SI9300313A - Hydroxamic acid derivatives - Google Patents

Abstract

THE INVENTION PROVIDES HYDROXAMIC ACID DERIVATIVES OF THE FORMULA WHEREIN RL REPRESENTS 1-7C ALKYL; R2 REPRESENTS HYDROGEN, 1-6C ALKYL OR A GROUP OF THE FORMULA -(CH2)N-ARYL OR -(CH2)N-HET IN WHICH N STANDS FOR 1-4 AND HET REPRESENTS A 5- OR 6-MEMBERED N-HETEROCYCLIC RING WHICH (A) IS ATTACHED VIA THE N ATOM, (B) OPTIONALLY CONTAINS N, 0 AND/OR S AS ADDITIONAL HETERO ATOM(S) IN A POSITION OR POSITIONS OTHER THAN ADJACENT TO THE LINKING N ATOM, (C) IS SUBSTITUTED BY OXO ON ONE OR BOTH C ATOMS ADJACENT TO THE LINKING N ATOM AND (D) IS OPTIONALLY BENZ-FUSED OR OPTIONALLY SUBSTITUTED ON ONE OR MORE OTHER CARBON ATOMS BY 1-6C ALKYL OR OXO AND/OR ON ANY ADDITIONAL N ATOM(S) BY 1-6C ALKYL; R3 REPRESENTS THE CHARACTERIZING GROUP OF A NATURAL OR NON-NATURAL a-AMINO ACID IN WHICH ANY FUNCTIONAL GROUP PRESENT MAY BE PROTECTED, WITH THE PROVISO THAT R3 DOES NOT REPRESENT HYDROGEN; R4 REPRESENTS CARBOXYL, (L-6C ALKOXY)CARBONYL, CARBAMOYL OR (1-6C ALKYL)CARBAMOYL; R5 REPRESENTS THE CHARACTERIZING GROUP OF A NATURALLY OCCURRING A-AMINO ACID IN WHICH ANY FUNCTIONAL GROUP PRESENT MAY BE PROTECTED; AND R6 REPRESENTS HYDROGEN; OR R4, R5 AND R6 EACH INDIVIDUALLY REPRESENT HYDROGEN OR 1-6C ALKYL, AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS, WHICH ARE MATRIX METALLOPROTEINASE INHIBITORS USEFUL FOR THE CONTROL OR PREVENTION OF DEGENERATIVE JOINT DISEASES SUCH AS RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS OR FOR THE TREATMENT OF INVASIVE TUMOURS, ATHEROSCLEROSIS OR MULTIPLE SCLEROSIS. THEY CAN BE MANUFACTURED ACCORDING TO GENERALLY KNOWN METHODS BY DEPROTECTING A CORRESPONDING NOVEL BENZYLOXYAMINO COMPOUND OR HYDROXAMIDATING A CORRESPONDING NOVEL AMINO ACID OR ACTIVATED DERIVATIVE THEREOF.

Description

The present invention relates to hydroxamic acid derivatives.

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

in which

R1 represents 1-7C alkyl ·,

R ² represents hydrogen, 3-6C alkyl or a group of formula - (CH 2) _n -aryl or - (CH 2) _n -Het, where n is 1 to 4 and Het represents a 5- or 6-membered N-heterocyclic ring, which is (a) bonded via an N atom, (b) optionally contains N, O and / or S as additional or additional heteroatoms (e) in a position or positions different from adjacent to the N-atom bond, (e) is substituted by oxo on one or both Catoms adjacent to the bonding N atom and (d) is optionally benzo-coupled or optionally substituted on one or more other C atoms by 1-6C alkyl or oxo and / or on any or any additional N atoms with 1-6C alkyl;

R ³ represents a characteristic group of natural or unnatural (synthetic) α-amino acid in which any functional group present may be protected, with the proviso that R ³ does not represent hydrogen;

represents carboxyl, (1-6C alkoxycarbonyl, carbamoyl or (1-6C alkylcarbamoyl; R4 represents a characteristic group of naturally occurring α-amino acid in which any functional group present may be protected;

R 4 represents hydrogen; or

R4, r5 and r6 each represent hydrogen or 1-6C alkyl;

and pharmaceutically acceptable salts thereof.

The compounds of formula I have valuable pharmacological properties. They are, in particular, inhibitors of the matrix metalloproteinase 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.

A 1-6C or 1-7C alkyl group alone or in combination, e.g. in alkoxy, preferably contains up to 4 carbon atoms. It can be straight or branched, e.g. methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, sec.butyl, tert.butyl and the like. Methoxycarbonyl, ethoxycarbonyl, npropoxycarbonyl, isopropoxycarbonyl and the like. are examples of (1-6C alkoxycarbonyl groups. (1-6C alkylcarbamoyl group may be, for example, methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, etc. The aryl moiety - (CH2) _n -aryl groups may be phenyl or naphthyl which is in in the present case substituted, for example, by halogen, such as fluorine chlorine, bromine or iodine, 1-6C alkyl, 1-6C alkoxy, trifluoromethyl and the like.

A natural or unnatural (synthetic) α-amino acid characteristic group is a group R in natural or unnatural α-amino acid of formula H2N-CH (R) -C00H. Examples of such characteristic groups derived from natural α-amino acids are the following, listing the corresponding natural α-amino acid for it in parentheses: hydrogen (glycine), methyl (alanine), isopropyl (valine), isobutyl ( leucine), benzyl (phenylalanine), phidroxybenzyl (tyrosine), hydroxymethyl (serine), mercapto methyl (cysteine), 1-hydroxyethyl (threonine), 2-methylthioethyl (methionine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamine) ) and 4-aminobutyl (lysine). Examples of such characteristic groups derived from unnatural (synthetic) α-amino acids are the following, with the corresponding unnatural α-amino acid indicated for it in parentheses: ethyl (α-amino-butyric acid), n-propyl (α- amino-n-pentanoic acid), n-butyl (α-amino-n-hexanoic acid), tert-butyl (α-amino-neo-hexanoic acid), neopentyl (α-aminoneoheptanoic acid), n-heptyl (α-amino-n) -nanoic acid), cyclohexylmethyl (cyclohexylalanine), phenyl (α-amino-phenylacetic acid), 2-phenyl-ethyl (homophenylalanine), 1-naphthyl (α-amino-1-naphthylacetic acid), 2-naphthyl (α-amino) -2-naphthylacetic acid), phenethyl (α-amino-3-phenylbutyric acid), α-methylbenzyl (O-methylphenylalanine), α, adimethylbenzyl (β, β-dimethylphenylalanine) and the like.

All functional (i.e. reactive) groups present in R ³ and R ⁵ may be protected in a manner known per se in peptide chemistry. So e.g. the amino group is protected by a tert-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, trifluoroacetyl, 2 (biphenyl) isopropoxycarbonyl group or an isobornyloxycarbonyl group in the form of a phthalimido group. The carboxy group can be protected e.g. in the form of an easily fissionable ester such as methyl-, ethyl-, tert-butyl-, benzyl ester or the like. The hydroxy group protection may be in the form of an ether as methyl, tert-butyl, benzyl or tetrahydropyranyl ether, or in the form of an ester as acetate. The mercapto group can be protected e.g. with a tert.butyl, benzyl or similar group.

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.

In the compounds of formula I above, R ¹ preferably represents ethyl, isopropyl, n-butyl or nhexyl, in particular ethyl.

R ² preferably represents hydrogen, methyl, a group of formula - (CH 2) _n -anl, wherein the aryl group is phenyl, or a group of formula - (CH 2) _n -Het, where n has the above meaning and Het represents 5 or 6 - a membered n-heterocyclic ring, optionally containing as an additional or additional hetero atom (s) one or two N atoms, one N atom and one O atom or one O atom. Het preferably represents a group of formula

in which

R? and R8 each represent hydrogen or together represent an additional bond or residue of a closed benzene ring;

R 4 represents hydrogen or C 1-6 alkyl;

X is -CO-, -CH2-, -CH (J-6alkyl), -C (1-6Calkyl) ₂ ·, -NH-, -N (1-6Calkyl) or -O; and

Υ stands for -Ο-, -NH- or -N (1-6C alkyl) -.

In a particularly preferred embodiment, Het represents a group of formula (b), especially phthalimido, or (c) in particular 3-methyl-2,5-dioxo-1-imidazolidinyl.

Regarding the symbol n, it preferably stands for 1 if it represents a group of formula - (CH2) _n -Het and for 3 if it represents a group of formula - (CH2) _n -aryl.

R 4 preferably represents methyl, isobutyl, tert-butyl, protected 4-aminobutyl, neopentyl, n-heptyl, cyclohexylmethyl, benzyl, α-methylbenzyl or a, o: -dimethylbenzyl. 4-Phthalimidobutyl is a preferred protected 4-aminobutyl group.

Preferably, R represents a ^ (1-6C alkiljkarbamoil, especially methylcarbamoyl or ethylcarbamoyl, R represents an isobutyl, and hydrogen, or R ^, R5 jn R ⁶ each represent hydrogen, or L 3 and R ^ each represent hydrogen and R ^ represents tert-butyl , or R ^, r5 and r6 each represent methyl.

The most preferred compounds of formula I are:

[4- (N-hydroxyamino) -2- (R or S) -heptylsuccinyl] -L-leveyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (R or S) -nonylsuccinyl-L- leucyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (R or S) -heptyl-3 (S) -methylsuccinyl] -L-leucyl-L-leucine ethylamide, [4- (N-hydroxyamino) ) -2- (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -L-leucyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -nonylsuccinyl] - L-tert-butylglycine methylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-phenylalanine methylamide, [4- (N-hydroxyamino) -2- (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -L-tert.butylglycine methylamide and [4- (N-hydroxyamino) -2- (R) -heptyl-3 (R or S) - (3-phenylpropyl) succinyl] -L -leucyl-L-leucine ethylamide.

Examples of other interesting compounds of formula I are:

[4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-leucine methylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-leucine neopentylamide, [4- ( N-hydroxyamino) -2 (RS) -heptyl] succinyl] -L-alanyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptilsukcinil] -L- (N ^fi -ftaloil ) 'lysyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -undecylsuccinyl] -L-leucyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-phenylalanil-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-nonalyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2 - (RS) 'heptylsuccinyl] -L-phenylalanine tert.butylamide, [4- (N-hydroxyamino) -2 * (RS) -heptylsuccinyl] -L-tert.butylglycine methylamide, [4- (N-hydroxyamino) -2 - (RS) -heptylsuccinyl] -L-neopentylglycine methylamide, N - (N-hydroxyamino) RSj-heptylsuccinyl-L-homophenylalanyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-cyclohexylalanine methylamide, [4- (N-hydroxyamino) -2- (RS) -isooctylsuccinyl] -L-phenylalanine methylamide, [4- (N-hydroxyamino) -2- (R) -heptylsuccinyl] -L-neopentylglycine methylamide, [4- (N-hydroxyamino) '2- (R) -heptylsuccinyl] - (D or L) -0,0-dimethylphenylalanine methylamide, [4- (N-hydroxyamino) -2- (R ) -heptylsuccinyl] - (D or L) -treo - N- methylphenylalanine methylamide, [4- (N-hydroxyamino) -2- (R) -heptylsuccinyl] -DL-erythro-3-methylphenylalanine methylamide and [4- ( N-hydroxyamino) -2- (R) -heptyl-3 (R or S) - [(3-methyl-2,5-dioxo-1-imidazolidinyl) methylsuccinyl-L-leucyl-L-leucine ethylamide.

In accordance with the method provided by the present invention, the compounds of the above formula I and their pharmaceutically acceptable salts are prepared by (a) catalytically hydrogenating a compound of the general formula

(Π) wherein R ¹ , R ² , R ⁴ , R ⁴ , R 8 and R ⁴ have the meanings given above and B ² represents benzyl, or (b) an acid of the general formula

(ΠΙ) in which R1, R4, r3, r4, r5} _n r6 p _re j have the stated meaning, or its activated ester reacts with a compound of the general formula

H ₂ N-OZ (IV) in which Z represents hydrogen, tri (1-6C alkyl) silyl or diphenyl (1-6C alkyl) silyl, and optionally cleaving any diphenyl (1-6C alkyl) silyl group present in the reaction product, and optionally converting the resulting compound of Formula I into a pharmaceutically acceptable salt.

The catalytic hydrogenation of a compound of formula II in accordance with embodiment (a) of the process can be carried out in a known manner, e.g. in an inert organic solvent using hydrogen in the presence of a precious metal catalyst. Suitable inert organic solvents are e.g. 1-6C alkanols such as methanol, ethanol, etc. With respect to the catalyst, for example, it may be e.g. platinum, palladium or rhodium catalyst, which may be supported on a suitable carrier material. Palladium on charcoal is the preferred catalyst. Temperature and pressure are not critical, although catalytic hydrogenation is preferably carried out at room temperature and atmospheric pressure for convenience.

The reaction of an acid of formula 111 or its activated ester with a compound of formula IV in accordance with embodiment (b) of the process can be carried out in a known manner. So e.g. when acid is used, the reaction can be conveniently carried out in an inert organic solvent such as dimethylformamide or the like using hydroxybenzotriazole in the presence of a condensing agent such as l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at about 0 ° C to about room temperature. When using an activated acid ester of formula III, the reaction can conveniently be carried out in an inert organic solvent such as tetrahydrofuran at about 0 ° C to room temperature. Preferred compounds of formula IV are those wherein Z represents hydrogen, tert-butyl-dimethylsilyl or tert-butyl-diphenylsilyl. If a compound of formula IV is used in which Z represents three (1-6C alkyl) silyl, this group is cleaved during the reaction and treatment and directly obtained is a compound of formula I. On the other hand, using a compound of formula IV in which Z represents diaryl - (1-6C alkyl) silyl, this group remains in the reaction product and must then be cleaved in a known manner, e.g. using fluoride ions.

The compounds of formula I can be converted to pharmaceutically acceptable salts by treatment with bases and the basic compounds of formula I can be converted to pharmaceutically acceptable salts by treatment with acids. Such treatments can be carried out in the usual manner.

The compounds of formulas II and III used as starting materials in the process are novel and are also contemplated by the present invention.

To prepare them for example. by condensation of a compound of the general formula

(V)

R ² where R 1 and R ^{2 have} the above meaning and R ¹ represents a protecting group, with a compound of the general formula

R * 'CO-NH

R ⁵⁰ (VI) wherein r ⁶ has the aforementioned meaning and R ³ , R ⁴ O and R ⁴ O have the meanings given earlier for R ³ , R ⁴ or R ³ , but any functional group present is protected by the cleavage of the protecting group denoted by R 4 from a condensation product of the general formula

wherein R ² , r 6, R 10, r 30 r 40 and r 50 have the aforementioned meanings to give a compound of the general formula

(IHa) wherein R ¹ , R ² , R ⁶ , R ³⁰ , R ⁴⁰ and R ³ ® have the above meaning, and (i) if the compound of formula Π is required, condense the compound of formula lyl, optionally before or after cleavage of one or more protecting groups present in r30, r40 and r50 with O-benzylhydroxylamine, or (ii) if a compound of formula III is required in which one or more functional groups present in R30, r40 j _and R50 , is not protected by cleavage of one or more protecting groups present in the compound of formula lil.

The symbol indicated by RW in formula (V) may represent any conventional carboxy protecting group, e.g. methyl, ethyl, benzyl or preferably tert-butyl.

The condensation of a compound of formula V with a compound of formula VI can be carried out by methods known per se in peptide chemistry; e.g. by the method with acid halide, acid azide, acid anhydride, activated amide, mixed carbonic anhydride or activated ester.

The separation of the protecting group R1 from the condensation product of formula VII can be carried out in a manner known per se, e.g. by hydrolysis, or in the case of a tert-butyl protecting group, by treatment with anhydrous trifluoroacetic acid. It is to be appreciated that one or more protecting groups present in R ^ O, r40 j _n r50 may be cleaved at the same time, depending on the nature of such groups.

The reaction of a compound of formula lyl with O-benzylhydroxylamine can be carried out in the usual way; e.g. as described above with respect to the condensation of a compound of formula V with a compound of formula VI.

The cleavage of the protecting groups present in R ^ O, r40 j _{and R} 50 in the above description of the preparation of starting materials of formulas II and III can be carried out by methods known per se in peptic chemistry; e.g. by saponification, treatment with anhydrous trifluoroacetic acid or hydrogenolysis, in accordance with the nature of the protecting group.

The acids of formula III can be converted to the corresponding activated esters, which are also novel and form a further object of the present invention, in a manner known per se, e.g. by reaction with n-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide to give the N-hydroxysuccinimide ester.

The compounds of the above formulas V and VI, insofar as the compounds or analogs of the known compounds are unknown, can be obtained as described in the Examples below or in analogy thereto.

As mentioned earlier, the hydroxamic acid derivatives provided by the present invention are inhibitors of the metalloproteinase matrix. This activity against stromelysin and gelatinase, two such enzymes, can be demonstrated using the assay procedures described below.

Stromelysin (Test A j

Prostromelysin was purified from human fibroblast culture medium by affinity chromatography with a prostromyelin antibody. [Ganja-Smith Z, Nagase H, Woessner

JF Jr., Biochem J. 1989, vol 285 (1) p. 115-119]. The latent pro-enzyme was activated by incubation with trypsin (5mg / ml) at 25 ° C for 2 hours and after that time trypsin was inactivated using a ten-fold excess trypsin inhibitor from soy. The inhibitory activity of the hydroxamic acid derivatives mentioned above was determined using a ^ C-acetylated b-casein substrate. Stromelysin (5 nM) was added to the substrate solution (4mg / ml) in 25 mM Tris HCl buffer, pH 7.5 containing 10 mM CaCl2 and 0.05% Brij ^R. The resulting solution was incubated for 20 hours at 37 ° C. The enzymatic digestion of the substrate was completed by the addition of 45% trichloroacetic acid and the precipitated, undigested substrate was pelleted by centrifugation at 10,000 g for 0.25 hours. The supernatant was aspirated and activity was determined by liquid scintillation spectrometry. IC50 is that concentration of hydroxamic acid derivative in enzymatic digestion that reduces the cleavage of the substrate to 50% of that achieved by the enzyme itself.

Stromelizin (Test B)

The latent pro-enzyme (30 Mg / ml) was activated by incubation with trypsin (0.5 Mg / ml) for 30 minutes at 25 ° C and then inactivated trypsin using a 20-fold excess trypsin inhibitor. The inhibitory activity of hydroxamic acid derivatives was determined using the fluorescent peptide substrate (7-methoxycoumarin-4yl) acetyl-L-prolyl-L-leucyl-L-alanyl-L-nonallyl- [3- (2,4-dinitrophenyl) -L- 2,3-diaminopropyl] L-arginyl-L-arginine. Stromelysin (final concentration 35 ng / ml) was added to a solution of substrate (4mM) and variable concentrations of hydroxylamine derivative in 50 mM Tris HCl buffer, pH 7.5 containing 200 mM NaCl, 10MM CaCl2, 0.05% Brij ^R 35 and 5% methanol. This solution was incubated for 16 hours at 37 ° C. The formation of the product was determined by spectrofluorometry using an excitation wavelength of 325 nm and an emission wavelength of 395 nm. IC50 is that concentration of the hydroxylamine derivative that reduces the cleavage of the substrate to 50% of that achieved by the enzyme itself.

Gelatinase (Test CJ

The in vitro inhibitory activity of hydroxylamine derivatives against gelatinase B obtained from human neutrophils can be demonstrated using the following test procedure. Pro-gelatinase B was purified from human neutrophils by first separating neutrophils from human blood by concentrated centrifugation and dextran sedimentation. The separated neutrophils were broken up by total treatment with 0.05% Triton X-100 ^R and sonication. Cell particles were removed by high speed centrifugation. Pro12 gelatinase B was purified from supernatant by gelatin agarose affinity chromatography, and the bound pro-enzyme was eluted from the affinity matrix by washing with 10% dimethylsulfoxide / buffer. Analysis of the purified material revealed a band of a single protein with a molecular weight of 95 kDa when visualized with SDS-Page. Gelatinase B was incubated overnight at 37 ° C with 1 mM p-aminophenyl mercuric acetate. The inhibitory activity of the hydroxamine derivatives present was determined using the synthetic N-acetyl-Pro-Gln-Gly-Leu-Leu-Gly ethyl ester substrate for this enzyme. Gelatinase was added to a solution of 0.25 mM substrate in 50 mM borate buffer (pH 7.5) containing 1 mM calcium chloride and a known concentration of hydroxylamine derivative. The resulting solution was incubated for 16 hours at 37 ° C. The enzyme activity was terminated by adding an equal volume of 2% (w / v) sodium hydrogen carbonate solution in 50% aqueous methanol containing 0.05% (w / v) picrylsulfonic acid. The resulting solution was incubated at 37 ° C for a further hour and the reaction was then terminated and stabilized by acidification with 1N hydrochloric acid. The concentration of the trinitrophenyl-Leu-Leu-Gly ethyl ester formed was determined by spectrophotometry at 335 nm.

IC50 is that concentration of a hydroxylamine derivative that reduces the cleavage of the substrate to 50% of the value achieved by the enzyme itself.

The results obtained in the above tests with the representative hydroxamic acid derivatives of the present invention are summarized in the following Table:

Table

Compound s formula I Test A IC ₅ o (mol) Test B 1C _5O (mol) Test C IC ₅₀ (mol) A 3.3 x IO ⁸ 1.25 x JO ' ⁸ 3.2 x IO ' ⁷ B 2.6 x IO ' ⁸ 9.3 χ 10 ' ⁹ 5.0x IO ⁸ C 1.1 χ 1O ⁸ 2.3 x IO ' ⁹ - D 1.0 x K) ' ⁸ 5.9x IO ^'10 * - E - 1.8 x 10 ' ⁸ 1.5 x IO ' ⁹ * F - 2.2 χ IO ' ⁸ 3.2 x IO ' ⁹ * Mr - 1.2 x IO ' ⁹ 9.0 χ] 0'1θ * H - 6.6 χ 1 () - ^{1 () ίί} -

An asterisk * indicates that the IC50 value was limited by the total depletion of the enzyme.

Compound A: [4- (N-hydroxyamino) -2- (R or S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide, Compound B: [4- (N-hydroxyamino) -2- (R or S ) -nonylsuccinyl] -L-leucyl-L-leucine ethylamide, Compound C: [4- (N-hydroxyamino) -2- (R or S) -heptyl-3 (S) -methylsuccinyl] -L-leucyl-L- leucine ethylamide,

Compound D: [4- (N-hydroxyamino) -2- (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -leucyl-L-leucine ethylamide,

Compound E: [4- (N-hydroxyamino) -2- (RS) -nonylsuccinyl] -L-tert.butylglycine methylamide, Compound F: [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L -phenylalanine methylamide, Compound G: [4- (N-hydroxyamino) -2- (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -Lterc.butylglycine methylamide,

Compound H: [4- (N-hydroxyamino) -2- (R) -heptyl-3 (R or S) - (3-phenylpropyl) succinyl] -Levyl-L-leucine ethylamide.

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 preparing 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. Generally, a daily dose of about 5 mg to about 30 mg, preferably from about 10 mg to about 15 mg, will be appropriate for administration, 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 illustrate the present invention. The product structure was confirmed by NMR spectroscopy and mass spectroscopy. The composition of thin-layer chromatographic systems was as follows:

System A: Chloroformin Acetic Acid: Water 120: 15: 3: 2;

System B: Chloroformin Acetic Acid: Water 240: 24: 3: 2.

Further, all temperatures are given in degrees Celsius.

Example 1

0.10 g (0.17 mmol) of [4- (N-benzyloxyamino) -2 (R or S) -heptylsuccinyl] -L-leucyl-leucine ethylamide (isomer 1) in 10 ml of methanol was hydrogenated for 1 hour in the presence of

0.05 g 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated and the residue was washed with diethyl ether and dried in vacuo to give 0.083 g (98%) of [4- (N-hydroxyamino) -2 (R or

S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide as a hygroscopic white solid;

Rf (system A) 0.54; MS: (M + H) < + > 485.

Analysis for C25H48N4O5 0.6H ₂ O:

Calc .: C 60.60 H 10.01 N 11.31%

Found: C 60.62 H 9.75 N 11.39% [4- (N-benzyloxyamino) -2 (R or S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide, used as starting material, was prepared as follows:

A) 25.95 g (0.15 mol) of DL-α-amino-nonanoic acid was dissolved in 900 ml of acetic acid while warming to 40 ° C. 20.7 g (0.3 moles) of sodium nitrite was added in portions over a period of 6 hours, after which heating was removed after the addition of about one-third of sodium nitrite. The mixture was stirred for 16 hours at room temperature, evaporated, water was added and the resulting oil was extracted with diethyl ether (2 x 200 ml). The combined ether extracts were dried over anhydrous sodium sulfate and evaporated to give 31.9 g of a clear brown oil. This oil was dissolved in 150 ml of methanol, a solution of 18 g of sodium hydroxide in 150 ml of water was added and the mixture was stirred for 2 hours at room temperature. The methanol was evaporated, water was added and the solution was acidified with 38 ml of concentrated hydrochloric acid. The product was extracted with diethyl ether (2 x 150 ml) and the extracts were dried over magnesium sulfate and evaporated to give a solid. Recrystallization from 120 ml of 60 to 80 ° petroleum ether gave 20.58 g (79%) of 2 (RS) -hydroxynanoic acid from m.p. at 67-69 ° C.

(B) 21.4 g (0.123 mol) of 2 (RS) -hydroxynanoic acid were dissolved in 240 ml of ethyl acetate. 17.3 ml (0.123 mol) of triethylamine and 14.8 ml (0.123 mol) of benzyl bromide were added and the mixture refluxed for 3 hours. The mixture was cooled, filtered, washed with 2M hydrochloric acid, water and 5% sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 25.4 g (78%) of benzyl 2 (RS) -hydroxynanoanoate as an oil; Rf (ethyl acetate / hexane 1: 1) 0.68.

(C) A solution of 24.3 g (92 mmol) of benzyl 2 (RS) -hydroxynanoanoate and 8.9 ml (110 mmol) of pyridine in 150 ml of dry dichloromethane was added while stirring for 0.5 hours to a solution of 18.6 ml (110 mmol) of trifluoromethanesulfonic acid anhydride in 200 ml of dry dichloromethane at 0 ° C. The mixture was stirred at 0 ° C for an additional hour. 3.7 ml (46 mmol) of pyridine and a solution of 7.7 ml (46 mmol) of trifluoromethanesulfonic acid anhydride in 100 ml of dry dichloromethane were added. The mixture was stirred for 1 hour at C, washed with water (2 x 100 ml), dried over magnesium sulfate and evaporated to give an oil. Chromatography on silica gel using ethyl acetate / hexane (1: 9) for elution gave 26.7 g (73%) of benzyl 2 (RS) -trifluoromethanesulfonyloxynanoate;

Rf (hexane / ethyl acetate 3: 1) 0.66.

(D) A solution of 26.5 g (67 mmol) of benzyl 2 (RS) -trifluoromethanesulfonyloxyinnanoate in 100 ml of dry dichloromethane was added dropwise to a suspension of 2.11 g (70 mmol) of 80% sodium hydride and 16.75 g (67 mmol) of benzyl tert-butyl malonate in 170 ml of dry dimethylformamide at 0 ° C. The mixture was stirred for 2 hours at 0 ° C and 16 hours at room temperature, diluted with dichloromethane, washed successively with water, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give an oil (34.6 g) containing dibenzyl 3-tert.butoxycarbonyl-2 (RS) -heptylsuccinate; Rf (ethyl acetate / hexane 3: 1) 0.49. The oil was dissolved in 540 ml of isopropanol and hydrogenated for 2 hours in the presence of 0.5 g of 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated, toluene was added and the mixture was evaporated to remove traces of isopropanol. The residue (27.8 g) in 400 ml of toluene and 9.1 ml (65 mmol) of triethyl amine was maintained at reflux for 2 hours, evaporated and the residue dissolved in ethyl acetate. The solution was washed with 0.5 M hydrochloric acid (2 x 80 ml) and water, dried over magnesium sulfate and evaporated to give 17.55 g (96%) of 4-tert-butyl hydrogen 2 (RS) -heptylsuccinate; Rf (ethyl acetate) 0.63; MS: (M + H) < ⁺ > 273.

(E) 1.5 g (4 mmol) of N-tert.butoxycarbonyl-L-leucyl-L-leucine ethylamide were dissolved in 20 ml of 4M hydrogen chloride in ethyl acetate, stirred at room temperature for 0.75 hours, evaporated and the residue was dried in vacuo. The residue in 10 ml of dry dimethylformamide was treated at 0 ° C in succession with 0.51 ml (4 mmol) of N-ethylmorpholine, a solution of 1.1 g (4 mmol) of 4 tert.butyl hydrogen 2 (RS) -heptylsuccinate in 5 ml of dichloromethane, 0.82 g (6 mmoles) of hydroxybenzotriazole and 0.92 g (4.4 mmoles) of dicyclohexylcarbodiimide. The mixture was stirred for 1 hour at 0 ° C and for 16 hours at room temperature. A few drops of 2-dimethylaminoethylamine were added, the suspension was cooled to 0 ° C for 3 hours, filtered and evaporated. The residue was taken up in ethyl acetate, washed successively with 5% citric acid solution, water, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Chromatography on silica gel using ethyl acetate / hexane (2: 1) for elution gave 1.5 g (71%) of [4-tert-butoxy 2 (RS) heptylsuccinyl] -L-leucyl-L-leucine ethylamide as a white solid;

Rf (dichloromethane / methanol 19: 1) 0.3; MS: (M + H) < ⁺ > 526.

(F) 0.8 g (1.5 mmol) of [4-tert-butoxy 2 (RS) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide were dissolved in 15 ml of trifluoroacetic acid and the solution was stirred for 2 hours and evaporated. The residue was evaporated three times with toluene, then dissolved in 10 ml of dry dichloromethane and cooled to 0 ° C. 0.37 ml (4.5 mmol) of pyridine and 0.64 g (1.5 mmol) of di (benzotriazolyl) carbonate (70%) were added and the mixture was stirred for 1 hour at 0 ° C. 0.22 ml (1.8 mmol) of O-benzylhydroxylamine was added and the mixture was stirred for 1 hour at 0 ° C and for 16 hours at room temperature. The resulting suspension was filtered, the solid was washed sequentially with dichloromethane, 5% sodium hydrogen carbonate solution, water, 2M hydrochloric acid and water and then dried in vacuo. Silica gel chromatography using methanol / dichloromethane (1:19) for elution gave 0.21 g (24%) of [4- (N-benzyloxyamino) -2 (R or S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamine (isomer 1); Rf (methanol / dichloromethane 1:19) 0.21; MS: (M + H) + 575; HPLC (ODS reverse phase eluted with 60% acetonitrile / triethylammonium phosphate buffer pH 2.5) Rt 6.4 min.

The dichloromethane filtrate was washed successively with 5% sodium hydrogen carbonate solution, 2M hydrochloric acid, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Silica gel chromatography using methanol / dichloromethane (1:40) for elution gave 0.42 g (49%) of [4- (N-benzyloxyamino) -2 (R or S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide as a mixture of isomers. Rf (methanol / dichloromethane 1:19) 0.20; MS: (M + H) ⁺ 575; HPLC (ODS reverse phase eluted with 60% acetonitrile / triethylammonium phosphate buffer pH 2.5) Rt 6.4 and 11.3 min .; isomer ratio 1 / isomer ratio 2: 1: 3.7

Analysis for

Calc .:

Found:

C32H54N4O5 (574.81)

C 66.87 H 9.47

C 66.51 H 9.41

N 9.75% N 9.68%

IX

Example 2

0.5 g (1.12 mmol) of [4- (N-benzyloxyamino) 2 (RS) -heptylsuccinyl] -L-leucine methylamide in 10 ml of methanol were hydrogenated for 2 hours in the presence of 0.01 g of 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated and the residue was dried in vacuo to give 0.36 g (90%) of [4- (N-hydroxyamino) 2 (RS) -heptylsuccinyl] -L-leucine methylamide as a white powder; Rf (methanol / dichloromethane 1:19) 0.47 and 0.39; MS: (M + H) < + > 358.

Analysis for CJ8H35N3O4 (357.50)

Calc .: C 60.48 H 9.87 N 11.75%

Found: C 60.71 H 9.93 N 11.34%

The starting material was prepared as follows:

(A) 1.08 g of benzyloxycarbonyl-L-leucine methylamide in 20 ml of methanol containing 3.7 ml of 1M hydrochloric acid was hydrogenated for 2 hours in the presence of 0.05 g of 5% palladium on carbon. The mixture was filtered, the filtrate was evaporated and the residue was re-evaporated with toluene and then dried in vacuo. The residue was taken up in 10 ml of dimethylformamide, cooled to 0 ° C and neutralized with 0.5 ml (3.9 mmol) of N-ethylmorpholine. A solution of 1.01 g (3.7 mmol) of 4-tert-butyl hydrogen 2 (RS) -heptylsuccinate in 20 ml of dimethylformamide was added followed by 0.6 g (4.4 mmol) of hydroxybenzotriazole and 0.84 g (4.08 mmol) of dicyclohexylcarbodiimide. The mixture was stirred for 1 hour at 0 ° C and for 16 hours at room temperature and then evaporated. The residue was taken up in dichloromethane, filtered and the filtrate washed successively with two portions of 5% sodium hydrogen carbonate solution, water, 0.5M hydrochloric acid and water, dried over magnesium sulfate and evaporated to give an oil. Chromatography on silica gel using methanol / dichloromethane (3:97) for elution gave 0.99 g (67%) of [tert-butoxy 2 (RS) -heptylsuccinyl] -L-leucine methylamide as an oil; Rf (ethyl acetate) 0.47 and 0.55; MS: (M + H) < + > 399.

(B) 0.96 g (2.4 mmol) of [tert-butoxy 2 (RS) -heptylsuccinyl] -L-leucine methylamide were dissolved in 20 ml of trifluoroacetic acid, stirred for 2 hours at room temperature and evaporated. The residue was evaporated three times with toluene, then dissolved in 10 ml of dimethylformamide and cooled to 0 ° C. The solution was neutralized by the addition of 0.61 ml (4.8 mmol) of N-ethyl morpholine. 0.39 g (2.89 mmol) of hydroxybenzotriazole and 0.57 g (2.97 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride were added and the mixture was stirred at 0 ° C for 1 hour. A solution of 0.35 g (2.8 mmol) of O-benzylhydroxylamine in 5 ml of dichloromethane was added, the mixture was stirred for 1 hour at 0 ° C and overnight at room temperature and then evaporated. The oil was distributed between a 5% solution of sodium hydrogen carbonate and dichloromethane. The organic layer was washed successively with water, 2M hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a solid. Silica gel chromatography using methanol / hexane (1: 9) for elution gave 0.56 g (52%) of [4- (N-benzyloxyamino) 2 (RS) -heptylsuccinyl] -L-leucine methylamide as a white solid; Rf (ethyl acetate) 0.24 and 0.36; MS: (M + H) < ⁺ > 448.

Example 3

In the analogous manner as described in the first paragraph of Example 2, [4- (Nhydroxyamino) 2 (RS) -heptylsuccinyl] -L was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-leucine of neopentylamide -leucine neopentylamide as foam;

Rf (methanol / dichloromethane 1: 9) 0.52; MS: (M + H) ⁺ 414.

The starting material was prepared as follows:

From N-tert.butoxycarbonyl-L-leucine neopentylamide using methods analogous to those described in Example 1 (EF), [4- (N-benzyloxyamino) 2 (RS) -heptylsuccinyl] L-leucine neopentylamide was obtained as a white foam ;

Rf (methanol / DCM 1:19) 0.59; MS: (M + H) < + > 504.

Example 4

In the analogous manner as described in the first paragraph of Example 2, [4- (Nhydroxyamino) -2 (RS) was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-alanyl-L-leucine ethylamide. -heptylsuccinyl] -L-alanyl-L-leucine ethylamide as a white solid; MS: (M + H) < + > 443.

Analysis for ^c 22 ^h 42 ⁿ 4 ° 5 (442.60)

Calc .:

Found:

C 59.70 C 59.95

H 9.57 H 9.59

N 12.66% N 12.25%

The starting material was prepared as follows:

From N-benzyloxycarbonyl-L-alanyl-L-leucine ethylamide using methods analogous to those described in Example 2 (AB), [4- (N-benzyloxyamino) 2 (RS) -heptylsuccinyl] -L-alanyl- L-leucine ethylamide as a glassy solid;

Rf (methanol / dichloromethane 1:19) 0.25 and 0.41; MS: (M + H) < ⁺ > 533.

Example 5

In an analogous manner, as described in the first paragraph of Example 2, from [4- (Nbenziloksiamino) -2 (RS) -heptilsukcinil] -L- (N ^£ -ftaloil) -L-lysyl-L-leucine ethylamide prepared [4 - (N-hydroxyamino) -2 (RS) -heptilsukcinil] -L- (N ^£ -ftaloil) -lizil-L-leucine ethylamide as a white solid; Rf (methanol / dichloromethane 1:19) 0.30; MS: (M + H) < ⁺ > 630.

The starting material was prepared as follows:

From N ^ -benzyloxycarbonyl-N ^ -phthaloyl-L-lysyl-L-leucine ethylamide using methods analogous to those described in Example 2 (AB), [4- (N-benzyloxyamino) 2 (RS) -heptylsuccinyl was obtained ] -L- (N ^£ -ftaloil) -Iizil-L-leucine ethylamide as a foam;

Rf (methanol / dichloromethane 1:19) 0.41 and 0.50; MS: (M + H) < ⁺ > 720.

Example 6

0.2 g (0.33 mmol) of [4- (N-benzyloxyamino) 2 (R or S) -nonylsuccinyl] -L-leucyl-L-leucinethylamide (isomer 1) in 20 ml of methanol was hydrogenated for 80 minutes in the presence of 0.07 g of 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated and the residue was dried in vacuo to give 0.166 g (98%) of [4- (N-hydroxyamino) 2 (R or S) -nonylsuccinyl] -L-leucyl-Lleucine ethylamide as a white solid; Rf (system B) 0.35; MS: (Μ + Η) + 513.

Analysis for C27H52N4O5 (512.74)

Calc .: C 63.25 H 10.22 N 10.93%

Found: C 62.83 H 10.14 N 10.74%

The starting material was prepared as follows:

(A) 6.25 ml (25 mmol) of dibenzylmalonate were dissolved in 25 ml of dry dimethylformamide under nitrogen and 0.75 g (80% sodium hydride) was added over 10 minutes. The mixture was stirred for 0.5 hours, cooled to 0 ° C and a solution of 4.75 ml added ( 25 mmol) of 1-bromononane in 10 ml of dry dimethylformamide, continued stirring for 1 hour at 0 DEG C., and left the mixture at room temperature for 64 hours. The solution was evaporated and the residue dissolved in diethyl ether. The organic phase was washed with water and saturated solution. of sodium chloride, dried over magnesium sulfate and evaporated. Silica gel chromatography using ethyl acetate / hexane (1: 5) for elution gave 5.85 g (56%) of dibenzyl nonylmalonate as an oil; Rf (ethyl acetate / hexane 1: 3) 0.58 .

(B) 5.85 g (14 mmol) of dibenzyl nonylmalonate was treated with 0.43 g (14 mmol) of 80% sodium hydride and 2.33 ml (14 mmol) of tert.butyl bromoacetate as described in paragraph (A). Chromatography on silica gel using ethyl acetate / hexane (1:19) for elution gave 6.24 g (33%) of benzyl 4-tert. butyl hydrogen (2-nonyl-2-benzyloxycarbonylsuccinate as an oil; Rt '(ethyl acetate / hexane 1:19) 0.74.

(C) Benzyl 4-tert-butyl hydrogen (2-nonyl-2-benzyloxycarbonyl) -succinate from paragraph B was dissolved in 80 ml of isopropanol and hydrogenated for 1 hour in the presence of 0.2 g of 5% palladium on charcoal. The suspension was filtered, the filtrate was evaporated, 100 ml of toluene was added and the mixture was refluxed for 3 hours. Evaporation gave 3.5 g (97%) of 4-tert.butyl hydrogen 2- (RS) nonylsuccinate as an oil; Rf (system A) 0.73.

(D) 1.5 g (4 mmol) of N-tert.butoxycarbonyl-L-leveyl-L-leucine ethylamide were dissolved in 20 ml of 4M hydrochloric acid in ethyl acetate, stirred at room temperature for 0.5 hours, evaporated, washed with diethyl ether and dried in a vacuum. The solid residue was taken up in 10 ml of dry dimethylformamide, treated with 0.6 ml (4.7 mmol) of N-ethyl morpholine, 1.2 g (4.0 mmol) of 4-tert-butyl hydrogen 2 (RS) -nonylsuccinate, 0.66 g (4.9 mmol) of hydroxy benzotriazole and 0.78 g (4.0 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred for 1 hour at 0 ° C, allowed to stand at room temperature for 16 hours and evaporated. The residue was taken up in ethyl acetate, washed successively with 5% sodium hydrogen carbonate solution, water, 5% citric acid solution, water, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, and evaporated to give a solid. Silica gel chromatography using ethyl acetate for elution gave 1.9 g (36%) of [4-tert-butoxy 2 (RS) -nonylsuccinyl] -L-leucyl-leucine ethylamide as a white solid; Rf (ethyl acetate) 0.60; MS: (M + H) < ⁺ > 554.

(E) 0.95 g (1.7 mmol) of [4-tert-butoxy 2 (RS) -nonylsuccinyl] -L-leucyl-L-leucine ethylamide was dissolved in 15 ml of trifluoroacetic acid and the solution was stirred for 2 hours at room temperature and evaporated. The residue was evaporated with toluene, dissolved in dichloromethane, washed with water, dried over magnesium sulfate and evaporated. The residue was taken up in 10 ml of dimethylformamide at -15 ° C and treated with 0.22 ml (1.7 mmol) of N-ethylmorpholine and 0.22 ml (1.7 mmol) of isobutyl chloroformate. After 10 minutes at -15 ° C, 0.42 ml (3.4 mmol) of O-benzylhydroxylamine was added and the mixture was stirred for 1 hour at 0 ° C and allowed to stand at room temperature for 16 hours. The mixture was diluted with water, the precipitated solid filtered off, washed successively with 5% citric acid solution, water and 5% sodium hydrogen carbonate solution, and then dried in vacuo. Chromatography of the residue on silica gel using methanol / dichloromethane (3:97) for elution gave 0.55 g (54%) of [4- (N-benzyloxyamino) -2 (RS) -nonylsuccinyl] -L-leucyl-L-leucine ethylamide as white solid; Rf (methanol / dichloromethane 1:19) 0.47; MS: (M + H) < + >603; HPLC (ODS reverse phase eluted with 70% acetonitrile / trimethylammonium phosphate buffer pH 2.5) Rt 4.7 and 7.7 min.

The isomer was separated as follows:

1.0 g (1.66 mmol) of the mixture was dissolved in 10 ml of hot dichloromethane and the solution was allowed to stand at room temperature for 2 hours and 16 hours at 4 ^W C. The solid was filtered off, washed with dichloromethane and dried in vacuo to give 0.41 g ( 41%) [4- (N-benzyloxyamino) -2 (R or S) -nonylsuccinyl] -L-leucyl-L-leucine ethylamide (isomer 1) as a solid; Rf (system B) 0.46. HPLC Rt 4.6 min.

The mother liquors were evaporated to give 0.47 g (47%) of [4- (N-benzyloxyamino) -2 (R or S) -nonylsuccinyl] -L-leucyl-L-leucine ethylamide (isomer 2) as a solid;

Rf (system B) 0.52. HPLC Rt 7.5 min.

Example 7

In the analogous manner as described in the first paragraph of Example 6, [4- (Nhydroxyamino) -2 (RS) -nonylsuccinyl was prepared from [4- (N-benzyloxyamino) -2 (RS) -nonylsukeinyl] -L-tert. ] -L-tere.butyl glycine methylamide as white foam;

Rf (system A) 0.58 and 0.64; MS: (M + H) < + > 386.

Analysis for

C20H39N3O4 O.4CH3OH

Calc .:

Found:

C 61.51

C 61.50

H 10.27 H 10.13

N 10.55% N 10.27%

The starting material was prepared as follows:

In the analogous manner as described in Example 6 (DE), only starting from L-tert.butyl glycine methylamide instead of the unprotected tert.butoxycarbonyl-L-leucyl-L-leucine ethylamide gave [4- (N-benzyloxyamino) - 2 (RS) -nonylsuccinyl] -L-tert.butylglycine methylamide as foam; Rf (methanol / dichloromethane 1:19) 0.27 and 0.34; MS (EI): M ⁺ 475.

Example 8

In the analogous manner as described in the first paragraph of Example 6, [4- (Nhydroxyamino) -2 (RS) was prepared from [4- (N-benzyloxyamino) -2 (RS) -undeeylsukeinyl] -L-leucyl-L-leucine ethylamide. -undecylsuccinyl] -L-leucyl-L-leucine ethylamide as foam;

Rf (system A) 0.62 and 0.66; MS: (M + H) < + > 541.

The starting material was prepared as follows:

In an analogous manner as described in Example 6 (AE), only using 1bromoundecane instead of 1-bromononane gave [4- (N-benzyloxyamino) -2 (RS) undecylsuccinyl-L-ivyl-L-leucine ethylamide as a gel ;

Rf (methanol / dichloromethane 1: 9) 0.70; MS: (M + H) < ⁺ > 631.

Example 9

0.3 g (0.536 mmol) of [4- (N-benzyloxyamino) 2 (R or S) -heptyl-3 (S) -methylsuccinyl] -leucyl-L-leucine-ethylamide (diastereoisomer 1) was hydrogenated in 50 ml of methanol for 1.5 hours in the presence of 0.1 g of 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated and the residue triturated with diethyl ether to give 0.23 g of [4- (N-hydroxyamino) 2 (R or S) -heptyl3 (S) -methylsuccinyl] -L-leucyl-L-leucine ethylamide ( diastereoisomer 1) as a white solid; MS: 499 (M + H) < + >.

Analysis for C26H50N4O5 0.4 PbO

Calc .: · C 61.72 H 10.12 N 11.08%

Found: C 61.92 H 10.05 N 10.85%

The starting material was prepared as follows:

(A) 2.0 g (0.11 mol) of L-lactic acid benzyl ester and 10.8 ml (0.13 mol) of pyridine in 220 ml of dichloromethane were added over 0.5 hours to a solution of trifluoromethanesulfonic acid anhydride in 250 ml of dichloromethane at 0 ° C. After a further 0.5 hours, the solution was washed twice with 250 ml of water each time and with 250 ml of saturated sodium chloride solution, then dried over anhydrous magnesium sulfate. The solution was then added over 0.5 hours to a solution of diethyl tert-butyl sodium malonate (0.11 moles) (prepared from 22.8 g of di-tert-butyl malonate and 3.48 g of 80% sodium hydride in oil) in 250 ml of dimethylformamide at 0 ° C. The mixture was allowed to warm to room temperature overnight and the solvent was evaporated. The residue was partitioned between 200 ml ethyl acetate and 200 ml 5% sodium hydrogen carbonate solution. The organic layer was washed with water (2 x 200 ml), dried over anhydrous magnesium sulfate and evaporated to give a yellow oil. Flash chromatography on silica gel using 10% ethyl acetate in hexane for elution gave 35.4 g (88%) of 1-benzyl 4-tert-butyl 3 (RS) -tert.butoxycarbonyl-2 (S) -methylsuccinate as a colorless oil; Rf (30% ethyl acetate in hexane) 0.63.

(B) 952 mg of 80% sodium hydride was added to a stirred solution of 10 g of 1-benzyl 4-tert-butyl 3 (RS) -tert-butoxy-carbonyl-2 (S) -methylsuccinate in 100 ml of dry dimethyl formamide. The solution was stirred at room temperature for 2 hours and then 6.23 ml of 1bromoheptane was added. The mixture was heated at 60 ° C for 4 hours and then stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed successively with 5% sodium hydrogen carbonate solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by flash chromatography using 5% ethyl acetate in hexane for elution to give 6.83 g of benzyl 3,3 (RS) -di-tert.butoxycarbonyl-2 (S) methyldecanoate as a colorless oil; Rf (10%) ethyl acetate in hexane) 0.5.

(C) 6.8 g of benzyl-3,3 (RS) -di-tert-butoxycarbonyl-2 (S) -methyldecanoate in 20 ml of trifluoroacetic acid was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was re-evaporated from toluene (2 x 25 ml) to give an orange oil. The oil was redissolved in 100 ml of toluene, treated with 3.64 ml of N-ethylmorpholine and heated at reflux for 1 hour. The solution was washed sequentially with 2M hydrochloric acid, water and sodium chloride solution, dried over anhydrous magnesium sulfate evaporated to give a brown oil. Purification by flash chromatography using 2% methanol in dichloromethane for elution gave 3.02 g of 1-benzyl-3 (RS) -carboxy-2 (S) -methyldecanoate as a yellow oil; Rf (5% methanol in dichloromethane) 0.47, 0.52; MS: 321 (M + H) < + >.

(D) In an analogous manner to that described in Example 1 (D-F), 1.5 g of benzyl

3 (RS) -carboxy-2 (S) -methyldecanoate gave 0.315 g of [4- (N-benzyloxyamino) -2 (R or S) heptyl-3 (S) -methylsuccinyl] -L-leucyl-L-leucine ethylamide ( diastereoisomer 1) as a dirty white solid.

Example 10

0.25 g of [4- (N-benzyloxyamino) -2 (R) -heptyl-3 (R or S) -phthalimidomethyl) succinyl] -L-leucyl-leucine ethylamide (diastereoisomer 1) in 100 ml of dimethylformamide were hydrogenated in the presence of 100 mg 10% palladium on charcoal for 24 hours. The catalyst was filtered off and the solvent was evaporated. Trituration of the residue with diethyl ether gave 0.17 g of [4- (N-hydroxyamino) -2 (R) heptyl-3 (R or S) -phthalimidomethyl) succinyl] -L-leucyl-L-leucine ethylamide (diastereoisomer 1) as a gray dust; Rf (10% methanol in dichloromethane) 0.5; MS: 644 (M + H) < ⁺ >.

Analysis for C34H53N5O7 0.8 H? O

Calc .: C 62.04 H 8.36 N 10.64%

Found: C 61.99 H 8.04 N 10.60%

The starting material was prepared as follows:

(A) In an analogous manner to that described in Example 1 (AD), 10.28 g of dibenzyl 3 (RS) -tert.butoxycarbonyl-2 (R) heptyl succinate was obtained from 20 g of D-amino nonanoic acid as pale yellow oil; Rf (10% ethyl acetate in hexane) 0.32.

(B) 8.2 g of dibenzyl-3 (RS) -ter t.butoxycarbonyl-2 (R) -heptyl succinate in 100 ml of dry dimethyl formamide were treated with 0.49 g of 80% sodium hydride dispersion. After 2 hours, the mixture was cooled to 0 ° C and 4.18 g of N-bromomethylphthalimide was added portionwise. The mixture was stirred at 0 ° C for an additional hour and then overnight at room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate and 5% sodium hydrogen carbonate solution. The organic phase was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by flash chromatography on silica gel using 20% ethyl acetate in hexane for elution to give 6.42 g of dibenzyl-3 (RS) -tert.butoxycarbonyl-2 (R) -heptyl-3 (RS) ( phthalimido-methyl) succinate.

(C) 3.5 g of dibenzyl 3 (RS) -ter t.butoxycarbonyl-2 (R) -heptyl-3 (RS) - (phthalimidomethyl) succinate in 50 ml of ethanol were hydrogenated in the presence of 0.35 g of 5% palladium on charcoal. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in 50 ml of toluene, treated with 0.58 ml of N-ethyl morpholine and heated at reflux for 2 hours. The solution was washed sequentially with 2M hydrochloric acid, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. Purification of the residue by flash chromatography on silica gel using 4% methanol in dichloromethane for elution gave 1.54 g of 4-tert-butyl hydrogen 2 (R) -heptyl-3 (RS) - (phthalimidomethyl) succinate as an oil; Rf (5% methanol in dichloromethane) 0.3.

(D) In an analogous manner to that in Example 1, paragraph (E) - (F), deer from 0.6 g of 4-tert-butyl 2 (R) -heptyl-3 (RS) - (phthalimidomethyl) succinate gave 0.27 g [4 - (N-Benzyloxyamino) 2 (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -L-leucyl-L-leucine ethylamide (diastereomer 1) as a white solid; MS: (M + H) < ⁺ > 734.

Analysis for C41H59N5O7 0.6 PbO

Calc .: C 66.12 H 8.15 N 9.4%

Found: C 66.08 H 8.08 N 9.53%

Example 11

In the analogous manner as described in the first paragraph of Example 2, [4 (N-hydroxyamino) -2 (4) was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-phenylalanyl-L-leucine-ethylamide. RS) -heptylsuccinyl] -L-phenylalanil-L-leucine ethylamide as a white solid; Rf (methanol / dichloromethane 1:19) 0.28 and 0.43; MS: (M + H) < ⁺ > 519.

Analysis for C28H46N4O5 0.3 PbO

Calc .: C 64.17 H 8.96 N 10.69%

Found: C 64.07 H 8.77 N 10.64%

The starting material was prepared as follows:

From N-tert-butyloxycarbonyl-L-phenylalanyl-L-leucine ethylamide, [4- (N-benzyloxyamino) -2 (RS) heptylsuccinyl was obtained using methods analogous to those described in Example I (E) - (F) ] -L-Phenylalanil-L-leucine ethylamide as a white solid;

Rf (methanol / dichloromethane 1:19) 0.64; MS: (M + H) < ⁺ > 609.

Example 12

In the analogous manner as described in the first paragraph of Example 2, [4- (Nhydroxyamino) -2 (4) was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-nona] yl-L-leucine ethylamide. RS) -heptylsuccinyl] -L-nonalyl-L-leucine ethylamide as a white solid; MS: (M + H) < + > 527.

Analysis for C28H54N4O5 (526.76)

Calc .: C 63.84 H 10.33 N 10.64%

Found: C 63.64 H 10.39 N 10.63%

The starting material was prepared as follows:

From N-tert.butoxycarbonyl-L-nonalyl-L-leucine ethylamide, [4- (benzyloxyamino) -2 (RS) heptylsuccinyl] -L-nonalyl- was obtained using methods analogous to those described in Example 1 (EF). L-leucine ethylamide as a white solid; Rf (methanol / dichloromethane 1:19) 0.55 and 0.62; MS: (M + H) < ⁺ > 617.

Example 13

In the analogous manner as described in the first paragraph of Example 2, [4- (Nhydroxyamino) -2 (RS) -heptylsuccinyl was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsukeinyl] -L-phenylalanine tert-butylamide ] -L-phenylalanine tert.butylamide as hygroscopic foam; Rf (methanol / chloroform 1:19) 0.31; MS (M + H) ⁺ 434.

The starting material was prepared as follows:

From N-tert-butoxycarbonyl-L-phenylalanine tert-butylamide, [4- (N-benzyloxyamino) -2 (RS) heptylsuccinyl] -L-phenylalanine tert was obtained using methods analogous to those described in Example 1 (EF) .butylamide as a white solid;

Rf (ethyl acetate) 0.75; MS: (M + H) < + > 524.

Example 14

In the analogous manner as described in the first paragraph of Example 2, [4- (N2Χ hydroxyamino) -2 (RS) -heptylsuccinyl was prepared from [4- (Nbenzyloxyamino) -2 (RS) -heptylsuccinyl] -L-phenylalanine methylamide. -L-Phenylalanine methylamide as a white solid; Rf (methanol / chloroform 1:19) 0.16 and 0.21; MS (M + H) + 392.

The starting material was prepared as follows:

From N-tert-butoxycarbonyl-L-phenylalanine methylamide, [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-phenylalanine methylamide was obtained using methods analogous to those described in Example 1 (EF). white solid;

Rf (methanol / chloroform 1:19) 0.29 and 0.36;

Analysis for C28H39N3O4 (481.64)

Calc .: C 69.83 H 8.16 N 8.72%

Found: C 69.56 H 8.05 N 9.00%

Example 15

In the analogous manner as described in the first paragraph of Example 2, [4- (Nhydroxyamino) -2 (RS) - was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsukeinyl] -L-tert-butyl glycine methylamide. heptyl.succinyl] -L-tert.butylglycine methylamide as foam;

Rf (methanol / dichloromethane 1:19) 0.23 and 0.29; MS: (M + H) < + > 358.

Analysis for C18H35N3O4. 0.3 CH3OH

Calc .: C 59.87 H 9.94 N 11.45%

Found: C 59.80 H 9.76 N 11.44%

The starting material was prepared as follows:

In the analogous manner as described in Example 1 (EF), only starting from L-tert.butylglycine methylamide instead of unprotected benzyloxycarbonyl-L-leucine-methylamide, [4- (N-benzyloxy.amino) -2 (RS) was prepared -heptylsuccinyl] -L-tert.butylglycine methylamide as a white foam; Rf (methanol / chloroform 1:19) 0.29 and 0.36; MS: (M + H) < + > 448.

Example 16

[4- (N29 hydroxyamino) -2 (RS) -heptylsuccinyl was prepared from [4- (Nbenzyloxyamino) -2 (RS) -heptylsuccinyl] -L-neopentylglycine methylamide in the analogous manner as described in the first paragraph of Example 2. -L-neopentylglycine methylamide as a white solid; MS: (M + H) < + > 372.

Analysis for C13H37N3O4 (371.52)

Calc .: C 61.43 H 10.04 N 11.31%

Found: C 61.04 H 9.93 N 11.13%

The starting material was prepared as follows:

From N-tert-butoxycarbonyl-L-neopentylglycine methylamide, [4- (N-benzyloxyamino) -2 (RS) heptylsuccinyl] -L-neopentylgliein methylamide was prepared using methods analogous to those described in Example 1 (EF) foam;

Rf (methanol / chloroform 1:19) 0.47 and 0.55; MS: (M + H) ⁺ 462.

Analysis for C26H43N3O4 (461.65)

Calc .: C 67.65 H 9.39 N 9.10%

Found: C 67.57 H 9.12 N 9.02%

Example 17

In the analogous manner as described in the first paragraph of Example 2, [4- (N-hydroxyamino) -2 (from [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-homophenylalanil-L-leucine) ethylamide was prepared. RS) -heptylsuccinyl] -L-homophenylalanil-L-levine as a white hygrocopen granular powder: MS: (N + H) ⁺ 533.

Analysis for C29H43N4O5. 0.4 H ₂ O

Calc .: C 64.51 H 9.11 N 10.38%

Found: C 64.59 H 8.94 N 10.14%

The starting material was prepared as follows:

[4- (N-Benzyloxyamino) -2 (RS) heptylsuccinyl] -L-homophenylalanine was prepared from N-benzyloxycarbonyl-L-homophenylalanil-L-leucine ethylamide using methods analogous to those described in Example 2 (AB). L-leucine ethylamide as a solid;

Rf (methanol / chloroform 1:19) 0.55; MS: (M + H) < + > 623.

Analysis for

Calc .:

Found:

C36H54N4O5 (622.85)

C 69.42 H 8.74 N 9.00%

C 69.02 H 8.85 N 8.87%

Example 18

In the analogous manner as described in the first paragraph of Example 2, [4 (N-hydroxyamino) -2 (RS) -L- was prepared from [4- (N-benzyloxyamino) -2 (RS) -heptylsuccinyl] -L-cyclohexylalanine methylamide. cyclohexylalanine methylamide as a white solid;

MS: (M + H) < + > 398.

Analysis for C21H39N3O4 (397.56)

Calc .: C 63.45 H 9.89 N 10.57%

Found: C 63.24 H 10.04 N 10.33%

The starting material was prepared as follows:

From N-tert.butoxycarbonyl-L-cyclohexylalanine methylamide, [4- (N-benzyloxyamino) -2 (RS) heptylsuccinyl-L-cyclohexylalanine methylamide was prepared as white solid using methods analogous to those described in Example 1 (EF). substance;

Rf (methanol / dichloromethane 1: 9) 0.30 and 0.37; MS: (M + H) < + > 488.

Example 19

0.6 g (1.14 mmol) of [4-tert.butoxy 2 (RS) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide [prepared in Example 1 (E)] were dissolved in 10 ml of trifluoroacetic acid and the solution was stirred for 3 hours and evaporated. The residue was evaporated four times from toluene then dissolved in 200 ml of dichloromethane containing 5 ml of methanol, washed twice with water, dried over magnesium sulfate and evaporated. The residue was dissolved in 1 ml of dimethylformamide and 10 ml of 1,2-dimethoxyethane at 0 ° C. 0.135 g (1.17 mmol) of Nhydroxysuccinimide and 0.243 g (1.17 mmol) of dicyclohexylcarbodiimide were added, and the mixture was stirred at 0 ° C for 1 hour and at 4 ° C for 16 hours. filtered and evaporated to give crude N-hydroxysuccinimide ester as a sticky solid. This ester was suspended in 5 ml of tetrahydrofuran, treated with a solution prepared from 0.178 g (2.56 mmol) of hydroxylamine hydrochloride and 0.094 g (2.35 mmol) of sodium hydroxide in 5 ml of water, stirred for 16 hours at room temperature, filtered and evaporated. The resulting rubber was washed with water by decantation and dried by evaporation of toluene. Chromatography on silica gel using 1% methanol in dichloromethane and then 2%, 3% and 5% methanol in dichloromethane for elution and evaporation gave [4- (N-hydroxyamino) -2 (R or S) -heptyl-succinyl] -L-leucyl-Lleucine ethylamide, isomers 1 and 2, as white solids.

Rf (methanol / dichloromethane 1: 12.5) 0.34 (isomer 2) and Rf 0.26 (isomer 1).

Isomer 1 was washed with dichloromethane and ethyl acetate and then dried to give 0.083 g (15%) of [4- (N-hydroxyamino) -2 (R or S) -heptyl-succinyl] -L-leucyl-L-leucine ethylamide (isomer 1) identical to that prepared in Example 1.

Rf (system A) 0.54. MS: (M + H) < + > 485.

Analysis for C25H4SN4O5 0.2 H ₂ O Calc .: C 61.50 H 9.99 N 11.47% Found: C 61.41 H 10.09 N 11.48% Example 20

0.30 g (0.6 mmol) of [4- (N-benzyloxyamino-2 (RS) -isooctylsuccinyl] -L-phenylalanine methylamide) in 200 ml of methanol was hydrogenated for 3 hours in the presence of 0.1 g of 10% palladium-on-carbon. The mixture was filtered and the filtrate was evaporated. to give 0.20 g of 81% [4- (Nhydroxyamino) -2 (RS) -isooctylsuccinyl] -L-phenylalanine methylamide as a white solid; MS: (M + H) + 406.

Analysis for C22H35N3O4 (405.54)

Calc .: C 65.16 H 8.70 N 10.36%

Found: C 65.04 H 8.75 N 10.20% [4- (N-Benzyloxyamino-2 (RS) -isooctylsuccinyl] -L-phenylalanine methylamide), used as starting material, was prepared as follows:

(A) A solution of 13.03 g (60 mmol) of diethyl acetamidomalonate in 50 ml of dry dimethylformamide was added over 0.5 hours to a suspension of 2.16 g (72 mmol) of 80% sodium hydride in 50 ml of dry dimethylformamide at 0 ° C under a nitrogen atmosphere. The mixture was stirred for 3 hours at room temperature, a solution of 15.05 g (78 mmol) of 1bromo-6-methylheptane in 50 ml of dry dimethylformamide was added and the mixture was stirred for 64 hours and evaporated in oil. The oil was extracted twice with ethyl acetate, the combined extracts were washed with water, dried over magnesium sulfate and evaporated. The residue was maintained at reflux for 4 hours in 6M hydrochloric acid (180 ml) for 4 hours, cooled and the waxy solid filtered off. The crude product in 120 ml of 50% aqueous ethanol was filtered, 7 ml of pyridine was added and the mixture was cooled on ice to give 6.49 g (57%) of DL-isooctylglycine as a finely dirty white powder.

(B) 6.45 g (34.5 mmol) of DL-isooctylglycine were suspended in 200 ml of acetic acid at room temperature. 4.8 g (69 mmol) of sodium nitrite were added portionwise over 3 hours. The clear solution was stirred for 16 hours at room temperature, evaporated, water was added and diethyl ether was added and the mixture was filtered. The ether solution was dried over magnesium sulfate and evaporated to an oil. The recovered and dried starting material (1.76 g) was recycled by the above procedure to give an ether-soluble oil. The combined product (7.43 g) was dissolved in 16 ml of methanol, a solution of 3.9 g of sodium hydroxide in 33 ml of water was added and the mixture was stirred for 2 hours at room temperature. The methanol was evaporated, water was added and the solution was extracted with diethyl ether and acidified with concentrated hydrochloric acid. The product was extracted with diethyl ether and after evaporation gave 5.88 g (91%) of 2 (RS) -hydroxyiso-octanoic acid as a clear oil which solidified under condition.

(C) 5.84 g (31.3 mmol) of 2 (RS) -hydroxy-isooctanoic acid were dissolved in 60 ml of ethyl acetate. 4.4 ml (31.3 mmol) of triethylamine and 3.8 ml (31.3 mmol) of benzyl bromide were added and the mixture was heated at reflux for 3 hours. The mixture was cooled, filtered, washed sequentially with 2M hydrochloric acid, water and 5% sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. Chromatography on silica gel using ethyl acetate / hexane (3: 7) for elution gave 5.55 g (64%) of benzyl 2 (RS) hydroxyisooctenoate as an oil; Rf (ethyl acetate / hexane 1: 1) 0.50.

(D) A solution of 5.45 g (19.6 mmol) of benzyl 2 (RS) -hydroxy-isoctanoate and 1.91 ml (23.5 mmol) of pyridine in 35 ml of dry dichloromethane was added with stirring for 0.5 hours to a solution of 4 ml (23.5 mmol) of trifluoromethanesulfonic anhydride acid in 40 ml of dry dichloromethane at 0 ° C. The mixture was stirred for 1 hour at 0 ° C and for 1 hour at room temperature. The solution was washed twice with water, dried over magnesium sulfate and evaporated to give 7.32 g (95%) of benzyl 2 (RS) -trifluoromethanesulfonyloxyisooctanoate; Rf (ethyl acetate / hexane 1: 4) 0.73.

(E) A solution of 7.31 g (18.55 mmol) of benzyl 2 (RS) -trifluoromethanesulfonyloxyisooctanoate in 30 ml of dry dichloromethane was added dropwise over 1 hour to the suspension.

0.58 g (19.5 mmol) of 80% sodium hydride and 4.64 g (18.55 mmol) of benzyl tert-butyl malonate in 50 ml of dry dimethylformamide at 0 ° C. The mixture was stirred for 6 hours at room temperature, allowed to stand at room temperature for 16 hours and evaporated in oil. The residue in dichloromethane was washed twice with water and with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Chromatography on silica gel using ethyl acetate / hexane (1: 4) for elution gave 6.08 g (64%) of dibenzyl 3 (RS) tert-butoxycarbonyl-2 (RS) -isooctyl succinate as pale amber oil;

Rf (ethyl acetate / hexane 1: 3) 0.49.

(F) 6.02 g (11.8 mmol) of the triester of paragraph (E) in 90 ml of isopropanol was hydrogenated for 16 hours in the presence of 0.2 g of 10% palladium on charcoal. The mixture was filtered, the filtrate was evaporated, toluene was added and the mixture was evaporated to remove traces of isopropanol. The residue in 75 ml of toluene and 1.65 ml (11.8 mmol) of triethylamine was maintained at reflux for 2 hours and evaporated and the residue dissolved in ethyl acetate. The solution was washed with 0.5M hydrochloric acid and water, dried over magnesium sulfate and evaporated to give 3.23 g (96%) of 4-tert-butyl hydrogen 2 (RS) -isooctylsuccinate as an oil.

(G) 1.25 g (4.5 mmol) of N-tert-butoxycarbonyl-L-phenylalanine methylamide were dissolved in 15 ml of 4M hydrogen chloride in ethyl acetate, stirred for 1 hour at room temperature, evaporated and dried in vacuo. The residue in K) ml of dry dimethylformamide was cooled to C and treated with (1.6 ml (4.7 mmol) of N-ethylmorpholine, solution of 0.86 g (3 mmol) 4 tert.butyl hydrogen 2 (RS) -isooctyl succinate in 15 ml of dichloromethane, 0.49 g (3.6 mmol) of hydroxybenzotriazole and 0.72 g (3.75 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride The mixture was stirred for 1 hour at 0 ° C, allowed to stand for 16 hours at 4 ° C and evaporated. was washed sequentially with 5% citric acid solution, water, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated Silica gel chromatography using ethyl acetate for elution gave 1.17 g (87%) [4 -terc.butoxy 2 (RS) isooctylsuccinyl] -L-phenylalanine methylamide as a solidifying oil;

Rf (ethyl acetate / hexane 1: 1) 0.34 and 0.44.

(H) 1.02 g (2.28 mmol) of [4-tert-butoxy 2 (RS) -isooctylsuccinyl] -L-phenylalanine methylamide were dissolved in 10 ml of trifluoroacetic acid, the solution was stirred for 1.5 hours and evaporated. The residue was evaporated three times with toluene, dissolved in chloroform, washed twice with water, dried and evaporated to give a solid. The solid was dissolved in 15 ml of dimethylformamide, cooled to 0 ° C and treated with 0.6 ml (4.6 mmol) of N-ethyl morpholine,

0.37 g (2.7 mmol) of hydroxybenzotriazole, 0.54 g (2.8 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride and 0.42 g (3.4 mmol) of O-benzylhydroxylamine. The mixture was stirred for 1 hour at 0 ° C and for 16 hours at room temperature, evaporated and water was added. The precipitated solid was washed successively with 5% sodium hydrogen carbonate solution, water, 5% citric acid solution, water, 5% sodium hydrogen carbonate solution and water and then dried in vacuo. The resulting solid was dissolved in methanol / chloroform (1: 1) and 0.71 g (63%) of [4- (N-benzyloxyamino) -2 (RS) -isooctylsuccinyl] -L-phenylalanine methylamide was obtained as a white solid after the addition of diethyl ether. . MS: (M + H) < ⁺ > 496.

Analysis for C29H41N3O4 0.2 CH3OH Calc .: C 69.85 H, 8.39 N 8.37% Found: C 69.81 H, 8.34 N 8.40% Example 21 1.0 g (2.17 mmol) [4- (N-benzyl looksiamino) -2 (R) -heptylsuccinyl] -L-neopentylglycine

of methylamide in 50 ml of methanol was hydrogenated for 1.5 hours in the presence of 0.33 g of 5% palladium on charcoal. The mixture was filtered and the filtrate evaporated to give 0.8 g (99%) of [4- (Nhydroxyamino) -2 (R) -he pti Is u kc i n yl] -L-neopent Iglicin methylamide as a white solid; MS: (M + H) < + > 372.

Analysis for C19H37N3O4 (371.52)

Calc .: C 61.43 H 10.04 N 11.31%

Found: C 61.21 H 10.17 N 11.35% [4- (N-benzyloxyamino-2 (R) -heptylsuccinyl] -L-neopentylglycine methylamide) used as starting material was prepared as follows:

(A) 5.6 g (22.8 mmol) of tert-butoxycarbonyl-L-neopentylglycine were dissolved in 50 ml of dichloromethane at 0 ° C. 1.85 ml (22.8 mmol) of pyridine and 9.67 g (22.8 mmol) of 70% di (J-benzotriazolyl) carbonate were added and the mixture was stirred at 0 ° C for 1 hour. 3.94 mi (45.6 mmol) of 40% aqueous methylamine were added and the mixture was stirred for 1 hour at 0 ° C and 16 hours at room temperature. The solution was flushed with 5% sodium hydrogen carbonate solution, water, 2M hydrochloric acid solution, water, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Recrystallization from ethyl acetate gave 5.26 g (89%) of tert-butoxycarbonyl-L-neopentylglycine methylamide as a white solid;

Rf (ethyl acetate) 0.47.

(B) 4.84 g (18.8 mmol) of tert-butoxycarbonyl-L-neopentylglycine methylamide were stirred with 50 ml of 4M hydrogen chloride in ethyl acetate for 1 hour at room temperature and evaporated. Ethyl acetate was added, the solution was evaporated and the residue was dried in vacuo. The resulting amine hydrochloride was dissolved in 15 ml of dry dimethylformamide at 0 ° C, neutralized by the addition of 3.58 ml (28.2 mmol) of N-ethylmorpholine and added to a cooled (0 ° C) solution of 4.25 g (15.6 mmol) of 4-tert.butyl hydrogen 2R -heptylsukeinate prepared in an analogous manner to Example 1 (AD), starting from Da-amino nonanoic acid, 2.87 g (18.8 mmol) of hydroxybenzotriazole hydrate and 3.74 g (19.5 mmol) of l-ethyl-3- (3dimethylaminopropyl-carbodiimide hydrochloride in 50 ml of dry dichloromethane at 0 ° C. The mixture was stirred at 0 ° C for 1 hour and at room temperature for 16 hours and then evaporated to an oil The residue in ethyl acetate was washed with 5% citric acid solution, water, 5% sodium solution hydrogen carbonate and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an oil. Silica gel chromatography using ethyl acetate / hexane (1: 1) for elution gave 5.13 g (80%) [4-tert.butoxy 2 (R ) heptylsuccinyl] -L-neopentylglycine methylamine as an oil;

Rf (ethyl acetate / hexane 1: 1) 0.49, MS: (M + H) ⁺ 413.

(C) 5.1 g (12.4 mmol) of [4-tert-butoxy 2 (R) heptylsuccinyl-L-neopentylglycine methylamide were dissolved in 50 ml of trifluoroacetic acid. The solution was stirred for 2.5 hours and then evaporated. The residue was evaporated twice with toluene and dissolved in dichloromethane. The solution was washed three times with water and with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue in 25 ml of dry dichloromethane was treated at 0 ° C with 3.2 ml (25 mmol) of N-ethylmorpholine, 2.28 g (14.9 mmol) of hydroxybenzotriazole hydrate and 3.0 g (15.6 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the solution was stirred at 0 ° C for 1 hour. 3.05 g (24.8 mmol) of O-benzylhydroxylamine were added and the mixture was stirred for 1 hour at 0 ° C and 16 hours at room temperature and then evaporated. Water was added and the resulting solid was washed sequentially with 2M hydrochloric acid, water, 5% sodium hydrogen carbonate solution, water and hexane and dried in vacuo. The resulting solid was warmed with diethyl ether and after addition of hexane and cooling, 5.2 g (91%) of [4- (N-benzyloxyamino) 2 (R) heptylsuccinyl-L-neopentylglycine methylamide were obtained as a hygroscopic gel, which was dried in vacuo; MS: (M + H) ⁺ 462.

Analysis for ^c 26 ^h 43 ⁿ 3 ° 4 . 0.6 H2O Calc .: C 66.10 H, 9.43 N 8.89% Found: C 66.13 H, 9.39 N 8.74%

Example 22

0.09 g (0.177 mmol) of [4- (N-benzyloxyamino) -2 (R) -heptylsuccinyl] - (D or L) -JS, / 3dimethylphenylalanine methylamide (isomer 1) in 10 ml of methanol was hydrogenated for 1.5 hours in the presence of 30 mg 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated and the residue was dried in vacuo to give 0.075 g (100%) of [4- (N-hydroxyamino) -2 (R) heptylsuccinyl] - (D or L) - / 3,3-dimethylphenylalanine methylamide like white foam;

MS: (M + H) < + > 420.

Analysis for C23H37N3O4. 0.4 PbO

Calc .: C 64.73 H 8.93 N 9.85%

Found: C 64.81 H 8.77 N 10.14% [4- (N-benzyloxyamino) -2 (R) -heptylsuccinyl] - (D or L) -3,0-dimethylphenylalanine methylamide (isomer 1), used as starting material, was prepared as follows:

(A) 2.3 g (11.9 mmol) of DL-O-dimethylphenylalanine were dissolved in 9 ml of water containing 0.48 g (12 mmol) of sodium hydroxide while stirring at 0 ° C. 6.0 ml of 4M sodium hydroxide solution and 3.4 ml (23.8 mmol) of benzyl chloroformate were added dropwise over 0.3 hours. The mixture was stirred for 1 hour at 0 ° C and for 16 hours at room temperature. The solution was extracted with diethyl ether, acidified to pH 2 with concentrated hydrochloric acid and the product extracted with ethyl acetate. The organic solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give 3.86 g (99%) of N-benzyloxycarbonyl-DLOdimethylphenylalanine as an oil; Rf (system A) 0.54; MS: (M + H) < ⁺ > 328.

(B) 3.8 g (11.6 mmol) of N-benzyloxycarbonyl-DLO-dimethylphenylalanine were converted to 2.45 g (62%) of N-benzyloxycarbonyl-DL-1S, N-dimethylphenylalanine methylamide according to the procedure described in Example 21 (A); Rf (ethyl acetate) 0.61; MS: (M + H) < ⁺ > 341.

(C) 2.4 g (7.06 mmol) of N-benzyloxycarbonyl-DL-0,0-dimethylphenylalanine methylamide were suspended in 30 ml of methanol and 3.5 ml of 2M hydrochloric acid and hydrogenated for hours in the presence of 0.24 g of 5% palladium on charcoal. The mixture was filtered, the filtrate was evaporated, the residue was evaporated three times with toluene and then dried in vacuo to give 1.75 g of DLO-dimethylphenylalanine methylamide hydrochloride containing a toluene trace;

Rf (system A) 0.31; MS: (M + H) < + > 207.

(D) 0.485 g (2 mmol) DL - $,) of 3-dimethylphenylalanine methylamide hydrochloride were dissolved in 2 ml of dry dimethylformamide and the solution cooled to 0 ° C. 0.35 ml (2.8 mmol) of N-ethylmorpholine, 0.544 g (2 mmol) of 4-tert.butyl hydrogen 2 (R) -heptylsuccinate and 0.46 g (2.4 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide were added of the hydrochloride and the mixture was stirred for 1 hour at 0 ° C and 64 hours at 4 ° C. Water was added to the suspension and the white solid filtered off, washed sequentially with 2M hydrochloric acid, water, 5% sodium hydrogen carbonate solution and water and dried in vacuo to give 0.72 g (78%) [4ter t.butoxy 2 (R) - heptylsuccinyl] -DL- [3, R] - dimethylphenylalanine methylamide;

Rf (ethyl acetate) 0.56 and 0.61; MS: (M + H) ⁺ 461.

(E) 0.71 g (1.54 mmole) of 4-tert-butoxy 2 (R) -heptylsuccinyl] -DL- [3,3-dimethylphenylalanine methylamide was dissolved in 7 ml of trifluoroacetic acid and the solution was stirred for 2.5 hours and evaporated. The residue was evaporated twice with toluene and dissolved in 30 ml of dichloromethane. The solution was washed with water, dried over magnesium sulfate and evaporated. The residue in ml of dimethylformamide was treated at 0 ° C with 0.31 g (2.02 mmol) of hydroxybenzotriazole hydrate and 0.37 g (1.93 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the solution stirred for 1 hour at 0 ° C. 0.38 g (3.08 mmol) of O-benzylhydroxylamine was added and the mixture was stirred for 1 hour at 0 ° C and 16 hours at room temperature and then evaporated. The residue in ethyl acetate was washed successively with 5% sodium hydrogen carbonate solution, water, 2M hydrochloric acid, water, 5% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Chromatography on silica gel using ethyl acetate / hexane (2: 1), then ethyl acetate / hexane (3: 1) and finally ethyl acetate for elution gave [4- (N-benzyloxyamino) -2 (R) -heptylsuccinyl] - (D or L) - N, N-dimethylphenylalanine methylamide (as 2 isomers).

Isomer 1 (0.18 g; 23%); Rt '(ethyl acetate / hexane 2: 1) () .32; MS: (M + H) + 510 and isomer 2 (0.27 g; 34%); Rf (ethyl acetate / hexane 2: 1) 0.22; MS: (M + H) < + > 510.

Example 23

0.09 g (0.18 mmol) of [4- (N-benzyloxyamino) -2 (R) -heptylsuccinyl] - (D or L) -treo-0methylphenylalanine methylamide (isomer 1) in 10 ml of methanol was hydrogenated for 4 hours in the presence of 0.03 g 5 % palladium on charcoal. The mixture was filtered, the filtrate was evaporated and the residue was dried in vacuo to give 0.072 g (98%) of [4- (N-hydroxyamino) -2 (R) heptylsuccinyl] - (D or L) -treo-O-methylphenylalanine methylamide as white hygroscopic foam; MS: (M + H) < ⁺ > 406.

Analysis for C22H35N3O4. 0.15 FbO

Calc .: C 64.73 H 8.72 N 10.29%

Found: C 64.69 H 8.93 N 10.09% [4- (N-benzyloxyamino) -2 (R) -heptylsuccinyl] - (D or L) -treo- / 3-methylphenylalanine methylamide (isomer 1), used as starting material, was prepared from Nbenzyloxycarbonyl-DL-threo - / - methylphenylalanine according to the procedure described in Example 22 (A) - (E). The isomers were separated by chromatography on silica gel using 1% methanol / dichloromethane, 2% methanol / dichloromethane and finally 3% methanol / dichloromethane for elution.

Isomer 1 had Rf (methanol / dichloromethane 1:19) 0.51 and MS: (M + H) ⁺ 496 and isomer 2 had Rf (methanol / dichloromethane 1:19) 0.41 and MS: (M + H) ⁺ 496.

Example 24

In the analogous manner as described in the first paragraph of Example 22, [4- (N-hydroxyamino) -2 was prepared from [4- (N-benzyloxyamino) -2 (R) -heptylsuccinyl] -DL-erythro- / 3-methylphenylalanine methylamide (R) -heptylsuccinyl] -DL-erythro- / 3-methylphenylalanine methylamide as a white hygroscopic foam;

Rf (system B) 0.22 and 0.29; MS: (M + H) < + > 406.

Analysis for C22H35N3O4 0.3 PbO

Calcd: C 64.30 H 8.73

Found: C 64.29 H 8.64

N 10.23% N 10.09%

The starting material was prepared as follows:

In the analogous manner as described in Example 22 (BE), only starting from Nbenzyloxycarbonyl-DL-erythro-f3-methylphenylalanine, [4- (N-benzyloxyamino) heptylsuccinyl] -DL-erythro-) 3-methylphenylalanine methylamide was obtained as white solid;

Rf (methanol / dichloromethane 7:93) 0.40 and 0.45; MS: (M + H) < + > 496.

Example 25

0.12 g [4- (N-Benzyloxyamino) -2 (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -L-tert, butyl glycine methylamide (diastereoisomer 1), prepared in an analogous manner as described in Example 10 (A) - (D), hydrogenated in 10 ml of methanol in the presence of 50 mg of 10% palladium on charcoal for 16 hours. The catalyst was filtered off and the filtrate was evaporated to give a gelatinous solid. Purification on silica gel using 5% methanol in dichloromethane for elution gave 0.06 g of [4- (N-hydroxyamino) -2 (R) -heptyl-3 (R or S) (phthalimidomethyl) -succinyl] -L-tert. .butylglycine methylamide (diastereoisomer 1) as a white solid; Rf (10% methanol in dichloromethane) 0.34; MS: (M + H) < ⁺ > 517.

Example 26

0.17 g of [4- (N-benzyloxyamino) -2 (R) -heptyl-3 (R or S) - (3-phenylpropyl) succinyl] -L-leucyl-leucine ethylamide (diastereoisomer 1), hydrogenated in 10 ml of methanol in the presence of 55 mg palladium on charcoal for 3 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.13 g of [4- (N-hydroxyamino) -2 (R) -heptyl-3 (R or S) - (3-phenylpropyl) -succinyl] -L-leucyl-leucine ethylamide diastereoisomer Γ) as a white solid;

Rf (10% methanol in dichloromethane) 0.36; MS: (M + H) < + > 603.

Analysis for C34H53N4O5 (602.83)

Calc .: C 67.74 H 9.70 N 9.30%

Found: C 68.00 H 9.93 N 9.20%

The starting material was prepared as follows:

In an analogous manner as described in Example 10 (B) - (D), 0.17 g was obtained from 2.0 g of dibenzyl 3 (RS) tert-butoxycarbonyl-2 (R) -heptyl-succinate and 0.84 g of cinnamyl bromide [4 ( N-benzyloxyamino-2 (R) -heptyl-3 (R or S) - (triphenylpropyl) succinyl] -L-leucyl] -L-leucine ethylamide (diastereoisomer 1) as an off-white solid;

Rf (5% methanol in dichloromethane) 0.47; MS: (M + H) < ⁺ > 693.

Example 27

0.25 g [4- (N-Benzyloxyamino-2 (R) -heptyl-3 (R or S) - (trimethyl-2,5-dioxo-1-imidazolidinyl) methyl] succinyl-L-leucyl-L-leucine ethylamide ( diastereoisomer 1) in 25 ml of methanol was hydrogenated in the presence of 100 mg of 5% palladium on charcoal for 6 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.16 g of [4- (N-hydroxyamino) -2 (R) -heptyl-3 (R or S) - [(3-methyl-2,5-dioxo-1-imidazolidinyl) methyl] succinyl] -L-leucyl-L-leucine ethylamide (diastereoisomer 1) as a white solid;

Rf (10% methanol in dichloromethane) 0.25; MS: (M + H) < + > 611.

Analysis for C30H54N0O7 0.6 H ₂ O

Calc .: C 57.91 H 8.95 N 13.51%

Found: C 58.17 H 8.99 N 13.23%

The starting material was prepared as follows:

In an analogous manner as described in Example 10 (B) - (D), 0.28 g of 2.0 g of dibenzyl 3 (RS) tert.butoxycarbonyl-2 (R) -heptylsuccinate and 0.88 g of 3-bromomethyl-1-methylhydantoin were obtained. [4- (N-Benzyloxyamino-2 (R) -heptyl-3 (R or S) - [(3-methyl-2,5-dioxo-limidazolidinyl) methyl] succinyl] -L-leucyl-L-leucine ethylamide ( diastereoisomer 1);

Rf (10% methanol in dichloromethane) 0.7; MS: (M + H) < ⁺ > 701.

The following Examples illustrate pharmaceutical preparations 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 ma 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:

F. HOFMANN-LA ROCHE AG

VRELIJA / GRTaU-GORJUP

Claims (32)

PATENT APPLICATIONS 1. Hydroxamic acid derivatives of the general formula R ¹ in which R 1 represents 1-7C alkyl; represents hydrogen, 1-6C alkyl or a group of the formula - (CH2) _n 'aryl or - (CH2) n ^_ Het, where n is 1 to 4 and Het represents a 5- or 6-membered N-heterocyclic ring which is (a) bonded via the N atom, (b) optionally containing N, O and / or S as additional or additional heteroatoms (e) in a position or positions different from adjacent to the bonding N atom, (c) substituted with oxo on one or both Catoms adjacent to the N-linking atom and (d) optionally benzyl contracted or optionally substituted on one or more other C atoms by 1-6C alkyl or oxo and / or optionally or any additional N atoms with 1-6C alkyl; r3 represents a characteristic group of natural or unnatural (synthetic) α-amino acid in which any functional group present may be protected, with the proviso that R1 does not represent hydrogen; R4 represents carboxyl, (1-6C alkoxy) carbonyl, carbamoyl or (1-6C alkyl) carbamoyl; RS represents a characteristic group of naturally occurring α-amino acid in which any functional group present may be protected; represents hydrogen; or R1, R5 and R5 each represent hydrogen or 1-6C alkyl; and pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein it represents hydrogen, 1-6C alkyl or a group of formula - (CH2) _n -Het and represents hydrogen. Compounds according to claim 1 or 2, wherein R1 represents ethyl, isopropyl, n-butyl or n-hexyl. Compounds according to claim 3, wherein R1 represents ethyl. Compounds according to any one of claims 1 to 4, wherein R ² represents hydrogen, methyl, a group of formula - (CH ₂ ) _n -aryl, wherein the aryl group is phenyl, or a group of formula - (CH 2) n'Het, wherein Het represents a 5- or 6-membered n-heterocyclic ring, optionally containing as an additional or additional hetero atom (s) one or two N atoms, one N atom and one O atom or one O atom. Compounds according to claim 5, wherein Het represents a group of the formula R < ² > and R < ² > each represent hydrogen or together represent an additional bond or residue of a contracted benzene ring; R 4 represents hydrogen or C 1-6 alkyl; X is -CO-, -CH ₂ -, -CH (1-6C alkyl), -C (1-6C alkyl) ₂ -, -NH-, -N (1-6C alkyl) or -O; and Υ stands for -Ο-, -NH- or -N (1-6C alkyl) -. Compounds according to claim 6, wherein Het represents a group of formula (b) or (c). Compounds according to claim 7, wherein Het represents phthalimido or 3-methyl-2,5-dioxo-limidazolidinyl. Compounds according to any one of claims 1 to 8, wherein n stands for 1 if R1 represents a group of formula - (CH2) n'Het and for 3 if R1 represents a group of formula - (CH2) _n- aryl. Compounds according to any one of claims 1 to 9, wherein R 1 represents methyl, isobutyl, tert-butyl, protected 4-aminobutyl, neopentyl, n-heptyl, cyclohexylmethyl, benzyl, amethylbenzyl or α, α-dimethylbenzyl. Compounds according to claim 10, wherein the protected 4-aminobutyl group is 4-phthalimidobutyl. Compounds according to any one of claims 1 to 11, wherein (1-6C alkyl) carbamoyl represents isobutyl and R 4 represents hydrogen. 13. Compounds according to claim 12, wherein R1 represents methylcarbamoyl or ethylcarbamoyl. 14. Compounds according to any one of claims 1 to 11, wherein R ^ r5 _and n6 each represent hydrogen, or R4 and each represent hydrogen and tert-butyl, or R4, r5, and R6 each represent methyl. 15. [4- (N-hydroxyamino) -2- (R or S) -heptylsuccinyl] -L-leucyl-L-leucine ethylamide. 16. [4- (N-Hydroxyamino) -2- (R or S) -nonylsuccinyl-L-leucyl-L-leucine ethylamide. 17. [4- (N-Hydroxyamino) -2- (R or S) -heptyl-3 (S) -methylcarbonyl] -L-leucyl-L-leucine ethylamide. 18. [4- (N-Hydroxyamino) -2- (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -L-leucylL-leucine ethylamide. 19. [4- (N-hydroxyamino) -2- (RS) -nonylsuccinyl] -L-tert-butylglycine methylamide. 20. [4- (N-Hydroxyamino) -2- (RS) -heptylsuccinyl] -L-phenylalanine methylamide. 21. [4- (N-Hydroxyamino) -2- (R) -heptyl-3 (R or S) - (phthalimidomethyl) succinyl] -Lterc.butylglycine methylamide. 22. [4- (N-Hydroxyamino) -2- (R) -heptyl-3 (R or S) - (3-phenylpropyl) succinyl] -L-leucyl-lleucine ethylamide. A compound according to claim 2 selected from: [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-leucine methylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-leucine neopentylamide, [4- ( N-hydroxyamino) -2- (RS) -heptiksukcinil] -L-alanyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptilsukcinil] -L- (N ^£ -ftaloil) - lysyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -undecylsuccinyl] -L-leucyl-L-leucine ethylamide, and [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl ] -L-Phenylalanil-L-] eucine ethylamide. A compound according to claim 1 selected from: [4- (N-hydroxyamino) -2- (RS) -heptiisuccinyl] -L-nonallyl-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-phenylalanine tert. butylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-tert-butylglycine methylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-neopentylglycine methylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-homophenylalanil-L-leucine ethylamide, [4- (N-hydroxyamino) -2- (RS) -heptylsuccinyl] -L-cyclohexylalanine methylamide, [4- (N-hydroxyamino) -2- (RS) -isooctylsuccinyl] -L-phenylalanine methylamide, [4- (N-hydroxyamino) -2- (R) -heptylsuccinyl] -L-neopentylglycine methylamide, [4- ( N-hydroxyamino) -2- (R) -heptylsuccinyl] - (D or L) - N, N-dimethylphenylalanine methylamide, [4- (N-hydroxyamino) -2- (R) 'heptylsuccinyl] - (D or L ) -Treo- / 3-methylphenylalanine methylamide, [4- (N-hydroxyamino) -2- (R) -heptylsuccinyl] -DL-erythro- / 3-methylphenylalanine methylamide, and [4- (N-hydroxyamino) -2- ( R) -heptyl-3 (R or S) - [(3-methyl-2,5-dioxo-1-imidazolidinyl) methylsuccinyl-L-leucyl-L-leucine ethylamide. 25. Compounds of General Formula II R ¹ (Π) wherein R 1> R ² 'R ² > r ⁴ , r 5 j _and r 6 have the meaning given in claim 1 and Bz represents benzyl. 26. Compounds of the general formula wherein R, R ^2, R ^, R ^, R5 and R6 have the meaning indicated in Claim 1, and their activated esters. Compounds according to any one of claims 1 to 24, useful as therapeutically effective substances. Compounds according to any one of claims 1 to 24, useful for the control or prevention of degenerative joint disease or for the treatment of invasive tumors, atherosclerosis or multiple sclerosis. A process for the preparation of compounds according to any one of claims 1 to 24, characterized in that (a) catalytically hydrogenates a compound of the general formula wherein R ⁴ , R ³ , R ³ , R 4, R ³ and r 6 have the meaning given in of claim 1, and Bz represents benzyl, or (b) an acid of the general formula R ¹ in which R ⁴ , R 2, R ³ , r ⁴ r 5 j _n r 6 has the meaning given in claim 1 or its activated ester is reacted with a compound of the general formula Η2ΝΌΖ (IV) in which Z represents hydrogen, tri (1-6C alkyl) silyl or diphenyl (1-6C alkyl) silyl, and optionally cleaving any diphenyl (1-6C alkyl) silyl group present in the reaction product, and if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable salt. A medicament comprising a compound according to any one of claims 1 to 24 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, characterized in that it contains a compound according to any one of claims 1 to 24 and a therapeutically inert carrier material. Use of a compound according to any one of claims 1 to 24 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.