RU2136657C1 - Derivatives of hydroxamic or carboxylic acid and pharmaceutical or veterinary composition on said - Google Patents

Abstract

FIELD: organic chemistry, biochemistry, pharmacy. SUBSTANCE: invention relates to derivatives of hydroxamic or carboxylic acid of the general formula (I)

where X is COOH or CONHOH; R - H, methoxy, alkyl, C_2-6-alkenyl, phenylalkyl or the group BSO_nA-; n = 0 or 1; B is 5- or 6-membered heterocyclic ring containing sulfur or nitrogen as a heteroatom; A means -CH₂-; R₂ - alkyl, phenylalkyl; R₃ - tert.-butyl, 1-benzylthio-1-methyleth-1-yl or the specific by-side chain of alanine, valine, leucine or phenylalanine; R₄ - phenyl or 5- or 6-membered heterocyclic ring containing sulfur or nitrogen as a heteroatom that can be condensed with benzene ring or 5-, 6- or 7-membered heterocyclic ring; R₅ - H or alkyl; or their salt or solvate that are inhibitors of metalloproteinases causing tissue degeneration and inhibitors of tumor necrosis factor release from cells. EFFECT: valuable biochemical properties of compounds. 6 cl, 1 tbl, 39 ex

Description

 The invention relates to therapeutically active hydroxamic acid and derivatives of carboxylic acids, methods for their preparation, to pharmaceutical compositions containing these compounds, and to the use of such compounds in medicine. In particular, these compounds are inhibitors of metalloproteinases involved in tissue degeneration and, in addition, are inhibitors of necrosis factor isolation from neoplasms from cells.

 Compounds having the property of inhibiting the action of metalloproteinases involved in the rejection of connective tissues, such as collagenase, stromelysin and gelatinase (known as matrix metalloproteinases), and referred to in this description of MMPs, are considered potentially suitable for the treatment or prevention of conditions associated with such tissue rejection, for example, rheumatoid arthritis, osteoarthritis, osteogenesis disorders, for example, osteoporosis, periodontitis, gingivitis, the formation of corneal, epidermal or gastric ulcers and metastasis, the spread and growth of tumors. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those that lead to the breakdown of myelin, for example, multiple sclerosis, as well as in the treatment of diseases associated with the development of blood vessels, which include aritritis and the growth of solid tumors, as well as psoriasis, proliferative retinopathy, revascular glaucoma, ocular neoplasms, angiofibromas and hemangiomas. However, the comparative contribution of individual MMPs to the development of the above diseases is still completely unclear.

 Metalloproteinases are characterized by the presence in the structure of sites containing zinc (II) ions. It is now known that there are a number of metalloproteinase enzymes that include fibroblast collagenase (Type 1), polymorphonuclear collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (JFWoessner, FASEB 1991. 5, 2145-2154). Many known MMP inhibitors are derivatives of peptides based on natural amino acids and are analogues of the collagen cleavage site. In a recent paper, Chapman et al. (J. Med. Chem. 1993, 36, 4293-4301) describes some information about the activity and general structure of a number of N-carboxyalkyl peptides. Other known MMP inhibitors are less similar in structure to peptides and can more likely be considered as pseudopeptides or peptide mimetics. Such compounds usually contain a functional group capable of binding to zinc (II) in the MMP; and known classes include compounds such as hydroxamic acid, carboxylic acid, compounds with a sulfhydryl group and a group containing oxygenated phosphorus (e.g., phosphinic acid and phosphonamidate, including aminophosphonic acid).

где X - связывающая цинк группа гидроксамовой кислоты (- CONHOH) или карбоксильная группа (-COOH) и R₁-R₅ имеют значения, меняющиеся в известных источниках, описывающих эти соединения. Примеры патентных документов, описывающих эти структуры, приведены ниже.Two well-known classes of pseudopeptide or mimetically peptide MMP inhibitors contain a hydroxamic acid group and a carboxy group, respectively, as a zinc binding group. With some exceptions, such known MMP inhibitors may be represented by structural formula I

where X is the zinc-binding hydroxamic acid group (- CONHOH) or the carboxyl group (-COOH) and R ₁ -R ₅ have the meanings varying in known sources describing these compounds. Examples of patent documents describing these structures are given below.

It is generally known in the art that differences in zinc binding groups and in substituents R ₁ , R _2, and R ₃ can significantly affect the inhibition of metalloproteinases. It is believed that group X interacts with metalloproteinases by binding of the zinc (II) ion in the active center. Typically, a hydroxamic acid group is more preferred than a carboxyl group in the sense of inhibitory effect on various metalloproteinases. However, the carboxyl group in combination with other substituents may have a selective inhibitory effect on gelatinase (EP 489,577-A). The substituents R ₁ , R ₂ and R ₃ are believed to occupy the P ₁ , P ′ ₁ and P ′ ₂ binding sites in the amino acid side chain in a substrate of the natural enzyme, respectively. There is evidence that a large volume R ₁ substituent can increase stromelysin activity and that (C ₁ -C ₆ ) alkyl (e.g. isobutyl) as R ₂ is preferred in the case of collagenase, while a phenylalkyl group (e.g. phenylpropyl) as R ₂ provides selectivity for gelatinase compared to other metalloproteinases.

 Tumor necrosis factor (TNF) is a cytokine that forms initially as a precursor associated with a 28kD cell. It stands out as an active 17kD form, which can produce a large number of harmful effects in vivo. In animals or humans, it causes inflammation, fever, cardiovascular disorders, bleeding, coagulation and acute reactions, similar to those observed in acute infections and shock conditions. Chronic presence can also cause cachexia and anorexia. Accumulation of excess TNF can be fatal.

 There is a sufficient amount of information obtained in the study of animal behavior that blocking the action of TNF with special antibodies can be beneficial in acute infections, shock conditions, body reactions to transplantation, and autoimmune diseases. TNF is also an autocrine growth factor for some myelomas and lymphomas and can inhibit hematopoiesis in patients with these lesions.

 Compounds that inhibit the formation or action of TNF are therefore considered potentially suitable for the treatment and prophylaxis of many inflammatory infections, immunological or malignant diseases. These include, but are not limited to, septic shock, hemodynamic shock and sepsis syndrome, reperfusion of post-ischemic effects, malaria, Crohn’s disease, microbacterial infection, meningitis, psoriasis, chronic heart failure, fibrotic diseases, cachexia, transplant rejection, cancer, autoimmune diseases , rheumatoid arthritis, multiple sclerosis, effects of radiation exposure, toxicosis caused by the use of immunosuppressive monoclonal antibodies, such as OKTZ or SAMRATH-1 and hyperoxic al veolyarnye injury.

 Since the formation of excess TNF has been noted in the case of certain diseases also characterized by tissue destruction caused by MMP, compounds that inhibit the formation of MMP and TNF can have particular advantages in the treatment or prevention of diseases or conditions in the development of which both mechanisms are involved.

 Recently, a class of hydroxamic acid-based MMP inhibitors, which are also active in inhibiting the formation of TNF, was described in WO 93/20047.

 As indicated above, MMP inhibitors with zinc-binding hydroxamic and carboxylic acid groups have been proposed. The following patent documents describe hydroxamic acid-based MMP inhibitors: US 459361 (Searie), EP-A-0236872 (Roche), EP-A-0274453 (Bellon), WO 90/05716 (British Bio-technology), WO 90 / 05719 (British Bio-technology), WO 91/02716 (British Bio-technology), EP-A-0489577 (Celltech), EP-A-0489579 (Celltech), EP-A-0497192 (Roche), WO 92/13831 (British Bio-technology), WO 92/17460 (SmithKIine Beecham), WO 92/22523 (Research Corporation Technologies), WO 93/09090 (Yamanouchi), WO 93/09097 (Sankyo), WO 93/20047 (British Bio- technology) WO 93/24449 (Celltech), WO 93/24475 (Celltech), EP-A-0574758 (Roche).

The following publications describe carboxylic acid-based MMP inhibitors:
EP-A-0489577 (Celltech), EP-A-0489579 (Celltech), WO 93/24449 (Celltech), WO 93/24475 (Celltech).

The present invention is based on the discovery that in the compounds of formula (I) above, wherein X is a hydroxamic or carboxylic acid group, an aromatic or heteroaryl substituent R ₄ has a generally unexpected and beneficial effect on the increase in activity with respect to stromelysin compared with compounds of a similar structure, but with the usual substituents R ₄ , while maintaining activity against collagenase and gelatinase. This pattern leads to the production of compounds that are inhibitors of known broad-spectrum metalloproteinases. The class of compounds according to this invention also includes compounds in which the ability to inhibit the formation of TNF is improved compared with compounds of a similar structure, but with the usual substituents R ₄ . This class also includes compounds administered orally.

In general, metalloproteinase inhibitors known to have good activity against stromeliain are those such as BB-94 (WO 90/05719, Example 2) which contain relatively large substituents R ₁ . However, BB-94 and compounds with large R ₁ substituents are less bioavailable when administered orally than compounds with less R ₁ substituents or without them. A particular advantage of the compounds of this invention is that the combination of aromatic or heteroaryl R ₄ substituents with or without small R ₁ substituents can provide oral activity along with a wide spectrum of activity against metalloproteinases, including good activity against stromelysin.

The prior art does not describe the role of aromatic or - heteroaryl R ₄ substituents in increasing the activity of pseudopeptide or mimetic MMP inhibitors based on hydroxamic or carboxylic acids against stromelysin. Of the publications related to hydroxamic acid-based MMP inhibitors mentioned above, only WO 93/09097 (Sakyo) refers to the possibility of having a phenyl group in a relevant position. When describing structurally different MMP inhibitors with zinc binding phosphinic acid groups, WO 93/14112 (Merck) indicates compounds with certain aryl groups in an equivalent position. In no case is there any mention of the role of this group in the full structure / activity relationship of the described compounds. In the field of analogues of natural peptides, the Chapmam et al. Publication cited above discloses that aryls at the position corresponding to the R ₄ position in the compounds of this invention were found to be preferred in terms of activity against stromelysin. WO 92/21360 (Merck) also describes analogues of natural peptides containing certain aryl groups at the position corresponding to the position of R ₄ in the compounds of the invention. However, it is not known that the structure / activity relationship occurring in the field of MMP inhibitors that are analogues of natural peptides will be the same in the field of pseudo-peptide or mimetic peptide MMP inhibitors to which this invention relates.

где X означает -CO₂H или -CONHOH, R₁ означает водород, метокси, C₁-C₆-алкил, C₂-C₆-алкенил, фенил /C₁- C₆/ алкил, или группу BSO_nA-, где n равен 0 или 1, и B означает 5- или 6-членное гетероциклическое кольцо, содержащее в качестве гетероатома серу или азот, и A означает - CH₂ -;
R₂ означает /C₁- C₆/ алкил или фенил-/C₁-C₆/алкил;
R₃ означает трет-бутил, 1-6ензилтио-1-метилэт-1-ил или отличительная боковая цепь аланина, валина, лейцина или фенилаланина;
R₄ означает фенил или 5 - или 6 -членное гетероциклическое кольцо, содержащее в качестве гетероатома серу или азот, причем любой атом азота может быть окислен до N-окиси, которое может быть конденсированным с бензольным кольцом или 5-, 6 - или 7 - членным гетероциклическим кольцом, причем любое кольцо может быть замещено
а/ одним или несколькими заместителями, независимо друг от друга выбранными из гидроксила, галогена, -CO₂H, - CO₂/C₁-C₆/ алкила, или
б/ группой, состоящей из /C₁-C₆/ алкила и фенила;
R₅ означает водород или /C₁-C₆/ алкил;
или его соль, гидрат или сольват, при том, что R₄ не является 2-пиридил или 2-тиазолил когда R₁ - водород, R₂ - n-пентил, R₃ - изопропил и R₅ - водород.This invention relates to compounds of the general formula I

where X is —CO ₂ H or —CONHOH, R ₁ is hydrogen, methoxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, phenyl / C ₁ –C ₆ / alkyl, or a BSO _n A- group where n is 0 or 1, and B is a 5- or 6-membered heterocyclic ring containing sulfur or nitrogen as the heteroatom, and A is —CH ₂ -;
R ₂ means / C ₁ -C ₆ / alkyl or phenyl- / C ₁ -C ₆ / alkyl;
R ₃ means tert-butyl, 1-6 benzylthio-1-methyleth-1-yl or the distinctive side chain of alanine, valine, leucine or phenylalanine;
R ₄ means phenyl or a 5- or 6-membered heterocyclic ring containing sulfur or nitrogen as a heteroatom, and any nitrogen atom can be oxidized to N-oxide, which can be fused to a benzene ring or 5-, 6 - or 7 - heterocyclic ring member, wherein any ring may be substituted
a) by one or more substituents independently selected from hydroxyl, halogen, —CO ₂ H, —CO ₂ / C ₁ -C ₆ / alkyl, or
b) a group consisting of / C ₁ -C ₆ / alkyl and phenyl;
R ₅ means hydrogen or / C ₁ -C ₆ / alkyl;
or a salt, hydrate or solvate thereof, wherein R _{4 is} not 2-pyridyl or 2-thiazolyl when R ₁ is hydrogen, R ₂ is n-pentyl, R ₃ is isopropyl and R ₅ is hydrogen.

As used herein, the term “(C ₁ -C ₆ ) alkyl” or “lower alkyl” means a linear or branched alkyl containing from 1 to 6 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec. butyl, tert-butyl, pentyl and hexyl.

The term "(C ₁ -C ₆ ) alkenyl" means a linear or branched alkenyl containing from 2 to 6 carbon atoms and containing in addition one double bond of E or Z-stereochemistry, where possible. This term includes, for example, vinyl, 1 propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.

 The term "cycloalkyl" means a saturated acyclic radical containing 3-8 carbon atoms, and includes, for example, cyclohexyl, cyclooctyl, cycloheptyl, cyclopeptyl, cyclobutyl and cyclopropyl.

 The term “cycloalkenyl” means a saturated acyclic radical containing 3-8 carbon atoms, and includes, for example, cyclohexenyl, cyclooctenyl, cycloheptenyl, cyclopentenyl, cyclobutenyl and cyclopropenyl. In the case of cycloalkenyl rings with 5-8 carbon atoms, the ring may contain more than one double bond.

 The term “heterocyclyl” or “heterocyclic” means (i) a 5-7 membered heterocyclic ring containing one or more heteroatoms selected from S, N and O, and optionally fused to a benzene ring, including, for example, pyrrolyl, furyl , thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinide, pyrimidinyl, morpholinyl, piperazinyl, indolyl, benzimidazolyl, maleimido, succinimido, phthalimido, 1,2-dimethyl-3,5-1,2-dimethyl-1,2 triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl and 3,4,4-trimethyl-2,5-dioxo-1-imidazolidini l, or (ii) naphthalimido (namely, 1,3-dihydro-1,3-dioxo-2H-benz [f] isoindol-2-yl), 1,3-dihydro-1-oxo-2H-benz [f ] isoindol-2-yl), 1,3-dihydro-1,3-dioxo-2H-pyrrolo [3,4-b] quinolin-2-yl, or 2,3-dihydro-1,3-dioxo-1H - benz [d, e] isoquinilin-2-yl.

 The term “5- or 6-membered heterocyclic ring” means such rings containing 5 or 6 atoms in a ring in which the heteroatom (s) may be one or more nitrogen, oxygen or sulfur atoms, and includes heterocycles containing nitrogen, oxygen or sulfur alone or containing two nitrogen atoms, nitrogen and oxygen atoms, nitrogen and sulfur atoms, two nitrogen atoms and an oxygen atom, two nitrogen atoms and one sulfur atom.

 “Heteroaryl” means a 5-7 membered substituted or unsubstituted aromatic heterocycle containing one or more heteroatoms. Examples of such cycles are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

Unless otherwise specified, the term "substituted" in the appendix to any substituent means substituted by 1 to 4 substituents, each of which independently may be (C ₁ -C ₆ ) alkoxy, hydroxy, mercapto, (C ₁ -C ₆ ) alkylthio, amino, halogen (including fluorine, chlorine, bromine and iodine), trifluoromethyl, nitro, —COOH, —CONH ₂ or —CONHR ^A where R ^A is (C ₁ -C ₆ ) alkyl or a residue of a natural alpha amino acid.

The term “distinctive natural alpha amino acid side chain” means a side chain attached to —CH (NH ₂ ) (COOH) in the following amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine , methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid.

Natural amino acids that contain functional substituents, for example, amino, carboxyl, hydroxyl, mercapto, gaunidyl, imidazolyl or indolyl groups in their distinctive side chains, include arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine tyrosine and cysteine. When R ₃ in the compounds of the invention is one of these side chains, the functional substituent may be protected.

 The term "protected" in relation to a functional substituent in the side chain of a natural alpha amino acid means a derivative of such a substituent that is not functional. In this context, protected amino groups include amido and acylamino, protected hydroxyl and mercapto groups include ether and thioether, protected carboxyl groups include ester, and imidazolyl, indolyl or guanidyl groups can be protected as tert-butoxycarbonyl. These are just examples of many protecting derivatives, the rest are obvious to a specialist.

 Salts of the compounds of the invention include physiologically acceptable addition salts, for example, hydrochlorides, hydrobromides, sulfates, methanesulfonates, n-toluenesulfonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts can be prepared by reaction with bases, for example, sodium, potassium, magnesium and calcium salts.

 In the compounds of the invention, there are several chiral centers due to the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms leads to the formation of a number of diastereomers with R or S stereochemistry at each chiral center. It should be borne in mind that the general formula (I) and (unless otherwise specified) all other formulas in this description include all such stereoisomers and mixtures thereof (for example, racemic mixtures).

The following stereochemistry is generally preferred in the compounds of the invention: a carbon atom containing R ₁ and X-S, a carbon atom containing R ₂ - R, a carbon atom containing R ₃ - S, but this also includes mixtures in which the above configurations dominate .

As indicated above, the compounds of the invention are fundamentally different from the compounds described in the patent documents mentioned above with the meaning of the substituent R ₄ . Accordingly, the groups R ₁ , R ₂ , R ₃ and R ₅ may be any that are present in the corresponding positions of the compounds described in any of the above patent documents. Without limiting the generalization of the following possibilities, the following classes of R ₃ substituents suitable for the compounds of the present invention have been described in known publications: (C ₁ -C ₆ ) alkyl, benzyl, hydroxybenzyl, benzyloxybenzyl, (C ₁ -C ₆ ) alkoxybenzyl, or benzyloxy (C ₁ -C ₆ ) alkyl; and a different group of the natural alpha amino acid in which any functional group can be protected, wherein any amino group can be acylated and any carboxy group present can be amidated, and the group is [Alk] _n R ₆ , where Alk is (C ₁ - C ₆ ) alkyl or (C ₁ -C ₆ ) alkenyl, which may contain one or more —O— or —S— or —N (R ₇ ) -group atoms in the chain [where R ₇ is a hydrogen atom or (C ₁ -C ₆ ) alkyl], n is 0 or 1; and R ₆ is unsubstituted or substituted cycloalkyl or cycloalkenyl; and a benzyl group substituted on the phenyl ring with a group of the formula —OCH ₂ COR ₈ , where R ₈ is hydroxyl, amino, (C ₁ -C ₆ ) alkoxy, phenyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkylamino, di [(C ₁ -C ₆ ) alkyl] amino, phenyl (C ₁ -C ₆ ) alkylamino, an amino acid or halide, ester or amide residue, said residue being linked via an amide bond, said amino acid is selected from glycine, α - or β-alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, argi ina, glutamic acid and aspartic acid; and a heterocyclic (C ₁ -C ₆ ) alkyl group unsubstituted or mono- or disubstituted in the heterocyclic ring with halogen, nitro, carboxy, (C ₁ -C ₆ ) alkoxy, cyan, (C ₁ -C ₆ ) alkanoyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, hydroxy, formyl, amino, (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) alkylamino, mercapto, (C ₁ -C ₆ ) alkylthio, hydroxy (C ₁ -C ₆ ) alkyl, mercapto (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkylphenylmethyl; R ₃ may also mean a —CR _a R _b R _c group in which: each of R _a , R _b , and R _c independently means hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, phenyl (C ₁ -C ₆ ) alkyl, (C ₃ -C ₈ ) -cycloalkyl, all of the above, provided that R _a , R _b , and R _c are not simultaneously hydrogen; or R _c is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₆ ) alkynyl, phenyl (C ₁ -C ₆ ) alkyl or (C ₃ -C ₈ ) β-cycloalkyl, and R _a and R _b, together with the carbon atom to which they are attached, form a 3-8 membered cycloalkyl or a 5-6 membered heterocyclic ring; or R _a , R _b , and R _c, together with the carbon atom to which they are attached, form a tricyclic ring (for example, adamantyl); or R _a and R _b each independently mean (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl,
phenyl (C ₁ -C ₆ ) alkyl, or the group indicated below for R _c , except hydrogen, or R _a and R _b together with the carbon atom to which they are attached form a 3-8-membered cycloalkyl or 5-6- heterocyclic membered ring, and R _c is hydrogen, —OH, —SH, halogen, —CN, —CO ₂ H, (C ₁ –C ₄ ) perfluoroalkyl, —CH ₂ OH, —CO ₂ (C ₁ –C ₆ ) alkyl, -O (C ₁ -C ₆ ) alkyl, -O (C ₂ -C ₆ ) alkenyl, -S (C ₁ -C ₆ ) alkyl,
-SO (C ₁ -C ₆ ) alkyl, -SO ₂ (C ₁ -C ₆ ) alkyl, -S (C ₂ -C ₆ ) alkenyl, -SO (C ₂ -C ₆ ) alkenyl,
-SO ₂ (C ₂ -C ₆ ) alkenyl or a group -QW, where Q is a bond or -O-, -S-, -SO- or -SO ₂ - and W is phenyl, phenylalkyl, (C ₃ -C ₈ ) -cycloalkyl, (C ₃ -C ₈ ) -cycloalkylalkyl, (C ₄ -C ₈ ) -cycloalkenyl, (C ₄ -C ₈ ) -cycloalkenylalkyl,
heteroaryl or heteroarylalkyl, wherein W may be substituted with one or more substituents independently selected from hydroxyl, halogen, —CN, —CO ₂ H, —CO ₂ (C ₁ –C ₆ ) alkyl, —CONH ₂ , —CONH (C ₁ -C ₆ ) alkyl, -CON (C ₁ -C ₆ alkyl) ₂ , -CHO, -CH ₂ OH, (C ₁ -C ₄ ) perfluoroalkyl, -O (C ₁ -C ₆ ) alkyl, -S (C ₁ -C ₆ ) alkyl, -SO (C ₁ -C ₆ ) alkyl, -SO ₂ (C ₁ -C ₆ ) alkyl, -NO ₂ , -NH ₂ , -NH (C ₁ -C ₆ ) alkyl, - N (C ₁ -C ₆ alkyl) ₂ , - NHCO (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, ( C ₃ -C ₈ cycloalkyl, (C ₄ -C ₈ ) -cycloalkenyl, phenyl or benzyl More specifically, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ in the compounds of the invention may take the following values.

Examples of specific R ₁ include hydrogen, methyl, ethyl, hydroxyl, allyl, thienylsulfanylmethyl, thienylsulfinylmethyl, tisnylsulfonylmethyl and phthalimidomethyl. Compounds in which R ₁ is hydrogen, hydroxyl, allyl or phthalimidomethyl are preferred.

Examples of specific R ₂ include isobutyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, diclohexylpropyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, phenylbutyl, propyloxymethyl and propylsulfanyl. Preferred are compounds in which R ₂ is isobutyl, n-heptyl or phenylpropyl.

Examples of specific R ₃ include benzyl, isobutyl or tert-butyl, 1-benzylthio-1-methylethyl and 1-mercapto-1-methylethyl. Compounds in which R ₃ is tert-butyl or 1-mercapto-1-methylethyl are preferred.

Examples of R ₄ include phenyl, which may be substituted, naphthyl, furanyl, thienyl, pyrroinyl, tetrahydrofuranyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyridinyl-N-oxides, piperazinyl, indolyl, benzimidazolyl, pyridazinyl, pyridazinyl , dithianil, benzo [b] thienyl, isoxazolyl or quinolinyl. Examples of specific R ₄ include phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 , 4-dichlorophenyl, 3,5-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4 dimethylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, 4-tert-butyl-2,6-dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3 -cyanophenyl, 4-dianophenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-methylsulfo nylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-N, N-dimethyl N, N-dimethylaminophenyl, 4-N, N-dimethylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-naphthyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, tetrahydrofuran- 2-yl, imidazol-2-yl, thiazol-2-yl, 4-ethoxycarbonylmethylthiazol-2-yl, 4-phenylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-tert-butylthiazol-2-yl, benzothiazol-2-yl, 1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4- xadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2, 4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2- yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxides of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperazin-1-yl, indol-2 -yl, benzimidazol-2-yl, benzotriazol-2-yl, pyrazin-2-yl, 1,2-pyridazin-3-yl, 1,3-pyrimidin-5-yl, 1,3-dithian-2-yl benzo [b] thien-2-yl, isoxazol-5-yl, quinolin-3-yl. In general, compounds in which R ₄ is thiazolyl or substituted thiazolyl are preferred in their activity to inhibit the release of TNF. Compounds in which R ₄ is phenyl, 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl and thiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, are preferred, 4-ethoxycarbonylmethylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 4- tert-bugylthiazol-2-yl. Compounds in which R ₄ is 3-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, thiazol-2-yl, 4-ethoxycarbonylmethylthiaol-2-yl, 5-methyl-1,3,4-thiadiazole are particularly preferred -2-yl and 4-tert-butylthiazol-2-yl.

Examples of specific R ₅ include hydrogen, methyl and ethyl. Compounds in which R ₅ is hydrogen are preferred.

 The compounds of this invention that are preferred due to the combination of high activity and good oral bioavailability are: 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2- il-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoylpropylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (5-methyl-1, 3,4-thiadiazol-2-ylcarbamoyl) propyl-carbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (3-methoxyphenyl) carbamoyl-propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-dimethyl-1S-pyridin-3-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid and 3R- (2,2-dimethyl-1S-pyridine -2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanohydroxamic acid, and their salts, solvates and hydrates.

 Compounds of this invention that are preferred in their activity to inhibit the release of TNF: 3R- (2,2-Dimethyl-1S- (thiazol-2-ylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (thiazol-2-ylcarbamoyl) propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid and 3R- (2,2-dimethyl-1S- (4-ethoxycarbonylmethylthiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, and their salts, solvates or hydrates thereof.

Further, specific compounds of the invention: 5-methyl-ZR- (2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl) hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) - 5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 2 Hydroxy-3R- (3-methyl-15-naphth-2-ylcarbamoylbutylcarbamoyl) -5-methylhexanohydroxamic acid, 2S-Hydroxy-3R- (3-methyl-1S- (4-methoxyphenyl) carbamoylbut lcarbamoyl) -5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (4-tert-butyl-2,6-dimethylphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2 , 2-Dimethyl-1S- (4-methoxyphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-pyridin-4-ylcarbamoyl-propylcarbamoyl) 5-methylhexanohydroxamic acid,
3R- (2,2-Dimethyl-1S- (4-hydroxyphenyl) carbamoyl-propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid,
3R- (2-Benzylthio-2-methyl-1S-pyridin-2-ylcarbamoyl) propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy -5-phenylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (4,5-dimethylthiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl- 1S- (5-bromothiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, - 3R- (2,2-Dimethyl-1S- (4-phenylthiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S -hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-dim ethyl-1S- (4-tert-butylthiadiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -5-methyl-2S- propene-2-yl-hexanohydroxamic acid, 3R- (2,2-dimethyl-1S- (4-methoxyphenylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2-benzylthio -2-methyl-1S- (pyridin-2-ylcarbamoyl) propyl-carbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridin-3- ilcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dime yl-1S- (4-hydroxyphenylcarbamoyl) propylcarbamoyl) - 5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (3-methoxyphenylcarbamoyl) -propylcarbamoyl) -5- methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridin-4-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R - (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl) - 5-methyl-2S-thien-2-ylsulfanylmethyl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridin-2- ilkarbamoyl) -propylcarbamoyl) -5- methyl-2S-thien-2-yl sulfanylmethyl-hexanohydroxy acid a, 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl) - 5-methyl-2S-thien-2-ylsulfinylmethyl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridine -2-ylcarbamoyl) -propylcarbamoyl) -5- methyl-2S-thien-2-yl-sulfinylmethyl-hexanohydrocamic acid, 3R- (2,2-dimethyl-1S-phenylcarbamoyl-propylcarbamoyl-5-hydroxy-methyl-2-hydroxy-methyl-2-hydroxy - (2,2-Dimethyl-1S- (N-hydroxypyridin-2-yl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, and their salts, solvates or hydrates.

или ее активированного производного с гидроксиламином, O- защищенным гидроксиламином или N,O-дизамещенным гидроксиламином или его солью, при этом R₁, R₂, R₃, R₄ и R₅ означают радикалы, указанные для общей формулы (I), за исключением того, что любые из заместителей в R₁, R₂, R₃, R₄ и R₅, который потенциально способен к реакции с гидроксиламином, O-защищенным гидроксиламином или N,O- дизамещенным гидроксиламином или их солями, могут сами быть защищены от такой реакции с последующим удалением любых защищающих групп из фрагментов образующейся гидроксамовой кислоты и из любых защищенных заместителей в R₁, R₂, R₃, R₄ и R₅ или
(b) разблокирование дизамещенного производного гидроксамовой кислоты формулы

где R₁, R₂, R₃, R₄ и R₅ имеют значения, указанные для общей формулы (I), R₁₄, означает группу, защищающую аминогруппу и R₁₅ означает группу", защищающую гидроксильную группу.Compounds of the invention in which X is a hydroxamic acid group —CONHOH may be prepared from the corresponding compounds of the invention in which X is a —COOH carboxyl group or from the corresponding protected hydroxamic acid derivatives. This method, forming another aspect of the invention, includes:
(a) the implementation of the interaction of the acids of General formula II

or an activated derivative thereof with hydroxylamine, O-protected hydroxylamine or N, O-disubstituted hydroxylamine or a salt thereof, wherein R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} the radicals indicated for the general formula (I), with the exception that any of the substituents in R ₁ , R ₂ , R ₃ , R ₄ and R ₅ , which is potentially capable of reacting with hydroxylamine, O-protected hydroxylamine or N, O-disubstituted hydroxylamine or their salts, may themselves be protected from such a reaction, followed by the removal of any protecting groups from fragments of the resulting hydroxides hydrochloric acid and from any protected substituents in R ₁ , R ₂ , R ₃ , R ₄ and R ₅ or
(b) unlocking the disubstituted hydroxamic acid derivative of the formula

where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the meanings indicated for the general formula (I), R ₁₄ means an amino protecting group and R ₁₅ means a hydroxyl protecting group.

 In method (a), the conversion of (II) into an activated derivative, for example, pentafluorophenyl, hydroxysuccinyl or hydroxybenzotriazoline ether, can be carried out by reacting with the corresponding alcohol in the presence of a dehydrating agent, for example, dicyclohexyl dicarbodiimide (DCC), N, N-dimethylaminopropyl-N'- ethyl carbodiimide (EDC) or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).

 The protecting (blocking) groups mentioned above are well known per se, for example, from peptide chemistry. Amino groups are often blocked by benzyloxycarbonyl, tert-butoxycarbonyl or acetyl groups, or as a phthalimide group. Hydroxyl groups are often blocked in the form of easily cleavable ethers, for example, tert-butyl or benzyl ether, or as easily cleavable esters, for example, acetates. Carboxyl groups are often blocked in the form of readily cleavable esters, for example tert-butyl or benzyl esters.

 Examples of O-protected hydroxylamines used in method (a) include O-benzylhydroxylamine, O-4-methoxybenzylhydroxylamine, O-trimethylsilyl hydroxylamine, and O-tert-butoxycarbonylhydroxylamine.

 Examples of ON-disubstituted hydroxylamines for use in method (a) include N, O-bis (benzyl) hydroxylamine, N, O-bis (4-methoxybenzyl) hydroxylamine, N-tert-butoxycarbonyl-O-tert-butyldimethylsilyl-hydroxylamine, N-tert-butoxycarbonyl-O- tetrahydropyranylhydroxylamine; and N, O-bis (tert-butoxycarbonyl) hydroxylamine.

For method (b), suitable blocking groups R ₁₄ and R ₁₅ are benzyl or substituted benzyl (e.g. 4-methoxybenzyl). Such blocking groups can be removed by hydrogenolysis, while the 4-methoxybenzyl group can also be removed by acid hydrolysis.

где группы R₁₂ и R₁₃ образованы из реагента, дающего диоксалон, и могут быть, например, водородом, алкилом, фенилом или замещенным фенилом. Диоксалоновое кольцо раскрывается при реакции с гидроксиламином с образованием требующего производного гидроксамовой кислоты формулы (I).In method (a), in the case where R ₁ in compound (I) is hydroxy, a particularly suitable method may be the reaction of hydroxylamine with a dioxalon of formula IIa

where the groups R ₁₂ and R _{13 are} formed from a reactant giving dioxalon, and may be, for example, hydrogen, alkyl, phenyl or substituted phenyl. The dioxalonic ring opens by reaction with hydroxylamine to form the hydroxamic acid derivative of formula (I), which is required.

где R₁, R₂, R₃, R₄ и R₅ указаны в случае общей формулы (I), за исключением того, что любые заместители в R₁, R₂, R₃, R₄ и R₅, которые потенциально являются реакционноспособными в реакции сочетания, могут сами быть блокированы от такой реакции, и R₁₁ означает группу, блокирующую гидроксильную группу, с последующим удалением блокирующей группы R₁₁ и любых блокирующих групп из R₁, R₂, R₃, R₄ и R₅.Compounds of this invention in which X is a —COOH carboxyl group can be prepared by a process comprising: combining an acid of formula III or an activated derivative thereof with an amine of formula IV

where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are indicated in the case of the general formula (I), except that any substituents in R ₁ , R ₂ , R ₃ , R ₄ and R ₅ that are potentially reactive in the coupling reaction can themselves be blocked from such a reaction, and R ₁₁ means a group that blocks a hydroxyl group, followed by removal of the blocking group R ₁₁ and any blocking groups from R ₁ , R ₂ , R ₃ , R ₄ and R ₅ .

где R₁, R₂, R₃, R₄ и R₅ указаны для общей формулы (I), за исключением того, что любые заместители в R₁, R₂, R₃, R₄ и R₅, которые являются потенциально реакционноспособными в реакции сочетания, могут сами быть блокированы от такой реакции, R₁₄ означает группу, блокирующую аминогруппу и R₁₅ означает группу, блокирующую гидроксильную группу, как указано в отношении формулы (llb) выше, с последующим удалением любых блокирующих групп из R₁, R₂, R₃, R₄ и R₅.Compounds of formula (IIb) can be prepared by a process comprising: reacting an acid of formula IIIa or an activated derivative thereof with an amine of formula IV

where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are indicated for the general formula (I), except that any substituents in R ₁ , R ₂ , R ₃ , R ₄ and R ₅ that are potentially reactive in a coupling reaction, they themselves can be blocked from such a reaction, R ₁₄ means a group blocking an amino group and R ₁₅ means a group blocking a hydroxyl group as indicated in relation to formula (llb) above, followed by the removal of any blocking groups from R ₁ , R ₂ , R ₃ , R ₄ and R ₅ .

Active derivatives of acids (III) and (IlIa) include activated pentafluorophenyl ether, acid anhydrides and acid halides, for example, acid chlorides. Suitable hydroxyl group R ₁₁ groups may be selected from those known in the art.

 The intermediate amines of formula (IV) are either known compounds, or can be obtained from known amino acids using standard methods and by analogy with the specific examples given here.

где группы R₁₂ и R₁₃ образованы из реагента, образующего диоксалон и могут означать, например, водород, алкил, фенил или замещенный фенил.In the special case, when R ₁ in the compound (III) or (IlIa) means hydroxy, the latter can also be blocked during the combination reaction of the compounds (III) or (IlIa) and (IV). In the case where R ₁ means a hydroxyl group in compound (III), a particularly suitable technique is to simultaneously protect two hydroxyl groups as in dioxalone V

where the groups R ₁₂ and R _{13 are} formed from a reagent forming dioxalon and may mean, for example, hydrogen, alkyl, phenyl or substituted phenyl.

 As mentioned above, the compounds of formula (I) are useful in medicine and veterinary medicine, since they exhibit inhibitory activity against MMPs and an additional advantage lies in their ability to inhibit the release of necrosis factor neoplasia factor (TNF) from cells.

According to another aspect, the invention relates to:
(i) a method of treating (which means treating or preventing) diseases or conditions caused by MMP and / or TNF in mammals, in particular in humans, which comprises administering to the mammal an effective amount of a compound characterized by the formula (I) above, or pharmaceutically acceptable salts thereof; and
(ii) a compound characterized by formula (I) for use in medicine or veterinary medicine, especially in the treatment (by which is meant treatment or prophylaxis) of diseases or conditions caused by MMP and / or TNF; and
(iii) the use of a compound characterized by formula (I) for the preparation of an agent for the treatment (by which is meant treatment or prevention) of diseases or conditions caused by MMP and / or TNF.

 Diseases or conditions caused by MMPs include those associated with tissue rejection, such as bone resorption, inflammatory or neuroinflammatory diseases, dermatological conditions, growth of solid tumors and the spread of tumors in secondary metastases, and diseases associated with angiogenesis, in particular rheumatoid arthritis , osteoarthritis, periodontitis, gingivitis, the formation of corneal ulcers, the growth of solid tumors and the spread of tumors in secondary metastases, neovascular glaucoma, multiple sclerosis and psoriasis al. Diseases and conditions caused by TNF include inflammation, flu, cardiovascular disease, bleeding, coagulation and acute reactions, cachexia and anorexia, acute infections, shock conditions, transplant conditions, and autoimmune diseases.

 According to another aspect, a pharmaceutical or veterinary composition is provided comprising a compound of formula (I) together with a excipient or carrier that is pharmaceutically acceptable in veterinary medicine. This aspect of the invention encompasses a pharmaceutical or veterinary composition comprising a compound of formula (I) together with a pharmaceutically acceptable excipient or carrier in veterinary medicine, characterized in that the composition is adapted for oral administration.

 One or more compounds of formula (I) are contained in the composition, along with one or more excipients or carriers.

 The compounds of the invention may be prepared for isolation by any means in accordance with pharmacokinetic properties. Compositions for oral administration may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, local or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients, for example, binders, for example, acacia syrup, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone, excipients, for example, lactose, sugar, maize starch, calcium phosphate , sorbitol or glycine, a lubricant, for example, magnesium stearate, talc, polyethylene glycol or silicon dioxide, grinders, for example, potato starch, or acceptable wetting agents, for example, sodium lauryl sulfate. Tablets may contain a coating applied by methods well known in the pharmaceutical art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable means before use. Such liquid preparations may contain conventional additives, for example, suspending agents, for example, sorbitol, syrup, methyl cellulose, glucose syrup, hydrogenated fats, gelatin; emulsifiers, for example, lecithin, sorbitan monooleate or acacia syrup; non-aqueous agents (which may include digestible fats), for example, almond oil, fractionated coconut oil, essential oils, for example glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

 The dose used for oral administration may contain about 1-250 mg, preferably about 25-250 mg, of a compound of the invention. A suitable daily dose for a mammal can vary widely depending on the condition of the patient. However, a suitable dose of a compound of general formula (I) is about 0.1-300 mg / kg body weight, in particular about 1-100 mg / kg / body weight.

 For topical application to the skin, the medicine may be in the form of a cream, lotion or ointment. Formulations of cream or ointments containing the drug are conventional formulations well known in the art, for example, described in conventional pharmaceutical textbooks, for example, British Pharmacopoeia.

 For topical administration to the eye, the drug may be in the form of a solution or suspension in a suitable sterile aqueous or non-aqueous agent. Additives may also be administered, for example, buffers such as sodium metabisulfite or disodium edeate; preservatives, including bactericidal and fungicidal agents, for example, phenylacetate mercury or nitrate, benzalkonium chloride or chlorhexidine, and thickeners, for example, hypromellose.

 The dose for local application will, of course, depend on the size of the surface to be treated. For the eyes, each dose is usually in the range of 10 to 100 mg of the drug.

 The active ingredient can also be administered parenterally in a sterile medium. Depending on the means used and the concentration, the drug can either be suspended or dissolved in this agent. Additives, for example, local anesthetics, preservative, buffering agents, can be dissolved in this product.

 When used to treat rheumatoid arthritis, the drug can be administered orally or by intra-arterial injection into a diseased joint. The daily dose for a mammal weighing 70 kg is 10 mg - 1 g.

 The following examples illustrate the invention.

 The amino acids used in the examples are commercially available or obtained by known methods.

The following abbreviations are used in the text:
DIPE - Diisopropyl ether
DMF - N, N-Dimethylformamide
HOBt - 1-Hydroxybenzotriazole
LDA - Lithium Diisopropylamide
m-CPBA - m-chloroperbenzoic acid
NMM - N-methylmorpholine
THF - Tetrahydrofuran
TFA - Trifluoroacetic Acid
TLC - Thin layer chromatography
EDC - N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride
¹ H and ¹³ NMR spectra were recorded using a Bruker AC 250E spectrometer at 250.1 and 62.9 MHz, respectively. Elementary microanalysis was performed at CHN Analysis Ltd. (Alpha House, Countesthorpe Road, South Wigston. Leicester LE8 2PJ, UK) or Medac Ltd. (Department of Chemistry, Brunel University, Uxbridge, Middlesex UB8 3PH).

 Example 1

 5-Methyl-3R- (2-phenyl-1S-phenylcarbamoylethylcarbamoyl) hexanohydroxamic acid.

Стадия A. N-(4-Метилпентаноил)-4S-фенилметил-оксазолидин-2-он.

Step A. N- (4-Methylpentanoyl) -4S-phenylmethyl-oxazolidin-2-one.

In a 500 ml dry flask with a magnetic stirrer, 4S-phenylmethyloxazodidin-2-one (17.72 g, 100 mmol) was placed, the flask was closed with a membrane inlet (stopper from the membrane) and nitrogen was purged. 300 ml of anhydrous THF are introduced through a needle and the resulting solution is cooled to -78 ^° C with an acetone / dry ice bath. A 1.47 M solution of n-butyllithium in hexane (68.4 ml, 101 mmol) is transferred through a tube into a dry, 100 ml dropping funnel through a tube. This solution was added dropwise to the THF solution in 10 minutes.

Upon completion of the addition of n-butyllithium, 4-methylvaleric acid chloride is added immediately (in one go) using a syringe. The resulting solution was stirred for 30 minutes at -78 ^° C and then left to warm to room temperature for 30 minutes. The excess acid chloride is decomposed by adding an aqueous solution of ammonium chloride (60 ml), and the solvent is distilled off in vacuo. The resulting suspension was extracted with methylene chloride (2 x 80 ml). The combined organic extracts were washed with 1M sodium hydroxide (75 ml), brine (75 ml), dried (anhydrous sodium sulfate) and filtered. The solvent was removed and a yellow oil (29.20 g, including solvent residue) was obtained, which was directly used in Step B. ¹ H NMR; δ (CDCl ₃ ), 7.34-7-19 (5H, m), 4.73-4.63 (1H, m), 4.25-4.16 (2H, m), 3.30 (1H, dd, J = 3.3 Hz), 3.05-2.85 (2H, m), 2.78 (1H, dd, J = 9.5Hz), 1.76-1.53 (3H, m) and 0.97 (6H, d, J = 6.2 Hz).

 Step B. N- (4-tert-Butyl) -2R-isobutyl-butan-1,4-dioyl) -4S-phenylmethyl-oxazolidin-2-one.

N- (4-Methylpentanoyl) -4S-phenylmethyl-oxazolidin-2-one (20 g, 72.6 mmol) was placed in a 1 liter dry 3-necked flask and dry THF (400 ml) was added. The mixture is cooled to -78 ^o C (dry ice / acetone) in a stream of argon. Sodium bis (trimethyl) silylamide (1M solution in THF, 72.6 ml, 72.6 mmol) is added dropwise from a dropping funnel. It is stirred for 20 minutes, tert-butyl bromoacetate (21.02 g, 15.8 ml, 109 mmol) is added dropwise over 1 minute to obtain an orange solution. The mixture is kept at a temperature of -78 ^o C, heated to -50 ^o C in 2 hours (by this time it becomes pink). The mixture is decomposed with acetic acid (10.90 g, 10.4 ml; 182 mmol) in ether (50 ml) at -50 ^o C, while the solution becomes colorless. The solvent was distilled off in vacuo and the resulting suspension was extracted with ethyl acetate / brine. The ethyl acetate layer was washed with brine, and the primary brine was washed with ethyl acetate. The combined organic extracts were dried, the solvent was removed to give a yellow oil, which crystallized on cooling overnight to give the title compound as a crystalline solid (21.36 g, 76%). ¹ H NMR; δ (CDCl ₃ ), 7.38-7-24 (5H, m), 4.67 (1H, m), 4.18-4.16 (2H, m), 3.36 (1H, dd, J = 3.3 Hz), 2.72 (1H, dd , J = 2.3 Hz), 2.49 (1H, dd, J = 4.6 Hz), 1.72-1.24 (3H, m), 1.44 (9H, s) and 0.91-0.96 (6H, dd, J = 4.5 Hz). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = + 66.9 (c = 1, MeOH).

 Step C. 2R-Isobutyl-butane-1,4-diic acid 4-tert-butyl ester.

N- (4- (tert-Butyl) - 2R-isobutyl-butan-1,4-dioyl) -4S-phenylmethyl-oxazolidin-2-one (15.30 g, 39 mmol) was placed in a 1 liter flask with stirrer and a mixture of THF (600 ml) and water (150 ml) was added to it. The solution was stirred and cooled to 0 ^° C (ice / acetone), 60% aqueous hydrogen peroxide (4.5 ml, 157 mmol) was added with a syringe in 5 minutes, and then lithium hydroxide (2.65 g, 63 mmol) in 100 ml of water. The reaction mixture was stirred for 1 hour at 0 ^° C. TLC analysis (10% methanol in methylene chloride) indicated that the reaction was complete (the product gave a yellow spot at TLC, which turns green when exposed to bromcresol and heating). The reaction mixture is decomposed with sodium nitrite (10.88 g, 157 mmol), with a pH at the end of 12-13. THF was distilled off in vacuo and the aqueous layer was extracted with methylene chloride (3 x 200 ml), thereby recovering an additional chiral compound. The organic extracts were dried (anhydrous magnesium sulfate), filtered and the solvent was distilled off in vacuo, and the resulting chiral additional compound (7.05 g, 39 mmol, 100%) was recrystallized from ethyl acetate / hexane (2: 1). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = - 13.0 (c = 1, MeOH).

The aqueous layer is cooled in an ice bath and acidified to pH 5-6 with 2M hydrochloric acid. The resulting suspension was extracted with ethyl acetate (4 x 200 ml), before each extraction, adjusting the pH to 5-6. The combined organic extracts were dried with magnesium sulfate, filtered, and the solvent was distilled off to obtain the above compound as a pale yellow oil (8.21 g, 91%). ¹ H NMR; δ (CDCl ₃ ), 2.59 (1H, dd, J = 16.9 Hz), 2.38 (1H, dd, J = 16.5 Hz), 1.64 (1H, m), 1.43 (9H, s) 1.28 (1H, m), and 0.93 (6H, dd, J = 7.8 Hz). [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ = + 10.4 (c = 1, MeOH).

Stage D. N ^α - Benzyloxycarbonyl-L-phenylalanine-N-phenylamide.

N ^α- Benzyloxycarbonyl-L-phenylalanine (4.95 g, 16.5 mmol) was dissolved in methylene chloride (70 ml), the solution was cooled to 0 ^° C and stirred by adding pentafluorophenyl (3.35 g, 18.2 mmol) and then EDC (3.49 g, 18.2 mmol). The mixture was brought to room temperature and stirred overnight. The solution was washed twice with 1M sodium carbonate, twice with 1M hydrochloric acid, and finally with brine, then dried with anhydrous magnesium sulfate. The solution was filtered and evaporated to give a colorless solid, which was crystallized from ethyl acetate / hexane. Yield: 2.57 g (41%). ¹ H NMR; δ (CDCl ₃ ), 7.87 (1H, br.s), 7.43-7.03 (15H, br.m), 5.62 (1H, m), 5.08 (2H, s), 4.59 (1H, s) and 3.15 (2H, s).

 Stage E. L-phenylalanine-N-phenylamide.

N ^α - Benzyloxycarbonyl-L-phenylalanine-N-phenylamide (2.50 g, 6.68 mmol) was dissolved in ethanol (20 ml) and cyclohexane (5 ml) and 10% palladium on carbon (250 mg) was added. The mixture is boiled for 1 hour, when (according to TLC) the original disappears. The catalyst was filtered off, the solvent was evaporated, and the above compound was obtained with an admixture of ethanol residue (1.74 g). ¹ H NMR; δ (CDCI ₃ ), 7.45 (2H, m), 7.18 (7H, m), 7.04 (1H, m). 3.56 (1H, m), 3.04 (1H. Dd. J = 6.4, 13.3 Hz) and 2.85 (1H, dd, J = 7.2, 13.3 Hz).

 Step F. 5-Methyl-3R- (2-phenyl-1S-phenylcarbamoyl-ethyl-carbamoyl) -hexanoic acid tert-butyl ester.

2R-Isobutyl-butane-1,4-diic acid 4-tert-butyl ester (1.17 g, 5.11 mmol) obtained by the procedure described in Step C was dissolved in DMF (30 ml) and the solution was cooled in an ice bath. HOBt (0.76 g, 5.62 mmol) and EDC (1.07 g, 5.62 mmol) are added and the reaction mixture is stirred at 0 ^° C. for 90 minutes and at room temperature for 30 minutes. The mixture was again cooled to 0 ^° C., L-phenylalanine-N-phenylamide (1.60 g, 6.65 mmol) was added, brought to room temperature and stirred overnight. TLC analysis showed that all of the original reacted. The solvent is distilled off, the residue is dissolved in ether and washed with water, 1M sodium carbonate, 1M hydrochloric acid and brine. The organic layer was dried (anhydrous magnesium sulfate), filtered and evaporated; get a white solid with a grayish tint. Recrystallization from ethyl acetate / hexane afforded the title compound (1.23 g, 53%). ¹ H NMR; δ (CDCl ₃ ), 8.16 (1H, s), 7.39 (2H, m), 7.28 (7H, m), 7.08 (1H, m), 6.53 (1H, d, J = 7.7 Hz), 4.82 (1H, dd. J = 7.2, 14.5 Hz) 3.56 (7H, m), 3.22 (2H, m), 2.66 (1H, m), 2.52 (1H, dd, J = 8.5, 16.4 Hz), 2.37 ( 1H, dd, J = 4.9, 16.4 Hz), 1.45 (2H, m), 1.34 (9H, s), 1.20 (1H, m), 0.86 (3H, d, J = 6.4 Hz) and 0.81 (3H d, J = 6.2 Hz).

 Step G. 5-Methyl-3R- (2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl-hexanoic acid.

5-Methyl-3R- (2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl) - hexanoic acid tert-butyl ester (1.22 g, 2.70 mmol) was dissolved in methylene chloride (7.5 ml) and TFA (7.5 ml) and the solution was left overnight at 4 ^o C. The solvent is distilled off in vacuo, the residue is dissolved in ethyl acetate and washed twice with water to remove residual TFA. The organic layer was dried (anhydrous magnesium sulfate), filtered and evaporated to give a foam (1.07 g, including solvent residue). ¹ H NMR; δ (CD ₃ OD), 7.41 (2H, m), 7.18 (7H, m), 7.02 (1H, m), 4.70 (1H, dd, J = 7.0, 8.1 Hz) 3.56 (7H, m), 3.17 ( 1H, dd, J = 7.0, 13.7 Hz), 3.03 (1H, dd, J = 8.1, 13.7 Hz), 2.76 (1H, m), 2.44 (1H, dts, J = 8.4, 16.5 Hz), 2.28 (1H , dd, J = 5.9, 16.5 Hz), 1.40 (2H, m), 1.21 (1H, m), 0.83 (3H, d, J = 6.3 Hz) and 0.76 (3H, d, J = 6.2 Hz) .

 Step H. O-Benzyl-5-methyl-3R- (2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl) -hexanohydroxanate.

5-Methyl-3R- (2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl) - hexanoic acid (1.00 g, 2.52 mmol) was dissolved in DMF (5 ml) and cooled to 0 ^° C in an ice bath. Add HOBt (0.41 g, 3.03 mmol), EDC (0.58 g, 3.03 mmol) and NMM; the mixture is stirred for 1 hour at 0 ^o C and 2 hours at room temperature. The mixture was again cooled to 0 ^° C. and O-benzylhydroxylamine (0.47 g, 3.78 mmol) was added, brought to room temperature and stirred overnight. The solvent was evaporated in vacuo to give an oil, which crystallized upon stirring in diethyl ether with water. Triturated with ethyl acetate to give the desired product (0.63 g, 50%), which is used in Step 1 without further purification. ¹ H NMR; δ (CD ₃ OD), 7.45 (2H, m), 7.38 - 7.08 (12H, m), 7.04 (1H, m), 4.76 (2H, m), 4.69 (1H, m), 3.19 (1H, dd, J = 6.7, 13.8 Hz), 3.00 (1H, dd, J = 8.6, 13.8 Hz), 2.75 (1H, m), 2.16 (1H, dd, J = 8.0, 14.5 Hz), 2.02 (1H, dd, J = 6.7, 14.5 Hz), 1.38 (2H, m), 1.18 (1H, m), 0.81 (3H, d, J = 6.3 Hz) and 0.75 (3H, d, J = 6.2 Hz).

 Stage I. 5-Methyl-3R- (2-phenyl-1S-phenylcarbamoylethylcarbamoyl) -hexanohydroxamic acid.

Hydrogen was passed through a suspension of O-beneyl-5-methyl-3R- (2-phenyl-1S-phenylcarbamoylethylcarbamoyl) -hexanohydroxanate (0.62 g, 1.23 mmol) and 10% palladium on carbon (0.12 g) in ethanol (30 ml) for 90 minutes there is no initial (TLC analysis). The catalyst was filtered off and the filtrate was evaporated to give a white (colorless) solid. Recrystallization from ethanol-ethyl acetate gave the title compound (0.37 g, 73%). T. pl. 183-184 ^° C. ¹ H NMR; δ (CD ₃ OD), 7.45 (2H, m), 7.20 (7H, m), 7.05 (1H, m), 4.70 (1H, dd, J = 7.0, 8.2 Hz), 3.17 (1H, dd, J = 7.0, 13.7 Hz), 2.99 (1H, dd, J = 8.3, 13.7 Hz), 2.76 (1H, m), 2.16 (1H, dd, J = 7.4, 14.5 Hz), 2.04 (1H, dd, J = 7.2 , 14.5 Hz), 1.41 (2H, m), 0.83 (3H, d, J = 6.4 Hz) and 0.77 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ (CD ₃ OD), 177.3, 170.6, 139.3, 138.5, 130.9, 129.7, 129.5, 127.7, 125.5, 121.8, 56.8, 42.5, 42.4, 39.0, 36.9, 26.9, 23.4 and 22.4. Found: C, 65.64; H, 6.96; N, 9.91%; C ₂₀ H ₃₁ N ₃ O ₅ • 0.5H ₂ O calculated: C 65.70, H 7.19, N 9.99%.

The following additional compounds can be obtained according to the methods of Example 1:
Example 2. 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -5-methyl-hexanohydroxamic acid.

Белый порошок. Т.пл. 151-153^oC. ¹H ЯМР; δ (CD₃OD), 7.48 (2H, д, J= 7.8 Гц), 7.26 (2H, т, J=7.6 Гц), 7.05 (1H, т, J=7.3 Гц), 4.40 (1H, с), 2.95 (1H, м), 2.31 (1H, дд, J=7.8, 14.6 Гц), 2.15 (1H, дд, J=6.6, 14.6 Гц), 1.51 (2H, м), 1.20 (1H, м), 1.03 (9H, с), 0.86 (3H, д, J=6,4 Гц) и 0.81 (3H, д, J=6,4 Гц). ¹³C ЯМР; δ (CD₃OD), 177.2, 171.2, 170.6, 139.3, 129.8, 125.5, 121.6, 62.7, 42.5, 41.9, 37.1, 35.8, 27.2, 27.0, 23.5 и 22.6. Найдено: C 62.86, H 8.29, N 10.71%; C₂₀H₃₁N₃O₄•0.3H₂O вычислено: C 62.74, H 8.32, N 10.97%.

White powder. Mp 151-153 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.48 (2H, d, J = 7.8 Hz), 7.26 (2H, t, J = 7.6 Hz), 7.05 (1H, t, J = 7.3 Hz), 4.40 (1H, s), 2.95 (1H, md), 2.31 (1H, dd, J = 7.8, 14.6 Hz), 2.15 (1H, dd, J = 6.6, 14.6 Hz), 1.51 (2H, m), 1.20 (1H, m), 1.03 (9H, s), 0.86 (3H, d, J = 6.4 Hz) and 0.81 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ (CD ₃ OD), 177.2, 171.2, 170.6, 139.3, 129.8, 125.5, 121.6, 62.7, 42.5, 41.9, 37.1, 35.8, 27.2, 27.0, 23.5 and 22.6. Found: C, 62.86; H, 8.29; N, 10.71%; C ₂₀ H ₃₁ N ₃ O ₄ • 0.3H ₂ O calculated: C 62.74, H 8.32, N 10.97%.

Светло-серое твердое соединение. Т. пл. 126-126^oC. ¹H ЯМР; δ (CD₃OD), 8.26 (1H, м), 8.04 (1H, д), 7.72 (1H, дт, J=1.9, 5.5 Гц), 7.07 (1H, м), 4.47 (1H, с), 2.97 (1H, м), 2.30 (1H, дд, J=7.8, 14.5 Гц), 2.18 (1H, дд, J=6.6, 14.5 Гц), 1.51 (2H, м), 1.03 (9H, с), 0.86 (3H, д, J=6.5 Гц) и 0.80 (3H, д, J= 6,4 Гц). ¹³C ЯМР; δ (CD₃OD), 177.3, 171.6, 170.6, 152.6, 149.1, 139.5, 121.1, 115.7, 62.8, 42.5, 41.9,37.0, 35.7, 27.2, 27.0, 23.5 и 22.5. Найдено: C 60.11, H 7.90, N 14.79%; C₁₉H₃₀N₄O₄ вычислено: C 60.30, H 7.99, N 14.80%.Example 3. 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methylhexanohydroxamic acid

Light gray solid. T. pl. 126-126 ^o C. ¹ H NMR; δ (CD ₃ OD), 8.26 (1H, m), 8.04 (1H, d), 7.72 (1H, dt, J = 1.9, 5.5 Hz), 7.07 (1H, m), 4.47 (1H, s), 2.97 (1H, m), 2.30 (1H, dd, J = 7.8, 14.5 Hz), 2.18 (1H, dd, J = 6.6, 14.5 Hz), 1.51 (2H, m), 1.03 (9H, s), 0.86 ( 3H, d, J = 6.5 Hz) and 0.80 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ (CD ₃ OD), 177.3, 171.6, 170.6, 152.6, 149.1, 139.5, 121.1, 115.7, 62.8, 42.5, 41.9,37.0, 35.7, 27.2, 27.0, 23.5 and 22.5. Found: C, 60.11; H, 7.90; N, 14.79%; C ₁₉ H ₃₀ N ₄ O ₄ calculated: C 60.30, H 7.99, N 14.80%.

 Example 4. 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Стадия A. Диизопропиловый эфир 2S-гидрокси-3R-иэобутенил-бутан-1,4-диовой кислоты.

Step A. 2S-Hydroxy-3R-Ieobutenyl-butane-1,4-diic acid diisopropyl ester.

2S-Hydroxybutane-1,4-diic acid diisopropyl ester (50 g, 230 mmol) is added to the LDA solution [from N, N-diisopropylamine (80 ml, 570 mmol) and 10 M n-butyl lithium (48.1 ml, 481 mmol) ] in dry THF (500 ml), while maintaining a temperature of -70 ^o C. After completion of the addition, the reaction mixture was brought to 15 ^o C and stirred for 8 hours. The reaction mixture is cooled to -70 ^° C and metalliodide (46 g, 252 mmol) is added slowly, the temperature should not be higher than -65 ^° C. The mixture is heated to -40 ^° C and stirred for 18 hours, then decomposed with citric acid at - 15 ^o C. The organic layer is separated and washed with 10% sodium hydroxide solution (500 ml) and brine (300 ml), dried (anhydrous magnesium sulfate). The solution was filtered and evaporated in vacuo to give a brown oil (64 g), which was purified by column chromatography (silica gel, 1 kg, eluent 20 to 35% ethyl ether in hexane). The desired product is isolated as a colorless oil (30.9 g, 49%), which, as found by NMR, is a 17: 1 mixture of diastereomers. ¹ H NMR; δ (CDCl ₃ , main diastereomer), 5.06 (1H, septet, J = 6.3 Hz), 4.97 (1H, septet, J = 6.3 Hz), 4.78 (2H, d, J = 7.1 Hz), 4.16 (1H, m ), 3.20 (1H, d, J = 6.2 Hz) 3.00 (1H, m), 2.50 (1H, dd, J = 7.0, 15.5 Hz), 2.35 (1H, dd, J = 8.7, 14.4 Hz), 1.72 ( 3H, s), 1.34 (9H, s) and 1.24-1.16 (12H, 2m).

 Stage B. 2S-Hydroxy-3R-isobutyl-butane-1,4-diic acid diisopropyl ester.

2S-Hydroxy-3R-isobutenyl-butane-1,4-diic acid diisopropyl ester (7.14 g, 26.2 mmol) was dissolved in ethanol (80 ml) and stirred overnight with 10% palladium-carbon as catalyst (1.0 g) in an atmosphere of hydrogen. The catalyst was filtered off and the filtrate was evaporated to dryness to give the product as a clear oil (7.03 g, 98%). ¹ H NMR; δ (CDCl ₃ ), 5.06 (1H, septet, J = 6.3 Hz), 4.97 (1H, septet, J = 6.3 Hz), 4.17 (1H, b.s.), 3.24 (1H, b.s.) 2.83 (1H, m), 1.68 (2H, m), 1.44 (1H, m), 1.24 (6H, d, J = 6.2 Hz), 1.18 (6H, d, J = 6.2 Hz) and 0.89 (6H, m) .

 Step C. 2S-Hydroxy-3R-Ieobutyl-butane-1,4-diic acid.

2S-hydroxy-3R-isobutyl-butane-1,4-diic acid diisopropyl ester (7.0 g, 25.6 mmol) is dissolved in dioxane (15 ml) and water (15 ml), a solution of potassium hydroxide (4.29 g) in water ( 22 ml) and the mixture was heated at 90 ^° C. overnight. The solution was cooled and passed through an ion exchange resin (Dowex 50x4-400, 200 ml) and evaporated. The above compound is obtained (4.82 g, 99%). ¹ H NMR; δ (CDCl ₃ ), 8.70 (2H, br.s.), 4.32 (1H, br.s.), 3.10 (1H, m), 1.85-1.55 (3H, m) and 0.96 (6H, m).

 Stage D. 2R- (2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl) - 4-methylpentanoic acid.

2S-Hydroxy-3R-isobutyl-butane-1,4-diic acid (5.19 g, 27.3 mmol) was dissolved in 2,3-dimethoxypropane (150 ml) and DMF (40 ml) and stirred overnight at 30 ^° C. the presence of a catalytic amount of p-toluenesulfonic acid. The solvent was removed to give the above compound with an admixture of solvent (6.87 g, crude). ¹ H NMR; δ (CDCl ₃ ), 4.41 (1H, d, J = 4.8 Hz) 2.91 (1H, m), 1.69 (3H, m), 1.54 (3H, s), 1.48 (3H, s) and 0.88 (6H, m )

 Step E. 2R- (2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl) -4-methylpentanoic acid pentafluorophenyl ester.

2R- (2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl) -4-methylpentanoic acid (558 mg, 2.4 mmol) in 10 ml of methylene chloride is cooled to 0 ^o C and pentafluorophenol (670 mg, 3.6 mmol) and EDC (560 mg, 2.9 mmol). The reaction mixture was stirred for 2 hours at 0 ^° C., then the solution was washed with 1M sodium carbonate (50 ml) and brine (20 ml). The organic layer was dried (magnesium sulfate), filtered, evaporated to dryness and purified by column chromatography (silica gel, methylene chloride); receive activated ester (552 mg, 58%). ¹ H NMR; δ (CDCl ₃ ), 4.57 (1H, d, J = 6.5 Hz) 3.32 (1H, m), 1.86 (3H, m), 1.67 (3H, s), 1.58 (3H, s) and 1.03 (6H, m )

 Stage F. L-tert-Leucine-N-phenylamide.

The above compound is prepared from N-benzyloxycarbonyl-L-tert-leucine by methods similar to those described in Example 1 (Steps D and E). ¹ H NMR; δ (CDCl ₃ ), 7.53 (2H, m), 7.28 (2H, m), 7.06 (1H, m), 3.13 (1H, s) and 1.00 (9H, s).

Step G. N ² - [2R- (2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl) -4-methylpentanoyl) -L-tert-leucine-N-phenylamide.

2R- (2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl) 4-methylpentanoic acid pentafluorophenyl ester (1.72 g, 5.77 mmol) and L-tert-leucine-N-phenylamide (1.25 g, 6.06 mmol) was dissolved in DMF (150 ml) and the mixture was stirred overnight at room temperature. The solvent is removed, an oil is obtained which is dissolved in diethyl ether and the solution is washed twice with 1M sodium carbonate and then with brine. The organic layer was dried (anhydrous magnesium sulfate), filtered and evaporated to give an oil. Crystallization from ethyl acetate-hexane gave the desired product as a white solid (1.55 g, 64%). ¹ H NMR; δ (CDCl ₃ ), 8.53 (1H, s), 7.49 (2H, m), 7.26 (2H, m), 7.09 (1H, m), 7.00 (1H, d), 4.58 (1H, d), 4.52 ( 1H, d), 2.84 (1H, m), 1.78-1.47 (3H, br.m), 1.64 (3H, s), 1.54 (3H, s), 1.09 (9H, s). 0.88 (3H, d, J = 5.9 Hz) and 0.83 (3H, d, J = 6.0 Hz).

 Step H. 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Sodium methylate (0.72 g, 13.36 mmol) was added to a solution of hydroxylamine hydrochloride (0.93 g, 13.36 mmol) in methanol (10 ml) and the mixture was stirred for 2 hours at room temperature, the precipitate was filtered off. The filtrate was cooled in an ice bath, N ² - [2R- (2,2-Dimethyl-4-oxo-1,3-dioxalan-5S-yl) -4-methyl-pentanoyl) -L-tert-leucine-N was added in portions. Phenylamide (1.40 g, 3.34 mmol). The mixture was stirred at 0 ^° C. for 10 minutes, brought to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel, washed with acid, 5% methanol in methylene chloride), followed by crystallization from ethyl acetate-hexane. Yield: 0.89 g (68%), mp. 122-124 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.51 (1H, d, J = 7.8 Hz), 7.27 (2H, m), 7.06 (1H, m), 4.40 (1H, s), 4.02 (1H, d, J = 6.1 Hz ), 2.86 (1H, m), 1.64 (1H, m), 1.51 (1H, m), 1.26 (2H, m), 1.03 (9H, s), 0.89 (3H, d, J = 6.4 Hz) and 0.84 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ (CD ₃ ) ₂ SO), 172.6, 169.2, 168.8, 138.7, 128.6, 123.3, 119.3, 71.4, 60.5, 47.7, 37.3, 34.5, 26.6, 25.3, 23.5 and 21.8. Found: C, 60.08; H, 7.97; N, 10.44%; C ₁₉ H ₃₁ N ₃ O ₅ • 0.4H ₂ O calculated: C 59.95, H 8.00, N 10.49%.

Кристаллическое вещество серо-белого цвета. T. пл. 186^oC. ¹H ЯМР; δ (CD₃OD), 8.24 (0.5H, д, J=7.8 Гц), 8.15 (1H, с), 7.80-7.64 (3H, м), 7.54 (1H, ш. д, J=7.4 Гц), 7.43-7.29 (2H, м), 4.70-4.50 (1H, м), 4.03 (1H, д, J= 6.8 Гц), 2.90-2.74 (1H, м), 1.83- 1.41 (5H, м), 1.27-1.10 (1H, м), 0.95 (3H, д, J=5.2 Гц), 0.93 (3H, д, J=5.4 Гц), 0.89 (3H, д, J=6.4 Гц) и 0.82 (3H, д, J= 6,4 Гц). C ЯМР; δ (CD₃OD), 176.0, 173.3, 171.5, 161.7, 136.9, 135.1, 132.1, 129.5, 128.5, 127.4, 126.0, 121.4, 118.2, 73.1, 54.1, 54.0, 41.8, 39.1, 26.9, 25.8, 23.8, 23.6, 22.2 и 22.0. IR; v_max (KBr), 3422, 2917, 2850, 2363 и 1636.The following additional compounds are obtained in accordance with the methods of Example 4:
Example 5. 2S-Hydroxy-3R- (3-methyl-15-naphth-2-ylcarbamoyl-butylcarbamoyl) -5-methyl-hexanohydroxamic acid

The crystalline substance is gray-white. T. pl. 186 ^o C. ¹ H NMR; δ (CD ₃ OD), 8.24 (0.5H, d, J = 7.8 Hz), 8.15 (1H, s), 7.80-7.64 (3H, m), 7.54 (1H, broad d, J = 7.4 Hz), 7.43-7.29 (2H, m), 4.70-4.50 (1H, m), 4.03 (1H, d, J = 6.8 Hz), 2.90-2.74 (1H, m), 1.83- 1.41 (5H, m), 1.27- 1.10 (1H, m), 0.95 (3H, d, J = 5.2 Hz), 0.93 (3H, d, J = 5.4 Hz), 0.89 (3H, d, J = 6.4 Hz) and 0.82 (3H, d, J = 6.4 Hz). C NMR; δ (CD ₃ OD), 176.0, 173.3, 171.5, 161.7, 136.9, 135.1, 132.1, 129.5, 128.5, 127.4, 126.0, 121.4, 118.2, 73.1, 54.1, 54.0, 41.8, 39.1, 26.9, 25.8, 23.8, 23.6 , 22.2 and 22.0. IR v _max (KBr), 3422, 2917, 2850, 2363, and 1636.

 Example 6. 2S-Hydroxy-3R- (3-methyl-1S- (4-methoxyphenyl) carbamoyl-butylcarbamoyl) -5-methylhexanohydroxamic acid.

Белый порошок. Т.пл. 192^oC. ¹H ЯМР; δ (CD₃OD), 7.33 (2H, д, J=8.8 Гц), 7.30-7.10 (5H, м), 6.80 (2H, д, J=8.8 Гц), 4.67 (1H, ш. дд, J=7.4, 7.3 Гц), 4.01 (1H, д, J= 5.9 Гц), 3.72 (3H, с), 3.19 (1H, дд, J=6.3, 13.6 Гц), 3.02 (1H, дд, J= 8.1, 13.9 Гц), 2.79-2.60 (1H, м), 1.58-1.40 (1H, м), 1.20-1.06 (1H, м), 0.80 (3H, д, J= 6.5 Гц) и 0.77 (3H, д, J=6.6 Гц). ¹³C ЯМР; δ (CD₃OD), 175.6, 171.5, 158.2, 138.4, 132.1, 130.4, 129.5, 127.8, 123.6, 114.8, 72.9, 56.7, 55.8, 39.2, 39.0, 26.7, 23.8, 23.6 и 22.1. IR; v_max (KBr), 3420, 2343, 1653 и 1636 см^-1.

White powder. Mp 192 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.33 (2H, d, J = 8.8 Hz), 7.30-7.10 (5H, m), 6.80 (2H, d, J = 8.8 Hz), 4.67 (1H, br dd, J = 7.4, 7.3 Hz), 4.01 (1H, d, J = 5.9 Hz), 3.72 (3H, s), 3.19 (1H, dd, J = 6.3, 13.6 Hz), 3.02 (1H, dd, J = 8.1, 13.9 Hz), 2.79-2.60 (1H, m), 1.58-1.40 (1H, m), 1.20-1.06 (1H, m), 0.80 (3H, d, J = 6.5 Hz) and 0.77 (3H, d, J = 6.6 Hz). ¹³ C NMR; δ (CD ₃ OD), 175.6, 171.5, 158.2, 138.4, 132.1, 130.4, 129.5, 127.8, 123.6, 114.8, 72.9, 56.7, 55.8, 39.2, 39.0, 26.7, 23.8, 23.6 and 22.1. IR v _max (KBr), 3420, 2343, 1653 and 1636 cm ^-1 .

 Example 7. 3R- (2,2-Dimethyl-1S- (4-tert-butyl-2,6-dimethylphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т.пл. 209-210^oC. ¹H ЯМР; δ (CD₃OD), 7.07 (2H, с), 4.53 (1H, с), 3.98 (1H, д, J=7.2 Гц), 2.87 (1H, м), 2.16 (6H, с), 1.64 (1H, м), 1,51 (1H, м), 1.25 (9H, с), 1.16 (1H, м), 1.10 (9H, с) и 0.87 (5H, м). ¹³C ЯМР; δ (CD₃OD), 175.5, 171.8, 151.4, 136.2, 132.7, 126.2, 73.3, 62.1, 39.4, 35.6, 35.1, 31.7, 27.4, 26.9, 24.0, 22.2 и 19.3. Найдено: C 64.23, H 8.91, N 8.69%; C₂₆H₄₃N₃O₅•0.5H₂O вычислено: C 64.17, H 9.11, N 8.63%.

White solid. Mp 209-210 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.07 (2H, s), 4.53 (1H, s), 3.98 (1H, d, J = 7.2 Hz), 2.87 (1H, m), 2.16 (6H, s), 1.64 (1H , m), 1.51 (1H, m), 1.25 (9H, s), 1.16 (1H, m), 1.10 (9H, s) and 0.87 (5H, m). ¹³ C NMR; δ (CD ₃ OD), 175.5, 171.8, 151.4, 136.2, 132.7, 126.2, 73.3, 62.1, 39.4, 35.6, 35.1, 31.7, 27.4, 26.9, 24.0, 22.2 and 19.3. Found: C, 64.23; H, 8.91; N, 8.69%; C ₂₆ H ₄₃ N ₃ O ₅ • 0.5H ₂ O calculated: C 64.17, H 9.11, N 8.63%.

 Example 8. 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexane hydroxycamic acid.

Белый порошок. Т. пл. 132.5-134.5^oC. ¹H ЯМР; δ (CDCl₃), 9.97 (1H, с), 9.52 (1H, с), 8.73 (1H, д, J=11.0 Гц), 8.18 (2H, м), 7.81 (2H, м), 7.13 (1H, м), 4.78 (1H, д, J=10.9 Гц), 4.19 (1H, м), 2.95 (1H, м), 2.00 (1H, м), 1.53 (1H, м), 1.42 (1H, м), 1.10 (9H, с), 0.86 (3H, д, J=6.2 Гц) и 0.85 (3H, д, J= 6.1 Гц), ¹³C ЯМР; δ (CDCl₃), 174.4, 170.1, 169.0, 152.0, 146.3, 139.9, 120.1, 116.2, 73.8, 63.2, 42.0, 39.8, 34.8, 27.0, 25.8, 23.0, и 21.8. Найдено: C 57.33, H 7.53, N 13.84%; C₂₆H₄₃N₃O₅•0.2H₂O вычислено: C 57.33, H 7.70, N 14.07%.

White powder. T. pl. 132.5-134.5 ^o C. ¹ H NMR; δ (CDCl ₃ ), 9.97 (1H, s), 9.52 (1H, s), 8.73 (1H, d, J = 11.0 Hz), 8.18 (2H, m), 7.81 (2H, m), 7.13 (1H, m), 4.78 (1H, d, J = 10.9 Hz), 4.19 (1H, m), 2.95 (1H, m), 2.00 (1H, m), 1.53 (1H, m), 1.42 (1H, m), 1.10 (9H, s), 0.86 (3H, d, J = 6.2 Hz) and 0.85 (3H, d, J = 6.1 Hz), ¹³ C NMR; δ (CDCl ₃ ), 174.4, 170.1, 169.0, 152.0, 146.3, 139.9, 120.1, 116.2, 73.8, 63.2, 42.0, 39.8, 34.8, 27.0, 25.8, 23.0, and 21.8. Found: C 57.33, H 7.53, N 13.84%; C ₂₆ H ₄₃ N ₃ O ₅ • 0.2H ₂ O calculated: C 57.33, H 7.70, N 14.07%.

 Example 9. 3R- (2,2-Dimethyl-1S- (4-methoxyphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Твердое вещество светло-коричневого цвета. Т.пл. 118- 120^oC. ¹H ЯМР; δ (CD₃OD), 7.39 (2H, д, J=9.4 Гц), 6.81 (2H, д, J=9.4 Гц), 4.37 (1H, с), 4.15 (1H, д, J= 6.9 Гц), 3.73 (3H, с), 2.91-2.79 (1H, м), 1.70-1.44 (2H, м), 1.33-1.13 (1H, м), 1.03 (9H, с), 0.89 (3H, д, J-6.3 Гц) и 0.85 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ (CD₃OD), 175.6, 171.5, 171.0, 158.2, 132.1, 123.6, 115.0, 73.1, 62.4, 55.9, 39.7, 35.9, 30.9, 27.2, 27.0, 23.6 и 22.4. IR; v_max (KBr), 3419, 2923, 2361, 1654, 1512, 1458, 1245, 1036 см^-1. Найдено: C 57.97, H 7.73, N 9.31%; C₂₁H₃₃N₃O₆•0.6H₂O вычислено: C 58.08, H 7.94, N 9.67%.

The solid is light brown in color. Mp 118-120 ^° C. ¹ H NMR; δ (CD ₃ OD), 7.39 (2H, d, J = 9.4 Hz), 6.81 (2H, d, J = 9.4 Hz), 4.37 (1H, s), 4.15 (1H, d, J = 6.9 Hz), 3.73 (3H, s), 2.91-2.79 (1H, m), 1.70-1.44 (2H, m), 1.33-1.13 (1H, m), 1.03 (9H, s), 0.89 (3H, d, J-6.3 Hz) and 0.85 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ (CD ₃ OD), 175.6, 171.5, 171.0, 158.2, 132.1, 123.6, 115.0, 73.1, 62.4, 55.9, 39.7, 35.9, 30.9, 27.2, 27.0, 23.6 and 22.4. IR v _max (KBr), 3419, 2923, 2361, 1654, 1512, 1458, 1245, 1036 cm ^-1 . Found: C, 57.97; H, 7.73; N, 9.31%; C ₂₁ H ₃₃ N ₃ O ₆ • 0.6H ₂ O calculated: C 58.08, H 7.94, N 9.67%.

 Example 10. 3R- (2,2-Dimethyl-1S-pyridin-4-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т. пл. 120-125^oC. ¹H ЯМР; δ ((CD₃)₂SO, смесь диастереомеров 9: 1), 10.62 (1H, с), 10.59 (0.9H, с), 10.43 (0.1H, с), 8.40 (2H, д, J=6.2 Гц), 7.80 (0.9H, д, J=8.6 Гц), 7.76 (0.1H, д, J=6.3 Гц), 7.60 (2H, д, J = 6.2 Гц), 5.60 (0.1H, с), 5.29 (0.9H, с), 4.44 (0.9H, д, J=8.7 Гц), 4.31 (0.1H, д, J=8.5 Гц), 3.72 (1H, ш. д), 2.90 (1H, м), 1.49 (3H, м), 1.04 (9H, с) и 0.81 (6H. м). ¹³C ЯМР; δ ((CD₃)₂SO, смесь диастереомеров 9: 1), 173.5, 172.9, 170.7, 170.6, 168.7, 150.1, 150.0, 145.3, 145.3, 113.5, 113.2, 71.2, 61.0, 60.8, 47.5, 46.6, 37.2, 36.1, 34.3, 34.1, 26.6, 26.4, 25.2, 23.8, 23.4, 21.7 и 21.4.

White solid. T. pl. 120-125 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO, mixture of diastereomers 9: 1), 10.62 (1H, s), 10.59 (0.9H, s), 10.43 (0.1H, s), 8.40 (2H, d, J = 6.2 Hz) , 7.80 (0.9H, d, J = 8.6 Hz), 7.76 (0.1H, d, J = 6.3 Hz), 7.60 (2H, d, J = 6.2 Hz), 5.60 (0.1H, s), 5.29 (0.9 H, s), 4.44 (0.9H, d, J = 8.7 Hz), 4.31 (0.1H, d, J = 8.5 Hz), 3.72 (1H, broad d), 2.90 (1H, m), 1.49 (3H , m), 1.04 (9H, s) and 0.81 (6H. m). ¹³ C NMR; δ ((CD ₃ ) ₂ SO, mixture of diastereomers 9: 1), 173.5, 172.9, 170.7, 170.6, 168.7, 150.1, 150.0, 145.3, 145.3, 113.5, 113.2, 71.2, 61.0, 60.8, 47.5, 46.6, 37.2, 36.1, 34.3, 34.1, 26.6, 26.4, 25.2, 23.8, 23.4, 21.7 and 21.4.

 Example 11. 3R- (2,2-Dimethyl-1S-pyridin-3-ylcarbamoyl-propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т. пл. 108-112^oC. ¹H ЯМР; δ ((CD₃)₂SO), 10.60 (1H, с), 10.26 (1H, с), 8.90 (1H, с), 8.74 (1H, с), 8.26 (1H, д, J=4.4 Гц), 8.05 (1H, д, J=8.2 Гц), 7.77 (1H, д, J=8.7 Гц), 7.36 (1H, м), 5.32 (1H, д, J=8.2 Гц), 4.45 (1H, д, J=8.9,Гц), 3.75 (1H, м), 2.81 (1H, м), 1.40 (3H, м), 0.98 (9H, с) и 0.80 (6H, дд, J=12.5, 6.2 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.7, 169.8, 168.7, 144.2, 140.9, 135.3, 126.2, 123.5, 71.2, 60.5, 47.6, 37.3, 34.3, 26.6, 26.5, 25.3, 23.4
и 21.7. Найдено: C 54.46, H 7.46, N 13.42%; C₁₉H₃₀N₄O₅•1.2H₂O вычислено: C 54.85, H 7.85, N 13.46%.

White solid. T. pl. 108-112 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.60 (1H, s), 10.26 (1H, s), 8.90 (1H, s), 8.74 (1H, s), 8.26 (1H, d, J = 4.4 Hz), 8.05 (1H, d, J = 8.2 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.36 (1H, m), 5.32 (1H, d, J = 8.2 Hz), 4.45 (1H, d, J = 8.9, Hz), 3.75 (1H, m), 2.81 (1H, m), 1.40 (3H, m), 0.98 (9H, s) and 0.80 (6H, dd, J = 12.5, 6.2 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.7, 169.8, 168.7, 144.2, 140.9, 135.3, 126.2, 123.5, 71.2, 60.5, 47.6, 37.3, 34.3, 26.6, 26.5, 25.3, 23.4
and 21.7. Found: C, 54.46; H, 7.46; N, 13.42%; C ₁₉ H ₃₀ N ₄ O ₅ • 1.2H ₂ O Calculated: C 54.85, H 7.85, N 13.46%.

 Example 12. 3R- (2,2-Dimethyl-1S- (4-hydroxyphenyl) carbamoyl-propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т. пл. 138-147^oC. ¹H ЯМР, δ ((CD₃)₂SO), 10.59 (1H, с), 9.71 (1H, с), 9.17 (1H, с), 8.88 (1H, с), 7.61 (1H;д, J=9.2 Гц), 7.36 (2H, д, J=8.7 Гц), 6.69 (2H, д, J=8.7 Гц), 5.29 (1H, д, J=8.7 Гд), 4.40 (1H, д, J=9.2,Гц), 2.80 (1H, м), 1.49 (2H, м), 1.29 (1H, м), 0.95 (9H, с), 0.80 (3H, д, J= 6.4 Гц) и 0.75 (3H, д, J=6.4 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.4, 168.7, 168.4, 153.3, 130.3, 121.1, 114.9, 71.3, 60.3, 47.7, 37.2, 34.7, 26.6, 25.3, 23.4 и 21.7. Найдено: C 57.28, H 7.67, N 10.17%; C₂₀H₃₁N₃O₆•0.5H₂O вычислено: C 57.40, H 7.71, N 10.04%.

White solid. T. pl. 138-147 ^o C. ¹ H NMR, δ ((CD ₃ ) ₂ SO), 10.59 (1H, s), 9.71 (1H, s), 9.17 (1H, s), 8.88 (1H, s), 7.61 ( 1H; d, J = 9.2 Hz), 7.36 (2H, d, J = 8.7 Hz), 6.69 (2H, d, J = 8.7 Hz), 5.29 (1H, d, J = 8.7 Gd), 4.40 (1H, d, J = 9.2, Hz), 2.80 (1H, m), 1.49 (2H, m), 1.29 (1H, m), 0.95 (9H, s), 0.80 (3H, d, J = 6.4 Hz) and 0.75 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.4, 168.7, 168.4, 153.3, 130.3, 121.1, 114.9, 71.3, 60.3, 47.7, 37.2, 34.7, 26.6, 25.3, 23.4 and 21.7. Found: C, 57.28; H, 7.67; N, 10.17%; C ₂₀ H ₃₁ N ₃ O ₆ • 0.5H ₂ O calculated: C 57.40, H 7.71, N 10.04%.

 Example 13. 3R- (2,2-Dimethyl-1S- (3-methoxyphenyl) carbamoyl-propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. T.пл. 97-102^oC. ¹H ЯМР; δ ((CD₃)₂SO), 10.58 (1H, с), 9.96 (1H, с), 8.87 (1H, с), 7.67 (1H, д, J=9.2 Гц), 7.29 (1H, с), 7.20 (1H, с), 6.64 (1H, д, J = 7.8 Гц), 5.29 (1H, д, J=7.9 Гц), 4.43 (1H, д, J= 9.0, Гц), 3.72 (3H, с), 2.77 (1H, м), 1.50 (3H, м), 0.97 (9H, с), 0.81 (3H, д, J = 6.4 Гц) и 0.78 (3H, д, J=6.4 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.6, 169.3, 168J, 159.4, 139.8, 129.4, 111.6, 108.6, 105.2, 7l.3, 60.5, 54.9, 47.6, 37.3, 34.4, 26.5, 23.4 и 21.8. Найдено: C 57.96%, H 7.58%, N 9.39%; C₂₁H₃₃N₃O₆•0.7H₂O вычислено: C 57.84%, H 7.95%, N 9.63%.

White solid. T.pl. 97-102 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.58 (1H, s), 9.96 (1H, s), 8.87 (1H, s), 7.67 (1H, d, J = 9.2 Hz), 7.29 (1H, s), 7.20 (1H, s), 6.64 (1H, d, J = 7.8 Hz), 5.29 (1H, d, J = 7.9 Hz), 4.43 (1H, d, J = 9.0, Hz), 3.72 (3H, s) , 2.77 (1H, m), 1.50 (3H, m), 0.97 (9H, s), 0.81 (3H, d, J = 6.4 Hz) and 0.78 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.6, 169.3, 168J, 159.4, 139.8, 129.4, 111.6, 108.6, 105.2, 7l.3, 60.5, 54.9, 47.6, 37.3, 34.4, 26.5, 23.4 and 21.8. Found: C 57.96%, H 7.58%, N 9.39%; C ₂₁ H ₃₃ N ₃ O ₆ • 0.7H ₂ O calculated: C 57.84%, H 7.95%, N 9.63%.

 Example 14. 3R- (2-Benzylthio-2-methyl-1S- (pyridia-2-ylcarbamoyl) propylcarbamoyl) -2S-hydroxy-5-methyl-hexanohydrocamic acid.

Белая пена. Т.пл. 112-115^oC ¹H ЯМР; δ (CD₃OD), 8.26 (1H, м), 8.06 (1H, д, J= 8,4 Гц), 7.73 (1H, м), 7.11-7.29 (5H, м), 7.07 (1H, м), 4.68 (1H, с), 4.15 (1H, д, J=4.7 Гц), 2.93 (1H, м), 1.55-1.71 (1H, м), 1.48 (3H, с), 1.44 (3H, с), 1.47-1.23 (2H, ш. м), 0.90 (3H, д, J=6.4 Гц) и 0.84 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ (CD₃OD), 175.7, 171.7, 170.5, 152.3, 149.0, 139.8, 138.8, 130.3, 129.4. 128.0,121.4, 115.9, 73.0, 61.4, 49.5, 49.3, 39.8, 34.2, 32.8, 26.9, 26.9, 26.2, 23.6 и 22.4. Найдено: C 59.78%, H 6.97%, N 10.86%; C₂₅H₃₄N₄O₅S вычислено: C 59.74%, H 6.82%, N 11.15%.

White foam. Mp 112-115 ^° C ¹ H NMR; δ (CD ₃ OD), 8.26 (1H, m), 8.06 (1H, d, J = 8.4 Hz), 7.73 (1H, m), 7.11-7.29 (5H, m), 7.07 (1H, m) , 4.68 (1H, s), 4.15 (1H, d, J = 4.7 Hz), 2.93 (1H, m), 1.55-1.71 (1H, m), 1.48 (3H, s), 1.44 (3H, s), 1.47-1.23 (2H, br m), 0.90 (3H, d, J = 6.4 Hz) and 0.84 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ (CD ₃ OD), 175.7, 171.7, 170.5, 152.3, 149.0, 139.8, 138.8, 130.3, 129.4. 128.0,121.4, 115.9, 73.0, 61.4, 49.5, 49.3, 39.8, 34.2, 32.8, 26.9, 26.9, 26.2, 23.6 and 22.4. Found: C, 59.78%; H, 6.97%; N, 10.86%; C ₂₅ H ₃₄ N ₄ O ₅ S calculated: C 59.74%, H 6.82%, N 11.15%.

 Example 15. 3R- (2,2-Dimethyl-1S- (thiazol-2-ylcarbamoyl) propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т. пл. 125-128^oC. ¹H ЯМР; δ ((CD₃)₂SO), 10.60 (1H, с), 8.86 (1H, с), 7.80 (1H, д, J=8.4 Гц), 7.47 (1H, д, J=3.5 Гц), 7.22 (1H, д, J=3.5 Гц), 5.22 (1H, д, J=7.9 Гц), 4.52 (1H, д, J=8.3,Гц), 3.74 (1H, м), 2.83 (1H, м), 1.45 (3H, м), 0.96 (911, с), 0.79 (3H, д, J=6.2 Гц) и 0.72 (3H, д, J=6.2 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.9, 169.3, 168.7, 157.4, 137.6, 113.5, 71.3, 59.9, 47.4, 37.2, 34:1, 26.4, 25.2, 23.5 и 21.7.

White solid. T. pl. 125-128 ^° C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.60 (1H, s), 8.86 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J = 3.5 Hz), 7.22 ( 1H, d, J = 3.5 Hz), 5.22 (1H, d, J = 7.9 Hz), 4.52 (1H, d, J = 8.3, Hz), 3.74 (1H, m), 2.83 (1H, m), 1.45 (3H, m), 0.96 (911, s), 0.79 (3H, d, J = 6.2 Hz) and 0.72 (3H, d, J = 6.2 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.9, 169.3, 168.7, 157.4, 137.6, 113.5, 71.3, 59.9, 47.4, 37.2, 34: 1, 26.4, 25.2, 23.5 and 21.7.

 Example 16. 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-phenylhexanohydroxamic acid.

Смесь диастереомеров (4:1, SRS:RRS).

A mixture of diastereomers (4: 1, SRS: RRS).

White solid. Mp 98 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.55-7.47 (2H, m), 7.28-7.21 (2H, m), 7.12-7.01 (6H, m), 4.47-4.44 (0.8H, m), 4.39-4.35 (0.2H , m), 4.26 (0.2H, d, J = 4.8 Hz), 4.06 (0.8H, d, J = 6.5 Hz), 2.87-2.83 (1H, m), 2.57-2.48 (2H, m), 1.81- 1.52 (4H, m) and 1.03 (9H, s). ¹³ C NMR; δ (CD ₃ OD), 175.7, 171.5, 171.3, 143.3, 139.2, 129.6, 129.4, 129.3, 126.7, 125.5, 121.8, 73.0, 62.6, 51.0, 36.7, 35.6, 30.3, 27.3 and 23.1. Found: C 65.05%, H 7.57%, N 8.78%; C ₂₅ H ₃₃ N ₃ O ₅ • 0.3H ₂ O calculated. C 65.06%, H 7.57%, N 8.78%.

 Example 17. 3R- (2,2-Dimethyl-1S- (4,5-dimethylthiazol-2-ylcarbamoyl) -propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т.пл. 191.5-192^oC. ¹H ЯМР; δ ((CD₃)₂SO, 11.84 (1H, с), 10.62 (1H, с), 8.87 (1H. с). 7.9 Гц), 4.48 (1H, д, J=8.5 Гц), 3.70 (1H, м), 2.79 (1H, м), 2.49 (3H; с), 2.22 (3H, с), 1.41 (2H, м). 0.94 (10H, с и ш. м), 0.72 (3H, д, J=6.2 Гц) и 0.78 (3H, д, J=6.2 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 171.5, 167.6, 167.4, 151.7, 140.4, 117.4, 70.1, 58.6, 46.2, 35.9, 32.9, 25.1, 24.0, 22.2, 20.5, 12.9 и 8.9. IR; v_max (KBr), 1.654 и 1535 см^-1
Пример 18. 3R-(2,2-Диметил-1S-(4-этoкcикapбoнилметилтиaзoл-2- илкарбамоил)-пропилкарбамоил)-2S-гидрокси-5- метилгексаногидроксамовая кислота.

White solid. Mp 191.5-192 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO, 11.84 (1H, s), 10.62 (1H, s), 8.87 (1H. s). 7.9 Hz), 4.48 (1H, d, J = 8.5 Hz), 3.70 (1H, m), 2.79 (1H, m), 2.49 (3H; s), 2.22 (3H, s), 1.41 (2H, m). 0.94 (10H, s and w / m), 0.72 (3H, d, J = 6.2 Hz) and 0.78 (3H, d, J = 6.2 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 171.5, 167.6, 167.4, 151.7, 140.4, 117.4, 70.1, 58.6, 46.2, 35.9, 32.9, 25.1, 24.0, 22.2, 20.5, 12.9 and 8.9. IR v _max (KBr), 1.654 and 1535 cm ^-1
Example 18. 3R- (2,2-Dimethyl-1S- (4-ethoxycarbonylmethylthiazol-2-ylcarbamoyl) propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т.пл. 104.5-110.5^oC. ¹H ЯМР; δ ((CD₃)₂SO), 12.17 (1H, с). 10.61 (1H, с), 8.87 (1H, с), 7.75 (1H, д, J=7.9 Гц), 6.97 (1H, с), 5.23 (1H, д, J=7.9 Гц), 4.48 (1H, д, J -= S.3 Гц), 4.06 (2H, кв, J=7.2 Гц), 3.67 (3H, м), 2.85 (1H, м), 1.40 (2H, м), 1.18 (3H, т, J=7.0), 0.96 (10H, с и ш. м), 0.78 (3H, д, J= 6.3 Гц) и 0.72 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 182.4, 178.9, 178.2, 166.6, 153.2, 119.9, 80.9, 69.8, 69.6, 56.9, 46.1, 45.9, 43.6, 35.9, 34.7, 33.0, 31.2 и 23.6. IR; v_max (KBr), 1654 и 1535 см^-1. Найдено: C 51.44, H 7.06, N 11.14%; C₂₁H₃₄N₄O₇S•0.2H₂O вычислено: C 51.46, H 7.07, N 11.43%.

White solid. Mp 104.5-110.5 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 12.17 (1H, s). 10.61 (1H, s), 8.87 (1H, s), 7.75 (1H, d, J = 7.9 Hz), 6.97 (1H, s), 5.23 (1H, d, J = 7.9 Hz), 4.48 (1H, d , J - = S.3 Hz), 4.06 (2H, q, J = 7.2 Hz), 3.67 (3H, m), 2.85 (1H, m), 1.40 (2H, m), 1.18 (3H, t, J = 7.0), 0.96 (10H, s and w.m), 0.78 (3H, d, J = 6.3 Hz) and 0.72 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 182.4, 178.9, 178.2, 166.6, 153.2, 119.9, 80.9, 69.8, 69.6, 56.9, 46.1, 45.9, 43.6, 35.9, 34.7, 33.0, 31.2 and 23.6. IR v _max (KBr), 1654 and 1535 cm ^-1 . Found: C, 51.44; H, 7.06; N, 11.14%; C ₂₁ H ₃₄ N ₄ O ₇ S • 0.2H ₂ O calculated: C 51.46, H 7.07, N 11.43%.

 Example 19. 3R- (2,2-Dimethyl-1S- (5-bromo-thiazol-2-ylcarbamoyl) -propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т.пл. 196-198^oC. ¹H ЯМР; δ ((CD₃)₂SO), 8.74 (1H, с), 7.70 (1H, д, J=8.2 Гц), 7.41 (1H, с), 5.09 (1H, д, J= 6.3 Гц), 4.36 (1H, д, J= 8.2 Гц), 3.63-3.52 (1H, м), 2.73-2.60 (1H, м), 1.35-1.14 (2H, м), 0.93-0.72 (1H, м), 0.81 (9H, с), 0.65 (3H, д, J=6.3 Гц) и 0.58 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.1, 170.0, 168.7, 157.7, 138.7, 101.7, 67.3, 59.9, 47.4, 37.2, 34.0, 26.4, 25.3, 23.5 и 21.8. IR; v_max (KBr), 3236, 2966, 1659 и 1534 см^-1.

White solid. Mp 196-198 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 8.74 (1H, s), 7.70 (1H, d, J = 8.2 Hz), 7.41 (1H, s), 5.09 (1H, d, J = 6.3 Hz), 4.36 ( 1H, d, J = 8.2 Hz), 3.63-3.52 (1H, m), 2.73-2.60 (1H, m), 1.35-1.14 (2H, m), 0.93-0.72 (1H, m), 0.81 (9H, s), 0.65 (3H, d, J = 6.3 Hz) and 0.58 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.1, 170.0, 168.7, 157.7, 138.7, 101.7, 67.3, 59.9, 47.4, 37.2, 34.0, 26.4, 25.3, 23.5 and 21.8. IR v _max (KBr), 3236, 2966, 1659 and 1534 cm ^-1 .

 Example 20. 3R- (2,2-Dimethyl-1S- (4-phenylthiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. Т.пл. 158-160^oC. ¹H ЯМР; δ ((CD₃)₂SO), 8.74 (1H, с), 7.80-7.64 (3H, м), 7.45 (1H, с), 7.33-7.12 (3H, м), 4.42 (1H, д, J=8.3 Гц), 5.39 (1H, д, J=8.6 Гц), 2.77-2.63 (1H, м), 1.39-1.16 (2H, м), 0.84 (9H, с), 0.93-0.73 (1H, м), 0.67 (3H, д, J=6.4 Гц) и 0.59 (3H, д, J=6.4 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.0, 169.8, 168.8, 157.4, 148.9, 134.3, 128.7, 127.7, 125.7, 108.1, 71.4, 60.1, 47.5, 37.2, 34.1, 26.5, 25.3, 23.5 и 21.8. IR; v_max (KBr), 3310, 2956, 1653 и 1541 см^-1. Найдено: C 55.69, H 6.82, N 11.15%; C₂₃H₃₂N₄O₅S•1.1H₂O вычислено: C 55.65, H 6.94, N 11.29%.

White solid. Mp 158-160 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 8.74 (1H, s), 7.80-7.64 (3H, m), 7.45 (1H, s), 7.33-7.12 (3H, m), 4.42 (1H, d, J = 8.3 Hz), 5.39 (1H, d, J = 8.6 Hz), 2.77-2.63 (1H, m), 1.39-1.16 (2H, m), 0.84 (9H, s), 0.93-0.73 (1H, m), 0.67 (3H, d, J = 6.4 Hz) and 0.59 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.0, 169.8, 168.8, 157.4, 148.9, 134.3, 128.7, 127.7, 125.7, 108.1, 71.4, 60.1, 47.5, 37.2, 34.1, 26.5, 25.3, 23.5 and 21.8. IR v _max (KBr), 3310, 2956, 1653 and 1541 cm ^-1 . Found: C, 55.69; H, 6.82; N, 11.15%; C ₂₃ H ₃₂ N ₄ O ₅ S • 1.1H ₂ O Calcd. C 55.65, H 6.94, N 11.29%.

 Example. 21. 3R .- (2,2-Dimethyl-1S- (5-methyl-1,3,4-thiadiazol-2-ylcarbamoyl) - propylcarbamoyl) -2S-hydroxy-5-methylhexanohydrosamic acid.

Белое твердое вещество. Т.пл. 159-161^oC. ¹H ЯМР; δ ((CD₃)₂SO), 8.73 (1H, м), 7.69 (1H, д, J=8.2 Гц), 5.10 (1H, м), 4.38 (1H, д, J=8.0 Гц), 3.58 (1H, м), 2.69 (1H, м), 2.45 (3H, с), 1.36-1.12 (2H, м), 0.94-0.73 (1H, м), 0.82 (9H, с), 0.65 (3H, д, J= 6.3 Гц) и 0.58 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.1, 169.6, 159.4, 157.9, 71.3, 60.2, 47.4, 37.2, 34.0, 28.4, 25.3, 23.5, 21.8 и 14.7. IR; v_max (KBr), 3260, 2959, 1655, 1540 и 1311 см^-1. Найдено: C 46.71, H 7.24, N 16.02%; C₁₇H₂₉N₅O₅S•1.2 H₂O вычислено: C 46.71, H 7.24, N 16.02%.

White solid. Mp 159-161 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 8.73 (1H, m), 7.69 (1H, d, J = 8.2 Hz), 5.10 (1H, m), 4.38 (1H, d, J = 8.0 Hz), 3.58 ( 1H, m), 2.69 (1H, m), 2.45 (3H, s), 1.36-1.12 (2H, m), 0.94-0.73 (1H, m), 0.82 (9H, s), 0.65 (3H, d, J = 6.3 Hz) and 0.58 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.1, 169.6, 159.4, 157.9, 71.3, 60.2, 47.4, 37.2, 34.0, 28.4, 25.3, 23.5, 21.8 and 14.7. IR v _max (KBr), 3260, 2959, 1655, 1540 and 1311 cm ^-1 . Found: C, 46.71; H, 7.24; N, 16.02%; C ₁₇ H ₂₉ N ₅ O ₅ S • 1.2 H ₂ O Calcd. C 46.71, H 7.24, N 16.02%.

 Example 22.3R- (2,2-Dimethyl-1S- (4-tert. Butylthiadiazol-2-ylcarbamoyl) -propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

Белое твердое вещество. T.пл. 169-171^oC. ¹H ЯМР; δ ((CD₃)₂SO), 8.73 (1H, с), 7.60 (1H, д, J=8.3 Гц), 6.58 (1H, с), 5.09 (1H, д, J= 7.9Гц), 4.34 (1H, д, J=8.3 Гц), 3.56 (1H, дд, J=8.3 Гц), 3.74-2.60 (1H, м), 1.39-1.03 (2H, м), 1.11 (9H, с), 0.92-0.70 (1H, м), 0.82 (9H, с), 0.65 (3H, д, J=6.3 Гц) и 0.58 (3H, д, J= 6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.9, 169.4, 168.7, 160.2, 156.7, 104.7, 71.4, 60.1, 47.4, 37.2, 34.1, 34.0, 29.8, 25.2, 23.6 и 21.8. IR; v_max (KBr), 3270, 2962, 1668, 1557, 1368, 1270 см^-1. Найдено: C 53.74, H 8.18, N 11.45%; C₂₁H₃₆N₄O₅S•0.9H₂O вычислено: C 53.35, H 8.06, N 11.85%.

White solid. T.pl. 169-171 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 8.73 (1H, s), 7.60 (1H, d, J = 8.3 Hz), 6.58 (1H, s), 5.09 (1H, d, J = 7.9 Hz), 4.34 ( 1H, d, J = 8.3 Hz), 3.56 (1H, dd, J = 8.3 Hz), 3.74-2.60 (1H, m), 1.39-1.03 (2H, m), 1.11 (9H, s), 0.92-0.70 (1H, m), 0.82 (9H, s), 0.65 (3H, d, J = 6.3 Hz) and 0.58 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.9, 169.4, 168.7, 160.2, 156.7, 104.7, 71.4, 60.1, 47.4, 37.2, 34.1, 34.0, 29.8, 25.2, 23.6 and 21.8. IR v _max (KBr), 3270, 2962, 1668, 1557, 1368, 1270 cm ^-1 . Found: C, 53.74; H, 8.18; N, 11.45%; C ₂₁ H ₃₆ N ₄ O ₅ S • 0.9H ₂ O Calculated: C 53.35, H 8.06, N 11.85%.

 Example 23. 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Стадия A. 4-трет-Бутиловый эфир 3R,S-аллил-2R-иэобутил- бутан-1,4-диовой кислоты.

Step A. 3R, S-allyl-2R-Ieobutyl-butane-1,4-diic acid 4-tert-butyl ester.

To a stirred solution of 4R-tert-butyl ether of 2R-isobutyl-1,4-diic acid (5 g, 21.7 mmol) in dry THF (100 ml) was added dropwise through a needle 1.5 M LDA (31.8 ml, 47.7 mmol) at - 78 ^o C in an argon atmosphere. After stirring for 1 hour at -78 ^° C, allyl bromide (2.44 ml, 28.2 mmol) was added via syringe. The resulting solution was brought to room temperature in 2 hours. Methanol (10 ml) was added to the stirred solution at room temperature. After 30 minutes, the reaction mixture was evaporated in vacuo. The residue was dissolved in methylene chloride (100 ml) and washed with 1M hydrochloric acid (100 ml) and brine (100 ml). The organic extracts are dried with anhydrous magnesium sulfate, filtered, the solvent is distilled off in vacuo and the above compound is obtained in the form of a golden oil (5.6 g, 97%) (1: 9 RS: RR). ¹ H NMR; δ (CDCl ₃ , main diastereomer), 5.78-5.63 (1H, m), 5.01-5.11 (2H, m), 2.57-2.72 (2H, m), 2.37 (2H, m), 1.52-1.67 (2H, m ), 1.42 (9H, s), 1.37 (1H, m) and 0.90 (6H, d, J = 6.3 Hz). ¹³ C NMR; δ (CDCl ₃ , basic diastereomer), 131.1. 172.9, 134.6, 117.3, 81.2, 47.8, 44.3, 38.4, 27.9, 25.9, 23.5 and 21.5.

Stage B. 3R.S-Allyl-2R-isobutyl-1,4-dioic acid 4-tert-butyl ester
(i) To a stirred solution of 4R-tert-butyl ether 3R, S-allyl-2R-isobutyl-1,4-diic acid (1: 9 RS: RR) (5.11 g, 18.9 mmol) in dry THF (100 ml) in an argon atmosphere at -78 ^° C, 1.5 M LDA (27.7 ml, 41.6 mmol) are added through a needle. The reaction mixture was brought to room temperature over 2 hours, then cooled again to -78 ^° C. and 8 ml of methanol was added via syringe. Over the next 2 hours, the reaction mixture was brought to room temperature. The solvent is removed in vacuo. The residue was dissolved in methylene chloride (150 ml) and washed with 1M hydrochloric acid (150 ml) and brine (150 ml). The organic layer was dried with anhydrous magnesium sulfate, filtered and the solvent was removed in vacuo to afford the title compound (3: 2, RS: RR) as a brown oil (4.7 g, 92%).

(ii) Using the epimerization process described in Example 23B (i), but carrying out the reaction after adding LDA at a temperature of -78 ^° C, instead of bringing the reaction mixture to room temperature, the title compound is obtained in the form of a basic diastereomer, a brown oil ( 4.6 g, 98%) (3: 1, RS: RR). ¹ H NMR; δ (CDCl ₃ , main diastereomer), 11.60 (1H, br.s), 5.75-5.61 (1H, br.m), 5.06-4.96 (2H, br.m), 2.70-2.52 (2H, br.m) , 2.36-2.19 (2H, br m), 1.65-1.44 (2H, br m), 1.40 (9H, s), 1.13 (1H, m) and 0.86 (6H, dd, J = 4.4, 2.1 Hz) . ¹³ C NMR; δ (CDCl ₃ , main diastereomer), 180.7, 172.2, 134.6, 117.1, 81.0, 48.6, 45.7.38.9, 34.8, 33.4, 27.9, 26.2 and 21.2.

 Step C. 1-Pentafluorophenyl-4-tert-butyl diester 3R, S-allyl-2R-isobutyl-1,4-diic acid.

To a solution of 3R, S-allyl-2R-isobutyl-1,4-diacid 4-tert-butyl ester (4.60 g, 17.2 mmol) (3: 1, RS: RR) in methylene chloride (50 ml) was added with stirring pentafluorophenol (6.13 g, 33.3 mmol). The reaction mixture was cooled to 0 ^° C. and NMM (2.02 g, 20.0 mmol) and EDC (3.94 g, 20.0 mmol) were added. The reaction mixture was brought to room temperature and stirred for 12 hours. The solvent was distilled off in vacuo. The residue was dissolved in methylene chloride (50 ml) and washed with 1M hydrochloric acid (3 x 50 ml), saturated sodium carbonate solution (3 x 50 ml) and brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate, filtered and the solvent was distilled off in vacuo to give a brown oil. Column chromatography (silica gel, methylene chloride) gives the title compound as a golden oil (5.47 g, 74%) (3: 1, RS: RR). ¹ H NMR; δ (CDCl ₃ , main diastereomer), 5.85-5.67 (1H, br.m), 5.17-5.05 (2H, br.m), 3.10-3.01 (1H, m), 2.79-2.69 (1H, m), 2.51 -2.29 (2H, m), 1.88-1.61 (2H, m), 1.46 (9H, s), 1.37-1.24 (1H, m) and 0.96 (6H, dd, J = 4.0, 4.5 Hz). ¹³ C NMR; δ (CDCl ₃ , main diastereomer), 171.5, 170.3, 134.1, 117.5, 81.4, 48.8, 45.8-39.5, 35.0, 27.9, 26.3, 23.5 and 21.0.

Stage D. L-tert-Leucine-N-pyridylamide
The named compound is obtained from N ^α benzyloxycarbonyl-L-tert-leucine according to methods similar to those described in Example 1 (Steps D and E). ¹ H NMR; δ (CDCl ₃ ), 8.26 (1H, m), 8.10 (1H, m), 7.74 (1H, m), 7.06 (1H, m), 3.25 (1H, s) and 1.00 (9H, s).

 Step E. 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanoic acid 1-tert-butyl ester.

1-Pentafluorophenyl-4-tert-butyl diester 3R, S-allyl-2R-isobutyl-1,4-diic acid (3: 1, RS: RR) (5.59 g, 12.8 mmol) and L-tert-leucine-N -pyridylamide (2.91 g, 14.1 mmol) was dissolved together in DMF (50 ml) and stirred at 30 ^o C for 40 hours. Pentafluorophenyl ether completely reacts (TLC). The solvent was removed and the residue was purified by column chromatography (silica gel, ethyl acetate: hexane, 1: 1) and crystallized from ethyl acetate: hexane. Yield: 1.41 g (24%, 5: 1 mixture of SRS: RRS diastereomers). ¹ H NMR; δ (CDCl ₃ , main diastereomer), 9.58 (1H, m), 8.52 (1H, m), 8.19 (1H, d, J = 8.3 Hz), 7.73 (1H, m), 7.12 (1H, m) , 6.49 (1H, d, J = 9.2 Hz), 5.76 (1H, m), 5.05 (1H, m), 4.62 (1H, d. J = 9.2 Hz), 2.68 (1H, m ), 2.53 (1H, m), 2.29 (2H, m), 1.73 (1H, m), 1.47 (1H, m), 1.45 (9H, s), 1.15 (1H, m), 1.02 (9H, s) 0.87 (3H, d, J-6.5 Hz) and 0.79 (3H, d, J = 6.5 Hz).

Stage F. 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanoic acid. 1R-3R- (2, 2-dimethyl-1S- (pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanoic acid (1.74 g, 3.78 mmol) is hydrolyzed by TFA according to the procedure described in Example 1 (Step G), the title compound is obtained with a small admixture of TFA. Yield: 1.61 g (contains solvent), mixture of diastereomers 5: 1. ¹ H NMR; δ (CD ₃ ) OD, main diastereomer), 8.29 (1H, m), 7.90 ( 2H, m), 7.23 (1H, m), 5.72 (1H, m), 4.99 (2H, m), 4.46 (1H, s), 2.80 (1H, dt, J = 3.3, 10.8 Hz), 2.52 (1H , dt, J = 4.3, 10.2 G ), 2.40-2.12 (2H, br m), 1.62 (1H, m). 1.42 (1H, m), 1.10 (2H, m), 1.08 (9H, s), 0.86 (3H, d, J = 6 5 Hz) and 0.75 (3H, d, J = 6.5 Hz).

 Step G. 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanoic acid (1.5 g, 3.71 mmol) was dissolved in DMF (5 ml), the solution is cooled to 0 ^° C. and HOBt (0.60 g, 4.46 mmol) and EDC (0.86 g, 4.46 mmol) are added.The mixture is stirred at 0 ^° C for 1 hour, then at room temperature for 2 hours to ensure complete formation of the active ester. cooled again to 0 ^o C, was added hydroxylamine hydrochloride (0.39 g, 5.57 mmol) and then NMM (0.56 g, 5.57 mmol), warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was p washed with diethyl ether (25 ml) and water (25 ml) and allowed to stand for 2 hours. The resulting solid was filtered off, recrystallized from methanol-DIPE mixture and dried under high vacuum at 60 ^o C for 24 hours. A title compound (0.62 g, 40%; one diastereomer) containing about 0.4 mol DIPE (NMR) mp 221-223 ^° C. ¹ H NMR; δ (CD ₃ OD), 8.26 (1H, m), 8.04 ( 1H, d, J = 8.3 Hz), 7.72 (1H, dt, J = 1.9, 5.5 Hz), 7.07 (1H, m), 5.64 (1H, m), 4.96 (2H, m), 4.52 (1H , with). 2.72 (1H, m), 2.26 (2H, m), 2.10 (1H, m), 1.50 (1H, m), 1.39 (1H, m), 1.06 (9H, s), 1.07 (1H, m), 0.84 (3H, d, J = 6.4 Hz) and 0.73 (3H, d, J = 6.5 Hz). ¹³ C NMR; δ (CD ₃ OD), 176.8, 172.4, 171.4, 152.7, 149.1, 139.4, 136.0, 121.1, 117.5, 115.7, 63.1, 48.2, 47.8, 41.8, 36.4, 35.3, 27.3, 27.0, 24.4 and 21.9. Found: C, 63.68; H, 8.66; N, 12.08%; C ₂₂ H ₃₄ N ₄ O ₄ • 0.4C ₆ H ₁₄ O calculated: C 63.79, H 8.69, N 12.20%.

The following additional compounds are prepared according to the procedures described in Example 23:
Example 24. 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество белого цвета. Т.пл. 211-212.5^oC. ¹H ЯМР; δ (CD₃OD), 7.45 (2H, м), 7.26 (2H, м), 7.05 (1H, м), 5.66 (1H, м), 4.96 (2H, м), 4.46 (1H, с), 2.73 (1H, м), 2.26 (2H, м), 2.11 (1H, м), 1.49 (1H, м), 1.48 (1H, м), 1.08 (1H, м), 1.06 (9H, с), 0.84 (3H, д, J=6.4 Гц) и 0.75 (3H, д, J=6.5 Гц). ¹³C ЯМР; δ (CD₃OD), 176.7, 173.0, 171.0, 139.3, 136.1, 129.8, 125.8, 121.6, 117.5, 62.9, 48.2, 41.8, 36.4, 27.3, 27.1, 24.4 и 21.9. Найдено: C 63.68, H 8.55, N 9.69%; C₂₃H₃₅N₃O₄•0.9H₂O вычислено: C 63.69, H 8.55, N 9.69%.

The solid is white. Mp 211-212.5 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.45 (2H, m), 7.26 (2H, m), 7.05 (1H, m), 5.66 (1H, m), 4.96 (2H, m), 4.46 (1H, s), 2.73 (1H, m), 2.26 (2H, m), 2.11 (1H, m), 1.49 (1H, m), 1.48 (1H, m), 1.08 (1H, m), 1.06 (9H, s), 0.84 ( 3H, d, J = 6.4 Hz) and 0.75 (3H, d, J = 6.5 Hz). ¹³ C NMR; δ (CD ₃ OD), 176.7, 173.0, 171.0, 139.3, 136.1, 129.8, 125.8, 121.6, 117.5, 62.9, 48.2, 41.8, 36.4, 27.3, 27.1, 24.4 and 21.9. Found: C, 63.68; H, 8.55; N, 9.69%; C ₂₃ H ₃₅ N ₃ O ₄ • 0.9H ₂ O Calcd. C 63.69, H 8.55, N 9.69%.

 Example 25. 3R- (2,2-Dimethyl-1S- (thiazol-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество белого цвета. Т. пл. > 300^oC. ¹H ЯМР; δ ((CD₃)₂SO), 12.10 (1H, с), 10.46 (1H, с), 8.77 (1H, с), 8.12 (1H, д, J=7.9 Гц), 7.45 (1H, д, J=3.5 Гц), 7.20 (1H, д, J=3.5 Гц), 5.62 (1H, м), 4.93 (2H, м), 4.51 (1H, д, J=4.5 Гц), 2.82 (1H, м), 2.30 (1H, м), 2.22 (2H, м), 1.43 (3H, м), 0.98 (9H, с), 0.88 (3H, д, J=6.3 Гц) и 0.78 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 174.1, 169.3, 169.2, 157.4, 137.7, 135.8, 116.2, 113.5, 60.3, 45.9, 45.3, 40.2, 34.9, 33.5, 26.5, 25.2, 24.0 и 21.7. Найдено: C 56.30%, H 7.70%, N 12.70%; C₂₀H₃₂N₄O₄S•0.2H₂O вычислено: C 56.10%, H 7.63%, N 13.09%.

The solid is white. T. pl. > 300 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 12.10 (1H, s), 10.46 (1H, s), 8.77 (1H, s), 8.12 (1H, d, J = 7.9 Hz), 7.45 (1H, d, J = 3.5 Hz), 7.20 (1H, d, J = 3.5 Hz), 5.62 (1H, m), 4.93 (2H, m), 4.51 (1H, d, J = 4.5 Hz), 2.82 (1H, m), 2.30 (1H, m), 2.22 (2H, m), 1.43 (3H, m), 0.98 (9H, s), 0.88 (3H, d, J = 6.3 Hz) and 0.78 (3H, d, J = 6.3 Hz ) ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 174.1, 169.3, 169.2, 157.4, 137.7, 135.8, 116.2, 113.5, 60.3, 45.9, 45.3, 40.2, 34.9, 33.5, 26.5, 25.2, 24.0 and 21.7. Found: C, 56.30%; H, 7.70%; N, 12.70%; C ₂₀ H ₃₂ N ₄ O ₄ S • 0.2H ₂ O calculated: C 56.10%, H 7.63%, N 13.09%.

 Example 26. 3R- (2,2-Dimethyl-1S - (4-methoxyphenylcarbamoyl) propylcarbamoyl) - 5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Кристаллическое вещество белого цвета. Т. пл. 213-228.5^oC. ЯМР; δ (CD₃OD), 8.13 (1H, д, J=9.0 Гц), 7.33 (2H, д, J = 9.0 Гц), 6.81 (2H, д, J= 9.0 Гц), 5.63 (1H, м), 4.97 (2H, м), 4.45 (1H, т, J=5.4, 3,6 Гц), 3.72 (3H, с), 2.73 (1H, м), 2.20 (3H, м), 1.43 (2H, м), 1.10 (1H, м), 1.09 (9H, с), 0.84 (3H, д, J=6,4 Гц) и 0.75 (3H, д, J=6,5 Гц). ¹³C ЯМР; δ (CD₃OD), 176.7, 172.4, 158.1, 136.0, 132.1, 123.5, 117.5, 115.0, 62.9, 55.9, 48.1, 41.9, 36.4, 35.4, 27.4, 27.1, 24.4 и 22.0. IR; v_max (KBr), 3308, 2958, 1644, 1513, 1245 и 830 см^-1. Найдено: C 63.39, H 8.26, N 9.30%; C₂₄H₃₇N₃O₅•0.4H₂O вычислено: C 63.39, H 8.38, N 9.24%.

The crystalline substance is white. T. pl. 213-228.5 ^o C. NMR; δ (CD ₃ OD), 8.13 (1H, d, J = 9.0 Hz), 7.33 (2H, d, J = 9.0 Hz), 6.81 (2H, d, J = 9.0 Hz), 5.63 (1H, m), 4.97 (2H, m), 4.45 (1H, t, J = 5.4, 3.6 Hz), 3.72 (3H, s), 2.73 (1H, m), 2.20 (3H, m), 1.43 (2H, m) , 1.10 (1H, m), 1.09 (9H, s), 0.84 (3H, d, J = 6.4 Hz) and 0.75 (3H, d, J = 6.5 Hz). ¹³ C NMR; δ (CD ₃ OD), 176.7, 172.4, 158.1, 136.0, 132.1, 123.5, 117.5, 115.0, 62.9, 55.9, 48.1, 41.9, 36.4, 35.4, 27.4, 27.1, 24.4 and 22.0. IR v _max (KBr), 3308, 2958, 1644, 1513, 1245 and 830 cm ^-1 . Found: C, 63.39; H, 8.26; N, 9.30%; C ₂₄ H ₃₇ N ₃ O ₅ • 0.4H ₂ O Calcd. C 63.39, H 8.38, N 9.24%.

 Example 27. 3R- (2-Benzylthio-2-methyl-1S- (pyridin-2-ylcarbamoyl) propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество белого цвета. Т.пл. 214-214.5^oC. ¹H ЯМР; δ (CD₃OD при 338 K), 8.36 (1H, м), 8.02 (1H, м), 7.72 (1H, м), 7.32-7.12 (5H, ш.м), 7.05 (1H, м), 5.62-5.53 (1H, ш.м), 4.96-4.82 (3H, ш.м), 3.87 (2H, с), 2.69 (1H, м), 2.37-2.21 (3H, м), 1.61-1.34 (2H, ш.м), 1.51 (3H, с), 1.45 (3H, с), 1.13 (1H, ш. м), 0.82 (3H, д, J=6.4 Гц) и 0.73 (3H, д, J=6.4 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.8, 168.1, 167.9, 146.8, 136.4, 134.9, 128.0, 127.0, 125.4, 118.4, 114.7. 112.5, 56.5, 47.2, 44.8, 44.4, 33.6, 31.2, 25.3, 24.2, 22.7, 22.64 и 20.4.

The solid is white. Mp 214-214.5 ^o C. ¹ H NMR; δ (CD ₃ OD at 338 K), 8.36 (1H, m), 8.02 (1H, m), 7.72 (1H, m), 7.32-7.12 (5H, m), 7.05 (1H, m), 5.62 -5.53 (1H, m), 4.96-4.82 (3H, m), 3.87 (2H, s), 2.69 (1H, m), 2.37-2.21 (3H, m), 1.61-1.34 (2H, m), 1.51 (3H, s), 1.45 (3H, s), 1.13 (1H, m), 0.82 (3H, d, J = 6.4 Hz) and 0.73 (3H, d, J = 6.4 Hz ) ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.8, 168.1, 167.9, 146.8, 136.4, 134.9, 128.0, 127.0, 125.4, 118.4, 114.7. 112.5, 56.5, 47.2, 44.8, 44.4, 33.6, 31.2, 25.3, 24.2, 22.7, 22.64 and 20.4.

 Example 28. 3R- (2,2-Dimethyl-1S- (pyridin-3-ylcarbamoyl-propylcarbamoyl) - 5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество белого цвета. Т.пл. 220-224^oC. ¹H ЯМР; δ ((CD₃)₂SO), 10.30 (1H, с), 10.00 (1H, с), 8.73 (1H, с), 8.26 (1H, д, J=4.1 Гц), 7.99 (1H, д, J= 8.2 Гц), 7.81 (1H, д, J = 8.5 Гц), 7.34 (1H, м), 5.65 (1H, м), 4.93 (2H, м), 4.43 (1H, д, J = 5.3 Гц), 2.74 (1H, м), 2.50-2.21 (3H, м), 1.50 (3H, м), 1.04 (9H, с), 0.83 (3H, д, J=6.4 Гц) и 0.77 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 174.0, 169.7, 169.2, 144.2, 140.7, 135.8, 135.4, 126.0, 123.6, 116.1, 61.0, 45.9, 45.5, 34.9, 33.7, 26.6, 25.3, 24.0 и 21.7.

The solid is white. Mp 220-224 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.30 (1H, s), 10.00 (1H, s), 8.73 (1H, s), 8.26 (1H, d, J = 4.1 Hz), 7.99 (1H, d, J = 8.2 Hz), 7.81 (1H, d, J = 8.5 Hz), 7.34 (1H, m), 5.65 (1H, m), 4.93 (2H, m), 4.43 (1H, d, J = 5.3 Hz), 2.74 (1H, m), 2.50-2.21 (3H, m), 1.50 (3H, m), 1.04 (9H, s), 0.83 (3H, d, J = 6.4 Hz) and 0.77 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 174.0, 169.7, 169.2, 144.2, 140.7, 135.8, 135.4, 126.0, 123.6, 116.1, 61.0, 45.9, 45.5, 34.9, 33.7, 26.6, 25.3, 24.0 and 21.7.

 Example 29. 3R- (2,2-Dimethyl-1S- (4-hydroxyphenylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество желтого цвета. ¹H ЯМР; δ ((CD₃)₂SO), 10.46 (1H, с), 9.70 (1H, с), 9.17 (1H, с), 8.77 (1H, с), 8.00 (1H, д, J=8.7 Гц), 7.31 (2H, д, J=8.8 Гц), 6.70 (2H, д, J=8.8 Гц), 5.67 (1H, м), 4.93 (2H, м), 4.38 (1H, д, J= 8.7 Гц), 2.70 (1H, м), 2.31-2.19 (3H, м), 1.44 (3H, м), 0.98 (9H, с), 0.81 (3H, д, J= 6.3 Гц) и 0.73 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.8, 169.3, 168.4, 153.3, 135.9, 130.4, 121.0, 116.1, 114.9, 60.8, 45.8, 45.7, 34.9, 33.9, 26.7, 25.3,24.0 и 21.7.

The solid is yellow. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.46 (1H, s), 9.70 (1H, s), 9.17 (1H, s), 8.77 (1H, s), 8.00 (1H, d, J = 8.7 Hz), 7.31 (2H, d, J = 8.8 Hz), 6.70 (2H, d, J = 8.8 Hz), 5.67 (1H, m), 4.93 (2H, m), 4.38 (1H, d, J = 8.7 Hz), 2.70 (1H, m), 2.31-2.19 (3H, m), 1.44 (3H, m), 0.98 (9H, s), 0.81 (3H, d, J = 6.3 Hz) and 0.73 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.8, 169.3, 168.4, 153.3, 135.9, 130.4, 121.0, 116.1, 114.9, 60.8, 45.8, 45.7, 34.9, 33.9, 26.7, 25.3,24.0 and 21.7.

 Example 30. 3R .- (2,2-Dimethyl-1S- (3-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество белого цвета. ¹H ЯМР; δ ((CD₃)₂SO), 10.45 (1H, с), 9.96 (1H, с), 8.77 (1H, с), 7.99 (1H, д, J=8 Гц), 7.40 (1H, с), 7.26 (2H, м), 6.60 (2H, д, J=7.8 Гц), 5.60 (1H, м), 4.93 (2H, м), 4.40 (1H, д, J=8.5 Гц), 3.72 (3H, с), 2.81 (1H, м), 2.10- 2.49 (2H, м), 1.99 (1H, м), 1.44 (2H, м), 1.09 (9H, с), 0.99 (1H, м), 0.82 (3H, д, J-6.3 Гц) и 0.72 (3H, д, J=6.3 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.9, 169.3, 159.5, 140.0, 135.9, 129.5, 116.2, 111.6, 108.5, 61.1, 55.0, 45.9, 45.6, 40.3, 34.9, 33.9, 26.7, 25.3, 24.1 и 21.7.

The solid is white. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.45 (1H, s), 9.96 (1H, s), 8.77 (1H, s), 7.99 (1H, d, J = 8 Hz), 7.40 (1H, s), 7.26 (2H, m), 6.60 (2H, d, J = 7.8 Hz), 5.60 (1H, m), 4.93 (2H, m), 4.40 (1H, d, J = 8.5 Hz), 3.72 (3H, s ), 2.81 (1H, m), 2.10- 2.49 (2H, m), 1.99 (1H, m), 1.44 (2H, m), 1.09 (9H, s), 0.99 (1H, m), 0.82 (3H, d, J-6.3 Hz) and 0.72 (3H, d, J = 6.3 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.9, 169.3, 159.5, 140.0, 135.9, 129.5, 116.2, 111.6, 108.5, 61.1, 55.0, 45.9, 45.6, 40.3, 34.9, 33.9, 26.7, 25.3, 24.1 and 21.7.

 Example 31. 3R- (2,2-Dimethyl-1S- (pyridin-4-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid.

Твердое вещество светло-розового цвета. Т.пл. 210^oC (с разл.). ¹H ЯМР; δ ((CD₃)₂SO), 10.15 (2H, с), 8.28 (2H, д, J=3.9 Гц), 7.73 (1H, д, J=8.1 Гц), 7.44 (2H, д, J=5.1 Гц), 5.51 (1H, м), 4.81 (2H, м), 4.26 (1H, д, J=8.4 Гц), 2.75 (1H, м), 2.36 (2H, м), 2.11 (1H, м), 1.24 (2H, м), 0.88 (9H, с), 0.84 (1H, м), 0.68 (3H, д, J= 6.4 Гц) и 0.59 (3H, д, J=6.4 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 172.8, 169.3, 167.9, 148.6, 144,3, 134.5, 114.8, 111.9, 60.1, 44.6, 44.1, 33.6, 32.3, 2S.2, 23.9, 22.7 и 20.3.

The solid is light pink. Mp 210 ^o C (decomp.). ¹ H NMR; δ ((CD ₃ ) ₂ SO), 10.15 (2H, s), 8.28 (2H, d, J = 3.9 Hz), 7.73 (1H, d, J = 8.1 Hz), 7.44 (2H, d, J = 5.1 Hz), 5.51 (1H, m), 4.81 (2H, m), 4.26 (1H, d, J = 8.4 Hz), 2.75 (1H, m), 2.36 (2H, m), 2.11 (1H, m), 1.24 (2H, m), 0.88 (9H, s), 0.84 (1H, m), 0.68 (3H, d, J = 6.4 Hz) and 0.59 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 172.8, 169.3, 167.9, 148.6, 144.3, 134.5, 114.8, 111.9, 60.1, 44.6, 44.1, 33.6, 32.3, 2S.2, 23.9, 22.7 and 20.3.

 Example 32. 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfanylmethyl-hexanohydroxamic acid.

Стадия A. Бензиловый эфир 2-бенэилоксикарбонил-3R-(2,2- диметил-1S-(2-метоксифенилкарбамоил)-пропилкарбамоил)-5-метил- гексаногидроксамовой кислоты.

Step A. 2-Beneyloxycarbonyl-3R- (2,2-dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-hexanohydroxamic acid benzyl ester.

2-Benzyloxycarbonyl-3R-carboxy 5-methylhexanoic acid benzyl ester (obtained by the procedure described in EP 446267) (20.1 g, 50.5 mmol) and L-tert-leucine-N ¹ - (2-methoxyphenyl) amide (obtained by the method described in Example 1, Steps D and E) (14.3 g, 60.6 mmol) are dissolved together in ethyl acetate (300 ml). HOBt (8.2 g, 60.6 mmol) and EDC (11.6 g, 60.6 mmol) are added and the mixture is boiled with stirring during night time; TLC indicated that the reaction was complete. The solution is cooled and washed sequentially with 5% aqueous sodium bicarbonate (2 x 200 ml), 5% citric acid (2 x 200 ml) and brine (1 x 200 ml), dried over anhydrous magnesium sulfate, filtered and evaporated; brown oil is obtained (32.75 g, contains a small admixture of solvent), which is used in Step B without further purification. ¹ H NMR; δ (CDCl ₃ ), 8.07 (1H, s), 8.52 (1H, m), 7.40-7.22 (10H, m), 7.15 (1H, m), 6.96 (1H, m), 6.75 (1H, m ), 6.65 (1H, m), 5.12-5.04 (3H, w. M), 4.37 (1H, d, J = 9.0 Hz), 3.85 (1H, d, J = 9.6 Hz), 3.76 (3H, s) 3.08 (1H, m). 1.80-1.37 (3H, br.m), 1.06 (9H. S), 0.79 (3H, d, J = 6.4 Hz) and 0.71 (3H, d, J = 6.5 Hz).

 Stage B. 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) - propylcarbamoyl) -2-methylene-5-methyl-hexanohydroxamic acid.

2-Benzyloxycarbonyl-3R- (2,2-dimethyl-1S- (2-methoxy-phenylcarbamoyl) -propylcarbamoyl) -5-methyl-hexanohydroxamic acid benzyl ester (28.7 g, 45.40 mmol) was dissolved in ethanol (200 ml) and a solution placed in an argon atmosphere. 10% palladium on carbon is added and a stream of hydrogen is gradually passed through the suspension with stirring for 3 hours. TLC shows that the reaction has passed. The system is purged with argon and the catalyst is filtered off. The filtrate was cooled in an ice bath with stirring, and piperidine (4.07 g, 47.4 mmol) was added dropwise, followed by a 37% formaldehyde solution (32.3 g, about 430 mmol). The reaction mixture was slowly brought to room temperature, then stirred overnight. The solvents were distilled off in vacuo and the remaining oil was disproportionated between ethyl acetate (300 ml) and 1M hydrochloric acid (300 ml). The organic layer was separated, washed with 1M hydrochloric acid and brine, dried over magnesium sulfate and evaporated to dryness. The remaining light brown foam (18.94 g, crude) contains a small amount of impurities, but it is used in Stage C without purification. ¹ H NMR; δ (CD ₃ OD), 7.55 (1H, m), 7.09 (3H, m), 6.95 (1H, m), 6.59 (1H, m), 6.26 (1H, s), 5.72 (1H, s), 4.30 (1H, d, J = 9.2 Hz), 3.67 (1H, s), 3.65 (1H, m), 1.70 (1H, m), 1.41 (2H, m), 0.91 (1H, s), 0.81 (3H, d, J = 6.3 Hz) and 0.76 (3H, d, J = 6.3 Hz).

 Step C. 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfanylmethyl-hexanoic acid.

3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) - propylcarbamoyl) -2-methylene-5-methyl-hexanohydroxamic acid (20.43 g, 48.7 mmol) is dissolved in methanol, placed in an argon atmosphere, and then 2 mercaptothiophene (20 ml). The mixture was stirred overnight in the dark under argon at 60 ^° C. The solvent was distilled off in vacuo, cold diethyl ether (200 ml) was added to the remaining oil. When standing in an ice bath, a product falls out; it is separated by filtration, washed thoroughly with cold diethyl ether. Then it is purified by trituration with hot ethyl acetate and then column chromatography (silica gel, eluent 0 ---> 20% methanol / methylene chloride). The fractions were combined and evaporated to give the title compound as an off-white foam (18.80 g, 72%). ¹ H NMR; δ (CDCl ₃ ), 7.33 (1H, m), 7.14-7.09 (2H, m), 7.10 (1H, m), 6.95-6.85 (2H, m), 4.31 (1H, s), 3.66 (3H , s), 2.99-2.58 (4H, m), 1.60-1.48 (1H, m), 1.37-1.18 (1H, m), 1.01 (1H, m), 0.95 (9H., s), 0.75 ( 3H, d, J = 6.5 Hz) and 0.68 (3H, d, J = 6.5 Hz).

Stage D. 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfanylmethyl-hexanohydroxamic acid
To a solution of 3R- (2,2-dimethyl-1S- (2-methoxyphenylcarbamoyl) - propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfanylmethyl-hexanoic acid (20.43 g, 38.1 mmol) in DMF (100 ml) at under ice-cooling, HOBt (6.18 g, 45.7 mmol) was added, followed by EDC (8.77 g, 45.7 mmol). The mixture was stirred at 0 ^° C. for 1 hour, then again at room temperature for 2 hours, cooled again to 0 ^° C. and hydroxylamine hydrochloride (3.97 g, 57.2 mmol) and NMM (5.78 g, 57.2 mmol) were added. The reaction mixture was stirred overnight at room temperature, evaporated, the oil was triturated (vigorously stirred) with 1: 1 diethyl ether / water (240 ml) and left to stand for 1.5 hours. The precipitate formed is filtered off and washed thoroughly with cold diethyl ether. HOBt was removed by crystallization from ethyl acetate and the mother liquor was evaporated; get the title compound as an orange foam (4.96 g, 24%). Mp 191-195 ^° C. ¹ H NMR; δ (CD ₃ OD), 8.07 (1H. d, J = 8.8 Hz), 7.31 (1H, m), 7.11 (2H, m), 7.02 (1H, m), 6.92 (1H, m), 6.86 (1H , m), 6.56 (1H, m), 4.28 (1H, m), 3.66 (3H, s), 3.00 (1H, m), 2.75 (1H, m), 2.62 (1H, m), 2.35 (1H, m), 1.43 (1H, m), 1.25 (1H, m), 1.03 (1H, m), 0.94 (9H, s), 0.75 (3H, d, J = 6.4 Hz) and 0.67 (3H, d, J = 6.6 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 176.2, 171.2, 165.4, 161.9, 140.8, 135.2, 131.0, 130.9, 128.0, 114.0, 111.3, 107.7, 63.4, 56.0, 46.2, 42.0, 40.8, 35.8, 27.7, 27.4, 24.7 and 22.2. IR v _max (KBr), 3294, 3087, 2959, 1771, 1644, 1547, 1439, 1386, 1245 and 1369 cm ^-1 . Found: C 57.80, H 6.99, N 7.74%; C ₂₅ H ₃₇ N ₂ O ₅ S ₂ • 0.3H ₂ O calculated: C 57.71, H 7.00, N 7.77%.

 The following additional compound is prepared according to the procedure described in Example 34.

 Example 33. 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-thien-2-yl sulfanylmethylhexanoic acid.

Белое кристаллическое вещество. Т.пл. 199-200^oC. ¹H ЯМР; δ ((CD₃)₂SO), 8.82 (1H, с), 8.15 (1H, м), 7.89 (1H, м), 7.86 (1H, м), 7.60 (1H, м), 7.44 (1H, м), 6.93 (2H, м), 6.87 (1H, м), 4.36 (1H, д, J=8.3 Гц), 3.04 (1H, м), 2.75 (1H, м), 2.56 (1H, м), 2.22 (1H, м), 1.29 (1H, м), 1.12 (1H, м), 0.90 (1H, м), 0.82 (9H, с), 0.65 (3H, д, J=6.4 Гц) и 0.55 (3H, д, J=6.5 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.1, 170.0, 167.9, 151.5. 148.0, 138.0, 133.8, 132.6, 129.6, 127.8, 119.3, 113.6, 60.7, 48.6, 46.0, 45.6, 33.6, 26.6, 25.2, 23.9 и 21.5. IR; v_max (KBr), 3256, 2890, 2871, 1651, 1579, 1520, 1466, 1435, 1369, 1298, 1217, 1152, 1054 и 1002 см^-1.

White crystalline substance. Mp 199-200 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 8.82 (1H, s), 8.15 (1H, m), 7.89 (1H, m), 7.86 (1H, m), 7.60 (1H, m), 7.44 (1H, m ), 6.93 (2H, m), 6.87 (1H, m), 4.36 (1H, d, J = 8.3 Hz), 3.04 (1H, m), 2.75 (1H, m), 2.56 (1H, m), 2.22 (1H, m), 1.29 (1H, m), 1.12 (1H, m), 0.90 (1H, m), 0.82 (9H, s), 0.65 (3H, d, J = 6.4 Hz) and 0.55 (3H, d, J = 6.5 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.1, 170.0, 167.9, 151.5. 148.0, 138.0, 133.8, 132.6, 129.6, 127.8, 119.3, 113.6, 60.7, 48.6, 46.0, 45.6, 33.6, 26.6, 25.2, 23.9 and 21.5. IR v _max (KBr), 3256, 2890, 2871, 1651, 1579, 1520, 1466, 1435, 1369, 1298, 1217, 1152, 1054 and 1002 cm ^-1 .

 Example 34. 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfinylmethyl-hexanohydroxamic acid.

3R-(2,2-Диметил-1S-(2-метоксифенилкарбамоил)- пропилкарбамоил)-5-метил-2S-тиен-2-илсульфанилметил- гексаногидроксамовую кислоту (полученную в Примере 32) (1.00 г, 1.81 ммоля) растворяют в метаноле (20 мл) и, охлаждая раствор до 0^oC (лед + вода), прибавляют к нему m-CPBA (0.34 г, 2.00 ммоля). Реакционную смесь доводят до комнатной температуры, перемешивают в течение 4 часов и растворитель отгоняют в вакууме. Остаток растирают с эфиром, образующийся твердый сырой продукт отфильтровывают. Перекристаллизацией из этилацетата получают двумя порциями названное соединение в виде белого порошка (304 мг, 30%). Т.пл. 210-211^oC. ¹H ЯМР; δ (CD₃OD), 7.31 (1H, м), 7.11 (2H, м), 7.01 (2H, м), 7.00 (1H, м), 6.81 (1H, м), 6.80 (1H, м), 6.56 (1H, м), 4.29 (1H, м), 3.56 (3H, с), 2.95 (1H, м), 2.73 (1H, м), 2.63 (1H, м), 2.37 (1H, м), 1.43 (1H, м), 1.26 (1H, м), 1.05 (1H, м), 0.95 (9H, с), 0,75 (3H, д. J= 6,4 Гц) и 0.68 (3H, д, J=6,5 Гц). ¹³C ЯМР; δ (CD₃OD), 175.5, 170.7, 170.6, 161.1, 140.0, 134.5, 130.3, 130.2, 128.2, 113.3, 110.6, 107.0, 62.6, 55.3, 41.3, 40.1, 35.1, 27.0, 26.7, 24.0 и 21.5. IR; v_max (KBr), 3292, 1614, 1538, 1489, 1428, 1371, 1232 и 1047 см^-1. Найдено: С 55.70, Н 6.68, N 7.39%; C₂₆H₃₇N₃O₆S₂•0.5H₂O вычислено: C 55.69, H 6.83, N 7.49%.

3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfanylmethyl-hexanohydroxamic acid (obtained in Example 32) (1.00 g, 1.81 mmol) is dissolved in methanol (20 ml) and, cooling the solution to 0 ^o C (ice + water), add m-CPBA (0.34 g, 2.00 mmol) to it. The reaction mixture was brought to room temperature, stirred for 4 hours and the solvent was distilled off in vacuo. The residue is triturated with ether, the resulting solid crude product is filtered off. Recrystallization from ethyl acetate gave the title compound in two portions as a white powder (304 mg, 30%). Mp 210-211 ^o C. ¹ H NMR; δ (CD ₃ OD), 7.31 (1H, m), 7.11 (2H, m), 7.01 (2H, m), 7.00 (1H, m), 6.81 (1H, m), 6.80 (1H, m), 6.56 (1H, m), 4.29 (1H, m), 3.56 (3H, s), 2.95 (1H, m), 2.73 (1H, m), 2.63 (1H, m), 2.37 (1H, m), 1.43 ( 1H, m), 1.26 (1H, m), 1.05 (1H, m), 0.95 (9H, s), 0.75 (3H, d.J = 6.4 Hz) and 0.68 (3H, d, J = 6.5 Hz). ¹³ C NMR; δ (CD ₃ OD), 175.5, 170.7, 170.6, 161.1, 140.0, 134.5, 130.3, 130.2, 128.2, 113.3, 110.6, 107.0, 62.6, 55.3, 41.3, 40.1, 35.1, 27.0, 26.7, 24.0 and 21.5. IR v _max (KBr), 3292, 1614, 1538, 1489, 1428, 1371, 1232 and 1047 cm ^-1 . Found: C 55.70, H 6.68, N 7.39%; C ₂₆ H ₃₇ N ₃ O ₆ S ₂ • 0.5H ₂ O calculated: C 55.69, H 6.83, N 7.49%.

 The following additional compound is prepared according to the procedure described in Example 34.

 Example 35. 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl) propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfinylmethyl-hexanohydroxamic acid.

Белый порошок. Т.пл. 166-166.5^oC ¹H ЯМР; δ (CD₃OD), 8.18 (1H, м), 7.94 (1H, м), 7.82 (1H, м), 7.64 (1H, м), 7.50 (1H, м), 7.10 (1H, м), 7.00 (1H, м), 4.42 (1H, м), 3.53 (1H, м), 2.99 (1H, м), 2.77 (1H, м), 1.53 (1H, м), 1.34 (1H, м), 1.13 (1H, м), 0.98 (9H, с), 0.77 (3H, м), и 0.65 (3H, м). ¹³C ЯМР; δ (CD₃OD), 175.4, 171.2, 169.9, 152.7, 149.2, 144.8, 139.4, 134.2, 133.5, 128.6, 121.1, 115.6, 63.2, 61.2, 59.8, 43.2, 41.2, 35.3, 27.4, 27.0, 24.3 и 21.8. IR; v_max (KBr), 3259, 2959, 1647, 1578, 1529, 1467, 1435, 1369, 1297, 1224, 1152 и 1034 см^-1. Найдено: C 53.64, H 6.52, N 10.33%; C₂₄H₃₄N₄O₅S₂•0.8H₂O вычислено: C 53.67, H 6.68, N 10.43%.

White powder. Mp 166-166.5 ^° C ¹ H NMR; δ (CD ₃ OD), 8.18 (1H, m), 7.94 (1H, m), 7.82 (1H, m), 7.64 (1H, m), 7.50 (1H, m), 7.10 (1H, m), 7.00 (1H, m), 4.42 (1H, m), 3.53 (1H, m), 2.99 (1H, m), 2.77 (1H, m), 1.53 (1H, m), 1.34 (1H, m), 1.13 ( 1H, m), 0.98 (9H, s), 0.77 (3H, m), and 0.65 (3H, m). ¹³ C NMR; δ (CD ₃ OD), 175.4, 171.2, 169.9, 152.7, 149.2, 144.8, 139.4, 134.2, 133.5, 128.6, 121.1, 115.6, 63.2, 61.2, 59.8, 43.2, 41.2, 35.3, 27.4, 27.0, 24.3 and 21.8 . IR v _max (KBr), 3259, 2959, 1647, 1578, 1529, 1467, 1435, 1369, 1297, 1224, 1152 and 1034 cm ^-1 . Found: C, 53.64; H, 6.52; N, 10.33%; C ₂₄ H ₃₄ N ₄ O ₅ S ₂ • 0.8H ₂ O calculated: C 53.67, H 6.68, N 10.43%.

 Example 36. 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-phenylhexanoic acid.

К раствору N²-[2R-(2,2-диметил-4-оксо-1,3-диоксалан-5S-ил)-6- фенилгексаноил]-L-трет-лейцин-N¹-фениламида (полученного по методике, аналогичной описанной в Примере 4) (1.00 г, 2.08 ммоля) в THF (15 мл) при охлаждении до 0^oC прибавляют 1М соляную кислоту (15 мл). Смесь перемешивают при комнатной температуре до исчезновения исходного соединения (ТСХ, несколько дней). Растворитель отгоняют в вакууме, получают пену бледно-желтого цвета; растворяют ее в этилацетате и фильтруют через слой силикагеля. Продукт дополнительно очищают экстракцией 1М раствором карбоната натрия, подкислением 1М соляной кислотой и повторной экстракцией этилацетатом. Этилацетатный слой сушат над сульфатом магния, фильтруют и упаривают в вакууме, получают названное соединение в виде пены беловатого цвета (320 мг, 35%; смесь диастереомеров 3: 1). Т.пл. 159^oC. ¹H ЯМР; δ (CD₃OD); 7.51- 7.48 (2H, м), 7.26-7.00 (8H, м), 4.39 (1H, с), 4.25 (0.25H, д, J=3,7 Гц), 4.18 (0.75H, д, J=2,7 Гц), 2.90 (1H, ш.с), 2.56-2.51 (2H, ш.м), 1.74-1.56 (4H, м) и 1.02 (9H, с). ¹³C ЯМР; δ (CD₃OD), 179.3, 176.9, 171.1, 143.4, 139.2, 129.7, 129.4, 126.7, 125.5, 121.8, 73.6, 63.1, 50.9, 36.6, 35.6, 30.5 и 27.4. Найдено: C 66.07, H 7.21, N 5.98%; C₂₅H₃₂N₂O₅•0.8H₂O вычислено: C 66.00, H 7.44, N 6.16%.

To a solution of N ² - [2R- (2,2-dimethyl-4-oxo-1,3-dioxalan-5S-yl) -6-phenylhexanoyl] -L-tert-leucine-N ¹ -phenylamide (obtained by the method, similar to that described in Example 4) (1.00 g, 2.08 mmol) in THF (15 ml), while cooling to 0 ^° C., 1M hydrochloric acid (15 ml) was added. The mixture was stirred at room temperature until the starting compound disappeared (TLC, several days). The solvent was distilled off in vacuo to give a pale yellow foam; dissolve it in ethyl acetate and filter through a layer of silica gel. The product is further purified by extraction with 1M sodium carbonate solution, acidification with 1M hydrochloric acid and repeated extraction with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give the title compound as a whitish foam (320 mg, 35%; 3: 1 mixture of diastereomers). Mp 159 ^o C. ¹ H NMR; δ (CD ₃ OD); 7.51- 7.48 (2H, m), 7.26-7.00 (8H, m), 4.39 (1H, s), 4.25 (0.25H, d, J = 3.7 Hz), 4.18 (0.75H, d, J = 2 , 7 Hz), 2.90 (1H, br.s), 2.56-2.51 (2H, br.m), 1.74-1.56 (4H, m) and 1.02 (9H, s). ¹³ C NMR; δ (CD ₃ OD), 179.3, 176.9, 171.1, 143.4, 139.2, 129.7, 129.4, 126.7, 125.5, 121.8, 73.6, 63.1, 50.9, 36.6, 35.6, 30.5 and 27.4. Found: C, 66.07; H, 7.21; N, 5.98%; C ₂₅ H ₃₂ N ₂ O ₅ • 0.8H ₂ O calculated: C 66.00, H 7.44, N 6.16%.

 Example 37. 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanoic hydroxycitric acid.

Стадия А. Бензиловый эфир 2-бензилоксикарбонил-3R-трет-бутоксикарбонил-5- метил-2-фталимидометилгексановой кислоты.

Stage A. 2-Benzyloxycarbonyl-3R-tert-butoxycarbonyl-5-methyl-2-phthalimidomethylhexanoic acid benzyl ester.

To a solution of 2-benzyloxycarbonyl-3R-tert-butoxycarbonyl-5-methylhexanoic acid benzyl ester (prepared according to the procedure described in EP 0446267) (39.4 g, 86.78 mmol) in dry DMF (400 ml) with cooling (ice) was added. sodium hydride (60% dispersed in mineral oil, 3.83 g, 95.46 mmol). The resulting mixture was kept at 0 ^o C for 20 minutes, brought to room temperature and stirred for another 2.5 hours. After cooling to 0 ^° C., (N-bromomethyl) phthalimide (25 g, 104.1 mmol) was added and the mixture was stirred for 0.5 hours at 0 ^° C. and then overnight at room temperature. The solvent was distilled off in vacuo, the remaining oil was extracted with diethyl ether (400 ml), and the solid residues were filtered off. The filtrate was washed successively with water (300 ml), 1M hydrochloric acid (300 ml) and brine (300 ml), dried over anhydrous magnesium sulfate and filtered. The solution was evaporated in vacuo to give a yellow oil, which was purified by column chromatography (silica gel, 50% diethyl ether and hexane) to give the title compound as a colorless oil (26.24 g, 49%). ¹ H NMR; δ (CDCl ₃ ), 7.78 (2H, m), 7.67 (2H, m), 5.28-5.05 (4H, m), 4.54-4.35 (2H, m), 3.03 (1H, m), 1.86 (1H, m), 1.68 (1H, m), 1.50 (9H, s), 1.49 (1H, m), 0.82 (3H, d, J = 6.6 Hz) and 0.78 (3H, d, J = 6.5 Hz) .

 Stage B. 3R-tert-Butoxycarbonyl-5-methyl-2-phthalimidomethylhexanoic acid.

2-Benzyloxycarbonyl-3R-tert-butoxycarbonyl-5-methyl-2-phthalimidomethylhexanoic acid benzyl ester (26.24 g, 42.8 mmol) is deesterified by catalytic hydrogenolysis in ethanol according to the procedure described in Example 32 (Step B). The solvent was distilled off in vacuo, the residue was dissolved in toluene (250 ml) and NMM (4.33 g, 42.8 mmol) was added. The mixture is boiled for 2 hours. The solvents were evaporated, the remaining oil was dissolved in ethyl acetate, and the solution was washed with 5% citric acid (2 x 200 ml) and brine (200 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to obtain the desired product as a yellow foam (16.58 g, including solvent), which was directly used in Step C. ¹ H NMR; δ (CDCl ₃ ), 7.83 (2H, m), 7.72 (10H, m), 4.12 (1H, m), 3.83 (1H, m), 3.21 (1H, m), 2.72 (1H, m), 1.81- 1.55 (1H, m), 1.48 (9H, s), 1.31 (1H, m) and 0.92 (6H, m).

 Stage C. 3R-Tert-butoxycarbonyl-5-methyl-2-phthalimidomethyl-hexanoic acid benzyl ester.

3R-tert-Butoxycarbonyl-5-methyl-2-phthalimidomethylhexanoic acid (16.58 g, 42.56 mmol) was dissolved in dry DMF and transferred to argon atmosphere. The solution was cooled in an ice bath, benzyl bromide (5.56 g, 46.82 mmol) and anhydrous sodium carbonate (4.96 g, 46.82 mmol) were added, and the mixture was allowed to stir at room temperature overnight. The solvent was distilled off in vacuo, and the remaining oil was dissolved in diethyl ether (300 ml) and washed successively with water (2 x 200 ml), 1M hydrochloric acid (2 x 200 ml) and brine (200 ml). The organic layer was dried (anhydrous magnesium sulfate), filtered and evaporated; get crude yellow oil; which is purified by column chromatography (silica gel, stepwise elution, 30 ---> 50% diethyl ether in hexane). The desired product is isolated as a pale yellow oil (18.2 g, 89%; 3: 2 mixture of diastereomers). ¹ H NMR; δ (CDCl ₃ ), 7.78 (2H, m), 7.24 (5H, m), 5.05 (2H, m), 4.18-4.04 (1H, m), 3.81 (1H, m), 3.15 (1H , m), 2.73 (1H, m), 1.72-1.53 (2H, b.m), 1.50 (5.4H, s), 1.41 (3.6H, s), 1.11 (1H, m) and 0.90 (6H, m )

 Stage D. 3R-Tert-carboxy-5-methyl-2-phthalimidomethylhexanoic acid benzyl ester.

The protection in 3R-tert-butoxycarbonyl-5-methyl-2-phthalamidomethylhexanoic acid benzyl ester was removed by acidification under the action of TFA according to the procedure described in Example 1 (Step G). The product was isolated as a pale yellow oil (16.54 g, containing residual solvent) and used in Step E without further purification. ¹ H NMR; δ (CDCl ₃ , mixture of diastereomers 3: 2), 8.28 (1H, br.s), 7.78 (2H, m), 7.68 (2H, m), 7.25 (5H, m), 5.08 (2H, m), 4.15 (1H.m), 3.89 (1H, m), 3.25 (1H, m), 2.88 (1H, m), 1.82-1.52 (2H, m), 1.25 (1H, m) and 0.89 (6H, m) )

 Step E. 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanoic acid benzyl ester.

ZR-tert-carboxy-5-methyl-2-phthalimidomethylhexanoic acid benzyl ester was dissolved in ethyl acetate (200 ml). HOBt (5.21 g, 38.58 mmol) and EDC (7.40 g, 38.58 mmol) were added and the reaction mixture was stirred for 3.5 hours to ensure complete formation of the activated ester. L-tert-leucine-N- (2-pyridyl) amide (7.32 g, 35.36 mmol) was added and the reaction mixture was boiled overnight. The solution was cooled and washed successively with 5% aqueous sodium bicarbonate (2 x 200 ml) and water (2 x 200 ml). The organic layer was dried (anhydrous magnesium sulfate), filtered and evaporated in vacuo; get yellow foam. Chromatography on a column (silica gel, stepwise elution, 20 ---> 50% ethyl acetate in hexane) gives the desired product as an indivisible mixture of diastereomers (16.89 g, 86%). ¹ H NMR; δ (CDCl ₃ ), 9.76 (0.6H, s), 9.58 (0.4H, s), 8.45 (1H, m). 8.25 (1H, m), 7.85-7.60 (5H, m), 7.23 (4H, m), 7.08 (2H, m), 5.05 (2H, m), 4.76 (0.6H, m), 4.57 (0.4 H, m), 4.03 (2H, m), 3.33 (0.6H, m), 3.22 (0.4H, m), 2.85 (0.6H, m), 2.70 (0.4H, m), 1.78 (1H, m) , 1.55 (2H, m), 1.10 (5.5H, s), 1.05 (3.5H, s) and 0.93-0.67 (6H, b.m).

 Step F. 3R- (2.2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) - 5-methyl-2S-phthalimidomethylhexanoic acid.

The protection of 3R- (2,2-dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanoic acid benzyl ester (5.08 g, 8.3 mmol) was removed by catalytic hydrogenolysis in ethanol according to the procedure described in Example 1 (Stage E). The product was isolated as a white solid (4.34 g, 75%) after evaporation of the solvent and was used without further purification. ¹ H NMR; δ (CD ₃ OD, mixture of diastereomers 3: 2), 8.31 (1H, m), 8.08 (1H, m), 7.81 (5H, m), 7.11 (1H, m), 4.61 (0.6H, s), 4.52 (0.4H, s), 4.11 (0.6H, m), 3.99 (0.4H, m), 3.76 (1H, m), 3.14-2.85 (2H, m), 1.73 (1H, m), 1.53 ( 2H, m), 1.14 (5.5H, s), 1.08 (3.5H, s), 0.92 (3.6H, m) n 0.82 (2.4H, m).

 Step G. 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanohydroxamic acid.

3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanoic acid is converted to the corresponding hydroxamic acid according to the procedure described in Example 32 (Step D). The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate, 5% citric acid and brine, dried (anhydrous magnesium sulfate), filtered and evaporated. The product is purified by column chromatography (water-washed silica gel, stepwise elution 0 ---> 5% methanol in methylene chloride). Yield: 2.10 g (63%). ¹ H NMR; δ ((CD ₃ ) ₂ SO) mixture of diastereomers 2: 1), 8.42-8.15 (1H, s), 8.15 (2H, b.m), 7.65 (5H, m), 6.99 (1H, m), 4.68 ( 0.75H, m), 4.55 (0.25H, m), 4.07 (1H, m), 3.52 (1H, m), 2.99-2.72 (2H, m), 1.34-1.24 (3H, m), 1.17 (6H, s), 0.95 (3H, s). 0.79 (3H, m) and 0.68 (3H, m).

 Example 38. 3R- (2,2-Dimethyl-1S- (N-hydroxy-pyridin-2-yl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanoic hydroxycamic acid.

3R-(2,2-Димeтил-1S-пиpидин-2-илкapбaмoил-пpопилкapбамоил) -2S-гидрокси-5-метилгексаногидроксамовую кислоту (Пример 8) (100 мг, 0.25 ммоля) растворяют в хлористом метилене (10 мл) и добавляют m-CPBA (48 мг, 0.28 ммоля). Реакционную смесь перемешивают 3 часа при комнатной температуре. ТСХ-анализ показывает, что исходное превратилось в более полярное соединение с положительной реакцией на хлористое железо. Растворитель отгоняют в вакууме и остаток чистят хроматографией на колонке (промытый водой силикагель, 10% метанол в хлористом метилене); получают названное соединение в виде стекловидного твердого вещества (60 мг, 58%). Т. пл. 150-152^oC. ¹H ЯМР; δ ((CD₃)₂SO), 8.42-8.26 (2H, м), 8.19 (1H, д, J=7.9 Гц), 7.53-7.43 (1H, м), 7.16-7.06 (1H, м), 4.47 (1H, д, J= 7.8 Гц), 4.02 (1H, д, J=6.1 Гц), 2.96-2.84 (1H, м), 1.63-1.38 (2H, м), 1.26-1.07 (1H, м), 0.99 (9H, с), 0.82 (3H, д, J=6.4 Гц) и 0.75 (3H, д, J=6.4 Гц). ¹³C ЯМР; δ ((CD₃)₂SO), 173.1, 170.3, 168.7, 143.2, 137.4, 127.2, 119.5, 114.5, 71.2, 62.1, 47.5, 37.2, 33.6, 26.6, 25.2, 23.6 и 21.8. IR; v_max (KBr), 3258, 2958, 1652, 1510 и 1430 см^-1.

3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid (Example 8) (100 mg, 0.25 mmol) was dissolved in methylene chloride (10 ml) and m -CPBA (48 mg, 0.28 mmol). The reaction mixture was stirred for 3 hours at room temperature. TLC analysis shows that the original has turned into a more polar compound with a positive reaction on ferric chloride. The solvent was distilled off in vacuo and the residue was purified by column chromatography (water-washed silica gel, 10% methanol in methylene chloride); get the title compound as a glassy solid (60 mg, 58%). T. pl. 150-152 ^o C. ¹ H NMR; δ ((CD ₃ ) ₂ SO), 8.42-8.26 (2H, m), 8.19 (1H, d, J = 7.9 Hz), 7.53-7.43 (1H, m), 7.16-7.06 (1H, m), 4.47 (1H, d, J = 7.8 Hz), 4.02 (1H, d, J = 6.1 Hz), 2.96-2.84 (1H, m), 1.63-1.38 (2H, m), 1.26-1.07 (1H, m), 0.99 (9H, s), 0.82 (3H, d, J = 6.4 Hz) and 0.75 (3H, d, J = 6.4 Hz). ¹³ C NMR; δ ((CD ₃ ) ₂ SO), 173.1, 170.3, 168.7, 143.2, 137.4, 127.2, 119.5, 114.5, 71.2, 62.1, 47.5, 37.2, 33.6, 26.6, 25.2, 23.6 and 21.8. IR v _max (KBr), 3258, 2958, 1652, 1510 and 1430 cm ^-1 .

Стадия A. Диметиловый эфир 2S-гидрокси-ЗR- изобутилянтарной кислоты.Example 39. N1- [2,2-dimethyl-1S- (pyridin-2-ylcarbamoyl) propyl] -N4-hydroxy-2R-isobutyl-3S-methoxy-succinamide

Stage A. 2S-hydroxy-3R-isobutyl succinic acid dimethyl ester.

2R- (2,2-dimethyl-5-oxo- [1,3] dioxolan-4S-yl) -4-methylpentanoic acid (75.0 g, 0.326 mmol) was dissolved in methanol (500 ml), cooled to 0 ^o C and saturate the resulting solution with gaseous hydrogen chloride. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure, the precipitate was dissolved in dichloromethane and washed successively with a saturated solution of sodium hydrogencarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain the desired compound as a yellow oil (53 g, 75%). ¹ H-NMR; δ (CDCl ₃ ), 4.10 (1H, d, J = 4.0 Hz), 3.60 (3H, s), 3.50 (3H, s), 3.18 (br s), 2, 78 (1H, m), 1.61-1.40 (2H, m), 1.28 (1H, m) and 0.76-0.73 (6H, m).

 Stage B. 2R-Isobutyl-3S-methoxy succinic acid dimethyl ester.

2S-hydroxy-3R-isobutyl succinic acid dimethyl ester (23.9 g, 110 mmol) was dissolved in DMF (200 ml) and distilled iodomethane (8.2 ml, 132 mmol) was added, followed by the introduction of silver oxide (I) (27, 95 g, 121 mmol). The reaction mixture was stirred at room temperature in the dark for 7 days. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, dichloromethane as eluent) to obtain the title compound as a viscous yellow oil (19.16 g, 75%). ¹ H-NMR; δ (CDCl ₃ ), 3.83 (1H, d, J = 7.5 Hz), 3.71 (3H, s), 3.62 (3H, s), 3.30 (3H, s), 2 85 (1H, m), 1.65-1.39 (2H, m), 1.10 (1H, m) and 0.83-0.81 (6H, m).

 Stage C. Dilithium salt of 2R-isobutyl-3S-methoxy succinic acid.

To a solution of 2R-isobutyl-3S-methoxy succinic acid dimethyl ester (4.70 g, 20.0 mmol) in methanol (30 ml) and water (30 ml) lithium hydroxide (1.76 g, 42.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, then the solvents were removed under reduced pressure to give the title compound as a yellow solid (4.40 g, quant.). ¹ H-NMR; δ (CD ₃ OD), 3.52 (1H, d, J = 5, l Hz), 3.27 (3H, s), 2.65 (1H, m), 1.56-1.53 (2H , m), 1.31 (1H, m) and 0.82-0.78 (6H, m).

 Step D. 2R-Isobutyl-35-methoxy succinic acid 4-methyl ester.

Dilithium salt of 2R-isobutyl-3S-methoxy succinic acid (25.14 g, 116 mmol) was dissolved in dry THF (150 ml) and the solution was cooled to 0 ^° C. Trifluoroacetic anhydride (30 ml) was added and the mixture was stirred at 0 ^° C. within 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous methanol (200 ml) at 0 ^° C. and the solution was stirred at room temperature overnight. The solvent was removed under reduced pressure to give the title compound as a yellow oil (54.3 g, including 2 equivalents of lithium trifluoroacetate), which was used without further purification in Step E. ¹ H-NMR; δ (CD ₃ OD), 7.71 (1H, d, J = 7.5 Hz), 3.65 (3H, s), 2.72 (1H, m), 1.56-1.42 (2H , m), 1.06 (1H, m) and 0.81-0.79 (6H, m).

 Stage E. Methyl ether ZR- [2,2 dimethyl-1S-pyridylcarbamoyl) propylcarbamoyl] -2S-methoxy-5-methylhexanoic acid.

The product obtained in Step D (25.06 g, equivalently 53.7 mmol of 2R-isobutyl-3S-methoxy succinic acid 4-methyl ester) was dissolved in DMF (200 ml) and the solution was cooled to 0 ^° C. during the addition of HOBt (8 70 g, 53.7 mmol) followed by the addition of EDC (12.35 g, 64.4 mmol). The mixture was stirred and allowed to warm to room temperature for 2 hours. The active ester solution thus obtained was cooled to 0 ^° C., L-tert-leucine-N- (2-pyridyl) amide (11.11 g, 53.7 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed sequentially with a 1M sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel, 0-5% methanol in dichloromethane) to give the title compound as a white substance (13.41 g, 61%). ¹ H-NMR; δ (CDCl ₃ ), 9.61 (1H, s), 8.47 (1H, m), 8.24 (1H, d, J = 8.4 Hz), 7.74 (1H, m), 7 07 (1H, m), 6.97 (1H, d, J = 8.9 Hz), 4.64 (1H, d, J = 8.9 Hz), 4.01 (1H, d, J = 7.6 Hz), 3.76 (3H, s), 3.41 (3H, s), 2.75 (1H, m), 1.79 (1H, m), 1.51 (1H, m) , 1.11 (1H, m), 1.02 (9H, s), 0.84 (3H, d, J = 6.3 Hz) and 0.82 (3H, d, J = 6.3 Hz).

 Stage F. Lithium salt of 3R- [2,2-dimethyl-1S- (pyridin-2-ylcarbamoyl) propylcarbamoyl] -2S-methoxy-5-methylhexanoic acid.

3R- [2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl) propylcarbamoyl] -2S-methoxy-5-methylhexanoic acid methyl ester (13.4 g, 32.9 mmol) was dissolved in a mixture of THF (265 ml) and water (65 ml) and lithium hydroxide monohydrate (1.396 g, 33.3 mmol) is added. The solution was stirred at room temperature for 2 hours, then evaporated under reduced pressure to give a yellow oil, which was dried by azeotropic distillation with toluene. The resulting product (13.4 g, containing residual solvent) was used without further purification. ¹ H-NMR; δ (CD ₃ OD), 3.5: 1 (mixture of diastereoisomers), 8.31 (1H, m), 7.99 (1H, d, J = 8.3 Hz), 7.66 (1H, m) , 7.00 (1H, m), 4.49 (0.23 H, s; a small amount of diastereoisomer), 4.37 (0.77 H, s, main diastereoisomer), 3.68 (0.23H, d, J = 7.6 Hz, small amount of diastereoisomer), 3.52 (0.77H, d, J = 7.6 Hz; main diastereoisomer), 3.21 (0.69H, s; small quantity of diastereoisomer) 3.20 (2.31 H, s, basic diastereoisomer), 2.64 (1H, m), 1.53 (2H, br, m), 1.18 (1H, m), 1.01 (9H , s), 0.85 (3H, d, J = 6.4 Hz), and 0.81 (3H, d, J = 6.3 Hz).

 Step G. N4-Benzyloxy-N1- [2,2-dimethyl-1S- (pyridin-2-ylcarbamoyl) propyl] -2R-isobutyl-3S-methoxy-succinamide.

The product from Stage F (13.4 g, approximately 33 mmol) was dissolved in dry DMF (250 ml), placed under argon atmosphere and cooled to -10 ^° C with stirring. Ethyl chloroformate (3.47 ml, 36 mmol) was then added dropwise and then NMM (1.8 ml, 16.5 mmol). The mixture was stirred for 30 minutes, then O-benzylhydroxylamine (6 g, 49 mmol) in DMF (10 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and was left stirring overnight. The solvent was removed under reduced pressure and the residue was separated with ethyl acetate and brine. The organic layer was washed with 1M sodium carbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica gel, 5% methanol in dichloromethane). Fractions containing the desired product are collected and evaporated. The resulting product was triturated with diethyl ether to remove a slightly colored impurity. Yield: 9.44 g (58%,> 10: 1 mixture of diastereoisomers). ¹ H-NMR; δ (CDCl ₃ , basic diastereoisomer), 10.26 (1H, s), 9.93 (1H, s), 8.32 (1H, m), 8.23 (1H, d, J = 8.2 Hz ), 7.63 (1H, m), 7.25 (5H, m), 7.12 (1H, d, J = 9.2 Hz), 7.02 (1H, m), 4.94 (1H , d, J = 10.8 Hz), 4.76 (2H, d, J = 3.8 Hz), 3.88 (1H, d, J = 5.5 Hz), 3.32 (3H, s ), 2.91 (1H, m), 1.72 (1H, m), 1.55 (1H, m), 1.35 (1H, m), 1.02 (9H, s), 0.89 (3H, d, J = 6.5 Hz) and 0.85 (3H, d, J = 6.5 Hz).

 Step H. N1- [2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl) propyl] -N4-hydroxy-2R-isobutyl-3S-methoxy-succinamide.

N4-benzyloxy-N1- [2,2-dimethyl-1S- (pyridin-2-ylcarbamoyl) propyl] -2R-isobutyl-3S-methoxy-succinamide was dissolved in a mixture of methanol (75 ml) and ethanol (75 ml) and placed into the atmosphere of argon. 10% palladium-carbon was added and hydrogen gas was passed through the solution for 2 hours, after which thin-layer chromatography (TLC) showed that all the starting material had been consumed. The mixture was washed with argon and the catalyst was filtered off. The solvents were removed under reduced pressure to give the title compound as a white solid (8.8 g, quant., 12: 1 mixture of diastereoisomers), mp. 163-164 ^° C. ¹ H-NMR; δ ((CD ₃ ) ₂ SO), 10.67 (1H, s), 10.13 (1H, s), 8.90 (1H, s), 8.15 (1H, m), 7.89 ( 1H, d, J = 8.4 Hz), 7.81 (1H, d, J = 8.8 Hz), 7.60 (1H, m), 6.93 (1H, m), 4.53 ( 0.12 H, d, J = 9.4 Hz), 4.43 (0.88 H, d, J = 8.8 Hz), 3.74 (0.12 H, d, J = 10.0 Hz) 3.32 (0.88H, d, J = 9.8 Hz), 2.98 (0.3H, s), 2.96 (2.64H, s), 2.78 (1H, m), 1.23 (2H, m), 0.84 (10H, s and m), 0.65 (3H, d, J = 6.4 Hz), and 0.56 (3H, d, J = 6.3 Hz) . ¹³ C-NMR; δ (CD ₃ OD), 172.6, 170.0, 166.0, 151.5, 147.9, 136.0, 119.5, 113.6, 61.2, 60.6, 56.7 , 46.2, 37.0, 34.0, 26.5, 25.2. 23.7 and 21.7. IR v _max (Kbr), 3255, 2957, 1700, 1645, 1524, 1467, 1435, 1370, 1301, 1213 and 1152 cm ^-1 . Found: C, 58.40; H, 7.92; N, 13.61%; C ₂₀ H ₃₂ N ₄ O ₅ • 0.2 H ₂ O requires C 58.29, H 7.92, N 13.60%.

Biological tests
The following table compares the effectiveness of the compounds of the present invention with the effectiveness of similar compounds known in the art; R ₄ = Me. (Comparison compounds 1 to 5).

 Comparison compound 1: 5-Methyl-3R- (1S-methylcarbamoyl-2-phenylethyl-carbamoyl) -hexanohydroxamic acid.

 Comparison compound 2: 3R- (2,2-Dimethyl-1S-methylcarbamoyl-propyl-carbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid.

 Compound Compound 3: 3R- (2,2-Dimethyl-1S-methylcarbamoyl-propyl-carbamoyl) -5-methylhexanohydroxamic acid.

 Comparison compound 4: 2S-Hydroxy-3R- (1S-methylcarbamoyl-2-phenyl-ethylcarbamoyl) - 5-methylhexanohydroxamic acid.

 Comparison compound 5: 2S-Hydroxy-3R- (1S-methylcarbamoyl-3-methyl-butylcarbamoyl) - 5-methylhexanohydroxamic acid.

The effectiveness of the compounds of the invention as collagenase inhibitors is determined by the method of Cawston and Barrett, (Anal. Biochim., 99, 340-345, 1979), indicated herein, as a reference, by which a 1 mM solution of the test compound, or dilution thereof, is thermostated 37 ^o C for 16 hours with collagen and collagenase (buffer with 25 mm Hepes, pH 7.5, containing 5 mm CaCl ₂ , 0.05% Brij 35 and 0.02% NaN ₃ ). Collagen is acetylated using ¹⁴ C collagen obtained by the method of Cawston and Murphy (Methods in Enzymology, 80, 711, 1981), herein incorporated by reference. Samples are centrifuged to precipitate undigested collagen, an aliquot of the supernatant is taken for quantitative analysis on a scintillation counter, i.e., to determine the degree of hydrolysis. The activity of collagenase in the presence of 1 mM of the test compound or its dilution is compared with the activity of the control sample not exposed to the inhibitor, and the result below is the concentration of the inhibitor causing 50% inhibition of collagenase activity (IC ₅₀ ).

The efficacy of the compounds of the invention as stromelysin inhibitors is determined by the method of Cawston et al. (Biochem. J., 195, 159-165, 1981), incorporated herein by reference, in which a solution of 1 mM of the test compound or its dilution is incubated at 37 ^° C. for 16 hours with stromelysin and ¹⁴ C casein acetylate ( buffer with 25 mM Hepes, pH 7.5, containing 5 mM CaCl ₂ , 0.05% Brij 35 and 0.02% NaN ₃ ). Casein is an acetylated ¹⁴ C casein obtained by the method of Cawston et al. (ibid). The activity of stromelysin in the presence of 1 mM of the test compound or its dilution is compared with the activity of the control sample not exposed to the inhibitor, and the result below is the concentration of the inhibitor causing 50% inhibition of the activity of stromelysin (IC ₅₀ ).

The effectiveness of the compounds of the invention as inhibitors of 72 kDa gelatinase is determined according to a method based on the method of Sellers et al., Biochem. J., 171, 493-496 (1979). 72 kDa gelatinase obtained from RPMI-7951 cells was purified by gelatin-agarose chromatography. The enzyme is activated by soaking with aminophenylmercury acetate and about 0.05 units are incubated with 50 μg of gelatin labeled with ¹⁴ C in a suitable buffer for 16 hours at 37 ^° C. At the end of the temperature control, 50 μg of calf serum albumin is added to terminate the reaction and precipitate any precipitated substrate. together with trichloroacetic acid (final concentration 16%). The reaction tubes are placed for 15 minutes in ice, and then centrifuged for 15 minutes at 10,000 rpm to seed the substrate. 200 μl — an aliquot — of the supernatant was collected and radioactivity was measured by a liquid scintillation counter. The effectiveness of the inhibitor is determined by the curve of sensitivity to power (absorbed) radiation dose. An IC ₅₀ (an inhibitor concentration causing a 50% decrease in enzyme activity) is obtained by correlating the data with a curve and calculating the inhibitor concentration that is required to obtain 50% inhibition of the enzyme. For each IC ₅₀ measurement, the effect of the inhibitor on gelatinase activity was determined at least at 8 concentrations of the inhibitor. The inhibitor is dissolved and diluted in DMSO.

Claims (6)

1. Derivatives of hydroxamic or carboxylic acids of the general formula I

where X is —CO ₂ H or —CONHOH;
R ₁ is hydrogen, methoxy, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, phenyl- (C ₁ -C ₆ ) alkyl or a BSO group _n A-, where n is 0 or 1, and B means A 5- or 6-membered heterocyclic ring containing sulfur or nitrogen as the heteroatom, and A is —CH ₂ -; R ₂ means (C ₁ - C ₆ ) alkyl or phenyl- (C ₁ - C ₆ ) alkyl; R ₃ means tert-butyl, 1-benzylthio-1-methyleth-1-yl or the distinctive side chain of alanine, valine, leucine or phenylalanine; R ₄ means phenyl or a 5- or 6-membered heterocyclic ring containing sulfur or nitrogen as a heteroatom, and any nitrogen atom can be oxidized to N-oxide, which can be fused to a benzene ring or 5-, 6- or 7- heterocyclic membered ring, wherein any ring may be substituted by a) one or more substituents independently selected from hydroxyl, halogen, —CO ₂ H, —CO ₂ (C ₁ –C ₆ ) alkyl, or b) a group consisting of from (C ₁ - C ₆ ) alkyl or phenyl; R ₅ means hydrogen or (C ₁ - C ₆ ) alkyl, or a salt, hydrate or solvate thereof, while R _{4 is} not 2-pyridyl or 2-thiazolyl when R ₁ is hydrogen, R ₂ is n-pentyl R ₃ is isopropyl and R ₅ is hydrogen. 2. The compound according to claim 1, in which there is the following stereochemistry: a carbon atom containing R ₁ and X - S, a carbon atom containing R ₂ - R, a carbon atom containing R ₃ - S. 3. The compound according to claim 1 or 2, where R ₁ means hydrogen, methyl, hydroxy, methoxy, allyl, thienylsulfanylmethyl or thienylsulfinylmethyl; R ₂ is isobutyl; R ₃ means benzyl, isobutyl or tert.butyl; R ₄ means phenyl, thiazolyl, thiadiazolyl, pyridinyl or N - pyridinyl oxide and R ₅ means hydrogen.  4. The compound according to claim 1, selected from the group comprising 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl / -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (5-methyl-1,3,4-thiadiazole -2-ylcarbamoyl) propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (3-methoxyphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- ( 2,2-Dimethyl-1S-pyridin-3-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-m tylhexanohydroxamic acid and 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-phthalimidomethylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (thiazol-2-ylcarbyl) -propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (thiazol-2-ylcarbamoyl) propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid and 3R - (2,2-Dimethyl-1S- (4-ethoxycarbonylmethylthiazol-2-ylcarbamoyl) -propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, and their salts, solvates or hydrates thereof.  5. The compound according to claim 1, selected from the group comprising 5-methyl-3R- (2-phenyl-1S-phenylcarbamoyl-ethylcarbamoyl) -hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) - 5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-pyridin-2-ylcarbamoyl-propylcarbamoyl) -5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) 5-methylhexanohydroxamic acid, 2S-Hydroxy-3R- (3-methyl-15-naphth-2-ylcarbamoylbutylcarbamoyl) -5-methylhexanohydroxamic acid, 2S-Hydroxy-3R- (3-methyl-1S- (4-methoxyphenyl) carbamoyl b Utylcarbamoyl) -5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (4-tert.butyl-2,6-dimethylphenyl) carbamoylpropylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2, 2-Dimethyl-1S- (4-methoxyphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-pyridin-4-ylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5 -methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (4-hydroxyphenyl) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2-Benzylthio-2-methyl-1S - (- pyridine -2-ylcarbamoyl) propyl carbam oyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-phenylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (4 5-dimethylthiazol-2-ylcarbamoyl) propyl carbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-dimethyl-1S- (5-bromothiazol-2-ylcarbamoyl) propylcarbamoyl) -2S- hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (4-phenylthiazol-2-ylcarbamoyl) -propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S - (4-tert. Butylthiadiazol-2-ylcarbamoyl) -propylcarbamoyl) - 2S-hydroxy-5-methylhexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S - (4-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2-Benzylthio-2-methyl-1S- (pyridin-2-ylcarbamoyl) propyl-carbamoyl) - 5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridin-3-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid , 3R- (2,2-Dimethyl-1S- (4-hydroxyphenylcarbamoyl) -propyl-carbamoyl) -5-methyl-2S-prop n-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (3-methoxyphenylcarbamoyl) propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2 -Dimethyl-1S- (pyridin-4-ylcarbamoyl-propylcarbamoyl) -5-methyl-2S-propen-2-yl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) -propylcarbamoyl) - 5-methyl-2S-thien-2-ylsulfanylmethyl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfanylmethyl-hexanohydro acid, 3R- (2,2-Dimethyl-1S- (2-methoxyphenylcarbamoyl) propylcarbamoyl ) -5-methyl-2S-thien-2-ylsulfinylmethyl-hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S- (pyridin-2-ylcarbamoyl) -propylcarbamoyl) -5-methyl-2S-thien-2-ylsulfinylmethyl -hexanohydroxamic acid, 3R- (2,2-Dimethyl-1S-phenylcarbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylphenylhexanoic acid, 3R- (2,2-Dimethyl-1S- (N-hydroxy-pyridin-2-yl ) carbamoyl-propylcarbamoyl) -2S-hydroxy-5-methylhexanohydroxamic acid, and their salts, solfates or hydrates.  6. A pharmaceutical or veterinary composition having the ability to inhibit matrix metalloproteinases, containing an effective amount of an active principle and a pharmaceutically or veterinary acceptable carrier, characterized in that it contains as an active principle a compound according to claims 1 to 5.

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