SI9300289A - Hydroxamic acid derivatives - Google Patents

Description

DERIVATIVE HYDROXAMIC ACIDS

The present invention relates to hydroxamic acid derivatives.

The hydroxamic acid derivatives of the present invention are compounds of the general formula

in which they represent

R1 is a 5- or 6-membered N-heterocyclic ring which is (a) bonded via the N atom, (b) optionally contains N, O and / or S as additional or additional heteroatoms in a position or positions different from the adjacent to the N bond atom, (c) is substituted by oxo on one or both C atoms adjacent to the N bond atom, and (d) is optionally benzene coupled or optionally substituted on one or more other C atoms with lower alkyl or oxo and / or on the possible or possibly additional N atoms with lower alkyl or aryl;

R ^ is lower alkyl and R ^ represents lower alkyl or aryl, or

NR ^ R ^ is a saturated 5-, 6- or 7-membered heterocyclic ring, optionally containing

-NR ^a , -Ο-, -S-, -SO- or -SO2- as the ring member and / or optionally substituted by hydroxy, lower alkoxy, oxo ketalized oxo, amino, mono (lower alkylamino, di (lower alkylamino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono (lower alkyl) carbamoyl, di (lower alkylcarbamoyl or hydroxyimino;

R ^{a is} hydrogen, lower alkyl, lower alkanoyl, aryl-lower alkanoyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl or mono (lower alkylcarbamoyl;

R ⁴ , R ⁵ , R ⁶ and R 6 each represent hydrogen or methyl, with the proviso that at least two of these symbols represent hydrogen; and n stands for 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 to control or prevent degenerative joint disease, such as rheumatoid arthritis and osteoarthritis, or in the treatment of invasive tumors, atherosclerosis, or multiple sclerosis.

The objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, alone and for use as therapeutically effective substances; a process for preparing said compounds and salts; intermediates useful in the said process; medicines containing said compounds and salts and the preparation of these medicines; and the use of said compounds and salts in the control or prevention of disease or in improving health, in particular in the control or prevention of degenerative joint disease, or in the treatment of invasive tumors or atherosclerosis, or in the preparation of a medicament for the control or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis.

As used herein, the term lower alkyl alone or in combination, is a straight or branched alkyl group containing not more than 6, preferably 1 to 4 carbon atoms, 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, means a straight or branched alkoxy group containing not more than 6, preferably 1 to 4, carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. The term aryl means phenyl optionally substituted e.g. with lower alkyl, lower alkoxy and / or halogen, e.g. fluorine, chlorine, bromine or iodine. The term lower alkanoyl alone or in combination, means an acyl group derived from alkanoic acid containing up to 6 carbon atoms, e.g. acetyl, propionyl, butyryl, isobutyryl and the like. The ketalized oxo group may be e.g. ethylenedioxy.

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. The compounds of formula I, which are basic, form pharmaceutically acceptable salts with acids. As such, salts not only include salts with inorganic acids such as hydrohalic acids (eg hydrochloric and hydrobromic acid), sulfuric acid, hydrochloric acid, phosphoric acid, etc., but also salts with organic acids such as acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic and p-toluenesulfonic acid, etc.

The compounds of formula I contain at least two asymmetric carbon atoms and may therefore exist as optically active enantiomers, as diastereoisomers or as racemates. The present invention should cover all of these forms.

Compounds of formula I in which the N-heterocyclic ring contains RA, optionally as additional or additional hetero atom (s) of one or two N atoms, one N atom and one O atom or one O atom, are preferred. Particularly preferred rings denoted by R1 are those of formulas

in which

R8 and in each case represent hydrogen or together represent an additional bond or the remainder of a closed benzene ring;

R10 is hydrogen, lower alkyl or aryl;

X -CO-, -CH2-, -CH (lower alkyl) -, -C (lower alkyl) 2 ~, -NH-, -N (lower alkyl) - or -O-; and Y is -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-methyl2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl and 2,6-dioxopiperidino. These rings of formulas (b) and (c), in particular phthalimido, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl or 3,4,4-trimethyl-2,5-dioxo-limidazolidinyl are particularly preferred.

Compounds of formula I in which NR 1 R 2 represents a 5-, 6- or 7-membered saturated heterocyclic ring, as previously defined, are preferred. 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 as indicated above; e.g. 2- (methylcarbamoyl) -1-pyrrolidinyl, 2- (hydroxymethyl) -1-pyrrolidinyl, 4-hydroxypiperidino, 2- (methylcarbamoyl) piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 1,4-dioxa-8-azaspiro- [ 4.5] decan-8-yl, hexahydro-3- (methylcarbamoyl) -2-pyridazinyl and hexahydro-1- (benzyloxycarbonyl) -2-pyridazinyl. Particularly preferred are compounds of formula I wherein NR ² R ^{2 represents a} 6-membered saturated heterocyclic ring, in particular morpholino, tetrahydro-1,4-thiazin-4-yl, 4-hydroxypiperidino or hexahydro-3- (methylcarbamoyl) -2- pyridazinyl.

Compounds of formula I in which R ^ r5 j _n R7 each represent hydrogen, and R ⁶ represents methyl, are also preferred.

Further preferred are compounds of formula I wherein n is 1 or 2.

The most preferred compounds of formula I are:

4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] morpholine, 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -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-triazolidin-4yl) ethyl] -4- methylvaleryl] piperidine,

4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyl-2,5'-dioxo-1-imidazolidinyl) ethyl] -4methyl valeryl] tetrahydro-1,4-thiazine , hexahydro-2- [2 (R) '[1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylphenyl] -Nmethyl-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.

In accordance with the method provided by the present invention, the compounds of formula I and their pharmaceutically acceptable salts are prepared such that (a) an acid of the general formula

in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n have the aforementioned meaning, reacts with a compound of the general formula

H ₂ N-OZ (III) in which Z represents hydrogen, tri (lower alkyl) silyl or diphenyl (lower alkyl) silyl, and optionally cleaving any diphenyl (lower alkyl) silyl group present in the reaction product, or

b) catalytically hydrogenate a compound of the general formula

where Rl, R ^, R3, R4, R5, R6, R7, j _nn p _re j as defined above and Bz represents benzyl, and, if desired, converting the resulting compound of formula Ϊ into a pharmaceutically acceptable salt thereof.

The reaction of an acid of formula II with a compound of formula lil according to embodiment (a) of the process can be carried out in a known manner, e.g. in an inert organic solvent such as dimethylformamide and the like, using hydroxybenzotriazole in the presence of a condensing agent such as l-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride at about 0 ° C to about room temperature. Preferred compounds of formula III are those wherein Z represents hydrogen, tert-butyl-dimethylsilyl or tert-butyl diphenylsilyl. If a compound of formula III is used in which Z represents three (lower alkyl) silyl, this group is cleaved during the reaction and treatment and directly obtained is a compound of formula I. On the other hand, when using a compound of formula 111 in which Z represents diaryl- (lower alkyl) silyl, this group remains in the reaction product and must subsequently be cleaved in a known manner, e.g. using fluoride ions.

The catalytic hydrogenation of compounds of formula IV in accordance with embodiment (b) of the process can be carried out in a manner known per se, e.g. in an inert organic solvent using hydrogen in the presence of a precious metal catalyst. Suitable inert organic solvents are e.g. lower alkanols than methanol, ethanol, etc. However, the catalyst may be e.g. platinum, palladium or rhodium catalyst, which may be applied on suitable nostril material. Preferred palladium catalysts on charcoal. Temperature and pressure are not critical, although catalytic hydrogenation is preferably carried out at room temperature and atmospheric pressure for convenience.

Compounds of formula I can be converted to pharmaceutically acceptable salts by treatment with bases, and basic compounds of formula I can be converted into pharmaceutically acceptable salts by treatment with acids, such treatment can be carried out in the usual way.

The acids of formula II used as starting materials in carrying out (a) of the process are novel compounds and form a further object of the present invention.

The acids of formula II can be prepared e.g. as shown in the following Reaction Scheme in which R1, R4, R- \ r4 r5, r7, g _with j _nn p _re j have the indicated meaning and tBu represents tert.butyl.

Reaction scheme

In view of the above Reaction Scheme, in the first step, αIcantricarboxylate of formula V is reacted with a bromoalkyl-substituted N-heterocycle of formula VI to give a compound of formula VIL This reaction can be carried out in a conventional manner, e.g. by treating alkantricarboxylate in an inert organic solvent as dimethylformamide with a strong base, e.g. alkali metal hydride as sodium hydride, then bromoalkylsubstituted N-heterocycle is added and the reaction is allowed to proceed, preferably at room temperature.

The resulting compound of formula VII is then debenzylated into the compound of formula VIII in a manner known per se, e.g. by hydrogenation in an inert organic solvent, e.g. in lower alkanol than methanol or ethanol, in the presence of a catalyst as palladium on charcoal.

The following decarboxylation of the compound of formula VIII into the compound of formula IX is also carried out in a known manner, e.g. by heating in an aromatic solvent such as benzene or toluene, in the presence of a base such as N-methylmorpholine.

In a further step, a compound of formula IX is reacted with an amine of formula X to yield a compound of formula XI. This reaction can be carried out in a manner known per se. So e.g. the reaction is conveniently 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 a compound of formula IX with oxalyl chloride into a suitable chloride and reacting it with an amine, preferably in the presence of a base such as triethylamine, at about 0 to triethylamine 25 ° C.

At the final step, the protection of the compound of formula XI is removed to obtain the desired acid starting material of formula II. This deprotection can be carried out in a manner known per se, e.g. by treatment with trifluoroacetic acid.

If desired, the compound of formula XI can be functionally modified prior to the deprotection step. So e.g. a compound of formula XI. in which NR ^ R ^ represents a saturated 5-, 6- or 7-membered heterocyclic ring containing -S- as a ring member, is oxidized in a manner known per se, e.g. using peracid as mChloroperbenzoic acid, into a suitable compound containing -SO- or -SO2- as a ring member.

The compounds of formula IV to be used as starting materials in carrying out (b) of the process are novel and form a further object of the present invention.

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

Other compounds used as intermediates or reagents in the preparation of compounds of formula I are known compounds or analogs of known compounds which can be prepared in a similar manner to known compounds.

As mentioned earlier, the compounds of formula I and their pharmaceutically acceptable salts are collagenase inhibitors. The activity of the present compounds and salts for in vitro inhibition of collagenase can be demonstrated using collagenase obtained from culture of human synovial fibroblasts according to the method of Dayer JM et. al., Contd. Natl. Acad.Sci. USa (1976), 73 945, following the activation of pro-collagenase in conditioned medium by trypsin treatment. Collagenase activity was measured using ⁴ C-acetylated type I collagen from rat tail tendons as substrate and using a microtiter plate assay method (Jonson-Wint, B, Anal. Biochem. (1980), 104, 175). IC5q is that concentration of a compound or salt of the present invention in the digestion of an enzyme that reduces substrate cleavage and solubilization to 50% of the value achieved by the enzyme itself.

The results obtained in the above test with representative compounds and salts of the present invention are summarized in the following Table 1:

Table I

A compound of formula I IC _{5 ()} (nM) A 10 B 6 C 5 D 15 E 7 F 1.2 Mr 6.9

Compound A: 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalim idoethyl] 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-thalimidoethyl 4-methylvaleryl] -4-piperidinol.

Compound D: 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl)] - 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-phthalimidoethyl] 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 acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, they can also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the preparation of the pharmaceutical compositions, the compounds of formula I and their pharmaceutically acceptable salts may be formulated with therapeutically inert inorganic or organic carriers. As such, carriers for tablets, coated tablets, dragees and hard gelatin capsules can be used e.g. lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. Depending on the nature of the effective ingredient, carriers in soft gelatin capsules are generally not required. Suitable carriers for the preparation of solutions and syrups are e.g. water, polyols, sucrose, invert sugar, glucose and the like. Suitable carriers for the preparation of injection solutions are e.g. water, alcohols, polyols, glycerin, vegetable oils, etc. Natural and solid oils, waxes, fats, semi-liquid polyols and the like. are suitable carriers for the preparation of suppositories.

Pharmaceutical preparations may also contain preservatives, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, osmotic pressure adjusting salts, buffers, coating agents or antioxidants.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically acceptable carrier as well as a process for the preparation of such medicaments are also objects of the present invention. This process involves mixing a compound of formula I or a pharmaceutically acceptable salt thereof with a therapeutically inert carrier material and formulating the mixture into a galenic preparation.

As mentioned above, the compounds of formula I and their pharmaceutically acceptable salts may be used in the control or prevention of diseases, especially in the control or prevention of degenerative joint diseases or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis. Dosage can vary within wide limits and will, of course, be tailored to the individual needs of each case. In general, a daily dose of about 5 mg to about 30 mg, preferably from about mg to about 15 mg, will be appropriate when administered to adults, although the upper limit may also be exceeded if this would prove useful. The daily dose can be given in a single dose or in divided doses.

The following Examples explain the present invention in more detail. In all these Examples, temperatures are indicated in ° C.

Example 1

A solution of 0.15 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -pyrrolidine (diastereoisomer 1) in 3 ml of dry dimethylformamide was cooled to 0 ° C with stirring under was treated with nitrogen and sequentially treated with 0.075 g of 1-hydroxybenzotriazole, 0.12 g of O (tert-butyldimethylsilyl) -hydroxylamine, 0.075 ml of N-methylmorpholine and 0.094 g of l-ethyl-3- (3dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was treated with 5 ml of 5% aqueous sodium hydrogen carbonate solution. The product was extracted with 3 parts of ethyl acetate and the combined extracts were washed with 1.0 M hydrochloric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was triturated with a mixture of ether and hexane. The solid was filtered off and dried to give 0.09 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4methylvalerylpyrrolidine (diastereoisomer 1) as a white powder: nmr (MeOD ): 7,847.71 (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 material was prepared as follows:

(i) A solution of 0.41 g of approximately 6: 1 mixture of diastereoisomer 1 and diastereoisomer 2 [2 (R) - [. 1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methyl] eric acid) in 5 ml of dry dimethylformamide was cooled to 0 ° C under stirring under nitrogen and treated sequentially with 0.16 g of 1-hydroxybenzotriazole, 0.1 g of pyrrolidine, 0.13 ml of N-methylmorpholine and 0.23 g of l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was treated with 20 ml of 5% aqueous sodium hydrogen carbonate solution. The product was extracted with 3 parts of ethyl acetate and the combined extracts were washed with 5% citric acid and aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated to give 0.5 g of colorless gum, which was purified by flash chromatography on silica gel using hexane / ethyl acetate (5: 4) for elution. Elution of the faster-traveling product (diastereoisomer 2) gave 0.365 g of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methyl-valeryl] pyrrolidine (diastereoisomer 1) as a colorless gum: nmr (MeOD): 7.88-7.79 (m, 4H); 3.99-3.93 (m.IH); 3.78-3.66 (m, 2H); 3.60-3.53 (m, 1H); 3.39-3.30 (m, 1H); 3.273.21 (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) A solution of 0.35 g of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvalerylpyrrolidine (diastereoisomer 1) in 10 ml of dichloromethane was treated with 3 ml of 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 evaporated three more times with 20 ml portions of toluene. The residue was crystallized from ether to give 0.161 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] pyrrolidine (diastereoisomer 1) as a white solid; 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); 2.06-1.90 (m, 2H); 1,871.77 (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 an analogous manner as described in the first paragraph of Example 1, 0.155 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) was obtained. prepared in an analogous manner as described in Example 1 (i) - (ii) gave 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 an analogous manner as described in the first paragraph of Example 1, 0.283 g of 4 [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) was prepared in an analogous manner as described in Example 1 (i) - (ii), 0.12 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] was obtained white powder morpholine (diastereoisomer 1); 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); 1.241.14 (m, 1H); 0.91 -0.84 (m, 6H); MS: 418 (M + H) < + >.

Example 4

In an analogous manner as described in the first paragraph of Example 1, 0.16 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] hexahydroazepine (diastereoisomer 1) are obtained. prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.13 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvalerylhexahydroazepine (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); 1.271.19 (m, 1H); 0.92 (d, 3H, J = 6); 0.88 (d, 3H, J = 6); MS: 430 (M + H) < + >.

Example 5

In an analogous manner to that described in the first paragraph of Example 3, 0.28 g of 4- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4- of the thiazine (diastereoisomer 1) prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.14 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- phthalimidoethyl] -4methylvaleryltetrahydro-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); 2,572.46 (m, 2H); 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 the analogous manner as described in the first paragraph of Example 1, 0.36 g of 1- [2 (R) [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -4-piperidinol (diastereoisomer 1) ) prepared in an analogous manner as described in Example 1 (i) - (ii), obtained after purification of the crude product by flash chromatography on silica gel using dichloromethane / methanol (16: 1) for elution, 0.053 g 1 - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -4-piperidinol (diastereoisomer 1) as a 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 Ί

In an analogous manner as described in Example 1, 0.557 g of 2 (R) - [1 (R or S) carboxy-2-phthalimidoethyl] -N, N, 4-trimethylvaleramide (diastereoisomer 1) is prepared in an analogous manner , as described in Example 1 (i) - (ii), obtained after purification of the product by flash chromatography using 2% methanol in dichloromethane to elute 0.053 g of 2 (R) - [1 (R or S) - (hydroxycarbamoyl) - 2-phthalimidoethyl] -N, N, 4-trimethylvaleramide as a white powder; 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 an analogous manner as described in the first paragraph of Example 1, 0.59 g of about 6: 1 is a mixture of diastereoisomer 1 and diastereoisomer 2 N ² - [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4 -methylvaleryl] -N ¹ -methyl-L-prolinamide, prepared in an analogous manner as described in Example 1 (i) - (ii), obtained after crystallization of the product from a mixture of dichloromethane and ether 0.12 g of diastereoisomer 1 N ² - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl]] - 4-methylvaleryl] -N 1-methyl-L-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 (m, 1H); 1.64-1.55 (m, 1H); 1.23-1.14 (m, 1H); 0.93 (d, 3H, J = 6); 0.86 (d, 3H, J = 6); MS: 458 (M) < + >.

Example 9

In the analogous manner as described in the first paragraph of Example 1, except that the reaction took only 3 hours, 0.31 g of 1- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] was obtained from 0.31 g. 4methylvaleryl] -2 (S) -pyrrolidinmethanol (diastereoisomer 1) after purification of the product by flash chromatography using dichloromethane / methanol (12: 1) for elution and crystallization from ethyl acetate / ether mixture, 0.06 g of 1- [2 (R ) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -2 (S) -pyrrolidinethanol (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); 1.281.17 (m, 1H), 0.97-0.83 (m, 6H); MS: 432 (M + H) < + >.

The starting material was prepared as follows:

A solution of 0.355 g of 1- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4methyl valeryl] -2 (S) -pyrrolidinmethanol (diastereoisomer 1) prepared in an analogous manner as in described in Example l (i), in 7 ml of toluene, was treated with 0.07 g of 3-methyl-3pentenol and 0.7 ml of trimethylsilyl bromide. The mixture was stirred under a dry nitrogen atmosphere for 1.5 hours and then the solvent was evaporated. After 3 further evaporations from each 10 ml of toluene, 0.31 g of a pale brown foam containing 1- [2 (R) - [1 (R or S) - (carboxy-2-phthalimidoethyl) -4-methylvaleryl] -2 (S) was obtained -Pyrrolidinmethanol (diastereoisomer 1), which was used without further purification.

Example 10

In an analogous manner, as described in the first paragraph of Example 1, from 0.568 g, approximately 6: 1 is a mixture of diastereoisomer 1 and diastereoisomer 2 1- [2 (R) - [1 (R or S) carboxy-2-phthalimidoethyl] -4 -methylvaleryl) -4-methylpiperazine hydrobromide, prepared in an analogous manner as described in Example 9 (i), obtained after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (12: 1) to elute and precipitate the hydrochloride with the addition of hydrogen chloride in ethyl acetate, 0.105 g 1- [2 (R) [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -4-methylpiperazine hydrochloride (diastereoisomer 1) 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 (br m, 6H); 2.93-2.84 (m, 4H); 1.761.67 (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 an analogous manner to that described in the first paragraph of Example 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) gave 0.13 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) 2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine 1,1 -dioxide (diastereoisomer 1) as 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); 1,341.25 (m, 1H), 0.93-0.84 (m, 6H); MS: 466 (M + H) < + >.

The starting material was prepared as follows:

(i) A solution of 0.3 g of 4- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4methyl valeryl] tetrahydro-1,4-thiazine (diastereoisomer 1) in 20 ml of dichloromethane was cooled to 0 ° C and treated with 0.3 g of 85% m-chloroperoxybenzoic acid. The mixture was stirred overnight at room temperature and then the solution was washed twice with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and evaporated to give a white foam. Purification by flash chromatography on silica gel using ethyl acetate / hexane (2: 3) for elution gave 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) in the form of a white foam which has solidified into 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), 1.611.59 (m, 1H); 1.40-1.32 (m, 1H); 1.28 (s, 9H); 0.95-0.88 (m, 4H).

(ii) In an analogous manner as described in Example l (ii), 0.33 g of 4- [2 (R) - [l (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4- methylvaryl] tetrahydro-1,4-thiazine 1,1 dioxide (diastereoisomer 1) afforded 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 white foam, which was used without further purification.

Example 12

In an analogous manner as described in the first paragraph of Example 1, 0.3 g of 8- [2 (R) [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -1,4-diox -8-azaspiro [4.5] decane (diastereoisomer 1) prepared in an analogous manner as described in Example I (i) - (ii) after purification of the product by flash chromatography on silica gel using ethyl acetate / methanol (200: 5) for elution to give 0.105 g of 8- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2-phthalimidoethyl-4-methylvaleryl] -1,4-dioxa-8-azaspiro [4.5 ] Dean (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); 1.891.80 (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-dioxol, 2,4-triazolidin-4-yl) ethyl] -4-Methyl valeryl] piperidine (diastereoisomer 1) in 7.0 ml of methanol was hydrogenated in the presence of 40 mg of 10% palladium on charcoal for 30 minutes. The catalyst was removed by filtration and the solution evaporated to give 0.076 g of 1 [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1. 2,4-triazolidin-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) < + >.

The starting material was prepared as follows:

(i) 0.284 g of 60% sodium hydride was added to a stirred ice-cold solution of 3.01 g

1,2-Dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate in 50 ml of dry dimethylformamide under nitrogen atmosphere. The mixture was stirred for 30 minutes at 0 ° C and for a further 1.5 hours at room temperature and cooled again to 0 ° C before the addition of 1.6 g of 4-bromomethyl 1,2,2-dimethylrazole. The mixture was allowed to return to room temperature and stirred for 3 hours. The volatile material was evaporated under high vacuum and the residue was dissolved in ethyl acetate and washed with 5% citric acid aqueous 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 hexane / ether (1: 1) followed by ether for elution. Thus, 2,464 g of 1,2-dibenzyl 1-tert-butyl 4-methyl-1 - [(1,2-dimethyl-3,5-dioxol-2,4-triazolidin-4-yl) methyl] -1 were obtained. 1,2 (R) -pentantricarboxylate 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-triazolidin4-yl) methyl] -1. 1,2 (R) -pentantricarboxylate was dissolved in 40 ml of methanol containing 0.25 g of 10% palladium-on-carbon catalyst. The mixture was hydrogenated for 2 hours, the catalyst was removed by filtration and the solvent was evaporated to give 1- (tert-butoxycarbonyl) 4-methyl-1 - [(1,2-dimethyl-3,5-dioxo-1,2,4- triazolidin-4-yl) methyl] -1,2 (R) -pentane-dicarboxylic acid as a colorless gum. This was dissolved in 60 ml of toluene containing 0.43 ml of N-methylmorpholine and the mixture was refluxed for 1 hour. The solution was washed with 5% citric acid aqueous solution, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated to give 1.422 g of 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) - 2- (1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) ethyl] -4-methylvaleric acid as a waxy solid as a mixture of diastereoisomer 1 and diastereoisomer 2, approximately 6: 1.

(iii) In an analogous manner as described in Example (i), from 0.831 g, approximately 6: 1 is a mixture of diastereoisomer 1 and diastereoisomer 2 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2 - (1,2-Dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) ethyl] -4-methyl valeric acid gave 0.462 g of 1- [2 (R) - [1 (R or S ) - (tert-Butoxycarbonyl) -2- (1,2-dimethyl-3,5-dioxol, 2,4-triazolidin-4-yl) ethyl] -4-methylvaleryl] -piperidine (diastereoisomer 1) as a colorless oil .

(iv) 0.462 g solution 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) in 7 ml of dichloromethane was treated with 0.85 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 1.5 hours and then toluene was added and the solvents were evaporated. After a further three evaporations from toluene, the residue was dissolved in a ml of dry dimethylformamide, cooled to 0 ° C and stirred under nitrogen during the subsequent additions of 0.13 g of O-benzylhydroxylamine, 0.152 g

Of 1-hydroxybenzotriazole, 0.25 ml of N-methylmorpholine and 0.20 (8 g of l-ethyl-3- (3-dimethylaminopropylcarbodiimide hydrochloride) The mixture was allowed to warm to room temperature and stirred overnight The solvent was evaporated and the residue was treated with 5% aqueous solution. The product was extracted with ethyl acetate and the ethyl acetate extract was washed with a 5% citric acid solution and aqueous sodium chloride solution. In addition to 0.14 g of starting material obtained, 0.142 g of 1 [2 (R) - [1 (R or S) - (benzyloxy-carbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1,2) was obtained , 4-triazolidin-4yl) 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); 3.703.63 (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 an analogous manner to that described in the first paragraph of Example 13, 0.182 g is obtained

1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,6-dioxopiperidino) ethyl] -4-methylvaleryl] 22 piperidine (diastereoisomer 1) gave 0.066 g of 1- [2 ( R) - [1 (R or S) - (hydroxycarbamoyl) 2- (2,6-dioxopiperidino) ethyl] -4-methylvaryl] piperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 4.06 (dd, 1H, J = 1, 1.6.5); 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 material was prepared as follows:

(i) In an analogous manner to that described in Example 13 (i) - (iii), 1,2-dibenzyl 1-tertbutyl 4-methyl-1,1,2 (R) -pentantricarboxylate and N-bromomethylglutarimide were obtained 1 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (2,6-dioxopiperidine) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a colorless gum.

(ii) A solution of 0.324 g of 1- [2 (R) - [1- (R or S) - (tert-butoxycarbonyl) -2- (2,6-dioxopiperidino) ethyl] -4-methylvaleryl] -piperidine (diastereoisomer 1 ) in 6.5 ml of toluene was treated with 0.065 g of 3-methyl-3-pentanol and 0.65 ml of trimethylsilyl bromide. The mixture was stirred under a dry nitrogen atmosphere for 1 hour and then the solvent was evaporated. After three further evaporations from toluene, the residue was dissolved in 10 ml of dry dimethylformamide, cooled to 0 ° C and stirred under nitrogen between successive additions of 0.095 g of obenzylhydroxylamine, 0.111 g of 1-hydroxybenzotriazole, 0.18 ml of N-methylmorpholine and 0.152 g of l-ethyl-ethyl and - (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was treated with 5% aqueous sodium hydrogen carbonate solution. The product was extracted with ethyl acetate and the ethyl acetate extract was washed with 5% citric acid solution and 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. Thus, 0.182 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,6-dioxopiperidino) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) was obtained as a white solid. ; nmr (CDCl3): 9.23 (s, 1H); 7.46-7.31 (m, 5H); 4.96-4.88 (m, 2H); 3.98 (dd, 1H, J = 1.5); 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); 1,941.37 (m, 10H); 1.24-1.14 (m, 1H); 0.88 (d, 3H, J = 6); 0.84 (d, 3H, J = 6).

Example 15

In an analogous manner to that described in the first paragraph of Example 13, 0.39 g is obtained

1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine ( diastereoisomer 1) afforded 0.255 g of 1- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4 -methyl-valeryl] 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 material was prepared as follows:

In an analogous manner as described in Example 14 (i) - (ii), 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 3-bromomethyl-1 , 5,5-trimethylhydantoin gave 1- [2 (R) - [1- (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) - ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a white foam; nmr (CDCl3); 9.50 (brs, 1H); 7.45-7.39 (m, 5H); 3.79-3.56 (m, 4H); 3.52-3.42 (m, 1H); 3.333.23 (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 an analogous manner as described in the first paragraph of Example 13, 0.335 g of 4- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,5-dioxo) is obtained from 0.335 g. 1-imidazolidinyl) -ethyl] 4-methylvaleryl] morpholine (diastereoisomer 1) gave 0.198 g of 4- [2 (R) - [1 (R or S) (hydroxycarbamoyl) -2- (3-methyl-2,5-dioxo) -1-imidazole idinyl) 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 = 1.5); 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 material was prepared as follows:

In an analogous manner as described in Example 15 (i) - (ii), 1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and 3-bromomethyl-1 -methylhydantoin gave 4 [2 (R) - [1- (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4methyl valerylmorpholine (diastereoisomer 1) in the form white solids;

MS: 475 (M + H) < + >.

Example 17

In an analogous manner as described in the first paragraph of Example 1, 0.273 g was obtained

1- [2 (R) - [1 (R or S) -carboxy-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) gave 0.023 g 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) 2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) in the form white solids; 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 material was prepared as follows:

In an analogous manner as described in Example 1 (ii), 0.325 g of 1- [2 (R) - [1 (R or S) (tert-butoxycarbonyl) -2- (3-methyl-2,5- dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) prepared in an analogous manner as described in Example 13 (i) - (iii) from 1,2-dibenzyl 1-tert.butyl 4 -methyl-l, 1,2 (R) -pentantricarboxylate and

3-Bromomethyl-1-methylhydantoin gave 0.273 g of 1- [2 (R) - [1- (R or S) -carboxy-2- (3-methyl2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl ] piperidine (diastereoisomer 1) in the form of a colorless gum, which was used without further purification.

Example 18

In an analogous manner as described in the first paragraph of Example 1, 0.45 g of 4- [2 (R) [1 (R or S) -carboxy-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) is obtained ) ethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine (diastereoisomer 1) afforded 0.155 mg 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 material was prepared as follows:

In an analogous manner as described in Example 13 (i) - (iii), 1,2-dibenzyl 1-tert.butyl

Of 4-methyl-1,1,2 (R) -pentantricarboxylate and 3-bromomethyl-1-methylhydantoin gave 425 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (3-methyl -2,5-dioxo-1-imidazolidinyl) ethyl] -4methylvaleryl] 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); 3.22-3.14 (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) A solution of 52 g of 4- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2- (3-methyl-2,5-dioxo-limidazolidinyl) ethyl] -4-methylvaryl] tetrahydro-1,4-thiazine (diastereoisomer 1) in 15 ml of dichloromethane was treated with 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. Three additional evaporations from 25 ml of toluene gave 0.45 g of 4- [2 (R) - [1 (R or S) carboxy-2- (3-methyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4 -methylvaleryl] tetrahitro-1,4-thiazine (diastereoisomer 1) in the form of a colorless gum, which was used directly without further purification.

Example 19

In an analogous manner to that described in the first paragraph of Example 13, 0.278 g of 4 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-1-pyrid id) and neither 1) tyl] -4-methylvaleryl] morpholine (diastereoisomer 1) gave 0.151 g of 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 (2,5-dioxo-1- pyrrolidinyl) ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as 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 material was prepared as follows:

In an analogous manner as described in Example 14 (i) - (ii), 4-methyl-1,2-dibenzyl 1-tert-butyl 4-methyl-1,2,2 (R) -pentantricarboxylate and N-bromomethylsuccinimide were obtained - [2 (R) [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; MS: 460 (M + H) < ⁺ >.

Example 20

In an analogous manner to that described in the first paragraph of Example 13, 0.19 g is obtained

4- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methyl-valeryl] 26 morpholine (diastereoisomer 1) gave 0.104 g 4 - [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 (2-oxo-1-pyrrolidinyl) ethyl] -4-methyl-valeryl] morpholine (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); 2,572.48 (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 material was prepared as follows:

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

Example 21

In the analogous manner as described in the first paragraph of Example 13, 0.335 g of 1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) afforded 0.19 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2 (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] 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); 2,632.54 (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 material was prepared as follows:

In an analogous manner to that described in Example 14 (i) - (ii), 1- [1- [b] methyl-l, 1,2,2 (R) -pentantricarboxylate and N-bromomethylpyrrolidine were obtained from 1,2-benzyl 1-tert-butyl 4-methyl-1,1 2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl] -4-methylvaleryl] piperidine (diastereoisomer 1) as a white solid; MS: 444 (M + H) < + >.

Example 22

In an analogous manner as described in the first paragraph of Example 1, 0.265 g of 4 [2 (R) - [1 (R or S) -carboxy-3-phthalimidopropyl] -4-methylvaleryl] -morpholine were obtained from 0.226 g 4 [ 2 (R) - [1 (R or S) - (hydroxycarbamoyl) -3-phthalimidopropyl] -4-methylvaleryl] morpholine (diastereoisomer 1) as a white solid; nmr (MeOD): 7.88-7.76 (m, 4H); 3.863.50 (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 material was prepared as follows:

In an analogous manner as described in Example l (i) - (ii), 0.65 g of about 5: 1 is a mixture of diastereoisomers of 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -3-phthalimidopropyl ] 4methyl-valeric acid and 0.17 ml of morpholine, 0.462 g of 4- [2 (R) - [1 (R or S) carboxy-3-phthalimidopropyl] -4-methylvaleryl] morpholine were obtained in the form of a colorless gum, which was used without further purification.

Example 23

In an analogous manner as described in Example 13, 0.2 g of N, N-diethyl-2 (R) [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleramide (diastereoisomer 1) was obtained prepared in an analogous manner as described in Example 13 (iii) - (iv) after purification of the product by flash chromatography using 3% methanol in dichloromethane for elution, 0.085 g of N, N-diethyl-2 (R) - [ 1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -4methyl-valeramide (diastereoisomer 1) as a white solid; nmr (MeOD): 7.85-7.75 (m, 4H); 3.97 (dd, J = 14.10.1 H); 3.68-3.6 (m, 1H); 3.57-3.48 (m, 2H); 3.38 (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 an analogous manner as described in Example 1, 0.16 g of 3- [2 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -thiazolidine (diastereoisomer 1) was obtained. prepared in an analogous manner as described in Example 1 (i) to (ii) after purification of the product by flash chromatography using 5% methanol in dichloromethane for elution, 0.039 g

3 - [- 2 (R) - [1- (R or S) - (hydroxycarabmoyl) -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); 0.85 (d, J = 6.3H); MS: 420 (M + H) < + >.

Example 25

In an analogous manner to that described in Example 13, 0.25 g of N-ethyl-2 (R) - [1 (RS) (bezyloxycarbamoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide (8: 1 mixture of diastereoisomers) were obtained prepared in an analogous manner as described in Example 13 (iii) - (iv) gave 0.083 g of N, ethyl-2 (R) - [1- (RS) - (hydroxycarabmoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide (8: 1 mixture of diastereoisomers) as 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 an analogous manner to that described in Example 13, 0.1 g of 4- [2 (R) - [1 (RS) (bezyloxycarbamoyl) -5-phthalimidopentyl] -4-methylarylaryl morpholine (5: 1 mixture of diastereoisomers) prepared from in an analogous manner as described in Example 1 (i) - (ii), 0.045 g of 4- [2 (R) - [1- (RS) - (hydroxycarabmoyl) -5-phthalimidopentyl] -4-methylvaleryl] morolin (0.045 g) was obtained 3: 1 mixture of diastereoisomers) as a cream colored solid; nmr (MeOD): 7.85-7.75 (m, 4H); 3.8-3.49 (m, 12H); 3.15 (d, t, 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 an analogous manner as described in Example 13, 1.06 g of N-phenyl-2 (R) [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide were obtained after purification of the product with flash chromatography using 2% methanol in dichloromethane for elution, 0.65 g of N-phenyl-2 (R) - [1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -N, 4-dimethylvaleramide as a white foam; nmr (MeOD): 7.75-7.68 (m, 4H); 7.28-7.17 (m, 4H); 7.087.04 (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 material was prepared as follows:

(i) A solution of 1.49 g of 2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methyl valeric acid (6: 1 mixture of diastereoisomer 1 and diastereoisomer 2) in 20 ml of toluene was obtained. 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 and then the solvent was evaporated under high vacuum at 10 ° C. The residue was redissolved in 10 ml of dichloromethane and cooled to 0 ° C. 0.5 ml of triethylamine was added followed by 0.4 ml of Nmethylaniline. 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 redissolved in 50 ml of ethyl acetate and washed successively with 5% sodium hydrogen carbonate solution, 2N hydrochloric acid and saturated brine. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give an orange oil. Purification by flash chromatography on silica gel using 3: 1 hexane / ethyl acetate for elution gave 1.23 g of N-phenyl-2 (R) [1 (R or S) - (tert-butoxy-carbonyl) -2-phthalimidoethyl] - N, 4-dimethylvaleramide (diastereoisomer 1) as a pale yellow oil; nmr (CDCl3) 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: 479 (M + H) < + >.

(ii) In an analogous manner as described in Example 13 (iv), 1.23 g of N-phenyl2 (R) - [1 (R or S) - (tert-butoxy-carbonyl) -2-phthalimidoethyl] was obtained. N, 4-dimethylvaleramide after purification of the product by 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, 4dimethylvaleramide as white foam; nmr (CDCl3) 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, 1H, 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 an analogous manner as described in the first paragraph of Example 13, 0.31 g of 1- [2 (R) - [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -2- (R) -Pyrrolidine methanol (diastereoisomer 1) after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (15: 1) for elution and by crystallization from ethyl acetate, 0.07 g 1- [2 (R) - [1 ( R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methyl30 valeryl] -2- (R) -pyrrolidine methanol (diastereoisomer 1) as 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 (n, 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 material was prepared as follows:

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

Example 29

In an analogous manner as described in the first paragraph of Example 13, 0.2 g of benzyl hexahydro-2- [2 (R) - [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl was obtained -3 (S) - (methylcarbamoyl) -1-pyridazinecarboxylate (diastereoisomer 1), after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (20: 1) for elution, 0.044 g hexahydro-2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methyl-valeryl] -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 material was prepared as follows:

(i) In an analogous manner 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 (6 : 1 mixture of diastereoisomer 1 and diastereoisomer 2) and 0.7 g of hexahydro-1- (benzyloxycarbonyl) - (3S) pyridazinecarboxylic acid, obtained by chromatography on silica gel using ether / hexane (1: 4) then ethyl acetate for elution, 0.6 g hexa hydro-1- (benzyloxycarbonyl) -2- [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl] 3 (S) -pyridazinecarboxylic acid as a colorless tires.

(ii) Solution of 0.6 g 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-hydroxybenzotriazole and 0.36 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added. After 40 minutes, 0.4 ml of 40% aqueous methylamine solution was added and the mixture was stirred for 2.5 hours. The solvent was evaporated and the residue was treated with 20 ml of 5% aqueous sodium hydrogen carbonate solution. 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, the solvent was evaporated to give 0.638 g of a colorless gum 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) -1- pyridazinecarboxylate as a colorless gum.

(iii) In an analogous manner to Example 13 (iv), 0.23 g of benzyl hexahydro-2 [2 (R) - [1 (R or S) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -4-methylvaleryl ] -3 (S) - (methylcarbamoyl) -1-pyridazinecarboxylate gave 0.2 g of benzyl hexahydro-2- [2 (R) - [1 (R or S) (benzyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -3 (S) - (Methylcarbamoyl) -lpyridazine carboxylate as a white solid.

Example 30

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

Example 31

In an analogous manner as described in the first paragraph of Example 13, 0.185 g of 1- [2 (R) - [1 (R or S) - (bezyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -N-methyl -2- (S) piperidine-carboxamide after purification of the product by flash chromatography on silica gel using dichloromethane / methanol (16: 1) for elution to give 0.06 g of 1- [2 (R) - [1 (R or S) (hydroxycarbamoyl) ) -2-phthalimidoethyl] -4-methylvaleryl] -N-methyl-2 (S) -piperidinecarboxamide (diastereoisomer 1) as a white solid; MS: 473 (M + H) < ⁺ >.

Example 32

In an analogous manner as described in the first paragraph of Example 1, 0.22 g of 1-2 (R) [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -4-methoxypiperidine] (diastereoisomer 1 ) prepared in an analogous manner as described in Example 1 (i) - (ii) gave 0.108 g of 1- [2 (R) - [1- (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] - 4-methyl-valeryl 4methoxypiperidine (diastereoisomer 1) as a white solid; nmr (MeOD): 7.867.74 (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 an analogous manner as described in the first paragraph of Example 1, 0.44 g of 12 (R) - [1 (R or S) -carboxy-2-phthalimidoethyl] -4-methylvaleryl] -4-piperidinone prepared for analog the procedure described in Example 1 (ii) - (iii) gave 0.157 g of 1- [2 (R) - [1- (R or S) - (hydroxycarabmoyl) -2-phthalimidoethyl] -4-methylvaleryl 4- oxime piperidinone (diastereoisomer 1) as a white solid; nmr (MeOD): 7.86-7.75 (m, 4H); 3,923.76 (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 the analogous manner as described in the first paragraph of Example 13, 0.32 g of N [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] -L-proline methyl ester (diastereoisomer 1) prepared in an analogous manner as described in Example 13 (iii) - (iv) gave 0.13 g of N- [2 (R) - [1- (R or S) - (hydroxycarbamoyl) - 2-phthalimidoethyl] -4methylvaleryl] -L-proline methyl ester (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 (m, 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 an analogous manner as 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) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.785 g of 1- [2 ( R) - [1- (R or S) (hydroxycarbamoyl) -2- (3,4,4-trimethyl-4-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvaleryl 4-piperidinol (diastereoisomer 1) in the form of a white solid; 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); 2,021.77 (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 the analogous manner as described in the first paragraph of Example 1, 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] -4methylvaleryl] -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: 385 (M + H) < + >.

The starting material was prepared as follows:

(i) In an analogous manner 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) -pentantricarboxylate and 2.05 g of 4-bromomethyl-2-tetrahydro2-methyl-3,5-dioxo-1,2,4-oxadiazole obtained 1.55 g 1- [2 (R) -1 (R or S) -carboxy-2- (tetrahydro-2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl) ethyl-4-methylvalery] -4-piperidine (diastereoisomer 1) in the form of a gum which was used without further purification.

Example 37

In an analogous manner as described in the first paragraph of Example 13, 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) prepared in an analogous manner as described in Example 14 (i) - (ii) from 1,2-dibenzyl 1-tert-butyl Of 4-methyl-1,2,2 (R) -pentane34 tricarboxylate and 1-bromomethyl-3-methyl-2,4,5-trioxo-1-imidazole, yielded 0.08 g of 1 [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyl-2,4,5-trioxo-1-imidazolidinyl) -ethyl] -4methyl valeryl] -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 an analogous manner to that described in the first paragraph of Example 13, 0.261 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-3-phenyl- 1-imidazolidinyl) ethyl] -4methylvaleryl] -4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.169 g 1- [2 (R) - [1 (R or S) - (hydroxy-carbamoyl) 2- (2,5-dioxo-3-phenyl-1-imidazolidinyl) -ethyl] -4-methylva leryl] -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, 2H); 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 an analogous manner as described in the first paragraph of Example 13, 0.146 g of 4 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,4,5- trioxo-1-imidazolidinyl) ethyl] 4-methylvalerylmorpholine (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 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,); 0.890.84 (m, 6H); MS: 399 (M + H) < + >.

Example 40

In an analogous manner as described in the first paragraph of Example 13, 0.363 g is obtained

N ² - [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) -ethyl] -4-methylvaleryl] N ¹ -methyl-L-prolinamide (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.234 g of N ² - [2 (R) - [1 (R or

S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] -4-methylvalerylmethyl-L-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 the analogous manner as described in the first paragraph of Example 13, 0.3 g of 1- [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2-oxo-1-pyrrolidinyl) ethyl ] -4-methylvaleryl] -4piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.116 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (2-oxo-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); 0.840.72 (m, 6H); MS: 370 (M + H) < + >.

Example 42

In the analogous manner as described in the first paragraph of Example 13, 0.16 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (2,5-dioxo-1-pyrrolidinyl) is obtained ethyl] -4-methylvaleryl] 4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.048 g of 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (2,5-dioxol-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); 1.181.09 (m, 1H); 0.92-0.80 (m, 6H); MS: 384 (M + H) < + >.

Example 43

In an analogous manner as described in the first paragraph of Example 13, 0.43 g of 1 [2 (R) - [1 (R or S) - (benzyloxycarbamoyl) -2- (3-methyl-2,5-dioxo) is obtained. 1-imidazolidinyl) ethyl] -4methylvaleryl] 4-piperidinol (diastereoisomer 1) prepared in an analogous manner as described in Example 14 (i) - (ii) gave 0.158 g of 1 - [2 (R) - [1 ( R or S) - (hydroxycarbamoyl) 36

2- (3-methyl-2,5-dixo-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 pharmaceutical compositions containing hydroxamic acid derivatives of the present invention.

Example A

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

Ingredient On the tablet Hydroxamic acid derivative 10.0 mg Lactose 125.0 mg Corn starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 tables The whole mass 215.0 mg

Example B

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

Ingredient Per capsule

Hydroxamic acid derivative 10.0 mg

Lactose 165.0 mg

Corn starch 20.0 mg

Talc 5.0 mg

Capsule fill weight 200.0 mg

For:

Claims (27)

PATENT APPLICATIONS 1. Hydroxamic acid derivatives of the general formula (D in which they represent R1 is a 5- or 6-membered N-heterocyclic ring which is (a) bonded via the N atom, (b) optionally contains N, O and / or S as additional or additional heteroatoms in a position or positions different from the adjacent to the N bond atom, (c) is substituted by oxo on one or both C atoms adjacent to the N bond atom, and (d) is optionally benzene coupled or optionally substituted on one or more other C atoms with lower alkyl or oxo and / or on the possible or possibly additional N atoms with lower alkyl or aryl; R4 is lower alkyl and represents lower alkyl or aryl, or NR ^ R ^ is a saturated 5-, 6- or 7-membered heterocyclic ring optionally containing -NR ^a , -O-, -S-, -SO- or -SO2- as the ring member and / or case 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 is} 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? in each case represents hydrogen or methyl, with the proviso that at least two of these symbols represent hydrogen; and n stands for 1- 4; and pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein R1 represents a 5- or 6-membered N-heterocyclic ring which is (a) bonded via the N atom, (b) optionally contains N, O and / or S as additional (e ) the hetero atom (s) in a position or positions not adjacent to the bonding N atom, (c) substituted by oxo on one or both C atoms adjacent to the bonding N atom and (d) optionally benzene or optionally substituted on one or more other lower alkyl atoms by oxo and / or on the possible or potential N lower alkyl atoms (s); R ² represents lower alkyl and represents lower alkyl or aryl, or NR ² R 3 represents a saturated 5-, 6- or 7-membered heterocyclic ring which optionally contains -NR ^a , -O-, -S-, -SO- or -SO 2 - as a ring member and / or optionally substituted by hydroxy, lower alkoxy, oxo, ketalized oxo, amino, mono (lower alkyl) amino, di (lower alkylamino, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoite, mono (lower alkyl) carbamoyl or di (lower alkyl) carbamoyl; R ^a represents hydrogen or lower alkyl; R 6, R 8, R 7 and n have the meaning given in claim 1. Compounds according to claim 1 or 2, wherein the N-heterocyclic ring contains R 1 optionally as additional or additional hetero atom (s) of one or two N atoms, one N atom and one O atom or one O atom. Compounds according to claim 3, wherein R ¹ represents a ring of formula (a) R.8 and in each case represent hydrogen, or together represent an additional bond or residue of a closed 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, wherein R1-θ represents hydrogen or lower alkyl. Compounds according to claim 4 or 5, wherein R ¹ represents a ring of formula (b) or (c). Compounds according to claim 6, wherein R ¹ represents phthalimido, 1,2-dimethyl-3,5-dioxol, 2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl or 3 , 4,4-trimethyl-2,5-dioxo-limidazolidinyl. Compounds according to any one of claims 1 to 7, wherein NR 1 R 5 represents a 5-, 6- or 7-membered saturated heterocyclic ring. Compounds according to claim 8, wherein NR 1 R 2 represents a 6-membered saturated heterocyclic ring. 10. Compounds according to claim 9, wherein NR ^ R ^ represents morpholino, tetrahydro-1,4-thiazin4-yl or 4-hydroxypiperidino. Compounds according to any one of claims 1 to 10, wherein R ⁴ , R ⁴ and R ⁷ each represent hydrogen and R 4 represents methyl. Compounds according to any one of claims 1 to 11, wherein n is 1 or 2. 13. 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] morpholine. 14. 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] tetrahydro-1,4-thiazine. 15. 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4-methylvaleryl] 4-piperidinol. 16. 1- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (1,2-dimethyl-3,5-dioxo-1,2,4triazolidin-4-yl) ethyl] - 4-methylvaleryl] piperidine. 17. 4- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2- (3-methyl-2,5-dioxo-limidazolidinyl) ethyl] -4-methylvaleryl] tetrahydro-1,3- thiazine. 18. Hexahydro-2- [2 (R) - [1 (R or S) - (hydroxycarbamoyl) -2-phthalimidoethyl] -4methylvaleryl] -N-methyl-3 (S) -pyridazinecarboxamide. 19. 1- [2 (R) [1 (R or S) - (hydroxycarbamoyl) -2- (3,4,4-trimethyl-2,5-dioxo-limidazolidinyl) -ethyl] -4-methylvaleryl] -4 -Piperidinol. 20. Compounds of general formula 11 wherein R ¹ 'R ^2' R3, R4, R5, R6, R7, j _nn meaning indicated in claim 1. Compounds of the general formula wherein R ¹ , R ² , R ⁴ , R ⁴ , R 8, R ⁶ , R ⁷ and n are as defined in claim 1 and B 2 represents benzyl. Compounds according to any one of claims 1 to 19 useful as therapeutically effective substances. Compounds according to any one of claims 1 to 19 useful for the control or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis. 24. A process for the preparation of compounds according to any one of claims 1 to 19, characterized in that it comprises (a) reacting an acid of the general formula wherein Rl, R ^, R ^, R4, R5 _(R6, R7, j _nn p _r i claim 1, said compound having the compound of the general formula H ₂ N-OZ (III) in which Z represents hydrogen, tri (lower alkyl ^ silyl or diphenyl (lower alkyl) silyl, and optionally cleaving any diphenyl (lower alkyl) silyl group present in the reaction product, or b) catalytic hydrogenation of a compound of the general formula wherein R ¹ , R ⁴ , r ³ , R ⁴ , r 5, r 6 R? and n in claim 1 said meaning and Bz represents benzyl, and optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt. A medicament comprising a compound according to any one of claims 1 to 19 and a therapeutically inert carrier material. A medicament for use in the control or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis, comprising a compound of any one of claims 1 to 19 and a therapeutically inert carrier material. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for the control or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis.