Derivatives of cyclic peptides or their pharmaceutically acceptable salts, method of production, the pharmaceutical composition

 

(57) Abstract:

Describes new compounds of formula I,

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where the values of the radicals indicated in paragraph 1 of the formula

pharmaceutically acceptable salts exhibiting antifungal and antiparasitic activity. Also described is a method of obtaining the above-mentioned compounds and pharmaceutical composition based on compounds of the formula I, with protivokariosnoe and protivorevmaticski activity. 3 c. and 14 C.p. f-crystals, 29 PL.

The invention relates to cyclic peptide antifungal agents. In particular it relates to acyl derivatives of cyclic peptide antifungal agents class echinocandin, to a method of treatment of fungal and parasitic infections and the drugs used in this way.

Connections offered by the invention are semi-synthetic antifungal agents, since they are derived cyclic pipinich antifungal agents produced by the cultivation of various microorganisms. There are a large number of cyclic peptide antifungal agents. Among them echinocandin B (A30912A), aculeate, malodoranzien, sporophores L-671329, FP 901379 kinogruppa one of the amino acids of the loop, carrier of acyl fatty acid, forms a side chain outside the nucleus. For example, echinocandin B contains linoleoyl in the side chain, whereas culiacancito. These fatty acid side chains of the cyclic hexapeptides can be removed by enzymatic diallylammonium with getting free kernel /see formula I: where R2- hydrogen/. New acylation of the amino group core network semisynthetic antifungal compounds. For example, the core echinocandin B gives a large number of antifungal agents when reanimirovany unnatural radicals lateral groups /see Debono, U.S. patent N 4293489, C 07 C 103/52, 1981/. Among these antifungal compounds proposed cilofungin represented by formula I, where R is methyl, R1is hydrogen and R2- n (n-octyloxy)benzoyl.

Enzymatic diallylamine cyclic hexapeptides carry deacylase produced by the microorganism Actino planes utahensis and close microorganisms as described by Bottom in U.S. patent N 4293482, C 07 C 103/52, 1981.

In the present invention proposed acylated cyclic Hexapeptide unique side acyl groups, which give increased antifungal and antiparasitic activity, for example, protracte dideoxycytidine formula I, where R is hydrogen.

Summary of the invention.

The proposed compounds of formula I

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R1- methyl

RII and RIII are independently methyl or hydrogen;

R and RV is, independently, hydroxy-group or hydrogen

R1is hydrogen,

R7is hydroxy, hydrogen or phosphonooxy, and

1) R2- substituted benzoyl formula:

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where

A) R3- polyoxyethyl formula

-O-(CH2)m-/O-(CH2)n/p-O-C1-C12-alkyl

where m and n = 2 to 4, p = 0 - 1, or

B) R3unsaturated hydrocarbon group of the formula:

-Y-C1-C12-alkyl,

where Y - group or-CH=CH-, or

C) R3group of the formula-O-(CH2)mG, where m is defined above and G - (C7-C10-bicycloalkyl or C7-C14-tricyclohexyl, or

II) R2- acyl formula

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in which Z is a group-O-, -CH=CH-, -CH2-CH2-, CH2- or carbon-carbon bond".

A) R4is hydrogen, (C2-C12)-quinil, substituted (C2-C12)-quinil, (C1-C12)-alkoxy or (C3-C12-cycloalkanes, phenyl, or

B) R4is phenyl, substituted amino group, (C1-C12-alkylthiol, halogen, (C1 is an alkyl, (C2-C12) substituted by alkenyl, (C2-C12) substituted by quinil, (C1-C12-alkoxygroup, cryptomeria, phenyl, substituted phenyl or polyoxyalkylene formula:

-O-(CH2)m/O-(CH2)n/p-O- (C1-C12)-alkyl,

where n, m, p, defined above, or

C) R4is phenyl, substituted (C1-C6-alkoxygroup, the latter may be replaced by fluorine, bromine, chlorine or iodine, or

D) R4- (C1-C12-alkoxygroup, substituted (C3-C12-cycloalkyl (C2-C12)-alkyl or by phenyl which, in turn, replaced by polyoxyalkylene identified above, or

E) R4group of the formula

-O-(CH2)p'-W-R5,

where p' = 2-4, W - pyrrolidino, piperidino-or piperazinone and R5is hydrogen, (C1-C12)-alkyl, (C3-C12-cycloalkyl, benzyl or (C3-C12-cyclooctylmethyl or

F) R4group of the formula: -Y-R6where R6- (C1-C12)alkyl, substituted (C1-C12)alkyl, (C7-C10)bicycloalkyl; (C7-C14)tricyclohexyl, phenyl, unsubstituted or substituted amino group, (C1-C12)-alkoxy, triptime is hydrogen, (C1-C12)-alkyl, (C3-C12)cycloalkyl, benzyl, (C3-C12)cycloalkenyl, or (C1-C6)alkoxygroup substituted by bromine, fluorine, iodine or chlorine;

Y values defined above;

III) R2group of the formula

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or

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or

IV) R2- naphtol substituted by a group R4; where R4is hydrogen, phenyl, (C1-C12)alkoxygroup

or their pharmaceutically acceptable salts, provided that when RIis methyl, RVis methyl, RIIIis methyl, R and RVthe hydroxy - group, R1is hydrogen, R7is hydroxy or phosphonooxy, R2is not a group of the formula

< / BR>
in which R3group-O-(CH2)m-/O-(CH2)n/p-O- (C1-C12)-alkyl, where p = 0,

neither group of the formula

< / BR>
in which Z is a carbon-carbon bond or-O-; R4- (C1-C12-alkoxygroup;

neither naftilan, substituted R4where R4is hydrogen, phenyl or (C1-C12-alkoxygroup.

Suggested preparations and methods of inhibiting parasitic and fungal activity using the compounds according to the invention, and the method of obtaining detoxify connections.

The term "C2-C12alkenyl" denotes vinyl, 1-propen-2-yl, 1-butene-4-yl, 1-penten-5-yl, 1-butene-yl and the like.

The term "C2-C12-quinil" means ethinyl, PROPYNYL, pennil, butynyl and the like.

The term "C1-C12-allylthiourea" means methylthio, ethylthio or tert-butylthiourea and the like.

The term "C1-C12-alkoxygroup" refers to normal or branched oxyalkyl, for example, methoxy, ethoxy-, propoxy-, butoxy, heptyloxy-, octyloxy-, or dodecyloxy and the like.

The term "C3-C12-cycloalkanes" means callproperty or cyclobutene and the like.

The term "C3-C12-cycloalkenyl" means tilapainen, cyclobutenyl, cyclopentenyl and the like.

The term "C1-C12-alkyl" substituted C2-C12alkenyl", substituted C2-C12-quinil" denotes alkyl, alkenyl or quinil substituted by one or two groups such as halogen, hydroxy, protected hydrox is, is iano, methylsulfonylamino or C1-C12-alkoxygroup, carbarnoyl, phenyl, substituted phenyl.

The term "substituted phenyl" refers to phenyl, substituted with 1-3 groups such as halogen, hydroxy, substituted hydroxy-, cyano-, nitro-, C1-C12-alkoxy, carboxy, substituted carboxy-, amino - or methylsulfonylamino, C1-C12-alkyl-, carboxymethyl, hydroxymethyl, aminomethyl or trifluoromethyl.

The term "C3-C12-cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "C1-C4-alkylamino" means methylamino, ethylamino-, or n-butylamino and the like.

The term "di (C1-C4-alkylamino" denotes a dimethylamino, diethylamino-, di-n-propylamino-, di-n-butylamino, methylethylamine - or methyl-n-butylamino and other tertiary amino group.

The term "C1-C12-alkanolamine" means allmenalp, a derivative of carboxylic C1-C12acid, such as formamide-, acetylamino-, propionamido or bucillamine and the like.

The term "C3-C12-cycloalkylation" represents C3 the keel" and C7-C14-tricyclohexyl" denotes a bicyclo/2,2,1/hept/2-yl, bicyclo/2,2,1/hept-4-EN-2-yl, bicyclo/3,3,1/ion-3-yl, bicyclo/3,3,1/non-2-yl, bicyclo/3,2,1/Oct-2-yl, bicyclo/2,2,2/Oct-2-yl, bicyclo/2,2,2/Oct-5-EN-2-yl, substituted or similar.

The term "dideoxy" refers to compounds of the formula where R is hydrogen.

The term "inhibition" in connection with the methods of inhibiting parasitic and fungal activity is set to the normal definition, that is, to stop, to slow down or prophylactically to inhibit or prevent.

The term "activity" in connection with parasitic and fungal activity includes its growth and related characteristics and the existence of the parasite or fungus. The term "contacting" in connection with the methods of inhibiting parasitic and fungal activity in contact with the compounds of the invention is set to the usual definition. However, the term does not imply any other restrictions, such as imposed by the mechanism of inhibition, and methods enter into the spirit of the invention, which consists in the inhibition of parasitic and fungal activity under the action of the compounds or, in other words, the compounds used in the methods are preleukaemia, for example, 2-methoxyethoxy (p = 0, m = 1) 2-ethoxyethoxy-, 2-(2-maxitaxi)ethoxy- (m = 2, p = 1, n = 2), 3-(2-ethoxyethoxy)propoxy or 3-(2-methoxyethoxy)butoxypropyl and the like.

Examples of groups R3if R2- benzoyl, substituted unsaturated group Y - C1-C12-alkyl include acetylene group-C C- (C1-C12-alkyl, and-CH2= CH-C1-C12the alkyl in the CIS - or the transform, for example, propenyl, butenyl, hexenyl, decenyl and the like, PROPYNYL, butynyl, hexenyl, undecenyl and similar Alikina.

Examples of acyl groups, if R2group of the formula

< / BR>
are diphenyl ethers (Z is a group-O-), diphenylacetylene the stilbene (Z - group-CH=CH-) and biphenyls (Z - carbon-carbon bond). Examples of such biphenylene groups, where Z is a carbon-carbon bond, for example, communication phenyl-phenyl, 4-(4-butoxyphenyl)benzoyl, 4-(4-cyclobutylmethyl)benzoyl, 4-(4-cyclobutylmethyl)benzoyl, 4-(4-cyclohexanedimethanol)benzoyl, 4-(4-n-hexyloxyphenyl)benzoyl, 4-vinylbenzoic: 4-/11-aminoindazole)phenyl/benzoyl, 4-/4-11-formamidopyrimidine)phenyl/benzoyl, 4-(4-isopentylamine)benzoyl, and the like. Examples diphenylamine acyl groups, R2if Z is-O-, are 4-(4-b is, -/4-(3-chloroethoxy)phenoxy/benzoyl, 4-(4-dodecyloxyphenyl)benzoyl, 4-/4-(3-dimethylaminopropoxy)phenoxy/benzoyl and the like. Examples diphenylacetylene and stilinovich acyl groups, if Z is a triple or double carbon-carbon bond, is 4-steelbezel, 4-(4-methoxystyrene)benzoyl, 4-(4-butoxyethyl)benzoyl, 4-feniletinilpireny, 4-(4-ethoxybenzylidene)benzene, 4-(4-cyclohexylpiperidine)benzoyl and the like. Examples of acyl groups R2if Z is a bond and R4group-O-(CH2)pW-R5are 4-[4(2-N-cyclohexylpiperidine-4-yl-ethoxy/phenylbenzyl, 4-[4-(4-benzylpyridine)ethoxy/phenylbenzyl, 4-4-(2-(4-cyclohexylpiperidine)ethoxy/phenyl] benzoyl, and the like. Examples of acyl groups, where R4group y-R6are 4-/4-(phenyl-ethinyl)phenoxy/benzoyl, 4-(4-hexylphenyl)benzoyl, 4-(4-sterigenics)benzoyl, 4-(4-(4-benzylpiperidine)phenyl/benzoyl, 4-[4-/4-(4-methylpiperidino)phenylethynyl/phenyl] benzoyl, and similar atilov. Acyl group, where R4group-O-(CH2)p'WR5form a salt of the basic amino groups of the piperidine and piperazine with organic and inorganic acids such as hydrochloric acid, Hydrobromic acid, sulphuric acid and FOSFA manna, malic, succinic, malonic acid and other acids.

Table (1 - 25) provide more examples of the cyclic peptides of formula I. table 1 contains examples of cyclic peptides with an acyl group, R2formula

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Table 2 illustrate the compounds of formula I, where R2group of the formula

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Table 3 illustrates compounds of formula I, where R3has the values listed in table 2 and R4represents a group of formula (PL.3).

Arylcyclohexylamine formula I possess anti-parasitic activity, for example, they are especially active against infections by fungi and Candida Parapsi Josis. They also possess significant activity against Aspergillus Junu-gatus.

They are active both in vitro and in vivo and, accordingly, useful in the fight against systemic fungal infections.

Compounds of the invention also inhibit the growth of some organisms, initially responsible for opportunistic infections in individuals with a depressed immune system. For example, the compounds of the invention inhibit the growth of Pneumocystics carinii causal organism Pneumocystis pneumonia in patients with AIDS.

Antifungal activity of the compounds of the invention determine the in vitro standard Tracii (MIC). Standard in vivo methods in mice are used to determine the effective dose (ED) of the test compounds in the regulation of systemic fungal infections.

Table 4A-E (see below) contain MICK in micrograms per milliliter (μg/ml) for compounds of the invention against Candida albicns and Candida parapsilosis and for some compounds, effective dose, ED50on mice.

In tables 4A-E RIis methyl, RIIis methyl, RIIIis methyl, RVthe hydroxy-group, R7the hydroxy-group, R1-hydrogen. In table E - R-hydrogen.

In table 4A R2group of the formula

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where R3has the values shown in table 4.

In table 4B R2group of the formula

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where R3has the above values.

In table 4C, all values are the same as in table 4B, except that Z is a carbon-carbon bond.

In table 4D shows the activity of compounds with a value of R2as defined.

In table 4E specified activity dideoxycytidine (R - hydrogen for the R2).

Medicationcanine formula I are obtained from aminogram cyclic hexapeptides formula I, when R2is hydrogen, Aminoate obtained from known is arodnogo connection. For example, echinocandin B represented by formula I, where RI-RIIIis methyl, R and RV-hydroxyprop, and R1is hydrogen, R7- OH, R2-linalool, detailyou to obtain kernel echinocandin B (R2- hydrogen)deacylase produced by the body Actinoplanes utahensis as described in U.S. patent N 4293482 and 4304716.

Known natural cyclic Hexapeptide, N-diallylamine to obtain the source aminoether include echinocandin B (also known as A-30912A), Culiacan (palmifolia side chain), tetrahydroaminoacridine B (caarolina side chain), mountainmen (branched side C15-chain L-671329 (branched side C16-chain), S 31794/F1 (tetradecanoyl side chain), sporophores (branched side C15-chain) FR 901379 (palmifolia side chain). Aminoate obtained N-diallylammonium, then acelerou by known methods to obtain the N-acylated cyclic hexapeptides formula I, where R2- acyl, as defined above. Allermuir reagent preferably is an active ester of carboxylic acid RCOOH, such as 2,4,5-trichlorophenoxy ether. Acid - precursor of R2COOH is obtained by hydrolysis of NITRILES R2CN or esters R2COO-(CEmaticheskie connection (for example, phenyl and biphenyl), are presented in tables 5 to 10, get one of the two following methods:

A. Hydroxyaromatic compound (1 equivalent) is dissolved in acetonitrile (200-300 ml) and a base such as tert-piperonyl potassium or potassium carbonate (1 equivalent), add. Then add allylbromide-, iodide or para - toluensulfonate (1 equivalent) and the solution refluxed for 6 hours. The solvent is evaporated in vacuum, the residue is dissolved in ether and 2H the sodium hydroxide. The ether layer is dried over magnesium sulfate and evaporated. The remainder represents alkoxyamine product.

B. Hydroxyaromatic compound (1 equivalent), alkanol (1 equivalent) and triphenylphosphine (1 equivalent) is dissolved in tetrahydrofuran (200 to 300 ml and add diethylazodicarboxylate (1 equivalent) is added dropwise within 10 minutes at room temperature. After 17 hours the solvent is removed in vacuum, the residue is dissolved in ether. The organic layer is extracted with 2N-sodium hydroxide solution, dried over magnesium sulfate and evaporated with the formation of the product, which crystallized from a mixture of ether - pentane or, if the product contains tertiary amine, hydrochloric get salt and crystallized from a mixture of meta which are as follows way.

The aromatic bromide, iodide or triftorbyenzola (1 equivalent) is dissolved in acetonitrile (600 ml 0.1 mol of aromatic reagent) in a nitrogen atmosphere. Add the alkyl or alkene (1 equivalent), triethylamine (2 equivalents), palladium dichloride (0.05 equivalent), triphenylphosphine (0.1 equivalent) and copper iodide (0,025 equivalent) and the solution boiled for 17 hours. The solvent is removed in vacuo and the residue suspended in ether (300 ml). The solid material is removed by filtration and the filtrate washed with 1N-hydrochloric acid. The organic layer is dried over magnesium sulfate and evaporated to obtain the product.

Aromatic boranova acid, are shown in table 15, was prepared as follows:

Aromatic halide (1 equivalent) in tetrahydrofuran is cooled to -78 deg.C. Add utility (1.2 equivalent). After 15 minutes add triisopropylsilyl (2 equivalent) and after 10 minutes of mixing, remove the cooling bath. When the reaction mixture is warmed to room temperature, water is added to decompose the reaction mixture, and then 1N HCl. The organic layer is removed under reduced pressure, the solid residue are filtered, washed with hexane and get clean borono the Aromatic Bronevoy acid (1 equivalent), methyl-4-identit (1 equivalent) and potassium carbonate (1.5 equivalents) are mixed in toluene and purged with nitrogen. Alternative you can use trichloranisole ether of identity. Add tetrakis (triphenylphosphine)palladium (0.03 equivalent) and refluxed for 7 hours. The solution is decanted to remove calcium carbonate and evaporated in vacuum. The residue is triturated with acetonitrile and the solid product are filtering.

Aromatic NITRILES or esters of carboxylic acids from tables 5 to 16, can be transformed into a carboxylic acid by one of the following two methods of hydrolysis:

A. Aromatic natrel dissolved in ethanol and an excess 50% sodium hydroxide solution and boiled for 2 hours. Add water to the formation of a solid residue. The precipitate is collected by filtration, added dioxane and 6N hydrochloric acid solution is boiled for 17 hours. Add water and the resulting carboxylic acid crystallizes. Her evolve by filtration and dried under vacuum.

B. Methylcarbamoyl dissolved in methanol, add an excess of 2N sodium hydroxide solution and the solution is refluxed for 6 hours. The solution is acidified with excess hydrochloric acid and doom.

Carboxylic acid is transformed into 2,4,5-trichlorophenolate esters are given in tables 17-25 following General way:

Aromatic acid (1 equivalent), 2,3,4,5-trichlorophenol (1 equivalent) and N, N'-dicyclohexylcarbodiimide (1 equivalent) is dissolved in methylene chloride. The mixture is stirred for 17 h and filtered. The filtrate is evaporated until dry and dissolved in ether, filtered and added pentane prior to the crystallization. Crystalline product produce by filtration and dried under vacuum.

Dideoxycytidine formula I is obtained by removal of the benzyl and eminalley hydroxyl groups. The method includes processing medicationcanine formula I, where R2is hydrogen or acyl, a strong acid, such as trichloroacetic or triptocaine acid or athirat of boron TRIFLUORIDE, and a reducing agent, such as cyanoborohydride sodium or triethylsilane, preferably by triethylsilane. The reaction is carried out at a temperature of from -5 to 70 degrees.C in a solvent such as methylene chloride, chloroform or acetic acid, preferably in methylene chloride. The acid must be present in an amount of 2-60 mol per mole of the substrate, the reducing agent must be present in an amount of 2-60 mol per mole of the substrate. Way ol who have superior properties compared to previously known N-acyl Hexapeptide antifungal agents. For example, in General, compounds have oral suitability of the property, which is important for any systemic antifungal agents.

Numerous N-acyl compounds of the formula have high antifungal activity and increased solubility.

Among the N-allexamples formula I are preferred variant of the invention. Compounds in which R2- diphenylene acyl group

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in which Z is a carbon-carbon bond and R4-alkoxy, cycloalkane or cycloalkylcarbonyl, are the preferred antifungal agents. Also, preference is given to compounds with Z - carbon-carbon bond, and R4group of the formula-Y-R6where R6- (C1-C12)-alkenyl phenyl or substituted phenyl and Y-acetylene bond.

Hereinafter, the preferred compounds are those where Z is a carbon-carbon bond and R4the group-O-(CH2)p-W-R5(R5-piperidine).

Examples of preferred compounds of the first group include compounds with 4-(4-alkoxyphenyl)benzoic group, in which alkoxygroup(C5-C10-alkoxygroup or (C5-C

Examples of preferred compounds of the second group with R4group of the formula - Y - R6include 4-/4-(phenylethynyl)phenyl/benzoyl and 4-/4-(n-butylamine)phenyl/benzoyl.

Examples of preferred compounds of the third group R4group-O-(CH2)p-W-R5represented by the compounds with R5groups of the formula

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where R5- piperidino-, 4-n-propylpiperidine-, 4-benzylpiperidine-, 4-cyclohexylpiperidine-, and 4-cyclohexylpiperidine and their farmatsevticheskii acceptable salts with acids, for example, chlorhydrate, sulfates or phosphates.

Preferred cyclopentapeptide compounds represented by formula I, where RIand RIIis methyl, R1is hydrogen and R2preferred acyl defined above.

In table 26 lists the preferred substituents R2if R, R7and RVthe hydroxy - group, RI- RIIIis methyl and RI- hydrogen.

N-Allequipped of the invention is used to treat fungal infections as systemn the which provides for the introduction of the master of effective non-toxic amount of N-arylcyclohexylamine formula I. Preferably the method is the introduction of N-allequipped formula I, where RIand RIIis methyl, R1is hydrogen and R2preferred acyl defined above.

Antifungal connection, you can enter parenterally, for example intramuscularly, intraperitoneally or subcutaneously, nasal, oral or topically for skin infections. Enter the dose will vary depending on such factors as the nature and severity of the infection, the age and General health of the host and the stability of the individual owner to a specific antifungal agent. The regimen may also vary depending on such factors and antifungal agent can be introduced in a single daily dose or in multiple doses during the day. Treatment can last from 2-3 days to 2-3 weeks or longer.

The invention also provides pharmaceutical preparations for the introduction of the antifungal compounds of the invention. The preparations contain N-allequipped formula I or pharmaceutical acceptable non-toxic salts and pharmaceutically acceptable carrier.

For parenteral administration, the preparation contains the compound of the formula I and physiologically acceptable diluent, so report may contain solubilizers tool, such as a polyethylene glycol or polypropyleneglycol or other solubilizing means. Drugs can be manufactured in a sterile vessel containing an antifungal agent and a filler in the form of a dry or lyophilized powder. Before use add a physiologically acceptable diluent and the solution taken by syringe for administration to the patient. For oral administration antifungal agent make in gelatin capsules or pressed into tablets, such tablets also contain a binder, a dispersant or a suitable filler, suitable for the manufacture of tablets of the desired size. For demetrie and geriatrics antifungal agent can be introduced in the aromatic liquid suspensions, solutions or emulsions. The preferred system oral media contains (by volume): 80% linoleic acid, 5% cremophor PH-60 and 87% of sterile water. The connection is added to the system in the amount of 2.5-40 mg/kg of the Drug N-allequipped for injection contains 50-500 mg per capsule, for oral administration gelatin or acid tablet contains 100-500 mg of the active component.

Preferred preparations contain Akti is soil, in a gelatin capsule or the active ingredient of the formula I, where RIand RIIis methyl, R1is hydrogen and R2-4-4-/2-(4-cyclohexylpiperidine)ethoxy/phenyl benzoyl, or its hydrochloride in a tablet or gelatin capsule.

Also we propose a method for the treatment of patients with Pneumocystis pneumonia. The method can be applied prophylactically to prevent infection caused by Pneumocystis organisms carinis. N-Acylceramide you can enter parenterally, e.g. intramuscularly, intravenously or intraperitoneally, by injection, orally or by inhalation directly into the respiratory tract and lungs. Preferred cyclic peptides is administered by inhalation using aerosol products connections.

An effective amount of a cyclic peptide is 3 to 100 mg/kg weight of the patient. Medicine you can enter in a single daily dose or in several doses, for example 2 to 4 during the day. The number of individual doses, the flow path, the frequency of dosing and duration of therapy will vary according to factors such as the intensity and degree of infection, the age and General health of the patient, the response of the patient to therapy and resistance of the patient to the medication. It is known that Pneumocystis pneumonia (N is participating infections of the surface of the airway tube bodies clogged infectious substance, because the parasite is actively developing in the lung tissue. A patient with progressive infection, respectively, require high doses of medication for a long time. On the contrary, immunodeficient patients, which netzero infected and susceptible to PCP, can be treated with lower and less frequent doses.

Activity cyclopeptides formula I shown in immunomodulary rats. The texts were performed as follows.

A week after the beginning of immunomodulary rats were infected with the parasite nutritarian and maintained in mode immunomodulary over the next testing time. Prophylactic treatment was started one day after infection, therapeutic treatment started 3-4 weeks after development of moderate PCP. 8 or 120 animals were identified in the following groups: animals receiving the test compound, positive control animals not subjected to treatment, animals were treated with trimethoprim-sulfamethoxazole, and uninfected control animals not subjected to treatment. The effectiveness of the different treatments was assessed by monitoring the weight of animals and for the duration of their existence within the research who painted brushstrokes-prints light and painted the homogenates of the lungs.

Immunodeficient rats used in the experiments was prepared as follows.

Female Lewis rats, weighing 120-140 g each, were subjected to immune suppression acetate methylprednisolone 4 mg/100 g in the second week and 2 mg/100 g in the following weeks. All rats, except uninfected control rats were infected nutritarian 0.1-0.2 ml of the modified environment Dulbecco containing 105- 106P. Carinii (trophozoites, Prezista and cysts), collected from the lungs severely infected donor animals (incidence 6) stored in the cold (liquid nitrogen). Rats maintained in mode immunomodulary for the development of PCP within 3-4 weeks before starting therapy test compounds. Body weight was recorded daily and the rats were assigned to treatment groups such that each group had a homogeneous distribution of the percentage loss of weight among animals.

Rats were treated with test compounds for 2-3 weeks, then made the autopsy. Prophylactic studies the introduction of the test compounds was started one day after infection and continued until mortem. Following the evaluation period of the test compounds in rats after opening the using homogenates of the lungs, painted cerebrotendinous (S. below). An autopsy was performed as follows. The experimental rats were narcoticyou with a mixture of ketamine hydrochloride and xylazine and were bled via the right atrium. The internal organs of the abdominal and thoracic cavities were examined to detect violations. A small part of the lung tissue from the left lobe of each rat was used for the preparation of smears, fingerprints, described below.

To determine the total number of parasites (trophozoites, predict and cysts) was applied brushstrokes-prints, colored Giemsa. Brushstrokes-prints of the rats in groups, the treatment of which showed any antipneumococcal activity (judging by the rate of infection obtained in preparations stained with Giemsa), and from rats in the control group were also stained metamin-cerbère - specific colour for the walls of cysts organisms. Used as pokazateli infection:

Indicator - Based

0 - p parasites not found

1 - 1-5 parasites/10 oil sites

2 about 1 parasite/site

3 - 2-10 parasites/site

4 - 10-100 parasites/site

5 - 100-1000 parasites/site

Figure 6 left for infections, strokes/prints which contain > what roscope with a final magnification of H, and drugs, okrashivanie methenamine-silver - with a final magnification of 400X.

Quantification of cysts in the lung tissue of rats was carried out as follows.

A small part of the lung tissue from the left lobe of each rat was used for the preparation of smears, fingerprints. The remainder of each lung was weighed, placed in a tube containing balanced salt solution Hank (SRH), taken in a 40-fold amount relative to the weight of the lung, and homogenized in a tissue homogenizer of Brinkmann. 2 μl of the homogenized sample, diluted SRCH 1:4, was placed in a cell covered with a Teflon fixture with 12 cells were stained with methenamine-silver and counted the number of cysts are as described above for smears, fingerprints.

Below is the activity and efficiency of the two preferred N-arylcyclohexylamines for experimental animals.

The compound of formula I, in which RIand RIIis methyl, R4is hydrogen, R2- 4-/4-(phenylethynyl)phenyl/benzoyl, with the introduction in the form of an aerosol solution with a concentration of 5 mg/ml for 1 hour, twice a week for 6 weeks leads to a 90% reduction of cysts of P. Carinii in the lungs. When administered orally in the amount and by the media.

Preferred N-acylceramide oral or injected intraperitoneally effectively remove cysts of the lung severely infected rats. For example, with the introduction of compounds in quantities of 10 or 40 mg/kg for 4,8 or 12 days, the number of cysts in the lungs severely infected rats is reduced by 99%, the same effectiveness is observed with intraperitoneal injection (1 mg/kg

The oral study on preventive activity preferred connection shows a reduction of 99% of cysts in one of two trials with the introduction in the amount of 1 mg/kg and higher doses of 5 or 4 mg/kg

Another preferred compound of the invention represented by formula I, in which RIand RIIis methyl, R1is hydrogen, R2- 4-[4-(2-cyclohexylpiperidine)ethoxy] phenyl-benzoyl, in the form of the hydrochloride is also effective in the treatment of PCP. Aerosol prevention (2 of treatment for 60 min twice a week for 5 weeks) proved to be highly effective for prevention of PCP in HIV-positive immunomodulary rats. Aerosol therapy solution with a concentration of 5, 10, 25 or 50 mg/ml reduces the number of cysts in the lungs 99% compared to the control animals. Podobn the receipt of the following is the description.

N-Alderaani cyclopentapeptide kernel.

To obtain the derivatives of the kernel AA proposed the following General method.

In table 27 are derived.

Example.

The core AA and 2,4,5-trichlorophenol ester is dissolved in dimethylformamide (25-50 ml) and stirred at room temperature 17-65 hours. The solvent is removed in vacuo and the residue suspended in ether and separated by filtration. The solid product is washed with metilenhloride and dissolve in methanol or in a mixture of acetonitrile/water (1,1 by volume). The solution is injected in prepreparation chromatographic system Waters 600E with column reversed-phase Rainin Dynamax-60A C18. Column elute first 20-40% aqueous acetonitrile and 0.5% monobasic ammonium phosphate (mass-volume concentration) (see by UV at 230 nm and at a flow rate of 20 ml/min) before elution of unreacted core AA, remove the buffer and elute the product water acetonitrile. The fraction containing the product, evaporated in vacuum or lyophilizer to obtain pure compounds. The product can be analyzed by the same HPLC using column Waters C18Micro Bondpak and elution of 40% aqueous acetonitrile containing 0.5% uniaxial can be analyzed by a mass spectroscopy with fast atom bombardment (FABS). (Used in compounds RI- RIIIis methyl, R and RVthe hydroxy - group, R1is hydrogen, R7the hydroxy - group and R2defined above).

Compounds such as are shown in table 27 can be further modified by the phenolic hydroxy-group to form compounds with R7group OPO3NHa, are shown in table 28.

Method modification.

Lipopeptide (1 equivalent) and tetraethylpyrophosphate (2 equivalent) is dissolved in dimethylformamide, dried molecular sieves H. Add the monohydrate of lithium hydroxide (5 equivalents) and stir the solution observed by HPLC. Between 0.5 and 1 hour and add lithium hydroxide (5 equivalents). Between 1 and 2 h and the reaction stopped by the addition of glacial acetic acid, the solvent is removed under vacuum, the residue is purified prepreparation chromatography using columns with reversed phase and aqueous acetonitrile as eluent. The purified product was dissolved in a mixture of acetic acid/water (1:1) containing sodium acetate (1 equivalent) and 10% palladium catalyst on coal. The solution is placed in an atmosphere of hydrogen and stirred for 1 h After removal of the catalyst by filtration the solution lyophilizers-spectroscopy with fast atom bombardment (FABMS).

Getting dideoxynucleotide.

To obtain dideoxycytidine proposed the following method. The compounds obtained are shown in table 29.

To a suspension of medicationcanine formula I, in which R is a hydroxy-group, and R2is hydrogen or acyl, in dichloromethane add the restorer of triethylsilane in dichloromethane. The solution is stirred and volatile components removed under reduced pressure. The residue is triturated with diethyl ether. Connection cleanse HPLC and the product lyophilizer.

Example.

Dimethoxyfuran K suspension cilofungin (10,00 g, 9,71 mmol) in dichlormethane (100 ml) add a solution of triethylsilane (96 ml, 602 mmole) in dichloromethane (50 ml). After 15 minutes add triperoxonane acid (46.4 ml, 602 mmole) in solution in dichloromethane (50 ml). The solution is stirred at room temperature for 2 h the Volatile components of the reaction are removed under reduced pressure and the residue triturated with diethyl ether. Connection cleanse HPLC with reversed-phase instrument Prep LC/System 500 (waters, Associates Inc. Milford, mA) using column Prep Pak 500/ (Walters Associates Inc.) as the stationary phase. Column elute with a gradient mobile phase, espoli reduced pressure and lyophilizers of p-dioxane to obtain dideoxyinosine (6.66 g, 68.7 per cent). Data mass spectroscopy with fast atom bombardment: m/z Rasch. for C49H72N7O15998,5086 found 998.512, UV(EtOH) nm(); 202.60 (61012,), 256.20 (18569).

Table 29 shows R2the number of cyclic Hexapeptide and reagents and the output of dideoxycytidine RI-RIIIis methyl, R1is hydrogen, R, RVand R7the hydroxy - group, TES - triethylsilane, TFA - triperoxonane acid, the weight in grams.

1. Derivatives of cyclic peptides of the formula I

< / BR>
or their pharmaceutically acceptable salt,

where RIis methyl;

RIIand RIIIindependently, methyl or hydrogen;

R and RVindependently a hydroxy-group or hydrogen;

R1is hydrogen;

R7is hydroxy or phosphonooxy;

I) R2- substituted benzoyl formula

< / BR>
in which

A) R3- polyoxyethyl formula

-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12)-alkyl,

where m and n=2-4, p = 0-1,

or

B) R3unsaturated hydrocarbon group of the formula:

-Y-(C1-C12)-alkyl,

where Y - group or-CH=CH-,

or

C) R3group of the formula

-O-(CH2)m-G

where m is defined above, G = (C>/BR>< / BR>
in which Z is a group-O-, -CH=CH-, -CH2-CH2-, -CH2- or carbon-carbon bond;

A) R4is hydrogen, (C2-C12)-quinil, substituted (C1-C12)-quinil, (C1-C12)-alkoxy or (C3-C12-cycloalkanes, phenyl or

B) R4is phenyl, substituted amino group, (C1-C12)alkylthiol, halogen, (C1-C12)alkyl, (C2-C12)alkenyl, (C2-C12)quinil, (C1-C12)substituted alkyl, (C2-C12)replaced by alkenyl, (C2-C12)replaced by quinil, (C1-C12)alkoxygroup, trifluoromethyl, phenyl, substituted phenyl, or polyoxyalkylene formula

-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12)-alkyl,

where m, n and p are defined above;

or

C) R4is phenyl, substituted (C1-C6-alkoxygroup, the latter may be replaced by fluorine, bromine, chlorine or iodine, or

D) R4- (C1-C12-alkoxygroup, substituted (C3-C12-cycloalkyl, (C2-C12)-alkyl or by phenyl which, in turn, replaced by polyoxyalkylene defined above,

or

E) R4group of the formula
)-alkyl, (C3-C12-cycloalkyl, benzyl or (C3-C12-cyclooctylmethyl,

or

F) R4group of the formula

-Y-R6,

where Y is defined above, and R6= (C1-C12)-alkyl, substituted (C1-C12)-alkyl, (C7-C10-bicycloalkyl; (C7-C14-tricyclohexyl; phenyl, unsubstituted or substituted amino group, a group: (C1-C12)alkoxy, trifloromethyl; or the group-O-(CH2)p'-W-R5and p' = 2-4, W - pyrrolidino, piperidino; R5is hydrogen, (C1-C12)-alkyl, (C3-C12-cycloalkyl, benzyl or (C3-C12-cycloalkenyl, or (C1-C6-alkoxygroup substituted by bromine, fluorine, iodine or chlorine; or R6is phenyl, substituted by polyoxyalkylene defined above;

III) R2group of the formula

< / BR>
or

< / BR>
or

IV) R2- naphtol substituted by a group R4where R4is hydrogen, phenyl or (C1-C12-alkoxygroup, or their pharmaceutically acceptable salts, provided that when RIis methyl; RIIand RIIIis methyl; RYand R is the hydroxy-group, and R1is hydrogen, R7- hydroxy - or phosphonooxy, R2neither group
l;

where p = 0;

neither group

< / BR>
where Z is a bond or-O-;

R4- (C1-C12-alkoxygroup;

neither naftilan substituted by a group R4where R4is hydrogen, phenyl or (C1-C12-alkoxygroup.

2. Derivatives of cyclic peptides of the formula I under item 1

< / BR>
where R1is methyl;

RIIand RIII- independently methyl or hydrogen;

R and RVis independently a hydroxy-group or hydrogen;

R1is hydrogen, R7the hydroxy - group;

R2- matter referred to in subparagraphs A, B, C, D and E of paragraph 1

or their pharmaceutically acceptable salts.

3. Derivatives of cyclic peptides of General formula I under item 1 or 2, where the group RI- RIIIis methyl; R1is hydrogen, R7and Rvthe hydroxy - group.

4. Derivatives of cyclic peptides of General formula I under item 1 or 2, where R2group of the formula

< / BR>
where Z is a carbon-carbon bond,

R4- (C1-C12)-alkoxy or (C3-C7-cycloalkanes, or (C1-C6-alkoxygroup, substituted (C3-C7-cycloalkyl; or R4is phenyl, substituted (C1-C12-alkoxygroup or polyoxyalkylene formula

-O-(CH2a group of the formula

-Y-R6,

where Y - acetylene communication;

R6- (C1-C6)-alkyl, phenyl or phenyl substituted by polyoxyalkylene defined above.

5. Derivatives of cyclic peptides of General formula I on p. 1, where R2group

< / BR>
where Z is the group ;

R4is phenyl, substituted (C1-C12-alkoxygroup or polyoxyalkylene listed above.

6. Derivatives of cyclic peptides of General formula I under item 1 or 2, where R2group

< / BR>
with Z - link

R4group-O-(CH2)p-W-R5;

W - piperidinium;

the values of p and R5above.

7. Derivatives of cyclic peptides of General formula I under item 1 or 2, where R1- hydrogen.

8. Derivatives of cyclic peptides of General formula I under item 1 or 2, where R2group selected from

4-(4-H-hexyloxy-phenyl)benzoyl,

4-(4-H-heptyloxybiphenyl)benzoyl,

4-(4-H-octyloxyphenyl)benzoyl,

4-[4-(3,3-Dimethylbutane)phenyl]benzoyl;

4-[4-(2-cyclopentyloxy)phenyl]benzoyl;

4-[4-(2-cyclohexylmethoxy)phenyl]benzoyl;

4-[4-(phenylethyl)phenyl]benzoyl;

4-[4-(H-butylamine)phenyl]benzoyl;

4-[4-(2-(4-cyclohexylpiperidine)ethoxy)phenyl]benzoyl.

9. hydrogen or methyl; R and RVis independently hydrogen or a hydroxy-group, R1is hydrogen, R7is hydroxy or phosphoroscope, R2group of the formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
RI- RIIIis methyl, R1is hydrogen, R7and RVthe hydroxy - group

or their pharmaceutically acceptable salts.

10. Derivatives of cyclic peptides of General formula I on p. 1, where RIis methyl; RIIis methyl or hydrogen; R1is hydrogen; R7- hydroxy - or phosphonooxy; R2- substituted benzoyl formula

< / BR>
in which R3- polyoxyethyl formula

-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12)-alkyl,

m and n = 2-4 and p = 0 to 1, or R3unsaturated hydrocarbon group of the formula-Y-(C1-C12)-alkyl, where the Y - group or-CH=CH-, or R3group of the formula-O-(CH2)m-G, where m is definitely above and G = (C7-C10-bicycloalkyl or (C7-C14-tricyclohexyl,

or R2- acyl formula

< / BR>
where Z is the group-O-, -CH=CH-, -CH2-CH2or communication;

R4is hydrogen, (C3-C12-cycloalkyl, (C7-C10-bicycloalkyl, (C7-C14-tricyclohexyl, phenyl, AMINOPHENYL rmeil, phenyl or (C1-C6-alkoxygroup, substituted with halogen; or R4- (C3-C12)-cycloalkane, (C1-C12)-alkoxy, or (C1-C12-alkoxygroup, substituted (C3-C12-cycloalkyl, (C7-C12)bicycloalkyl, (C7-C14-tricyclohexyl, amino, (C1-C4)-alkylamino, di(C1-C4)-alkylamino, or (C1-C12-alkanolamine or a group of the formula NHC(O)R8where R8- (C1-C6-alkoxygroup, possibly substituted by phenyl; or R4group of the formula-O-(CH)p'-W-R5where p' = 2-4, W - pyrrolidino-, piperidino-or piperazinone and R5is hydrogen, (C1-C12)-alkyl, (C3-C12-cycloalkyl cycloalkenyl or benzyl; or R4group of the formula Y-R6where Y is defined above and R6- (C1-C12)-alkyl, (C1-C12)-alkyl substituted by phenyl; (C3-C12-cycloalkyl, -cycloalkenyl, phenyl, naphthyl; benzothiazol-2-yl or phenyl, substituted by halogen, (C1-C12)-alkyl, (C1-C12-alkenyl, (C1-C12)-alkoxy, (C1-C12)-alkylthio - or amino group, trifluoromethyl, a group of the formula-O-(CH2)p, -W,-R5or (C1-C6>- naphtol substituted by a group R4provided that if RIis methyl, RIIis methyl, R is the hydroxy-group, R1is hydrogen and R7- phosphonooxy, R2is or a group of the formula

< / BR>
in which R3group-O-(CH2)m-[O-(CH2)n]p-O-(C1-C12)-alkyl, where p = 0,

or group

< / BR>
in which Z is a bond or a group-O-;

R4- (C1-C12-alkoxygroup or naphtol, substituted R4where R4is hydrogen, phenyl, or (C1-C12-alkoxygroup.

11. Derivatives of cyclic peptides of General formula I on p. 9, where R1is hydrogen, R7the hydroxy - group.

12. Derivatives of cyclic peptides of General formula I on PP.1 - 10 with the ability to inhibit parasitic activity.

13. Derivatives of cyclic peptides of General formula I on PP.1 - 10 with the ability to inhibit fungal activity.

14. Derivatives of cyclic peptides of General formula I on PP.1 - 10 with the ability to inhibit the growth of organisms responsible for opportunistic infections in individuals with depressed immune systems.

15. Derivatives of cyclic peptides obsevation General formula I under item 1

< / BR>
where R1is methyl;

RIIand RIIIis methyl or hydrogen;

RVis hydrogen or a hydroxy-group;

R7the hydroxy - group;

R is hydrogen;

R1is hydrogen;

R2- acyl,

characterized in that the cyclic peptides of the formula I on p. 1, where R is the hydroxy-group, the values of the other radicals mentioned above, is subjected to the interaction with a strong acid in the presence of a reducing agent in a solvent.

17. Pharmaceutical composition having protivokariosnoe and protivorevmaticski activity, containing the active ingredient and pharmaceutically acceptable carrier, characterized in that the active ingredient it contains the compounds of formula I on PP.1 - 10 effective number.

Priority signs:

19.03.92 - p. 10 formulas;

16.12.92 - PP. 1-9 formula.

 

Same patents:

The invention relates to certain Aza cyclopentapeptide compounds having a nitrogen atom attached to cyclohexadienone ring on the 5th carbon atom of the component 4-hydroxy-ornithine (C-5-orn"), formula I, where R1Is H or OH; R2- H, CH3or OH; R3- H, CH3CH2CN, CH2CH2NH2or CH2CONH2; RI- C9-C21-alkyl, C9-C21alkenyl, C1-C10-alkoxyphenyl or C1-C10alkoxyaryl; RII- H, C1-C4-alkyl, C3-C4alkenyl, (CH2)2-4OH, CO(CH2)1-4NH2, (CH2)2-4NRIVRV; RIIand RIIItaken together, -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -(CH2)2NH(CH2)2-; RIV- H or alkyl; RVIs H or alkyl and salt additive

The invention relates to new polypeptide compound and its pharmaceutical acceptable salts

The invention relates to medicine

The invention relates to new peptides with organizaitnal activity with high biological activity of the same type as the natural compound HRV, but with a shorter amino acid chain

The invention relates to new biologically active compounds, specifically, the peptides of General formula: Trp-X-Gly-Gly-Asp-R, where X is the residue of the hydroxyl - containing amino acids L-or D-configuration, R-Ala-Ser-Gly-Glu or Ala-Ser-Gly or Ala-Ser, or Ala; and their pharmaceutically acceptable salts having anti-stress, anticonvulsant and neuroprotective action

The invention relates to peptides of formula (I): X - A1- A2- Thr - Ala - Val - Gly - His - Leu - psi - A9- Q, where X represents a hydrogen, a simple relationship linking the alpha-amino group of A1with gamma-carboxyl part 3-propionyloxy part of A2if A2is Glu[-], or a group of the formula R1CO-, where R1selected from the group comprising: hydrogen, C1- C10- alkyl, or phenyl C1- C10- alkyl, A1is a D - or L-amino acid residue selected from the group consisting of: Phe, p - Hl - Phe, pGlu, Nal, Pal, Tpi, unsubstituted Trp or Trp substituted in the benzene ring by one or more substituents from the group comprising C1- C3- alkyl, or A1represents a peptide bond linking the acyl part of R1CO with alpha aminocyclo A2if A2represents Gln, Glu/-/ Glu (Y) or His, where /-/ is a simple relationship linking the gamma-carboxyl group of A2with the alpha-amino group of A1if A2is Glu, where X represents a simple bond, Y represents - or SIG5where R5is hydrogen, C1- C3- alkyl or phenyl; Leu - psi - is a reduced form Lой adjacent A9- balance is pseudopeptides communication; A9is a TAS, Ista, or DМТас; and Q represents NH2or CQ1where Q1is hydrogen, and pharmaceutically acceptable acids or salts, and pharmaceutical compositions, which has antagonistic activity against bombezin and to a method of treating cancer in mammals on the basis of the peptides of formula (I)

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The invention relates to the field of natural physiologically active peptides, specifically to an improved method for producing a peptide-sleep formula I:

TrpAlaGlyGlyAspAlaSerGlyGlu

Peptide-sleep has anti-stress [1], protivoallergennoy [2], antimetastatic [3] and other types of biological activity

The invention relates to certain Aza cyclopentapeptide compounds having a nitrogen atom attached to cyclohexadienone ring on the 5th carbon atom of the component 4-hydroxy-ornithine (C-5-orn"), formula I, where R1Is H or OH; R2- H, CH3or OH; R3- H, CH3CH2CN, CH2CH2NH2or CH2CONH2; RI- C9-C21-alkyl, C9-C21alkenyl, C1-C10-alkoxyphenyl or C1-C10alkoxyaryl; RII- H, C1-C4-alkyl, C3-C4alkenyl, (CH2)2-4OH, CO(CH2)1-4NH2, (CH2)2-4NRIVRV; RIIand RIIItaken together, -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -(CH2)2NH(CH2)2-; RIV- H or alkyl; RVIs H or alkyl and salt additive

The invention relates to the field of medicine

The invention relates to new peptides with high biological activity of the same type, which is inherent in the known natural compound BPC, but with a shorter amino acid chain

The invention relates to new polypeptide compound and its pharmaceutical acceptable salts

The invention relates to polypeptides or their salts, with a strong tool to lipopolysaccharides, particularly endotoxins
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