 g, from 0.76 mmol) and DMF (12 ml).

Ac-YfR(NO2)-OH (71)

Following the method of obtaining compounds of 29 additional stage joint evaporation of THF (5 ml), get a mixture of 71 and two equivalents of LiCl 70 (0.08 g, 0.14 mmol), LiOH (0,007 g, 0.28 mmol), water (0.2 ml) and MeOH (4 ml).

Ac-YfR-tryptamide (73)

Following the method of obtaining compounds 28, obtain the crude product of the interaction of a mixture of 72 Ac-YfR(NO2)-OH/2LiCl (71, 0,091 g, 0,136 mmol), tryptamine (0,025 ml, 0.15 mmol), HOBt (0,021 g, 0.15 mmol), TEA (0.1 ml, 0.7 mmol), EDCI (0.03 g, 0.16 mmol) and DMF (6 ml). Specified product hydronaut by the method used to obtain compound 32,

in the presence of 5% Pd/BaSO4(0.2 g, unrestored) and MeOH (8 ml), with 73 in the form of solids.

Example 87

Synthesis hydrocinnamic-fRW-NH2(77)

The compound of this example receive in accordance with the scheme IX:

Hydrocinnamic-fR(NO2)-OH 3(74)

Following the method of obtaining compounds of 28 receive 74 27 (0.25 g, 0.43 mmol), hydracarina acid (0,068 g, 0.45 mmol), HOBt (0,068 g, 0.5 mmol), TEA (0.16 ml, 1.1 mmol), EDCI (0,097 g, 0.51 mmol) and DMF (20 ml).

Hydrocinnamic-fW(NO2)-OH (75)

Following the method of obtaining compounds 29, receive 75 74 (0,22 g, 0.43 mmol), LiOH (0,014 g of 0.56 mmol), water (0.3 ml) and MeOH (8 ml).

Hydrocinnamic-fRW-NH2(77)

Following the method of obtaining compounds 28, obtain the crude product of the interaction 76 75 (0.2 g, 0.4 mmol),

H-W-NH2·l (0.1 g, 0.42 mmol), HOBt (0,068 g, 0.5 mmol), TEA (of 0.14 ml, 1 mmol), EDCI (0.1 g, 0.52 mmol) and DMF (12 ml). Specified product hydronaut by the method used to obtain compound 32, in the presence of 5% Pd/BaSO4(0.2 g, unrestored) and MeOH (10 ml), with 77.

Example 88

Synthesis of 3-(4-OHPh)propanol-(4-F-f)RW-NH2(82)

The compound of this example receive in accordance with the scheme X:

Boc-(4-F-f)R(NO2)-OMe (78)

Following the method of obtaining compounds of 26 receive 78 of Boc-(4-F-f)-OH (1.5 g, 5.3 mmol), H-R(NO2)-OMe·HCl (1,46 g, 5.4 mmol), HOBt (0.87 g, 6.4 mmol), TEA (of 1.86 ml, 13.3 mmol), EDCI (1,33 g, 6,9 mmol) and DMF (35 ml).

H-(4-F-f)R(NO2)-OMe (79)

TFA (4 ml) was added to a solution of 78 (2,48 g, 5 mmol) in DCM (20 ml) at 0° C. the Mixture is stirred under ice cooling for 30 minutes and then stirred at room is based temperature

throughout the night. The solvent is removed, the residue is evaporated together with ether (2× 30 ml) and the obtained residue is dried in vacuum, obtaining 79 in the form of solids.

3-(4-OHPh)propanol-(4-F-f)R(NO2)-OMe (80)

Following the method of obtaining compounds of 26 receive 80 79 (2 g, 5 mmol), 3-(4-hydroxyphenyl)propanoic acid (0,92 g, 5.5 mmol), HOBt (0.8 g, 5.9 mmol), TEA (1.7 ml, 12.6 mmol), EDCI (to 1.15 g, 6 mmol) and DMF (25 ml).

3-(4-OHPh)propanol-(4-F-f)R(NO2)-OH (81)

Following the method of obtaining compounds 29, receive 81 80 (0.75 g, 1.4 mmol), LiOH (0,065 g, 2.7 mmol), water (0.4 ml) and MeOH (8 ml).

3-(4-OHPh)propanol-(4-F-f)R(NO2)W-NH2(82)

Using the method of obtaining compounds 30, followed by purification preparative HPLC, get the product of the interaction of 81 (0.4 g, 0.75 mmol), H-W-NH2·HCl (0.2 g, 0.82 mmol), HOBt (0.12 g, 0.9 mmol), TEA (of 0.26 ml, 1.9 mmol), EDCI (0.17 g, 0.9 mmol) and DMF (20 ml). Specified product hydronaut by the method used to obtain compound 32, in the presence of 5% Pd/BaSO4(0.25 g, unrestored) and MeOH (15 ml), with 82.

Examples 89-91

Synthesis of 3-(4-OHPh)propanol-fR-tryptamide (88), 3-(2-OHPh)propanol-fR-tryptamide (89) and hydrocinnamic-fR-tryptamide (90)

The compounds of these examples receive in accordance with the submitted scheme XI:

Boc-fR(NO2-tryptamide (83)

Boc-fR(NO2)-OH (43, 507,9 mg of 1.09 mmol), reptomin (172,9 mg, a 1.08 mmol), HOBt (163,3 g at 1.08 mmol), TEA (0.16 ml, 0.12 mmol) and DMF (6 ml, anhydrous) are mixed, cooled at 0° and with stirring, add EDCI (226,9 mg, 1.18 mmol). After stirring at 0° C for 45 min bath with ice is removed, the mixture is heated and stirred at room temperature for a period of 14.5 hours the Mixture is diluted with EtOAc (20 ml) and washed with 2N aqueous HCl (3× 5 ml), the aqueous acidic layer is again extracted with EtOAc (1× 10 ml) and the combined EtOAc layers washed with 1M NaHCO3(3× 5 ml) and saturated salt solution (10 ml). Then the organic extract is dried with anhydrous Na2SO4the desiccant is removed by filtration and the filtrate concentrated on a rotary evaporator. The obtained solid is dried in vacuum, obtaining 83.

p-TSA• H-fR(NO2-tryptamide (84)

TFA (3 ml) was added to a solution of Boc-fR(NO2)-tryptamide (83)

(0,58 g, 0.95 mmol) in DCM (6 ml) at 0° C. After stirring at 0° C for 30 minutes the reaction mixture was stirred at room temperature for 1.25 hours Add monohydrate p-toluenesulfonic acid (176,2 mg of 0.93 mmol) and the volatiles removed on a rotary evaporator, getting a brown oil. The oil is triturated with ether (10 ml) and the residue is dried in vacuum, obtaining 84.

3-(4-OHPh)propanol-fR(NO2-tryptamide (85)

p-TSA• H-fR(NO2-tryptamide (84, 149,9 mg, 220 μmol), 3-(4-hydroxyphenyl)propanoic acid is (to 39.6 mg, 238 μmol), HOBt (33,7 mg, 233 mmol), NMM (0,37 ml, 337 mmol) and DMF (1.5 ml, anhydrous) are mixed, cooled at 0° and with stirring, add EDCI (44,6 mg, 233 mmol). After stirring at 0° for 1,3 h bath with ice is removed, the mixture is heated and stirred at room temperature for 100 hours, the Mixture is diluted with EtOAc (20 ml) and washed with 2N aqueous HCl (3× 5 ml), the aqueous acidic layer is again extracted with EtOAc (1 × 10 ml) and the combined EtOAc layers washed with 1M NaHCO3(3× 5 ml) and saturated salt solution (10 ml). Then the organic extract is dried with anhydrous Na2SO4the desiccant is removed by filtration and the filtrate concentrated on a rotary evaporator, receiving 85.

3-(2-OHPh)propanol-fR(NO2-tryptamide (86)

Following the methodology used for connection 85, get the crude product of the interaction of 84 (151,7 mg, 223 μmol), 3-(2-hydroxyphenyl)propanoic acid (39,2 mg, 236 μmol), HOBt (35,3 mg, 231 μmol), NMM (and 0.40 ml, 364 mmol),

EDCI (45.0 mg, 235 μmol) and DMF (1.5 ml, anhydrous). Then the resulting material purified preparative HPLC (C4), receiving 86.

Hydrocinnamic-fR(NO2-tryptamide (87)

Following the methodology used for connection 85, get 87 84 (to 150.6 mg, 221 mcmol), hydracarina acid (35.6 mg, 237 μmol), HOBt (to 34.4 mg, 225 μmol), NMM (0,37 ml, 337 mmol), EDCI (45.1 mg, 235 μmol) and DMF (1.5 ml, anhydrous)./p>

3-(4-OHPh)propanol-fR-tryptamide (88)

Following the technique used to obtain compound 32, receive 88 of 95 mg (145 mmol) of 85 and 5% Pd-BaSO4(68 mg, unrestored).

3-(2-OHPh)propanol-fR-tryptamide (89)

Following the technique used to obtain compound 32, except that the resulting product lyophilized from a mixture of acetonitrile-water, not purified HPLC, get 89 of 33,7 mg (51 μmol) of 86 and 5% Pd-BaSO4(31 mg, unrestored).

Hydrocinnamic-fR-tryptamide (90)

Following the technique used to obtain compound 32, receive 90 of 106 mg (165 μmol) 87 and Pd-BaSO4(63 mg, unrestored).

Example 92

Synthesis of 3-(4-OHPh)propanol-Me-fR-tryptamide (95)

The compound of this example receive in accordance with the scheme XII:

Boc-Me-fR(NO2)-OMe (91)

Boc-Me-f-OH (1,0008 g, 3.6 mmol), H-R(NO2)-OMe•HCl (0,9659 g, 3.6 mmol), HOBt (0,5515 g, 3.6 mmol), TEA (0,525 ml, 3.8 mmol) and DMF (20 ml, anhydrous) are mixed, cooled at 0° and with stirring, add EDCI (0,7211 g, 3.8 mmol). After stirring at 0° C for 1 h bath with ice is removed, the mixture is heated and stirred at room temperature for 23 hours, the Mixture is diluted with EtOAc (20 ml) and washed with 2N aqueous HCl (3× 8 ml), the aqueous acidic layer is again extracted with EtOAc (1× 10 ml) and the combined EtOAc layers washed with 1M NaHCO3(3× 8 ml) and saturated salt solution (10 ml). Then the organic extract is dried with anhydrous Na2SO4the desiccant is removed by filtration and the filtrate concentrated on a rotary evaporator, receiving 91.

p-TSA• H-Me-fR(NO2)-OMe (92)

Following the method of obtaining compounds of 84 get 92 in the form of hydrated p-TSA salt of 91 (0,4989 g, 1.0 mmol).

3-(4-OHPh)propanol-Me-fR(NO2)-OMe (93)

p-TSA•H-Me-fR(NO2)-OMe (92, 282,8 mg, 500 mcmol), 3-(4-hydroxyphenyl)propanoic acid (85,7 mg, 516 mmol), HOBt

(77,4 mg, 505 mmol), NMM (of 0.60 ml, 546 μmol) and DMF (3 ml, anhydrous) are mixed, cooled at 0° and with stirring, add EDCI (101,9 mg, 532 mmol). After stirring at 0° for 1,3 h bath with ice is removed, the mixture is heated and stirred at room temperature for 24 hours Add EDCI (41,2 mg, 215 μmol), and the mixture is stirred at room temperature for 64 h, again added EDCI (29,9 mg, 156 μmol) together with a small amount of NMM (of 0.60 ml, 546 μmol) and the mixture is heated at 50° C for 8 h and Then the mixture is left at room temperature for 21 h and treated according to the method obtain connection 91, receiving 93.

3-(4-HPh)propanol-Me-fR(NO2)-OH (94)

A mixture of 3-(4-OHPh)propanol-Me-fR(NO2)-OMe (93, the 96.3 mg, 177 μmol), LiOH monohydrate (21,3 mg, 508 mmol) in a mixture of THF-MeOH-water (6 ml, 4:1:1) was stirred at room temperature for 1 h Add 6% aqueous KHSO4(1.3 ml) and the volatiles removed on a rotary evaporator. The moist residue add water (1.4 ml), adjusted pH to ~2 a few additional drops of 6% aqueous KHSO4and the aqueous mixture extracted with EtOAc (3× 2 ml). The combined organic layers washed with water and saturated salt solution and dried over anhydrous Na2SO4. Used desiccant is removed by filtration and the filtrate concentrated on a rotary evaporator, receiving 94.

3-(4-OHPh)propanol-Me-fR-tryptamide (95)

3-(4-OHPh)propanol-Me-fR(NO2)-OH (94, 77.0 mg, 146 μmol),

tryptamine (23.9 mg, 149 μmol), HOBt (25.1 mg, 164 μmol), NMM (0.17 ml, 155 mmol) and DMF (5 ml, anhydrous) are mixed, cooled at 0° and with stirring, add EDCI (32.4 mg, 169 μmol). After stirring at 0° C for 1.5 h bath with ice is removed, the mixture is heated and stirred at room temperature for 4 h the Mixture was processed according to the method for obtaining compounds 85, receiving the crude product interaction, which is purified preparative HPLC (C4). Then the purified product was dissolved in a mixture of 10% acetic acid-MeOH (20 ml) and hydronaut when the hydrogen pressure of 40 pounds/inch2(276 kPa) at room temperature for 15 h using 5% Pd-BaS4(31,3 mg, unrestored) as a catalyst. The catalyst is removed Phi is trevanian through celite, volatiles are removed in vacuo, the residue re-dissolved in a mixture of 10% acetonitrile-water (15 ml) and the mixture is frozen and lyophilized, receiving 95.

Example 93

Synthesis of [1-carbarnoyl-2-(1H-indol-3-yl)ethyl]amide 5-[2-acetylamino-3-(4-chlorophenyl)propionamido]-4-oxo-6-phenyl-2-(2-pyridin-2-retil)hexanoic acid (103)

The compound of this example receive in accordance with the schemes XIII and XIV:

(R)-3-(tert-Butoxycarbonylamino)-1-diazo-4-phenylbutane-2-he (96)

To a solution of Boc-f-OH (5.30 g, 20 mmol) in anhydrous THF (100 ml) is added TEA (2,02 g, 20 mmol) and ethylchloride (2.16 g, 20 mmol) at -15° C in argon atmosphere. The mixture was stirred at -15° C for 30 min, and then heated to 0° C. Add a solution of diazomethane in the air [100 ml, obtained from Me(NO)NCONH2(4.0 g, 40 mmol) and 50% aqueous KOH (20 ml)]. The mixture is heated and stirred at room temperature for 3 hours the Mixture was washed with saturated aqueous NaHCO3(30 ml), saturated aqueous ammonium chloride (30 ml) and saturated salt solution (2× 30 ml). The organic layer is dried over Na2SO4and concentrate on a rotary evaporator. The residue is crystallized from a mixture of hexane-EtOAc with 5° receiving the desired product. The mother liquor is concentrated and purified by chromatography (hexane-EtOAc, 80:20), receiving an additional quantity t is bamogo product.

(R)-3-(tert-Butoxycarbonylamino)-1-chloro-4-phenylbutane-2-he (97)

To a solution of diazoketone (96, 115 mg, 0.4 mmol) in ether (3 ml) is added a mixture of 4N HCl/1,4-dioxane (of 0.11 ml, 0.44 mmol, obtained by dilution conc. HCl 1,4-dioxane) dropwise at 0° C. the resulting mixture was stirred at 0° C for 30 minutes Add a few drops of TEA to neutralize the solution, and the mixture is diluted with EtOAc (20 ml), washed with saturated aqueous NaHCO3(10 ml) and saturated salt solution (3 × 10 ml). The organic layer is dried over Na2SO4and the solvent is evaporated. The residue is purified by chromatography (hexane-EtOAc, 90:10)to give 108 mg (92%) of colorless solid: TPL: 101-102°;1H NMR (CDCl3, 400 MHz) δ of 1.43 (s, 9H), 3,03, 3,10 (AVH, JAB= to 13.8 Hz, JOH= 7,1 Hz, JBX= 6,8 Hz, 2H), 4,00, 4,19 (AB, JAB= 16.2 Hz, 2H), 4,70 (m, 1H), 5,04 (sird, J = 6,8 Hz, 1H), 7.18 in-7,37 (m, 5H).

Methyl 2-methoxycarbonyl-4-(2’-pyridinyl)butanoate (98)

To a freshly prepared NaOMe [of 2.3 g (0.1 mol) of sodium] in MeOH (25 ml) add diethylmalonate (32 g, 0.24 mmol). A solution of 2-vinylpyridine) - derivatives (10.5 g, 0.1 mol) in MeOH (15 ml) is added dropwise over 40 min to a solution of NaOMe while boiling under reflux. The resulting mixture was refluxed for 2.5 h MeOH removed under reduced pressure, the residue treated with 2N HCl (150 ml), then extracted with ether (2× 60 ml)to UDA who spend excessive diethylmalonate. The aqueous phase is alkalinized 2N NaOH and extracted with ether (3× 100 ml). The combined organic phases are washed with saturated salt solution (3× 60 ml) and dried over Na2SO4. The filtrate is concentrated under reduced pressure, then most

part of the excess 2-vinylpyridine) - derivatives are removed in vacuum. The residue is purified by chromatography (hexane-EtOAc, 60:40 to 50:50 to 30:70)to give the desired product.

Methyl (R)-5-(tert-butoxycarbonylamino)-2-methoxycarbonyl-6-phenyl-2-[2’-(2"-pyridinyl)ethyl]-4-oxohexanoate (99)

To a solution α -chloroethane (97, 150 mg, 0.5 mmol) in anhydrous 1,2-dimethoxyethane (3.0 ml) is added NaI (75 mg, 0.5 mmol) and the mixture is stirred in an argon atmosphere for 15 min (Mixture A). To a solution of diapir (98, 142 mg, 0.6 mmol) in anhydrous 1,2-dimethoxyethane (3.0 ml) is added freshly prepared NaOMe (32 mg, 0.6 mmol) and the mixture is stirred in an argon atmosphere for 15 min (Mixture B). Mixture B is added to mixture A and the mixture was stirred at room temperature for 1 h the Mixture was diluted with EtOAc (30 ml) and washed with saturated salt solution (2× 10 ml). The organic layer is dried over Na2SO4the solvents are removed on a rotary evaporator and the residue purified by chromatography (hexane-i-D, 80:20), receiving 99.

(2RS,5R)-5-(tert-Butoxycarbonylamino)-6-phenyl-2-[2’-(2"-pyridinyl)ethyl]-4-oxohexanoate acid (100)

To a solution of diapir (99, 165 mg) is MeOH (10 ml) is added 5N NaOH (1.0 ml) and the resulting mixture was stirred at room temperature for 2 hours The mixture is concentrated on a rotary evaporator and the residue is dissolved in water (10 ml) and acidified with 3N HCl to pH=3. The mixture is extracted with DCM (3× 10 ml) and the combined organic phases are washed with saturated salt solution (10 ml) and dried over Na2SO4. The solvents are removed on a rotary evaporator, receiving decollato. Crude decollato suspended in toluene

(10 ml) and the mixture is refluxed in an argon atmosphere for 3 hours the Solvent is evaporated and the residue purified by chromatography (DCM-MeOH, 98:2 to 95:5)to give a mixture of two diastereoisomers, which can be separated by preparative HPLC.

tert-Butyl ether {1-benzyl-4-[1-carbarnoyl-2-(1H-indol-3-yl)ethylcarbamate]-2-oxo-6-pyridin-2-elexis}carbamino acid (101)

Mixed acid 100 (44 mg, 0.1 mmol), H-W-NH2·l (26 mg, 0.11 mmol), HOBt (16 mg, 0.12 mmol), TEA (24 mg, 0.24 mmol), EDCI (24 mg, 0.12 mmol) and DMF (1 ml, anhydrous). The mixture is stirred at room temperature overnight, then poured into water (10 ml) and extracted with EtOAc (4× 9 ml). The combined extract was washed with 1N HCl (2 × 8 ml), saturated NaHCO3(1× 8 ml), saturated salt solution (8 ml), then dried with anhydrous Na2SO4. After filtration, the filtrate concentrated on a rotary evaporator, getting 101.

[1-Carbarnoyl-2-(1H-indol-3-yl)ethyl]amide 5-the Mino-4-oxo-6-phenyl-2-(2-pyridin-2-retil)hexanoic acid (102)

Peptide 101 (97 mg, 0.16 mmol) is mixed with solution (1 ml) anisole-TFA-DCM (1:8:9). The mixture is stirred at room temperature over night. After removal of solvent

the resulting residue is evaporated together with ether (2 x 8 ml), receiving 0,81 g (99%) 102.

Ac-(4-Cl-F)-OH

A mixture of Boc-(4-Cl-F)-OH (54 mg, 0.18 mmol), DCM (0.5 ml) and TFA (0.5 ml) was stirred at room temperature for 2 hours After removal of the solvent, the obtained residue is mixed with DCM (1 ml), acetic anhydride (17 mg, 0.2 mmol) and TEA (40 mg, 0.4 mmol). The mixture is stirred at room temperature overnight, then concentrated on a rotary evaporator, receiving Ac-(4-Cl-F)-OH.

[1-Carbarnoyl-2-(1H-indol-3-yl)ethyl]amide 5-[2-acetylamino-3-(4-chlorophenyl)propionamido]-4-oxo-6-phenyl-2-(2-pyridin-2-retil)hexanoic acid (103)

EDCI (36 mg, 0,19 mmol) are added to a mixture of peptide 102 (81 mg, 16 mmol), Ac-(4-Cl-F)-OH (41 mg, 0,17 mmol), HOBt (24 mg, 0.18 mmol), TEA (35 mg, 0.35 mmol) and DMF (2 ml, anhydrous) at 0° C. the Reaction mixture was stirred at room temperature overnight and then treated according to the method for obtaining compounds of 101. The crude product is purified preparative HPLC getting 103.

Example 94

Synthesis of N-{3-[9-benzyl-12-(4-Chlorobenzyl)-3-(1H-indol-3-ylmethyl-2,5,8,14-tetraoxo-1,4,7,13-tetraazacyclotetradecane-6-yl]propyl}guanidine (110)

In the above example, receive in accordance with the submitted scheme is Oh XV:

Boc-R(Pbf)W-OMe (104)

NMM (of 0.48 ml, 4.4 mmol) is added to a mixture of Boc-R(Pbf)-OH (1,053 g, 2.0 mmol), H-W-OMe• HCl (0,509 g, 2.0 mmol), HOBt (0,270 g, 2.0 mmol), EDCI (0,422 g, 2.2 mmol) in DMF (10 ml) at 0° and the resulting mixture was stirred at 0° C for 1 h and then at room temperature for 4 h The reaction mixture was diluted with EtOAc (100 ml) and washed successively with water (2× 10 ml), 1N HCl (2× 10 ml), saturated NaHCO3(2× 10 ml) and saturated salt solution (2× 10 ml). The organic layer is dried over MgSO4the desiccant moisture is removed by filtration and the filtrate concentrated on a rotary evaporator, getting 1,454 g (100%) of the crude product 104.

p-TSA• H-R(Pbf)W-OMe (105)

A solution of 104 (1,454 g, 2.0 mmol) in a mixture of TFA-DCM-water

(10:40:0.5m, 20 ml) and DCM (20 ml) was stirred at room temperature for 6 hours Add monohydrate p-toluenesulfonic acid (0,380 g, 2.0 mmol) and the mixture stirred for 10 min at room temperature. The solvent is removed on a rotary evaporator and the residue triturated with a mixture of ether-hexane (1:1, 100 ml), receiving 1,598 g (99,9%) untreated 105.

Boc-(carb-4-Cl-Ff)-R(Pbf)W-OMe(106)

EDCI (105,5 mg, 0.55 mmol) and NMM (to 0.12 ml, 1.1 mmol) is added to a stirring mixture of 5 (216 mg, 0.5 mmol), 105 (399,5 mg, 0.5 mmol) and HOBt (67,6 mg, 0.5 mmol) in DMF (9 ml) at 0° C. the resulting mixture was stirred at 0° C for 1 h, and then when to the room temperature for 5 hours The mixture is treated according to the method for obtaining compounds 104, receiving 508 mg (98%) 106.

p-TSA• H-(carb-4-Cl-Ff)-R(Pbf)W-OMe (107)

A solution of 106 (508 mg, 488 μmol) in a mixture of TFA-DCM-water (10:90:0.5 to 15 ml) was stirred at room temperature for 17 hours HPLC Analysis indicates that the reaction is not yet fully completed, so add a mixture of TFA-DCM-water (10:90:0.5 to 10 ml) and water (1 ml) and the resulting mixture was stirred at room temperature for 7 days Add monohydrate p-toluenesulfonic acid (92,8 mg, 488 μmol) and the mixture is stirred for 10 min at room temperature. The solvent is removed on a rotary evaporator and the residue triturated with ether (25 ml)to give crude 107.

Fmoc-11-Aun-(carb-4-Cl-Ff)-R(Pbf)W-OMe (108)

Follow the method for obtaining compounds 104 and receive

untreated 108 of Fmoc-11-Aun-OH (207 mg, 488 μmol), 107 (543 mg, 488 μmol), HOBt (66,0 mg, 488 μmol), EDCI (103,0 mg, 537 mmol) and NMM (amount of 0.118 ml, 1.07 mmol).

[11-Aun-(carb-4-Cl-Ff)-R(Pbf)W] (109)

1N NaOH (2.2 ml, 2.2 mmol) are added to a solution of 108 (520 mg, 387 μmol) in a mixture of THF-MeOH (1:1) at room temperature and the resulting mixture was stirred at room temperature for 2 hours the Mixture was acidified with 1N HCl to pH ~3 and partitioned between EtOAc (100 ml) and water (20 ml). Then the aqueous phase is extracted with EtOAc (2 × 20 ml), the combined organic phase was washed with saturated salt solution (20 ml) and dried over MgSO4. The desiccant moisture UDA is Aut filtering the filtrate is concentrated on a rotary evaporator and the residue triturated with ether (20 ml)to give crude amino subject to cyclization. Added NMM (47 μl, 460 mmol) to a mixture of the above crude amino acid (430 mg, 387 μmol), HOBt (53 mg, 387 mmol) and EDCI (82,5 mg, 430 μmol) in DMF at 0° C. the resulting mixture was stirred at 0° C for 1 h and then at room temperature for 14 hours, the Mixture is treated according to the method for obtaining compounds 104, and purified preparative HPLC, getting 109.

[11-Aun-(carb-4-Cl-Ff-RW] (110)

A mixture of 109 (42 mg, 39 μmol) in a mixture of TFA-DCM-water (10:10:0,5; 5 ml) was stirred at room temperature for 20 h, the volatiles removed on a rotary evaporator and the residue purified preparative HPLC. The fractions containing the product are pooled, concentrated, frozen and lyophilized, receiving

110 in the form of the TFA salt.

Examples 95-99

Method combination (CP) for the formation of the peptide bond, carried out in solution:

Amine component (1 equivalent), the acid component (1 equivalent) and HOBt (2 equivalent) was dissolved in DMF (2 ml/mmol substrate). The solution is treated with N-methylmorpholine (3-4 equivalent), EDCI (1.2 equivalents) and stirred at room temperature until, until the formation of the product (usually 1-5 hours). The product precipitated after adding to the reaction mixture water (6-10 ml/m is DMF), and it is separated from the liquid by filtration or by decantation.

A. Synthesis of the skeleton of the dipeptide Boc-DPhe-Arg(NO2)OH (A-2)

A-1. Boc-DPhe-Arg(NO2)OMe

Reactant/ReagentMM:Moth:Number:Units:
Boc-D-Phe265,310,0513,26g
DMF  50ml
EDCI191,170,0611,5g
H-Arg(OMe)HCl260,690,0513,48g
HOBt135,130,113,5g
NMM101,140,1516,5ml

For the formation of peptide bonds using the method of combination (CP) in solution.

A-2. Boc-DPhe-Arg(NO2)OH

Reactant/ReagentMM:Moth:Number:Units:
Boc-DPhe-Arg(NO2)OMe480,230,014,8g
LiO 23,950,0230,55g
THF  20ml
Water  10ml

A solution of Boc-DPhe-Arg(NO2)OMe in THF cooled in a bath of ice and treated at 0° With aqueous LiOH solution. The reaction mixture was stirred in a bath with ice for 4 hours. The solvent is evaporated to a small residual volume, which is treated with 1N HCl (approximately 25 ml) to pH 2-3. The product is extracted with ethyl acetate, washed with a mixture of water/saturated salt solution, dried with anhydrous magnesium sulfate; the solvent is evaporated to dryness, obtaining specified in the header of the connection.

B. Synthesis aminobenzene groups

B-1. 3-(4-Benzyloxyphenyl)propionic acid

Reactant/ReagentMM:Moth:Number:Units:
p-hydroxypropionic acid166,170,04687,78g
benzylbromide171,030,0488,17g
NaOH, 1N  100 ml
EtOH  150ml

Use the procedure described in JACS 1955, 77, p. 4887-4892. The product precipitates after the reaction mixture is acidified to pH 2-3.

B-2. 3-(4-Benzyloxyphenyl)propionate

Reactant/ReagentMM:Moth:Number:Units:
3-(4-benzyloxyphenyl)propionic acid256,110,0389,73g
PCl5, 95%208,240,04189,15g
toluene  400ml

Solid PCl5added to a solution of 3-(4-benzyloxyphenyl)propionic acid in toluene for 1 hour. The reaction mixture was stirred at room temperature for 3 hours and the solvent is evaporated. The residue is stirred with hexane through the night, getting a crystalline substance is filtered off and dried in vacuum.

B-3. 4-(S)-Benzyl-3-[3-(4-benzyloxyphenyl)propionyl]oxazolidin-2-he

Reactant/ReagentMM:Moth:Number:Units:
benzyloxypropionic274,740,0051,37g
(S)-(-)-4-benzyloxypyridine177,20,0050,89g
t-BuLi to 1.7 in pentane 0,00513ml
THF, anhydrous  6ml
THF, anhydrous  6ml

Use the procedure described in Tetrahedron 52(43), 1996, p.13733-13738. Salt Li-(S)-(-)-4-benzyloxypyridine get at temperatures from -65° to -72° C. a Solution of decanoylamino in THF is cooled to -72° and treated With a solution of Li-(S)-(-)-4-benzyloxypyridine at the same temperature. The reaction mixture is stirred at a temperature of from -70° C to -75° C for 1 hour and overnight at room temperature, treated with a solution of NH4Cl and extracted with ethyl acetate. The organic layer was washed with a mixture of water/saturated salt solution, dried with MgSO4and evaporated. The residue is purified on a column of silica, using a solution of hexa is/ethyl acetate 7/3 as eluent, getting listed at the beginning of the connection.

B-4. 4-(S)-Benzyl-3-[2-(4-benzyloxybenzyl)Penta-4-enoyl]oxazolidin-2-he

Reactant/ReagentMM:Moth:Number:Units:
4-(S)-Benzyl-3-[3-(4-benzyloxyphenyl)propionyl]oxazolidin-2-he415,480,0031,24g
Allylbromide, d=1,398120,980,0060,52ml
THF30ml
NaHMDS, 0,6M in THF0,0035ml

NaHMDS added to a solution of 4-(S)-benzyl-3-[3-(4-benzyloxyphenyl)propionyl]oxazolidin-2-she's in THF at a temperature of from -70° C to -75° C for 15 minutes the Mixture is stirred for 1 hour and treated with allylbromide at -70° C. Stirring is continued at the same temperature for 1 hour. The reaction mixture is allowed to warm to 0° C for 3 hours and quenched with 10% NH4Cl. The product is extracted with ethyl acetate, washed with a mixture of water/saturated salt solution and dried with anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified is and a column of silica, using a mixture of hexane/ethyl acetate 4:1, receiving specified in the header of the connection.

B-5. 2-(4-Benzyloxybenzyl)Penta-4-ANOVA acid

Reactant/ReagentMM:Moth:Number:Units:
Amide455,540,0041,85g
H2O2, 30% 0,0161,82ml
LiOH23,950,0080,19g
THF  10ml

Use the procedure described in JO 1992, 57(10), 2888-2902 (p.2894).

B-6. 4-(4-(S)-Benzyl-2-oxoacridine-3-yl)-3-(4-benzyloxybenzyl)-4-oxobutyrate

To obtain B-6 use a technique similar to that used to obtain B-4.

B-7. The hydrochloride of the ethyl ester of 4-amino-2-(4-hydroxybenzyl)butyric acid

2-Cyanomethyl-3-phenylpropionate acid (8,16 g, 43 mmol) in ethanol (75 ml) and concentrated HCl (10 ml) hydronaut over night at 40 lbs/inch2(276 kPa) in the presence of 10% Pd/C. the Catalyst is removed filter is receiving; the filtrate is concentrated under reduced pressure to dryness, obtaining specified in the header of the connection.

B-8. Methyl ester of 3-(4-benzyloxyphenyl)-2-decanoylamino acid

Reactant/ReagentMM:Moth:Number:Units:
H-Tyr(Bzl)-OMe HCl321,80,0030,965g
decanolide, 98% d=0,919190,710,0061,27ml
TEA, d=0,726101,190,0162,2ml
DCM  15ml

TEA added to a solution of the remaining reactants in DCM at temperatures between -2° C to +3° C. the Reaction mixture was stirred at room temperature for 4 hours and diluted with 0,1N HCl. The product is extracted with DCM, washed with water, dried with MgSO4and the solvent is evaporated under reduced pressure. The residue is crystallized from hexanol, getting listed at the beginning of the connection.

B-9. 3-(4-Benzyloxyphenyl)-2-technologyoperating acid

reactant/Reagent: MM:Moth:Number:Units:
Ester439,590,002230,98g
1N NaOH 0,00232,3ml
THF  4,3ml
Water  0,7ml

The reactants are stirred at room temperature for 5 hours. The solvent is evaporated under reduced pressure; the residue is diluted with water and acidified to a pH of about 2. The precipitate product is filtered off, washed with water until the pH of the filtrate reaches about 6, and dried in vacuum over night.

C. Synthesis of carboxyl end groups

C-1. N1-Benzyl-3-(1H-indol-3-yl)-N1-methylpropan-1,2-diamine

2M solution of complex BH3·Me2S in THF (40 ml) was added to a solution of amide substrate (4.5 g, 8.4 mmol) in anhydrous THF (50 ml). The reaction mixture is heated at 75° With, while slowly warded off the liquid collected in the fridge. After 2 hours, add a new portion of a 2M solution of complex BH3·Me2S in THF (10 ml) and continue heating with simultaneous disti is the transmission for another 3 hours. The reaction mixture is cooled to room temperature and carefully treated with MeOH until there is no further gas evolution, and 3N NaOH. The crude product is extracted with ethyl acetate and purified on a column of silica using a solution of 1.5% MeOH in AcOEt, and then a solution of EtOAc/DCM/MeOH/Et3N 4/5/0,5/0,3, receiving specified in the header of the connection.

C-2. N1-Benzyl-N1-hexyl-3-(1H-indol-3-yl)propane-1,2-diamine

To obtain C-2 uses a technique similar to that used to obtain C-1.

C-3. N1-Hexyl-3-(1H-indol-3-yl)-N1-methylpropan-1,2-diamine

To obtain C-3 use methods similar to those used to obtain C-1.

D. Assembly tetrapeptide mimetics

D-1. tert-Butyl methyl ether (1-{4-nitroguanidine-1-[2-(hexylamino)-1-(1H-indol-3-ylmethyl)ethylcarbamate]butylcarbamoyl}-2-phenylethyl)carbamino acid

Reactant/Reagent:MM:Moth:Number:Units:
dipeptide466,490,00050,233g
N1-Hexyl-3-(1H-indol-3-yl)-N1-methylpropan-1,2-diamine287,24,0005 0,143g
HOBt135,120,001is 0.135g
NMM, d=0,92101,140,00150,17ml
EDCI191,170,00060,114g
DMF  1ml

For the formation of peptide bonds using the method of combination (CP) in solution. The crude product is purified on a column of silica using a mixture of hexane/ethyl acetate 6/1, getting listed at the beginning of the connection.

To obtain the following compounds D-2, D-3, D-4 and D-5 using methods similar to those used to obtain D-l.

D-2. Methyl ester 2-[2-(2-tert-butoxycarbonylamino-3-phenylpropionylamino)-5-nitrosalicylanilide]-3-(1H-indol-3-yl)propionic acid

D-3. tert-Butyl methyl ether (1-{1-[2-(benzylpenicillin)-1-(1H-indol-3-ylmethyl)ethylcarbamate]-4-nitrogengeneratorer}-2-phenylethyl)carbamino acid

D-4. tert-Butyl methyl ether (1-{4-nitroguanidine-1-[2-(1H-indol-3-yl)-1-(methylpropanoyl)ethylcarbamate]butylcarbamoyl}-2-phenylethyl)carbamino acid

D-5. t is et-Butyl methyl ether (1-{1-[1-(carbamoylmethyluridine)-2-(1H-indol-3-yl)ethylcarbamate]-4-nitrogengeneratorer}-2-phenylethyl)carbamino acid

D-6. [2-(hexylamino)-1-(1H-indol-3-ylmethyl)ethyl]amide of 2-(2-amino-3-phenylpropionylamino)-5-nitroguanidine acid

Reactant/Reagent:MM:Moth:Number:Units:
the Tripeptide  0,15g
TFA/DCM/H2O (1/2/0,1)  2ml

The reaction mixture was stirred at room temperature for 4 hours and diluted with 1,2-dichloroethane. The solvent is evaporated under reduced pressure; the residue is dried in vacuum over night.

D-7. (1-{4-nitroguanidine-1-[2-(hexylamino)-1-(1H-indol-3-ylmethyl)ethylcarbamate]butylcarbamoyl}-2-phenylethyl)amide 2-(4-benzyloxybenzyl)Penta-4-ene acid

0,09
Reactant/Reagent:MM:Moth:Number:Units:
The formation of the amide bond749,820,0002260,17g
acid296,360,0003g
HOBt135,120,00060,08g
NMM, d=0,92101,140,0010,11ml
EDCI191,170,000360,069g
DMF  0,7ml

For the formation of peptide bonds using the method of combination (CP) in solution. The crude product is purified preparative HPLC with reversed phase, receiving specified in the header of the connection.

Example 95

Synthesis of (1-{4-guanidino-1-[2-(hexylamino)-1-(1H-indol-3-ylmethyl)ethylcarbamate]butylcarbamoyl}-2-phenylethyl)amide 2-(4-hydroxybenzyl)pentanol acid

Reactant/Reagent:MM:Moth:Number:Units:
The original substance (D-7)913,15 0,1g
EtOH  15ml
Pd(OH)2    

The reaction mixture hydronaut at room temp is the temperature, at 45 lb/in2(310 kPa) throughout the night. The catalyst is separated by filtration through celite. The solvent is evaporated under reduced pressure. The crude product is purified preparative HPLC with reversed phase, receiving specified in the header of the connection.

Example 96

Synthesis of [1-(1-{4-guanidino-1-[2-(hexylamino)-1-(1H-indol-3-ylmethyl)ethylcarbamate]butylcarbamoyl}-2-phenylethanol)-2-(4-hydroxyphenyl)ethyl]amide decanoas acid

Reactant/ReagentM.M.:Moth:Number:Units:
acid426,560,000230,1g
Amin635,80,000190,12g
HOBt135,120,00050,07g
NMM, d=0,92101,140,0010,11ml
EDCI191,170,00030,06g
DMF  1ml
Pd(OH)2    

For education the education of the peptide bond using the method of combination (CP) in solution. The hydrogenation is carried out in ethanol at 45 lb/in2(310 kPa) within 48 hours. The catalyst is removed by filtration; the crude product is purified preparative HPLC with reversed phase, receiving specified in the header of the connection.

To obtain compounds of Examples 97-99 use a technique similar to that used to obtain the compound of Example 95.

Example 97

Synthesis of methyl ester of 2-(5-guanidino-2-{2-[2-(4-hydroxybenzyl)pentanediamine]-3-phenylpropionylamino}pentanediamine)-3-(1H-indol-3-yl)propionic

acid

Example 98

Synthesis of (1-{1-[1-(benzylaminocarbonyl)-2-(1H-indol-3-yl)ethylcarbamate]-4-guanidinopentanoic}-2-phenylethyl)amide 2-(4-hydroxybenzyl)pentanol acid

Example 99

Synthesis of tert-butyl methyl ether [2-(1-{1-[1-(carbamoylmethyluridine)-2-(1H-indol-3-yl)ethylcarbamate]-4-guanidinopentanoic}-2-phenylethanol)-3-(4-hydroxyphenyl)propyl]carbamino acid

C. Solid-phase synthesis of peptides manually

These peptides are synthesized manually using Fmoc chemistry and Rink amide resin as a solid substrate. The removal of the Fmoc protective groups is achieved with 20% piperidine in DMF for 30 min followed by washing DMF (3× 35 ml), MeOH (3× 35 ml) and DMF (3× 35 ml). Black is tnou reaction with ninhydrin is used to control the completion of the reaction. Acetylation of the terminal amino groups carried out with a mixture of 5% Ac2O/a 0.25% NMM/0,2% HOBt in DMF for 30 min followed by extensive washing DMF and DCM and brief drying in vacuum. The crude product otscheplaut from the resin and the protective group is removed using 93% TFA and 2.3% identicial in water for 3 hours at room temperature. After removing the resin by filtration and wash with 3% TFA (3× 18 ml) the filtrate is extracted with ether (6× 20 ml), frozen and lyophilized. Then the crude product is dissolved in 30% aqueous acetic acid and the solution purified preparative HPLC (particle size 10mk made, Vydac C18, 10× 250 mm, gradient elution with a mixture of 6-60% acetonitrile-water with 0.1% TFA) for 1.5 hours). The fractions containing the product are combined and lyophilized, receiving purified peptides.

Example 100

Synthesis of Ac-Y-(4-Py)ala-RW-NH22TFA

Fmoc-W(Boc)-OH and Fmoc-R(pbf)-OH (each a 2-fold excess) are added sequentially to the Rink amide resin (4,28 g, 3 mmol)using PyBOP (2-fold excess) and NMM (4-fold excess). After washing DMF (3× 35 ml), ether (4× 35 ml) and drying in vacuum is achieved the increase in mass. Resin

(1,17 g, 0.35 mmol) suspended in DMF (10 ml), remove the Fmoc group, successively added PyBOP (0.6 g, 1.15 mmol), NMM (of 0.26 ml, 2.8 mmol) and Fmoc-(4-Py)ala-OH (0,447 g, 1.15 mmol) and the mixture shaken for 1 h After removal of the protective the group Fmoc again repeat the procedure binding with Fmoc-Y(t-Bu)-OH (0,528 g, 1.1 mmol). Then remove the protection from the peptide will acetimidoyl and otscheplaut from resin, receiving the product.

Example 101

Synthesis of Ac-Y-(3-Py)ala-RW-NH2•2TFA

Specified in the header connection receive in accordance with example 100, except that Fmoc-(3-Py)ala-OH used instead of Fmoc-(4-Py)ala-OH.

Example 102

Synthesis of Ac-Y-(2-Py)ala-RW-NH2•2TFA

Adding Fmoc-(2-Py)ala-OH to a solution of PyBop and NMM in DMF leads to a very rapid decomposition of amino acids. Therefore, the compound of this example will be received, using a modification of the method used for Example 100, which NMM (88 μl, 0.8 mmol) are added to a solution of Fmoc-(2-Py)ala-OH (0,311 g, 0.8 mmol) and PyBrop (0,373 mg, 0.8 mmol). After 15 minutes add the second equivalent of NMM. After 100 min any unreacted aminocore will acetimidoyl and then follow the rest of the stages described in example 100, receiving specified in the header of the connection.

VIII. Examples of the compositions and method of treatment

Example

Suffering obese woman weighing 130 kg, put

treatment of the above with the aim of losing weight. In particular, once a day over a period of time of 6 months, the patient is administered using intravenous injection of 15 ml of an aqueous solution, including:

ComponentConcentration (mg/ml)
With the unity of Approx. 15
The sodium bisulfate1
Sodium chloride7
Chlorbutanol5
Citric acid10
Sterile waterdost. quantity. to 1 ml
Sodium hydroxideto bring to pH 5

At the end of the treatment period the patient demonstrates measurable weight loss.

Example B

Suffering from obese man weighing 150 kg, is exposed to programs aimed at reducing body mass, which provides the body weight loss due to the reduction of obesity through combination therapy, including a limited diet and increased physical activity. In particular, once a day over a period of time of 6 months after weight loss, the patient is administered using intravenous injection of 15 ml of an aqueous solution, including:

ComponentConcentration (mg/ml)
Connection Approx. 95
The sodium bisulfate1
Sodium chloride7
Chlorbutanol5
Citric acid10
STERI the other water dost. quantity. to 1 ml
Sodium hydroxideto bring to pH 5

At the end of the treatment period, the patient showed a steady weight loss and reducing obesity.

Example C

Suffering from obese man weighing 165 kg expose program aimed at reducing body mass, which provides the mass loss through combination therapy, including a limited diet, increased physical activity and subcutaneous daily injection of 15 ml of an aqueous solution, including:

ComponentConcentration (mg/ml)
Connection Approx. 885
The sodium bisulfate1
Sodium chloride7
Chlorbutanol5
Citric acid10
Sterile waterdost. quantity. to 1 ml
Sodium hydroxideto bring to pH 5

After the desired weight loss has been achieved,

the weight loss of the patient support with the help of continuing intravenous injection once a day for an additional period of time of 6 months. At the end of the period laciniated demonstrated support the body weight loss and reducing obesity.

Example D

Suffering obese woman weighing 140 kg, they were treated in a specified way in order to achieve weight loss body. In particular, it is treated with subcutaneously implanted pump that delivers 0.1 mg/kg compound of Example 31 for 24-hour time period. The pump contains a solution of the compound dissolved in a solution of 50% propylene glycol and 50% sterile water. Pump replaced on a monthly basis, and the treatment lasts for six months, and during this time the patient demonstrates a loss of body weight and reducing obesity.

Example E

Suffering from obese man weighing 150 kg, is subjected to the treatment using the above method with the aim of losing weight. In particular, it is treated by oral pill taken twice a day, containing 300 mg of the compound of Example 29. The treatment lasts for 12 months, and at this time the patient shows the body weight loss and reduce obesity.

1. The compound having a structure corresponding to formula (I):

where

(A) X is selected from hydrogen, OR1, -NR1R1’and-CHR1R1’where R1and R1’independently selected from the group consisting of hydrogen, (C1-C6) alkyl, and acyl;

(B) (1) each R2independently selected from the group consisting of in Dorada, (C1-C6) alkyl; or

(2) (a) R2associated with the carbon atom that is associated with X and Z1and the substituent R5may not necessarily be connected, forming a carbocyclic or heterocyclic ring, which is condensed with a phenyl ring J; or;

(b) R2associated with the carbon atom, which is connected with the ring Ar, can connect with R7forming a ring condensed with the ring of Ar; or

(C) each of the Z1, Z2and Z3independently selected from-N(R3e)C(R3)(R3a)-; -C(R3)(R3a)N(R3e)-; -C(O)N(R3d)-; -N(R3d)C(O)-; -C(R3)(R3a)C(R3b)(R3c)-; -SO2N(R3d)- and-N(R3d)SO2-; where each R3, R3a,R3band R3swhen present, independently selected from hydrogen and (C1-C6) alkyl;

(2) R3dwhen present, is selected from hydrogen and (C1-C6) alkyl;

(3) R3ewhen present, is selected from hydrogen and (C1-C6) alkyl;

(D) p is 0, 1, 2, 3, 4 or 5; where, when p is greater than 0, each R4and R4’independently selected from hydrogen, (C1-C6) alkyl and aryl;

(E) R5is 5 substituents (i.e. position 2-6) in the phenyl ring J, where each R5independently selected from hydrogen, hydroxy, halogen tiola, -OR12, -N(R12)(R12’), (C1-C6) alkyl, nitro, aryl; where each R12and R12’independently selected from hydrogen and (C1-C6) alkyl; or two substituent R5may not necessarily be connected with the formation of a carbocyclic or heterocyclic ring, which is condensed with a phenyl ring J;

(F) q is 0, 1, 2, 3, 4 or 5; where q is greater than 0, each R6and R6’independently selected from hydrogen and (C1-C6) alkyl;

(G) Ar represents aryl or heteroaryl ring selected from the group consisting of phenyl, thiophene, furan, oxazole, thiazole, pyrrole and pyridine;

(H) R7denotes the substituents on the ring Ar, where each R7selected from hydrogen, halogen, -NR13R13’, (C1-C6) alkyl and nitro; where each R13and R13’independently selected from hydrogen and (C1-C6) alkyl;

(I) r is 0, 1, 2, 3, 4, 5, 6 or 7; where, when r is greater than 0, each R8and R8’independently selected from hydrogen and (C1-C6) alkyl;

(J) B is selected from-N(R14)C(=NR15)NR16R17, -NR20R21, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualbnogo ring containing at least one nitrogen atom in the ring, where R14, R15 R16, R17, R20and R21independently selected from hydrogen, (C1-C6) alkyl;

(K) s is 0, 1, 2, 3, 4 or 5; where, when s is greater than 0, each R9and R9’independently selected from hydrogen and (C1-C6) alkyl;

(L) R10selected from the group consisting of optionally substituted bicyclic aryl ring, and optionally substituted bicyclic heteroaryl ring;

(M) D is independently selected from hydrogen, amino, and-C(O)R11; where R11selected from the group consisting of hydroxy; alkoxy; amino; alkylamino; -N(R19)CH2C(O)NH2where R19is (C1-C6)alkyl; -NHCH2CH2OH and-N(CH3)CH2CH2OH;

or its optical isomer, diastereoisomer or enantiomer; its pharmaceutically acceptable salt, hydrate or biohydrology ester, amide or imide.

2. The compound according to claim 1, where X is selected from-NR1R1’and-CHR1R1’and where R1represents hydrogen or (C1-C6) alkyl, and R1’represents acyl.

3. The compound according to claim 1 or 2, where each R2represents hydrogen.

4. The compound according to any one of the preceding paragraphs, where Z1, Z2and Z3independently selected from-C(R3)(R3a)N(R3e)-; -C(O)N(R3d)-; -C(R3)(R3a)C(R3b)(R 3c- and-SO2N(R3d)-.

5. The compound according to claim 4, where each R3, R3a, R3band R3cif present, independently selected from hydrogen and (C1-C6) alkyl; R3dif present, is selected from hydrogen and (C1-C6) alkyl; R3eif present, is selected from hydrogen and (C1-C6) alkyl.

6. The compound according to claim 1, where p is 1 or 2.

7. The compound according to claim 1, where each R4if present, is hydrogen and each of R4’if present, represents hydrogen or (C1-C6) alkyl.

8. The compound according to claim 1, where each R5independently selected from hydrogen; hydroxy; halogen; thiol, and-N(R12)(R12’), where R12and R12’each represents hydrogen or C1-C6)alkyl, preferably four of the substituents R5in the ring J represent hydrogen, preferably in position 4 of the ring is Deputy other than hydrogen.

9. The compound according to any one of the preceding paragraphs, where q is 0, 1 or 2, preferably, where q is greater than 0, each R6is hydrogen and each R6’represents hydrogen or (C1-C6) alkyl.

10. The compound according to claim 1, where Ar is selected from phenyl, thiophene and furan, preferably phenyl, where the substituent in position 4 of the phenyl ring selected from hydrogen, fluorine, chlorine, bro is a, iodine, nitro and (C1-C6) alkyl, and the remaining four positions of the substituents are hydrogen.

11. The compound according to any one of the preceding paragraphs, where r is 2, 3 or 5 and each R8and R8’independently selected from hydrogen and (C1-C6) alkyl.

12. The compound according to any one of the preceding paragraphs, where B is selected from-N(R14)C(=NR15)NR16R17, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualbnogo ring containing at least one nitrogen atom in the ring, preferably represents-N(R14)C(=NR15)NR16R17where R14, R15, R16and R17independently selected from hydrogen and (C1-C6) alkyl.

13. The compound according to any one of the preceding paragraphs, where s is 1 or 2 and R9is hydrogen and each R9’represents hydrogen or (C1-C6) alkyl.

14. The compound according to any one of the preceding paragraphs, where R10selected from 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutene, benzocyclobutene, indole, indoline, pyridine, dihydropyridines, octagenerian, benzothiophene, benzofuran, benzimidazole, benzopyran, quinoline, quinolone and isoquinoline.

15. The compound according to any one of the preceding paragraphs, where D is selected from amino and -- C(O)R11.

Any, having a structure corresponding to the formula (A):

where

(A) R1and R1’independently selected from the group consisting of hydrogen, (C1-C6)alkyl, and acyl;

(B) R2selected from the group consisting of hydrogen and (C1-C6) alkyl;

(C) Z1selected from-N(R3e)C(R3)(R3a)-; -C(R3)(R3a)N(R3e)-; -C(O)N(R3d)-; -N(R3d)C(O)-; -C(R3)(R3a)C(R3b)(R3c)-; -SO2N(R3d)-; -N(R3d)SO2-; where

(1) each of R3, R3a, R3band R3sif present, independently selected from hydrogen and (C1-C6) alkyl;

(2) R3dif present, is selected from hydrogen and (C1-C6) alkyl;

(3) R3eif present, is selected from hydrogen and (C1-C6) alkyl;

(D) p is 1 or 2 and each R4and R4’independently selected from hydrogen, (C1-C6) alkyl and aryl;

(E) R5selected from hydrogen, hydroxy, chlorine, fluorine, -N(R12)(R12’), where R12and R12’each independently selected from hydrogen and (C1-C6) alkyl;

(F) q is 0, 1 or 2; where, when q is greater than 0, each R6and R6’independently selected from hydrogen and (C1-C6) alkyl;

(G) R7selected and is hydrogen, halogen, -NR13R13’, (C1-C6) alkyl, nitro; where each R13and R13’independently selected from hydrogen and (C1-C6) alkyl;

(H) B is selected from-N(R14)C(=NR15)NR16R17, heteroaryl ring containing at least one nitrogen atom in the ring, and geteroseksualbnogo ring containing at least one nitrogen atom in the ring; where R14, R15, R16and R17independently selected from hydrogen and (C1-C6) alkyl;

(I) R10represents an optionally substituted bicyclic ring selected from 1-naphthyl, 2-naphthyl, indane, 1H-indene, benzocyclobutene, benzocyclobutene, indole, indoline, pyridine, dihydropyridine, octahydrophenanthrene, benzothiophene, benzofuran, benzimidazole, benzopyran, quinoline, quinolone and isoquinoline;

(J) R11selected from the group consisting of amino; alkylamino; -N(R19)CH2C(O)NH2where R19is (C1-C6)alkyl; -NHCH2CH2OH; -N(CH3)CH2CH2OH; or an optical isomer, diastereoisomer or enantiomer; its pharmaceutically acceptable salt, hydrate or biohydrology ester, amide or imide.

17. Pharmaceutical composition having a selectivity for receptors MC-4 and/or MC-3, including (a) a safe and eff is active, the number of cyclic analogue of a peptide according to any one of the preceding paragraphs. and (b) pharmaceutically acceptable filler.

18. The pharmaceutical composition according to 17, used for the treatment of disorders selected from the group consisting of insulin resistance, intolerance to glucose, diabetes type II, coronary heart disease, high blood pressure, hypertension, dyslipidemia, cancer (such as endometrial cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, gallbladder cancer, colon cancer), menstrual abnormalities, hirsutism, infertility, gallbladder disease limited to the lungs, seizures sleep apnea, gout, osteoarthritis and thromboembolic disease in an animal subject, preferably the disease is the disease associated with abnormalities in body weight, selected from the group consisting of obesity, anorexia and cachexia.



 

Same patents:

FIELD: medicine, immunology, peptides.

SUBSTANCE: invention relates to a new composition of biologically active substances. Invention proposes the composition comprising of peptides of the formula: Arg-Gly-Asp and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys that elicits ability to inhibit the proliferative response for phytohemagglutinin, to induce the suppressive activity of mononuclear cells and ability of peptides to induce secretion of immunosuppressive cytokines of grouth-transforming factor-β1 and interleukin-10 (IL-10). The composition can be prepared by a simple procedure.

EFFECT: valuable biological properties of composition.

3 cl, 16 tbl, 9 ex

The invention relates to compounds of the prodrugs of inhibitors dipeptidylpeptidase IV (DP IV) the General formula a-b-C, and And denotes the amino acid refers to a chemical bond between a and C or the amino acid and stable inhibitor of DP IV with the missing C-terminal phosphonate residue, which represents AMINOETHYLPIPERAZINE, aminoacetanilide or N-dipeptidyl, O-arylhydroxylamine

The invention relates to compounds of unstable inhibitors dipeptidylpeptidase IV (DP IV), which have the General formula a-b-C, where a denotes an amino acid, A denotes a chemical bond between a and C or the amino acid and C indicates an unstable inhibitor of DP IV, namely the derived dipeptidylpeptidase, except derived peralkylated as derived dipeptidylpeptidase, the rest of peptidylglycine, dipeptidase or dipeptidylpeptidase

The invention relates to a synthetic amide of opioid peptide or its pharmaceutically acceptable salt having affinity against-opioid receptor, which is at least 1000 times greater than its affinity in relation to-opioid receptor, and which reveals long-term effect when introduced in vivo, and this peptide has the following formula:

H-Xaa1-Xaa2-Xaa3-Xaa4-Q

where Xaa1shown are (A)D-Phe,D-Tyr, D-Tic, or D-Ala (cyclopentyl or thienyl), and A - N, NO2, F, Cl or CH3; Xaa2(A')D-Phe, D-1Nal, D-2Nal, D-Tyr or D-Trp, where A' - or 3,4 Cl2; XAA3- D-Nle, (B)D-Leu, D-Hle, D-Met, D-Val, D-Phe or D-Ala (cyclopentyl), and In - N or CMe; XAA4represents the D-Arg, D-Har, D-nArg, D-Lys, D-i.l.y bit, D-Arg (Et2), D-Har(Et2), D-Amf, D-Gmf, D-Dbu, D-Orn or D-Ior; a Q - NR1R2morpholinyl, thiomorpholine, (C)piperidinyl, piperazinil, 4-one or 4,4-disubstituted piperazinil or-lysyl, where R1is lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, and the laminitis)-polymethene or 4-polyoxyethylene group, a R2is H or lower alkyl; C - H, 4-hydroxy or 4-oxo
The invention relates to a group of new protected linear peptides containing the amino acid sequence, which can be used as starting compounds to obtain RGD-containing cyclopeptides, the General formula

R3-Arg-Gly-Asp(OR1)-OR2,

where R1is benzyl or tert-butyl; R2not equal to R1and is selected from the group of tert-butyl; benzyl; 4-methoxybenzyl; 4-nitrobenzyl; diphenylmethyl; 2,2,2-trichloroethyl; 2,2,2-trichloro-1,1-dimethylethyl; allyl; 9-fluorenylmethyl; carboxamidine; substituted 2-sulfonylated type AND-SO2-CH2-CH2- where a is substituted or unsubstituted phenyl or benzyl; R3is a hydrogen atom or a urethane protective group of the B1O-CO-, where1not equal to R1and can take values tert-butyl, benzyl, 4-methoxybenzyl, 9-fluorenylmethyl, 2-(4-nitrophenyloctyl)ethyl; or is a peptidyl containing from one to three amino acid residues; and the peptides, where R3- peptidyl structure E-Z-Y-X-, in which E is a hydrogen atom or a urethane protective group IN2O-CO-, where2not equal to R1and can take values tert-butyl; benzyl; 4-methoxybenzyl; 9-fluorenylmethyl; 2-(4-nitrophen is IN3O-CO-, in which3= R1attached to the omega-amino group; Z can take values Phe or D-Phe

The invention relates to Bioorganic chemistry and pharmacology, namely the tools, potentiating the analgesic effect of morphine hydrochloride

The invention relates to a new compound - tritium-labeled tartino and method for determining taphrina in biological samples, including the introduction of pre in the sample vysokobarnogo tritium captina, extraction, transformation into the prepared extract captina and its labeled analog in them benzoic or ortho-derivative, which is then analyzed by HPLC with fluorescence detection

The invention relates to peptides-immunoregulators and their therapeutic use

The invention relates to medicine and can be used to prevent premature aging

The invention relates to compounds of the prodrugs of inhibitors dipeptidylpeptidase IV (DP IV) the General formula a-b-C, and And denotes the amino acid refers to a chemical bond between a and C or the amino acid and stable inhibitor of DP IV with the missing C-terminal phosphonate residue, which represents AMINOETHYLPIPERAZINE, aminoacetanilide or N-dipeptidyl, O-arylhydroxylamine

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

-interleukin" target="_blank">

The invention relates to compounds of General formulaand-

< / BR>
< / BR>
where n = 0, 1, or 2, m and m' = 1 or 2; R11is

< / BR>
or

< / BR>
R2'= R2= H, R3is-CH2Ar or 5-15 membered non-aromatic monocyclic group which may contain from 0 to 2 endocycles nitrogen atoms; R4is a branched (C1-5) alkyl group; R5choose from a group comprising-C(O)R7, -C(O)OR9, -C(O)C(O)R7; R7selected from the group: phenyl, naphthyl, isoquinoline, and phenyl may be substituted with halogen, (C1-6) alkoxy, 1,2-methylenedioxy or - N(H)C(O)(C1-6)-alkyl, R9independently selected from straight line (C1-5) alkyl group, optionally substituted by phenyl; R12and R13independently selected from the group comprising-R7-C(O)-R7and-C(O)-N(H)-R7or R12and R13together form a 4-8-membered saturated cyclic group, f is -interleukin (ICE), method of inhibiting ICE activity, methods of treating or preventing IL-mediated diseases

The invention relates to the compounds of formula I or formula II, where R1denotes N(R10)(R11); R2means thio-lower alkyl; each of R3and R5independently represents CH2or C(O); R4denotes a substituted or unsubstituted dionissia alkyl, where the Deputy is CH2NHC(O)R13and he added to the specified tighrope; R6denotes the residue synthetic heteroaromatic-amino acids; R7denotes a residue of natural or synthetic-amino acids; R8IT denotes or lower alkoxy, or together with R7forms homoserine; R9denotes H; each of R10and R11, independently, is H; R12denotes a substituted or unsubstituted fragment selected from aryl, allyssia of alkyl, where the substituents are one or more lower Akilov or halogen; R13denotes lower alkyl; R18denotes H; provided that if R4denotes unsubstituted dionissia alkyl, available tigraphy of R2and R4can form a disulfide bond; or pharmaceutically acceptable salts

The invention relates to new compounds of General formula 1: R1- SO2- B - X - Z - C(O) - Y, where R1represents a (1-12C)alkyl, which optionally may be substituted CF3, (7-15C)aralkyl or Campari; represents a bond, an amino acid of formula-NH-CH[(CH2)pC(O)OH]-C(O)-, where R = 1, 2, or 3, D-3-Tiq, or L - or D-amino acid containing a hydrophobic or neutral side chain; X represents an amino acid with a hydrophobic side chain, glutamine, cyclic amino, -NR2-CH2-C(O) -, or a group:

< / BR>
where n = 2, 3 or 4, W represents CH; R3represents H, (1-6C)alkyl; Z represents a lysine or 4-aminocyclohexanol; Y represents-NH-(1-6C)alkylene-C6H5, -OR4where R4represents H, (2-6C)alkyl, or NR5R6and R5and R6independently represent H, (1-6C)alkoxy or (1-6C)alkyl, optionally substituted with halogen, or R5and R6together represent a (3-6C)alkylene, or R5and R6together with the nitrogen atom to which they are attached, represent< / BR>
where V carts is naphthyl-SO2-Asp-Pro-Lys[COCO]-OH,having anticoagulant activity; and the pharmaceutical composition having inhibitory by combinationally

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to new derivatives of Proline, and more specifically to individual forms new derivative of 1-substituted N-[2-methyl-1-(TRIFLUOROACETYL)- propyl]pyrrolidin-2-carboxamide, which are inhibitors of elastase of human leukocytes (ALC), also known as elastase human neutrophils (ANC), which are important, for example, as a means of research work in pharmacological, diagnostic and related studies and in the treatment of diseases of mammals, which also involved ALC

The invention relates to new cyclic peptides of General formula 1

< / BR>
where is a bridging group; E=H, halogen, -NO2, -NR8R8'or or13, R8and R8'each independently represents hydrogen or methyl; R13represents hydrogen or methyl; X - substituents on the phenyl ring, selected from hydrogen, halogen, -NR2or8; Z is one or more substituents on the phenyl ring, independently selected from hydrogen, halogen, -OR9or two groups Z may be taken together with the formation of a condensed aryl ring; R9is hydrogen or methyl; D

< / BR>
< / BR>
substituted or unsubstituted, imidazolyl; R2, R3, R4and R5each represents hydrogen, methyl, or any two radicals of R2, R3, R4and R5can be connected to form heterocyclic or heteroaryl ring; R = 1 to 3; and to a pharmaceutical composition having a selectivity for receptors MC-3 and/or MC-4 compared with other receptors melanocarcinoma
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