Peptide ketones, pharmaceutical composition and method of inhibiting interleukin-1protease

 

(57) Abstract:

Peptide ketones of the formula I or their pharmaceutically acceptable salts, where R2- H, halogen, phenyl or benzyl; R3and R4- H or lower alkyl; A - D or L-isomer amino acids (valine or alanine); Z is CH2or O; n = 0-2, and Farmaceutici based on them detect selective inhibition of the enzyme that converts the enzyme interleukin-1, and can be useful in the treatment of inflammatory, immune disease and cancer. 3 S. and 12 C.p. f-crystals.

The invention relates to a series of new analogues of amino acids which exhibit selective inhibition of the enzyme that converts the enzyme interleukin-1, to compositions containing the new analogues of amino acids, and to methods of using them for medicinal purposes. Specifically, inhibitors of the enzyme that converts interleukin-1 described in the present invention include new amino acid methylketone, which is particularly useful in the treatment of inflammatory, immune diseases and cancer.

Interleukin-1-protease (also known as an enzyme that converts interleukin-1, or ICE) is the enzyme responsible for processing biologically inactive 31 to D-predecessor 1989, 86, 5227-5231 and Black R. A.; Kronheim. S. R.; Sleath, P. R., FEBS Let 1989, 247, 386-391). In addition to the action as one of the earliest responses of the body to injury and infection, it is assumed that 1L-1 also acts as an intermediary in many diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel, sepsis, and acute and chronic myeloid leukemia (Dinarello, C. A.; Wolff. S. M.; New Engl. J. Med., 1993, 328, 106). To demonstrate mediation 1L-1 for some human diseases, and some types of animals, use of naturally occurring antagonist 1L-1 receptor (Hannum. C. H.; Wilcox. C. J.; Arend. W. P.; Joslin G. G.; Dripps. D. J.; Heimdal. P. L.; Armes. L. G.; Sommer. A.; Eisenberg. S. P.; Thompson. R. G, Nature, 1990, 343, 336-340; Eisenberg. S. P., Evans. R. J. ; Arend. W. P.; Verderber. E.; Brewer. M. T.; Hannum. C. H.; Thompson. R. G., Nature 1990, 343, 341-346; Ohlsson. K.; Bjork. P.; Bergenfeldt, M.; Hageman. R. ; Thompson. R. C., Nature 1990, 348, 550-552; and Wakabayashi. G., GASEB, 1991, 338-343). The specific role of 1L-1 in inflammation and immunomodulation supported by the recent observations that the vaccinia virus uses the ICE inhibitor to suppress the inflammatory response of the host (Ray, C. A., and others, Cell, 1992, 69, 597-604).

The present invention also relates to modulation processing 1L-1 for the treatment of rheumatoid arthritis. It is known that in this disease the contents 1L-1 in synovial fluid pacientovi, such as collagenase and PLA2and produces the destruction of the joint, which is very similar to rheumatoid arthritis, following intraarticular injection in animals.

A limited number of analogues of peptidylglycine is a well-known class of compounds having inhibitory activity against cysteinate (papain, cathepsin B). These analogues peptidylglycine discussed in D. Rich, in Chapter 4, "Proteinase Inhibitors", Barrett, A. J.; and Salvensen, G. , eds., Elsevier 1986. Later as inhibitors cysteinate also described aryloxy - and-relationshipmarketing (A. Krantz and others, Biochemistry, 30, p. 4678-4687, 1991).

However, these peptide analogs essentially do not have the efficiency and selectivity in the inhibition of ICE.

Effective techniques for the treatment of inflammatory diseases, mediator, which is 1L-1, yet to be developed. Therefore, there is a need for remedies that are effective for the treatment and prevention of these diseases.

In accordance with the present invention offers a new peptide ketones having the formula (I) and their pharmaceutically acceptable salts

< / BR>
where R1represents (CR5R6)n5R6)-aryl or X-(CR5R6)n-heteroaryl, in which the aryl or heteroaryl may be optionally substituted;

X represents O or R5;

R5and R6independently represent H or lower alkyl;

R2represents H, lower alkyl or (CR5R6)-aryl;

R3and R4independently represent H or alkyl;

A represents a D - or L-isomer amino acids selected from the group consisting of alanine, valine, leucine, isoleucine, Proline, phenylalanine, glycine, tyrosine, methionine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine and - tierralinda;

Z represents a CH2or O;

n is 0 to 4.

Used here, the term "amino acid" includes both D-and L - their isomers, and the term "pharmaceutically acceptable salts" means salts of the accession of acids and bases.

The term "salt accession acid" or "acid additive salts" refers to salts that retain the biological effectiveness and properties of the free bases and which are not biologically or inappropriate for other reasons, and obrazovanja acid, phosphoric acid, etc. and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, p-toluensulfonate acid, salicylic acid, etc.

The term "salt accession grounds" includes salts formed with inorganic bases, such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., Particularly preferred are the salts of ammonium, potassium, sodium, calcium and magnesium salts formed pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines, including substituted amines, found in nature, cyclic amines and cation exchange resins, i.e., salts of such bases as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-Diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucono preferred organic non-toxic bases are Isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

"Alkyl" means a radical as saturated and unsaturated aliphatic hydrocarbon which may be either linear or branched chain. Preferred groups contain not more than 12 carbon atoms and may be methyl, ethyl, and structural isomers of propyl, butyl, penttila, hexyl, heptyl, Attila, Manila, decyl, undecyl and dodecyl.

"Lower alkyl" means alkyl group of the above-mentioned alkyl groups containing from 1 to 7 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, n-propyl, butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and n-heptyl.

"Aryl" means phenyl, naphthyl and substituted phenyl.

"Substituted phenyl" means a phenyl group in which one or more hydrogen atoms replaced by identical or different substituents including halogen, lower alkyl, nitro-group, amino group, allmenalp, hydroxyl, lower alkoxygroup, aryl, heteroaryl, lower alkoxygroup, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholinoethyl and carbaminohemoglobin.

"Halogen" oznake is alil, triazinyl, chinosol and ethanolic.

"Substituted heteroaryl" means a heteroaryl group in which one or more hydrogen atoms substituted by identical or different substituents including halogen, lower alkyl, nitro-group, amino group, allmenalp, hydroxyl, lower alkoxygroup, aryl, heteroaryl, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholinoethyl and carbaminohemoglobin.

The present invention relates to a method of inhibiting ICE in a mammal in need of such treatment, which consists in the introduction referred to the mammal an effective inhibiting amount of the compounds of formula (I) or pharmaceutical compositions containing a compound of the formula (I) in a pharmaceutically acceptable carrier. The method of inhibition is directed to the treatment of painful conditions and disorders, mediator, which is 1L-1, and which include infectious diseases such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions such as arthritis, cholangitis, colitis, encephalitis, Indianola (endocerolitis), hepatitis, pancreatitis and reperfusion injury, immune diseases, such as increased Cusi.

The pharmaceutical composition of the present invention includes an active ingredient a compound of the formula (I) in a mixture with pharmaceutically acceptable non-toxic carrier. Such compositions can be prepared for use by parenteral (subcutaneous, intra-articular, intramuscular or intravenous) administration, in particular in the form of liquid solutions or suspensions; by oral or transbukkalno introduction, in particular in the form of tablets or capsules; by transdermal injection or intranasally, particularly in the form of powders, nasal drops or aerosols.

For oral (or rectal) administration of the compounds will typically be formulated in the form of a unit dose, such as a tablet, capsule gelatin or starch or suppository. Such preparative form (finished products), typically include solid, semi-solid or liquid carrier or diluent. Examples of carriers and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, Arabic gum, calcium phosphate, mineral oil, cocoa butter, alginate, tragakant, gelatin, syrup, methyl cellulose, monolaurate polyoxyethylenesorbitan, metalhead any means, well known in pharmaceutical technology, for example as described in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985. Ready-made forms for parenteral administration may contain as common excipients sterile water or saline solution, alkalophile, such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, etc., Examples of carriers for parenteral administration include water, aqueous media, such as saline, ringer's solution (Ringer), dextrose solution, Hank (Hank), and non-aqueous media, such as non-volatile oils (such as corn oil, cottonseed oil, peanut oil and sesame oil), etiloleat and isopropylmyristate. Sterile saline is the preferred medium, and the compounds are sufficiently soluble in water to form solutions for all measurable foresight needs. The media may contain small amounts of additives such as substances that enhance solubility, isotonicity and chemical resistance, for example, antioxidants, buffering agents and conservative. Ready-made forms for oral administration can the CSO introduction can be solid and contain as fillers, for example, lactose or dextran, or may be aqueous or oily solutions for administration in the nose drops or spray metered. Typical fillers for transbukkalno introduction include sugar, calcium stearate, magnesium stearate, previously gelatinising starch, etc.

When making ready-made forms for nasal injection to enhance absorption through the mucosa add surface-active acid, such as, for example, glikoholeva acid, cholic acid, human beings need it to acid, Athalia acid, desoxycholic acid, chenodesoxycholic acid, dehydrocholic acid, glikogenofiksiruta acid, etc., (see B. H. Vickery "LHPH and its Analogs-Contraception and Therapeutic Applications" Pt. 2. B. H. Vickery and J. S. Nester, Eds., MTP Press, Lancaster, UK 1987).

In General for this application, as described in the present invention, suitable is the introduction of the active ingredient in an amount of from 0.1 to 30 mg per kg of body weight (mg/kg) in the treatment of human, most preferably from 0.1 to 30 mg/kg, and preferably the active ingredient in an amount of from 0.1 to 20-50 mg/kg/day. Such introduction can be carried out only once, spread over several times or implemented by the introduction in the form of single dose, most preferably from 0.1 to 10 mg/kg

The exact dose and mode of administration of these compounds and compositions will depend on the needs of the individual patient being treated, type of treatment and extent of disease development or need. In General, parenteral administration requires lower doses than other routes of administration that are more dependent on absorption.

Compounds of the present invention receive in accordance with schemes I and II (see below).

These schemes R2, R3, R4and Z have the values stated above for formula (I), R represents R1CO(A)nwhere R1, A and n have the meanings specified above for formula (I).

The first stage of this procedure lies in the synthesis of promotility N-protected amino acid (formula 2). Methods of obtaining various amino acids and peptides (formula 1) is well developed in the art. N-protected amino acids, dipeptides and polypeptides, which in some cases are commercially available or they are obtained by standard techniques as described in The Practice of Peptide Synthesis, M. Bodansky, Springer-Verlag, NU 1984, then turn in bromeilles aspartic acid (formula 2) by acid catalyzed decomposition of the intermediate diazomethylene (Krantz, A. atronomy acids or cyclopentadiene. This reaction is carried out, affecting bromeilles excess of tetronic acid or cyclopentadiene in DMF containing sodium hydride or potassium or potassium fluoride. The reaction is conveniently monitored by thin-layer chromatography (TLC) and as soon as TLC will show that the substitution of the bromide of tetronic acid or cyclopentadiene completed, the product distinguish using standard techniques. The desired mono-tert-butyl ester of aspartic acid tetramolecular or cyclopentadienylzirconium (formula 3) can be cleaned in the usual ways, including recrystallization and column chromatography on silica gel.

Teranova acid and cyclopentadiene used in the reaction with bromoethylene can be either purchased or synthesized using known procedures (Haynes, L. J., J. Chem. Soc., Part 1, 1956, 4103-4106; White, J. D., and others, J. Amer. Chem. Soc. 1982, 104, 3923; Ramage. R. and others, J. Chem. Soc. Perkin Trans. 1, 1984, 1539-1545; Martinez. R. A., and others, Syn. Commun., 1989, 19, 373-377; B. Pandey and others, Syn. Commun, 1989, 19, 2741-2747). These syntheses can be easily developed by experts in the field of organic synthesis. As an example, in scheme II presents obtain 3-benzyl-5,5-dimethylethanol acid (formula 8).

The following examples illustrate the P CLASS="ptx2">

Example 1

2-Fenstermanagementliste N-benzyloxycarbonyl-L-aspartic acid (formula 1)

Prepare the reaction mixture containing bromeilles-butyl ether N-benzyloxycarbonyl-L-aspartic acid (formula 2) (0,63 mmol, 0.25 g), 1,2 EQ. phenyltetrazole acid (0.75 mmol, of 0.13 g) and 2.5 EQ. KF (1.57 mmol, 0.09 g) in a solution of anhydrous DMF (7 ml). The reaction mixture was stirred overnight at 25oC. the Reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous NaHCO3, with brine and dried over Na2SO4. The extract is filtered and solvent is removed under reduced pressure to obtain the crude product as oil. The oil is dissolved in 2 ml of ethyl acetate and adding hexane until then, until you get a slightly cloudy solution, which was then cooled at 4oC for 12 hours. Get pure for analysis tert - butyl ester 2-phenyltetrahydropyridine N-benzyloxycarbonyl-L-aspartic acid (formula 3) in the form of a white solid (0.2 g, 69%).

So pl. 85-87oC.

1H-NMR (300 MHz, CDCl3) : 7,82 (D., J = EUR 7.57 Hz, 2H), 7,41 and 7.36 (m, 8H), 7,60 (D. , J = 8.0 Hz, 2H), 5,12-5,08 (m, 4H), 4,71-of 4.66 (m, 2H), 4,48-4,37 (D. D. D., J = 8.0 a, 5,1, 4,4 Hz, 1H), is 3.08 3.00 for (D. D., J = 17.7 and, of 4.4 Hz, 1H), who oruktusai acid in methylene chloride (volume. 15 ml) and toluene (2 ml). The reaction mixture was stirred at 25oC and assess the completeness of the reaction (TLC) within 1 hour. The solvents are removed under reduced pressure and the remains of the distilled azeotrope with methylene chloride several times. The desired end product is obtained in the form of a pure white solid (0,123 g, 82%).

So pl. 64-67oC.

1H-NMR (300 MHz, DMSO) : 7,98 (D., J = 7,6 Hz, 2H), 7,87 (D., J = 7,15 Hz, 2H), 7,43-7,27 (m, 8H), 5,34 (S., 2H), 5,11 (S., 2H), 4,90 (m, 2H), 5,58-4,87 (D. D. D., J = 7,6, 7,1, 5.8 Hz, 1H), 2,84-2,77 (D. D., J = 16,9, 5.8 Hz, 1H), 2,67-2,58 (D. D., J = 17,0, and 7.1 Hz, 1H).

Calculated for C23H21NO80,25 H2O:

Calculated, %: C 62,23; H 4,88; N 3,16.

Found, %: C 62,20; H 4,89; N 3,07.

Using appropriate starting materials and reagents and following the methods described in schemes I and II in example 1, to obtain the following compounds of formula 4.

Example 2

2-(3,4-Dichlorophenyl)tetrakaidecahedron N-benzyloxycarbonyl-L-aspartic acid

Calculated for C23H19Cl2NO8:

Calculated, %: 54,35; N. Of 3.77; N Was 2.76.

Found, %: C 54,30; N. Of 3.80; N 2,67.

Example 3

2-Benzyl-5,5-dimethylethanolamine N-benzyloxycarbonyl-L-aspartic acid

Vechicle the 5,70; N 2,88.

Example 4

Tetrakaidecahedron N-benzyloxycarbonyl-L-aspartic acid

Define the content of C, H, N for C17H17NO8< / BR>
Calculated, %: C 56,20; H 4,72; N 3,86.

Found, %: C 55,83; H 4,63; N 3,80.

Example 5

2-(4-Methoxyphenyl)tetrakaidecahedron N-benzyloxycarbonyl-L-aspartic acid

FAB mass spectrum: m/z = 470 [M+H]+.

1H-NMR (300 MHz, DMSO) : 7,82 (D., J = 8,9 Hz, 2H), 7,38-7,34 (m, 5H), 6,97 (D., J = 8,9 Hz, 2H), 5,3 (S., 2H), 5,07 (S., 2H), 4,88-a 4.86 (m, 2H), 4.53-in-4,51 (m , 1H), 3,75 (C., 3H), 2,84-2,77 (D. D., J = 17,0, 5.7 Hz, 1H), 2,66-2,58 (D. D., J = 17,0, 7,0 Hz, 1H).

Example 6

2-Benzylethanolamine N-benzyloxycarbonyl-L-aspartic acid

1H NMR (300 MHz, DMSO) : of 7.96 (D., J = 7,4 Hz, 1H), and 7.4 to 7.1 (m, 10H), 5,2 (S. , 2H), 5,06 (S., 2H), 4,77 (m, 2H), 4,50 (m, 1H), 3,44 (S., 1H), 2,80 (D. D., J = 17,0, 6.0 Hz, 1H), 2,62 (D. D., J = 17,0, 7,0 Hz, 1H).

Example 7

2-Fenstermanagementliste N-benzyloxycarbonyl-L-valine-L - aspartic acid

1H NMR (300 MHz, DMSO) : cent to 8.85 (D., J = 6,5 Hz, 1H), 7,86 (D., J = 7,6 Hz, 2H), 7,53 (D., J = 6,6 Hz, 1H), 7,43-7,33 (m, 8H), 5,24 (S., 2H), 5,02 (S. , 2H), 4,84-4,71 (m , 2H), 4,58-4,51 (m, 1H), 3,85-of 3.80 (m, 1H), 2,88-2,81 (D. D., J = 17,0, and 4.4 Hz, 1H), 2,62-2,54 (D. D., J = 17,3, 8.0 Hz, 1H), 1,97-1,90 (m, 1H), 0,86 (D., J = 6.9 Hz, 6H).

Example 8

2-Phenyl-5,5-S="ptx2">

Example 9

2-Benzylethanolamine N-benzyloxycarbonyl-L-valine-L - aspartic acid

The mass spectrum of the low resolution m/z 553 (M+H), 509, 273.

Example 10

5,5-Dimethylethanolamine N-benzyloxycarbonyl-L-aspartic acid

Define the content of C, H, N for C19H21NO80,8 H2O:

Calculated, %: C 56,23; H 5,61; N 3,45.

Found, %: C 56,22; H Lower Than The 5.37; N 3,42.

Example 11

2-Chlortetracycline N-benzyloxycarbonyl-L-aspartic acid

Define the content of C, H, N for C17H16ClNO8:

Calculated, %:C 51,33; H Of 4.05; N 3,52.

Example 12

2-Benzylethanolamine N-benzyloxycarbonyl-L-valine-L - alanine-L-aspartic acid

1H NMR (300 MHz, DMSO), 0,82 (D., 3H), 90 (D., 3H), 1,20 (D., 3H), 2,55 (D. D. , 1H), 2,80 (D. D., 1H), 3.15 in (D., 1H), 3,30 (D., 1H), 3,80 (m, 1H), 4,15 (m , 1H), and 4.40 (m, 1H), 4,60 (D., 1H), 4,70 (D., 1H), 5,0 (m, 2H), 5,15 (D. D., 1H), 5.25-inch (D. D., 1H), 7,25 (m, 10H), 8,20 (D., 1H), cent to 8.85 (D., 1H).

Example 13

2-Methylcyclopentadienylmanganese N-benzyloxycarbonyl-L-aspartic acid

Define the content of C, H, N for C19H21NO7:

Calculated: %C %H %N

60,79 5,64 of 3.73

Found: %C %H %N

60,59 5,64 3,50

Example 14

2 Fenell.

1H NMR (300 MHz, DMSO) : 7,99 (D., J = 7,6 Hz, 1H), 7,72 (D., J = 7.2 Hz, 2H), 7,37-7,34 (m, 8H), 5,35 (S., 2H), 5,07 (S., 2H), to 4.52-4,50 (m, 1H), 2,83-2,77 (D. D., J = 17,0, 6,1 Hz, 1H), 2,63-of 2.58 (m, 4H), 2.49 USD is 2.43 (m, 2H).

In example 15 presents tetronic acid, which is used in example 3.

Example 15

3-Benzyl-5,5-dimethyltitanocene acid (formula 8, scheme II)

Mix together ethyl-2-hydroxyisobutyrate (3,69 g, 0.30 mol) (formula 5, scheme II) and pyridine (80 ml) and cooled to 0oC. Upon cooling and mechanical stirring is added dropwise hydrocinnamaldehyde (formula 6, scheme II) (67,4 g, 0.40 mol). The resulting heterogeneous mixture is stirred for 5 hours. The mixture was poured into water. Adding 10% H2SO4helps break the resulting emulsion. The aqueous layer was extracted with ether. The organic layer is then washed with 10% H2SO4and feast upon. NaHCO3, dried over Na2SO4and concentrate. Then by distillation get complex fluids (formula 7, scheme II) as a colourless oil (26,8 g, 34%) by distillation (112-115oC, 0.1 mm RT.verse).

To ice the solution ethylacetamide (- 2.0 M solution in TMF, 150 ml, 0.30 mol) add Diisopropylamine (30,3 g, 0.30 mol) in 50 ml of ether. Reaction for 20 minutes, add a solution of complex diapir, obtained above (26,8 g, 0.1 mol). After heating to 40oC, the reaction mixture becomes homogeneous. After stirring for 20 min the reaction mixture was poured into ice and concentrated HCl. The acidic aqueous layer is extracted with ether. The ether phase is then washed with 5% HCl (2x) and extracted with a 5% solution of K2CO3(4). The alkaline aqueous phase is then washed with ether (2x) and acidified by adding diluted HCl. The oil that is separated, dissolved in ether. Evaporation of the ether gives a yellow oil, which after scratching gradually hardens. Get named in the title compound (formula 8, scheme II).

Compounds of the present invention have inhibitory activity against 1L-1-protease in accordance with the following further method.

Partially purified 1L-1-protease stored at -80oC, thawed on ice and pre-incubated for 10 minutes at 37oC with 2.5 mm dithiothreitol in a buffer solution containing 10 mm in core solutions in dimethyl sulfoxide (DMSO). Protease pre-incubated with the inhibitor in a volume of 20 μl in a polypropylene tube for microcentrifuge volume of 1.5 ml for 15 minutes at 37oC. the Amount of connections, ILO <15% (vol.). A sample of the enzyme was then stimulated by the addition of substrate (TRITC-AYVHDAPVRS-NH2to obtain a final concentration of 67 μm in a final volume of 30 µl. The reaction is carried out for 60 minutes at 37oC in the dark and cut them by adding 10 ál of 10% triperoxonane acid (TFA). After adding 115 ál of 0.1% TFA samples analyze liquid chromatography high pressure using a column of reversed phase (C18) and elution with a mixture of acetonitrile, water and TFA with a gradient. The substrate and product track by their absorption at 550 nm and the elution for 4.2 and 5.2 minutes, respectively.

Found that the compound have inhibitory activity against 1L-1 - protease IC50< 10 μm.

1. Peptide ketones of the formula I and their pharmaceutically acceptable salt

< / BR>
in which R2represents H, halogen, lower alkyl, phenyl or benzyl;

R3and R4are independently H or lower alkyl;

And is D or L isomer of an amino acid selected from the group consisting of valine and alanine;

Z is CH2or O;

n = 0-2.

2. Connection on p. 1, in which R2represents phenyl or phenyl substituted by halogen or lower ecologicaland - L-aspartic acid, 2-(3,4-dichlorophenyl)tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid, 2-benzyl-5,5-dimethylethylenediamine N-benzyloxycarbonyl - L-aspartic acid, tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid and 2-(4-methoxyphenyl)tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid.

4. Connection on p. 1, selected from the group consisting of 2-benzylhydroxylamine N-benzyloxycarbonyl - L-aspartic acid, 2-phenyltetrahydropyridine N-benzyloxycarbonyl - L-valine - L-aspartic acid, 2-phenyl - 5,5-dimethylethylenediamine N-benzyloxycarbonyl - L-aspartic acid, 2-benzylhydroxylamine N-benzyloxycarbonyl - L-valine - L-aspartic acid and 5,5-dimethylethylenediamine N-benzyloxycarbonyl - L-aspartic acid.

5. Connection on p. 1, selected from the group consisting of 2-chlortetracycline N-benzyloxycarbonyl - L-aspartic acid, 2-benzylhydroxylamine N-benzyloxycarbonyl - L-valine - L-alanine - L-aspartic acid, 2-methylcyclopentadienylmanganese N-benzyloxycarbonyl - L-aspartic acid, and 2-phenylcyclopropanecarboxylic what I compound of the formula I or its pharmaceutically acceptable salt

< / BR>
in which R2represents H, halogen, lower alkyl, phenyl or benzyl;

R3and R4is independently H or lower alkyl;

And is D or L isomer of an amino acid selected from the group consisting of valine and alanine,

Z represents CH2or O;

n = 0 - 2,

in a pharmaceutically acceptable carrier.

7. The composition according to p. 6, in which the specified connection selected from the group consisting of 2-phenyltetrahydropyridine N-benzyloxycarbonyl - L-aspartic acid, 2-(3,4-dichlorophenyl)tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid, 2-benzyl-5,5-dimethylethylenediamine N-benzyloxycarbonyl - L-aspartic acid, tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid and 2-(4-methoxyphenyl)tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid.

8. The composition according to p. 6, in which the specified connection selected from the group consisting of 2-benzylhydroxylamine N-benzyloxycarbonyl - L-aspartic acid, 2-phenyltetrahydropyridine N-benzyloxycarbonyl - L-valine - L-aspartic acid, 2-phenyl - 5,5-dimethylethylenediamine N-benzyloxycarbonyl - what you and 5.5-dimethylethylenediamine - N-benzyloxycarbonyl - L-aspartic acid.

9. The composition according to p. 6, in which the specified connection selected from the group consisting of 2-chlortetracycline N-benzyloxycarbonyl - L-aspartic acid, 2-benzylhydroxylamine N-benzyloxycarbonyl - L-valine - L-aspartic acid, 2-methylcyclopentadienylmanganese N-benzyloxycarbonyl - L-aspartic acid and 2-phenylcyclopropanecarboxylic N-benzyloxycarbonyl - L-aspartic acid.

10. A method of inhibiting the activity of interleukin-1 protease in a mammal in need of such treatment, comprising the introduction of a given mammal an effective inhibitory amount of a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt:

< / BR>
in which R2represents H, halogen, lower alkyl, phenyl or benzyl;

R3and R4are independently H or lower alkyl;

And is D or L isomer of an amino acid selected from the group consisting of valine and alanine;

Z is CH2or O;

n = 0 - 2,

in a pharmaceutically acceptable carrier.

11. The method according to p. 10, in which the indicated compound selected from the group consisting of 2-phenyltetrazole jocstarbunny - L-aspartic acid, 2-benzyl-5,5-dimethylethylenediamine N-benzyloxycarbonyl - L-aspartic acid, tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid and 2-(4-methoxyphenyl)tetrakaidecahedron N-benzyloxycarbonyl - L-aspartic acid.

12. The method according to p. 10, in which the indicated compound selected from the group consisting of 2-benzylhydroxylamine N-benzyloxycarbonyl - L-aspartic acid, 2-phenyltetrahydropyridine N-benzyloxycarbonyl - L-valine - L-aspartic acid, 2-phenyl - 5,5-dimethylethylenediamine N-benzyloxycarbonyl - L-aspartic acid, 2-benzylhydroxylamine N-benzyloxycarbonyl - L-valine - L-aspartic acid and 5,5-dimethylethylenediamine - N-benzyloxycarbonyl - L-aspartic acid.

13. The method according to p. 10, in which the indicated compound selected from the group consisting of 2-chlortetracycline N-benzyloxycarbonyl - L-aspartic acid, 2-benzylhydroxylamine N-benzyloxycarbonyl - L-valine - L-alanine - L-aspartic acid, 2-methylcyclopentadienylmanganese N-benzyloxycarbonyl - L-aspartic acid, and 2-phenylcyclopropanecarboxylic - N-benzyloxycarbonyl - L-is of evani, inflammatory conditions, immune diseases, autoimmune diseases, inflammatory bone diseases.

15. The method according to p. 14 for the treatment of meningitis and salpingitis, septic shock, sepsis, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, cholangitis, colitis, encephalitis, hepatitis, pancreatitis, reperfusion injury, hypersensitivity, multiple sclerosis and chronic and acute myelogenous leukemia.

 

Same patents:

The invention relates to a new class of neytralizuya analogues, split by aspartates peptides, namely derivatives of hydrazine and their pharmacologically acceptable salts, having the properties to inhibit the activity of the enzyme HIV-protease and anti-virus activity; pharmaceutical agent based on them, are suitable for combating viral diseases, as well as to new AMINOETHYLPIPERAZINE intermediate product to obtain the derivatives of hydrazine

The invention relates to medicine, namely to methods of producing biologically active substances that have immunoregulatory properties, and may find application in medicine, veterinary medicine and experimental biochemistry
The invention relates to medicine, namely to psychiatry

The invention relates to derived-amino acids, which are isostere dipeptide link Gly - Asp

The invention relates to a therapeutic effect, in particular a drug for the prophylaxis or therapy of metabolic diseases

The invention relates to new peptide compound and its pharmaceutically acceptable salts, namely to a new peptide compound and its pharmaceutically acceptable salts, which have pharmacological activity, for example endothelialisation and so forth, to methods for their preparation, to pharmaceutical compositions containing them and method of using them therapeutically in the treatment and prevention endotheliopathy diseases such as hypertension and so on

The invention relates to medicine and can be used for the prevention and treatment of diseases in which appropriate stimulation of endogenous production of cytokines and hemopoietic factors

FIELD: medicine, immunology, peptides.

SUBSTANCE: invention relates to a new composition of biologically active substances. Invention proposes the composition comprising of peptides of the formula: Arg-Gly-Asp and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys that elicits ability to inhibit the proliferative response for phytohemagglutinin, to induce the suppressive activity of mononuclear cells and ability of peptides to induce secretion of immunosuppressive cytokines of grouth-transforming factor-β1 and interleukin-10 (IL-10). The composition can be prepared by a simple procedure.

EFFECT: valuable biological properties of composition.

3 cl, 16 tbl, 9 ex

FIELD: organic chemistry, medicine.

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

EFFECT: valuable medicinal properties of compounds.

18 cl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: it is suggested to apply Pro-Gly-Pro tripeptide known as anticoagulant to keep stable norglycemia and stable normoinsulinemia in circulation at no side effects because the above-mentioned tripepetide is being natural human and animal metabolite.

EFFECT: higher efficiency of application.

3 cl, 5 ex, 2 tbl

FIELD: pharmaceutics.

SUBSTANCE: the set of components is suggested containing: (a) pharmaceutical preparation including low-molecular thrombin inhibitor or its pharmaceutically acceptable derivative in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier; and (b) pharmaceutical preparation including pre-medicine of low-molecular thrombin inhibitor or pharmaceutically acceptable derivative of this pre-medicine in the mixture with pharmaceutically acceptable adjuvant, solvent or carrier, where components (a) and (b), each of them, should be taken in the form suitable to be introduced together; it is, also, suggested to apply this set of components for treating the state at which it is necessary or preferably to inhibit thrombin. The innovation enables to treat thrombotic states such as thrombosis of deep veins and pulmonary embolism.

EFFECT: higher efficiency of application.

30 cl, 1 tbl

FIELD: medicine, experimental medicine.

SUBSTANCE: one should introduce tripeptide Pro-Gly-Pro for laboratory animals as injections at the quantity of 0.09-1.0 mg/kg body weight, and, also, gelatin as fodder additive. The method suggested enables to suppress appetite, decrease the quantity of fodder intake that leads to decreased body weight as a result.

EFFECT: higher efficiency.

2 cl, 5 dwg, 5 ex

FIELD: medicine, chemistry of peptides, amino acids.

SUBSTANCE: invention relates to novel biologically active substances. Invention proposes the novel composition comprising peptides of the formula: H-Arg-Gly-Asp-OH and H-Tyr-X-Y-Glu-OH wherein X means Gln and/or Glu; Y means Cys(acm) and/or Cys. The composition shows ability to inhibit proliferative activity of mononuclear cells, to induce suppressive activity and their ability for secretion of cytokines TNF-1β (tumor necrosis factor-1β) and IL-10 (interleukin-10 ).

EFFECT: simplified method for preparing composition, valuable medicinal properties of composition.

4 cl, 16 tbl, 9 ex

FIELD: biotechnology.

SUBSTANCE: invention relates to a method for preparing foodstuff containing hypotensive peptides and it using as an anti-hypertensive agent that can be used as a foodstuff. Method involves stages for fermentation of casein-containing fermenting material with lactobacillus microorganism, nanofiltration of the prepared peptide-containing fermentation product and isolation of the product. Prepared product is used as an anti-hypertensive agent and as a foodstuff also. Invention provides preparing a foodstuff with the high content of hypotensive peptides enriched by bivalent ions.

EFFECT: improved preparing method of foodstuff.

22 cl, 1 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agent used for correction of metabolic vascular syndrome and diseases accompanying with vascular wall penetrability disorder and capillaries fragility and can be used as agent enhancing resistance of capillaries. Invention proposes peptide lysyl-glutamyl-aspartic acid of the general formula: H-Lys-Glu-Asp-OH corresponding to the sequence 1 [SEQ ID NO:1] possessing biological activity and eliciting enhancing effect on resistance of capillaries. Also, invention proposes pharmaceutical composition enhancing resistance of capillaries and containing effective amount of peptide lysyl-glutamyl-aspartic acid of the general formula: H-Lys-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] as an active component and a pharmaceutically acceptable carrier. Pharmaceutical composition is prepared in form suitable for parenteral administration. Also, invention proposes a method for prophylaxis and/or treatment of microcirculation disorders in organs and tissues and involves administration in patient pharmaceutical composition containing effective amount of peptide lysyl-glutamyl-aspartic acid of the general formula: H-Lys-Glu-Asp-OH of the sequence 1 [SEQ ID NO:1] as an active component in the dose 0.01-100 mcg/kg of body mass for at least once per a day for period necessary for providing the therapeutic effect. Administration is carried out by parenteral route. Proposed group of inventions provides preparing a novel peptide possessing biological activity eliciting in enhancing resistance of capillaries and using this peptide for preparing pharmaceutical composition enhancing resistance of capillaries.

EFFECT: enhanced and valuable medicinal properties of peptide and pharmaceutical composition.

7 cl, 3 tbl, 2 dwg, 6 ex

FIELD: peptides, medicine, hepatology, pharmacy.

SUBSTANCE: groups of inventions relates to medicinal agents used in treatment of liver diseases. Invention proposes a pharmaceutical composition stimulating regeneration of liver tissue and comprising the effective amount of peptide glutamyl-aspartyl-leucine as an active component of the general formula: H-Glu-Asp-Leu-OH of the sequence 1 [SEQ ID NO:1] and a pharmaceutically acceptable carrier. Invention proposes peptide glutamyl-aspartyl-leucine of the general formula: H-Glu-Asp-Leu-OH of the sequence 1 [SEQ ID NO;1] stimulating regeneration of liver tissue. Also, invention proposes a method for stimulating liver tissue involving administration in a patient a pharmaceutical composition containing peptide glutamyl-aspartyl-leucine of the general formula: H-Glu-Asp-Leu-OH of the sequence 1 [SEQ ID NO:1] as an active component used in the dose 0.01-100 mcg/kg of body mass for at least once per a day for period required for appearance of the therapeutic effect. Invention provides the development of peptide possessing the biological activity eliciting in stimulating regeneration of liver tissue, and pharmaceutical composition containing this peptide as an active component. Using this composition stimulates regeneration of liver tissue based on recovery of synthesis of tissue-specific proteins and normalization of functions of liver cells.

EFFECT: valuable properties of peptide and pharmaceutical composition.

7 cl, 5 tbl, 1 dwg, 6 ex

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