Cyclopeptide, the strain of the fungus, the method of obtaining cyclopeptide, the therapeutic composition

 

(57) Abstract:

The invention covers a new class of cycloheptatrien formula I, where A, B, R1Ieu, C, X and Y are defined in the description, and their therapeutic use as inhibitors of the expression of adhesion molecules for the treatment of many painful conditions. This connection can be achieved by cultivation of a strain of the fungus Bartalinia sp. NRRL21123 in a nutrient medium, followed by separation from the environment specified connection. The invention also describes a therapeutic composition having the ability to inhibit the expression of adhesion molecules, comprising as active ingredient a compound of formula I in an effective amount, and targeted supplements. 4 S. and 2 C.p. f-crystals, 6 tab., 7 Il.

The invention concerns of cyclopeptides and their therapeutic use as inhibitors of the expression of adhesion molecules. Cell adhesion molecules such as ICAM-1, VCAM-1 and E-selectin is expressed on endothelial cells and keratinocytes in the case of ICAM-1 in response to proinflammatory mediators, including TNF, IFN, IL1 and LPS. Appropriate contrivance, such as LFA-1, VLA-4 and SLExexpressed on p processes, as well as intercellular interaction outside of blood vessels are regulated by the interaction between these adhesion molecules and their controlhandle. Therefore, it is possible to use inhibitors of the expression of adhesion molecules for the treatment of many painful conditions. However, to date no suitable low molecular weight inhibitors of the expression of adhesion molecules.

Cyclopeptide are substances with closed cycle molecules containing amino acid residues, connected by peptide bonds, and at least one replacement the remainder of the carboxylic acid, which is connected through the Deputy hydroxyl group with the neighboring acidic residue by broadcasting connection.

We have discovered a new class of cyclopeptides, are inhibitors of the expression of ICAM-1, VCAM-1 and E-selectin.

The present invention relates to cycloheptatriene formula I

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where a denotes the residue butyric acid, substituted by a hydroxyl group which may be optionally substituted in position by the radical R6denoting CN, COOR2, CONR3R4, COR5, CSNH2or alkyl which may be substituted by sidegroups, shall be substituted by alkyl, a halogen atom or a CN group, cycloalkyl, tetrazolyl or group-CCH; where R2denotes hydrogen or alkyl, which can optionally be substituted by aryl, R3and R4- same or different and represent hydrogen or alkyl or form together with the nitrogen atom a ring of 3-6 atoms, 20 which may contain a second heteroatom, and R5represent hydrogen or lower alkyl;

B denotes the remainder-amino--methylamino octanoic acid;

R1denotes hydrogen or methyl;

C denotes tryptophan or N-methyltryptophan formula VI

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where R8denotes hydrogen, alkoxygroup, alkyl or benzyl, R9denotes hydrogen or halogen, R10denotes hydrogen or methyl, and a represents a single or double bond,

X represents the residue-aminosilanes (C2-C14)carboxylic acid, and Y represents the residue of amino - or N-methyl--aminosilanes (C2-C10)carboxylic acid.

The location of amino acid residues in the formula I is such that the direction from the C-Terminus to the N-end is oriented clockwise, and pettalidae the ester linkage is located between residues A and Y. If R1is stands, the R2where R2represents hydrogen, lower alkyl with the number of carbon atoms from 1 to 4 or diphenylmethyl; CONR3R4where R3represents a hydrogen atom or methyl, and R4is a hydrogen atom or alkyl, or R3and R4form together with the nitrogen atom of the ring containing 3 to 6 atoms, or morpholino ring; COR5where R5represents a hydrogen atom or a lower alkyl containing from 1 to 4 carbon atoms; vinyl, which can be additionally substituted by the group CN, Br, or lower alkyl containing from 1 to 4 carbon atoms; alkyl, which may optionally be substituted azido-, amino-, hydroxy-, chloro - or alkoxygroup; CSNH2or-CCH.

And can also be substituted in-position CH2OH, tetrazolium or cyclopropyl.

It is preferable that C was a residue of N-methyltryptophan formula VI, where R8represents a hydrogen atom, (C1-C4)alkoxygroup mainly a methoxy group, or alkyl, and R9is a hydrogen atom or a halogen.

The preferred residue X is the residue of aminazine>alkyl substituent. Most preferably, X represents-amino-or -(C1-C4)alkyl-, mainly methyl-substituted residue octane or butyric acid.

The preferred residue Y is the residue of N-methyl--aminosilanes (C2-C4)carboxylic acid, which can optionally be substituted or(C1-C4)alkyl substituent. Most preferably, Y was N-methylalanine or N-methylvaline.

The compounds of formula I have asymmetric carbon atoms, and compounds can have both R-and S-configuration.

Peptides or pathology can be open circuit. These connections open circuit normally receive by gap broadcasting communication between residues Y and A, and by breaking amide bond between any other pair of adjacent acidic residues. For example, derivatives with an open circuit can be compounds of formulas IV and V:

H-C-X-Y-A-B-R1Leu-LeuOR7IV

HA-B-R1Leu-Leu-C-X-YOR7V

where R7represents a hydrogen atom or alkyl.

A preferred subgroup of compounds according to the invention are the compounds of formula Ip

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where Apto depict the R6pthat represents a CN group, possibly protected groups CH2OH, COOR2p, CONR3pR4p, COR5por-CH= CH2where R2pis a hydrogen atom or alkyl, which can optionally be substituted by aryl, R3pand R4p- same or different and represent a hydrogen atom or alkyl, or form together with the nitrogen atom a 5 - or 6-membered ring which may contain a second heteroatom, and R5prepresents a hydrogen atom or lower alkyl;

Bpis the remainder-amino--methylamino octanoic acid;

R1pis a hydrogen atom or stands;

represents a residue of tryptophan or N-methyltryptophan, which can be N'-(C1-C4)alkoxy-substituted;

Xpis aminosilanes (C2-C14)the remainder of the carboxylic acid; and

Ypis an amino - or N-methyl--aminosilanes (C2-C10)the remainder of the carboxylic acid.

The following subgroup of compounds according to the invention are the compounds of formula I'p< / BR>
< / BR>
where A'prepresents the balance-hydroxy-substituted butyric acid, which may be substituted in position by a group R'2prepresents a hydrogen atom or alkyl which may be substituted by aryl, R'3pand R'4p- same or different and represent a hydrogen atom or alkyl, or form together with the nitrogen atom ring consisting of 3 to 6 atoms, and which may contain a second heteroatom, and R'5prepresents a hydrogen atom or lower alkyl;

B'pis the remainder-amino--methylamino octanoic acid;

R'1pis a hydrogen atom or stands;

C'prepresents a residue of tryptophan or N-methyltryptophan formula

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where R'8prepresents a hydrogen atom, alkoxygroup, alkyl or benzyl, R'9p- the atom of hydrogen or halogen, R'10pis a hydrogen atom or methyl, a represents a single or double bond;

X'pis aminosilanes (C2-C14)the remainder of the carboxylic acid; and

Y'pis an amino - or N-methyl--aminosilanes (C2-C10)the remainder of the carboxylic acid.

< Most preferred are compounds of formulas II and III (referred to hereinafter as compounds A and B, respectively)

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and cyclopeptide formula I, where

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R1= CH3< / BR>
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The object of the present invention is also a strain of the fungus Bartalinia sp. NRRL 21123 - producer cyclopeptide formula I.

The object of the invention is also a method of obtaining the compounds of formula I, namely, that carry out the cultivation of strains of the fungus Bartalinia sp. NRRL 21123 in a nutrient medium, followed by separation from the environment specified connection.

Cycloheptatriene formulas A and B were isolated from cultures of the fungal strain F92-4471/08, isolated from samples of deciduous litter collected near La Plata (La Plata, Argentina), for which it was established experimentally that it belongs to the genus Bartalinia. Samples of strain F92-4471/08 in accordance with the terms of the Budapest Treaty were deposited by the Department of Agriculture U.S. collection (NRRL-cultures), 2 July 1993, and this strain was assigned Deposit number NRRL 21123. Characteristics of fungal strain F92-4471/08 described in example 1.

Thus, the present invention includes both strain F92-4471/08 (NRRL 21123) in isolated form.

Compounds A and B and related compounds can be obtained by culting compounds, for example, as described in example 2.

Characteristics of compounds A and B are given in example 3.

Compounds according to the invention can be obtained by modifications of compounds A and B, including:

a) to obtain compounds of the formula I, in which R6is a group COOR2'where R2' is alkyl which may be substituted by aryl, interaction of compounds of formula I, where R6presents CN-group, with nucleophiles, preferably with alcohols, with the corresponding basic or acidic catalyst, preferably hydrochloric acid, in an organic solvent, preferably ether, or

b) for compounds of formula I in which R6is Isoalkyl, the interaction of the compounds of formula I, where R6presents CN-group, using as nucleophiles organometallics compounds, preferably compounds Grignard or socialgrow that interact in an aprotic organic solvent, preferably the esters, in the presence of a catalyst or without it, or

to obtain compounds of the formula I, in which R6is a group COOH, hydrolysis of compounds of formula I, where R6
g) for compounds of formula I in which R6is a group COOR2'the esterification of compounds of formula I, where R6represented by a group COOH, standard methods, preferably by conversion into the acid chloride of the acid with, for example, thionyl chloride, and treatment with a suitable alcohol in the presence or absence of an acid binder, or

d) for compounds of formula I in which R6represents a group CH2OH, the restoration of the compounds of formula I, where R6represented by a group COOR2using metal hydrides or boron hydrides, preferably brandimensions complex, organic solvents, or

e) for compounds of formula I in which R6is a group CONR3R4the conversion of compounds of formula I, where R6represented by a group COOR2the reaction with amines, preferably by conversion of the free acid to the acid chloride of the acid and then the reaction with the amine of the formula HNR3R4or

g) to obtain compounds of the formula I, in which R6represents a group CHO, oxidation of compounds of formula I, where R6presents a group of CH26presented by CHO and methyl derivative of the Wittig reagent, or

and) to obtain compounds of the formula I, in which R6represents a possibly substituted alkyl of compounds of formula I, where R6presents a group of CH2OH, or

K) to obtain compounds of the formula I, in which R6represents a group CH2NH2the recovery of the compounds of formula I, where R6presents a group of CH2N3or

l) to obtain compounds of the formula I, in which R6represents a group-CCH, from compounds of the formula I, where R6presents the group CH=CBr2or

m) to obtain compounds of the formula I, in which R6is cyclopropyl, the interaction of the compounds of formula I, where R6presents vinyl, with diazomethane, or

n) to obtain compounds of the formula I, in which R6represents tetrazolyl, the interaction of the compounds of formula I, where R6presented by CN, azide, or

o) to obtain compounds of the formula I, in which R8represents a hydrogen atom, remove metoxygroup of the compounds of formula I, where R8submissions to the relationship, the recovery of the compounds of formula I, where the symbol represents a double bond, or

p) to obtain compounds of the formula I, in which R8represents alkyl or benzyl, the introduction of these groups in the compounds of formula I, where R8presents a hydrogen atom, or

(C) to obtain compounds of the formula I, in which R9represents a halogen atom, halogenoalkane compounds of formula I, where R9presents a hydrogen atom, or

t) to obtain compounds of the formula I, in which R8is alkoxygroup, and the symbol represents a double bond, the interaction of the compounds of formula I, where R8presents a hydrogen atom, and the symbol denotes a single bond, with an alkaline tungstate and hydrogen peroxide and alkylation of N-hydroxyindoles intermediate compounds, or

y) to obtain compounds of the formula I, in which R6is a group CSNH2the interaction of compounds of formula I derived from sulfur, preferably with diphenylphosphinomethyl acid.

Compounds of the present invention can also be obtained by chemical synthesis, for example, using conventional methods of peptide synthesis. Tipin atole, containing connected to each other in the order you want the remnants of A, B, R1Leu, Leu, C, X and Y are locked in a cycle due to the formation of amide or ether linkages.

Thus, the invention encompasses a method of obtaining a cyclic Pepeliaev formula I, comprising the cyclization of linear peptides or Pepeliaev containing residues A, B, R1Leu, Leu, C, X and Y, connected to each other in the appropriate order.

Compounds of the present invention exhibit pharmacological activity and can therefore be used as pharmaceuticals. In particular, these compounds are inhibitors induced expression of cell adhesion molecules, in particular inhibitors of VCAM-1 expression compared with expression of E-selectin and ICAM-1. The effect of inhibition of VCAM-1 appears both on the transcriptional and posttranscriptional levels. Methods of analysis, with which you can register the inhibition of the expression of ICAM-1, VCAM-1 and E-selectin under the action of the compounds according to the invention, described after the section "Examples". Therefore, these compounds may be useful for the treatment or prevention of the diseases in which the expression of cell mol at which the movement of leukocytes plays a significant role in the pathogenic process, especially in acute and chronic inflammatory process (e.g., allergies, asthma, psoriasis, injury during reperfusion, rheumatoid arthritis and septic shock and autoimmune conditions (e.g., multiple sclerosis). Other indications for the use of compounds according to the invention include cancer metastases (eg, melanoma, osteocarcinoma) and the rejection of ALLO/xenograft, as it is known that the inhibition of adhesion molecules vessels can significantly improve the predictions of these processes.

In addition, the compounds of this invention may be used to treat hyperproliferative (psoriasis), and a variety of malignant diseases of the skin due to the fact that they possess inhibitory activity in submicromolar concentrations that were detected during testing within 72 hours as in based on measurements of keratinocytes and other tests on the proliferation.

The compounds of this invention show inhibitory activity against induced TNF and IL6 reproduction of HIV in the U1 cell line culture of monocytes, as quantitatively installed using p24 ELISA, and because of this can also be useful in the treatment of immunodeficiencies and Viru is the change of the compounds according to the invention and containing therapeutic compositions.

In the treatment and prevention of diseases caused by expression of adhesion molecules, is administered to a subject therapeutically and prophylactically effective amount of the compounds provided by the invention.

The invention also relates to a therapeutic composition having the ability to inhibit the expression of adhesion molecules and comprising as active ingredient a compound of formula I in an effective amount and the target additives.

Compounds according to the invention can be used to produce medicines for the treatment and prevention of diseases caused by expression of adhesion molecules.

The compositions can be used for parenteral, oral, aerosol and local applications and typically include one or more acceptable carriers, diluents or excipients and may contain stabilizers and other additives.

The applied dose of the compounds may, among other things, vary depending on the condition or disease, are not used for treatment or prevention, and the method and route of administration of the medicinal product. In General, however, satisfactory results are obtained when peraino 0.1 to about 7.5 mg/kg/day, more preferably from about 0.1 to about 2 mg/kg/day in a single dose or divided into doses, administered 2 to 4 times a day. Alternatively, for parenteral administration, for example by intravenous drip or infusion can be used in a dose of from about 0.01 to about 5 mg/kg/day, preferably from about 0.05 to about 1 mg/kg/day and more preferably from approximately 0.1 to approximately 1.0 mg/kg/day.

Suitable for human daily dose is thus with a dose from about 2.5 to 500 mg, preferably from about 5 to 250 mg, more preferably approximately from 5 to 100 mg; or intravenously approximately from 0.5 to 250 mg, preferably from about 2.5 to 125 mg, more preferably from about 2.5 to 50 mg.

Consider the compounds can be administered in any suitable way, including enteral, parenteral, local or using the inhaler. Acceptable for enteral introduction forms are solutions for drinking, tablets and capsules. Acceptable for parenteral administration forms are rastvorny, containing from 0.01 to 10%, preferably from 0.1 to 1% by weight of the major ingredient. Acceptable single dose of the compounds according to the invention by oral administration may be in the range from 1 to 50 mg, it usually ranges from 1 to 10 mg of the Compound from example 4 is the preferred compound according to the invention and may be higher mammals, for example humans, using the same techniques and the same or lower doses, which are usually used to connect to known standards for such indications.

Further description of the invention given in the following examples, data only for the purpose of illustration and referring to the chart, on which:

Fig. 1 shows the UV spectra of compounds A and B (b).

Fig. 2 shows the IR spectrum of the compound A.

Fig. 3 shows the IR spectrum of the compound B.

Fig. 4 shows the spectrum of the proton NMR of compound A.

Fig. 5 shows the spectrum of the proton NMR of compound B.

Fig. 6 shows the range of13C NMR of compound A.

Fig. 7 shows the range of13C NMR of compound B.

In the following examples illustrating the invention without limiting it, the temperature dprg - n-propyl;

HBa - modified 2-hydroxipropionic acid;

TFA - triperoxonane acid;

THF - tetrahydrofuran;

db - double bond;

sb - single bond;

br - wide;

d - doublet;

m - multiplet;

q - Quartet;

t - triplet;

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Example 1. Description strain F/92-4471/08 (NRRL 21123)

Fungal strain NRRL 21123 producing compounds A and B, was isolated from a sample of deciduous litter collected near La Plata, Argentina.

During growth on malt Medium (2% malt extract, 0.4% of yeast extract, 2% agar in deionized water) strain NRRL 21123 forms after 3 days incubation at 27oC colony diameter from 25 to 35 mm Colonies usually give a short aerial mycelium white to gray or grayish-brown color.

On the basis of a measurement of the diameter of the colonies on the Environment And we can say that the optimal growth temperature is between 21 to 30oC and the minimum temperature from 0 to 6oC and a maximum of 33 to 38oC. after 4 days of incubation at a temperature of from 21 to 33oC observe the formation of spores.

Fungal strain NRRL 21123 forms of hyalin for light brown conditionthat of the five cells, are cylindrical in shape, usually slightly curved and in most cases have a size 24-26 x 2.6-4 μm. Each conidia carries at one end a single unbranched hyaline process, and on the other end of the cage from 2 to 4 (typically 3) hyaline and unbranched appendages.

Based on these morphological characteristics, and following the identification rules [B. C. Sutton (1960): The Coelomycetes (publication Commonwealth Mycological Institude, Surrey, England)], strain NRRL 21123 can be assigned to the genus Bartalinia Tassi.

Example 2. Fermentation

Strain NRRL 21123 grown for 15 days at a temperature of 21oC on the jamb of agar containing Medium (2% malt extract, 0.4% of yeast extract, 2% agar, and deionized water). Conidia from one jamb suspended in 10 ml of sterile tap water. A suspension of conidia (1 ml) inoculant each of the two Erlenmeyer flasks with a capacity of 500 ml containing 200 ml of Medium B (2% malt extract, 0.4% of yeast extract in deionised water). To obtain the seed culture flasks incubated for 6 days at a temperature of 21oC on a rotary shaker at 200 rpm Seed culture (2 ml) inoculant each of the 200 Erlenmeyer flasks with a capacity of 500 ml containing 200 the temperature of the 21oC on a rotary shaker at 200 rpm and obtained after 6 days of cell culture combine for further processing.

Example 3. The selection of metabolites, compounds A and B

50 l deep culture of strain NRRL 21123 grown as described in example 2, filtered, using as accelerator filtering Clarcel. The collected wet mycelium is extracted with a mixture of methanol-acetone (1:1) (3 x 15 l). The combined extracts are concentrated in vacuo to circulation evaporator to a residual fluid volume of approximately 3 liters, which extracts (4 x 1 l) with ethyl acetate. An ethyl acetate extracts are combined and concentrated in vacuo to obtain 25 g of oily residue, which is then fractionary three distribution in the solvent system: 90% aqueous methanol and hexane, obtaining after concentration in vacuum in the lower phase 4.5 g of the crude solid material. The resulting material was applied on a column of silica gel (Merck, Kieselgel 60, 40-63 μm) with a size of 5.5 cm EXT. dia. x 38 cm chromatographic, elwira first 1.4 liters of a solvent mixture of methyl tert-butyl ether/methanol (98: 2), then 1 l of the same solvent mixture, taken in the ratio 95:5. The feed rate of the solvent support equally the hurt (example 4) and containing either compound A (N 9-10) or compound B (N 11-25).

Connection A

Combined fractions 9-10, obtained as described above, the chromatography was carried out on silica gel, evaporated in vacuum, obtaining 1 g of the crude material. Further, it is purified using preparative Ehud using column firm Merck (50 mm EXT. dia. x 250 mm) with media LiChrosper RP-18 (7 μm). Elution carried out with a linear gradient of methanol in water (80-100%) for 60 min at a flow rate of 25 ml/min during chromatography was carried out perform detection at a wavelength of 220 nm and collecting fractions of 25 ml based On data of the absorption in the UV, TLC and biological activity of selected fractions 56-62, combined and concentrated in vacuo, receiving 0.6 g of residue. Final purification is carried out using chromatography on Sephadex LH-20 using column size 2.7 cm EXT. dia. x 86 cm and elwira methanol. Erwerbende fractions containing according to TLC, the compound A in purified form, are combined and evaporated to dryness in a vacuum, getting 580 mg of colorless powder. Properties of compound A shown below in table 1.

Compound B

Combined fractions 11-25 give after evaporation of the solvent in vacuum of 2 g of crude material which was further purified pickup perform linear gradient of methanol in water (80-100%) for 60 min at a flow rate of 25 ml/min In the process of chromatography was carried out perform detection at a wavelength of 220 nm and collecting fractions of 25 ml Fractions 47-55 contain the main part of the compound B according to the absorption in the UV, TLC and biological activity. They are combined and concentrated in vacuo, gaining 0.4 g of residue. Further purification is done by chromatography on Sephadex LH-20 column size 2.7 cm EXT. dia. x 86 cm by elution with methanol. In process chromatography perform detection at a wavelength of 220 nm and collecting fractions with a volume of 12 ml On the basis of data on the absorption in the UV, TLC and biological activity of fractions 23-27 combined and evaporated in a vacuum, receiving 0.3 g of residue. The final phase chromatographic purification using a column (2.2 cm EXT. dia. x 16 cm), filled with Kieselgel 60, 40-63 μm company Merck, elution with solvent system toluene-ethanol (95:5) gives pure according to TLC connection B. the Obtained fractions are combined and evaporated to dryness in a vacuum, getting 145 mg of colorless powder. Connection properties B is also shown below in table 1.

In table 1 with references to Fig. 1-7.

Example 4. The compound of the formula I

(A = A', R6= COOCH3, B = B', R1= CH3oC) and the mixture was incubated for 3 days at -20oC. After the reaction mixture was poured into aqueous bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. The crude product is dissolved in 30 ml of methanol/conc. aq. HCl (9/1) and stirred at room temperature for 3 hours. Then, the solution was diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. The crude reaction mixture was purified using chromatography with reversible phase on LiChroprep RP-8 (gradient: methanol/water = 8/2 to 10/0) and subsequent chromatography on silica gel (gradient: toluene/methanol = 100/0 to 95/5), getting mentioned in the title compound as a colourless foam and derivative compounds of formula IV with an open circuit (R6= 15 COOCH3, R7= CH3) as a colourless solid.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,41 (specified in the header connection), Rf = 0,38 (derived from open-chain); chromatography with reversible phase RP-8, methanol/water/triperoxonane acid = 95/4/1, Rf = 0.34 in (specified in segalove
= COOH, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

The solution containing 209 mg of the compounds of formula I from example 4 in 15 ml of a mixture of tert-butanol/conc. aq. HCl (9/1), heated at 60oC for 8 hours. The reaction mixture was poured into saturated aqueous bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with buffer solution pH 7, dried over sodium sulfate, filtered and evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol = 100/0 to 95/5), getting mentioned in the title compound as a colourless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,25; chromatography with reversible phase RP-8, methanol/water = 92/8, Rf = 0.34 in.

Example 6. The compound of the formula I

(A = A', R6= CONHCH3, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

To a cooled to 0oC the solution containing 10 mg of the compound from example 5 in 0.5 ml of dichloromethane, are added 50 μl of thionyl chloride. The reaction mixture was kept at 0oC for 1.5 hours, then evaporated in vacuum at 0oC. the Remaining yellow oil was dissolved in 1 ml dichloromethane at 0oC and K, xtraceroute with ethyl acetate and distributed between ethyl acetate and saturated aqueous bicarbonate solution. The organic phase is washed with saline, dried over sodium sulfate and evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/ethyl acetate/methanol = from 100/0/0 to 65/25/10), getting mentioned in the title compound as a colourless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,25; chromatography with reversible phase RP-8, methanol/water = 95/5, Rf = 0,33.

In the same way as described in example 6, to obtain the compounds of formula I (A = A' B = B' C = C' X = X' Y = Y' and R1= CH3), are presented in table. A.

Example 13. The compound of the formula I

(A = A', R6= COO-iPr, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

To a cooled to 0oC solution containing 15 mg of the compound from example 5 in 0.75 ml of dichloromethane, add 75 μl of thionyl chloride. The reaction mixture was kept at 0oC for 2 hours, then evaporated in vacuum at 0oC. the Remaining yellow oil was dissolved in 1 ml dichloromethane at 0oC and to it add 30 ál of isopropanol. After 3 hours at 0oC seatworm, dried over sodium sulfate and evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol = 100/0 to 95/5), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,47; chromatography with reversible phase RP-8, methanol/water = 95/5, Rf = 0,37.

In the same way as described in example 9, to obtain the compounds of formula I (A = A' B = B' C = C' X = X' Y = Y' and R1= CH3), are presented in table. B.

Example 16. The compound of the formula I

(A = A', R6= COCH3, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution of 200 mg of compound A in 2 ml are added to a solution of methyl derivative of the Grignard reagent (2 mmole in 5 ml of ether and stirred at room temperature for 24 hours then add a further 2 mmole MeMgJ in ether and again stirred for 24 hours at room temperature. The reaction mixture was poured into 0.1 M HCl solution and extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated in vacuum. The crude reaction mixture was purified using chromatographs, and a significant number of the original connection.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,30.

Example 17. The compound of the formula I

(A = A', R6= CH2OH, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

0.5 ml of 2 M solution brandimensions complex added at room temperature to a solution containing 27 mg of the compound from example 5 in 2 ml of tetrahydrofuran. The reaction mixture is stirred for 2.5 hours, poured into 0.1 M HCl and extracted with ethyl acetate. The organic phase is washed with phosphate buffer solution (pH 7), dried over sodium sulfate and evaporated in vacuum. The crude material is purified by means of chromatography on silica gel (gradient: toluene/methanol = 100/0 to 95/5), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,27; chromatography with reversible phase RP-8, methanol/water = 92/8, the original connection is not separated.

Example 18. The compound of the formula I

(A = A', R6= CN, B = B', R1= CH3C = C', R8= H, double bond, X = X' Y = Y')

18 mg of palladium on charcoal (10%) are added to a solution containing 53 mg of compound A and 66 mg of azeta Dorada for 20 hours (50% conversion according to TLC), poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated in high vacuum. The crude material is purified by means of chromatography with the reversible phase medium RP-8 (gradient: methanol/water = 80/20 to 100/0), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,33; chromatography with reversible phase RP-8, methanol/water = 92/8, Rf = 0.50 in (the original connection Rf = 0,44).

Example 19. The compound of the formula I

(A = A', R6= CHO, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

To a solution containing 50 mg of the compound from example 17 in 4 ml of dichloromethane, add 35 mg periodically reagent dess-Marbin (1,1,1-Tris(atomic charges)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one) and the suspension is stirred at 20oC for 3 hours. After this crude", the reaction mixture was applied to silica gel and elute with ethyl acetate. The fractions containing the product are pooled, evaporated in vacuo and purify by chromatography on silica gel (gradient: toluene/methanol = 100/0 to 95/5), getting mentioned in the title substance as a colorless foam.

Example 20. Connection f= Y')

A solution of methyl reagent Witting obtained by mixing 15 methyltriphenylphosphonium and sodium amide in dry THF, is added slowly at a temperature of 20oC to a solution containing of 24.7 mg of the compound from example 19 in dry THF until then, until the yellow color of the reagent. After the reaction mixture was poured into 0.1 M hydrochloric acid and extracted with ethyl acetate. The organic extract was evaporated in vacuum and the remaining after evaporation the crude product is purified by chromatography on silica gel (gradient: toluene/methanol = 100/0 to 97/3), getting mentioned in the title compound as a colourless foam.

Example 21. The compound of the formula I

(A = A', R6= CH=CH-C2H5, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

Specified in the header of the connection receives the same way as described in example 20.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,44.

Example 22. The compound of the formula I

(A = A', R6= CH2N3, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

To a solution containing 30 mg of the compound from example 17 and 12 mg of triphenylphosphine in 3 ml of dry THF, add 150 ál of 0.38 M Rast is th temperature diethylazodicarboxylate and the mixture is stirred at room temperature for 10 minutes. The crude reaction mixture was applied to 5 g of neutral aluminium oxide and elute with ethyl acetate. The fractions containing the product, evaporated in vacuo and purify by chromatography on silica gel (gradient: toluene/methanol = from 99.5/0.5 to 95/5), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,46; chromatography with reversible phase RP-8, methanol/water/TFA = 95/4/1, Rf = 0,41.

Example 23. The compound of the formula I

(A = A', R6= CH2NH2, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution containing 20 mg of the compound from example 22 in 2 ml of methanol, stirred in hydrogen atmosphere with 4 mg of palladium on coal (10%) for 20 hours. The catalyst was removed by filtration and the reaction mixture is evaporated in vacuum. The crude product was then purified using chromatography with reversible phase RP-8 (gradient: methanol/0.5% aq. TFA = 80/20 to 100/0), getting mentioned in the title substance as a colorless foam.

TLC: with the reversible phase RP-8, methanol/water/TFA = 95/4/1, Rf = 0,69.

Example 24. The compound of the formula I

(A = A', R6= CH= CBr2, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

Raaga powder, 120 mg of triphenylphosphine and 150 mg tetrabromomethane, and stirred for 30 minutes at room temperature. After this mixture is applied in 5 g of aluminum oxide and elute with ethyl acetate. The fractions containing the product, evaporated in vacuo and purify by chromatography on silica gel (gradient: toluene/methanol = from 99.5/0.5 to 97/3), getting mentioned in the title substance as a colorless solid foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,27.

Example 25. The compound of the formula I

(A = A', R6= CCH, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution of n-utility in hexane (3 mol equivalent) is added at a temperature of -78oC for 2 hours to 50 mg of the compound from example 24. The reaction mixture was poured into 0.1 M aqueous HCl and extracted with ethyl acetate. The organic phase is washed with bicarbonate and saline solutions and evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol = from 99.5/0.5 to 97/3), getting mentioned in the title substance as a colorless solid foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,44.

Example 26. The compound of the formula I

(A = A'. R6= C= CH-CN, B = B', R1= CH3

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,39.

Example 27. The compound of the formula I

(A = A', R6= CH2Cl, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution containing 20 mg of the compound from example 17 in 1 ml of toluene, are added to a solution of 10 mg of dichlorotriphenylphosphorane in 1 ml of toluene and stirred at a temperature of 60oC. After 2 hours the reaction mixture contribute an additional 35 mg of dichlorotriphenylphosphorane. After 1 hour the reaction mixture was filtered through neutral alumina and elute with ethyl acetate. The fractions containing the product, evaporated and the crude material purified by chromatography on silica gel (gradient: toluene/methanol = 100/0 to 97/3), getting mentioned in the title substance as a colorless solid foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0.34 in.

Example 28. The compound of the formula I

(A = A', R6

TLC: silica gel, toluene/methanol = 9/1, Rf = 0.34 in.

Example 29. The compound of the formula I

(A = A', B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution containing 13 mg of the compound from example 20 and 2.8 mg of palladium acetate in 2.5 ml of dichloromethane, is treated at room temperature the ether solution diazomethane until then, until you react all the source material. The crude reaction mixture was filtered through silica gel and elute with a mixture of toluene/methanol. The fractions containing the product, evaporated and the crude product is purified by chromatography on silica gel (gradient: toluene/methanol = from 99.5/0.5 to 97/3), getting mentioned in the title substance as a colorless solid foam.

TLC: silica is 2">

Example 30. The compound of the formula I

(A = A', R6= COOCH(C6H5)2, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution containing 8.2 mg of the compound from example 5 and 3.1 mg diphenyldiazomethane in 0.5 ml of toluene, heated at 60oC for 3 hours. Then, the solution directly purified by chromatography on silica gel (gradient: toluene/methanol = 100/0 to 97/3), getting mentioned in the title substance as a colorless solid foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,46.

Example 31. The compound of the formula I

(A = A', B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution containing 50 mg of compound A in 1 ml of dimethylformamide, heated to 125 mg of chloride of tributyltin and 25 mg of sodium azide at a temperature of 100oC for 8 days. The mixture is then poured into 1 M aqueous HCl, extracted with ethyl acetate. The organic phase is washed with saline, dried over sodium sulfate and evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol = 100/0,25 to 100/2,5), receiving specified in title 25 of the substance in the form of a colorless foam.

TLC: silica gel, talwalker 32. The compound of the formula I

(A = A', R6= CN, B = B' C = C', R8= CH3, a double bond, X = X' Y = Y')

A solution containing 20 mg of the compound from example 18 in 1 ml of dry dimethylformamide, stirred 1 ml of iodomethane, then added a solution of 5 mg of bis(trimethylsilyl)amide sodium in 0.3 ml of dimethylformamide. After stirring the reaction mixture for 1.5 hours at room temperature it was poured into 0.1 M aqueous HCl, extracted with ethyl acetate and distributed between ethyl acetate and saturated aqueous bicarbonate solution. The organic phase is washed with saline, dried over sodium sulfate and evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol = 100/0,25 to 100/2,5), receiving specified in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,43.

In the same way as described in example 32, obtain the compounds of formula I (A = A', R6= CN, B = B' X = X' Y = Y'), are presented in table. Century

Example 35. The compound of the formula I

(A = A', R6= CN, B = B' C = C', R8= CH2C(CH3)3, a double bond, X = X' Y = Y')

To a solution containing 38 mg of the compound from example 18 in 2 ml ukces stirred for 5 minutes at room temperature. After that, the mixture was poured into sodium bicarbonate/ethyl acetate, and thereto is added a small amount of water. The organic layer is separated, washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining colorless oil (TLC: silica gel, toluene/methanol 9/1, Rf = 0,53) dissolved in 3 ml of THF and to it at room temperature, add a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in THF (8 mg in 0.2 ml) up until the mixture becomes dark. The mixture is filtered through 5 g of silica gel and a gradient elute the solvent system toluene/methanol = 100/0,5 to 95/5, getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol 9/1, Rf = 0,49.

In the same way as described in example 35 to obtain compounds of formula I (A = A', R6= CN, B = B' X = X' Y = Y'), are presented in table. ,

Example 38. The compounds of formula I

(A = A', R6= CN, V = V', C = C', R8= H, double bond, X = X' Y = Y')

A heterogeneous mixture consisting of 25 mg of the compound from example 18, 1 ml triperoxonane acid and 0.3 ml of triethylsilane vigorously stirred in an argon atmosphere at 4oC for 20 h Then the reaction mixture was poured into saturated aqueous bicarbonate solution and euprepius in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol in the ratio of from 100/0,5 to 100/5), getting listed in the title compound as a colourless foam.

TLC: silica gel, toluene/methanol = 9/1, indolin A Rf = 0,16, indolin B Rf = 0.10; this chromatography with reversible phase RP-8, methanol/water/TFA = 95/4/1, indolin A + B Rf = 0,71.

Example 39. The compound of the formula I

(A = A', R6= CN, B = B' C = C', R8= O(CH2)2CH3, a double bond, X = X' Y = Y')

To a solution containing 30 mg of the compound from example 38 (mixture of diastereomers) in 1 ml of methanol, add 100 mg of sodium tungstate (Na2WO42H2O) and 100 µl of 30% hydrogen peroxide. The reaction mixture was stirred for 20 minutes at room temperature and then directly purified by gel permeation chromatography (Sephadex LH-20, methanol/ethyl acetate = 1:1). The fractions containing N-hydroxyindole intermediate connection, evaporated, the residue is transferred in 2 ml dry DMF, to which is added 2 ml of propyliodide and 7.5 mg of bis(trimethylsilyl)amide sodium. After stirring at room temperature for 30 minutes the contents of the reaction mixture was poured into 0.1 M hydrochloric acid and extracted with ethyl acetate. The organic is by using chromatography on silica gel (gradient: toluene/methanol = 100/0,5 to 98/2) and chromatography reverse phase (RP-8, the gradient of aqueous solution of methanol at a concentration of from 75 to 100%), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 90/10, Rf = 0,51; RP-8; methanol/phosphate buffer pH 7 = 92/8, Rf = 0,30.

Example 40. The compound of the formula I

(A = A', R6= CN, B = B' C = C', R8= OC2H5, a double bond, X = X' Y = Y')

Specified in the header of the connection receives the same way as described in example 39.

Example 41. The compound of the formula I

(A = A', R6= CN, B = B' C = C', R8= OCH3, R9= Br, double bond, X = X' Y = Y')

A solution containing 50 mg of compound A in 2 ml of carbon tetrachloride, mixed with 3 mg of iron powder and to him within 1 hour, add a solution of bromine (10 mg) in carbon tetrachloride. The crude reaction mixture was poured into aqueous bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with sodium thiosulfate solution and brine, and then evaporated in vacuum. The crude product was then purified using chromatography on silica gel (gradient: toluene/methanol = from 99.5/0.5 to 97/3), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 90/10, Rf = 0.48 chromatography = CSNH2, B = B', R1= CH3C = C', R8= OCH3, a double bond, X = X' Y = Y')

A solution containing 50 mg of compound A and 50 mg of diphenylmethanediisocyanate in 4 ml of isopropanol is heated at 60oC for 3 days. The reaction mixture is cooled to -20oC, the precipitate is removed by filtration, the solution was diluted with ethyl acetate and extracted with aqueous sodium bicarbonate solution. The organic phase is evaporated in vacuum and the crude product purified via chromatography on silica gel (gradient: toluene/methanol = 100/0,5 to 96/4), getting mentioned in the title substance as a colorless foam.

TLC: silica gel, toluene/methanol = 9/1, Rf = 0,29.

Biological activity

The active compounds according to the invention tested in assays for cytotoxicity and inhibition of expression of ICAM-1, VCAM-1 and E-selectin, and analyses on cell proliferation. The concentration of compounds required for the manifestation of inhibitory effect of the size of half of the maximum (IC50), for each type of analysis are given below in table 2.

The analysis was carried out as follows:

in both types of analyses, as on cell proliferation and ELISA analysis for ICAM-1, used aconservative phenotypic characteristics of normal differentiation of keratinocytes [(BouKamp et al., 1988, J. Cell. Biol. 106, 761-771)].

A. Cell ELISA analysis for ICAM-1

I. Cell ELISA analysis for ICAM-1 keratinocytes

Cell ELISA analysis for ICAM-1 is used for determining the inhibition of the expression of ICAM-1 in substantially the same way as described in [WinisKi and Foster (1992, J. Inverst, Dermatol., 99, 48-52)]. HaCaT cells were seeded in 96-well plates to micrometrology (2 of 104cells per well in culture medium of the following composition: DMEM with 5% FSC 100 u/ml penicillin, 100 μg/ml streptomycin, 2 mm glutamine, 1 mm sodium pyruvate), grown to confluence, and then incubated for approximately 24 hours in fresh test environment (same as culture, but with 0.5% FSC instead of 5%) in the presence and absence of an enabling environment with IFN-/TFN- (test environment, containing 1000 u/ml IFN-/3 ng/ml TNF-) in both cases in the presence and absence of compounds A and B. then 1 again wash the culture medium and cell monolayers fixed with 1% paraformaldehyde. Monolayers incubated with saturating amounts of primary (mouse monoclonal antisym-1) and secondary (goat, artemisinin conjugated with peroxidase) antibodies. In subsequent peroxidase reaction using 3-amino-9-ethylcarbazole (AEC) as the substrate is formed is octene tablets.

II. The degree of cytotoxicity

Upon completion of the reaction detection of ICAM-1 using AEC monolayers HaCaT cells rinsed PBS (200 μl), PBS is removed from the tablets are then dried by shaking on a paper towel. The bottom surface of the tablet gently wipe with a damp cloth for face care, then dry cloth and measure the absorption of light at 492 nm. Before monolayers dry, to each well was added 0.1 ml of 0.1% solution purple crystal in PBS (pre-filtered through 0.2 μm filter). The tablets are then incubated at room temperature for 10 minutes, thoroughly washed 5 times with PBS to remove excess fluid in the same way as before, and before monolayers dries, measure the absorption of light at 492 nm. The difference of optical densities before and after dyeing gives value, due to the binding purple crystal, and therefore, indicates the number of the cell monolayer in the hole. These values are used for correction of data obtained by AEC.

B. Cell ELISA analysis on VCAM-1, ICAM-1 and E-selectin on endothelial cells

The method is based on cell ELISA analysis using 96-Lu the veins of the human (HUVEC). The cells were pre-treated within four hours of the test compounds A and B, stimulate over the next 8-16 hours with TNF, and then fixed with paraformaldehyde for subsequent evaluation of the expression of VCAM-1, ICAM-1 or E-selectin using indirect immunoperoxidase coloration technique. Cytotoxic effects determined by counting the relative number of cells with nuclear dye Giemsa) after incubation with the test substances in comparison with control wells (only the solvent and the environment). It is believed that the compounds have a positive effect if they cause inhibition of VCAM-1, ICAM-1 or E-selectin 50% loss of cell < 25%.

Methodology

I. Cell line: in the analysis of the inhibition of expressi. VCAM-1 and ICAM-1 using immortalizing (large T-antigen of the virus SV-40) line of endothelial cells of microvessels person (HMEC-1 [Ades et al. Irl Invest Dermatol 99: 683-690, 1992]). This cell line constitutively expresses in a small amount of ICAM-1, which is regulated by inflammatory mediators. However, after cytokine stimulation they Express only VCAM-1. Experiments were carried out to determine the optimal conditions for the induction of ex is up in T-75 flasks (Nunc) in standard conditions (37oC, 5% CO2) with 1.5 106cells per ml of culture medium (CM) (CM = main medium for endothelial cells [EBM; Clonetics], supplemented with 10% FSC, 10 mg/ml human EGF (Boehringr), 1 μg/ml hydrocortisone (Sigma # 0888), 2.2 g/l NaHCO3, 15 mm HEPES, 0.11 g/l sodium pyruvate, 4 mm glutamine, 100 u/ml penicillin and 100 μg/ml streptomycin). After trypsinization under mild conditions (0.25% trypsin with 0.1% EDTA for 8 min) and resuspendable cells subcultured every 2-3 days, sharing in the ratio of 1:3.

III. Cell ELISA analysis on VCAM-1 and ICAM-1

The surface of the wells of flat-bottomed 96-well plates for micrometrology pre-cover bovine fibronectin (FN; Sigma # F1141), after which the wells seeded with cells (2 of 104cells per well in 200 μl of EBM-environment for growth) and incubated over night. The next day the culture medium (CM) replace the first EBM-based environment for analysis (CM) with 5% FCS instead of 10%), then on Wednesday (180 μl per well) containing either (1) the desired concentration of the compound A or B, or (2) the appropriate concentration environment, extracted with a solvent/methanol, or (3) only one EBM-based environment for analysis, and incubated for 4 h at a temperature of 37oC. Each of the 96-well assays performed in two iterations. Polecenie 16 hours at a temperature of 37oC.

The cell monolayer was washed with 1% paraformaldehyde in EBM medium, fixed with 2% paraformaldehyde for 15 min at room temperature (RT) and rinsed several times by PBS. After removal of PBS monolayers incubated for 30 min in PBS containing 10% normal goat serum (NGS). The solution NGS replace with a solution of monoclonal anti-VCAM-1 and anti-ICAM-1 antibody (100 μl per well) and incubated overnight at 4oC. After removal of the solution of monoclonal antibodies (mAb) cells rinsed with PBS, followed by incubation for 30-60 min at RT in PBS containing 10% NGS. Remove the NGS solution in the wells add 100 ál of conjugate of horseradish peroxidase and goat F(Ab')2-antibodies against mouse IgG (Tago; dilution 1:500 in PBS containing 5% NGS and incubated for 1 h at RT. At the end of the incubation, remove the secondary antibody, the cells are rinsed by PBS, which replace then freshly filtered solution AEC (3-amino-9-ethylcarbazole; Sigma; 150 μl per well) and incubated for 45-60 min at RT. The peroxidase substrate were removed and the cells rinsed by PBS. Next, using the equipment to read the tablets produce a measurement of light absorption AEC at 550 nm and the obtained values are correct with regard to avodat, using freshly isolated HUVEC cells, essentially as described for the analysis of VCAM-1 and ICAM-1, except for a short period of stimulation under the action of TNF (6-8 hours).

V. the Degree of cytotoxicity (accounting for the loss of cells based on staining of cell nuclei)

Endothelial cells are washed, substituting PBS for 20 min in 95% ethanol (2 shifts of 10 min) with control under the microscope. Following this, the cells rinsed in distilled water (Aquadest) and monolayers cover 33% Giemsa solution in Aquadest for 5 min at RT. The wells are washed with Aquadest and are air-dried for at least 15 minutes. With the help of the microscope is controlled so that the staining was subjected to only the nucleus but not the cytoplasm. Conduct measurements of light absorption at 550 nm, due to the binding of Giemsa dye and the obtained values are correct with regard to acquisitions "Blanca" (the rows of wells without cells) at 690 nm.

VI. Data processing: the results of the analysis with AEC for constitutive expression of VCAM-1 or E-selectin (control wells without stimulation) coincide largely with the results for izotopicheskii paired control mAb and reflect the background color. For each of the 96 wells average value constituent exploitation group (for control on EBM and the solvent, and for the test substance), resulting in getting a number that expresses the value of the variable in the case of ICAM-1 and induced in the case of VCAM-1 or E-selectin expression of cell adhesion molecules (CAM), designated here as AEC-CAM. Is AEC-CAM in each case is then divided by the corresponding value defined in the analysis with Giemsa, getting the number, giving an estimate of the level of expression of CAM in relation to the density of the cells, measured on the basis of staining of cell nuclei (denoted here as the ratio of the AEC:Giemsa).

AEC (stimulated) - AEC (nstimerevent) = AEC-CAM AEC-CAM/Giemsa = ratio AEC:Giemsa

Thus, the "true" values of the IC50the expression of CAM determined by comparing the magnitude of the AEC:Giemsa obtained in the samples of the test compounds with the corresponding values for stimulated control samples (EBM, solvent). The values of these quantities are compared with the values IC50only for Giemsa. Strict criterion, indicating the presence of CAM inhibition in comparison with the profile of cytotoxicity (Giemsa) means "real" goal that must be achieved.

C. analysis of the proliferation of HaCaT cells

HaCaT cells were cultured in DMEM (Gibro # 074-02100) supplemented with 2.2 g/l NaHCO3, 0.11 g/l PG/ml) and glutamine (to increase the final concentration to 4 mm). For analysis on the proliferation of cells treated with trypsin, suspended in fresh medium and sown in 96-well plates to micrometrology, the value of the final density of the cell suspension corresponds to 4000 cells/0.2 ml per well. After 24 hours (day 0), the medium is replaced by fresh, containing a set of concentrations of the test compounds. After 3 days of incubation at 37oC/5% CO2the degree of cell proliferation compared to controls (solvent) measure colorimetrically, determining relative cell mass using dye sulforhodamine B [(Skehan et al., 1990, I. Natt. Cancer Inst. 82, 1107-1112)]. "Starting cell number determined by measuring the relative cell mass at day 0. The results are expressed as % inhibition = 100% - % of control removals (where 100% is the control with the solvent) and represent the results of three dimensions in the form of average values of standard deviations. Schedule dependent on the dose build in semi-logarithmic scale, determining the concentration needed to inhibit half of the maximum (IC50) using linear interpolation. The maximum inhibition without the loss of cells is expressed by the value of the starting cell is research on the example of the compounds according to example 15.

Tested in vitro against micronucleus test.

Cells Chinese hamster V79 was treated with the test compound dissolved in dimethyl sulfoxide, in the presence or without S9 liver homogenate (10%) of the male rats, pre-treated Aroclor 1254. Revealed the fraction of cells containing the micronucleus test as indicators of chromosomal rearrangements.

Based on the conditions of this test (cells were treated with different doses of compounds) tested the connection is not clastogenic or aneugens.

Ames test

Tested the following concentrations: the first test of 5, 50 and 5000 µg/plate; second test: 250, 750, and 2500 ág/plate.

Based on the conditions of this analysis was not obtained evidence of bakteriostaticheskogo effect of a test compound at concentrations up to 5000 µg/plate (the highest studied concentration). In addition, cyclopeptide not increased corresponding provision under other circumstances analysis.

< / BR>
Example 4.

Range:

(3 conformer 55: 44:3, main and complement the conformers marked*andoACC. ): 8.80*(d, J = 10 Hz, NH); 7.89*(d, J = 10 Hz, NH); 7.78o(d, J = 10 Hz, NH); 7.57o(d, J = 10 Hz, NH); 7.50*o*o(2dd, MeMeOTrp H-5'); 6.16o(d, J = 10 Hz, Leu NH); 5.95*(d, J = 6 Hz, Leu NH); 5.30o(m, al-H); 5.10*(dd, hydoxybutyric acid al-H); 5.03-4.98 (m, al-H); 4.91 (dd, al-H); 4.85 (m, al-H); 4.71o(m, al-H); 4.45*(dd, al-H); 4.29*(m, al-H); 4.03*, 4.02o(2s, N-OMe); 3.87 (dd); 3.72*, 3.64o(2s, COOMe); 3.63-3.50 (m); 3.47*(q, J = 7 Hz, MeAla al-H); 3.41o(s, N-Me); 3.36*(dd, MeMeOTrp-H); 3.23-3.17 (m); 3.20*(s, MeAla N-Me); 3.19o(s, N-Me); 2.91*(s, MeMeOTrp N-Me); 2.53*(s, MeLeu N-Me); 2.51o(s, MeMeOTrp N-Me); 2.43-2.09 (m); 2.03-1.89 (m); 1.83-1.75 (m); 1.68-1.07 (m); 1.52*(d, J = 7 Hz, MeAla-Me); 1.48o(d, J = 7 Hz, MeAla-Me); 1.04 (d, J = 6.5 Hz); 0.98-0.83 (m); 0.53*(d, J = 6.6 Hz, Leu Me); 0,01*(d, J = 6.6, Leu Me); -0.32 (ddd, J = 3.6 Hz, J = 11.1 Hz, J = 14.5 Hz, Leu-CH).

(derived from open-chain of the formula (IV): (two conformer 68:32, main and complement the conformers marked*andoACC.): 8.16, 8.12, 8.05, 8.00 (4d, NH); 7.58o, 7.55*(2d, J = 8 Hz, MeMeOTrp 4'-H); 7.38*o(d, MeMeOTrp H-7'); 7.22*, 7.20o(2m, MeMeOTrp H-6'); 7.15*, 7.12o(2s, MeMeOTrp H-2'); 7.07*, 7.03o(2m, MeMeOTrp H-5'); 6.57 (br s, NH); 5.10o(dd, al-H); 5.17*(dd, hydroxybutyric acid al-H); 5.11*o(m, MeLeu al-H); 5.04*o(dd, al-H); 4.99*(ddd, al-H); 4.88o(ddd, al-H); 4.51o(dd); 4.53*(m, Leu al-H); 4.48o(m); 4.42*(m br, MeAla al-H); 4.05*, 4.03o(2s, N-OMe); 3.88o(q, J = 7 Hz, MeAla al-3.2 (m, MeMeOTrp-Ha); 3.00*(s, NMe); 2.9 (m, MeMeOTrp-Hb); 2.64o(s, NMe); 2.32*, 2.28o(2s, NMe); 2.33-2.13 (m); 2.20 (m); 1.86 (m); 1.7-1.1 (m); 1.50o, 1.48*(2d, J = 7 Hz, MeAla-Me); 0.97-0.93 (m); 0.90-0.76 (m).

Example 5.

(3 conformer 2:2:1, complement, conformer marked*): 8.81 (d, J = 10 Hz, NH); 7.93 (d, J = 10 Hz, NH); 7.79 (d, J = 9 Hz, NH); 7.65 (m, br, NH); 7.54 (m, H MeMeOTrp-4'); 7.38, 7.37, 7.34*(3d, J = 8 Hz, MeMeOTrp H-7'); 7.19 (m, MeMeOTrp, H-6'); 7.08-6.98 (m, MeMeOTrp H-5'); 7.02 (s, MeMeOTrp H-2'); 6.14 (d, J = 10 Hz, Leu NH); 6.29*(d, J = 7 Hz, Leu NH); 6.07 (d, J = 6 Hz, Leu NH); 5.25 (m, al-H); 5.12-4.92 (al-H); 4.84 (m, al-H); 4.69 (m, al-H); 4.43 (m, al-H); 4.29 (m, al-H); 4.03*, 4.02, 4.00 (3s, N-OMe); 3.98 (m, al-H); 3.63-3.3 (m); 3.39-3.34*(br s NMe); 3.21 (s, NMe); 3.18*(s, NMe); 3.13 (m); 3.07*(s, NMe); 3.04*(s, NMe); 2.91 (s, N-Ms); 2.53 (s, NMe); 2.37 (br s, NMe); 2.5-1.05 (m); 1.47, 1.43, 1.41*(3d, J = 7 Hz, MeAla-Me); 1.03 (d, J = 6.5 Hz); 0.98-0.83 (m); 0.68*, 0.55, 0.47*, -0.02 (4d, J = 6.6 Hz, Leu Me); -0.32 (ddd, Leu-CH).

Example 6.

(3 conformer 4:3:1, complement, conformer marked*): 8.82 (d, J = 10 Hz, NH); 7.95*(d, J = 9.3 Hz, NH); 7.90 (d, J = 9.8 Hz, NH); 7.80 (d, J = 9.4 Hz, NH); 7.59, 7.53 (2d, J = 8 Hz, MeMeOTrp H-4'); 7.45-7.30 (m, MeMeOTrp H-7'); 7.23-7.15 (m, MeMeOTrp, H-6'); 7.20, 7.18 (2s, MeMeOTrp H-2'); 7.11-7.03 (m, MeMeOTrp H-5'); 6.86*(q, J = 5 Hz, NHMe), 6.23 (d, 9.5 Hz, Leu NH); 5.95 (d, J = 6.5 Hz, Leu NH; q, NHMe); 5.84*(d, J = 8.9 Hz, Leu NH); 5.55 (q, 5 Hz, NHMe); 5.3-4.95 (m, al-H); 4.84 (ddd, al-H); 4.69 (ddd, al-H); 4.42 (dd, MeLeu al-H); 4.34 (ddd, Leu al-H); 4.05*, 4.03, 4.02 (3s, N-OMe); 3.98 (m, al-H); 3.63-3.52 (m, al-H); 3.47 (q, Ala al-H); 33 (m); 1.85-1.05 (m); 1.53, 1.47, 1.44*(3d, J = 7 Hz, MeAla-Me); 1.03 (d, J = 6.5 Hz); 0.98-0.80 (m); 0.57*, 0.55, 0.38*, 0.08 (4d, J = 6.6 Hz, Leu Me); -0.30 (ddd. Leu-CH).

Example 7.

(3 conformer 40: 53: 7, marked*, oand '): 8.81*(d, J = 10 Hz, C9AA NH); 7.88*(d, J = 10 Hz, C9AA NH); 7.78o(d, J = 10 Hz, NH); 7.57o(d, J = 10 Hz, NH); 7.52*o(2d, J = 7 Hz, MeMeOTrp H-4'); 7.39*, 7.37o(2d, J = 8 Hz, MeMeOTrp H-7'); 7.27*(s, MeMeOTrp H-2'); 7.20, 7.18 (2m, MeMeOTrp, H-6'); 7.17*(s, MeMeOTrp H-2'); 7.03o, 7.01*(2m, MeMeOTrp H-5'); 6.17o(d, J = 10 Hz, Leu NH); 5.98*(d, J = 6 Hz, Leu NH); 5.77' (d, J = 10 Hz, Leu NH); 5.31o(ddd, MeAla al-H); 5.19*(dd, hydroxybutyric acid al-H); 5.05-4.94 (m, al-H); 4.88-4.83 (m, al-H); 4.70-4.64 (m, al-H); 4.48*(dd, MeLeu al-H); 4.32*(m, Leu al-H); 4.03*, 4.02o(2s, N-OMe); 3.93o(m, al-H); 3.7-3.5 (m, morpholine); 3.5-3.2 (m); 3.40o(s, N-Me); 3.34o(dd, MeMeOTrp H-a); 3.22 (m, MeMeOTrp H-b), 3.20o(s, N-Me); 3,17*(s, N-Me); 2.93*(s, MeMeOTrp N-Me); 2.54*(s, MeLeu N-Me); 2.53o(s, N-Me); 2.4-2.35 (m); 2.2-1.9 (m); 1.83-1.05 (m); 1.53*, 1.50o(2d, J = 7 Hz, MeAla-Me); 1.04 (d, J = 6.5 Hz, MeLeu Me); 1.00-0.77 (m); 0.57*(d, J = 6.6 Hz, Leu Me); 0.52', 0.34' (2d, J = 6.6 Hz, Leu Me); 0.09*(d, J = 6.6 Hz, Leu Me); -0.25 (ddd, Leu-CH).

Example 8.

(2 conformer 45: 55, marked*,o): 8.84*(d, J = 10 Hz, C9AA NH); 7.87*(d, J = 10 Hz, C9AA NH); 7.77o(d, J = 10 Hz, NH); 7.57o(d, J = 10 HzUP> (s, MeMeOTrp H-2'); 7.20, 7.17 (2m, MeMeOTrp, H-6'); 7.03o, 7.01*(2m, MeMeOTrp H-5'); 6.17o(d, J = 10 Hz, Leu NH); 5.95*(d, J = 6 Hz, Leu NH); 5.31o(ddd, MeAla al-H); 5.24*(dd, hydroxybutyric acid al-H); 5.05-4.97 (m, al-H); 4.93 (dd, al-H); 4.87 (dd, al-H); 4.88-4.83 (m, al-H); 4.66-4.60 (m, al-H); 4.48*(dd, MeLeu al-H); 4.38*(ddd, Leu al-H); 4.15-4.00 (m); 4.03*, 4.02o(2s, N-OMe); 3.98o(m, al-H); 3.7-3.2 (m); 3.40o(s, N-Me); 3.20o(s, N-Me); 3.17*(s, N-Me); 3.05-2.9 (m); 2.99, 2.98 (2s, CON-Me); 2.96 (s, 2xCON-Me); 2.92*(s, MeMeOTrp N-Me); 2.54 (s, MeLeu N-Me and N-Me); 2.4-2.25 (m); 2.15-1.9 (m); 1.83-1.05 (m); . 1.53*, 1.50o(2d, J = 7 Hz, MeAla-Me); 1.04 (d, J = 6.5 Hz, MeLeu Me); 1.00-0.83 (m); 0.79o, 0.74o(2d); 0.57*(d, J = 6.6 Hz, Leu Me); 0.13*(d, J = 6.6 Hz, Leu Me); -0.25 (ddd, Leu-CH).

Example 9.

(3 conformer 0: 28:2, marked *,o, '): 8.89*(d, 10 Hz, PrLeu6 NH); 7.89*(d, 10 Hz, PrLeu2 NH); 7.77o(d, 10 Hz, PrLeu6 NH); 7.52o(d, 8 Hz, indole H-4'); 7.50o(d, PrLeu2 NH); 7.48*(d, 8 Hz, indole H-4'); 7.38*(d, 8 Hz, indole H-7'); 7.37o(d, 8 Hz, indole H-7'); 7.19o(dd, indole H-6'); 7.18*(dd, indole H-6'); 7.13o(s, indole H-2'); 7.02*(s, indole H-2'); 6.99o(dd, indole H-5'); 6.90*(dd, indole H-5'); 6.18o(d br, 10 Hz, Leu NH); 5.93*(d, 6 Hz, Leu NH); 5.83' (d, Leu NH); 5.30o(ddd, PrLeu6-H); 5.30*(dd, Hba-H); 5.02*(ddd, PrLeu6-H); 5.00o(ddd, PrLeu2-H); 4.89*(dd, MeTrp-H); 4.84*(ddd, PrLeu2-H); 4.71o(ddd, -H); 4.44*(dd, MeLeu-H); 4.37**(s, MeAla N-Me); 3.21o(s, N-Me); 2.93*(s, MeTrp N-Me); 2.53*(s, MeLeu N-Me); 2.52o(s, N-Me); 2.45-1.75; 2.33, 2.15 (2m, aziridine); 1.56-1.07; 1.50*(d, 7Hz, MeAla-Me); 1.47o(d, 7Hz, MeAla-Me); 1.03*(d, 6.5 Hz, MeLeu-d-Me); 0.98-O. 83; 0.48*(d, 6.6 Hz, Leu Me); -0.13*(d, 6.6 Hz, Leu Me); -0.48*(ddd, Leu-CH).

Example 10.

(3 conformer 45:51:4, marked*, oand '): 8.86*(d, 10 Hz, PrLeu6 NH); 7.87*(d, 10 Hz, PrLeu2 NH); 7.75o(d, 10 Hz, PrLeu6 NH); 7.57*(d, 8 Hz, indole H-4'), 7.55o(d, PrLeu2 NH); 7.51o(d, 8 Hz, indole H-4'); 7.41o(s, indole H-2'); 7.38*(d, 8 Hz, indole H-7'); 7.36o(d, 8 Hz, indole H-7'); 7.29*(s, indole H-2'); 7.18*(dd, indole H-6'); 7.17o(dd, indole H-6'); 7.03o(dd, indole H-5'); 7.01*(dd, indole H-5'); 6.17o(d br, 10 Hz, Leu NH); 5.94*(d, 6 Hz, Leu NH); 5.79' (d, Leu NH); 5.30o(ddd, PrLeu6-H); 5.27*(dd, -H); 5.00*(ddd, PrLeu6-H); 4.98o(ddd, -H); 4.93o(dd, -H); 4.87*(dd, -H); 4.85*(ddd, PrLeu2-H); 4.63o(ddd, -H); 4.47*(dd, MeLeu-H); 4.40 (m); 4.02*(ddd, Leu-H); 4.02, 4.01 (2s, N-OMe); 3.68-3.22; 3.40o(s, N-Me); 3.20o(s, N-Me); 3.18*(s, MeAla N-Me); 2.91*(s, MeTrp N-Me); 2.55o(s, N-Me); 2.53*(s, MeLeu N-Me); 2.35-1.05; 1.54*(d, 7 Hz, MeAla-Me); 1.50o(d, 7 Hz, MeAla-Me); 1.03*(d. 6.5 Hz, MeLeu-d-Me); 0.98-0.83; 0.78o(d, 6 Hz, Leu Me); 0.73o(d, 6 Hz, Leu Me); 0.57*(d, 6.6 Hz, Leu Me); 0.16*(d, 6.6 Hz, Leu Me); -0.27 (ddd, Leu-CH).

The prima.76o(d, 10 Hz, PrLeu6 NH); 7.56o(d, PrLeu2 NH); 7.55*(d, 8 Hz, indole H-4'); 7.52o(d, 8 Hz, indole H-4'); 7.37 (d, 8 Hz, indole H); 7.36 (d, 8 Hz, indole H); 7.36o(s, indole H-2'); 7.22*(s, indole H-2'); 7.20*(dd, indole H-6'); 7.18o(cc, indole H-6'); 7.03o(dd, indole H-5'); 7.00o(dd, indole H-5'); 6.16o(d, 10 Hz, Leu NH); 5.94*(d, 6 Hz, Leu NH); 5.78' (d, Leu NH); 5.31o(ddd, PrLeu6-H); 5.27*(dd, -H); 5.06-4.80; 4.65 (ddd, -H); 4.47*(dd, MeLeu-H); 4.33 (m); 4.03, 4.01 (2s, N-OMe); 4.00 (ddd, -H); 3.75-3.20; 3.40 (s, N-Me); 3.20 (s, N-Me); 3.18*(s, MeAla N-Me); 2.91*(s, MeTrp MeMe); 2.53 (s, N-Me); 2.53o(s, MeLeu N-Me); 2.45-1.07; 1.53*(d, 7 Hz, MeAla-Me); 1.49o(d, 7 Hz, MeAla-Me); 1.03*(d. 6.5 Hz, MeLeu

d-Me); 0.98-0.83; 0.79 (d, 6 Hz, Me); 0.74 (d, 6 Hz, Me); 0.55*(d, 6.6 Hz, Leu Me); 0.07*(d, 6.6 Hz, Leu Me); -0.36*(ddd, Leu-CH).

Example 12.

(4 conformer 27:33:17:33 tagged*,o, ', "): 8.9*(d, 10 Hz, PrLeu6 NH); 8.82' (d, 10 Hz, PrLeu6 NH); 7.9*(d, 10 Hz, PrLeu2 NH); 7.86' (d, 10 Hz, PrLeu2 NH); 7.76o(d, 10 Hz, PrLeu6 NH); 7.75 (d, 10 Hz, PrLeu6 NH); 7.24*(s, indole); 7.03*(dd, indole); 6.17 (d br, 10 Hz, Leu NH); 6.17o(d br, 10 Hz, Leu NH); 6.03' (d, 6Hz, Leu NH); 5.98*(d, 6 Hz, Leu NH); 4.02 (s); 4.02o(s); 4.02*(s); 4.02' (s); 3.40 (s, N-Me); 3.40 (s, N-Me); 3.20 (s, N-Me); 3.20 (s, N-Me); 3.17 (s, N-Me); 2.97 (s, N-Me); 2.94 (s, N-Me); 2.94 (s, N-Me); 2.93 (s, N-Me); 2.91 (s, N-Me); 2.56 (s, N-Me); 2.56 (s, N-Me); 2.53' (s, MeLeu N-Me); 2.53*(s, MeLeu N-Me); 1.53*(d, 7 Hz, MeAla-Me); 1.53' (d, 7 Hz, MeAla-Me); 1.50o(d, 7 Hz, MeAla-Me); 1.50 (d, 7 Hz,SUP> (d, 6.6 Hz, Leu Me); 0.61' (d, 6.6 Hz, Leu Me); 0.55*(d, 6.6 Hz, Leu Me); 0.21' (d, 6.6 Hz, Leu Me); 0.12*(d, 6.6 Hz, Leu Me); -0.17' (ddd, Leu-CH); -0.31*(ddd, Leu-CH).

Example 13.

(2 conformer 55: 45, main and complement. the conformers are marked*ando): 8.80*(d, J = 10 Hz, NH); 7.88*(d, J = 10 Hz, NH); 7.77o(d, J = 10 Hz, NH); 7.57o(d, J = 10 Hz, NH); 7.52*, 7.51o(2d, J = 7 Hz, MeMeOTrp H-4'); 7.39*, 7.37o(2d, J = 8 Hz, MeMeOTrp H-7'); 7.20*o(m, MeMeOTrp, H-6'); 7.16o, 7.09*(2s, MeMeOTrp H-2'); 7.03*o(2dd, MeMeOTrp H-5'); 6.17o(d, J = 10 Hz, Leu NH); 5.97*(d, J = 6 Hz, Leu NH); 5.31o(m. MeAla al-H); 5.11-4.96 (m, al-H); 4.92*(dd, MeMeOTrp al-H); 4.87 (ddd, al-H); 4.69o(m, Leu al-H); 4.47*(dd, MeLeu al-H); 4.27*(dd, Leu al-H); 4.03*, 4.02o(2s, N-OMe); 3.92 (dd); 3.65-3.15 (m); 3.47*(q, J = 7 Hz; MeAla al-H); 3.41o(s, N-Me); 3.21*(s, MeAla NMe); 3.20o(s, N-Me); 2.92*(s, MeMeOTrp N-Me); 2.53*(s, MeLeu N-Me); 2.51o(s, N-Me); 2.35-2.75 (m); 1.7-1.05 (m); 1.53*(d, J = 7 Hz, MeAla-Me); 1.49o(d, J = 7 Hz, MeAla-Me); 1.28*, 1.25*, 1.23o, 1.18o(4d, J = 6 Hz, COOCHMe2); 1.04 (d, J = 6.5 Hz, MeLeu Me); 0.98-0.83 (m); 0.55*(d, J = 6.6 Hz, Leu Me); 0.05*(d, J = 6.6, Leu Me); -0.31 (ddd, Leu-CH).

Example 14.

(3 conformer 55: 43: 2, marked,*,oand '): 8.82*(d, J = 10 Hz, C9AANH); 7.85*(d, J = 10 Hz, C9AANH), 7.78o(d, J = 10 /SUP>, 7.21o(2m, MeMeOTrp, H-6'); 7.14o, 7.08*(2s, MeMeOTrp H-2'); 7.03*o(2dd, MeMeOTrp H-5'); 6.17o(d, J = 10 Hz, Leu NH); 5.95*(d, J = 6 Hz, Leu NH); 5.78' (d, J = 10 Hz, Leu NH); 5.31o(ddd, MeAla al-H); 5.12*(dd, hydroxybutyric acid al-H); 5.05-4.98 (m, al-H); 4.91*(dd, MeMeOTrp al-H); 4.86*(ddd, C9AA al-H), 4.73-4.68 (m, Leu al-H); 4.47*(dd, MeLeu al-H); 4.32-4.26 (m, Leu al-H); 4.25 (dq, J = 11 Hz, J = 7 Hz, COOCH2-); 4.15-4.07 (m, COOCH2-); 4.04*, 4.03o(2s, N-OMe); 3.84 (m, al-H); 3.64-3.50 (m); 3.47*(q, J = 7 Hz, MeAla al-H); 3.41o(s, N-Me); 3.34o(dd, MeMeOTrp H-a); 3.22 (m, MeMeOTrp H-b); 3.20*(s, MeAla NMe); 3.19o(s, N-Me); 2.93*(s, MeMeOTrp N-Me); 2.53*(s, MeLeu N-Me); 2.52o(s, N-Me); 2.4-2.1 (m); 2.05-1.9 (m); 1.83-1.76 (m); 1.7-1.07 (m); 1.53*, 1.49o(2d, J = 7 Hz, MeAla-Me); 1.30, 1.25 (2t, J = 7 Hz, COOCH2CH3); 1.04 (d, J = 6.5 Hz, MeLeu Me); 1.00-0.84 (m); 0.55*(d, J = 6.6 Hz, Leu Me); 0.03*(d, J = 6.6 Hz, Leu Me); -0.32 (ddd, Leu-CH).

Example 15.

(3 conformer 57: 41: 2, marked*,oand '): 8.82*(d, J = 10 Hz, C9AA NH); 7.90*(d, J = 10 Hz, C9AA NH); 7.78o(d, J = 10 Hz, NH); 7.58o(d, J = 10 Hz, NH); 7.52*o(2d, J = 7 Hz, MeMeOTrp H-4'); 7.39*, 7.38o(2d, J = 8 Hz, MeMeOTrp H-7'); 7.22*, 7.21o(2m, MeMeOTrp, H-6'); 7.14o, 7.08*(2s, MeMeOTrp H-2'); 7.03o, 7.02*(2m, MeMeOTrp H-5'); 6.17o(d, J = 10 Hz, Leu NH); 5.98*(d, J = 6 Hz, Leu NH); 5.82' (d, J = 10 Hz, Leu NH); 5.31o(ddd, MeAla al-H); 5.12*(m, Leu al-H); 4.2-3.95 (m, COOCH2); 4.03*, 4.02o(2s, N-OMe); 3.90o(m, al-H); 3.64-3.42 (m); 3.47*(q, J = 7 Hz, MeAla al-H); 3.41o(s, N-Me); 3.34o(dd, MeMeOTrp H-a); 3.22 (m, MeMeOTrp H-b); 3.20*(s, MeAla NMe); 3.19o(s, N-Me); 2.93*(s, MeMeOTrp N-Me); 2.53*(s, MeLeu N-Me); 2.52o(s, N-Me); 2.4-2.1 (m); 2.03-1.9 (m); 1.83-1.76 (m); 1.72-1.58 (m, COOCH2CH2CH3); 1.55-1.07 (m); 1.53*, 1.49o(2d, J = 7 Hz, MeAla-Me); 1.04 (d, J = 6.5 Hz, MeLeu Me); 1.00-0.84 (m); 0.54*(d, J = 6.6 Hz, Leu Me); 0.02*(d, J = 6.6 Hz, Leu Me); -0.34 (ddd, Leu-CH).

Example 16.

(2 conformer 70:30, marked*and o): 8.92*, 7.87, 7.75o, 7.58o(4d, J = 10 Hz, NH); 7.49*(d, J = 8 Hz, MeMeOTrp H-4'); 7.37*(d, J = 8 Hz, MeMeOTrp H-7'); 7.20*(dt, MeMeOTrp H-6'); 7.18o, 7.03*(2s, MeMeOTrp H-2'); 7.03o, 6.97*(2 dt, MeMeOTrp H-5'); 6.20o(d, J = 10 Hz, Leu NH); 5.96*(d, J = 7 Hz, Leu NH); 5.33*(m, hydroxybutyric acid al-H); 5.02 (m, al-H); 4.90*(dd, al-H); 4.83*(ddd, al-H); 4.79*(dd, al-H); 4.70o(m, al-H); 4.39*(dd, al-H); 4.38o(m, al-H); 4.03*(s, N-OMe); 3.92o(m); 3.63-3.53 (m); 3.44-3.40 (m); 3.39o, 3.20o(2s, NMe); 3.32-3.18 (m); 3.17*(s, MeAla NMe); 2.94*(s, MeMeOTrp NMe); 2.53*(s, MsLeu NMe); 2.52o(s, NMe); 2.5-2.3 (m); 2.1-1.1 (m); 2.17*, 2.11o(2s, COMe); 1.51*, 1.48o(2d, J = 7 Hz, MeAla-Me); 1.03*(d, J = 6.5 Hz); 0.98-0.83 (m); 0.52*, -0.11*(d, J = 6.6 Hz, Leu (d, J = 9.9 Hz, NH); 7.83*(d, J = a 9.7 Hz, NH); 7.76' (d, NH); 7.59' (d, J = 7.8 Hz, MeMeOTrp H-4'); 7.57 (d, J = 9.5 Hz, NH); 7.56, 7.53 (2d, J = 8 Hz, MeMeOTrp H-4'); 7.46' (s, MeMeOTrp H-2'); 7.42*, 7.39o, 7.34' (3d, J = 8.2 Hz, MeMeOTrp H-7'); 7.24*, 7.22o, 7.18' (3t, MeMeOTrp H-6'); 7.11*, 7.08', 7.06o(3t, MeMeOTrp H-5'); 7.04*, 7.03o(2s, MeMeOTrp H-2'); 6.25o(d, J = 9.5 Hz, Leu NH); 6.03*(d, J = 7 Hz, Leu NH); 5.99' (d, J = 8.8 Hz, Leu NH); 5.28*(m, al-H); 5.13' (t, J = 4 Hz, OH); 5.09-4.98 (m, al-H); 5.02 (t, J = 4 Hz, OH); 4.97 (dd, al-H), 4.88 (dd, al-H); 4.84 (m, al-H); 4.78-4.70 (m, al-H); 4.41 (dd, MeLeu al-H); 4.18 (ddd, Leu al-H); 4.04, 4.02 (2s, N-OMe); 3.78 (m, al-H); 3.65-3.35 (m); 3.42o, 3.32', 3.22*, 3.20o(4s, NMe); 3.17-3.08 (m); 3.03', 2.92', 2.90*, 2.52*, 2.51o(5s, NMe); 2.01-1.1 (m); 1.53, 1.49, 1.40' (3d, J = 7 Hz, MeAla-Me); 1.04 (d, J = 6.5 Hz); 0.98-0.83 (m); 0.72', 0.60*, 0.56', 0.03*(4d, J = 6.6 Hz, Leu Me); -0.16 (ddd, Leu-CH).

Example 18.

(3 conformer 73: 20: 7, is marked *,o, '): 8.54o(d, J = 10 Hz, NH); 8.38' (br s, MeTrp N'-H); 8.26*, 8.17o(2d br, J = 2 Hz, MeTrp N'-H); 8.13*, 8.03o, 8.01' (3d, J = 9.7 Hz, NH); 7.78*(d, J = 7.7 Hz, H MeTrp-4'); 7.74', 7.70', 7.63o, 7.63o(4d); 7.46*, 7.44o, 7.40' (3d, J = 8 Hz MeTrp H-7'); 7.27*(dt, MeTrp H-6'); 7.20*, 7.17o(2dt, MeTrp H-5'); 7.09o, 7.03*(2d, J = 2 Hz, MeTrp H-2'); 6.33o(d, J = 10 Hz, Leu NH); 6.17*(d, J = 7.4 Hz, Leu NH); 5.97' (d, J = 9 Hz, Leu NH); 5.38o(m, al-H); 5.27*(dd, hydroxybutyric acid al-H); 5.21o(dd, al-H); 5.12*(ddd, al-H); 5.07); 3.49o, 3.36' (2s, NMe); 3.13*(s, MeAla NMe); 3.29o, 3.13' (2s NMe); 3.02*(s, MeTrp NMe); 2.62o(s, NMe); 2.60*(s, MeLeu NMe); 2.38-1.15 (m); 1.62*, 1.56o, 1.51' (3d, J = 7 Hz, MeAla-Me); 1.13*(d, J = 6.5 Hz MeLeu); 1.07-0.93 (m); 0.73', 0.63*, 0.58', 0.02*(4d, J = 6.6 Hz, Leu Me); -0.28*(ddd, Leu-CH).

Example 19.

(3 conformer 67:29:4, marked*,oand '): 9.52*(t, J = 1.5 Hz, CHO); 9.41o(t, J = 1 Hz, CHO); 9.05' (m, CHO); 8.73*(d, J = 10 Hz, C9AA NH); 7.86*(d, J = 10 Hz, C9AA NH); 7.77o(d, J = 10 Hz, NH); 7.60o(d, J = 10 Hz, NH); 7.47*o(2d, J = 7 Hz, MeMeOTrp H-4'); 7.38*o(2d, J = 8 Hz, MeMeOTrp H-7'); 7.20*o(2t, MeMeOTrp, H-6'); 7.15o, 7.04*(2s, MeMeOTrp H-2'); 7.03o(m, MeMeOTrp H-5'); 7.00*(dd, MeMeOTrp H-5); 6.22o(d, J = 10 Hz, Leu NH); 6.02*(d, J = 6 Hz, Leu NH); 5.87' (d, J = 10 Hz, Leu NH); 5.29o(ddd, MeAla al-H); 5.17*(dd, hydroxybutyric acid al-H); 5.03-4.93 (m, al-H); 4.91*(dd, MeMeOTrp al-H); 4.84*(ddd, C9AA al-H); 4.79-4.64o(m, Leu al-H); 4.43*(dd, MeLeu al-H); 4.35*(ddd, Leu al-H); 4.04', 4.03*, 4.02o(3s, N-OMe); 3.81o(m, al-H); 3.63o(dd); 3.57-3.50 (m); 3.48-3.42 (m); 3.43*(q, J = 7 Hz, MeAla al-H); 3.38o(s, N-Me); 3.30-3.12 (m); 3.20o(s, N-Me); 3.15*(s, MeAla NMe); 2.93*(s, MeMeOTrp N-Me); 2.58o(s, N-Me); 2.53*(s, MeLeu N-Me); 2.25 (m, CH2-CHO); 2.15-1.9 (m); 1.85-1.74 (m); 1.65-1.08 (m); 1.48*, 1.45o(2d, J = 7 Hz, MeAla-Me); 1.0 emer 20.

(2 conformer 1: 1): 8.77 (d, J = 10 Hz, C9AA NH); 7.79 (d, J = 10 Hz, C9AA NH); 7.73 (d, J = 10 Hz, NH); 7.65 (d, J = 10 Hz, NH); 7.44, 7.44, 7.42, 7.39 (4d, MeMeOTrp H-4' and H-7'); 7.25, 7.22 (2t, MeMeOTrp, H-6'); 7.13-7.03 (m, MeMeOTrp H-5'); 7.02, 6.98 (2s, MeMeOTrp H-2'); 6.19 (d, J = 10 Hz, Leu NH); 6.00 (d, J = 6 Hz, Leu NH); 5.80-5.53 (m, olefin-H); 5.31 (ddd, MeAla al-H); 5.08-4.67 (m, al-H, olefin-H); 4.47 (dd, MeLeu al-H); 4.15-3.98 (m); 4.05, 4.02 (2s, N-OMe); 3.7-3.0 (m); 3.44, 3.21, 3.20, 2.92, 2.52, 2.44 (6s, N-Me); 2.15-1.90 (m); 1.90-1.08 (m); 1.55, 1.50 (2d, J = 7 Hz, MeAla-Me); 1.05 (d, J = 6.5 Hz, MeLeu Me); 1.0-0.8 (m); 0.60, 0.06 (2d, J = 6.6 Hz, Leu Me); -0.20 (ddd, Leu-CH).

Example 21.

(3 conformer 44: 53:3 marked*, o, '): 8.81*(d, 10 Hz, PrLeu6 NH); 7.78, 7.73, 7.67 (3d, 10 Hz, NH); 7.43, 7.42 (2d, 8 Hz, indole H-4'); 7.37 (d, 8 Hz, indole H-7'); 7.28-7.00; 7.02, 6.97 (2s, indole H-2'); 6.21o(d, 10 Hz, Leu NH); 5.97*(d, 6 Hz, Leu NH); 5.75' (d, Leu NH); 5.50-4.65; 4.47*(dd, MeLeu-H); 4.05 (ddd, -H); 4.04 (s, OMe); 4.02 (s, OMe); 3.65-3.10; 3.44o(s, MeAla N-Me); 3.22 (s, MeAla N-Me); 3.19 (s, N-Me); 2.93*(s, MeTrp N-Me); 2.52, 2.39 (2s, N-Me); 2.15-0.82; 1.54*, 1.50o(2d, 7 Hz, MaAla-Me); 1.04*(d, 6.5 Hz, MeLeu-d-Me); 0.57*(d, 6.6 Hz, Leu Me); 0.48' (d, Leu Me); 0.26' (d, Leu Me); -0.04*(d, 6.6 Hz, Leu Me).

Example 22.

(3 conformer 47:48:5, marked*,o, '): 8.63, 7.87, 7.77, 7.63 (4d, 10 Hz, PrLeu NH); 7.49*(d, 7 Hz, indole H-4'); 7.48o(d, 7 Hz, indole H-4'); 7.43*(d, 8 Hz, indole H-7'); 7.41o(d, 8 Hz, indole H-7'); 7.27*(dd, indole H-6'); 7.23o(dd, indole H-6'); 7.13*(dd, indole H-5'); 7.08o(dd, indole H-5'); 7.04o(s, indole H-2); 5.07*(dd, Hba-H); 5.03*(ddd, PrLeu6-H); 4.86*(ddd, PrLeu2-H); 4.79 (dd, MeTrp-H); 4.47*(dd, MeLeu-H); 4.18*(ddd, Leu-H); 4.06 (s, N-OMe); 4.05' (s, N-OMe); 4.03 (s, N-OMe); 3.71-3.50; 3.42 (s, N-Me); 3.23-3.05; 3.20 (s, N-Me); 3.18 (s, N-Me); 2.92 (s, N-Me); 2.52 (s, N-Me); 2.51 (s, N-Me); 2.03-1.08; 1.54*(d, 7 Hz, MeAla-Me); 1.50o(d, 7 Hz, MeAla-Me); 1.05*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.84; 0.63*(d, 6.6 Hz, Leu Me); 0.53' (d, 7 Hz, Leu Me); 0.34' (d, 7 Hz, Leu Me); 0.11*(d, 6.6 Hz, Leu Me); -0.13*(ddd, Leu-CH).

Example 23.

[3 conformer 40:40:20 marked*,o, '): 8.50*(d, 10 Hz, PrLeu6 NH); 8.20 (m); 7.98*(d, 10 Hz, PrLeu2 NH); 7.57*(d, 8 Hz, indole H-4'); 7.53-7.35; 7.25-7.18; 7.23*(s, indole H-2'); 7.13-7.06; 7.05o(s, indole H-2'); 6.69 (d); 6.29 (d, br); 6.22 (d, br); 6.14o(d, 7 Hz, Leu NH); 6.07*(d, 9 Hz, Leu NH); 5.5o(ddd, PrLeu6-H); 5.26-4.63 (m-H); 4.36 (m, MeLeu-H); 4.18*(ddd, Leu-H); 4.04 (s, OMe); 4.03' (s, OMe,); 4.02 (s, OMe); 3.68-2.78; 3.34 (s, N-Me); 3.19 (s, N-Me); 3.12 (s, N-Me); 3.03 (s, N-Me); 2.91 (s, N-Me); 2.53 (s, N-Me); 2.10-1.05; 1.03-0.78; 0.76 (d); 0.71 (d, 6.5 Hz, Leu g-Me); 0.60 (d, 6.6 Hz, Leu g-Me); 0.08 (d, 6.6 Hz, Leu g-Me); -0.10 (ddd, Leu-CH).

Example 24.

(3 conformer 43:47:5, marked*,oand '): 8.68*(d, 10 Hz, PrLeu6 NH); 7.87*(d, 10 Hz, PrLeu2 NH); 7.80o(d, 10 Hz, NH); 7.63o(d, 10 Hz, NH); 7.55-7.37 (m, indole); 7.27-7.10 (m, indole); 7.08o(s, indole H-2'); 7.03*(s, indole H-2'); 6.58 (t, 8 Hz, C=C); 6.23 (t, 8 Hz, C=C); 6.18o(d, 6.7 Hz, Leu NH); 6.03*(d, 10 Hz, Leu NH), 5.80' (d. Leu NH); 5.31o(ddd, PrLeu6-H); 5.08-4.91 (-H); .71o(q, 7 Hz, MeAla-H); 3.60*(q, 7 Hz, MeAla-H); 3.53-3.00; 3.44o(s, MeAla N-Me); 3.23 (s, N-Me); 3.20 (s, N-Me); 2.93*(s, MeTrp N-Me); 2.52 (s, N-Me); 2.44 (s, N-Me); 2.20-0.83; 1.56*(d, 7 Hz, MeAla-Me); 1.51o(d, 7 Hz, MeAla-Me); 1.05*(d, 6.5 Hz, MeLeu-d-Me); 0.62*(d, 6.6 Hz, Leu Me); 0.57' (d, Leu Me); 0.40' (d, Leu Me); 0.10*(d, 6.6 Hz, Leu Me); -0.17*(ddd, Leu-CH).

Example 25.

(3 conformer 51:45:4, marked*,oand '): 8.68*(d, 10 Hz, PrLeu6 NH); 7.87*(d, 10 Hz, PrLeu2 NH); 7.81o(d, 10 Hz, PrLeu6 NH); 7.63o(d, 10 Hz, PrLeu2 NH); 7.53 (d, 8 Hz, indole H-4'); 7.51 (d, 8 Hz, indole H-4'); 7.43 (d, 8 Hz, indole H-7'); 7.40 (d, 8 Hz, indole H-7'); 7.26 (dd, indole H-6'); 7.23 (dd, indole H-6'); 7.13 (dd, indole H-5'); 7.07o(s, indole H-2'); 7.07 (dd, indole H-5'); 7.03*(s, indole H-2'); 6.21o(d, 10 Hz, Leu NH); 6.05*(d, 6 Hz, Leu NH); 5.79' (d. 10 Hz, Leu NH); 5.32o(ddd, PrLeu6-H); 5.14*(dd, Hba-H);) 5.03*(ddd, PrLeu6-H); 4.87*(ddd, PrLeu2-H); 4.83*(dd, MeTrp-H); 4.77o(ddd, Leu - H); 4.51*(dd, MeLeu-H); 4.13*(ddd, Leu-H); 4.06o(s, OMe); 4.03*(s, OMe); 3.68*(m); 3.57*(q, 7 Hz, MeAla-H); 3.44o(s, MeAla N-Me); 3.36*(dd, MeTrp-Ha); 3.23 (dd, MeTrp-Hb); 3.22 (s, N-Me); 3.17 (s, N-Me); 3.14 (dd); 2.96 (m, CCH); 2.93*(s, MeTrp N-Me); 2.53 (s, N-Me); 2.49 (s, N-Me); 2.25-1.97; 1.86-1.78; 1.55*(d, 7 Hz, MeAla-Me); 1.52o(d, 7 Hz, MeAla-Me); 1.50-1.09; 1.06*(d, 6.5 Hz, MeLeu-d-Me); 1.00-0.85; 0.63*(d, 6.6 Hz, Leu Me); 0.58' (d, Leu Me); 0.38' (d, Leu Me); 0.07*(d, 6.6 Hz, Leu Me); -0.11*(ddd, Leu-CH).

); 7.52 (d, 8 Hz, indole); 7.08 (s, indole H-2'), 6.44, 6.22 (2dt, CH=CHCN); 6.36-6.26 (m); 6.13, 6.07, 5.87 (3d, Leu NH); 5.33-5.28 (m); 5.24, 5.20 (2dm, CH= CHCN); 5.06-4.97.(m); 4.92 (2d); 4.87-4.75 (m); 4.49, 4.46 (2dd, MeLeu-H); 4.28, 4.18 (2ddd, Leu-H); 4.07, 4.06, 4.05, 4.03 (4s, N-OMe); 3.88, 3.82 (2q, 7 Hz, MeAla-H); 3.43, 3.40, 3.23, 3.21, 3.19, 3.12, 2.93, 2.55, 2.53, 2.52, 2.51 (11s, N-Me); 1.54-1.49 (5d, MeAla-Me); 1.06, 1.04 (2d, 7 Hz, MeLeu-d-Me); 0.74, 0.65, 0.52, 0.26, 0.08 (5d, Leu g-Me); -0.04 (ddd, Leu-CH).

Example 27.

(3 conformer 51: 46:3 marked*,o, '): 8.71*(d, 10 Hz, PrLeu6 NH); 7.90*(d, 10 Hz, PrLeu2 NH); 7.76o(d, 10 Hz, PrLeu6 NH); 7.6o(d, 10 Hz, PrLeu2 NH); 7.52*(d, 8 Hz, indole H-4'); 7.48o(d, 8 Hz, indole H-4'); 7.42 (d, 8 Hz, indole); 7.40 (d, 8 Hz, indole); 7.26*(dd, indole H-6'); 7.13*(dd, indole H-5'); 7.07o(dd, indole H-5'); 7.03*(s, indole H-2'); 7.02o(s, indole H-2'); 6.16 (d br, 10 Hz, Leu NH); 6.01*(d, 6 Hz, Leu NH); 5.77' (d, Leu NH); 5.31 (ddd, -H); 5.05-4.97; 4.86 (ddd, -H); 4.82 (dd, -H); 4.74 (m); 4.46*(dd, MeLeu-H); 4.17*(ddd, Leu-H); 4.05*(s, N-OMe); 4.03o(s, N-OMe); 3.68 (m); 3.57 (m); 3.47*(m, CH2Cl); 3.43 (s, N-Me); 3.28*(dd, MeTrp-Ha); 3.23*(s, MeAla N-Me); 3.21 (s, N-Me); 3.20*(dd, MeTrp-Hb); 2.92*(s, MeTrp N-Me); 2.53*(s, MeLeu N-Me); 2.49 (s, N-Me); 2.23o(dd, indole H-6'); 2.05-1.1; 1.54*(d, 7 Hz, MeAla-Me); 1.50o(d, 7 Hz, MeAla-Me); 1.05*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.85; 0.57*(d, 6.6 Hz, Leu Me); 0.52' (d, Leu Me); 0.28' (d, Leu Me); 0.06*(d, 6.6 Hz, Leu Me); -0.32*(ddd, Leu-CH).

Example 28.

(3 conformer 37: 59:4 markedo(d, 8 Hz, indole H-4'); 7.47*(d, 8 Hz, indole H-4'); 7.42*(d, 8 Hz, indole H-7'); 7.38o(d, 8 Hz, indole H-7'); 7.25 (dd, indole); 7.22o(dd, indole H-6'); 7.12*(dd, indole H-5'); 7.06o(dd, indole H-5'); 7.04 (s, indole H-2'); 7.03 (s. indole H-2'); 6.22o(d br, 10 Hz, Leu NH); 6.00*(d, 6 Hz, Leu NH); 5.78' (d, Leu NH); 5.31o(ddd, PrLeu6-H); 5.07 (dd, -H); 5.05-4.90; 4.87 (ddd, -H); 4.79 (dd, -H); 4.72 (m); 4.49*(dd, MeLeu-H); 4.11*(ddd, Leu-H); 4.05*(s, N-OMe); 4.03o(s, N-OMe); 3.75-3.50; 3.43 (s, N-Me); 3.38-3.13; 3.28 (s, OMe); 3.28 (s, OMe); 3.23 (s, N-Me); 3.21o(s, N-Me); 2.92*(s, MeTrp N-Me); 2.53*(s, MeLeu N-Me); 2.48o(s, N-Me); 2.00-1.08; 1.55*(d, 7 Hz, MeAla-Me); 1.50o(d, 7 Hz, MeAla-Me); 1.05*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.85; 0.60*(d, 6.6 Hz, Leu Me); 0.05*(d, 6.6 Hz, Leu Me); -0.18*(ddd, Leu-CH).

Example 29.

(2 conformer 50:50, marked*ando): 8,70*(d, 10 Hz, PrLeu6 NH); 7.80*(d, 10 Hz, PrLeu2 NH); 7.71o(d, 10 Hz, PrLeu6 NH); 7.69o(d, 10 Hz, PrLeu2 NH); 7.47-7.35; 7.24 (dd, indole); 7.21 (dd, indole); 7.04 (dd, indole); 7.01 (dd, indole); 7.01 (s, indole H-2'); 6.97 (s, indole H-2'); 6.25o(d br, 10 Hz, Leu NH); 6.00*(d, 6 Hz, Leu NH); 5.30o(ddd, PrLeu6-H); 5.10-4.69; 4.49*(dd, MeLeu-H); 4.07*(ddd, Leu-H); 4.04*(s); 4.02o(s); 3.72-3.02; 3.41 (s, N-Me); 3.20 (s, N-Me); 3.20*(s, MeAla N-Me); 2.91*(s, MeTrp N-Me); 2.53 (s, N-Me); 2.45 (s, N-Me); 2.07-0.82; 1.55*(d, 7 Hz, MeAla-Me); 1.50o(d, 7 Hz, MeAia-Me); 1.04*(d, 6.5 Hz, MeLeu-d-Me); 0.6*(d, 6.6 Hz, Leu Me); 0.41 (m, cyPr); -0.03*and '): 8.78o(d, 10 Hz, PrLeu6 NH); 7.93*, 7.77o(2d, 10 Hz, PrLeu2 NH); 7.47*(d, 8 Hz, indole H-7'); 7.43*(d, 8 Hz, indole H-4'); 7.40-7.23; 7.17o, 7.13*(2dd, indole H-6'); 7.04, 7.03 (2s, indois H-2'); 6.93o(dd, indole H-5'); 6.97, 6.93 (2s, CH-Ph2,); 6.74*(dd, indole H-5'); 6.14o(d, 10 Hz, Leu NH); 5.92*(d, 6 Hz, Leu NH); 5.78' (d, Leu NH); 5.27o(ddd, PrLeu6-H); 5.12*(dd, Hba-H); 4.98*(ddd, PrLeu6-H); 4.96*(dd, MeTrp-H); 4.85*(ddd, PrLeu2-H); 4.70o(ddd, -H); 4.47*(dd, MeLeu-H); 4.18*(ddd, Leu-H); 4.00*, 3.97o(2s, OMe); 3.57o(dd, MeTrp-Ha); 3.53o(dd, MeTrp-Hb); 3.37*(dd, MeTrp-Ha); 3.27*(dd, MeTrp-Hb); 3.20, 3.19, 2.93, 2.83 (4s, N-Me); 2.66 (q, 7 Hz); 2.55-2.33; 2.52 (s, N-Me); 2.46 (s, N-Me); 2.27-1.92; 1.80 (m); 1.68-1.05; 1.35o, 1.28*(2d, 7 Hz, MeAla-Me); 1.03*(d, 6.5 Hz, MeLeu-d-Me); 0.96-0.83; 0.53' (d, Leu Me); 0.49*(d, 6.6 Hz, Leu Me); 0.32' (d, Leu Me); -0.12*(d, 6.6 Hz, Leu Me); -0.49*(ddd, Leu-CH).

Example 31.

(mixture of conformers, which gives only one signal): 7.13, 7.03 (2s, indole H-2'); 4.56, 4.40 (2m, -H); 4.03 (s, N-OMe); 3.42, 3.23, 3.07, 2.94, 2.53 (5s, N-Me); 0.57, 0.53, (2d, 6.6 Hz, Leu Me); 0.17, 0.03 (2d, 6.6 Hz, Leu Me); -0.03,-0.27 (2ddd, Leu-CH).

Example 32.

(3 conformer 78: 16:6, marked*,o, '): 8.45*(d, J = 10 Hz, PrLeu6 NH); 8.04*(d, J = 10 Hz, PrLeu2 NH); 7.83o(d, J = 10 Hz, NH); 7.68*, 7.53o(2d, J = 7 Hz, indole H-4'); 7.30*(d, J = 8 Hz, indole H-7'); 7.23*(m, indole H-6'); 7.10*(dd, indole H-5'); 6.875.18*(dd, Hba-H); 5.13o(dd, Hba-H); 5.05*(ddd, PrLeu6-H); 4.98o(ddd, Leu-H); 4.93*(dd, MeTrp-H); 4.84*(ddd, PrLeu2-H); 4.78o(ddd, PrLeu2-H); 4.47*(dd, MeLeu-H); 4.13*(ddd, Leu-H); 3.8-3.5 (m); 3.72*o(2s, MeTrp N1'-Me); 3.69*(q, J = 7 Hz, MeAla-H); 3.40o(s, MeAla N-Me); 3.28*(s, MeAla N-Me); 3.20 (dd, MeTrp-Hb); 3.12*(dd, MeTrp-Ha); 2.93*(s, MeTrp, N-Me); 2.53o(s, N-Me); 2.52*(s, MeLeu N-Me); 3.21o(s, N-Me); 2.25-2.08 (m, Hba-CH2, Ha); 1.92*(m, Hba-Hb); 1.83-1.75 (m); 1.7-1.07 (m); 1.53*, 1.48o(2d, J = 7 Hz, MeAla-Me); 1.04 (d, J = 6.5 Hz, MeLeu-Me); 0.97-0.84 (m); 0.53*(d, J = 6.6 Hz, Leu Me) 0.28' (d); -0.17*(d, J = 6.6 Hz, Leu Me); -0.53*(ddd, Leu-CH).

Example 33.

(3 conformer 80:14:6, marked*,o, '): 8.48*(d, 10 Hz, PrLeu6 NH); 8.06*(d, 10 Hz, PrLeu2 NH); 7.94o(d, 10 Hz, PrLeu NH); 7.68*(d, 8 Hz, indole H-4'); 7.54o(d, indole); 7.33*(d, 8 Hz, indole H-7'); 7.31o(d, 8 Hz, indole); 7.22*(dd, indole H-6'); 7.1*(dd, indole H-5'); 7.53o(d, PrLeu NH); 6.93o(s, indole H-2'); 6.84*(s, indole H-2'); 6.26o(d, br, Leu NH); 6.05*(d, 7.5 Hz, Leu NH); 5.84' (d, Leu NH); 5.31o(ddd, PrLeu6-H); 5.18*(dd, Hba-H); 5.13o(dd, Hba-H); 5.06*(ddd, PrLeu6-H); 4.99o(ddd, Leu-H); 4.93*(dd, MeTrp-H); 4.87*(ddd, PrLeu2-H); 4.8o(ddd, PrLeu2-H); 4.47*(dd, MeLeu-H); 4.16*(ddd, Leu-H); 4.1*(m, N-CH2); 3.78-3.57; 3.69*(q, 7 Hz, MeAla-H); 3.47-2.90; 3.42*(s, MeLeu N-Me); 2.52o(s, N-Me); 2.32-2.10; 1.93*(m, Hba-CHb); 1.83-1.08; 1.53*(d, 7 Hz, MeAla-Me); 1.48o(d, 7 Hz, MeAla-Me); 1.04*(d, 6.5 Hz, MeLeu-d-Me); 0.97-0.84; 0.52*(d, 6.6 Hz, Leu Me); 0.26' (d, Leu Me); -0.17*(d, 6.6 Hz, Leu Me); -0.55*(ddd, Leu-CH).

Example 34.

(3 conformer 71:24:5, marked*,oand '): 8.50*(d, 10 Hz, PrLeu6 NH); 8.06*(d, 10 Hz, PrLeu2 NH); 7.94o(d, 10 Hz, PrLeu NH); 7.77o(d, 8 Hz, indole H-4'); 7.72*(d, 8 Hz, indole H-4'); 7.53o(d, 10 Hz, PrLeu NH); 7.40-7.05, 6.92o(s, indole H-2'); 6.88*(s, indole H-2'); 6.23o(d, 9.4 Hz, Leu NH); 6.09*(d, 7.4 Hz, Leu NH); 5.87' (d, Leu NH); 5.32o(ddd, PrLeu6-H); 5.23*(AB; N1'-CH2); 5.20*(AB; N1'-CH2); 5.17*(dd, Hba-H); 5.14o(dd, Hba-H); 5.04*(ddd, PrLeu6-H); 4.99o(ddd, PrLeu2-H); 4.96*(dd, MeTrp-H); 4.87*(ddd, PrLeu2-H); 4.78o(ddd, Leu-H); 4.47*(dd, MeLeu-H); 421*(ddd, Leu-H); 3.76o(q, 7 Hz, MeAla-H); 3.73-3.65, 3.67*(q, 7 Hz, MeAla-H); 3.58o(dd, MeLeu-H); 3.50-3.37, 3.42o(s, MeAla N-Me); 3.33*(dd, MeTrp-Ha); 3.27*(s, MeAla N-Me); 3.23o(s, N-Me); 3.23*(dd, MeTrp-Hb); 2.92*(s, MeTrp N-Me); 2.53*(s, MeLeu N-Me); 2.52o(s, N-Me); 2.28-1.08; 1.53*(d, 7 Hz, MeAla-Me); 1.49o(d, 7 Hz, MeAla-Me); 1.06*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.82, 0.50' (d, Leu Me); 0.45*(d, 6.6 Hz, Leu Me); 0.28' (d, Leu Me); -0.11*(d, 6.6 Hz, Leu Me); -0.47*(ddd, Leu-CH).

Example 35.

Example 36.

(3 conformer 73: 23:4, marked *,oand '): 8.53*(d, J = 10 Hz, PrLeu NH); 8.06*(d, J = 10 Hz, PrLeu' NH); 7.95o(d, J = 10 Hz, NH); 7.67*, 7.52o(2d, J = 7 Hz, indole H-4'); 7.55o(d, J = 10 Hz, NH); 7.33*, 7.31o(2d, J = 8 Hz, indole

H-7'); 7.19*, 7.17o(2dd, indole H-6'); 7.08*, 7.04o(2dd, indole H-5'); 6.98', 6.88o, 6.80*(3s, indole H-2'); 6.23o(d, J = 9.3 Hz, Leu NH); 6.05*(d, J = 7.5 Hz, Leu NH); 5.84' (d, Leu NH); 5.33o(ddd, PrLeu-H); 5.18*(dd, Hba-H); 5.14o(dd, Hba-H); 5.05*(ddd, PrLeu-H); 4.98o(ddd, Leu-H); 4.93*(dd, indole-H); 4.87*(ddd, PrLeu' -H); 4.81o(ddd, Leu-H); 4.47*(dd, MeLeu-H); 4.22*(ddd, Leu-H); 3.86-3.67 (m); 3.83*(s, t-Bu-CH2N); 3.69*(q, J = 7 Hz, MeAla-H); 3.5-3.2 (m); 3.43o(s, MeAla N-Me); 3.30*(s, MeAla N-Me); 3.22o(s, N-Me); 2.93*(s, MeMeTrp, N-Me); 2.53*(s, MeLeu N-Me); 2.53o(s, N-Me); 2.25 (m, g Hba-CH2); 2.18 (m, Hba-Ha); 2.0-1.08 (m); 1.54*, 1.49o(2d, J = 7 Hz, MeAla-Me); 1.05 (d, J = 6.5 Hz, MeLeu Me); 0.97-0.84 (m); 0.52*(d, J = 6.6 Hz, Leu Me); 0.28' (d); -0.06*(d, J = 6.6 Hz, Leu Me); -0.49*(; .06*(d, 10 Hz, PrLeu2 NH); 7.94o(d, 10 Hz, PrLeu NH); 7.68*(d, 8 Hz, indole H-4'); 7.53o(d, 8 Hz, indole H-4'); 7.52o(d, 10 Hz, PrLeu NH); 7.36*(d, 8 Hz, indole H-7'); 7.33o(d, 8 Hz, indole H-7'); 7.2*(dd, indole H-6'); 7.17o(dd, indole H-6'); 7.09*(dd, indole H-5'); 7.05o(dd, indole H-5'); 7.02o(s, indole H-2'); 6.91*(s, indole H-2'); 6.23o(d, 9.5 Hz, Leu NH); 6.03*(d, 7.4 Hz, Leu NH); 5.87' (d, Leu NH); 5.32o(ddd, PrLeu6-H); 5.18*(dd, Hba-H); 5.14o(dd, Hba-H); 5.05*(ddd, PrLeu6-H); 4.98o(ddd, PrLeu2-H); 4.93*(dd, MeTrp-H); 4.87*(ddd, PrLeu2-H); 4.81o(ddd, Leu-H); 4.60 (m, N-CH); 4.46*(dd, MeLeu-H); 4.16*(ddd, Leu-H); 3.75o(q, 7 Hz, MeAla-H); 3.70 (m); 3.69*(q, 7 Hz, MeAla-H); 3.57o(dd, MeLeu-H); 3.45 (m); 3.42o(s, MeAla N-Me); 3.32*(dd, MeTrp-Ha); 3.31*(s, MeAla N-Me); 3.23*(dd, MeTrp-Hb); 3.21o(s, N-Me); 2.93*(s, MeTrp N-Me); 2.53*(s, MeLeu N-Me); 2.50o(s, N-Me); 2.28 (AB, XY); 2.18 (AB-XY, Hba g-CH2); 2.13*(m, Hba-CHa); 1.93*(m, Hba-CHb); 1.85-1.08; 1.53*(d, 7 Hz, MeAla-Me); 1.47 (m, N-CHMe2); 1.04*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.83; 0.52' (d, Leu Me); 0.51*(d, 6.6 Hz, Leu Me); 0.34' (d, Leu Me); -0.2*(d, 6.6 Hz, Leu Me); -0.60*(ddd, Leu-CH).

Example 38.

Indolin A (3 conformer 46:27:27 marked*,o,o): at 8.62*(d, J = 10 Hz, PrLeu NH); 8.13o(d, J = 10 Hz, NH); 8.02o(d, J = 10 Hz, NH); 7.92o(d, J = 10 Hz, NH); 7.86*(d, J = 10 Hz, PrLeu' NH); 7.oline arom. H); 6.76o, 6.72*, 6.71o(3dd, indoline arom. H); 6.64o, 6.62o, 6.58*(3d, J = 7.7 Hz, indoline arom. H); 6.32o(d, J = 8 Hz, Leu NH); 6.10o(m br, Leu NH); 5.94*(d, J = 9 Hz, Leu NH); 5.28-4.73 (m); 4.60o(dd, -H); 4.13*(dd, -H); 3.75-2.85 (m); 3.45*, 3.33o, 3.33*, 3.23o, 3.20o, 3.02*, 2.81o, 2.79o, 2.57o(9s, N-Me); 2.45-0.83 (m); 1.52o, 1.46o, 1.42*(3d, J = 7 Hz, MeAla-Me).

Indolin B (3 conform. 1:1:1): 8.62, 8.43, 8.07, 7.94, 7.87, 7.42 (6d, J = 10 Hz, NH); 7.12 (s, J = 7.4 Hz, indoline arom. H); 7.08-6.99 (m, indoline arom. H); 6.72, 6.69, (2dd indoline arom. H); 6.66-6.63 (m, indoline arom. H); 6.58 (d, J = 8 Hz, indoline arom. H); 6.29 (d, J = 8 Hz, Leu NH); 6.15 (m br, Leu NH); 5.88 (d, J = 8 Hz, Leu NH); 5.28-4.98 (m-H); 4.93 (ddd, -H); 4.74 (ddd, -H); 4.65 (m-H); 4.54 (dd, -H); 4.43 (dd, -H), 3.80-3.66 (m); 3.55-3.0 (m); 3.46, 3.35, 3.31, 3.24, 3.22, 3.12, 3.00, 2.82, 2.57 (9s, N-Me); 2.55-1.1 (m); 1.52, 1.48, 1.43 (3d, J = 7 Hz, MeAla-Me); 1.13 (d, J = 7 Hz); 1.03-0.83 (m); 0.78, 0.76, 0.73 (3d, J = 6.5 Hz).

Example 39.

(3 conformer 76:18:6, marked *,oand '): 8.49*(d, 10 Hz, PrLeu6 NH); 8.05*(d, 10 Hz, PrLeu2 NH); 7.94o(d, 10 Hz, PrLeu6 NH); 7.67*(d, 8 Hz, indoie H-4'); 7.53o(d, 8 Hz, indole H-4'); 7.52o(d, 10 Hz, PrLeu2 NH); 7.4*(d, 8 Hz, indole H-7'); 7.38o(d, 8 Hz, indole H-7'); 7.23*(dd, indoie H-6'); 7.19o(dd, indole H-6'); 7.11*(dd, indoie H-5'); 7.07o(dd, indole H-5'); 7.05o(s, indole H-2'); 7.01*(s, indole H-2'); 6.22o(d, br, Leu NH); 6.05*(d, 7.5 Hz, Leu NH); 5.84' (d, Leu NH); 5.31o*(ddd, PrLeu2-H); 4.81o(ddd, Leu-H); 4.67' (ddd, Leu-H); 4.45*(dd, MeLeu-H); 4.18*(ddd, Leu-H); 4.14 (s, OPr); 3.80-3.55; 3.67*(q, 7 Hz, MeAla-H); 3.50-3.40; 3.42o(s, N-Me); 3.29*(dd, MeTrp-Ha); 3.27*(s, MeAla N-Me); 3.21o(s, N-Me); 3.18*(dd, MeTrp-Hb); 3.04' (s, N-Me); 2.93*(s, MeTrp N-Me); 2.55o(s, N-Me); 2.53*(s, MeLeu N-Me); 2.30-1.90; 1.80 (m, OPr); 1.53*(d, 7 Hz, MeAla-Me); 1.48o(d, 7 Hz, MeAla-Me); 1.08o(t, OPr); 1.07 (t, OPr); 1.05*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.85; 0,59' (d, Leu Me); 0.57*(d, 6.6 Hz, Leu Me); 0.37' (d, Leu Me); -0.07*(d, 6.6 Hz, Leu Me).

Example 40.

(3 conformer 73:21:6 marked*,o, '): 8.49*(d, 10 Hz, PrLeu6 NH); 8.05*(d, 10 Hz, PrLeu2 NH); 7.94o(d, 10 Hz, PrLeu6 NH); 7.67*(d, 8 Hz, indole H-4'); 7.53o(d, 8 Hz, indole H-4'); 7.52o(d, 10 Hz, PrLeu2 NH); 7.4*(d, 8 Hz, indole H-7'); 7.38o(d, 8 Hz, indole H-7'); 7.23*(dd, indole H-6'); 7.19o(dd, indole H-6'); 7.11*(dd, indole H-5'); 7.07o(dd, indole H-5'); 7.05o(s, indole H-2'); 7.01*(s, indole H-2'); 6.22o(d, 9.4 Hz, Leu NH); 6.05*(d, 7.3 Hz, Leu NH); 5.86' (d, Leu NH); 5.31o(ddd, PrLeu6-H); 5.19*(dd, Hba-H); 5.16o(dd, Hba-H); 5.03*(ddd, PrLeu6-H); 5o(ddd, PrLeu2-H); 4.94*(dd, MeTrp-H); 4.87*(ddd, PrLeu2-H); 4.81o(ddd, Leu - H); 4.65' (ddd, Leu-H); 4.46*(dd, MeLeu-H); 4.26*(q, OEt); 4.26o(q, OEt); 4.19*(ddd, Leu-H); 3.80-3.56; 3.67*(q, 7 Hz, MeAla-H); 3.45-3.33; 3.41o(s, MeAla N-Me); 3.29*; .52*(s, MeLeu N-Me); 2.32-1.08; 1.53*(d, 7 Hz, MeAla-Me); 1.48o(d, 7 Hz, MeAla-Me); 1.40o(t, OEt); 1.40*(t, OEt); 1.05*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.84; 0.60' (d, Leu Me); 0.57*(d, 6.6 Hz, Leu Me); 0.37' (d, Leu Me); -0.07*(d, 6.6 Hz, Leu Me); -0.36*(ddd, Leu-CH).

Example 41.

(3 conformer 63:32:5, marked*,o, '): 8.45*(d, 10 Hz, PrLeu6 NH); 8.06*(d, 10 Hz, PrLeu2 NH); 7.97o(d, 10 Hz, PrLeu6 NH); 7.90' (d, 10 Hz, PrLeu6 NH); 7.63*(d, 8 Hz, indole H-4'); 7.56o(d, 10 Hz, PrLeu2 NH); 7.45o(d, 8 Hz, indole H-4'); 7.4*(d, 8 Hz, indole H-7'); 7.38o(d, 8 Hz, indole H-7'); 7.23*(dd, indole H-6'); 7.22o(dd, indole H-6'); 7.13*(dd, indole H-5'); 7.08o(dd, indole H-5'); 6.2o(d, 10 Hz, Leu NH); 6.07*(d, 7.5 Hz, Leu NH); 5.77' (d, 8.5 Hz, Leu NH); 5.32o(ddd, PrLeu6-H); 5.26' (dd, Hba-H); 5.2*(dd, Hba-H); 5.16o(dd, Hba-H); 5.03*(ddd, PrLeu6-H); 4.97*(dd, MeTrp-H); 4.87*(ddd, PrLeu2-H); 4.67o(ddd, -H); 4.46*(dd, MeLeu-H); 4.13*(ddd, Leu-H); 4.09*(s, N-OMe); 4.04' (s, N-OMe); 4.03o(s, N-OMe); 3.74o(q, 7 Hz, MeAla-H); 3.71*(q, 7 Hz, MeAla-H); 3.70-3.60; 3.54-3.50; 3.47o(s, MeAla N-Me); 3.28-3.17; 3.25*(s, MeAla N-Me); 3.20o(s, N-Me); 2.97*(s, MeTrp N-Me); 2.52*(s, MeLeu N-Me); 2.42o(s, N-Me); 2.40-2.14; 1.97 (m); 1.79 (m); 1.65-1.08; 1.53*(d, 7 Hz, MeAla-Me); 1.5o(d, 7 Hz, MeAla-Me); 1.04*(d, 6.5 Hz, MeLeu-d-Me); 0.98-0.83; 0.62' (d, Leu Me); 0.57*(d, 6.6 Hz, Leu Me); 0.37' (d, Leu Me); -0.09*(d, 6.6 Hz, Leu Me); -0B>2
); 8.60 (d, PrLeu6 NH); 8.17 (d, CSNH2); 8.03, 8.00 (2d, NH); 7.88 (m, CSNH2); 7.6-7.1; 6.28*(d, 10 Hz, Leu NH); 6.07o(d, 7 Hz, Leu NH); 5.87' (d, 9 Hz, Leu NH); 6.26*(ddd, PrLeu2-H), 5.22 (dd, Hba-H); 5.15-4.95, 5.08*, (dd, Hba-H); 4.83o(ddd, PrLeu2-H); 4.50*(ddd, Leu-H); 4.37*(dd, MeTrp-H); 4.25o(ddd, Leu-H); 4.09, 4.05, 4.03*(3s, OMe); 3.89 (m-H); 3.65*, 3.63', 3.52o(3q, 7 Hz, MeAla-H); 3.57 (m), 3.17, 3.16, 3.15, 3.22, 3.20, 3.05, 2.92, 2.55, 2.53 (9s, NMe); 1.8-1.1; 1.05 (d, 7 Hz); 0.99-0.82, 0.60o, 0.55', 0.23', 0.17o(4d, 7 Hz, Leu Me); -0.15o, -0.17' (ddd, Leu-CH).

1. Cyclopeptide formula I

< / BR>
where A denotes the residue butyric acid, substituted by a hydroxyl group which may be optionally substituted in position by the radical R6denoting CN, COOR2, CONR3R4, COR5, CSNH2or alkyl which may be substituted by sidegroups, a halogen atom, alkoxygroup possibly protected hydroxyl or amino group, vinyl which may be substituted by alkyl, a halogen atom or a CN group, cycloalkyl, tetrazolyl or group-CCH; where R2denotes hydrogen or alkyl, which can optionally be substituted by aryl, R3and R4- same or different and represent hydrogen or alkyl or form together with the nitrogen atom a ring consisting of from 3 which indicates the balance-amino--methylamino octanoic acid;

R1denotes hydrogen or methyl;

C indicates the tryptophan or N-methyltryptophan formula VI

< / BR>
where R8denotes hydrogen, alkoxygroup, alkyl or benzyl;

R9denotes hydrogen or halogen;

R10denotes hydrogen or methyl;

denotes a single or double bond,

X represents the residue-aminosilanes (C2-C14)carboxylic acid, and Y represents the residue of amino - or N-methyl--aminosilanes (C2-C10) carboxylic acid.

2. Cyclopeptide under item 1 of the formula II or III

< / BR>
< / BR>
3. Cyclopeptide under item 1 of the formula I, where

< / BR>
< / BR>
R1= CH3;

< / BR>
< / BR>
< / BR>
4. The strain of the fungus Bartalinia sp.NRRL 21123 producer cyclopeptide under item 1.

5. A method of obtaining a connection on p. 1, characterized in that conduct the cultivation of a strain of the fungus Bartalinia sp. NRRL 21123 in a nutrient medium, followed by separation from the environment specified connection.

6. therapeutic composition having the ability to inhibit the expression of adhesion molecules, comprising as active ingredient a compound of formula I under item 1 in an effective amount and the target additives.

Priority signs:

27.07.94 - compounds falling under formula which form together with the nitrogen atom a 5 - or 6-membered ring; C - N methyltryptophan, which can be N'-(C1-C4)alkoxy-substituted;

03.03.95 - compounds falling under formula I, where R6- alkyl which can be substituted by sidegroups, a halogen atom, alkoxygroup, possibly protected by a hydroxyl or amino group, vinyl (can be substituted by alkyl, a halogen atom or a CN group), cycloalkyl, tetrazolyl or group-CCH; R3and R4form together with the nitrogen atom ring consisting of 3 to 6 atoms; C - N methyltryptophan formula

< / BR>
where R8is a hydrogen atom, alkoxygroup, alkyl or benzyl;

R9is a hydrogen atom or halogen;

R10is a hydrogen atom or methyl;

a single or double bond.

 

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