HRP950251A2 - Hydroxamic acid derivatives with tricyclic substitution - Google Patents

Description

The present invention relates to hydroxamic acid derivatives.

Hydroxamic acid derivatives presented in the presented invention are compounds of the general formula:

[image]

where

R1 represents cyclopropyl. cyclobutyl, cyclopentyl or cyclohexyl,

R2 represents a saturated five- to eight-membered monocyclic or bridged heterocyclic ring which is attached via an N atom and which, if the ring is monocyclic, may contain NR4, O, S, or SO2 as members of the ring and/or may be substituted on one or more C atoms with hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)- carbamoyl, di(lower alkyl)carbamoyl or hydroxyamino group,

R3 represents a five- or six-membered heterocyclic ring which (a) is connected via an N atom, (b) may contain N, O and/or S, SO or SO2 as additional ring members, (c) is substituted with oxo on one or both C atoms that are in the neighborhood of the N atom through which the ring is attached, and (d) can be fused with benzene or can be substituted with one or more C atoms with a lower alkyl or oxo group and/or on an additional N atom (thiomine) with a lower alkyl or aryl group,

R4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group,

m is 1 or 2, and

n is from 1-4,

and pharmaceutically acceptable salts thereof.

The compounds of formula I have valuable pharmacological properties. In particular, they are collagenase inhibitors and can be used in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis, or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis.

The subject of the presented invention are compounds of formula I and their pharmaceutically acceptable salts per se and in use as therapeutically active substances, the process of preparing said compounds and salts, intermediate products useful in said processes, drugs containing said compounds and salts and the preparation of said drugs, and the use of said compounds and salts in the control or prevention of diseases or for the improvement of general health status, in particular in the control or prevention of degenerative joint diseases or in the therapy of invasive tumors or atherosclerosis, or for the preparation of drugs for the control or prevention of degenerative joint diseases or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis.

In this specification, the term "lower alkyl" alone or in combination, refers to straight or branched alkyl groups containing up to six, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert -butyl, n-pentyl, n-hexyl and the like. The term "lower alkoxy" alone or in combination, refers to straight or branched alkoxy groups containing up to six, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-buloxy, tert-butoxy and the like. The term "aryl" means phenyl which may be substituted, for example with lower alkyl, lower alkoxy and/or halogen, for example with fluorine, chlorine, bromine or iodine. The term "aralkII" refers to a lower alkyl group as defined above in which one or more hydrogen atoms have been replaced by an aryl group as defined above, such as benzyl and the like. The ketalized oxo group can be, for example, ethylenedioxy.

The protecting group denoted as R4 can be any conventional protecting group, eg those known in peptide chemistry such as benzyloxycarbonyl, tert-butoxycarbonyl, acetyl and the like.

Examples of monocyclic N-heterocyclic rings designated as R2 are: 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-aryl-1-piperazinyl, hexahydro-1-pyridazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl , tetrahydro-1,4-thiazin-4-yl 1-oxide, tetrahydro-1,4-thiazin-4-yl 1,1-dioside, thiazolidin-3-yl, hexahydroazepino and octahydroazocino which could be substituted in the previously indicated manner , for example 2-(methylcarbamoyl)-1-pyrrolidinyl, 2-(hydroxymethyl)-1-pyrrolidinyl, 4-hydroxypiperidine, 2-(methylcarbamoyl)piperidine, 4-hydroxyiminopiperidine,

4-methoxypiperidine, 4-methyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1,4-dioxa-8-azaspito[4.5]decan-8-yl, hexahydro-3-(methylcarbamoyl)-2-pyridazinyl , hexahydro-1-(benzyloxycarbonyl)-2-pyridazimyl, 5,5-dimethyl-4-methylcarbamoyl-thiazolidin-3-yl and 5,5-dimethyl-4-propylcarbamoyl-thiazolidin-3-yl.

Examples of bridged N-heterocyclic rings designated as R2 are: 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.1]heptane, 7-azabicyclo[2.2.]heptane, 3-azabicyclo[3.2.1]- octane, 2-azabicyclo[3.2.2]nonane and 3-azabicyclo|3.2.2]nonane.

Examples of N-heterocyclic rings designated as R3 have the following formulas:

[image]

where

R5 and R6 each represent hydrogen or together represent an additional bond or residue of a fused benzene ring,

R7 represents hydrogen, lower alkyl or aryl, and

X represents -CO-, -CH2-, -CH(lower alkyl))-, -C(lower alkyl)2-, -NH-, -N(lower alkyl)- or -O-, or when R7 represents lower alkyl , and X represents -N(lower alkyl)-, then the lower alkyl group can be attached to form a five-, six- or seven-membered ring,

R8 represents hydrogen, lower alkyl or aryl,

R9 and R10 each represent hydrogen or lower alkyl,

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

Z represents S, SO or SO2.

Examples of such rings are 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidino, flalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-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-oxadiaxole-4- yl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl and 2,6-dioxopiperidino, 5,5-dimethyl-2,4-diosco- 3-phenyl-1-imidazolidinyl, 2,6-dioxopiperidino, 5,5-dimethyl-2,4-dioxo-3-oxazoludinyl,

and hexahydro-1,3-dioxopyrazolo[1,2-a][1,2,4]triazol-2-yl.

One group of preferred compounds of formula I includes those in which R 2 represents:

1-pyrrolidinyl, piperidino, 4-aryl-1-piperazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl 1,1-dioxide, thiazolidin-3-yl , hexahydroazepino or octahydroazocino which can be substituted on one or more C atoms with hydroxy, lower alkyl, lower alkoxy, ketalized oxo or with mono(lower alkyl)-carbamoyl, especially with piperidino which can be substituted with hydroxy, especially 4- hydroxypiperidino, or 3-azabicyclo[3.2.2]nonane.

Also preferred are compounds of formula I in which R3 represents a group of formulas (b), (c), especially one in which R7 represents lower alkyl, and X represents -C(lower alkyl)2-, and especially 3,4,4-trimethyl -2,5-dioxole-imidazolidinyl, or (h).

Preferably, both N and m are 1.

The most preferred compounds of formula I are:

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(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-inidazolidinyl)ethyl]propionyl]- 4-

pipendinol,

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

bicyclo[3.2.2]nonane,

1-[3-cyclobutyl-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-pipe

ridinol,

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

bicyclo[3.2.2]nonane,

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

piperidinol,

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

bike(3.2.2]nonan, te

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

piperidine.

Other preferred compounds of formula I shown above are:

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,

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-

imidazolidines])ethyl]propionyl]tetrahydro-1,4-thiazine S,S-dioxide,

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)-thiazolidinecarboxamide,

4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-

imidazolidinyl)ethyl]propionyl]morpholine,

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)-thiazolidinecarboxamide,

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]morpholine ,

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-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-

imidazolidinyl)ethyl]propionyl]octahydroazocine,

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]hexahydroazepine,

1-[3-cyclobutyl-2(R)-(2-(hexahydro-1,3-dioxopyrazolo[1,2-a][1.2.4]triazol-2-yl-1(R or S)-

(hydroxycarbamoyl)ethyl]propionyl]piperidine, and

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

The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali metal hydroxides (eg sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (eg calcium hydroxide and magnesium hydroxide), ammonium hydroxide and the like. Compounds of formula I which are bases form pharmaceutically acceptable salts with acids. Such salts that come into consideration are not only salts of inorganic acids such as hydrohalic acid (eg hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc., but also salts of organic acids such as acetic acid, tartaric acid. acid succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

The compounds of formula I contain at least two asymmetric carbon atoms and accordingly can exist as optically active enantiomers, as well as diastereomers and racemates. The intention of the presented invention is to cover all these forms.

According to the presented invention, the compounds of formula I and their pharmaceutically acceptable salts are prepared in the following way:

(a) by the reaction of an acid of the general formula:

[image]

where R1, R2, R3, m and n have previously given meanings with the compound of the general formula

H2N-OZ (III)

where Z represents hydrogen, tri(lower alkyl)silyl or diphenyl(lower alkyl)silyl, and where it is necessary to remove the diphenyl(lower alkyl)silyl group present in the reaction product, or

(b) by catalytic hydrogenation of a compound of the general formula:

[image]

where R1, R2, R3, m and n have previously given meanings, and Bz represents benzyl, and, if necessary, converting the obtained compound of formula I into a pharmaceutically acceptable salt.

The reaction of an acid of formula II with a compound of formula III according to unit (a) can be carried out in a known manner, for example in an inert organic solvent such as dimethylformamide and the like using hydroxybenzotriazole in the presence of a condensing agent such as 1-ethyl-3-(3 -dimethylaminopropionyl)carbodiimide hydrochloride at from about 0°C to room temperature. Preferred compounds of formula III are those in which Z represents hydrogen, tert-butyldimethylsilyl or tert-butyldiphenylsilyl. When a compound of formula III is used in which Z represents diaryl(lower alkyl)silyl, this group remains in the reaction product and must subsequently be cleaved off in a known manner, for example with fluoride ions.

Catalytic hydrogenation of the compound of formula IV in accordance with part (b) can be carried out in a manner known per se, for example in an inert organic solvent using hydrogen in the presence of a noble metal as a catalyst. Suitable inert organic solvents are, for example, lower alkanols such as methanol, ethanol, etc. Regarding the catalyst, it can be, for example, platinum, palladium or rhodium, which can be on a suitable support. Palladium on charcoal is the preferred catalyst. Temperature and pressure are not decisive, although for convenience, catalytic hydrogenation is preferably performed at room temperature and atmospheric pressure.

Compounds of formula I can be converted into pharmaceutically acceptable salts by reaction with bases, and basic compounds of formula I can be converted into pharmaceutically acceptable salts by reaction with acids. Such conversions can be performed in a conventional manner.

Acids of formula II prepared in new processes, which are used as starting compounds, are also objects of this invention.

Acids of formula II can be prepared as illustrated in the following Reaction Scheme in which R1, R2, R3, m and n have the previously given meanings, Bz represents benzyl and tBu represents tert-butyl.

[image]

Bearing in mind the preceding Reaction Scheme, its individual steps can be carried out according to methods known per se. Thus, in the first stage, the amino acid of formula V, which can be obtained according to the process described by Chenault H. K., Dahmer J, and Whitesides G. M., J. Am. Chem. Soc. 1989, 111, 6354-6364, can be converted by treatment with sodium nitrite in the presence of concentrated sulfuric acid to the hydroxy acid of formula VI, which is then reacted with benzyl bromide in the presence of an organic base, eg a trialkylamine such as triallylamine, to give the corresponding benzyl ester of formula VII. This is then activated, eg by reaction with trifluoromethanesulfonic acid anhydride, and reacted with tert-butyl malonate in the presence of a strong base, eg an alkali metal hydride such as sodium hydride, whereby the compound of formula VIII is obtained. By acting with a strong base, e.g. alkali metal hydride, and reacting the compound of formula IX, dibenzyl-tert-butyl-butanedicarboxylate (formula X) is obtained, which is then debenzylated by catalytic hydrogenation, e.g. in the presence of a palladium catalyst, such as palladium on charcoal, whereby tert-butyl dihydrogenbutanedicarboxylate of formula XI was obtained. By decarboxylation of this compound, e.g. by heating in toluene with triethylamine, which can be carried out in situ, tert-butyl hydrogen succinate of formula XII is obtained, which is condensed with a cyclic amine of formula XIII, e.g. .according to the acid clone method using 1-hydroxybenzotriazole in the presence of a condensing agent such as 1-ethyl-3-(3-dimethylaniminopropyl)carbodiimide hydrochloride to give a deprotected compound of formula XVI (eg by treatment with trifluoroacetic acid ), and the acid of formula II was obtained.

The compounds of formula IV which were used as starting compounds in the whole (b) are new and form a further content of the presented invention.

Compounds of formula IV can be prepared, for example, by reacting the acid of formula II with O-benzylhydroxylamine. This reaction can be carried out in a known manner, for example in an inert organic solvent such as dichloromethane or dimethylformamide using 1-hydroxybenzotriazole in the presence of a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

Other compounds used as intermediates or reactants in the preparation of compounds of formula I are known compounds or are analogues of known compounds and can be prepared in a similar way as known compounds.

As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable salts are collagenase inhibitors. The inhibitory activity of the proposed compounds of formula I and their salts on collagenase can be demonstrated in vitro using collagenase obtained from the culture of human fibroblasts from synovial fluid according to Dayer J-M et al., Proc. Nall. Acad. Sci USA (1976), 73 945, after activation of procollagenase in the appropriate medium by treatment with trypsin. Collagenase activity was measured using a substrate of 14C-acetylated type I collagen from rat tail tendon, using the microtiter well method according to Johnson-Wint, B, Anal. Biochem. (1980), 104, 175. IC50 is that concentration of a compound or its salt from the presented invention in an enzymatic reaction that reduces substrate cleavage and solubilization to 50% compared to that achieved by the enzyme itself.

The results obtained from the previous test with representatives of the compounds and salts of the present invention are shown in the following Table I:

[image]

The compounds of formula I and their pharmaceutically acceptable salts can be used as drugs, for example in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally, eg tablets, film-coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, they can also be administered rectally, eg in the form of suppositories, or parenterally, eg in the form of injectable solutions.

For the production of pharmaceutical preparations of compounds of formula I and their pharmaceutically acceptable salts, therapeutically indifferent, organic or inorganic auxiliaries can be used.

Lactose, corn starch or their derivatives, talc, stearic acid or its salts are examples of such auxiliaries that can be used for tablets, film tablets, dragees, hard and soft gelatin capsules. Suitable excipients for soft gelatin capsules are, for example, oils, waxes, fats, semi-solid and liquid polyols and the like.

In general, no excipients are required for soft gelatin capsules, depending on the nature of the active substance. Suitable auxiliary agents for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable auxiliary agents for the preparation of injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Natural and hardened oils, waxes, fats, semi-liquid polyols, etc. are suitable auxiliary means for the preparation of suppositories.

Pharmaceutical preparations may also contain preservatives, stabilizers, glidants, emulsifiers, sweeteners, colors, flavors, salts for adjusting osmotic pressure, buffers, coating agents or antioxidants.

Medicines containing compounds of formula I or their pharmaceutically acceptable salts and therapeutically acceptable excipients, as well as methods of preparing these medicines are also subject of the presented invention. Preparation procedures include mixing the compounds of formula I or their pharmaceutically acceptable salts with therapeutically inert auxiliaries, and shaping the mixture into a galenic form suitable for administration.

As already mentioned, the compounds of formula I and their pharmaceutically acceptable salts can be used for the control and prevention of diseases, especially in the control and prevention of degenerative joint diseases or in the therapy of invasive tumors, arteriosclerosis or multiple sclerosis. The dose can vary within a wide range and will, of course, need to be adjusted to the individual requirement in each case. Generally, when administered to adults, the daily dose is from about 5 mg to about 30 mg, preferably from about 10 mg to about 15 mg, although the upper limit can be increased when found necessary. The daily dose can be given as a single dose or divided.

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

Example 1

Solution 0.575 g 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl ]piperidine (diastereomer 1) in 10 mL of ethanol was hydrogenated in the presence of 0.4 g of 5% palladium on charcoal for 6 hours. The catalyst was removed by filtration and the solution was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (96:4) as eluent to give 0.37 g of 1-[3-cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl) )-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (diastereomer 1) in the form of a white foam.

NMR(MeOD): 3.78-3.64 (m, 3H), 3.62 (dd, 1H, J=15, 8), 3.49-3.41 (m, 1H), 3.39 (dd, 1H, J=15, 5), 3.33 -3.27 (m. 1H). 2.95-2.87 (m, 1H), 2.83 (s, 3H), 1.74-1.46 (m, 7H), 1.33 (s, 3H), 1.31 (s, 3H), 1.20-1.13 (m, 1H), 0.61- 0.50 (m, 1H), 0.44-0.33 (m, 2H), 0.06- -0.05 (m, 2H), MS: 409 (M+H)+

The starting compound is prepared in the following way:

(i) A solution of 4.9 g of 2(R)-amino-3-cyclopropylpropionic acid (prepared as described by Chenault H.K., Dahmer J., and Whitesides G.M., J. Am. Chem. Soc. 1989, 111, 6354- 6364) in 50 mL of water containing 4.05 mL of concentrated sulfuric acid was heated at 45°C. A solution of 10.5 g of sodium nitrite in 20 mL of water was added dropwise over 30 minutes. The solution was stirred for 4 h at 45°C and cooled to room temperature. The solution was extracted with three portions of 50 mL of ethyl acetate. The combined extracts were washed with water and dried over magnesium sulfate. The solvent was evaporated and 3.95 g of yellow oil containing 3-cyclopropyl-2(R)-hydroxypropionic acid remained, which was used in the next step without further purification. Rf [dichloromethane/methanol (9:1)]=0.65.

(ii) 5.32 mL of triethylamine and 3.8 mL of benzyl bromide were added to a solution of 3.95 g of the product from (i) in 50 mL of ethyl acetate. The mixture was stirred and heated under reflux for 3 hours, and was left overnight to cool to room temperature. The suspension was washed with 2 M hydrochloric acid, water, and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to give 3.36 g of benzyl 3-cyclopropyl-2(R)-hydroxypropionate as a yellow oil. NMR (CDCl3): 7.39-7.28 (m, 5H), 5.19 (d, 1H, J=14), 5.15 (d, 1H, J=14), 4.31-4.24 (m, 1H), 2.81 (broad d, 1H), 1.69-1.54 (m, 2H), 0.87-9.74 (m, 1H), 0.45-0.34 (m, 2H), 0.08-0.07 (m, 2H).

(iii) A solution of 3.36 g of the product from (ii) and 1.49 mL of pyridine in 10 mL of dichloromethane was added dropwise over 30 minutes to a solution of 3.07 mL of trifluoromethanesulfonic acid anhydride in 15 mL of dichloromethane at 0°C with stirring. The mixture was stirred at 0°C for 2 hours and washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, whereby 5.37 g of benzyl-3-cyclopropyl-2(R)-trifluoromethanesulfonylpropionate were obtained in the form of an orange oil, which was used in the next step without further purification.

Rf-(hexane/ethyl acetate (4:1))=0.5.

(iv) 0.504 g of 80% dispersed sodium hydride in mineral oil was added to a solution of 3.8 g of benzyl tert-butyl malonate in 50 mL of 1,2-dimethoxyethane. The mixture was stirred at room temperature for 30 minutes and cooled to 0°C. A solution of 5.37 g of the product from (iii) in 20 mL of dichloromethane was added dropwise at 0°C. The mixture was stirred for 2 hours at 0°C and allowed to warm to room temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, whereby 6.54 g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R),3(R,S),3-propanetricarboxylate was obtained in the form of an orange oil .

NMR (CDCl3): 7.46-7.36 (m, 20H), 5.19-5.07 (m, 8H), 3.89 (d, 1H, .1=10), 3.85 (d, 1H, J=10) 3.37-3.26 (m , 2H), 1.68-1.52 (m, 3H), 1.52-1.38 (m, 2H), 1.41 (s, 9H), 0.79-0.63 (m, 2H), 0.49-0.38 (m, 4H), 0.12-0.07 (m, 4H).

(v) 0.446 g of 80% dispersed sodium hydride in mineral oil was added to a solution of 6.4 g of the product from (iv) in 30 mL of 1,2-dimethoxyethane. The mixture was stirred for 30 minutes at room temperature. A solution of 3.84 g of 1-(bromoethyl)-3,4,4-trimethyl-2,5-imidazolidene-dione in 20 mL of 1,2-dimethoxyethane was added dropwise over 15 minutes. The mixture was stirred at room temperature for 36 hours, the solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (7:3) and then hexane/ethyl acetate (6:4) as eluent to give 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-butanetricarboxylate, mixture of diastereomers in the ratio 1:1 , in the form of a clear oil.

NMR (CDCl3): 7.47-7.28 (m, 20H), 5.31-5.03 (m, 8H), 4.32-4.18 (m, 4H), 3.19-3.15 (m, 1H), 3.16-3.12 (m, 1H), 2.86 (s, 6H), 2.00-1.9 (m, 1H), 1.89-1.79 (m, 1H), 1.64-1.49 (m, 1H), 1.48-1.38 (m, 1H), 1.37 (s, 12H), 1.36 (s, 9H), 1.32 (s, 9H), 0.9-0.8 (m, 2H), 0.41-0.3 (m, 4H), 0.15-0.05 (m, 2H), 0.04- -.04 (m, 2H ).

(vi) A solution of the product from (v) in 30 mL of 2-propanol was hydrated in the presence of 0.3 g of 5% palladium on charcoal as a catalyst for 2 hours. The catalyst was removed by filtration, and the solution was evaporated. The residue was re-evaporated from 20 mL of toluene and dissolved in 50 mL of toluene. 0.693 mL of triethylamine was added to the solution and the mixture was heated under reflux for 2 hours. The solution was cooled to room temperature and washed with 2 M hydrochloric acid, water, and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, whereby 1.85 g of 4-tert-butyl hydrogen 2(R)-(cyclopropylmethyl)-3(R or S)-[(3,4,4-trimethyl- 2,5-dioxo-1-imidazolidinyl)methyl]succinate, a mixture of diastereomers in a ratio of approximately 6:1, as a yellow oil.

MS: 383 (M+H) +

Rf [dichloromethane/methanol (9:1)]=0.41.

(vii) A solution of 1.0 g of the product from (vi) in 10 mL of dichloromethane was cooled to 0°C, and 0.665 mL of N-ethylmorpholine was added, then 0.481 g of 1-hydroxybenzotriazole, and 0.602 g of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for 30 minutes at 0°C, and 0.517 mL of piperidine was added. The solution was left overnight to warm to room temperature. The solution was washed with 5% aqueous sodium hydrogen carbonate solution, 2 M hydrochloric acid, and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated, yielding 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-cyclopropylpropionyl]piperidine, a mixture of diastereomers in a ratio of approximately 6:1, in the form of a yellow gum.

MS: 450 (M+H)+

Rf [dichloromethane/methanol (95:5)]=0.51.

(viii) A solution of 1.0 g of the product from (vii) in 2 mL of trifluoroacetic acid was stirred for 2.5 hours at room temperature. The solvent was evaporated and the residue was re-evaporated from toluene. The residue was dissolved in diethyl ether, and the solution was extracted twice with two portions of 5% aqueous sodium hydrogen carbonate solution. The combined extracts were acidified to pH 2 with concentrated hydrochloric acid and the product was extracted with two portions of dichloromethane. The combined organic extracts were washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate.

The solvent was evaporated, yielding 0.634 g of a white foam containing 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-3-cyclopropylpiopionyl]piperidine, a mixture of diastereomers in a ratio of approximately 6:1, which was used in the next step without further purification.

Rf [dichloromethane/methanol (9:1)]=0.31.

(ix) A solution of 0.634 g of the product from (viii) in 10 mL of dichloromethane was cooled to 0°C. 0.41 mL of N-ethylmorpholine, then 0.296 g of 1-hydroxybenzotriazole, and 0.371 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the solution. The mixture was stirred for 30 minutes at 0°C. A solution of 0.238 g of 0-benzylhydroxylamine in 2 mL of dichloromethane was added. The mixture was allowed to warm to room temperature and stirred overnight. The solution was washed with two portions of 5% aqueous solution of sodium hydrogencarbonate, then with 2 M hydrochloric acid, water, and a saturated solution of sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by "flash" chromatography on silica gel using dichloromethane/methanol (98:2) for elution, whereby 0.592 g of l-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-3-cyclopropylpropionyl]piperidine (diastereomer 1) in the form of a white foam.

NMR (MeOD): 7.45-7.31 (m, 5H), 4.87 (d, 1H, J=13), 4.79 (d, 1H, J=13), 3.78-3.65 (m, 3H), 3.63 (dd, 1H , J=15, 8), 3.53-3.45 (m, 1H), 3.44 (dd, 1H, J=15, 5), 3.34-3.27 (m, 1H), 2.87 (s, 3H), 2.84-2.78 ( m, 1H), 1.78-1.49 (m, 7H), 1.49-1.40 (m, 1H), 1.36 (s, 3H), 1.32 (s, 3H), 1.12-1.04 (m, 1H), 0.61-0.50 ( m, 1H), 0.48-0.37 (m, 2H), 0.07- -0.06 (m, 2H), MS: 499 (M+H)+

Example 2

In an analogous manner to that described in the first paragraph of Example 1, from 0.391 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclopropylpropionyl)-4-piperidinol (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.33 g of 1-[3- cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidin-yl)ethyl]propionyl]-4-piperidinol (diazstereomer 1) in the form of a white foam.

NMR (MeOD): 4.22-4.02 (m, 2H), 3.90-3.81 (m, 1H), 3.69-3.56 (m, 1H), 3.49-3.38 (m, 2H), 3.37-3.18 (m, 2H), 3.11-3.01 (m, 1H), 2.97-2.86 (m, 1H), 2.83 (d, 3H, J=5), 2.01-1.78 (m, 2H), 1.68-1.36 (m, 3H), 1.33 (s , 3H), 1.31 (d, 3H, J=5), 1.24-1.13 (m, 1H), 0.62-0.50 (m, 1H), 0.49-0.33 (m, 2H), 0.09- -0.05 (m , 2H), MS: 425 (M+H) +

Example 3

In an analogous way to that described in the first paragraph of Example 1, from 0.822 g of 3-(2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclopropyl]-3-azabicyclo[3.2.2]nonane (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.5 g 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 (diastereomer 1) in the form of a white foam.

NMR (MeOD): 4.0-3.1 (m, 5H), 3.48-3.31 (m, 2H), 2.96-2.86 (m, 1H), 2.82 (s, 3H), 2.14-2.03 (m, 2H), 1.80- 1.68 (m, 4H), 1.68-1.53 (m, 5H), 1.32 (s, 3H), 1.31 (s, 3H), 1.21-1.12 (m, 1H), 0.64-0.52 (m, 1H), 0.45- 0.33 (m, 2H), 0.08--0.05 (m, 2H), MS: 449 (M+H)4.

Example 4

In an analogous manner to that described in the first paragraph of Example 1, from 0.6 g of 1-1-[2(R)-[1(Ryl S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]piperidine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 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 (diastereomer 1) in the form of a white foam .

NMR (MeOD): 3.67 (dd, 1H, J=15, 10), 3.64-3.46 (m, 4H), 3.34 (dd, 1H, J=15, 8), 3.12(dt, 1H,J= 13, 3), 292-2.84 (m, 1H), 2.82 (s, 3H), 2.22-2.09 (m, 1H), 2.07-1.93 (m, 2H), 1.90-1.42 (m, 12H), 1.33 (s, 3H), 1.32 (s.3H),

MS: 423 (M+H) + .

Example 5

In an analogous manner to that described in the first paragraph of Example 1, from 0.4 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]-4-piperidinol (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.294 g of l-[3- cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-propionyl]-4-piperidinol ( diastereomer 1) in the form of a white foam.

NMR(MeOD): 4.15-4.05 (m, 1H), 4.04-3.90 (m, 1H), 3.90-3.80 (m, 1H), 3.72-3.57 (m, 1H), 3.45-3.30 (m, 2H). 3.18-3.06 (m, 2H), 2.94-2.85 (m, 1H), 2.84 (d, 3H, J=5), 2.21-1.36 (m, 13H), 1.33 (d, 3H, J=3), 1.31 (d, 3H, J=6), MS: 439 (M+H)4.

Example 6

In an analogous manner to that described in the first paragraph of Example 1, from 0.642 g of 3-[2(R)-[1(Ryl S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)-ethyl]-3-cyclobutyl]-3-azabicyclo[3.2.2]nonane (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.5 g was obtained 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 (diastereomer 1) in the form of a white foam.

NMR (MeOD): 3.92-3.83 (m, 2H), 3.76 (dd, 1H, J=15, 13), 3.67-3.57 (m, 2H), 3.34 (dd, 1H, J=15, 5), 3.28 -3.21 (m, 1H), 2.96-2.87 (m, 1H), 2.83 (s, 3H), 2.23-2.13 (m, 1H), 2.12-1.92 (m, 4H), 1.91-1.48 (m, 14H) , 1.35 (s, 3H), 1.34 (s, 3H), MS: 463 (M+H) + .

Example 7

In an analogous manner to that described in the first paragraph of Example 1, from 0.5 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclopentylpropionyl]-4-piperidinol (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.4 g of 1-[3- cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol (diastereomer 1) in the form of white foam.

NMR (MeOD): 4.20-4.02 (m, 2H), 3.91-3.83 (m, 1H), 3.76-3.64 (m, 1H), 3.48-3.32 (m, 2H), 3.26-3.08 (m, 3H), 2.05-1.42 (m, 12H), 1.38-1.25 (m, 7H), 1.18-1.01 (m, 3H), MS: 453 (M+H) + .

Example 8

In an analogous manner to that described in the first paragraph of Example 1, from 0.57 g of 3-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclopentyl]-3-azabicyclo[3.2.2]nonane (diastereomer 1), which was prepared in an analogous way to that described in Example 1 (i)-(ix), obtained 0.48 g 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 (diastereomer 1) in the form of a white foam.

NMR (MeOD): 3.88-3.67 (m, 5H), 3.39-3.31 (m, 2H), 2.92-2.85 (m, 4H), 2.15-2.06 (m, 2H), 1.83-1.45 (m, 16H), 1.36-1.28 (m, 7H), 1.16-1.02 (m, 2H), MS: 477 (M+H) + .

Example 9

A solution of 0.421 g of a mixture of diastereomer 1 and diastereomer 2 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl] -3-Cyclopentylpropionyl]piperidine with an approximate ratio of 6:1, which was prepared in an analogous manner to that described in Example 1 (i)-(viii), in 10 mL of dichloromethane was cooled to 0°C. 0.211 g of 1-hydroxybenzotriazole, 0.24 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.22 mL of N-methylmorpholine were added to the solution. The mixture was stirred for 15 minutes at 0°C. 0.295 g of 0-(tert-butyldimethylsilyl)hydroxylamine and 0.223 mL of N-methylmorpholine in 5 mL of dichloromethane were added to the solution. The mixture was allowed to warm to room temperature and stirred overnight. The solution was washed with two portions of 5% aqueous sodium hydrogencarbonate solution, then with 2M hydrochloric acid and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (96:4) as eluent to give 0.123 g of 1-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl) -2-(3,4,4-tri-methyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (diastereomer 1) in the form of a white foam.

NMR (MeOD): 3.74-3.66 (m, 3H), 3.53-3.45 (m, 2H), 3.34 (dd, J=14, 7, 1H), 3.23 (dt, J=4, 14, 1H), 2.90 -2.84 (m, 4H), 1.80-1.45 (m, 14H), 1.38-1.23 (m, 7H), 1.15-1.01 (m, 2H), MS: 437 (M+H)+.

Example 10

In an analogous manner to that described in the first paragraph of Example 1, starting from 0.328 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5- dioxo-1-imida-zolidinyl)ethyl]-3-cyclohexylpropionyl]piperidine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.269 g of 1-[3-cyclo -hexyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (diazstereomer 1) in the form of white foam.

NMR (MeOD): 3.87-3.77 (m, 2H), 3.7 (dd. 1H, J=14, 9), 3.64-3.56 (m, 2H), 3.38-3.28 (m, 2H), 2.9-2.83 (m , 4H), 1.84-1.45 (m, 12H), 1.35 (s. 3H), 1.33 (s, 3H), 1.25-1.05 (m, 5H), 0.98-0.78 (m, 2H), MS: 451 (M+H)+.

Example 11

In an analogous manner to that described in the first paragraph of Example 9, starting from 0.8 g of 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]tetrahydro-1,4-thiazine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(viii), 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 (diastereomer 1) in the form of white foam.

NMR (MeOD): 4.02-3.96 (m, 2H), 3.92-3.85 (m, 2H), 3.7 (dd, J=13, 9, 1H), 3.37 (dd, J=13, 6, 1H), 3.25 -3.18 (m, 1H), 2.9-2.84 (m, 4H), 2.82-2.75 (m, 1H), 2.7-2.55 (m, 3H), 1.78-1.45 (m, 8H), 1.35 (s, 3H) , 1.34 (s, 3H). 1.18-1.04 (m. 2H), MS: 455 (M+H)+.

Example 12

In an analogous manner to that described in the first paragraph of Example 1, starting from 0.3 g of 4-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5- dioxo-1-imidazolidin-yl)ethyl]-3-cyclopentylpropionyl]tetrahydro-1,4-thiazine S,S-dioxide (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix) , 0.2 g of 4-(3-cyclopentyl-2(R)-[1(Ryli S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) was obtained )ethyl]propionyl]tetrahydro-1,4-thiazine S,S-dioxide (diastereomer 1) as a white solid.

NMR (MeOD): 4.45-4.3 (m, 2H), 4.0-3.943 (m, 1H), 3.78-3.65 (m, 2H), 3.55-3.39 (m, 2H), 3.30-3.21 (m, 2H), 3.14-3.03 (m, 2H). 2.9-2.85 (m, 4H), 1.78-1.45 (m, 9H), 1.36 (s, 3H), 1.34 (s, 3H), 1.18-1.0 (m, 2H), MS: 487 (M+H)+ .

Example 13

In an analogous manner to that described in the first paragraph of Example 9, starting from 0.8 g of 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-3-cyclo-butylpropionyl]tetrahydro-1,4-thiazine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(viii), 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 (diazstereomer 1) in the form of a white solid.

NMR (MeOD): 3.98-3.75 (m, 4H), 3.64 (dd, J=13, 8, 1H), 3.35 (dd, J=15, 6, 1H), 3.07 (td, J=10, 4, 1H), 2.9-2.83 (m, 4H), 2.82 (s, 1H), 2.78-2.72 (m, 1H), 2.66-2.52 (m, 3H), 2.18-2.08 (m, 1H), 2.05-1.93 ( m, 2H), 1.85-1.45 (m, 6H), 1.13 (s, 3H), 1.11 (s, 3H), MS: 441 (M+H) + .

Example 14

In an analogous manner to that described in the first paragraph of Example 9, starting from 1.22 g of 1-[2(R)-[1(R or S)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-3-cyclohexylpropionyl]tetrahydro-1,4-thiazine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(viii), 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 (diazstereomer 1) in the form of a white solid.

NMR (MeOD): 4.12-4.03 (m, 2H), 3.95-3.88 (m, 1H), 3.75-3.65 (m, 2H), 3.38 (dd, J=14, 6, 1H), 2.88-2.82 (m , 4H), 2.78-2.72 (m, 1H), 2.68-2.55 (m, 3H), 1.82-1.53 (m, 7H), 1.35 (s, 3H), 1.34 (s, 3H), 1.26-0.8 (m , 8H) MS: 469 (M+H) + .

Example 15

In an analogous manner to that described in the first paragraph of Example 9, starting from 1,164 g of a mixture of diastereomers of 3-[2(R)-[1(RS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide, which was prepared in an analogous manner to that described in Example 1 (i)-(viii), obtained is 0.329 g of 3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-11-imidazolidinyl)ethyl] propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidine-carboxamide (diazstereomer 1) as a white solid.

NMR (MeOD): 5.09-4.72 (m, 2H), 4.51 and 4.46 (both s, total 1H), 3.84 and 3.64 (both dd, J=14, 8, total 1H), 3.40-3.05 (m, 4H), 2.90-2.73 (m, 4H), 1.94-1.25 (m, 23H), 1.23--1.01 (m, 2H), 0.99-0.85 (m, 3H), MS: 554 (M+H)+.

Example 16

In an analogous manner to that described in the first paragraph of Example 1, from 0.223 g of 4-[2(R)-[(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)-ethyl]-3-cyclopentylpropionyl)morpholine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 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]morpholine (diazstereomer 1) as a white solid.

NMR(MeOD); 3.83-3.56 (m, 9H), 3.41 (dd, J=14, 6, 1H), 3.19 (dt, J=4, 11, 1H). 2.91-2.81 (m, 4H). 1.77-1.42(m, 8H), 1.38-1.23 (m, 7H), 1.19-0.99 (m, 2H), MS: 439 (M+H) + .

Example 17

In an analogous manner to that described in the first paragraph of Example 9, from 1,289 g of a mixture of diastereomers 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)-thiazolidinecarboxamide (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(viii), obtained is 0.629 g of 3-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-tri-methyl-2,5-dioxo-1-imidazolidinyl) ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide (diastereomer 1) as a white solid.

NMR (MeOD): 4.09-4.51 (m, 2H), 4.47 and 4.43 (both s, total 1H), 3.82 and 3.62 (both dd, J=14, 10, total 1H), 3.37 and 3.17 (both dd, J =14.5, total 1H), (3.13-2.70 (m, 8H), 1.96-1.25 (m, 21H), 1.23-0.99 (m, 2H), MS: 526 (M+H)+

Example 18

In an analogous manner to that described in the first paragraph of Example 1, from 0.289 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]-4-phenylpiperazine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 0.121 g of l-(3- cyclobutyl-2(R)-[1(R or S)-[(hydroxycarbamoyl)methyl]-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]propionyl]-4 -phenylpiperazine (diastereomer 1) in the form of a white solid.

NMR (MeOD): 7.25 (m. 2H), 7.00 (m, 2H), 6.85 (m, 1H), 3.94-3.73 (m, 4H), 3.66 (dd, J=14, 7, 1H), 3.43 ( dd, .1=14, 6, 1H), 3.23-3.09 (m, 4H), 2.96-2.84 (m, 1H), 2.84 (s, 3H), 2.27-2.13 (m, 1H), 2.09-1.95 ( m, 2H), 1.90-1.48 (m, 6H), 1.35 (s, 3H), 1.34 (s, 3H), MS: 499 (M+H)+

Example 19

In an analogous manner to that described in the first paragraph of Example 1, from 0.455 g of 4-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]morpholine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 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]morpholine (diastereomer 1) as a white solid .

NMR (MeOD): 3.80-3.51 (m, 9H), 3.42 (dd, J=14, 6, 1H), 3.14-3.06 (dt, J=4J 1 1H), 3.04-2.86 (m, 1H), 2.85 (s, 3H), 2.23-2.11 (m, 1H), 2.06-1.95 (m, 2H), 1.91-1.73 (m, 3H), 1.71-1.46 (m, 4H), 1.35 (s, 3H), 1.34 (s,3H), MS: 425 (M) + .

Example 20

In an analogous way to that described in the first paragraph of Example 1, from 0.625 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]pyrrolidine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 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]morpholine (diastereomer 1) as a white solid .

NMR (MeOD): 3.77-3.69 (m, 1H), 3.61 (dd, J=14, 6, 1H), 3.53-3.44 (m, 2H), 2.93-2.85 (m, 2H), 2.84 (s, 3H) ), 2.26-2.13 (m, 1H), 2.07-1.71 (m, 8H), 1.69-1.46 (m, 4H), 1.36 (s. 3H), 1.33 (s, 3H), MS: 409 (M+H )+

Example 21

In an analogous way to that described in the first paragraph of Example 1, from 0.176 g of 8-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]-1,4-doxa-8-azaspiro[4.5]decane (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix) , 0.084 g of 8-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) was obtained ethyl]propionyl]-1,4-doxa-8-azaspiro [4.5]decane (diazstereomer 1) as a white solid.

NMR (MeOD): 4.02 (s, 4H), 3.81-3.60 (m, 5H), 3.99 (dd, J=14, 6, 1H), 3.20-3.10 (m, 1H), 2.93-2.85 (m, 1H ), 2.84 (s, 3H), 2.21-2.09 (m, 1H), 2.06-1.93 (m, 2H), 1.80-1.46 (m, 10H), 1.35 (s, 3H), 1.33 (s, 3H), MS: 481 (M+H) + .

Example 22

In an analogous manner to that described in the first paragraph of Example 1, from 0.443 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl)-4-methoxypiperidine (diastereomer 1), 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 (diazstereomer 1) as a white solid.

NMR (MeOD): 3.96-3.80 (m, 2H), 3.69-3.59 (m, 1H), 3.54-3.23 (m, 7H), 3.18-3.09 (m, 1H), 2.93-2.80 (m, 4H), 2.21-2.09 (m, 1H), 2.07-1.41 (m, 12H), 1.41-1.38 (m, 6H), MS: 453 (M+H)+

The starting compound is prepared in the following way:

(i) Solutions 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-cyclopropylpropionyl]-4-hydroxypiperidine, 1.08 g of methyl iodide and 1.79 g of silver oxide were added to 8 mL of dimethylformamide. The mixture was stirred for 2 days at room temperature in a dark place. A new portion of 0.54 g of methyl iodide and 0.895 g of silver oxide was added, and the mixture was stirred for another 3 days. The solvent was evaporated, and the residue was suspended in ethyl acetate and filtered. The ethyl acetate solution was concentrated and the residue was purified by flash chromatography on silica gel using ethyl acetate as eluent. 0.61 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]- 3-cyclopropyl]propionyl]-4-methoxypiperidine in the form of a colorless gum.

(ii) In an analogous manner to that described in Example 1 (viii)-(ix), from 0.61 g of 1-|2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(3,4, 4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-4-methoxypiperidine yielded 0.443 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2 -(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidine (diastereomer 1) in the form of a colorless gum.

Example 23

In an analogous manner to that described in the first paragraph of Example 1, from 0.94 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]octahydroazocine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 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]octahydroazocine (diastereomer 1) in the form of white solids.

NMR (MeOD): 3.77 (dd, J=14, 10, 1H), 3.66-3.43 (m, 4H), 3.33 (dd, J=14, 5, 1H), 3.07 (dt, J=10, 4, 1H), 2.91-2.81 (m, 4H), 2.29-2.16 (m, 1H), 2.10-1.95 (m, 2H), 1.90-1.46 (m, 16H), 1.34 (s, 6H), MS: 451 ( M+H)+

Example 24

In an analogous manner to that described in the first paragraph of Example 1, from 0.37 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3 -oxazolidinyl)ethyl]-3-cyclobutylpropionyl]piperidine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (v)-(ix) using 3-(bromomethyl)-5,5-dimethyloxazolidine-2,4 -dione instead of l-(bromomethyl)-3,4,4-trimethyl-2,5-imidazolidinone, 0 131 g of l-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl) -2-(5,5-dimethyl-2,4-dioxo-3-oxazolidin-yl)ethyl]propionyl]piperidine (diazstereomer 1) as a white solid.

NMR (MeOD): 3.72-3.53 (m, 5H), 3.39 (dd, J=14, 6, 1H), 3.14 (dt, J=10, 4, 1H), 2.95-2.86 (m, 1H), 2.23 -2.11 (m, 1H), 2.08-1.94 (m, 2H), 1.90-1.44 (m, 18H), MS: 410 (M+H)+

Example 25

In an analogous manner to that described in the first paragraph of Example 1, from 0.42 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo -1-imidazolidinyl)-ethyl]-3-cyclobutylpropionyl]hexahydroazepine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix), 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]hexahydroazepine (diastereomer 1) in the form of white solids.

NMR (MeOD): 3.77-3.64 (m, 2H), 3.62-3.45 (m, 3H), 3.33 (dd, J=14, 5, 1H), 3.07 (dt, J=10, 4, 1H), 2.91 -2.81 (m, 4H), 2.24-2.13 (m, 1H), 2.09-1.95 (m, 2H), 1.90-1.47 (m, 14H), 1.35 (s, 3H), 1.34 (s, 3H), MS : 451 (M+H)+

Example 26

In an analogous manner to that described in the first paragraph of Example 1, from 0.37 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-hexahydro-1,3-dioxopyrazolo[1.2-a][1.2 .4]-triazol-2-yl)ethyl]-3-cyclobutylpropionyl]piperidine (diastereomer 1), which was prepared in an analogous manner to that described in Example 1 (i)-(ix) using 2-(bromomethyl)-hexa- hydro-1,3-dioxopyrazolo[1.2-a][1.2.4]triazole, 0.118 g of 1-[3-cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxopyrazolo[1.2 -[1.2.4]triazol-2-yl)-1(R or S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine as a white solid.

NMR (MeOD): 3.68-3.56 (m, 8H), 3.52-3.39 (m, 2H), 3.17-3.09 (m, 2H), 2.97-2.90 (m, 1H), 2.35-2.27 (m, 2H), 2.21-2.11 (m, 1H), 2.07-1.95 (m, 2H), 1.88-1.44 (m, 12H), MS: 422 (M+H) + .

Example 27

In an analogous manner to that described in the first paragraph of Example 1, from 0.222 g of 1-[2(R or S)-(benzoicoxycarbamoyl)-2-phthalimidoethyl]-3-cyclobutylpropionyl]piperidine, which was prepared in an analogous manner to that described in Example 1 (i)-(ix) using N-(bromo-ethyl)-phthalimide gave 0.013 g of 1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl] propionyl]piperidine (diastereomer 1) as a white solid.

NMR (MeOD): 7.87-7.75 (m, 4H), 3.83 (dd, J=14, 8, 1H), 3.66-3.58 (m, 3H), 3.53-3.45 (m, 1H), 3.35-3.25 (m , 1H), 3.20-3.12 (m, 1H), 3.04-2.97 (m, 1H), 2.23-2.11 (m, 1H), 2.08-1.95 (m, 2H), 1.89-1.41 (m, 12H), MS : 428 (M+H)+

The following Examples illustrate pharmaceutical compositions containing hydroxamic acid derivatives disclosed in this invention:

Example A

Tablets containing the following components can be prepared in the usual way:

Component per tablet

hydroxamic acid derivative 10.0 mg

lactose 125.0 mg

corn starch 75.0 mg

talc 4.0 mg

magnesium stearate 1.0 mg

total mass 215.0 mg

Example B

Capsules containing the following components can be prepared in the usual way:

Component per capsule

hydroxamic acid derivative 10.0 mg

lactose 165.0 mg

corn starch 20.0 mg

talc 5.0 mg

total mass 200.0 mg

Claims (28)

1. Compounds of the general formula [image] indicated by that R1 represents cyclopropyl. cyclobutyl, cyclopentyl or cyclohexyl, R2 represents a saturated five- to eight-membered monocyclic or bridged heterocyclic ring which is attached via an N atom and which, if the ring is monocyclic, may contain NR4, O, S, or SO2 as ring members and/or may be substituted on one or more C atoms with hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)- carbamoyl, di(lower alkyl)carbamoyl or hydroxyamino group, R3 represents a five- or six-membered heterocyclic ring which (a) is connected via an N atom, (b) may contain N, O and/or S, SO or SO2 as additional ring members, (c) is substituted with oxo on one or both C atoms that are in the neighborhood of the N atom through which the ring is attached, and (d) can be fused with benzene or can be substituted with one or more C atoms with a lower alkyl or oxo group and/or on an additional N atom (thiomine) with a lower alkyl or aryl group, R4 represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group, m is 1 or 2, and n is from 1-4, and pharmaceutically acceptable salts thereof. 2. Compounds from patent claim 1, characterized in that R1 represents cyclopropyl, diclobutyl or cyclopentyl, R2 represents a saturated five-, six- or seven-membered monocyclic or bridged heterocyclic ring which is attached via an N atom and which, in case the ring is monocyclic, may contain NR4, O, S, or SO2 as ring members and/or may be substituted on one or more C atoms with hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyamino group, R3 represents a five- or six-membered heterocyclic ring which (a) is connected via an N atom, (b) may contain N, O and/or S, SO or SO2 as additional ring members, (c) is substituted with oxo on one or both C atoms that are in the neighborhood of the N atom through which the ring is attached, and (d) can be fused with benzene or can be substituted with one or more C atoms by a lower alkyl or oxo group and/or on an additional N atom (thiomine) by a lower alkyl or an aryl group, and R4 represents hydrogen, lower alkyl, aryl, or a protecting group, 3. Compounds from claim 1 or claim 2, characterized in that R2 represents: 1-pyrrolidinyl, piperidino, 4-aryl-1-piperazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1 ,4-thiazin-4-yl 1,1-dioxide, thiazolidin-3-yl, hexahydroazepino or octahydroazocino which may be substituted on one or more C atoms with hydroxy, lower alkyl, lower alkoxy, ketalized oxo or with mono(lower alkyl )-carbamoyl, or R 2 represents 3-azabicyclo[3.2.2]nonane. 4. Compounds from claim 3, characterized in that R2 represents a piperidino or hydroxypiperidino group. 5. Compounds from claim 4, characterized in that hydroxypiperidino is a 4-hydroxypiperidino group. 6. Compounds from any of claims 1 to 5, characterized in that R3 represents a group of the formula [image] where R5 and R6 each represent hydrogen or together represent an additional bond or residue fused benzene ring, R7 represents hydrogen, lower alkyl or aryl, and X represents -CO-, -CH2-, -CH(lower alkyl)-, -C(lower alkyl)2-, -NH-, -N(lower alkyl)- or -O-, or when R7 represents lower alkyl, and X represents -N(lower alkyl)-, then the lower alkyl group can be attached to form a five-, six- or seven-membered ring, and Z represents S, SO or SO2. 7. Compounds according to patent claim 6, characterized in that R3 represents lower alkyl and X represents -C(lower alkyl)2. 8. Compounds from claim 7, characterized in that R3 represents 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl. 9. Compounds from any of claims 1 to 8, characterized in that m and n are 1. 10. 1-[3-Cyclopropyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] propionyl ]piperidine. 11. 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. 1-[3-Cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl]propionyl ] piperidine. 13. 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. 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. 1-[3-Cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl--2,5-dioxo-1-imidazolidinyl)ethyl] propionyl] piperidine. 16. Compound according to patent claim 2, characterized in that it is selected from the following group: 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]propionyl1-3 -azabicyclo[3.2.2]nonane, te 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. 17. The compound from claim 1, characterized in that it is selected from the following group: 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, 4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1- imidazolidines])ethyl]propionyl]tetrahydro-1,4-thiazine S,S-dioxide, 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)-thiazolidinecarboxamide, 4-[3-cyclopentyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl)ethyl]propionyl]morpholine, 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)-thiazolidinecarboxamide, 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]morpholine, 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-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl)ethyl]propionyl]octahydroazocine, 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]hexahydroazepine, 1-[3-cyclobutyl-2(R)-(2-(hexahydro-1,3-dioxopyrazolo[1,2-a][1.2.4]triazol-2-yl-1(R or S)- (hydroxycarbamoyl)ethyl]propionyl]piperidine, and 1-[3-cyclobutyl-2(R)-(1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]propionyl]-piperidine. 18. Compounds of the general formula [image] indicated that R1, R2, R3, m and n have the meanings given in patent claim 1. 19. Compounds of the general formula [image] indicated that R1, R2, R3, m and n have the meanings given in patent claim 1. 20. Compounds from any patent claim from 1-17, indicated that they are used in the control and prevention of degenerative joint diseases or in the therapy of invasive tumors, atherosclerosis or multiple sclerosis. 21. Processes for the preparation of the compounds reported in any of the patent claims from 1-17, characterized in that they include: (a) acid reaction with general formula: [image] in which R1, R2, R3, m and n have the meanings given in claim 1, with a compound of the general formula H2N-OZ (III) in which Z represents hydrogen, tri(lower alkyl)silyl or diphenyl(lower alkyl)silyl, or (b) catalytic hydrogenation of a compound of the general formula: [image] in which R1, R2, R3, m and n have the meanings given in claim 1, and Bz represents benzyl, and, if desired, converting the obtained compound of formula I into a pharmaceutically acceptable salt. 22. The method of preparation of medicines, especially for use in the prevention of degenerative joint diseases or in the therapy of invasive tumors, atherosclerosis or multiple sclerosis, characterized by the fact that it includes the joining of the compound from any patent claim from 1-17 with a therapeutically inert auxiliary agent, and introducing the mixture into the galenic form of administration. 23. Medicines, characterized in that they contain the compound of any one of claims 1-17, together with a therapeutically inert auxiliary agent. 24. Medicines for the prevention of degenerative joint diseases or for the therapy of invasive tumors, atherosclerosis or multiple sclerosis, characterized in that they contain the compound from any patent claim from 1-17, as well as therapeutically indifferent auxiliaries. 25. The use of the compounds of any patent claim from 1-17, characterized in that it is for the control or prevention of degenerative joint diseases or for the therapy of invasive tumors, atherosclerosis or multiple sclerosis. 26. The use of compounds from any patent claim from 1-17, indicated in that it is for the preparation of drugs for the purpose of controlling or preventing degenerative joint diseases or for the therapy of invasive tumors, atherosclerosis or multiple sclerosis. 27. Compounds from any patent claim from 1-17, characterized in that they are prepared according to the procedure from patent claim 21. 28. New compounds, intermediates, processes, formulations and methods previously described herein.