Derivatives of hydroxamic acid, the retrieval method, the drug and its production method

 

(57) Abstract:

Derivatives of hydroxamic acids with three cyclic substituents of formula 1, where R1- cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R2- rich 5-8-membered monocyclic or bridged nitrogen-containing heterocyclic ring which is attached via a nitrogen atom and which, as a monocycle, not necessarily contain as ring NR4, O, S or SO2and/or possibly substituted by one or more carbon atoms by hydroxyl, lower alkyl, lower alkoxy, oxo or detalizirovannoi exography, carbamoyl, monoalkylammonium or dialkylamino; R3- 5 - or 6-membered nitrogen-containing heterocyclic ring which is attached via the nitrogen atom, optionally contain nitrogen or oxygen as an additional member ring, optionally substituted by oxopropoxy one or two carbon atoms, the adjacent connecting them with the nitrogen atom and possibly condensed with a benzene ring; R4- H, alkyl, phenyl, or a protective group; m=1 or 2; n= 1-4, and their pharmaceutically acceptable salts are inhibitors of collagenase and can be used to delay development or profilate to new derivatives of hydroxamic acid, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method of its production.

Derivatives of hydroxamic acids covered by the present invention are compounds of General formula

< / BR>
in which R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R2represents a saturated 5-8-membered monocyclic or bridged nitrogen-containing heterocyclic ring which is attached by a nitrogen atom and, if it is monocyclic, may optionally contain in the ring NR4, O, S or SO2and/or may be optionally substituted on one or more carbon atoms by hydroxyl, lower alkyl, lower alkoxy, oxo or metallizovannoj exography, carbamoyl, mono(lower alkyl)carbamoyl or di(lower alkyl)carbamoyl;

R4represents hydrogen, lower alkyl, phenyl or a protective group;

m is 1 or 2;

n is 1-4,

and their pharmaceutically acceptable salts.

Preferred compounds of formula I, in which

R1is cyclopropyl, cyclobutyl or cyclopentyl;

R2represents a saturated 5-,6 - or 7-membered monocyclic or bridged azotsoderzhashchie heterocyclic ring which is attached via a nitrogen atom and which, if it is monocyclic, optionally additionally contains in the ring NR4, O, S or SO2and/or optionally substituted on one or more carbon atoms by hydroxyl, lower alkyl, lower alkoxy, oxo or metallizovannoj exography, carbamoyl, mono(lower alkyl)carbamoyl or di(lower alkyl)carb) is attached via the nitrogen atom, (b) optionally contains an additional ring N or in any position other than adjacent to the linking nitrogen atom of (in) maybe replaced by oxopropyl two carbon atoms adjacent connecting them with the nitrogen atom, and (g) optionally condensed with a benzene ring or optionally substituted on one or more carbon atoms by lower alkyl or anywhere(s) additional(s) atom(s) of nitrogen is lower alkyl;

R4represents hydrogen, lower alkyl or a protective group.

Of these the most preferred compounds of formula I in which R2represents 1-pyrrolidinyl, piperidino, 4-phenyl-1-piperazinil, morpholinyl, tetrahydro-1,4-thiazin-4-yl, 1,1-dioxide, tetrahydro-1,4-thiazin-4-yl, thiazolidin-3-yl, hexahydroazepin or octahydrate, optionally substituted on one or more carbon atoms, hydroxy, lower alkyl, lower alkoxy, metallizovannoj oxopropoxy or mono(lower alkyl)carbamoyl; or 3-azabicyclo[3.2.2]nonan.

Especially preferred compounds of formula I in which R2is piperidinyl or hydroxypiperidine.

In particular, the compounds of formula I, where hydroxypiperidine is 4-hydroxy is s I, where R3represents a group of the formula

< / BR>
in which R5and R6each represents hydrogen or together represent an additional bond or the residue of a condensed benzene ring;

R7represents hydrogen or lower alkyl;

X represents-CO-, -CH2- , -C(lower alkyl)2-, -N-lower alkyl-; or, if R7represents lower alkyl and X represents-N-lower alkyl-, these lower alkyl groups may together form a 5-, 6 - or 7-membered ring; and

R9and R10each represents hydrogen or lower alkyl.

Especially preferred compounds in which R3represents a group of formula (C), R7represents lower alkyl and X represents-C(lower alkyl)2-.

In particular, compounds in which R3is a 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl.

Usually the above compounds m and n are equal to 1.

Among the preferred compounds should be named 1-[3-cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-piperidine;

1-[3-cyclopropyl-2(R)-[1 shall clopotel-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-piperidine;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4 - piperidinol;

1-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol;

1-[3 - cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] piperidine or compounds selected from

3-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3 - azabicyclo[3.2.2]nonane;

3-[3-cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3 - azabicyclo[3.2.2]nonane and

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo-[3.2.2]nonane;

or compounds selected from

1-[3-cyclohexyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-piperidine;

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine;

S, S-dioxide 4-[3-cyclopentyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl] propio original)ethyl]propionyl]-tetrahydro-1,4-thiazine;

4-[3-cyclohexyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine;

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -5,5-dimethyl-N-propyl-4(R)-thiazolecarboxamide;

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]the research;

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -N,5,5-trimethyl-4(R)-thiazolecarboxamide;

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine;

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]the research;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl]pyrrolidine;

8-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl]-1,4-dioxa-8 azaspiro[4,5] decane;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4 - methoxypiperidine;

1-[3-cicla;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine;

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]- hexahydroazepin;

1-[3-cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxabicyclo[1,2-a] -[1,2,4] triazole-2-yl)-1(R or S)-(hydroxycarbamoyl)ethyl]propionyl]-piperidine and

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2 - phthalimidomethyl] propionyl]piperidine.

The present invention also relates to new intermediate products of General formula

< / BR>
in which R1, R2, R3, m and n have the meanings mentioned above,

or compounds of General formula (IV'):

< / BR>
in which R1, R2, R3, m and n have the meanings specified above.

The object of the present invention is a method of obtaining compounds of General formula I, which is that the acid of General formula (II):

< / BR>
subjected to interaction with the compound of General formula (III):

H2N-OZ,

where Z represents hydrogen, three(lower)alkylsilane, diphenyl(lower)alkylsilane or benzyl, to obtain the compounds of General formula (IV):

< / BR>
where Z denotes a hydrogen atom is relating diphenyl(lower)alkylsilanes or benzyl group and/or converting the obtained compounds of General formula (I) into a pharmaceutically acceptable salt.

The removal of the benzyl group in compound of General formula (IV'), where Z is a benzyl, as a rule, is carried out by catalytic hydrogenation.

The present invention also relates to medicinal drug, possessing inhibiting collagenase activity and intended to deter development or prevention of diseases of degeneration of the joints, or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis, which contains derivatives of hydroxamic acids of General formula I and a therapeutically inert carrier.

Used in this description, the term "lower alkyl" alone or in combination means a straight or branched alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, sec. -butyl, isobutyl, tert.-butyl, n-pentyl, n-hexyl and the like. The term "lower alkoxy" alone or in combination means a straight or branched alkoxygroup containing a maximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert. -butoxy and the like. The term "aryl" denotes phenyl, which is optionally substituted, for example, the lower AP-chlorophenyl or the like. Metalizowana oxoprop can represent, for example, Ethylenedioxy.

Protecting group denoted by R4may be any conventional protective group, for example, known in the chemistry of peptides, such as benzyloxycarbonyl, tert.-butoxycarbonyl, acetyl or the like.

Examples of the monocyclic nitrogen-containing heterocyclic rings in the radical R2are 1-pyrrolidinyl, piperidino, 1-piperazinil, 4-aryl-1-piperazinil, hexahydro-1-pyridazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl, 1-oxide, tetrahydro-1,4-thiazin-4-yl, 1,1-dioxide, tetrahydro-1,4-thiazin-4-yl, thiazolidin-3-yl, hexahydroazepin, octahydrate, which can be substituted as indicated above; for example, 2-(methylcarbamoyl)-1-pyrrolidinyl, 2-(hydroxymethyl)-1 - pyrrolidinyl, 4-hydroxypiperidine, 2-(methylcarbamoyl)-piperidine, 4-hydroxylaminopurine, 4-methoxypiperidine, 4-methyl-1-piperazinil, 4-phenyl-1-piperazinil, 1,4-dioxa-8 azaspiro[4.5]Decan-8-yl, hexahydro-3-(methylcarbamoyl)-2-pyridazinyl, hexahydro-1-(benzyloxycarbonyl)-2-pyridazinyl, 5,5-dimethyl-4-methylcarbamoylmethyl-3-yl, and 5,5-dimethyl-4-propylgallate-illusorily-C-Il.

Examples of bridged N-heterocyclic rings in the radical R

Examples of nitrogen-containing heterocyclic rings in the radical R3are rings formulas

< / BR>
< / BR>
< / BR>
in which R5and R6each represents hydrogen or together represent an additional bond or the residue of a condensed benzene ring;

R7represents hydrogen, lower alkyl or aryl;

X represents-CO-, -CH2-, -CH(lower alkyl)-, -C(lower alkyl)2-, -NH-, -N(lower alkyl)- or-O-; or, if R7represents lower alkyl and X represents-N(lower alkyl)-, lower alkyl group may be connected with the formation of 5-, 6 - or 7-membered ring;

R8represents hydrogen, lower alkyl or aryl;

R9and R10each represents hydrogen or lower alkyl;

Y represents-O-, -NH - or-N(lower alkyl)-;

Z represents S, SO or SO2.

Examples of such rings are 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidino, phthalimido, 1,2-dimethyl-3,5 - dioxo-1,2,4-triazolin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl, 3-methyl-2,4,5-triol, hexahydro-1,3-dioxaspiro[1,2-a] [1,2,4]triazole-2-yl.

One group of preferred compounds of formula I includes those in which R2represents 1-pyrrolidinyl, piperidino, 4-aryl-1-piperazine derivatives, morpholino, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl, 1,1-dioxide, thiazolidin-3-yl, hexahydroazepin or octahydrate, optionally substituted by one or more C atoms, hydroxy, lower alkyl, lower alkoxy, detalizirovannoi oxopropoxy or mono(lower alkyl)carbamoyl primarily piperidino, which is optionally substituted by hydroxy, in particular 4-hydroxypiperidine, or 3-azabicyclo[3.2.2]nonan. Also preferred are the compounds of formula I in which R3represents a group of formula (b), (C), first of all, in which R7represents lower alkyl and X represents-C(lower alkyl)2- in particular 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, or (h).

Preferably m and n are both equal to 1.

The compounds of formula I form pharmaceutically acceptable salts with bases, as the hydroxides of alkali metals (e.g. sodium hydroxide and potassium hydroxide, hydroxides of alkaline earth metals (e.g. calcium hydroxide and magnesium hydroxide), ammonium hydroxide and the like. The connection is such salts are not only salts with inorganic acids, such as halogen acids (e.g. hydrochloric acid and Hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and so on, but also salts with organic acids such as acetic acid, grape acid, succinic acid, fumaric acid, maleic acid, malonic acid, salicylic acid, citric acid, methanesulfonate acid, p-toluensulfonate etc.

Compounds of General formula I contain at least two asymmetric carbon atom and can therefore exist as optically active enantiomers, and in the form of diastereoisomers or in the form of racemates. The present invention includes all these forms.

In accordance with the method covered by this invention, the compounds of formula I and their pharmaceutically acceptable salts get

(a) interaction of the acid of General formula

< / BR>
where R1, R2, R3, m and n have the meanings stated above, with the compound of General formula

H2N-OZ, (III)

where Z represents hydrogen, three(lower alkyl)silyl or diphenyl(lower alkyl)silyl, and, if desirable, with the subsequent withdrawal of any diphenyl(lower alkyl)-silyl groups is their compounds of General formula

< / BR>
where R1, R2, R3, m and n have the meanings mentioned above, and Bz represents a benzyl,

and, if it is desired, transfer the obtained compound of formula I in a pharmaceutically acceptable salt.

The interaction of the acid of formula II with the compound of the formula III in accordance with variant (a) of the method can be carried out by ordinary methods. For example, an acid of formula II can be subjected to interaction with the compound of the formula III in an inert organic solvent, such as dichloromethane, dimethylformamide and the like, using 1-hydroxybenzotriazole, in the presence of a condensing agent such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide at a temperature of from about 0oC to about room temperature. Alternatively, the acid of formula II can be converted into the corresponding acid chloride (for example, using oxalylamino) and the acid chloride of the acid may then be subjected to interaction with the compound of the formula III. Preferred compounds of formula III are those in which Z represents a tert.-butyldimethylsilyl or tert.-butyldiphenylsilyl. When used as a compound of the formula III in which Z represents three (the other side, when used as a compound of the formula III in which Z represents a diphenyl (lower alkyl)silyl, this group remains in the reaction product and must be subsequently removed in a known manner, for example by using a fluoride ion.

Catalytic hydrogenation of the compounds of formula IV' in accordance with variant (b) of the method can be well-known in the art, for example in an inert organic solvent in the presence of a catalyst of a noble metal. Suitable inert organic solvents are, for example, lower alcohols such as methanol, ethanol, etc. as the catalyst, it may be, for example, platinum, palladium or rhodium catalyst, which can be applied on a material suitable media. Palladium on coal is the preferred catalyst. Temperature and pressure are not critical, although usually catalytic hydrogenation was performed at room temperature and at atmospheric pressure.

The compounds of formula I can be converted into pharmaceutically acceptable salts by treatment with a base, and the main compounds of formula I can be converted into pharmaceutically acceptable salts by treatment with acids. Faceste initial products in the process, are new and also belong to the present invention.

Acids of formula II can be obtained, for example, as shown in the following reaction scheme, where R1, R2, R3, m and n have the meanings mentioned above, Bz represents benzyl and tBu represents a tert.-butyl (see diagram at the end of the description).

With regard to the above reaction scheme, each stage can be carried out in accordance with methods known in the art. So, in the first stage, the amino acid of formula V, which can be obtained in accordance with the method described Chenault N. R., Dahmer G. M., J. Am.Chem.Soc. 1989, 111, 6354-6364, is subjected to the conversion by treatment with sodium nitrite in the presence of concentrated sulfuric acid in gidrokshikislotu formula VI, which is then subjected to interaction with benzylbromide in the presence of organic bases, such as trialkylamine, such as triethylamine, to obtain the corresponding benzyl ether of formula VII. The latter then activates, for example, by reaction with the anhydride triftormetilfullerenov acid and treated with benzyl-tert.-butyl-malonate in the presence of a strong base, for example alkali metal hydride such as sodium hydride, n is La, as sodium hydride, and the interaction with the compound of the formula IX can lead to dibenzyl-tert.-butyl-butandikislota formula X, which is then dibenzyline catalytic hydrogenation, for example, in the presence of a palladium catalyst such as palladium on charcoal, to obtain monocrat.-butyl-butandikislota formula XI. The decarboxylation of this connection, for example by heating in toluene with triethylamine, which may be conducted in situ, get monocrat.-butyl succinate of formula XII, which is condensed with a cyclic amine of formula XIII, for example, according chloranhydride method or using 1-hydroxybenzotriazole in the presence of a condensing agent such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, obtaining the compounds of formula XIV, which is subjected to processing for removing the protective group (for example, processing triperoxonane acid), resulting in a gain acid of formula II.

The compound of formula IV', which is used as the source of the product when carrying out variant (b) of the process is new and is also in the scope of claims of the present invention.

The compounds of formula IV can be obtained, for example, Vimodrone, in an inert solvent such as dichloromethane or dimethylformamide, using 1-hydroxybenzotriazole in the presence of a condensing agent such as hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

Other compounds that are used as intermediates in obtaining the compounds of formula I are known compounds or analogues of known compounds which can be obtained by methods analogous to obtain the known compounds.

As noted previously, the compounds of formula I and their pharmaceutically acceptable salts are inhibitors of collagenase. Inhibiting collagenase activity in vitro of these compounds and salts can be demonstrated using collagenase obtained from cultures of human synovial fibroblast method Dayer J-M et al., Proc. Natl. Acad. Sci. USA (1976), 73. 945, with subsequent activation of procollagenase in air-conditioned environment by treatment with trypsin. The collagenase activity was measured using a14C-acetylated collagen type I from the tail tendons of rats as a substrate and using the method of micrometrology samples on the tablet Johnson-Wint, B., Anal. Biochem. (1980), 104, 175. IC50

The results obtained in the above study presents for compounds and salts of this invention, to the following:

The product from example N - IC50(nm)

2 - 18,0

4 - 7,0

5 - 2,5

7 - 6,5

9 - 8,5

16 - 4,1

17 - 2,35

23 is 34.0

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. Pharmaceutical drugs can be prescribed orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, they can also be assigned rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

Medicines prepared from compounds of formula I and their pharmaceutically acceptable salts may contain therapeutically inert, inorganic or organic carriers. Examples of such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be lactose, corn starch or its derivatives, talc, stearic acid or its salts. Prigodin and liquid polyols and the like. In the case of soft gelatin capsules usually do not require carriers due to the nature of the active ingredient. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, inert sugar, glucose and the like. Suitable carriers for the preparation of injection solutions are, for example, water, alcohols, polyols, glycerine, vegetable oils and the like. Natural and hardened oils, waxes, fats, semi-solid polyols and the like are suitable carriers for the preparation of suppositories.

The pharmaceutical preparations can also contain preservatives, stabilizers, moisturizing agents, emulsions, sweeteners, colouring agents, flavouring agents, salts for regulating the osmotic pressure, buffer agents for coating or antioxidants.

Pharmaceutical preparations containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically acceptable carrier and a method of preparation of such drugs are also objects of the present invention. This method consists of mixing the compounds of formula I or its pharmaceutically acceptable salts with therapeutically inert inania formula I or its pharmaceutically acceptable salt can be used to limit the development or prevention of diseases, first of all to limit the development and prevention of diseases associated with degeneration of the joints, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis. The dosage can vary within wide limits and, of course, is set to suit the individual requirements in each particular case. Usually when you assign an adult is suitable daily dose from about 5 mg to about 30 mg, preferably from about 10 mg to about 15 mg, although the upper limit may be raised if appropriate. The daily dose may be entered as a single dose or in separate doses.

The following examples illustrate the present invention in more detail. In these examples, all temperatures are in degrees Celsius.

Example 1

The solution 0,575 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3 - cyclopropylamino]piperidine (diastereoisomer 1) in 10 ml of ethanol hydronaut in the presence of 0.4 g of the catalyst is 5% palladium on coal for 6 hours. The catalyst was removed by filtration and the solution evaporated. The residue is purified flash chromatography on silica gel using dichloromethane/methanol (96: 4) for the elution to obtain 0,37 g is Idina (diastereoisomer 1) as a white foam.

NMR (MeOD): 3,78-to 3.64 (m, 3H); 3,62 (dd, 1H, J= 15,8); 3,49-to 3.41 (m, 1H); 3,39 (dd, IH, J=15,5); 3,33-of 3.27 (m, 1H); 2.95 and-2,87 (m, 1H); and 2.83 (s, 3H); 1,74 of 1.46 (m, 7H); of 1.33 (s, 3H); to 1.31 (s, 3H); 1,20-of 1.13 (m, 1H); 0,61-0,50 (m, 1H); 0,44 is 0.33 (m, 2H); 0,06-0,05 (m, 2H); MS: 409 (M+H)+.

The original product was obtained as follows.

(i) a Solution of 4.9 g of 2(R)-amino-3-cyclopropylamino acid (obtained by the method similar to that described H. R. Chenault, Dahmer J. and Whitesides, G. M. J. Am.Chem.Soc. 1989, 111, 6354-6364) in 50 ml of water containing of 4.05 ml of concentrated sulfuric acid, heated to 45o. For more than 30 minutes added dropwise a solution of 10.5 g of sodium nitrite in 20 ml of water. The solution is stirred at 45ofor 4 hours and then cooled to room temperature. The solution is extracted with three portions of ethyl acetate, 50 ml combined extracts washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated to a residue of 3.95 g of yellow oil containing 3-cyclopropyl-2(R)-hydroxypropionic acid, which is used in the next stage without additional purification.

Rf[dichloromethane/methanol(9:1)]=0,65.

(ii) a Solution of 3.95 g of the product of stage (i) in 50 ml of ethyl acetate is treated 5,32 ml of triethylamine and 3.8 ml of benzylbromide. The mixture is stirred and heated under reflux in techau, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated. The residue is purified flash chromatography on silica gel using hexane/ethyl acetate (2:1) for elution, obtaining 3,36 g benzyl-3-cyclopropyl-2(R)-hydroxypropionate in the form of a yellow oil.

NMR (CDCl3): 7,39-7,28 (m, 5H); 5,19 (d, 1H, J=14); of 5.15 (d, 1H, J=14); or 4.31-4,24 (m, 1H); 2,81 (Shir. d, 1H); 1,69-and 1.54 (m, 2H); 0,87-0,74 (m, 1H); 0,45-0,34 (m, 2H); 0,08-0,07 (m, 2H).

(iii) the Solution to 3.36 g of the product of stage (ii) and (1,49 ml of pyridine in 10 ml of dichloromethane are added dropwise to a solution of 3.07 ml of anhydride triftormetilfullerenov acid in 15 ml dichloromethane at 0owithin 30 minutes under stirring. The mixture was stirred at 0ofor 2 hours and then washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated with getting lower than the 5.37 g of benzyl-3-cyclopropyl-2(R)-triftormetilfullerenov in the form of an orange oil, used in the next stage without additional purification.

Rf[hexane/ethyl acetate(4:1)]=0,5.

(iv) a Solution of 3.8 g of benzyl-tert.-butylmalonate in 50 ml of 1,2-dimethoxyethane process 0,504 g of 80% dispersion of sodium hydride o. The solution is lower than the 5.37 g of the product of stage (iii) in 20 ml of dichloromethane are added dropwise at 0o. The mixture was stirred at 0ofor 2 hours and then left to warm to room temperature over night. The solvent is evaporated and the residue is dissolved in ethyl acetate. The solution is washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated to obtain 6,54 g of 2,3-dibenzyl 3-tert. bugil-1-cyclopropyl-2(R), 3(R,S),3-propanetricarboxylate in the form of a mixture of diastereoisomers 1:1 as an orange oil.

NMR (CDCl3): 7,46 and 7.36 (m, 20H); 5,19 is 5.07 (m, 8H); the 3.89 (d, 1H, J=10); of 3.85 (d, 1H, J=10); 3,37-3,26 (m, 2H); 1,68-of 1.52 (m, 2H); 1,52-to 1.38 (m, 2H); of 1.41 (s, 9H); 1.39 in (s, 9H); 0,79 to 0.63 (m, 2H); 0,49-0,38 (m, 4H); 0,12-0,07 (m, 4H).

(v) a Solution of 6.4 g of the product of stage (iv) in 30 ml of 1,2-dimethoxyethane process 0,446 g of 80% dispersion of sodium hydride in mineral oil. The mixture is stirred at room temperature for 30 minutes. A solution of 3.84 g of 1-(methyl bromide)-3,4,4 - trimethyl-2,5-imidazolidinedione in 20 ml of 1,2-dimethoxyethane added dropwise over 15 minutes. The mixture is stirred at room temperature for 36 hours, the solvent evaporated and the residue is dissolved in ethyl acetate and washed with water and saturated aqueous rastut flash chromatography on silica gel, using hexane/ethyl acetate (7:3) and then hexane/ethyl acetate (6:4) for the elution, to obtain 6.4 g of 2,3-dibenzyl-3-tert.-butyl-1-cyclopropyl-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2(R),3(R,S),3-butandikislota in the form of a mixture of diastereoisomers 1:1 in the form of a clear oil.

NMR (CDCl3): 7,47-7,28 (m, 20H); 5,31-to 5.03 (m, 8H); 4,32-4,18 (m, 4H); 3,19-3,15 (m, 1H); 3,16-of 3.12 (m, 1H); of 2.86 (s, 6H); 2.00 in 1,90 (m, 1H); 1,89-to 1.79 (m, 1H); 1,64-1,49 (m, 1H); 1,48-to 1.38 (m, IH); to 1.37 (s, 12H); of 1.36 (s, 9H); to 1.32 (s, 9H); 0,9-0,8 (m, 2H); 0,41-0,3 (m, 4H); 0,15-0,05 (m, 2H); from 0.04 to 0.04 (m, 2H).

(vi) a Solution of 3.0 g of the product of stage (v) in 30 ml of 2-propanol hydronaut in the presence of 0.3 g of 5% palladium on coal for 2 hours. The catalyst was removed by filtration and the solution evaporated. The residue is again evaporated from 20 ml of toluene and then dissolved in 50 ml of toluene. The solution process 0,693 ml of triethylamine and the mixture is heated under reflux for 2 hours. The solution is cooled to room temperature and washed with 2 M hydrochloric acid, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated to obtain 1.85 g of mono-4-tert.- butyl ether-2(R)-(cyclopropylmethyl)-3(R or S)-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl] salcinovic acid in the form of a mixture of diastereoisomers vii) Solution of 1.0 g of the product of stage (vi) in 10 ml of dichloromethane is cooled to 0oand treated sequentially 0,665 ml of N-ethylmorpholine, 0,481 g 1-gidroekstruziya and 0,602 g of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The mixture was stirred at 0ofor 30 minutes and then treated 0,517 ml of piperidine. The solution is allowed to warm to room temperature and stirred over night. The solution was washed with 5% aqueous sodium hydrogen carbonate solution, 2 M hydrochloric acid and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated to obtain 1.01 g of 1-[2(R)-[1(R or S)-(tert.-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylamino] piperidine in a mixture of diastereoisomers approximately 6:1 in the form of a yellow resin.

MS: 450 (M+N)+;

Rf[dichloromethane/methanol(95:5)] = 0,51.

(viii) a Solution of 1.0 g of the product of stage (vii) in 2 ml of triperoxonane acid is stirred at room temperature for 2.5 hours. The solvent is evaporated and the residue is again evaporated from toluene. The residue is dissolved in diethyl ether and the solution extracted with two portions of 5% aqueous sodium hydrogen carbonate solution. The combined extracts are acidified to pH 2 with concentrated hydrochloric acid is saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain 0,634 g of white foam containing 1-[2(R)-[1(R or S)- carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3 - cyclopropylamino] piperidine in a mixture of diastereoisomers 6:1, which is used in the next stage without additional purification.

Rf[dichloromethane/methanol(9:1)] = 0,31.

(ix) the Solution 0,634 g of the product of stage (viii) in 10 ml of dichloromethane is cooled to 0o. The solution is treated successively 0,41 ml of N-ethylmorpholine, 0,296 g 1-gidroekstruziya and 0,371 g of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The mixture was stirred at 0owithin 30 minutes. Add a solution 0,238 g O-benzylhydroxylamine in 2 ml of dichloromethane. The mixture is left to warm to room temperature and stirred over night. The solution was washed with two portions of 5% aqueous sodium hydrogen carbonate solution and successively with 2 M hydrochloric acid, water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated. The residue is purified flash chromatography on silica gel using dichloromethane/methanol (98:2) for the elution to obtain 0,592 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imides-7,31 (m, 5H); to 4.87 (d, 1H, J=13); 4,79 (d, 1H, J=13); 3,78-the 3.65 (m, 3H); 3,63 (dd, 1H, J=15,8); 3,53 is-3.45 (m, 1H); 3,44 (dd, 1H, J= 15,5); 3,34-of 3.27 (m, 1H); 2,87 (s, 3H); 2,84-2,78 (m, 1H); 1,78 - 1,49 (m, 7H); 1,49-of 1.40 (m, 1H); of 1.36 (s, 3H); 1.32 to (s, 3H); 1,12 was 1.04 (m, 1H); 0,61-0,50 (m, 1H); 0,48 is 0.37 (m, 2H); of 0.07 and 0.06 (m, 2H).

MS: 499 (M+H)+.

Example 2

By the way, similar to that described in the first paragraph of example 1, from 0,391 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3 - cyclopropylamino]-4-piperidinol (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) obtain 0.33 g of 1-[3-cyclopropyl-2-(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4 - trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol (diastereoisomer 1) as a white foam.

NMR (MeOD): 4,22-was 4.02 (m, 2H); 3,90-3,81 (m, 1H); 3,69 of 3.56 (m, IH); 3,49-to 3.38 (m, 2H); 3,37-3,18 (m, 2H); 3,11-a 3.01 (m, 1H); 2,97-of 2.86 (m, 1H); and 2.83 (d, 3H, J=5); 2,01-of 1.78 (m, 2H); 1,68-of 1.36 (m, 3H); of 1.33 (s, 3H); to 1.31 (d, 3H, J= 5); 1,24 is 1.13 (m, 1H); 0,62-0,50 (m, 1H); 0,49 is 0.33 (m, 2H); 0,09-0,05 (m, 2H);

MS: 425 (M+H)+.

Example 3

By the way, similar to that described in the first paragraph of example 1, from 0,822 g of 3-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,496 g of 3-[3-cyclopropyl-2-(R)-[1(R or reasoner 1) as a white foam.

NMR (MeOD): 4,03-3,1 (m, 5H); 3,48-of 3.31 (m, 2H); 2,96-of 2.86 (m, 1H); 2,82 (s, 3H); 2,14-2,03 (m, 2H); 1,80 by 1.68 (m, 4H); 1,68-of 1.53 (m, 5H); to 1.32 (s, 3H); to 1.31 (s, 3H); 1,21-1,12 (m, 1H); 0,64-0,52 (m, 1H); 0,45-0,33 (m, 2H); and 0.08 to 0.05 (m, 2H).

MS: 449 (M+H)+.

Example 4

By the way, similar to that described in the first paragraph of example 1, 0.6 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3 - cyclobutylmethyl]piperidine (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) obtain 0.5 g of 1-[3-cyclobutyl-2-(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (diastereoisomer 1) as a white foam.

NMR (MeOD): to 3.67 (dd, 1H, J=15,10); 3,64-of 3.46 (m, 4H); to 3.34 (dd, 1H, J= 15,8); 3,12 (td, 1H, J=13,3); 2,92-2,84 (m, 1H); 2,82 (s, 3H); 2,22-of 2.09 (m, 1H); 2,07-of 1.93 (m, 2H); 1,90-of 1.42 (m, 12H); of 1.33 (s, 3H); of 1.32 (s, 3H).

MS: 423 (M+H)+.

Example 5

By the way, similar to that described in the first paragraph of example 1, 0.4 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclobutylmethyl] -4-piperidinol (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,294 g of 1-[3-cyclobutyl-2-(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol in the 84 (d, 3H, J=5); 2,21-of 1.36 (m, 13H); of 1.33 (d, 3H, J=3); is 1.31 (d, 3H, J=6). MS: 439 (M+H)+.

Example 6

By the way, similar to that described in the first paragraph of example 1, from 0,642 g of 3-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,348 g of 3-[3-cyclobutyl - 2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyl)ethyl] propionyl] -3-azabicyclo[3.2.2]nonane (diastereoisomer 1) as a white foam.

NMR (MeOD): 3,92-a 3.83 (m, 2H); 3,76 (dd, 1H, J=15,13); 3,67 is 3.57 (m, 2H); to 3.34 (dd, 1H, J=15,5); 3,28-is 3.21 (m, 1H); 2,96-2,87 (m, 1H); and 2.83 (s, 3H); 2.23 to and 2.13 (m, 1H); 2,12-of 1.92 (m, 4H); 1.91 a is 1.48 (m, 14H); of 1.35 (s, 3H); of 1.34 (s, 3H).

MS: 463 (M+H)+.

Example 7

By the way, similar to that described in the first paragraph of example 1, 0.5 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclopentylpropionyl]-4-piperidinol (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) obtain 0.4 g of 1-[3-cyclopentyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 imidazolidin - nil)ethyl]propionyl]-4-piperidinol (diastereoisomer 1) as a white foam.

NMR (MeOD): 4,20-was 4.02 (m, 2H); 3,91-a 3.83 (m, 1H); 3,76-to 3.64 (m, 1H); 3, obom, like described in the first paragraph of example 1, from 0,57 g of 3-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) obtained in the manner similar to that described in example 1(i) to(ix), gain of 0.48 g of 3-[3-cyclopentyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane (diastereoisomer 1) as a white foam.

NMR (MeOD): 3,88-to 3.67 (m, 5H); 3,39-of 3.31 (m, 2H); 2,92-to 2.85 (m, 4H); 2,15-to 2.06 (m, 2H); 1,83-of 1.45 (m, 16H); 1,36 of 1.28 (m, 7H); 1,16-1,02 (m, 2H).

MS: 477(M+N)+.

Example 9

The solution 0,421 g of a mixture of about 6:1 diastereoisomer 1 and diastereoisomer 2 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine obtained in the manner similar to that described in example 1(i) - (viii), in 10 ml of dichloromethane is cooled to 0o. The solution process 0,211 g of 1-hydroxybenzotriazole, 0.24 g of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.22 ml of N-methylmorpholine. The mixture was stirred at 0owithin 15 minutes. Adds solution 0,295 g O-(tert.-butyldimethylsilyl)-hydroxylamine and 0.22 ml of N-methylmorpholine in 5 ml of dichloromethane. The mixture is left to warm to room the the atrium and consistently 2 M hydrochloric acid and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent is evaporated. The residue is purified flash chromatography on silica gel using dichloromethane/methanol (96:4) for the elution to obtain 0,123 g of 1-[3-cyclopentyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] piperidine (diastereoisomer 1) as a white foam.

NMR (MeOD): 3,74-3,66 (m, 3H); 3,53 is-3.45 (m, 2H); to 3.34 (dd, J=14,7, 1H); 3,23 (dt, J=4,14, 1H); 2,90-2,84 (m, 4H); 1,80-of 1.45 (m, 14H); 1,38 is 1.23 (m, 7H); 1,15-a 1.01 (m, 2H).

MS: 437 (M+H)+.

Example 10

By the way, similar to that described in the first paragraph of example 1, based on 0,328 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclohexylpropionic]- piperidine (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,269 g of 1-[3-cyclohexyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyl)ethyl] propionyl] piperidine (diastereoisomer 1) as a white foam.

NMR (MeOD): a 3.87-of 3.77 (m, 2H); 3,7 (dd, J=14,9, 1H); 3,64 of 3.56 (m, 2H); 3,38 of 3.28 (m, 2H); 2,9-and 2.83 (m, 4H); 1,84-of 1.45 (m, 12H); to 1.35 (s, 3H); of 1.33 (s, 3H); 1,25-of 1.05 (m, 5H); 0,98-0,78 (m, 2H).

MS: 451 (M+H)+.

Example 11

By the way, similar to that described in example 9, on the basis of 0.8 g of 1-[2(R)-[1(R or S)-ka is isomer 1), obtained in the manner similar to that described in example 1(i)-(viii) obtain 0.3 g of 4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl] -tetrahydro-1,4-thiazine (diastereoisomer 1) as a white foam.

NMR (MeOD): was 4.02-of 3.96 (m, 2H); 3,92-of 3.85 (m, 2H); 3,7 (dd, J=13,9, 1H); 3,37 (dd, J= 13,6, 1H); 3.25 to 3,18 (m, 1H); 2,9-2,84 (m, 4H); 2,82 is 2.75 (m, 1H); 2,7-to 2.55 (m, 3H); 1,78-of 1.45 (m, 8H); to 1.35 (s, 3H); of 1.34 (s, 3H) 1,18 of-1.04 (m, 2H).

MS: 455(M+H)+.

Example 12

By the way, similar to that described in example 1, from 0.3 g of S,S-dioxide 4-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclopentylpropionyl] -tetrahydro-1,4-thiazine (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) obtain 0.2 g S,S-dioxide 4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl]-tetrahydro-1,4-thiazine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 4,45-4,3 (m, 2H); 4,0-3,93 (m, 1H); 3,78-the 3.65 (m, 2H); 3,55-3,39 (m, 2H); 3.30 is-is 3.21 (m, 2H); 3,14-3,03 (m, 2H); 2,9-to 2.85 (m, 4H); 1,78-of 1.45 (m, 9H); of 1.36 (s, 3H); of 1.34 (s, 3H); 1.18 to 1,0 (m, 2H).

MS: 487 (M+N)+.

Example 13

By the way, similar to that described in example 9, on the basis of 0.8 g of 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1 - milovice described in example 1(i)-(viii), obtain 0.24 g of 4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 3,98 of 3.75 (m, 4H); to 3.64 (dd, J=13,8, 1H); at 3.35 (dd, J=15,6, 1H); of 3.07 (td, J=10,4, 1H); 2,9-and 2.83 (m, 1H); 2,82 (s, 3H); 2,78-of 2.72 (m, 1H); 2.66 per-2,52 (m, 3H); 2,18-of 2.08 (m, 1H); 2,05-of 1.93 (m, 2H); 1,85-of 1.45 (m, 6H); of 1.13 (s, 3H); 1,11 (s, 3H).

MS: 441 (M+H)+.

Example 14

By the way, similar to that described in example 9, on the basis of 1.22 g of 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyl)ethyl]-3-cyclohexylpropionic]-tetrahydro-1,4-thiazine (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(viii) obtain 0.45 g of 4-[3-cyclohexyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl]propionyl]tetrahydro-1,4-thiazine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 4,12-a 4.03 (m, 2H); 3.95 to 3,88 (m, 1H); 3.75 to the 3.65 (m, 2H); to 3.38 (dd, J=14,6, 1H); 2,88-2,82 (m, 4H); 2,78-of 2.72 (m, 1H); 2,68 is 2.55 (m, 3H); 1,82-of 1.53 (m, 7H); to 1.35 (s, 3H); of 1.34 (s, 3H); 1.26 in-0,8 (m, 8H).

MS: 469 (M+H)+.

Example 15

By the way, similar to that described in example 9, on the basis of 1,164 g of a mixture of diastereoisomers 3-[2(R)-[1(RS)-carboxy-2-(3,4,4-trimethyl - 2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclopentylpropionyl] -5,5-timeout 0,329 g of 3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4 - trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolecarboxamide (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 5,09-4,72 (m, 2H); 4,51 and 4,46 (both s, total 1H); 3,84 and to 3.64 (both dd, J=14,8, 1H); 3,40 was 3.05 (m, 4H); 2,90-by 2.73 (m, 4H); 1,94-1,25 (m, 23H); 1,23-a 1.01 (m, 2H); 0,99-of 0.85 (m, 3H).

MS: 554 (M+H)+.

Example 16

By the way, similar to that described in the first paragraph of example 1, from 0,223 g of 4-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]- research (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,112 g of 4-[3-cyclopentyl - 2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyl)ethyl]propionyl]the research (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 3,83 of 3.56 (m, 9H); to 3.41 (dd, J=14,6, 1H); 3,19 (dt, J=4,11, 1H); 2.91 in-of 2.81 (m, 4H); 1,77-of 1.42 (m, 8H); 1,38 is 1.23 (m, 7H); 1,19-0,99 (m, 2H);

MS: 439 (M+H)+.

Example 17

By the way, similar to that described in example 9, on the basis of 1,289 g of a mixture of diastereoisomers 3-[2(R)-[1(RS)-carboxy-2-(3,4,4-trimethyl - 2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclopentylpropionyl] -N, 5,5-trimethyl-4(R)-thiazolecarboxamide (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(viii), get 0,629 g of 3-[3-cyclopentyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -N,5,5-trimethyl-4(R)-thiazolecarboxamide (Dias dd, J=14,10, total 1H); 3,37 and 3,17 (both dd, J=14.5 m, total 1H); 3,13-2,70 (m, 8H); 1,96-1,25 (m, 21H); 1,23-0,99 (m, 2H).

MS: 526 (M+N)+.

Example 18

By the way, similar to that described in the first paragraph of example 1, from 0,289 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylmethyl]-4 - phenylpiperazine (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,121 g of 1-[3-cyclobutyl-2(R)-[1(R or S)-[(hydroxycarbamoyl)methyl] -2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -4-phenylpiperazine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD):7,25 (m, 2H); 7,00 (m, 2H); 6,85 (m, 1H); 3,94-to 3.73 (m, 4H); 3,66 (dd, J=14,7, 1H); of 3.43 (dd, J=14,6, 1H); 3,23-to 3.09 (m, 4H); 2,96-2,84 (m, 1H); 2,84 (s, 3H); 2,27 and 2.13 (m, 1H); 2,09-of 1.95 (m, 2H); 1,90 is 1.48 (m, 6H); to 1.35 (s, 3H); of 1.34 (s, 3H).

MS: 499 (M)+.

Example 19

By the way, similar to that described in the first paragraph of example 1, from 0,455 g of 4-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3 - cyclobutylmethyl] the research (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,194 g of 4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl]the research (diastereoisomer 1) 2,23-2,11 (m, 1H); 2.06 to 1,95 (m, 2H); 1.91 a-at 1.73 (m, 2H); 1,71 of 1.46 (m, 4H); to 1.35 (s, 3H); of 1.34 (s, 3H).

MS: 425 (M)+.

Example 20

By the way, similar to that described in the first paragraph of example 1, from 0.625 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3-cyclobutylmethyl] pyrrolidine (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,384 g of 1-[3-cyclobutyl-2-(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]the research (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): of 3.77 at 3.69 (m, 1H); 3,61 (dd, J=14,6, 1H); 3,53-3,44 (m, 2H); 3,39-of 3.31 (m, 2H); 2,93-to 2.85 (m, 2H); 2,84 (s, 3H); 2.26 and and 2.13 (m, 1H); 2,07-1,71 (m, 8H); 1,69 of 1.46 (m, 4H); of 1.36 (s, 3H); of 1.33 (s, 3H).

MS: 409 (M+H)+.

Example 21

By the way, similar to that described in the first paragraph of example 1, from 0,176 g of 8-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3 - cyclobutylmethyl]-1,4-dioxa-8 azaspiro[4,5]decane (diastereoisomer 1) obtained in the manner similar to that described in example 1(i) to(ix), get 0,084 g of 8-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl] -1,4-dioxa-8 azaspiro[4,5] decane (diastereoisomer 1) in the form of a white solid matter what 10H); of 1.35 (s, 3H); of 1.33 (s, 3H).

MS: 481 (M+H)+.

Example 22

By the way, similar to that described in the first paragraph of example 1, from 0,443 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3 - cyclobutylmethyl]-4-methoxypiperidine (diastereoisomer 1) get 0,319 g of 1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4 - methoxypiperidine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 3,96-of 3.80 (m, 2H); 3,69-3,59 (m, 1H); 3,54 is 3.23 (m, 7H); 3,18-to 3.09 (m, 1H); 2.93 which is 2.80 (m, 4H); 2,21-of 2.09 (m, 1H); 2,07-of 1.41 (m, 12H); 1,41-to 1.38 (m, 6H).

MS: 453 (M+N)+.

The original product was obtained as follows.

(i) the Solution 0,925 g of 1-[2(R)-[1(R or S)-(tert.- butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3 - cyclopropylamino] -4-hydroxypiperidine in 8 ml of dimethylformamide is treated with 1.08 g under the conditions and 1.79 g of silver oxide. The mixture is stirred at room temperature in the dark for 2 days. Then add a further portion of 0.54 g under the conditions and 0,895 g of silver oxide and the mixture is stirred for further 3 days. The solvent is evaporated and the residue suspended in ethyl acetate and filtered. An ethyl acetate solution is concentrated and the residue purified f the em. -butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3 - cyclobutylmethyl]-4-methoxypiperidine in the form of a colourless resin.

(ii) by the Method similar to that described in example 1(viii) (ix), and 0.61 g of 1-[2(R)-[1(R or S)-(tert.-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -4-cyclobutylmethyl] -4 - methoxypiperidine get 0,443 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 - imidazolidinyl)ethyl] -3-cyclobutylmethyl] -4-methoxypiperidine (diastereoisomer 1) in the form of a colourless resin.

Example 23

By the way, similar to that described in the first paragraph of example 1, from 0,94 g of 1-[2(R)-[1(RS)-(benzyloxycarbonyl)-2-(3,4,4 - trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylmethyl]-octahedrally (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,663 g of 1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl - 2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]octahydrate (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): of 3.77 (dd, J=14,10, 1H); 3,66-of 3.43 (m, 4H); to 3.33 (dd, J=14.5 m, 1H); of 3.07 (dt, J=10,4, 1H); 2.91 in-of 2.81 (m, 4H); 2,29-of 2.16 (m, 1H); 2,10-of 1.95 (m, 2H); 1,90 of 1.46 (m, 16H); of 1.34 (s, 6H).

MS: 451 (M+H)+.

Example 24

By the way, similar to that described in the first paragraph is propionyl]piperidine (diastereoisomer 1), obtained in the manner similar to that described in example 1(v) - (ix) using 3-(methyl bromide)-5,5 - dimethyloxazolidine-2,4-dione instead of 1-(methyl bromide)-3,4,4 - trimethyl-2,5-imidazolidine get 0,131 g of 1-[3-cyclobutyl - 2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3 - oxazolidinyl)ethyl] propionyl] piperidine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 3,72-of 3.53 (m, 5H); 3,39 (dd, J=14,6, 1H); 3,14 (dt, J=10,4, 1H); 2.95 and-of 2.86 (m, 1H); 2.23 to-2,11 (m, 1H); 2,08-of 1.94 (m, 2H); 1,90-of 1.44 (m, 18H).

MS: 410 (M+H)+.

Example 25

By the way, similar to that described in the first paragraph of example 1, from 0,42 g of 1-[2(R)-[1(R or S)-(benzyloxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylmethyl]hexahydroazepin (diastereoisomer 1) obtained in the manner similar to that described in example 1(i)-(ix) receive 0,197 g of 1-[3-cyclobutyl-2(R)-[1(R or S)- (hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepin (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): of 3.77-to 3.64 (m, 2H); 3,62 is-3.45 (m, 3H); to 3.33 (dd, J=14.5 m, 1H); of 3.07 (dt, J=10,4, 1H); 2.91 in-of 2.81 (m, 4H); 2,24 and 2.13 (m, 1H); 2,09-of 1.95 (m, 2H); 1,90 to 1.47 (m, 14H); to 1.35 (s, 3H); of 1.34 (s, 3H).

MS: 437 (M+H)+.

Example 26

By the way, similar to that described in the first paragraph of example 1, from 0,37 g 1 is of IMT] piperidine (diastereoisomer 1), obtained in the manner similar to that described in example 1(i)-(ix) using 2-(methyl bromide)hexahydro-1,3-dioxabicyclo[1,2-a] [1,2,4] triazole, receive the amount of 0.118 g of 1-[3-cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxabicyclo[1,2-a][1,2,4]triazole-2-yl)-1(R or S)- (hydroxycarbamoyl)ethyl] propionyl] piperidine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 3,68 of 3.56 (m, 8H); 3,52-3,39 (m, 2H); 3,17-to 3.09 (m, 1H); 2,97-2,90 (m, 1H); 2,35-of 2.27 (m, 2H); 2.21 are 2,11 (m, 1H); 2,07-of 1.95 (m, 2H); 1,88-of 1.44 (m, 12H).

MS: 422 (M+H)+.

Example 27

By the way, similar to that described in the first paragraph of example 1, from 0,222 g of 1-[2(R or S)-(benzyloxycarbonyl)-2-phthalimidomethyl] -3-cyclobutylmethyl] piperidine obtained in the manner similar to that described in example 1(i)-(ix) using N-(methyl bromide)phthalimide get 0,013 g of 1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidomethyl]propionyl]piperidine (diastereoisomer 1) in the form of a white solid.

NMR (MeOD): 7,87 to 7.75 (m, 4H); a 3.83 (dd, J=14,8, 1H); 3,66-to 3.58 (m, 3H); 3,53 is-3.45 (m, 1H); 3,35-of 3.25 (m, 1H); 3,20-of 3.12 (m, 1H); 3.04 from-of 2.97 (m, 1H); 2.23 to-2,11 (m, 1H); 2,08-of 1.95 (m, 2H); 1,89-of 1.41 (m, 12H).

MS: 428 (M+H)+.

The following examples illustrate pharmaceutical compositions containing derivatives of hydroxamic acids covered by the present invention.

Ingredient - a tablet

Derived hydroxamic acid 10.0 mg

Lactose - 125,0 mg

Corn starch is 75.0 mg

Talc - 4.0 mg

Magnesium stearate 1.0 mg

Total weight - 215,0 mg

Example B

Capsules containing the following ingredients can be obtained in the usual way:

Ingredient - capsules

Derived hydroxamic acid 10.0 mg

Lactose - 165,0 mg

Corn starch - 20.0 mg

Talc - 5.0 mg

The total weight of the capsule - 200.0 mg

The efficiency effect of the compound obtained in example 9, on the frequency of occurrence of malignant lesions of the lung and liver of male mice mice C57BI/6Hsd after inoculation B16F10 melanoma cells.

Description of the experiment.

Females of mice C57BI/6Hsd, age 8-9 weeks, was introduced in the form of injection in the lateral tail vein 1105cultured B16F10 cells tissue murine melanoma. Treatment was started on the third day after the injection of tumor cells. The compound of example 9 was used in combination with a carrier SMS/Acetate (in accordance with the Protocol Weiwyn) and administered orally in a volume of 0.1 ml twice a day, seven days a week. All animals were treated for 13 days. The experiment was completed the morning the bodies, affected by the tumor. The results are presented in table 1.

Extra example tests inhibitory effect of the compound obtained in example 9.

Test method: the effectiveness of the inhibitory effect on matrix metalloproteinases was defined as the ability to inhibit loss in the body hydroxyproline (a marker of collagen) of the nasal cartilage cylinders cattle were implanted subcutaneously in the back of the rats. There were three series of tests in which animals were injected with the inhibitor of matrix metalloproteinases (IDRM) for 14-21 days. The degree of destruction of the cartilage tissue was evaluated by weight loss animals. The results are presented in table 2.

1. Derivatives of hydroxamic acids with three cyclic substituents of the formula I

< / BR>
in which R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R2represents a saturated 5 - to 8-membered monocyclic or bridged nitrogen-containing heterocyclic ring which is attached via a nitrogen atom and which, as a monocycle, not necessarily contain as a ring member NR is an alkyl, lower alkoxy, oxo or metallizovannoj exography, carbamoyl, mono(lower alkyl)carbamoyl or di(lower alkyl)carbamoyl;

R3represents 5 - or 6-membered nitrogen-containing heterocyclic ring which (a) is attached via the nitrogen atom, (b) optionally contains nitrogen or oxygen as an additional member of the ring, (C) optionally substituted by oxopropoxy one or two carbon atoms, the adjacent connecting them with the nitrogen atom, and (g) optionally condensed with a benzene ring or optionally substituted by one or more carbon atoms by lower alkyl and/or at any time additional time atom(s) of nitrogen is lower alkyl;

R4represents hydrogen, lower alkyl, phenyl or a protective group;

m = 1 or 2;

n = 1 to 4

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which R1is cyclopropyl, cyclobutyl or cyclopentyl;

R2represents a saturated 5-, 6 - or 7-membered monocyclic or bridged nitrogen-containing heterocyclic ring which is attached via a nitrogen atom and which, as a monocycle, not necessarily contain as a ring member NR4, , issim alkoxy, oxo or metallizovannoj exography, carbamoyl, mono(lower alkyl)carbamoyl or di(lower alkyl)carbamoyl;

R3represents 5 - or 6-membered nitrogen-containing heterocyclic ring which (a) is attached via the nitrogen atom, (b) optionally contains N or O as an additional member of the ring in any position other than adjacent to the connecting nitrogen atom, (b) substituted by oxopropyl two carbon atoms adjacent connecting them with the nitrogen atom, and (g) optionally condensed with a benzene ring or optionally substituted by one or more carbon atoms by lower alkyl or any time extra time atom(s) of nitrogen by lower alkyl;< / BR>
R4represents hydrogen, lower alkyl or a protective group.

3. Connection under item 1 or 2, in which R2represents 1-pyrrolidinyl, piperidino, 4-phenyl-1-piperazinil, morpholinyl, tetrahydro-1,4-thiazin-4-yl, 1,1-dioxide, tetrahydro-1,4-thiazin-4-yl, thiazolidin-3-yl, hexahydroazepin or octahydrate, optionally substituted by one or more carbon atoms, hydroxy, lower alkyl, lower alkoxy, metallizovannoj oxopropoxy or mono(lower alkyl)carbamoyl; or 3 ethoxypyridine.

5. Connection on p. 4, where hydroxypiperidine is a 4-hydroxypiperidine.

6. Compounds according to any one of paragraphs.1 - 5, where R3represents a group of the formula

< / BR>
< / BR>
< / BR>
in which R5and R6each represents hydrogen or together represent an additional bond or the residue of a condensed benzene ring;

R7represents hydrogen or lower alkyl;

X represents-CO-, -CH2-, -C(lower alkyl)2-, -N(lower alkyl)-, or, if R7represents lower alkyl and X represents-N(lower alkyl)-, these lower alkyl groups may be combined with the formation of 5-,6 - or 7-membered ring;

R9and R10each represents hydrogen or lower alkyl.

7. Connection on p. 6, in which R3represents a group of formula (C), R7represents lower alkyl and X represents-C(lower alkyl)2-.

8. Connection on p. 7, in which R3is a 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl.

9. Compounds according to any one of paragraphs.1 to 8, in which m and n are equal to 1.

10. Connection on p. 1, representing 1-[3-cyclopropyl-2(R)-[1(R or S)-(the s on p. 1, represents 1-[3-cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol.

12. Connection on p. 1, representing 1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-piperidine.

13. Connection on p. 1, representing 1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol.

14. Connection on p. 1, representing 1-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol.

15. Connection on p. 1, representing 1-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidine.

16. Connection on p. 2, selected from

3-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane,

3-[3-cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane and

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 is logiciel-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine,

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine,

S, S-dioxide-4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -tetrahydro-1,4-thiazine,

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine,

4-[3-cyclohexyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine,

3-[3-cyclopentyl-2(R)-[1(R or S)-hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolecarboxamide,

4-[3-cyclopentyl-2(R)-[1(R or S)-hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]the research,

3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -N,5,5-trimethyl-4(R)-thiazolecarboxamide,

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine,

4-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]the research,
8-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] -1,4-dioxa-8 azaspiro[4,5] decane,

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine,

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]octahydronaphthalene,

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine,

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepin,

1-[3-cyclobutyl-2(R)-[2-hexahydro-1,3-dioxabicyclo[1,2-a][1,2,4]triazole-2-yl)-1(R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine and

1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimido-ethyl] propionyl]piperidine.

18. Compounds of General formula II

< / BR>
in which R1, R2, R3, m and n have the meanings specified in paragraph 1.

19. Compounds of General formula IV

< / BR>
in which R1, R2, R3, m and n have the meanings specified in paragraph 1.

20. Compounds according to any one of paragraphs.1 - 17 with inhibiting collagenase activity, which I invasive tumors, atherosclerosis or multiple sclerosis.

21. The method of obtaining the compounds according to paragraphs.1 - 17 or their pharmaceutically acceptable salts, characterized in that conduct the interaction of the acid of General formula II

< / BR>
with a compound of General formula III

H2N - OZ,

where Z represents hydrogen, three(lower)alkylsilane, diphenyl(lower)alkylsilane or benzyl,

obtaining compounds of General formula IV

< / BR>
where Z denotes a hydrogen atom, defanyl(lower)alkylsilane or benzyl,

and, if necessary, with subsequent stages remove any existing diphenyl(lower)alkylsilanes or benzyl groups and/or conversion of the compounds of General formula I in a pharmaceutically acceptable salt.

22. The method according to p. 21, characterized in that the removal of the benzyl group in compound of General formula IV where Z is a benzyl, carried out by catalytic hydrogenation.

23. The method of obtaining the drug, possessing inhibiting collagenase activity, designed to limit the development or prevention of diseases of degeneration of the joints or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis, in which the herbal form for injection.

24. Drug possessing inhibiting collagenase activity, designed to limit the development or prevention of diseases of degeneration of the joints or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis, containing a compound according to any one of paragraphs.1 - 17 and a therapeutically inert carrier.

Priority signs: 25,04,94 in R1is cyclopropyl, cyclobutyl, cyclopentyl;

R2represents a saturated 5 - to 8-membered monocyclic or bridged nitrogen-containing heterocyclic ring which is attached via a nitrogen atom and which, as a monocycle, not necessarily contain as a ring member NR4, O, S or SO2and/or optionally substituted by one or more carbon atoms by hydroxyl, lower alkyl, lower alkoxy, oxo or metallizovannoj exography, carbamoyl, mono(lower alkyl)carbamoyl or di(lower alkyl)carbamoyl;

R3represents 5 - or 6-membered nitrogen-containing heterocyclic ring which (a) is attached via the nitrogen atom, (b) optionally contains nitrogen or oxygen as an additional member of the ring, (b) optionally substituted oxopropionate with a benzene ring or optionally substituted by one or more carbon atoms by lower alkyl and/or at any time additional time atom(s) of nitrogen is lower alkyl;

R4represents hydrogen, lower alkyl, phenyl or a protective group:

m = 1 or 2;

n = 1 to 4

and their pharmaceutically acceptable salts.

30.01.95 in R1- cyclohexyl.

 

Same patents:

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to optically active derivative of carboxamides with a strong analgezirutuyu activity and low toxicity, or their pharmacologically suitable salts

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to new intermediate compounds and an improved method of producing compounds that inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular L-735524, or their pharmaceutically acceptable salts

The invention relates to new substituted benzopyranones that have antiatherosclerotic and antithrombotic action

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines

The invention relates to a new compound N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl methyl)-1H-indol-3-yl] ethylamine sulphate salt (2:1) structural formula I and its pharmaceutically acceptable hydrate
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