HRP930978A2 - Hydroxamic acid derivatives - Google Patents

Description

The present invention relates to hydroxamic acid derivatives.

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

[image]

where

R1 represents a five- or six-membered N-heterocyclic ring which: (a) is connected through an N atom, (b) may contain N, O and/or S as heteroatom(s) in a position or positions that are not adjacent to the N atom through which it is attached, (c) is substituted with an oxo group on one or both C atoms adjacent to the N atom through which the ring is attached and (d) may be fused with benzene or may be substituted on one or more C atoms with lower alkyl or oxo and/or on each additional N atom(s) with lower alkyl or aryl;

R 2 represents lower alkyl and R 3 represents lower alkyl or aryl, or

NR2R3 represents a five-, six- or seven-membered heterocyclic ring which may contain -NRa, -O-, -S-, -SO- or -SO2- as members of the ring and/or which may be substituted with hydroxy, 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 hydroxyimino;

Ra represents hydrogen, lower alkyl, lower alkanoyl, aryl-lower alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or mono(lower alkyl)carbamoyl;

R 4 , R 5 , R 6 and R 7 each represent hydrogen or methyl, with at least two of these symbols representing hydrogen and n being 1-4;

and their pharmaceutically compatible salts.

The compounds of formula I possess valuable pharmacological properties. Namely, they are collagenase inhibitors and can be used in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis, or in the therapy of invasive tumors, arteriosclerosis or multiple sclerosis.

The subject of the presented invention are the compounds of formula 1 and their pharmaceutically compatible salts per se and in use as therapeutically active substances; the process of preparation of the mentioned compounds and salts; intermediate products useful in the mentioned processes; medicines containing the mentioned compounds and salts and the preparation of these medicines; the use of the mentioned compounds and salts in the control or prevention of diseases or for improving the general health status, especially 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 chains containing at most six, preferably from one to four carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl . carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, etc. The term "aryl" denotes phenyl which can be substituted for example by lower alkyl, lower alkoxy and/or halogen, e.g. fluorine, chlorine, bromine or iodine. The term "lower alkanoyl" alone or in combination denotes an acyl group derived from alkanoic acids containing up to six carbon atoms, eg acetyl, propionyl, butyryl, isobutyryl, etc. The ketalized oxo group can be, for example, ethylenedioxy.

Compounds of formula I form pharmaceutically compatible salts with bases such as 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, etc. Compounds of formula I which are bases form pharmaceutically compatible salts with acids. Such salts that come into consideration are not only salts of inorganic acids such as hydrohalic acid (e.g. hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc., but also salts of organic acids such as acetic acid, tartaric 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.

In the compounds of formula I, the N-heterocyclic ring R1 can preferably contain one or two N atoms, one N atom and one O atom or one O atom as an additional heteroatom(s). Particularly preferred rings marked with R1 have the following formulas

[image]

where

R 8 and R 9 each represent hydrogen or together represent an additional bond or residue of a fused benzene ring;

R 10 represents hydrogen or lower alkyl;

X represents -CO-, -CH2-, -CH(lower alkyl)-, -C(lower alkyl)2-, -NH-, -N(lower alkyl)- or -O-, and

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

Examples of such rings are 2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidino, phthalimido, 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-oxadiaxol-4-yl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl and 2,6-dioxo-piperidino. Particularly preferred are the rings of formula (b) and (c), especially phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo -1-imidazolidinyl or 3,4,4-trieneethyl-2,5-dioxo-1-imidazolidinyl.

Preferred compounds of formula 1 are those in which NR 2 R 3 represents a five-, six- or seven-membered heterocyclic ring, as previously defined. Such rings include 1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-methyl-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-dioxide and octahydro-1-azocinyl which may be substituted in the manner given earlier, e.g. 2-(methylcarbamoyl)-1-pyrrolidinyl, 2-(hydroxy-methyl)-1-pyrrolidinyl, 4-hydroxypiperidino, 2-(methylcarbamoyl)piperidino, 4-hydroxy-iminopiperidino, 2-methoxypiperidino, 1,4-dioxa-8-azaspiro-[4.5]deca-8- yl, hexahydro-3-(methylcarbamoyl)-2-pyridazinyl and hexahydro-1-(benzyloxycarbonyl)-2-pyridazinyl. Particularly preferred are compounds of formula I in which NR 2 R 3 represents a saturated six-membered heterocyclic ring, especially morpholino, tetrahydro-1,4-thiazin-4-yl, 4-hydroxypiperidino, or hexahydro-3-(methylcarbamoyl)-2-pyridazinyl.

Also preferred are compounds of formula I in which R 4 , R 5 and R 7 represent hydrogen and R 6 represents methyl.

Furthermore, compounds of formula I are preferred in which n is 1 or 2. Particularly preferred compounds of formula I are:

4-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-morpholine,

4-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-tetrahydro-1,4-thiazine,

1-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-4-piperidinol,

1-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-tri-azolidin-4-yl) )ethyl]-4-methylvaleryl]piperidine.

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

hexahydro-2-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methyl-valeryl]-N-methyl-3(S)-pyridazinecarboxamide, and

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

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

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

[image]

where R1, R2, R3, R4, R5, R6 and R7 have the 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 separate 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, R4, R5, R6 and R7 have the previously given meanings, and Bz represents benzyl,

and,

if necessary, converting the obtained compound of formula I into a pharmaceutically compatible salt.

The reaction of an acid of formula II with a compound of formula III according to (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 according to (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 wastes 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 critical, although for convenience, catalytic hydrogenation is preferably performed at room temperature and atmospheric pressure.

Compounds of formula I can be converted into pharmaceutically compatible salts by reaction with bases, and basic compounds of formula I can be converted into pharmaceutically compatible 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, R4, R5, R6, R7, Bz and n have the previously given meanings and tBu represents tert-butyl.

[image]

In the first step in the presented reaction scheme, the alkane tricarboxylate of formula V reacts with the bromoalkyl substituted N-heterocyclic compound of formula VI to give the compound of formula VII. This reaction can be carried out in a generally known manner, for example by reacting a base, for example an alkali metal hydride such as sodium hydride, in an inert organic solvent such as dimethylformamide, with an alkane tricarboxylate, followed by the addition of a bromoalkyl-substituted N-hetero -cyclic compound, and allowing the reaction to complete, preferably at room temperature.

Benzyl is then removed from the thus obtained compound of formula VII, whereby the compound of formula VIII is formed in a manner known per se, for example by hydrogenation in an inert organic solvent, e.g. in a lower alkalinol such as methanol or ethanol in the presence of a catalyst such as palladium on charcoal.

The next step, the decarboxylation of the compound of formula VIII, which gives the compound of formula IX, is also carried out in a known manner, for example by heating in an aromatic solvent such as benzene or toluene in the presence of a base such as N-methylmorpholine.

In the next step, the compound of the formula IX reacts with the amine of the formula X and the compound of the formula XI is formed. This reaction can be carried out in a manner known per se. For example, the reaction is usually carried out 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-dimethylaminopropyl)carbodiimide hydrochloride or by converting the compound of formula IX to the corresponding chloride with oxalyl -chloride, and by reacting the resulting chloride with an amine using a base such as triethylamine at about 0-25°C.

In the last step, the protecting group from the compound of formula XI is removed, whereby the desired acid of formula II is formed, which is the compound obtained. This removal of the protecting group is carried out in a manner known per se, for example by reaction with trifluoroacetic acid.

A compound of formula XI may be optionally substituted with a functional group prior to removal of the protecting group. Thus, for example, the compound of formula XI, in which NR2R3 represents a saturated five-, six- or seven-membered heterocyclic ring containing -S- as a ring member, can be oxidized in a known manner, for example using a peracid such as m-chloroperbenzoic acid, into the corresponding a compound containing -SO- or -SO2 as a ring member.

Compounds of formula IV used as starting compounds according to this invention under (b) in processes and forms which are new are also subject of the presented invention.

Compounds of formula IV can be prepared, for example, by reacting an 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 dimethylformamide using hydroxybenzotriazole in the presence of a condensing agent such as 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride.

Other compounds that were used as intermediates or reactants for the preparation of compounds of formula I are known compounds or are analogues of known compounds, and can be prepared in the manner described for these known compounds.

As mentioned earlier, the compounds of formula I and their pharmaceutically compatible 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. Natl. 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 Johnson-Wint microwell method. 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:

Table I

[image]

Compound A: 4-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]morpholine

Compound B: 4-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine

Compound C: 1-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-4-piperidinol

Compound D: 1-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidine-4- yl)ethyl]-4-methylvaleryl]piperidine.

Compound E: 4-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]tetrahydro -1,4-thiazine

Compound F: hexahydro-2-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-N-methyl-3(S)-pyridazinecarboxamide.

Compound G: 1-[2(R)-[1(R) or (S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl ]-4-piperidinol.

The compounds of formula I and their pharmaceutically compatible 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 compatible salts, therapeutically indifferent, organic or inorganic auxiliaries can be used. Lactose, corn starch or their derivatives, talc, stearic acid or its salts are, for example, such auxiliaries that can be used for tablets, film tablets, dragees, hard and soft gelatin capsules. Suitable auxiliaries for soft gelatin capsules are, for example, oils, waxes, fats, semi-solid and liquid polyols, etc. In general, no auxiliaries are required for soft gelatin capsules, but depending on the nature of the active substance. Suitable auxiliaries 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 agents 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.

Medicinal products containing compounds of formula I or their pharmaceutically compatible salts and therapeutically compatible excipients as well as methods for the preparation of these medicinal products are also subject of the presented invention. Preparation procedures include mixing the compounds of formula I or their pharmaceutically compatible salts with therapeutically inert auxiliary agents, and shaping the mixture into a galenic form suitable for administration.

As already mentioned, the compounds of formula I and their pharmaceutically compatible 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 presented invention in more detail, all temperatures are given in degrees Celsius.

Example 1

A solution of 0.15 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methyl-valeryl]pyrrolidine (diastereoisomer 1) in 3 mL of dry dimethylformamide was cooled to 0°C with stirring in a nitrogen atmosphere, and successively added: 0.075 g of 1-hydroxy-benzotriazole, 0.12 g of O-(tert-butyldimethylsilyl)hydroxylamine, 0.075 mL of N-methyl-morpholine and 0.094 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and 5 mL of 5% aqueous sodium hydrogencarbonate solution was added to the residue. The product was extracted three times with ethyl acetate and the combined extracts were washed with LOM hydrochloric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was slurried with a mixture of ether and hexane. The solid was filtered off and dried, and 0.09 g of 1-[2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]pyrrolidine (diastereoisomer 1) was obtained in the form of a white powder: nmr (MeOD): 7.84-7.71 (m, 4H); 3.78-3.70 (m, 3H); 3.54-3.43 (m, 1H); 3.23-3.15 (m, 1H); 3.05-2.90 (m, 3H); 2.06-1.86 (m, 2H); 1.83-1.71 (m, 2H); 1.58-1.49 (m, 1H); 1.43-1.32 (m, 1H): 1.23-1.14 (m, 1H); 0.87 (d, 3H J=6): 0.81 (d, 3H, J=6); MS: 402 (M+H) + .

The starting compound is prepared in the following way:

(i) A solution of 0.41 g of 2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleric acid, a mixture of diastereoisomers in a ratio of approximately 6:1, in 5 mL of dry dimethylformamide was cooled to 0 °C with stirring in a nitrogen atmosphere, and the following were added one after the other: 0.16 g of 1-hydroxybenzotriazole, 0.1 g of pyrrolidine, 0.13 g of N-methylmorpholine and 0.23 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and 20 mL of 5% aqueous sodium hydrogen carbonate solution was added to the residue. The product was extracted with three portions of ethyl acetate and the combined extracts washed with 5% citric acid solution and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and 0.5 g of colorless gum was obtained, which was purified by "flash" chromatography on silica gel using hexane/ethyl acetate (5:4) for elution. After elution of the first product (diastereoisomer 2), 0.365 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl]pyrrolidine (diastereoisomer 1) was obtained in the form of colorless rubber; nmr (MeOD) 7.88-7.79 (m, 4H); 3.99-3.93 (m, 1H); 3.78-3.66 (m, 2H); 3.60-3.53 (m, 1H); 3.39-3.30 (m, 1H); 3.27-3.21 (m, 1H); 3.19-3.13 (m, 1H); 3.06-2.99 (m, 1H); 2.10-1.96 (m, 2H): 1.92-1.83 (m, 2H); 1.76-1.68 (m, 1H); 1.53-1.42 (m, 1H); 1.33 (s. 9H); 1.30-1.20 (m, 1H); 0.95 (d, 3H, J=6); 0.88 (d, 3H, J=6).

(ii) To a solution of 0.35 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl]pyrrolidine (diastereoisomer 1) in 10 mL of dichloromethane was added 3 mL trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours, and 10 mL of toluene was added. The solvent was evaporated and the residue was re-evaporated three times with 20 mL of toluene each. After crystallization of the residue from ether, 0.161 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]pyrrolidine (diastereoisomer 1) was obtained: nmr (MeOD): 7.86-7.75 (m, 4H); 3.92 (dd, 1H, J=11.6); 3.80 (dd, 1H, J=11.6): 3.74-3.67 (m, 1H); 3.55-3.46 (m, 1H); 3.32-3.18 (m, 2H); 3.13-2.99 (m, 2H): 2.06-1.99 (m, 2H); 1.87-1.77 (m, 2H); 1.71-1.62 (m, 1H); 1.52-1.40 (m, 1H): 1.33-1.25 (m, 1H): 0.92 (d. 3H, J=6); 0.86 (d, 3H, J=6); MS: 387 (M+H) + .

Example 2

In a manner analogous to that described in the first paragraph of Example 1, from 0.155 g of 1-(2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) which was prepared in the manner analogous to that described in Example 1(i)-(ii), 0.1 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]piperidine (diastereoisomer 1 ) in the form of a white powder: nmr (MeOD): 7.88-7.76 (m, 4H); 3.89 (dd, 1H, J=11.6); 3.86-3.77 (m, 1H); 3.70-3.58 (m, 3H) ; 3.37-3.24 (m, 2H); 2.99-2.93 (m, 1H); 1.78-1.53 (m, 6H); 1.52-1.36 (m, 2H); 1.23-1.14 (m, 1H); 0.93-0.85 ( m, 6H); MS: 416 (M+H) + .

Example 3

In a manner analogous to that described in the first paragraph of Example 1, from 0.283 g of 4-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]morpholine (diastereoisomer 1) which was prepared in the manner analogous to that described in Example 1 (i)-(ii), 0.12 g of 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]morpholine (diastereoisomer 1 ) in the form of a white powder: nmr (MeOD): 7.87-7.76 (m, 4H); 3.87 (dd, 1H, J=11.6); 3.83-3.70 (m, 3H); 3.68-3.60 (m, 3H); 3.59-3.51 (m, 2H); 3.47-3.39 (m, 1H): 3.32-3.23 (m, 1H); 2.99-2.92 (m, 1H); 1.66-1.58 (m, 1H): 1.47-1.36 (m, 1H); 1.24-1.14 (m, 1H); 0.91-0.84 (m, 6H); MS: 418 (M+H) + .

Example 4

In a manner analogous to that described in the first paragraph of Example 1, from 0.16 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]hexahydroazepine (diastereoisomer 1) which was prepared in the manner analogously to that described in Example 1(i)-(ii), 0.13 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-hexahydroazepine (diastereoisomer 1) in the form of a white powder: nmr (MeOD): 7.88-7.76 (m, 4H); 3.95 (dd, 1H, J=11.6); 3.84-3.76 (m, 1H); 3.70-3.54 (m, 3H); 3.37-3.25 (m, 2H); 2.97-2.89 (m, 1H); 1.94-1.77 (m, 2H): 1.75-1.53 (m, 7H); 1.51-1.40 (m, 1H); 1.27-1.19 (m, 1H): 0.92 (d, 3H, J=6) 0.88 (d, 1H, J=6); MS: 430 (M+H)+.

Example 5

In a manner analogous to that described in the first paragraph of Example 1, from 0.28 g of 4-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine (diastereoisomer 1 ) which was prepared in a manner analogous to that described in Example 1(i)-(ii), 0.14 g of 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4- methylvaleryl]tetrahydro-1,4-thiazine (diastereoisomer 1) as a white solid: nmr (MeOD): 7.84-7.73 (m, 4H); 4.09-4.01 (m, 1H); 3.93-3.81 (m, 3H); 3.63-3.53 (m, 2H); 3.29-3.21 (m, 1H); 2.95-2.87 (m, 1H); 2.76-2.69 (m, 1H); 2.67-2.59 (m, 1H); 2.57.2.46 (m, 1H); 1.63-1.55 (m, 1H); 1.43-1.32 (m, 1H); 1.20-1.12 (m, 1H); 0.86 (d, 3H, J=6); 0.83 (d, 3H, J=6); MS; 434 (M+H)+.

Example 6

In a manner analogous to that described in the first paragraph of Example 1, from 0.36 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) which prepared in a manner analogous to that described in Example 1(i)-(ii), after purification of the crude product by "flash" chromatography on silica gel using dichloromethane/methanol (16:1) for elution, 0.053 g of 1-[2(R )-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) as white powder: nmr (MeOD): 7.88-7.76 (m, 4H ); 4.15-3.79 (m, 4H); 3.67-2.84 (m, 5H): 2.06-1.73 (m, 2H); 1.70-1.14 (m, 5H); 0.95-0.84 (m, 6H); MS: 432 (M+H) + .

Example 7

In a manner analogous to that described in the first paragraph of Example 1, from 0.557 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-N,N,4-trimethylvaleramide (diastereoisomer 1) which was prepared in a manner analogous to that described in Example 1(i)-(ii), after purification of the crude product by "flash" chromatography on silica gel using 2% methanol in dichloromethane for elution, 0.053 g of 2(R)-[1(R or S) was obtained -(hydroxycarbamoyl)-2-phthalimidoethyl]-N,N,4-trimethylvaleramide (diastereoisomer 1) as a white solid: nmr (MeOD): 7.85-7.75 (m, 4H); 3.84 (dd, J=14.7, 1H); 3.68 (dd, J=14.10, 1H): 3.18 (s, 3H): 2.98-2.93 (m, 1H); 2.75 (s, 3H); 1.6-1.53 (m, 1H); 1.4-1.3 (m, 1H): 1.23-1.14 (m, 1H): 0.88 (d. J=8, 3H); 0.84 (d, J=8, 3H): MS: 376 (M+H) + .

Example 8

In a manner analogous to that described in the first paragraph of Example 1, from 0.59 g of N2-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]-N1-methyl-1-prolinamide of a mixture of of diastereoisomer 1 and diastereoisomer 2 approximately 6:1, which was prepared in a manner analogous to that described in Example 1(i)-(ii), 0.12 g of N2-[2(R)-[1(R or S)- (hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-N1-methyl-1-prolinamide as a white solid: nmr (MeOD): 7.86-7.75 (m, 4H); 4.12-4.07 (m, 1H); 3.92-3.83 (m, 2H); 3.74-3.64 (m, 2H); 3.13-3.04 (m, 1H); 2.93-2.86 (m, 1H); 2.67 (s, 3H); 2.19-1.96 (m, 3H); 1.91-1.82 (m, 1H); 1.75-1.65 (d, 3H, J=6); MS: 458 (M)+.

Example 9

In a manner analogous to that described in the first paragraph of Example 1, except that the reaction was left for 3 hours, from 0.31 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methyl-valeryl] -2(S)-pyrrolidinemethanol (diastereoisomer 1), after purification of the product by "flash" chromatography using dichloromethane/methanol (12:1) for elution, 0.06 g of 1-[2(R)-[1(R or S)] was obtained -(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-2(S)-pyrrolidinemethanol (diastereoisomer 1) as a white solid: nmr (MeOD): 7.88-7.77 (m, 4H); 3.86-3.73 (m, 4H); 3.63-3.50 (m, 2H); 3.98-3.27 (m, 1H); 3.10-2.92 (m, 2H): 2.07-1.83 (m, 4H); 1.62-1.43 (m, 2H); 1.28-1.17 (m, 1H); 0.97-0.83 (m, 6H); MS: 432 (M+H) + .

The starting compound is prepared in the following way:

0.355 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methyl-valeryl]-2(S)-pyrrolidinemethanol (diastereoisomer 1) which was prepared on in an analogous manner to that described in Example 1(i), it was dissolved in 7 mL of toluene and 0.07 g of 3-methyl-3-pentenol and 0.7 mL of trimethylsilyl bromide were added. The mixture was stirred under a nitrogen atmosphere for 1.5 hours, after which the solvent was evaporated. After three more evaporations with 10 mL of toluene each, 0.31 g of a pale brown foam containing 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl] was obtained. -2(S)-pyrrolidinemethanol (diastereoisomer 1) and which was used without further purification.

Example 10

In a manner analogous to that described in the first paragraph of Example 1, from 0.568 g of 1-(2(R)-[1(R or S)-carboxy-2-phthalimidoethyl-4-methylvaleryl]-4-methylpiperazine hydrobromide, a mixture of diastereoisomer ratios of 1 and of diastereoisomer 2 approximately 6:1, which was prepared in a manner analogous to that described in Example 9(i), after purification of the product by "flash" chromatography on silica gel using dichloromethane/methanol (12:1) for elution, and after precipitation of the hydrochloride by addition of hydrogen chloride in ethyl -acetate, 0.105 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methyl-valeryl]-4-methylpiperazine hydrochloride was obtained as a white solid: nmr ( MeOD): 7.89-7.79 (m, 4H); 4.18-3.80 (m, 4H); 3.74 (dd, 1H, J=11.5); 3.48-3.18 (broad m, 6H); 2.93-2.84 (m, 4H); 1.76-1.67 (m, 1H); 1.52-1.42 (m, 1H); 1.35-1.27 (m, 1H); 0.93 (d, 3H, J=6); 0.89 (d, 3H, J=5.5 ); MS: 431 (M+H)+.

Example 11

In a manner analogous to that described in the first paragraph of Example 1, from 0.29 g of 4-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine 1,1 -dioxide (diastereoisomer 1), 0.13 g of 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine 1,1 was obtained -dioxide (diastereoisomer 1), in the form of a white solid: nmr (MeOD): 7.88-7.75 (m, 4H): 4.33-4.23 (m, 1H): 4.20-4.04 (m, 2H); 3.93 (dd, 1H, J=11.6): 3.87-3.78 (m, 1H): 3.73 (dd, 1H, J=11.5); 3.44-3.28 (m, 3H); 3.22-3.03 (m, 3H); 2.97-2.90 (m, 1H); 1.67-1.57 (m, 1H); 1.51-1.38 (m, 1H); 1.34-1.25 (m, 1H); 0.93-0.84 (m, 6H); MS: 466 (M+H) + .

The starting compound is prepared in the following way:

(i) A solution of 0.3 g of 4-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine (diastereoisomer 1) in 20 mL of dichloromethane was cooled to 0°C and 0.3 g of 85% m-chloroperbenzoic acid was added. The mixture was stirred at room temperature overnight, and then the solution was washed twice with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and a white foam was obtained by evaporation. After purification by "flash" chromatography on silica gel using ethyl acetate/hexane (2:3) for elution. 0.33 g of 4-[2(R[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl-4-methylvaleryl]tetrahydro-1,4-thiazine 1,1-dioxide (diastereoisomer 1) was obtained in the form white foam which solidified on standing to a white solid; nmr (MeOD): 7.89-7.78 (m, 4H): 4.36-4.23 (m, 2H): 4.11 (dd, 1H, J=11.7); 4.07-3.98 ( m, 1H); 3.85-3.73 (m, 2H); 3.44-3.18 (m, 2H); 3.21-3.05 (m, 4H); 1.73-1.64 (m, 1H); 1.61-1.59 (m, 1H); 1.40-1.32 (m, 1H); 1.28 (s, 9H); 0.95-0.88 (m, 4H).

(ii) In a manner analogous to that described in the first paragraph of Example 1(ii), from 0.33 g of 4-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl] tetrahydro-1,4-thiazine 1,1-dioxide (diastereoisomer 1), 0.29 g of 4-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]tetrahydro- 1,4-thiazine 1,1-dioxide (diastereoisomer 1), in the form of a white foam which was used without further purification.

Example 12

In a manner analogous to that described in the first paragraph of Example 1, from 0.3 g of 8-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]-1,4-dioxa-8-azaspiro [4.5]decane (diastereoisomer 1) which was prepared in a manner analogous to that described in Example 1(i)-(ii), after purification of the product by "flash" chromatography on silica gel using ethyl acetate/methanol (200:5) for elution, obtained is 0.105 g of 8-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-1,4-dioxa-8-azaspiro[4.5]decane (diastereoisomer 1) as a white solid: nmr (MeOD): 7.87-7.75 (m, 4H); 3.97 (m, 4H); 3.91-3.81 (m, 2H); 3.79-3.60 (m, 3H); 3.45-3.26 (m, 2H); 3.00-2.91 (m, 1H); 1.89-1.80 (m, 1H); 1.74-1.51 (m, 4H): 1.45-1.31 (m, 1H); 1.23-1.13 (m, 1H); 0.88 (d, 3H, J=6); 0.85 (d, 3H, J=5.5); MS: 474 (M+H) + .

Example 13

Solution 0.13 g 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) ethyl]-4-methylvaleryl]-piperidine (diastereoisomer 1) in 7.0 mL of methanol was hydrogenated in the presence of 40 mg of 10% palladium on charcoal for 30 min. The catalyst was removed by filtration, and after evaporation of the solution, 0.076 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1) was obtained. 2,4-tri-azolidin-4-yl)ethyl]-4-methylvaleryl]-piperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.81-3.72 (m, 2H); 3.67 (dd, 1H, J=11.7): 3.64-3.55 (m, 1H): 3.44 (dd, 1H, J=11.5); 3.39-3.23 (m, 2H); 3.11 (s. 6H); 2.96-2.88 (m, 1H): 1.77-1.33 (m, 8H): 1.19-1.11 (m, 1H); 0.87 (d. 3H, J=6); 0.85 (d, 3H, J=6); MS: 398 (M+H) + .

(i) 0.284 g of 60% sodium hydride was added under a nitrogen atmosphere to a solution of 3.01 g of 1,2-dibenzyl-1-tert-butyl-4-methyl 1,1,2(R)-pentanetricarboxylate in 50 mL of dry dimethylformamide which was previously cooled in an ice bath. The mixture was stirred for 30 minutes at 0°C and for the next 1.5 hours at room temperature, and before the addition of 1.6 g of 4-bromomethyl-1,2-dimethylurazole, it was cooled again to 0°C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The volatile components were evaporated under high vacuum, the residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by "flash" chromatography on silica gel using first hexane/ether (1:1) and then ether for elution. 2,464 g of 1,2-dibenzyl-1-tert-butyl 4-methyl-1-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]- 1,1,2(R)-pentantriclarboxylate in the form of a colorless oil.

(ii) 2,464 g of 1,2-dibenzyl-1-tert-butyl 4-methyl-1-[(1,2-dimethyl-3,5-dioxo-1,2,4-tri-azolidin-4-yl) methyl]-1,1,2(R)-pentanetriclarboxylate was dissolved in 40 mL of methanol containing 0.25 g of catalyst. 10% palladium on charcoal. The mixture was hydrated for 2 hours, the catalyst was removed by filtration and after evaporation of the solvent, (tert-butylcarbonyl) 4-methyl-1-[(1,2-dimethyl-3.5-dioxo-1,2,4-triazolidin-4-yl) was obtained )methyl]-1,2(R)-pentanedicarboxylic acid in the form of a colorless gum. It was dissolved in 60 mL of toluene containing 0.43 mL of N-methylmorpholine and the mixture was heated under reflux for 1 hour. The solution was washed with 5% citric acid, water, saturated sodium chloride solution, dried over magnesium sulfate, and after evaporation, 1,422 g of 2(R)-[(R or S)-(tert-butoxycarbonyl)-2-( 1,2-dimethyl-3,5-dioxo-1,2,4-tri-azolidin-4-yl)ethyl]-4-methylvaleric acid in the form of a waxy solid in the ratio of diastereoisomer 1 to diastereoisomer 2 approximately 6:1.

(iii) In a manner analogous to that described in Example 1(i) from 2(R)-[(R or S)-(tert-butoxycarbonyl)-2-(1,2-dimethyl-3,5-dioxo-1,2 ,4-triazolidin-4-yl)ethyl]-4-methylvaleric acid, a mixture of diastereoisomer 1 and diastereoisomer 2 in a ratio of approximately 6:1, 0.462 g of 1-[2(R)-(1(R or S)-( tert-butoxycarbonyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) as a colorless oil.

(iv) Solutions 0.462 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidine -4-yl)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) in 7 mL of dichloromethane, 0.85 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1.5 hours, after which toluene was added and the solvents were evaporated. After three more evaporations with toluene, the residue was dissolved in 1 mL of dry dimethylformamide, cooled to 0 °C and stirred in a nitrogen atmosphere, during which the following were added one after the other: 0.13 g of O-benzylhydroxylamine, 0.152 g of 1-hydroxybenzotriazole, 0.25 mL of N-methyl-morpholine and 0.208 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and a 5% aqueous solution of sodium hydrogencarbonate was added to the residue. The product was extracted with ethyl acetate, and the ethyl acetate was washed with a 5% citric acid solution and an aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by "flash" chromatography on silica gel using ethyl acetate for elution. In addition to 0.14 g of the isolated starting compound, 0.142 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2, 4-Triazolidin-4-yl)ethyl]-4-methylvaleryl]-piperidine (diastereoisomer 1) as a white solid: nmr (CDCl 3 ): 9.77 (s, 1H); 7.44-7.29 (m, 5H); 4.90 (q, 2H, J=8): 3.78 (dd, 1H, J=11.5): 3.70-3.63 (m, 2H); 3.62-3.53 (m, 1H); 3.49-3.42 (m, 1H); 3.41-3.33 (m, 1H): 3.28-3.22 (m, 1H); 3.10 (s, 6H); 3.00-2.93 (m, 1H); 1.81-1.38 (m, 8H); 1.29-1.23 (m, 1H); 0.88 (d, 3H, J=6); 0.85 (d, 3H, J=6).

Example 14

In a manner analogous to that described in the first paragraph of Example 13, from 0.182 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2,6-dioxopiperidino)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1), 0.066 g of 1-[2(R)-|1(R or S)-(hydroxycarbamoyl)-2-(2,6-dioxopiperidino)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) was obtained as a white solid: nmr (MeOD): 4.06 (dd, 1H, J=11, 6.5): 3.80-3.57 (m, 4H); 3.53-3.46 (m, 1H); 3.34-3.24 (m, 1H); 2.68-2.54 (m, 5H): 1.92-1.82 (m, 2H); 1.76-1.45 (m, 7H); 1.44-1.32 (m, 1H); 1.14-1.06 (m, 1H); 0.87 (d, 3H, J=6): 0.83 (d, 3H, J=6); MS: 382 (M+H) + .

The starting compound is prepared in the following way:

(i) In a manner analogous to that described in Example 13(i)-(iii), 1 was obtained from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentantriclarboxylate and N-bromomethylglutarimide -[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(2,6-dioxopiperidine)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) in the form of a colorless gum.

(ii) Solutions 0.324 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(2,6-dioxo-piperidino)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1 ) 0.065 g of 3-methyl-3-pentanol and 0.65 mL of trimethylsilyl bromide were added to 6.5 mL of toluene. The mixture was stirred under a dry nitrogen atmosphere for 1 hour, after which the solvent was evaporated. After three more evaporations with toluene, the residue was dissolved in 10 mL of dry dimethylformamide, cooled to 0 °C and stirred under a nitrogen atmosphere, adding one after the other: 0.095 g of O-benzylhydroxylamine, 0.111 g of 1-hydroxybenzotriazole, 0.18 mL N-methylmorpholine and 0.152 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and a 5% aqueous solution of sodium hydrogencarbonate was added to the residue. The product was extracted with ethyl acetate, and the ethyl acetate extract was washed with a 5% citric acid solution and an aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by "flash" chromatography on silica gel using hexane/ethyl acetate (7:2) for elution. 0.182 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2,6-dioxopiperidino)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) was obtained in the form of a white solid; nmr (CDCl 3 ): 9.23 (s, 1H); 7.46-7.31 (m, 5H); 4.96-4.88 (m, 2H): 3.98 (dd, 1H, J=11.5); 3.89-3.76 (m, 2H); 3.74-3.64 (m, 1H); 3.52-3.42 (m, 1H); 3.33-3.21 (m, 2H); 2.76-2.67 (m, 1H); 2.63-2.52 (m, 4H); 1.94-1.37 (m, 10H); 1.24-1.14 (m, 1H); 0.88 (d. 3H, J=6): 0.84 (d. 3H, J=6).

Example 15

In a manner analogous to that described in the first paragraph of Example 13, from 0.39 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1- imidazolidinyl)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1), 0.255 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl- 2,5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl)piperidine (diastereoisomer 1) as a white solid: nmr (MeOD): 3.84-3.63 (m, 4H); 3.49-3.41 (m, 1H); 3.38-3.25 (m, 2H); 2.90-2.83 (m, 4H); 1.80-1.28 (m, 14H): 1.19-1.11 (m, 1H); 0.89 (d, 3H, J=5.5); 0.86 (d, 3H, J=5.5); MS: 411 (M+H) + .

The starting compound is prepared in the following way:

In a manner analogous to that described in Example 14(i).(ii) from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentantriclarboxylate and 3-bromomethyl-1,5,5- of trimethylhydranthion, 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]- 4-methylvaleryl]piperidine (diastereoisomer 1) in the form of a white foam; nmr (CDCl 3 ): 9.50 (broad, 1H); 7.45-7.39 (m, 5H); 3.79-3.56 (m, 4H); 3.52-3.42 (m, 1H); 3.33-3.23 (m, 2H); 2.94-2.80 (m, 4H); 1.93-1.29 (m, 14H); 1.26-1.16 (m, 1H); 0.87 (d, 3H, J=6); 0.84 (d, 3H, J=6).

Example 16

In a manner analogous to that described in the first paragraph of Example 13, from 0.335 g of 4-[2(R)-(1(R or S)-(benzyloxycarbamoyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl) -ethyl]-4-methylvaleryl]morpholine (diastereoisomer 1), 0.198 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3-methyl-2,5-dioxo) was obtained -1-imidazolidinyl)ethyl]-4-methylvaleryl]-morpholine (diastereoisomer 1) as a white solid: nmr (MeOD): 3.78 (s, 2H); 3.73-3.45 (m, 9H); 3.36 (dd, 1H, J=11.5): 3.18-3.10 (m, 1H); 2.85 (s, 3H); 2.82-2.75 (m, 1H): 1.57-1.47 (m, 1H): 1.38-1.26 (m, 1H): 1.14- 1.05 (m, 1H): 0.82-0.75 (m, 6H): MS: 385 (M+H)+.

The starting compound is prepared in the following way:

In a manner analogous to that described in Example 15(i),(ii) from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentanetriclarboxylate and 3-bromornethyl-1-methylhydranthion, it was obtained 4-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)-ethyl-4-methylvaleryl]morpholine (diastereoisomer 1 ) as a white solid: MS: 475 (M+H)+.

Example 17

In a manner analogous to that described in the first paragraph of Example 1, from 0.273 g of 1-[2(R)-[1(R or S)-carboxy-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl] -4-methylvaleryl]-4-piperidine (diastereoisomer 1), 0.023 g of 1-[2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3-methyl-2,5 -dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidine (diastereoisomer 1) in the form of a white powder: nmr (MeOD): 3.78 (s, 2H); 3.74-3.64 (m, 2H); 3.63-3.48 (m, 2H); 3.35-3.26 (m, 2H); 3.25-3.15 (m, 1H); 2.85 (s, 3H); 2.82-2.73 (m, 1H); 1.68-1.25 (m, 8H); 1.10-1.03 (m, 1H); 0.82 (d, 3H, J=6); 0.75 (d, 3H, J=6): MS: 383 (M+H)+.

The starting compound is prepared in the following way:

In a manner analogous to that described in the first paragraph of Example l(ii). from 0.325 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-4-methylvaleryl] -4-piperidine (diastereoisomer 1), which is prepared in a manner analogous to that described in Example 13(i)-(iii), from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R) -pentantriclarboxylate and 3-bromomethyl-1-methylhydranthion yielded 0.273 g of 1-[2(R)-[1(R or S)-carboxy-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl ]-4-methylvaleryl]-4-piperidine (diastereoisomer 1) as a colorless gum which was used without further purification.

Example 18

In a manner analogous to that described in the first paragraph of Example 1, from 0.45 g of 4-[2(R)-[1(R or S)-carboxy-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl) -4-methylvaleryl]-tetrahydro-1,4-thiazine (diastereoisomer 1). 0.155 g of 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3-methyl-2.5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]-tetrahydro -1,4-thiazine (diastereoisomer 1) as a white solid: nmr (MeOD): 4.09-3.88 (m, 3H); 3.86 (s, 2H); 3.78-3.70 (m, 1H); 3.66 (dd, 1H, J=11.7): 3.42 (dd, 1H, J=11.5): 3.29-3.21 (m, 1H); 2.92 (s, 3H); 2.88-2.82 (m, 1H); 2.78-2.71 (m, 1H); 2.68-2.54 (m, 3H): 1.65-1.57 (m, 1H); 1.46-1.34 (m, 1H): 1.22-1.15 (m, 1H); 0.90-0.84 (m, 6H); MS: 401 (M+H) + .

The starting compound is prepared in the following way:

(i) In a manner analogous to that described in the first paragraph of Example 13(i)-(iii), from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentantriclarboxylate and 3-bromomethyl- 1-methylhydranthione, 4-[2(R)-[1-(R or S)-(tert-butoxycarbonyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4- methylvaleryl]tetrahydro-1,4-thiazine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.98-3.84 (m, 6H); 3.77 (dd, 1H, J=11.7); 3.47 (dd, 1H, J=11.5); 3.22-3.24 (m, 1H); 3.09-3.03 (m, 1H); 2.95 (s, 3H); 2.81-2.73 (m, 1H); 2.69-2.55 (m, 3H); 1.77-1.68 (m, 1H); 1.53-1.39 (m, 10H); 1.26-1.18 (m, 1H); 0.94-0.86 (m, 6H).

(ii) Solutions 0.52 g of 4-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(3-methyl-2,5-di-oxo-1-imidazolidinyl)ethyl]- 4-methylvaleryl]tetrahydro-1,4-thiazine (diastereoisomer 1) was added to 15 mL of dichloromethane and 1.05 mL of 4M hydrogen chloride in dioxane. The solution was stirred at room temperature for 3.25 hours and then 25 mL of toluene was added and the solvents were evaporated. After three more evaporations with 25 mL of toluene each, 0.45 g of 4-[2(R)-[1(R or S)-carboxy-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl] was obtained -4-methylvaleryl]tetrahydro-1,4-thiazine (diastereoisomer 1) as a colorless gum which was used without further purification.

Example 19

In a manner analogous to that described in the first paragraph of Example 13, from 0.278 g of 4-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2,5-dioxo-1-pyrrolidinyl)ethyl]-4 -methyl-valeryl]morpholine (diastereoisomer 1). 0.151 g of 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(2,5-dioxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl]morpholine (diastereoisomer 1) was obtained in in the form of a white solid: nmr (MeOD): 3.73-3.49 (m, 9H): 3.34 (dd, 1H, J=11.5); 3.19-3.11 (m, 1H); 2.74-2.66 (m, 1H); 2.55 (s, 4H); 1.57-1.49 (m, 1H): 1.38-1.26 (m, 1H): 1.12-1.03 (m, 1H): 0.82-0.75 (m, 6H); MS: 370 (M+H) + .

The starting compound is prepared in the following way:

In a manner analogous to that described in Example 14(i),(ii) from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentanetriclarboxylate and N-bromomethylsuccinimide. 4-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(2,5-dioxo-1-pyrrolidinyl)ethyl]-4-methyl-valeryl]morpholine (diastereoisomer 1 ) in the form of a white solid; MS: 460 (M+H) + .

Example 20

In a manner analogous to that described in the first paragraph of Example 13, from 0.19 g of 4-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2-oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl ]morpholine (diastereoisomer 1), 0.104 g of 4-[2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(2oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl]morpholine were obtained (diastereoisomer 1) as a white solid: nmr (MeOD): 3.70-3.39 (m, 8H); 3.36-3.17 (m, 4H); 3.14-3.05 (m, 1H); 2.57-2.48 (m, 1H); 2.28-2.17 (m, 2H); 1.96-1.84 (m, 2H); 1.62-1.52 (m, 1H); 1.58-1.24 (m, 1H); 1.13-1.03 (m, 1H); 0.83-0.75 (m, 6H); MS: 356 (M+H) + .

The starting compound is prepared in the following way:

In a manner analogous to that described in Example 14(i),(ii) from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentantriclarboxylate and N-bromomethylpyrrolidine, 4-(2 (R)-[1(R or S)-(tert-butoxycarbonyl)-2-(2-oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl]morpholine (diastereoisomer 1) as a white solid; MS: 446 ( M+H)+.

Example 21

In a manner analogous to that described in the first paragraph of Example 13, from 0.335 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2-oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl ]piperidine (diastereoisomer 1), 0.19 g of 1-[2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(2-oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl was obtained ]piperidine (diastereoisomer 1) as a white solid: nmr (MeOD): 3.78-3.58 (m, 3H): 3.53-3.33 (m, 4H): 3.27-3.17 (m, 2H); 2.63-2.54 (m, 1H); 2.34-2.26 (m, 2H); 2.03-1.93 (m, 2H): 1.77-1.45 (m, 7H); 1.43-1.30 (m, 1H); 1.20-1.08 (m, 1H); 0.93-0.83 (m, 6H): MS: 354 (M+H) + .

The starting compound is prepared in the following way:

In a manner analogous to that described in Example 14(i),(ii) from 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentantriclarboxylate and N-bromomethylpyrrolidine. 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-(2-oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl]piperidine (diastereoisomer 1) was obtained in the form of white solid no: MS: 444 (M+H)+.

Example 22

In a manner analogous to that described in the first paragraph of Example 13, from 0.226 g of 4-[2(R)-[1(R or S)-carboxy-3-phthalimidopropyl]-4-methylvaleryl]morpholine. 0.065 g of 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-3-phthalimidopropyl]-4-methylvaleryl]-morpholine (diastereoisomer 1) was obtained in the form of a white solid: nmr (MeOD): 7.88 -7.76 (m, 4H); 3.86-3.50 (m, 8H); 3.24-3.15 (m, 1H); 2.32-2.23 (m, 1H); 1.99-1.89 (m, 1H); 1.83-1.73 (m, 1H); 1.66-1.57 (m, 1H): 1.43-1.29 (m, 1H); 1.17-1.09 (m, 1H); 0.89-0.83 (m, 6H); MS: 432 (M+H) + .

The starting compound is prepared in the following way:

In a manner analogous to that described in Example 1(i),(ii) from 0.65 g of 2(R)-[1(R or S)-(tert-butoxycarbonyl)-3-phthalimidopropyl]-4-methylvaleric acid, a mixture of diastereoisomers with a ratio of approximately 5 :1, and 0.17 mL of morpholine, 0.462 g of 4-[2(R)-[1(R or S)-carboxy-3-phthalimidopropyl]-4-methylvaleryl]morpholine (diastereoisomer 1) was obtained in the form of a colorless gum, which used in the further process without cleaning.

Example 23

In a manner analogous to that described in Example 13, from 0.2 g of N,N-diethyl-(2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleramide (diastereoisomer 1), which was prepared is in a manner analogous to that described in Example 13(iii)-(iv), after purification by "flash" chromatography using 3% methanol in dichloromethane for elution, 0.085 g of N,N-diethyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl)-4-methyl-valeramide (diastereoisomer 1) as a white solid: nmr (MeOD): 7.85-7.75 (m, 4H); 3.97 (dd, J=14.10, 1H); 3.68-3.6 (m, 1H); 3.57-3.48 (m, 2H); 3.3S (q.J=7.2H); 3.2 (dt, J=12.4, 1H); 2.84 (dt, J=14.5 1H); 1.67-1.59 (m, 1H); 1.47-1.36 (m, 1H); 1.26 (t, J=8, 3H); 1.25-1.16 (m, 1H); 1.13 (t, J=8, 3H); 0.9 (d, J=6 3H); 0.85 (d, J=6, 3H): MS: 404 (M+H) + .

Example 24

In a manner analogous to that described in Example 1, from 0.16 g of 3-[2(R)-[1(R or S)--carboxy-2-phthalimidoethyl]-4-methylvaleryl]thiazolidine (diastereoisomer 1) which was prepared in the manner analogous to that described in Example 1(i)-(ii), after purification by "flash" chromatography using 5% methanol in dichloromethane for elution, 0.039 g of 3-[2(R)-[1(R or S)-(hydroxycarbamoyl) was obtained )-2-phthalimidoethyl]-4-methylvaleryl]-thiazolidine (diastereoisomer 1) as a white solid: nmr (MeOD): 7.86-7.75 (m, 4H); 4.8 (d, J=10, 0.5H): 4.63 (d, J=10, 0.5H); 4.36 (d, J=10, 0.5H); 4.13-4.07 (m, 0.5H); 4.03 (d, J=10.0.5H); 3.87-3.72 (m, 2H); 3.63-3.55 (m, 0.5H); 3.45-3.36 (m, 0.5H); 3.24-2.95 (m, 2.5H); 1.62-1.54 (m, 1H); 1.46-1.37 (m, 1H); 1.29-1.2 (m, 1H): 0.9 (d, J=6, 3H); 0.8 (d. J=6, 3H): MS: 420 (M+H)+.

Example 25

In a manner analogous to that described in Example 13, from 0.25 g of N-ethyl-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-N,4-dimethylvaleramide (a mixture of diastereomers 8:1) which was prepared in a manner analogous to that described in Example 13(iii)-(iv), 0.083 g of N-ethyl-2(R)-[1(RS)-(hydroxycarbamoyl)-2-phthalimidoethyl]-N,4 -dimethylvaleramide (a mixture of diastereomers 8:1) in the form of a white solid: nmr (MeOD): 7.85-7.75 (m, 4H); 3.95-3.83 (m, 1H); 3.75-3.62 (m, 1H); 3.4-3.08 (m, 10H): 2.95-2.87 (m, 1H); 2.83 (m, 1H); 1.65-1.55 (m, 1H); 1.43-1.33 (m, 1H); 1.28-1.13 (m, 2H); 1.03 (t, J=6.2H); 0.89 (d, J=6.3H); 0.85 (d, J=6, 3H); MS: 390 (M+H)+.

Example 26

In a manner analogous to that described in Example 13, from 0.1 g of 4-[2(R)-[1(RS)-(benzyloxycarbamoyl)-5-phthalimidopentyl]-4-methylvaleryl]morpholine (a mixture of diastereomers 5:1), which was prepared in a manner analogous to that described in Example 1(i)-(ii), 0.045 g of 4-[2(R)-[1(RS)-(hydroxycarbamoyl)-5-phthalimidopentyl]-4-methyl-valeryl]morpholine ( mixture of diastereoisomers 3:1) in the form of a pale solid: nmr (MeOD): 7.85-7.75 (m, 4H); 3.8-3.49 (m, 12H); 3.15 (dt, 1H, J=14.3); 2.18 (dt, 1H, J=12.3); 1.68-1.5 (m, 4H); 1.38-1.05 (m, 5H); 0.86-0.82 (m, 6H); MS: 460 (M+H) + .

Example 27

In a manner analogous to that described in Example 13, from 1.06 g of N-phenyl-2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-N,4-dimethylvaleramide (mixture of diastereomers 5:1), and after purification by "flash" chromatography using 2% methanol in dichloromethane for elution, 0.65 g of N-phenyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-N,4- dimethylvaleramide in the form of a white foam: nmr (MeOD): 7.75-7.68 (m, 4H); 7.28-7.17 (m, 4H): 7.08-7.04 (m, 1H); 3.77 (dd, 1H, J=14.8); 3.69 (dd, 1H, J=14.7); 3.14 (s, 3H); 2.78-2.65 (m, 2H): 1.62-1.55 (m, 1H); 1.42-1.32 (m, 1H); 1.25-1.18 (m, 1H); 0.7 (d, 3H, J=7); 0.54 (d. 3H, J=7); MS: 438 (M+H) + .

The starting compound is prepared in the following way:

(i) A solution of 1.49 g of 2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleric acid (ratio of diastereoisomer 1 to diastereoisomer 2 6:1) in 20 mL toluene it was cooled to -10°C. A few drops of N,N-dimethylformamide were added, followed by 0.34 mL of oxalyl chloride. The mixture was stirred for 1 hour at -10°C, after which the solvent was evaporated in vacuo at 10°C. The residue was redissolved in 10 mL of dichloromethane and cooled to 0°C. 0.5 mL of trimethylamine was added, followed by 0.4 mL of N-methylaniline. The mixture was stirred for 1 hour at 0°C and allowed to warm to room temperature overnight. The solvent was evaporated and the residue was dissolved in 50 mL of ethyl acetate and washed with a 5% sodium hydrogencarbonate solution, then with a 2M hydrochloric acid solution, and with a saturated sodium chloride solution. The organic phase was dried over alkaline magnesium sulfate, and after evaporation an orange oil was obtained. After purification by "flash" chromatography on silica gel using hexane/ethyl acetate 3:1 for elution, 1.23 g of N-phenyl-2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl] was obtained. -N,4-dimethylvaleramide (diastereoisomer 1) in the form of pale yellow oil; nmr (CDCl 3 ): 7.83-7.78 (m, 2H); 7.73-7.68 (m, 2H); 7.32-7.05 (m, 5H); 4.0 (dd, 1H, J=13.9); 3.74 (dd, 1H, J=14.6); 3.26 (s, 3H); 3.03-2.96 (m, 1H); 2.83-2.76 (m, 1H); 1.78-1.68 (m, 1H); 1.57-1.46 (m, 1H); 1.1 (s, 9H); 0.87 (d, 3H, J=7); 0.65 (d, 3H, J=7), MS: 4.79 (M+H)+.

(ii) In a manner analogous to that described in Example 13(iv) from 1.23 g of N-phenyl-2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-N,4-dimethylvaleramide, after "flash" chromatography using 2% methanol in dichloromethane for elution, 1.06 g of N-phenyl-2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-N,4-dimethylvaleramide was obtained in in the form of white foam; nmr (CDCl 3 ) 7.8-7.74 (m, 4H); 7.45-7.28 (m, 6H); 7.04-6.85 (m, 4H); 4.96 (d, 1H, J=10); 4.89 (d, J=11); 3.95 (dd, 1H, J=14.6); 3.72 (dd, 1H, J=14.9); 3.17 (s, 3H); 3.05-2.98 (m, 1H); 2.64-2.58 (m, 1H); 1.68-1.6 (m, 1H); 1.49-1.32 (m, 2H); 0.79 (d, 3H, J=6); 0.66 (d, 3H, J=6); MS: 528 (M+H) + .

Example 28

In a manner analogous to that described in the first paragraph of Example 13, from 0.31 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-2(R)-pyrrolidinemethanol ( diastereoisomer 1), after purification by "flash" chromatography on silica gel using dichloromethane/methanol (15:1) for elution, and after crystallization from ethyl acetate, 0.07 g of 1-[2(R)-[1(R or S) was obtained )-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-2(R)-pyrrolidinemethanol (diastereoisomer 1) in the form of a white solid; nmr (MeOD): 7.86-7.74 (m, 4H); 4.20-4.10 (m, 1H); 4.05-3.97 (m, 1H); 3.81-3.57 (m, 5H); 3.10-3.02 (m, 1H); 2.84-2.76 (m, 1H); 2.14-1.87 (m, 4H): 1.73-1.63 (m, 1H): 1.50-1.35 (m, 1H); 1.24-1.14 (m, 1H); 0.94-0.84 (m, 6H); MS: 432 (M+H) + .

The starting compound is prepared in the following way:

In a manner analogous to that described in the second paragraph of Example 9, from 0.41 g of 1-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl]-2(R)- of pyrrolidinemethanol (diastereoisomer 1), which was prepared in a manner analogous to that described in Example 1(i), 0.31 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4 was obtained -methylvaleryl]-2(R)-pyrrolidinemethanol (diastereoisomer 1) as a pale brown foam which was used without further purification.

Example 29

In a manner analogous to that described in the first paragraph of Example 13, from 0.2 g of benzyl hexahydro-2-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-3(S) -(methylcarbamoyl)-pyridazinecarboxylate (diastereoisomer 1), after purification by "flash" chromatography on silica gel using dichloromethane/methanol (20:1) for elution, 0.044 g of hexahydro-2-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-N-methyl-3(S)-pyridazinecarboxamide (diastereoisomer 1) as a white solid: nmr (MeOD): 7.83-7.69 (m, 4H); 5.06 (m, 1H); 3.99 (dd, 1H, J=14.9); 3.57 (dd, 1H, J=14.5); 3.04-2.95 (m, 1H); 2.86-2.74 (m, 2H): 2.70 (s, 3H); 2.07-1.86 (m, 2H); 1.68-1.35 (m, 5H); 1.18-1.10 (m, 1H); 0.88 (d. 3H, J=5.5); 0.80 (d, 3H, J=6.0); MS: 474 (M+H) + .

The starting compound is prepared in the following way:

(i) In a manner analogous to that described in Example 27(i), from 1.02 g of 2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleric acid (diastereoisomer ratio 1 to diastereoisomer 2 6:1) and 0.7 g of hexahydro-1-(benzyloxycarbonyl)-(3S)-pyridazinecarboxylic acid, after chromatography on silica gel using first ether/hexane (1:4) and then ethyl acetate for elution, 0.6 g was obtained hexahydro-1-(tert-butoxycarbonyl)-2-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-3(S)-pyridazinecarboxylic acid in the form colorless rubber.

(ii) A solution of 0.6 g of hexahydro-1-(benzyloxycarbonyl)-2-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl]-3(S) -pyridazinecarboxylic acid in 5 mL of dimethylformamide was cooled to 0°C and 0.27 g of 1-hydroxy-benzotriazole and 0.36 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. After 40 minutes, 0.4 mL of a 40% aqueous solution of methylamine was added and the mixture was stirred for 2.5 hours. The solvent was evaporated and 20 mL of a 5% aqueous solution of sodium hydrogencarbonate was added to the residue. The product was extracted with ethyl acetate and the extract was washed with 5% citric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and evaporation of the solvent, 0.638 g of a colorless gum was obtained, which was purified by "flash" chromatography using ether/hexane (3:1) for elution. 0.467 g of benzyl hexahydro-2-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl]-3(S)-(methylcarbamoyl)-pyridazinecarboxylate were obtained in in the form of colorless rubber.

(iii) In a manner analogous to that described in Example 13(iv) from 0.23 g of benzyl hexahydro-2-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-4-methylvaleryl] -3(S)-(methyl-carbamoyl)-pyridazinecarboxylate, 0.2 g of benzyl hexahydro-2-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]- 3(S)-(methylcarbamoyl)-pyridazinecarboxylate as a white solid.

Example 30

In a manner analogous to that described in the first paragraph of Example 1 and part (ii) of Example 1, from 0.273 g of benzyl hexahydro-2-[2(R)-[1(R or S)-(tert-butoxycarbonyl)-2-phthalimidoethyl]- 4-methylvaleryl]-3(S)-(methylcarbamoyl)-1-pyridazinecarboxylate yielded 0.12 g of benzyl hexahydro-2-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimido-ethyl] -4-methylvaleryl]-3(S)-(methylcarbamoyl)-pyridazinecarboxylate as a white solid. MS: 608 (M+H) + .

Example 31

In a manner analogous to that described in the first paragraph of Example 13, from 0.185 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-N-methyl--2( S)-piperidinecarboxamide, after purification by flash chromatography on silica gel using dichloromethane/methanol (16:1) as eluent. 0.06 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl-N-methyl-2(S)-piperidinecarboxamide (diastereoisomer 1) was obtained in in the form of a white solid. MS: 485 (M+H) + .

Example 32

In a manner analogous to that described in the first paragraph of Example 1, from 0.22 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]-4-methoxypiperidine (diastereoisomer 1) which is prepared in a manner analogous to that described in Example 1(i)-(ii), 0.108 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl] was obtained -4-methoxypiperidine (diastereoisomer 1) in the form of a white solid; nmr (MeOD) 7.86-7.74 (m, 4H); 4.05-3.83 (m, 2.5H); 3.70-3.44 (m, 3.5H); 3.41-3.27 (m, 4.5H); 3.10-3.01 (m, 0.5H); 2.97-2.90 (m, 1H); 2.10-2.00 (m, 0.5H); 1.94-1.84 (m, 1H); 1.80-1.68 (m, 1H); 1.66-1.31 (m, 3.5H); 1.21-1.13 (m, 1H); 0.92-0.82 (m, 6H); MS: 446 (M+H) + .

Example 33

In a manner analogous to that described in the first paragraph of Example 1, from 0.44 g of 1-[2(R)-[1(R or S)-carboxy-2-phthalimidoethyl]-4-methylvaleryl]-4-piperidinone, which was prepared in an analogous manner described in Example 1(ii)-(iii), 0.157 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-4-piperidinone oxime was obtained (diastereoisomer 1) in the form of a white solid; nmr (MeOD): 7.86-7.75 (m, 4H); 3.92-3.76 (m, 3H): 3.72-3.58 (m, 2H); 3.38-2.82 (m, 3H); 2.71-2.25 (m, 4H); 1.66-1.57 (m, 1H); 1.48-1.34 (m, 1H); 1.26-1.17 (m, 1H); 0.92-0.82 (m, 6H); MS: 445 (M+H) + .

Example 34

In a manner analogous to that described in the first paragraph of Example 13, from 0.32 g of methyl ester N-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-4-methylvaleryl]-1--proline ( diastereoisomer 1) which was prepared in a manner analogous to that described in Example 13(iii)-(iv), 0.13 g of methyl ester N-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2- phthalimidoethyl]-4-methylvaleryl]-1-proline (diastereoisomer 1) as a white solid; nmr (MeOD): 7.86-7.77 (m, 4H); 3.95-3.84 (m, 2H); 3.78 (d. 2H.J=8); 3.69-3.61 (m, 1H): 3.60 (s. 3H): 3.11-3.04 (m, 1H): 3.00-2.92 (m, 1H): 2.21-2.12 fm, 1H): 2.10-1.95 (m, 2H) : 1.90-1.82 (m, 1H): 1.74-1.63 (m, 1H); 1.60-1.52 (m, 1H); 1.22-1.14 (m, 1H); 0.94 (d, 3H, J=6); 0.86 (d, 3H, J=6); MS: 460 (M+H) + .

Example 35

In a manner analogous to that described in the first paragraph of Example 13, from 1,116 g of 1-[2(R)-[1 (R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) which was prepared in a manner analogous to that described in Example 14(i)-(ii), 0.785 g of 1-[2(R)-[ 1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) in the form of white solids; nmr (MeOD): 4.24-4.01 (m, 2H); 3.93-3.81 (m, 1H); 3.78-3.64 (m, 1H); 3.52-3.22 (m, 4H); 3.10-2.81 (m, 4H): 2.02-1.77 (m, 2H); 1.67-1.26 (m, 10H); 1.19-1.09 (m, 1H); 0.93-0.82 (m, 6H); MS: 427 (M+H) + .

Example 36

In a manner analogous to that described in the first paragraph of Example 1, from 1.55 g of 1-[2(R)-[1(R or S)-carboxy-2-(tetrahydro-2-methyl-3,5-dioxo-1,2, 4-oxadiazol-4-yl)ethyl]-4-methylvaleryl]-4-piperidine (diastereoisomer 1), 0.572 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2- (tetrahydro-2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl)ethyl]-4-methylvaleryl]-4-piperidine (diastereoisomer 1) as a white solid: nmr (MeOD): 3.70-3.46 (m, 4H); 3.42-3.29 (m, 2H); 3.25-3.15 (m, 4H); 2.89-2.76 (m, 1H); 1.68-1.27 (m, 8H); 1.27-1.04 (m, 1H); 0.83-0.76 (m, 6H); MS: 386 (M+H) + .

The starting compound is prepared in the following way:

(i) In a manner analogous to that described in Example 18(i)-(ii), from 4.76 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1,1,2(R)-pentanetricarboxylate and 2.05 g of 4-bromomethyl- 2-tetrahydro-2-methyl-3,5-dioxo-1,2,4-oxadiazole, 1.55 g of 1-[2(R)-[1(R or S)-carboxy--2-(tetrahydro -2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl)ethyl]-4-methylvaleryl]-4-piperidine which was used without further purification.

Example 37

In a manner analogous to that described in the first paragraph of Example 13, from 0.184 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3-methyl-2,4,5-trioxo-1- imidazolidinyl)-ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) which was prepared in the manner described in Example 14(i)-(ii) from 1,2-dibenzyl 1-tert-butyl 4-methyl-1 ,1,2(R)-pentane-tricarboxylate and 1-bromo-3-methyl-2,4,5-trioxo-1-imidazole, 0.08 g of 1-[2(R)-[1(R or S )-(hydroxycarbamoyl)-2-(3-methyl-2,4,5-trioxo-1-imidazolidinyl)-ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.20, 3.95 (m, 2H); 3.93-3.75 (m, 2H); 3.57-2.97 (m, 7H): 2.90-2.81 (m, 1H); 2.02-1.76 (m, 2H); 1.66-1.29 (m, 4H): 1.20-1.12 (m, 1H); 0.91-0.82 (m, 6H); MS: 413 (M+H) + .

Example 38

In a manner analogous to that described in the first paragraph of Example 13, from 0.261 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2,5-dioxo-3-phenyl-1-imidazolidinyl) -ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) which was prepared in the manner described in Example 14(i)-(ii), 0.169 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(2,5-dioxo-3-phenyl-1-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 7.60-7.55 (m, 2H); 7.35-7.29 (m, 2H); 7.12-7.05 (m, 1H); 4.37-4.24 (m, 1H), 4.19-3.92 (m, 2H): 3.89-3.66 (m, 2H); 3.54-2.84 (m, 5H); 1.99-1.71 (m, 2H); 1.64-1.23 (m, 4H); 1.17-1.08 (m, 1H); 0.88-0.78 (m, 6H); MS: 461 (M+H) + .

Example 39

In a manner analogous to that described in the first paragraph of Example 13, from 0.146 g of 4-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3-methyl-2,4,5-trioxo-1- imidazolidinyl)-ethyl]-4-methylvaleryl]morpholine (diastereoisomer 1) which was prepared in the manner described in Example 14(i)-(ii), 0.085 g of 4-[2(R)-[1(R or S)-(hydroxy-carbamoyl)-2-(3-methyl-2,4,5-trioxo-1-imidazolidinyl)ethyl-4-methylvaleryl]morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 3.86-3.54 (m, 10H); 3.28-3.20 (m, 1H); 3.08 (s, 3H); 2.91-2.82 (m, 1H); 1.66-1.57 (m, 1H); 1.48-1.36 (m, 1H); 1.23-1.15 (m, 1H); 0.89-0.84 (m, 6H); MS: 399 (M+H) + .

Example 40

In a manner analogous to that described in the first paragraph of Example 13, from 0.363 g of N2-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo- 1-imidazolidinyl)ethyl]-4-methylvaleryl]-N1-methyl-1-prolinamide (diastereoisomer 1) which was prepared in the manner described in Example 14(i)-(ii), 0.234 g of N2-[ 2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidin-yl)ethyl]-4-methylvaleryl]-N1- methyl-1-prolinamide (diastereoisomer 1) as a white solid; nmr (MeOD): 4.35-4.29 (m, 1H); 3.92-3.83 (m, 1H); 3.74-3.58 (m, 2H); 3.47-3.41 (m, 1H); 3.10-3.01 (m, 1H); 2.88-2.75 (m, 4H); 2.59 (s, 3H); 2.26-1.84 (m, 4H); 1.74-1.55 (m, 2H); 1.34 (s, 3H); 1.32 (s, 3H); 1.18-1.11 (m, 1H); 0.92 (d, 3H, J=5.5); 0.86 (d, 3H, J=6); MS: 454 (M+H) + .

Example 41

In a manner analogous to that described in the first paragraph of Example 13, from 0.3 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2-oxo-1-pyrrolidinyl)ethyl-4-methylvaleryl] -4-piperidinol (diastereoisomer 1), which was prepared in the manner described in Example 14(i)-(ii), 0.116 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)- 2-(2-oxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD); 4.16-3.91 (m, 2H); 3.84-3.73 (m, 1H); 3.43-2.97 (m, 7H); 2.56-2.45 (m, 1H); 2.27-2.18 (m, 2H); 1.96-1.70 (m, 4H); 1.61-1.19 (m, 4H); 1.11-1.01 (m, 1H); 0.84-0.72 (m, 6H); MS: 370 (M+H) + .

Example 42

In a manner analogous to that described in the first paragraph of Example 13, from 0.16 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(2,5-dioxo-1-pyrrolidinyl)ethyl]-4 -methylvaleryl-4-piperidinol (diastereoisomer 1) which was prepared in the manner described in Example 14(i)-(ii), 0.048 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl) was obtained )-2-(2,5-dioxo-1-pyrrolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.25-4.01 (m, 2H); 3.94-3.80 (m, 1H); 3.78-3.63 (m, 1H); 3.52-3.02 (m, 4H); 2.82-2.73 (m, 1H); 2.63 (d, 4H, J=6); 2.04-1.76 (m, 2H); 1.64-1.27 (m, 4H); 1.18-1.09 (m, 1H); 0.92-0.80 (m, 6H); MS: 384 (M+H) + .

Example 43

In a manner analogous to that described in the first paragraph of Example 13, from 0.43 g of 1-[2(R)-[1(R or S)-(benzyloxycarbamoyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) which was prepared in a manner analogous to that described in Example 14(i)-(ii), 0.158 g of 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)ethyl]-4-methylvaleryl]-4-piperidinol (diastereoisomer 1) as a white solid; nmr (MeOD): 4.25-3.97 (m, 2H); 3.93-3.79 (m, 2H); 3.74-3.61 (m, 1H); 3.52-2.97 (m, 4H); 2.93-2.80 (m, 4H); 2.02-1.76 (m, 2H); 1.67-1.27 (m, 4H); 1.19-1.10 (m, 1H); 0.91-0.80 (m, 6H); MS: 399 (M+H) + .

The following Examples illustrate the pharmaceutical preparations containing hydroxamic acid derivatives disclosed in the present invention:

Example A

Tablets containing the following components can be prepared in a conventional manner:

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 a conventional manner:

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 (29)

1. Compounds of the general formula [image] indicated that R1 represents a five- or six-membered N-heterocyclic ring which: (a) is connected through an N atom, (b) may contain N, O and/or S as heteroatom(s) in a position or positions that are not adjacent to the N atom through which it is attached, (c) is substituted with an oxo group on one or both C atoms adjacent to the N atom through which the ring is attached and (d) may be fused with benzene or may be substituted on one or more C atoms with lower alkyl or oxo and/or on each additional N atom(s) with lower alkyl or aryl; R2 represents lower alkyl and R3 represents lower alkyl or aryl, or NR2R3 represents a five-, six- or seven-membered heterocyclic ring which may contain - NRa, -O-, -S-, -SO- or -SO2 - as ring members and/or which may be substituted with hydroxy, 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 hydroxyimino; R a represents hydrogen, lower alkyl, lower alkanoyl, aryl-lower alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or mono(lower alkyl)carbamoyl; R 4 , R 5 , R 6 and R 7 each represent hydrogen or methyl, with at least two of these symbols representing hydrogen and n being 1-4; and their pharmaceutically compatible salts. 2. Compounds according to claim 1, characterized in that R1 represents a five- or six-membered N-heterocyclic ring which (a) is attached via an N atom and (b) may contain N, O and/or S as an additional heteroatom(s) in a position or positions that are not adjacent to the N atom through which is attached, (c) is substituted by an oxo group on one or both C atoms adjacent to the N atom through which the ring is attached and (d) may be fused with benzene or may be substituted on one or more C atoms with lower alkyl or oxo and/ or on each additional N atom(s) it may be substituted with lower alkyl or aryl; R2 represents lower alkyl and R3 represents lower alkyl or aryl or NR2R3 represents a saturated five-, six- or seven-membered ring which may contain -NRa, -O-, -S-, -SO- or -SO2- as ring members and/or which may be substituted with the following groups: hydroxy, lower alkoxy, oxo, ketylized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl) carbamoyl or di(lower alkyl)carbamoyl; Ra represents hydrogen or lower alkyl, a R4, R5, R6, R7 and n have the meaning given in claim 1. 3. Compounds according to patent claim 1 or patent claim 2 characterized by the fact that the N-heterocyclic ring R1 can contain two N atoms, one N atom and one O atom or one O atom as an additional heteroatom (additional heteroatoms). 4. Compounds according to patent claim 3 characterized in that R1 represents a group of the formula [image] indicated that R 8 and R 9 each represent hydrogen or together represent an additional bond or residue of a fused benzene ring; R 10 represents hydrogen, lower alkyl or aryl; X represents -CO-, -CH2-, -CH(lower alkyl)-, -C(lower alkyl)2-, -NH-, -N(lower alkyl)- or -O-, and Y represents -O-, -NH- or -N(lower alkyl)-. 5. Compounds according to claim 4, characterized in that R10 represents hydrogen or lower alkyl. 6. Compounds according to claim 4 or claim 5, characterized in that R1 represents a ring of formula (b) or (c). 7. Compounds according to claim 6, characterized in that R1 represents phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazoldin-4-yl, 3-methyl-2,5-dioxo-1 -imidazolidinyl or 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl. 8. Compounds according to any patent claim from 1 to 7, characterized in that NR 2 R 3 represents a five-, six- or seven-membered saturated heterocyclic ring. 9. Compounds according to claim 8, characterized in that NR2R3 represents a six-membered saturated heterocyclic ring. 10. Compounds according to claim 9, characterized in that NR2R3 represents morpholino, tetrahydro-1,4-thiazin-4-yl or 4-hydroxypiperidino. 11. Compounds according to any one of claims 1-10, wherein n is not 1 or 12. 12. Compounds according to any one of claims 1-11, wherein n is 1 or 2. 13. A compound characterized in that it is 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]morpholine. 14. A compound characterized in that it is 4-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]tetrahydro-1,4-thiazine. 15. A compound characterized in that it is 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-4-piperidinol. 16. Compound characterized in that 1-[2(R)-[1(R or S)-hydroxycarbamoyl)-2-(1,2-dimethyl-3,5-dioxo-1,2,4-triazoldine -4-yl)ethyl]-4-methylvaleryl]piperidine. 17. A compound characterized in that it is 4-[2(R)-[1(R or S)-hydroxycarbamiol)-2-(3-methyl-2,5-dioxo-1-imidazoldinyl)ethyl]-4-methylvaleryl ]-tetrahydro-1,4-thiazine. 18. Compound characterized in that hexahydro-2-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-phthalimido-ethyl]-4-methylvaleryl]-N-methyl-3(S )-pyridazinecarboxamide. 19. Compound characterized in that it is 1-[2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl]-4-methylvaleryl]-4-piperidinol. 20. Compounds of the general formula [image] indicated that R1, R2, R3, R4, R5, R6, and R7 have the meanings specified in claim 1. 21. Compounds of the general formula [image] characterized in that R1, R2, R3, R4, R5, R6 and R7 have the meanings given in claim 1, and Bz denotes benzyl. 22. Compounds according to any patent claim from 1-19, characterized in that they are for use as therapeutically active substances. 23. Compounds according to any patent claim from 1-19, characterized in that they are for use in the control and prevention of degenerative joint diseases or for use in the therapy of invasive tumors, atherosclerosis or multiple sclerosis. 24. Processes for the preparation of the compounds reported in patent claims 1-19, which contain: (a) acid reaction of the general formula [image] characterized by the fact that R1, R2, R3, R4, R5, R6, and R7 have the meanings specified in patent claim 1, with a compound of the general formula H2N-OZ indicated that Z represents hydrogen, tri(lower alkyl)silyl or diphenyl(lower alkyl)silyl, and where it is necessary to separate the diphenyl(lower alkyl)silyl group present in the reaction product, or (b) catalytic hydrogenation of compounds of the general formula [image] indicated that R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 have the meanings given in claim 1, and Bz denotes benzyl. and, if necessary, translation of the obtained compound of formula I. into a pharmaceutically compatible salt. 25. Medicines, characterized in that they contain a compound according to any patent claim 1-19 as well as therapeutically indifferent auxiliary means. 26. Medicines for the prevention of degenerative joint diseases or for the therapy of invasive tumors, atherosclerosis or multiple sclerosis, characterized in that they contain a compound according to any patent claim 1-19, as well as therapeutically indifferent auxiliary agents. 27. Use of compounds according to any one of claims 1-19, characterized in that it is for disease control or prevention. 28. The use of compounds according to any patent claim from 1-19, 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. 29. The use of compounds according to any patent claim from 1-19, indicated by the fact that it is for the application of drugs for the control or prevention of degenerative joint diseases or for the therapy of invasive tumors, atherosclerosis or multiple sclerosis.