Carboxamide, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Describes new compounds of General formula I, where R1represents mercapto, acetylthio, carboxy, hydroxycarbamoyl, N-hydroxypropylamino, alkoxycarbonyl, aryloxyalkyl, arelaxation, benzyloxycarbonyl or a group of formula II, where R6denotes aryl or heteroaryl, R2denotes alkyl, cycloalkyl, aryl, heteroseksualci or heteroaryl, R3denotes alkyl, cycloalkyl, aralkyl or heteroalkyl, R7denotes aryl, heteroaryl or heteroseksualci, X denotes a group of the formula -(CH2)m-Y-(CH2)n- where Y denotes O, S or a simple link, m represents an integer from 0 to 4, n represents an integer from 0 to 4 and m + n represents an integer from 0 to 4, p represents an integer from 0 to 4, provided that R2-X is biphenylyl, when p is not equal to 0, and R2-X is not alkyl, aralkyl or cycloalkylation, if p is 0 and R7is phenyl, or its pharmaceutically acceptable salt. Carboxamide formula I are inhibitors of the active matrix metalloprotease and can be used for the treatment of painful conditions in mammals. Also described is a method of obtaining soedinenie relates to compounds and their pharmaceutically acceptable salts, having the ability to inhibit matrix metalloprotease and therefore suitable for the treatment of painful conditions in mammals, making it easier for as a result of inhibition of such matrix metalloprotease.

Background of the invention

Matrix metalloprotease (MMP) are a family of proteases (enzymes) involved in the decomposition and the reconstruction of connective tissues. Representatives of this family of enzymes-endopeptidase present in different types of cells that are found in connective tissue or associated with it, such as fibroblasts, monocytes, macrophages, endothelial cells and invasive or metastatic tumor cells. The expression of MMP stimulated by growth factors and cytokines in the immediate surrounding tissue, where these enzymes induce specific degradation of protein components of the extracellular matrix such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous components of the extracellular matrix present in the liners of the joints, interstitial connective tissue, basal membranes and cartilage. Excessive degradation of extracellular matrix by using MSE on the, aberrant angiogenesis, tumor growth and metastasis, corneal ulceration and complications in diabetes. Therefore, inhibition of MMPs is a good target for therapeutic intervention.

MMP have numerous properties, including the zinc - and calcium-dependent secretion as proenzymes and 40-50% homology to the sequence of amino acids. The MMP family consists of collagenase, stromelysin, gelatinase and matrilysin, as described in more detail below.

Interstitial collagenase catalyze the initial splitting and splitting with a limited speed of native collagen types I, II, III and X. Collagen - the chief structural protein in mammals is a major component of the matrix of many tissues, for example, cartilage, bone, tissues, tendons and skin. Interstitial collagenase are very specific matrix metalloprotease that breaks down collagen to produce two fragments, which spontaneously denature at physiological temperatures and therefore become sensitive to the splitting of the less specific enzymes. Cleavage by collagenase leads to the loss of structural integrity of the fabric is different, but the very close of the enzyme: the enzyme 72 kDa secretory fibroblasts and a wide variety of other types of cells, and the enzyme 92 kDa released from mononuclear phagocytes, neutrophils, epithelial cells of the cornea, tumor cells, cytotrophoblasts and keratinocytes. It was found that these gelatinase have the ability to degrade gelatin (the denatured collagen), collagen type IV (basement membrane) and V, fibronectin and insoluble elastin.

It was found that stromelysin (1 and 2) have the ability to cleave a wide range of matrix substrates, including laminin, fibronectin, proteoglycans and collagen types IV and IX in their despiralization areas.

Matrilysin (imaginary metalloprotease or PUMP) is a recently open a representative of a family of matrix metalloprotease. It was found that matrilysin has the ability to decompose a wide range of matrix substrates, including proteoglycans, gelatin, fibronectin, elastin, and laminin. His expression was detected in mononuclear phagocytes, explants of the uterus in rats and in isolated cases in tumors.

Inhibitors of matrix metalloprotease suitable for the treatment of diseases, obesit), diseases associated with bone resorption (such as osteoporosis), increased degradation of collagen associated with diabetes, periodontal disease, corneal ulceration, ulceration of the skin, tumor growth and metastasis, as well as aberrant angiogenesis.

The creation and use of MMP inhibitors are described, for example, in J. Enzyme Inhibition (1987), I. 2, pp. 1-22; Drug News & Prospectives (1990), I. 3, N 8, PP 453-458; Arthritis and Rheumatism (1993), T. 36, No. 2, pp. 181-189; Arthritis and Rheumatism (1991), T. 34, N 9, pp. 1073-1075; Seminars in Arthritis and Rheumatism (1990), T. 19, No. 4, Supplement 1 (February), pp. 16-20; Drugs of the Future (1990), T. 15, N 5, PP 495-508; and J. Enzyme Inhibition (1987), I. 2, pp. 1-22. Inhibitors of matrix metalloprotease are also the subject of various patents and patent applications, for example, U.S. patents 5189178 (Galardy) and 5183900 (Galardy), European published patent applications 0438223 (Beecham) and 0276436 (F. Hoffmann-La Roche) and published PCT International applications 92/21360 (Merck), 92/06966 (Beecham) and 92/09563 (Glycomed).

Summary of the invention

The invention relates to new compounds which can be used as inhibitors of matrix metalloprotease and which is effective for the treatment of painful condition caused by excessive activity of matrix metalloprotease.

Thus, one paragraph is about, carboxy, hydroxycarbamoyl, N-hydroxypropylamino, alkoxycarbonyl, aryloxyalkyl, arelaxation, benzyloxycarbonyl or a group of the formula

< / BR>
where R6denotes aryl or heteroaryl;

R2denotes alkyl, cycloalkyl, aryl, heteroseksualci or heteroaryl;

R3denotes alkyl, cycloalkyl, aralkyl or heteroalkyl;

R7denotes aryl, heteroaryl or heteroseksualci;

X denotes a group of the formula -(CH2)m-Y-(CH2)n- where

Y represents O, S or a simple link,

m denotes an integer from 0 to 4,

n denotes an integer from 0 to 4 and

m+n denotes an integer from 0 to 4;

p denotes an integer from 0 to 4, provided that R2-X is biphenylyl, when p is not 0;

and their pharmaceutically acceptable salts.

Another object of the invention relates to a method of synthesis of compounds and salts of formula (I).

Another object of the invention belongs to the subfamily of compounds of formula (I), i.e., the following compounds of the formula (II)

< / BR>
where R1represents mercapto, acetylthio, carboxy, hydroxycarbamoyl, alkoxycarbonyl, aryloxyalkyl, arelaxation, Benz is UP> denotes alkyl, aralkyl or cycloalkyl;

R3denotes cycloalkyl, alkyl (optionally substituted by cycloalkyl, hydroxy-, mercapto-, alkylthio, arakaki-, carboxy-, amino-, alkylamino, guanidinopropionic, carbamoyl, pyridium or indolium) or aralkyl (optionally substituted by hydroxy, carboxypropyl, alkyl or alkoxygroup);

R4denotes nitro, amino, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylsulfonyl, haloalkyl, alkoxycarbonyl, tetrazolyl, carbarnoyl (optionally substituted by alkyl or dialkylaminoalkyl) or aminosulfonyl (optionally substituted by alkyl); and

R5denotes hydrogen, halogen or hydroxy;

in the form of an individual stereoisomer or a mixture thereof; and to their pharmaceutically acceptable salts.

Another subject of the invention relates to compounds of the formula

< / BR>
where R2denotes alkyl, aryl or heteroaryl; and

X denotes a group of the formula -(CH2)m-Y-(CH2)n- where

Y represents O, S or a simple link,

m denotes an integer from 0 to 4,

n denotes an integer from 0 to 4 and

m+n denotes an integer from 0 to 4; or

R2and X together oboli

< / BR>
where R2denotes aryl or heteroaryl by

(a) hydrogenation of the compounds of formula

< / BR>
in the presence of palladium on coal as a catalyst; or

(b) interaction of the compounds of formula

< / BR>
with hexamethyldisilazide or sodium tert-butylbromide.

Another subject of the invention relates to compounds of the formula

< / BR>
where R2denotes aryl or heteroaryl, and to a method of synthesis of these compounds by

(a) interaction of the compounds of formula

< / BR>
where

R2denotes hydrogen, aryl or heteroaryl, with an excess of methylchloride in pyridine, followed by boiling under reflux in basic conditions and

(b) when R2denotes hydrogen, at stage (a) by reacting the product from step (a) with calidarium or galinhatrololo in the presence of a base and a palladium catalyst.

Another object of the invention relates to a method for inhibiting the activity of matrix metalloprotease in a mammal, comprising the administration to a mammal in case of need, a therapeutically effective amount of the compounds of formula (I) as defined above, in the form of an individual stereoisomer or ietticelli composition, suitable for inhibiting the activity of matrix metalloprotease in a mammal, which composition comprises a therapeutically effective amount of the compounds of formula (I) as defined above, in the form of an individual stereoisomer or a mixture thereof, or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

Detailed description of the invention

Definition

In the description and in the claims, unless otherwise specified, the following terms have the following values.

"BOC" refers to tert-butoxycarbonyl.

"CBZ" means benzyloxycarbonyl (carbobenzoxy).

"DCC" means N,N-dicyclohexylcarbodiimide.

"DMAP" means N,N-dimethylaminopyridine.

"DMF" means N,N-dimethylformamide.

"EDCI" denotes N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide.

"HOBT" denotes 1-hydroxybenzotriazol.

"Hydroxy" refers to a radical - HE.

"Amino" means a radical-NH2.

"Acetylthio" refers to the radical-SC(O)CH3.

"Halogen" denotes bromine, chlorine or fluorine.

"Carbarnoyl" means the radical-C(O)NH2.

"Carbocol" means the radical-C(O)NHOH.

"N-Hydroxypropylamino" refers to a radical-N(OH)C(O)H.

"Benzyloxycarbonyl" denotes-C(O)N(H)OCH2WITH6H5.

"Acylamino" refers to-NHC(O)Rawhere Radenotes alkyl.

"Mercapto" refers to the radical-SH.

"Alkyl" denotes a monovalent radical with a straight or branched chain consisting solely of carbon and hydrogen, containing no unsaturated bonds and having from one to ten carbon atoms, for example, methyl, ethyl, n-propyl, 2-methylpropyl (isobutyl), 1-methylethyl (isopropyl), n-butyl and 1,1-dimethylethyl (tert-butyl), heptyl, etc., which optionally may be substituted by cycloalkyl, hydroxy-, mercapto-, alkylthio, arakaki-, carboxy-, amino-, mono - and dialkylamino-, guanidino-, N,N - dialkylanilines, carbamoyl, aryl and heteroaryl.

"Alcander" or "alkylene" denotes a divalent radical with a straight chain consisting solely of carbon and hydrogen, containing no unsaturated bonds and having from one to five carbon atoms, for example, methylene, ethylene, propylene or propane-1,3 - diyl), etc.

"Lower alkenyl" denotes a monovalent hydrocarbon radical with a straight chain containing from two to six ATO>/P>"Alkylamino" refers to a radical of the formula-otherawhere Rarefers to alkyl as defined above, for example, methylamino, ethylamino, isopropylamino, n-butylamino etc.

"Haloalkyl" refers to a radical of the formula-RaRdwhere Rarefers to alkyl as defined above, substituted by one or more halide groups (Rd), as defined above, for example, 2-chloroethyl, 2-bromacil, trifluoromethyl, etc.

"Dialkylaminoalkyl" refers to a radical of the formula RaN(Ra)2where each Raindependently from each other represents an alkyl radical, as defined above, for example, dimethylaminoethyl, diethylamino-n-propyl, dimethylamino-n-propyl, etc.

"Aminosulfonyl" refers to-S(O)2NH2.

"Alkylsulfonyl" refers to a radical of the formula-S(O)2Rawhere Rarefers to alkyl as defined above, for example, methylsulphonyl, ethylsulfonyl, isopropylphenyl etc.

"Alkylsulfonyl" refers to a radical of the formula-S(O)Rawhere Rarefers to alkyl as defined above

"Alkylthio" refers to a radical of the formula-SRawhere Radenotes optionally substituted alkyl, as defined above, Rawhere Rarefers to alkyl as defined above, for example, methoxy, ethoxy, n-propoxy, 1 - methylethoxy, n-butoxy, tert-butoxy etc.

"Alkoxycarbonyl" refers to a radical of the formula-RaC(O)Rbwhere Rarefers to alkyl as defined above, a Rbmeans alkoxy as defined above, for example, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylethyl etc.

"Aryl" refers to monovalent unsaturated aromatic carbocyclic radical, which has a single ring (e.g. phenyl) or two condensed rings (e.g. naphthyl) or three condensed rings (e.g., phenanthrene or Florisil) and which optionally may be substituted by one or more substituents, independently selected from alkyl, hydroxy-, carboxypropyl, halogen, cyano, amino, nitro, tetrazolyl, heteroaryl, aminoethoxy, allylthiourea, haloalkyl, alkoxygroup, alkoxycarbonyl, alkoxycarbonylmethyl, alkylsulfonyl, alkylsulfanyl, aminosulfonyl, optionally substituted alkyl, carbamoyl, optionally substituted by Alila or dialkylaminoalkyl or Deputy may represent different alkyl is tion of the radical).

"Aryloxy" refers to a radical of the formula-ORbwhere Rbmeans aryl, as defined above, for example, phenoxy, China-2-yloxy, naphthas-1 iloxi or naphthas-2-yloxy.

"Aralkyl" refers to a radical of the formula-RaRbwhere Rarefers to alkyl as defined above, a Rbmeans aryl, as defined above, e.g. benzyl, phenylethylene, 3-phenylpropyl etc.

"Arakaki" refers to a radical of the formula-ORaRbwhere Rarefers to alkyl as defined above, a Rbmeans aryl, as defined above, for example, benzyloxy, 3-naphthas-2 - ylpropionic etc.

"Alkoxycarbonyl" refers to a radical of the formula - C(O)Rbwhere Rbmeans alkoxy as defined above, for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl etc.

"Arelaxation" refers to a radical of the formula-C(O)Rcwhere Rcindicates arakaki, as defined above, for example, benzyloxycarbonyl etc.

"Cycloalkyl" denotes a monovalent cyclic radical, consisting solely of carbon atoms and hydrogen, containing no unsaturated bonds and having from five to seven carbon atoms, for example, cyclopentyl, cyclohexyl and cycloheptyl is to defined above, a Redenotes cycloalkyl, as defined above, for example, cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl etc.

"Heteroaryl" refers to monovalent unsaturated aromatic carbocyclic radical having a single ring or multiple condensed rings containing at least one heteroatom such as N, O, S (for example, pyridyl, hinely, indolyl, carbazolyl, dibenzofurans, dibenzothiophenes, phenanthridine), which optionally can be substituted by one or more substituents, independently selected from alkyl, hydroxy-, carboxy-, halogen-, cyano-, amino-, nitro, tetrazolyl, aryl, aminoethoxy, allylthiourea, haloalkyl, alkoxygroup, alkoxycarbonyl, alkoxycarbonylmethyl, alkylsulfonyl, alkylsulfanyl, aminosulfonyl, optionally substituted alkyl, and carbamoyl, optionally substituted alkyl or dialkylaminoalkyl.

"Heteroalkyl" refers to a radical of the formula-RaRbwhere Rarefers to alkyl as defined above, a Rbdenotes heteroaryl, as defined above.

"Heteroseksualci" means a monovalent saturated carbocyclic radical having a single ring or is folino, piperazinil, piperidinyl, pyrrolidinyl).

"Optional" or "optionally" means that consistently describes the actions or circumstances may be or may not be, and that definition includes situations when the specified actions or circumstances, and situations when they are absent. For example, "optionally substituted henol-2-yl" means that China-2-ilen radical may be substituted or may be unsubstituted and the definition includes both substituted henol-2-ilen radicals and China-2-ilen radicals without substitution.

"Aminosidine group" in the context of the present description refers to organic groups intended to protect nitrogen atoms against undesirable reactions during the synthesis process, and includes, but is not limited to, benzyl, acyl, acetyl, benzyloxycarbonyl (carbobenzoxy), para - methoxybenzeneboronic, para-nitrobenzenesulfonyl, tert - butoxycarbonyl, TRIFLUOROACETYL, etc.,

"Basis" in the context of the present description includes a strong inorganic bases such as sodium hydroxide, lithium hydroxide, ammonium hydroxide, potassium carbonate, etc., and organic bases, that is rmaceuticals acceptable salt" refers to such salts, that retain the biological activity and properties of the free bases or free acids and which are not junk either biological or any other reasons. If the connection exists in the form of free base, the desired salt can be obtained by methods known to experts in the art, such as treatment compounds, inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and so on; or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methansulfonate acid, econsultancy acid, para - toluensulfonate acid, salicylic acid, etc., If the connection is presented in the form of the free acid, the desired salt may also be obtained by methods known to experts in the art, such as treatment of inorganic or organic base. Salt, the calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., Salts formed with organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ionoobmennye resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2 - Diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc.

"Mammal" includes humans and all domestic and wild animals, including, but not limited to, cattle, horses, pigs, sheep, goats, dogs, cats, etc.

"Therapeutically effective amount" refers to that amount of the compound of formula (I), which, being optionally assigned to the mammal is sufficient for treatment, as defined below, painful conditions, facilitated by the result of inhibiting the activity of matrix metalloprotease, such as activity trompettiste effective amount", will vary depending on the compound, the disease condition and the severity of the disease, as well as mammal undergoing treatment, however, it may be determined in a conventional manner an ordinary specialist in the field of engineering with regard to his own knowledge and the description.

The term "treatment" or "cure" in the context of the present description include the treatment of painful conditions in a mammal, especially humans, which facilitated the result of inhibiting the activity of matrix metalloprotease, such as activity stromelysin, gelatinase, matrilysin and/or collagenase, etc., and includes:

(I) prevention of the onset of a pathological state in a mammal, in particular if said mammal is predisposed to a painful condition, but have not established that such has occurred:

(II) inhibiting the disease condition, i.e., the cessation of its development; or

(III) relief of painful conditions, i.e. ensuring regression painful condition.

"Stereoisomers" refers to compounds that have the same molecular formula and the nature or sequence of links, but differing in orientation by their structure at least two asymmetric carbon atom and, therefore, may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. All these separate stereoisomers, racemates and mixtures thereof are included in the scope of the present invention.

When the designation of the individual stereoisomers of compounds of formula (I) absolute descriptor is R or S can be attributed to the chiral carbon atoms in accordance with the method of "rules of order" Kahn, Ingold and Prelog.

Nomenclature

Used in the present description, the item basically is a modified form of item I. U. P. A. C. (International Union of pure and applied chemistry), according to which the compounds according to the invention are named as derivatives of peptides. When R3in the formula (I) includes a side chain amino acid residue, then the part of the chemical structure, which includes R3together with the neighboring nitrogen atom (shown below and labeled as the nitrogen atom N in contrast to the nitrogen atom N') and the carbonyl group is assigned the name of the corresponding amino acids. The name and numbering of the compounds of the present invention are shown below for typical compounds of formula (I).

E.g. the biphenyl; R3denotes 4-(cyan)sensitivityfor; R7denotes phenyl; X represents propan-1,3-diyl and p is 0, is named N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-S-((4-tianfeng) methyl) penicillamine-N'-(phenyl)carboxamide.

Another name for this compound is N-(5-(bifen-4-yl)-2R - carboxymethylamino)-L-S-((4-tianfeng)methyl)penicillamine-N' - (phenyl)carboxamide.

For convenience of reference of the structure associated with the corresponding item.

The structure and names of several other typical compounds of formula (I) below.

< / BR>
The above compound is named N-(2R-carboxymethyl-5- (bifen-4-yl)pentanoyl)-L-tert-butylglycol-N'-(pyrid-4-yl)carboxamido. Name tert-butylglycol can be equivalently replaced by tert-leucine, and the name of the pyridyl may be substituted for the pyridinyl. Another name for the above compound is N-(5-(bifen-4-Il-2R-carboxymethylamino)-L-tert-leucine-N'- (pyridine-4-yl)carboxamide.

< / BR>
The above compound is named N-(2R-carboxymethyl-5-(7- (glycyl)aminopterin-2-yl)pentanoyl)-L-leucine-N'-(4 - methoxycarbonyl)phenyl)carboxamide.

Another name for this compound is N-(5-(7-(glycyl) aminopyrimidine compound is named N-((2R-carboxymethyl - 5-phenyl)pentanoyl)-L-6-(N,N'-dietilamida)lysyl-N'-(4 - etoxycarbonyl)phenyl)carboxamide. The name of guanido can be equivalently replaced by guanidine. Another name for this compound is N-((5-phenyl-2R-carboxymethyl)pentanoyl)-L-6-(N,N'- diethylaniline)lysyl-N'-(4-etoxycarbonyl) phenyl) carboxamide.

< / BR>
The above compound is named N-((2R-(N"-formyl-N"- hydroxyamino)methyl)-4-(((3-chloro-5-morpholino)fen-1 - yl)oxobutanoic)-L-cyclohexylglycine-N'-(4-(indol-5 - yl)butyl)carboxamido. Another name for this compound is N-(4- (3-chloro-5-morpholino)fen-1-yl)-2R-((N"-formyl-N"- hydroxyamino)methoxybutanol)-L-cyclohexylglycine-N'-(4- (indol-5-yl)butyl)carboxamide.

Application, research and assignment

Application

The compounds of formula (I) inhibit matrix metalloprotease mammals, such as stromelysin, gelatinase, matrilysin and collagenase, and therefore suitable for the treatment of diseases caused by excessive decomposition of the matrix and connective tissue in a mammal, which is induced MMP, such as arthritis (rheumatoid arthritis and osteoarthritis), diseases associated with bone resorption (such as osteoporosis), increased degradation of collagen associated with diabetes, periodontal disease, corneal ulceration, ulceration of the skin, growth of the tumor and meaty activity matrix metalloprotease, in particular the activity stromelysin, gelatinase, matrilysin and/or collagenase, can be demonstrated in various experiments in vitro and in vivo, known to experts in the art, for example, in such experiments, which are described in Anal.Biochem. (1985), I. 147, page 437, and with the help of enzymatic analysis of MMP described in FEBS (1992), I. 296(3), page 263, or using their modifications.

The purpose

Introduction compounds of formula (I) or their pharmaceutically acceptable salts, in pure form or in the form of appropriate pharmaceutical compositions can be made by any acceptable route of administration or agents that serve similar purposes. Thus, the introduction can be effected, for example, oral, nazalnam, parenteral, local, transdermal or rectal route in the form of solid, semi-solid dosage form, lyophilized powder, or liquid dosage forms, such as tablets, suppositories, pills, gelatin capsules, soft elastic or hard shell, powders, solutions, suspensions, or aerosols, etc., preferably in the form of standardized doses suitable for easy introduction with accurate dosage. The composition may include obion, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

Usually appointed by way of the introduction of pharmaceutically acceptable compositions can contain from about 1 wt.% to about 99 wt. % of compound(s) of formula (I) or its pharmaceutically acceptable(s) salt(s) and from 99 wt.% up to 1 wt.% pharmaceutically suitable excipient. Preferably the composition should contain from about 5 wt.% to about 75 wt.% connection(s) of formula (I) or its pharmaceutically acceptable(s) salt(s), while the rest fall to the share of pharmaceutically acceptable excipients.

The preferred route of administration is oral, using the usual daily dosage regimen which can be adjusted depending on the severity of the subject to treatment of painful conditions. For such oral administration of pharmaceutically acceptable composition comprising the compound(I) of the formula (I) or its pharmaceutically acceptable(s) g (and), are obtained by incorporating any commonly used excipients, such as, for example, pharmaceutically pure mannitol, lactose, starch, pregelatinized, citrate, propylgallate, etc., Such compositions are in the form of solutions, suspensions, tablets, pills, capsules, powders, compositions with the continuous release of drugs, etc.

Preferably, such compositions must be in the form of capsules, drops or tablets and, in addition, must include a diluent, such as lactose, sucrose, calcium diphosphate, etc., the agent that promotes disintegration, such as nitrocresols or its derivatives; a lubricant such as magnesium stearate, etc., and a binder, such as starch, gum acacia, polyvinylpyrrolidone, gelatin, ether derivatives of cellulose, etc.

The compounds of formula (I) or their pharmaceutically acceptable salts can also be prepared in the form of a suppository using, for example, from about 0.5% to about 50% active ingredient distributed in a slowly dissolving in the body of the carrier, for example, in polyoxyethyleneglycol and polyethylene glycol (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

A liquid composition intended for pharmaceutical purposes, may, for example, be prepared by dissolving, dispersing, etc. of the compound(s) of formula (I) from about 0.5% of new in the media, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., with obtaining the solution or suspension.

Optionally, the pharmaceutical composition according to the invention may also contain small amounts of additives, such as wetting or emulsifying agents, sautereau pH agents, antioxidants, etc. such as, for example, citric acid, sorbitanoleat, triethanolamine, bottled hydroxytrol etc.

Practical methods for such dosage forms are known or obvious to a person skilled in the art, for example, see Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, Easton, Pennsylvania, 1990). The applied composition in any case must contain a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salts for the treatment of painful conditions that can be alleviated as a result of inhibiting the activity of matrix metalloprotease in accordance with the recommendations of the present invention.

The compounds of formula (I) or their pharmaceutically acceptable salts are used in therapeutically effective amounts, which largely Daegu stability and duration of the connection, age, body weight, General health condition, sex of the patient, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular painful condition and therapy, which is exposed to the patient. Typically, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day for the compounds of formula (I) or its pharmaceutically acceptable salt, preferably from about 0.7 mg to about 10 mg/kg of body weight per day and most preferably from about 1.4 mg to about 7.2 mg/kg body weight per day. For example, in the appointment of a person weighing 70 kg, the dose range may be from approximately 10 mg to approximately 1.0 g of compound of formula (I) or its pharmaceutically acceptable salt per day, preferably from about 50 mg to about 700 mg per day and most preferably from about 100 mg to about 500 mg per day.

Preferred embodiments of the invention

Preferred are the compounds of formula (I) in which X denotes alkane-diyl and in which p is 0, 2 or 3.

Among the compounds in which p is 2 or 3, particularly preferred will jachet cyclohexyl and R7denotes optionally substituted phenyl (in particular, 4-(aminosulfonyl)phenyl] or N-morpholino.

Among the compounds in which p is 0, a particularly preferred group of compounds in which R2denotes alkyl, optionally substituted phenyl or a group of the formula

< / BR>
and R7denotes a 4-pyridyl or optionally substituted phenyl.

In this group a preferred subgroup of compounds are those compounds in which R1denotes a carboxy, hydroxycarbamoyl or N-hydroxypropylamino; R2denotes phenyl, biphenyl, 4-(pyridyl)phenyl or 2-methylpropyl; R3represents tert-butyl, 4-aminobutyl, acylaminoacyl, dialkylaminomethyl, 4-(N,N'-diethylaniline)butyl, propyl, 2 - methylpropyl, 1-hydroxyisopropyl, 1-hydroxyethyl or cyclohexyl; and X represents a simple bond, ethylene or propane-1,3-diyl.

In this subgroup, a preferred class of compounds are those compounds in which R2means biphenyl, R3represents tert-butyl and R7represents 4-pyridyl, in particular, in which R1denotes a carboxy, N - hydroxypropylamino or hydroxycarbamoyl.

Also, it is preferable SUB>; R10denotes H or acylamino; R11denotes H; R7denotes optionally substituted phenyl; and X denotes propane-1,3-diyl.

In this sub-group are preferred compounds in which R1denotes a carboxy, hydroxycarbamoyl or N - hydroxypropylamino; R3denotes alkyl (especially 2-methylpropyl); and R7denotes alkoxycarbonylmethyl [especially 4-(methoxycarbonyl) phenyl].

Also in this group is preferred subgroup of compounds in which R1represents carboxy; R2denotes phenyl; R3denotes alkyl [especially 4-(amino)butyl and 4-(diethylaniline)-N-butyl] or cycloalkyl (or primarily cyclohexyl); and X represents ethylene or propane-1,3-diyl.

This group also is preferred subgroup of compounds in which R1represents mercapto, carboxy, hydroxycarbamoyl or N-hydroxypropylamino; R2denotes 2 - methylpropyl; R3denotes alkyl (especially propyl, 2 - methylpropyl), cycloalkyl (or primarily cyclohexyl) or heteroalkyl (primarily 3-methylindole); R7denotes optionally substituted phenyl [first 4 - methoxyphenyl, 4 - carboxide in Addition, this group is preferred subgroup of compounds in which R1denotes a carboxy, R2denotes 4-(2-hydroxyethyl)phenyl, 4-(2-hydroxypropyl)phenyl, 4-(2 - hydroxybutyl)phenyl, 4-(pyridyl)phenyl, biphenyl, 4'- (aminoethoxy)biphenyl, 4'-(cyan)biphenyl or 4'-(hydroxy)biphenyl; R3denotes 2-methylpropyl; R7denotes 4- (methoxycarbonyl)phenyl; and X denotes propane-1,3-diyl.

Especially preferred subgroup of compounds in which R2means biphenyl, primarily in which R7denotes optionally substituted phenyl.

In this particularly preferred sub-group are preferred compounds in which R1represents carboxy; R3denotes alkyl or cycloalkyl [especially cyclohexyl, 4-(amino) butyl, 4-(isopropylamino)butyl, 1-hydroxyisopropyl, or tert-butyl]; X denotes propane-1,3-diyl; and R7denotes phenyl, 4-(hydroxyethylaminomethyl)phenyl, 4- (dimethylbenzenesulfonyl)phenyl, 4-(etoxycarbonyl)phenyl, 4- (N-morpholinepropanesulfonic)phenyl, 4- (methylaminomethyl)phenyl, 4-(hydroxyethylaminomethyl)phenyl or 4-(methylsulfinyl) phenyl.

Another preferred group carah R1means mercapto or acetylthio.

In this second group a preferred subgroup of compounds are those compounds in which R2denotes alkyl, aralkyl, cycloalkenyl; R3denotes cycloalkyl or alkyl (optionally substituted by cycloalkyl, hydroxy, Alcoxy, alkylthiol, pyridium or indolium); R4denotes a cyano, carboxy, hydroxy, alkoxy, alkoxycarbonyl, alkoxycarbonylmethyl, carbarnoyl (optionally substituted by aralkylamines) or aminosulfonyl (optionally substituted by alkyl); and R5denotes hydrogen.

In this subgroup, a preferred class of compounds are those compounds in which R2denotes alkyl; R3denotes cyclohexyl, alkyl (optionally substituted by cyclohexyl, hydroxy, benzyloxy-, methylthiourea, pyridium or indolium); and R4denotes a carboxy, alkoxycarbonyl and aminosulfonyl.

In this class of compounds, preferred are compounds in which R2denotes 2-methylpropyl. Especially preferred are compounds in which R3denotes 2-methylpropyl.

The third group, preferable on the Sabbath.">

In this third group a preferred subgroup of compounds are those compounds in which R2denotes alkyl, aralkyl, cycloalkenyl; R3denotes cycloalkyl or alkyl (optionally substituted by cycloalkyl, hydroxy, Alcoxy, alkylthiol, pyridium or indolium); R4denotes cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkoxycarbonylmethyl, carbarnoyl (optionally substituted by aralkylamines) or aminosulfonyl (optionally substituted by alkyl); and R5denotes hydrogen.

Within this subgroup, the preferred class of compounds are those compounds in which R2denotes alkyl; R3denotes cyclohexyl, alkyl (optionally substituted by cyclohexyl, hydroxy, benzyloxy-, methylthiourea, pyridium or indolium); and R4denotes a carboxy, alkoxycarbonyl and aminosulfonyl.

In this class of compounds, preferred are such compounds in which R2denotes 2-methylpropyl. Especially preferred are such compounds in which R3denotes cyclohexyl, 2-methylpropyl, pyridine-3-ylmethyl, 1-benzyloxyethyl, 1-methylpropyl, 1,1-dimethylethyl, 1-equipment for inhibition matrilysin, are the compounds of formula (II) in which R1indicates hydroxycarbamoyl.

In this fourth group a preferred subgroup of compounds are those compounds in which R2denotes alkyl, aralkyl, cycloalkenyl; R3denotes cycloalkyl or alkyl (optionally substituted by cycloalkyl, hydroxy, Alcoxy, alkylthiol, pyridium or indolium); R4denotes cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkoxycarbonylmethyl, carbarnoyl (optionally substituted by aralkylamines) or aminosulfonyl (optionally substituted by alkyl); and R5denotes hydrogen.

In this subgroup, a preferred class of compounds are those compounds in which R2denotes alkyl; R3denotes cyclohexyl, alkyl (optionally substituted by cyclohexyl, hydroxy, benzyloxy-, methylthiourea, pyridium or indolium); and R4denotes a carboxy, alkoxycarbonyl and aminosulfonyl.

In this class of compounds, preferred are such compounds in which R2denotes 2-methylpropyl. Especially preferred are such compounds in which R3means cyclo is 2-ylmethyl.

Thus, the most preferred compounds of formula (I) are the following:

N-(2R-(N-hydroxycarbamoyl)methyl-4-(methyl)pentanoyl) -L-tryptophan-N'-(4-(carboxy)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-4-(methyl)pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-4-(methyl)pentanoyl) -L-leucine-N'-(4-(carboxy)phenyl)carboxamide;

N-(2R-mercaptomethyl-4-(methyl)pentanoyl)-L-leucine - N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-acetyltributyl-4-(methyl)pentanoyl)-L-leucine-N'-(4- (ethoxycarbonylphenyl)carboxamide;

N-(2R-carboxymethyl-4-(methyl)pentanoyl)-L-leucine-N'- (4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-4-(methyl)pentanoyl) -L-cyclohexylglycine-N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-4-(methyl)pentanoyl)-L - tert-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(4-(pyrid-4-yl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'-(4- (pyridin-4-yl)carboxamide;

N-(2R-carboxymethyl-5- (bifen-4-yl)pentanoyl)-L-tert-leucine-N'-(4-((2-hydroxyethyl) aminosulfonyl)phenyl)carboxamide;

N-(2R-carbol-5-(bifen-4-yl)pentanoyl)-L- - hydroxylamin-N'-(phenyl)carboxamide;

N-(N"-formyl-N"-hydroxyamino)methyl-5-(bifen-4 - yl)pentanoyl)-L-tert-leucine-N'-(pyridine-4-yl)carboxamide;

N-(2R, S)-(N"-formyl-N"-hydroxyamino)methyl-4- (methyl)pentanoyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N' -(4R, S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(4-(methylaminomethyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)- L-tert-leucine-N'-(4-(3-(morpholine-4 - yl)propylaminosulfonyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5- (bifen-4-yl)pentanoyl)-L-cyclohexylglycine-N'-(4-((2 - hydroxyethyl)aminosulfonyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-cyclohexylglycine-N'- (4-((2-(dimethylamino)ethyl)aminosulfonyl)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-4-(matilal)pentanoyl)-D, L - Norvaline-N'-(4-(dimethylaminoethanol)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-lysine-N'-(4- (etoxycarbonyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(phenyl)pentanoyl)-L-(N-lysine-N'- (4-(etoxycarbonyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-(N-isopropyl)lysine-N'-(4-(ethylaminomethyl)phenyl)carboxamide; and

N-(2R-carboxymethyl-5-(phenyl)pentanoyl)-L-(N, N'-dietilamida) lysine-N-(4-(etoxycarbonyl)phenyl)carboxamide.

The synthesis of compounds of formula (I)

The compounds of formula (I) receive the following methods, for example, in accordance with the reaction schemes 1-7, in which is shown the replacement group (for example, R1, R2and so on) have the same values, unless otherwise noted, are specified in "Summary of the invention". Some of the reaction schemes illustrate the structure of formula (I), where p is 0 and R7denotes optionally substituted phenyl group, the substituents R4and R5have the meanings specified for formula (II) in the "Summary of the invention"] . For specialists in the art it is obvious that the same image can be obtained the corresponding compounds in which p is 1-4 and R7has other values and combinations of substituents and/or variables in the compounds of formula (I) and their intermediate products is acceptable only if such combinations result in stable compounds.

The compounds of formula (I) and their pharmaceutically acceptable salts as an individual stereoisomers, or as is ocelot, the components of these peptides. The standard method of the formation of peptide bonds described in M. Bodanszky and others in The Practice of Peptide Synthesis (1984), Springer-Verlag; M. Bodanszky in Principles of Peptide Synthesis (1984), Springer-Verlag; J. P. Greenstein and others in the Chemistry of the Amino Acids (1961), T. 1-3, John Wiley and Sons Inc.; in G. R. Pettit in Synthetic Peptides (1970), T. 1-2, Van Nostrand Reinhold Company.

The parameters of the synthesis reaction

The term "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under reaction conditions in which it is used [they include, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.,]. Unless otherwise stated, solvents used in the reactions according to the present invention are inert organic solvents.

The notion of q. s. " refers to the addition of such amount which is sufficient to achieve the specified function, for example, bringing the solution to the desired volume.

Unless otherwise stated, the reactions described herein, is performed at atmospheric pressure in the temperature range of 5oC to 100oC (preferably from 10oC to 50oC;/SUP>C). In addition, if there are no other instructions, time and reaction conditions must be understood as approximate, for example, the reaction is carried out at approximately atmospheric pressure in the temperature range from approximately 5oC to about 100oC (preferably from about 10oC to approximately the 50oC; most preferably at about 20oC) during the period of time from about 1 to about 10 hours (preferably about 5 hours). Assume that the parameters specified in the examples are specific, but not rough.

Amide combinations used for the formation of compounds of formula (I), usually performed using the carbodiimide method with reagents, as dicyclohexylcarbodiimide or N'-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDCI), in the presence of 1-hydroxybenzotriazole (HOBT) in an inert solvent, such as dimethylformamide (DMF). Other methods of formation of amide or peptide bond include, but are not limited to, methods of synthesis using a carboxylic acid, acylated, mixed anhydride or activated complex ester, such as nitrophenyl the selecting protective group for the terminal amino or carboxyl groups of compounds, used to obtain the compounds of formula (I), is partially determined by the specific conditions of the amide or peptide combinations, as well as partial components of amino acids and/or peptide involved in the combination. Usually used aminosidine groups include those well known in the art, for example, para-methoxybenzeneboronic, benzyloxycarbonyl (also called carbobenzoxy or CBZ), paranitroaniline, tert-butoxycarbonyl (VOS), etc., it is Preferable to use either VOS or CBS as a protective group for the amino group due to the relative ease of its removal of weak acids [for example, triperoxonane acid (TFA) or hydrochloric acid in ethyl acetate] or by using catalytic hydrogenation.

Isolation and purification of the compounds and intermediates described in this description may be implemented, if necessary, using any suitable for this purpose method of separation or purification, such as, for example, filtration, extraction, crystallization, chromatography on columns, thin layer chromatography or chromatography in a thick layer or by using a combination of these methods. Specific examples soo is used and other equivalent methods for the separation or purification.

Individual stereoisomers of compounds of formula (I) can be separated by methods known to experts in the art, for example, selective crystallization or chromatography, and/or the methods described in the description.

Obtaining compounds of formula (E)

The compounds of formula (E) are intermediate products used to produce compounds of formula (I), and receive them in accordance with reaction scheme 1, where R12indicates mesyl or tosyl.

Original products

The compounds of formula (Ea) can be obtained in accordance with methods known to experts in the art (see for example the publication of the European application 0276436), or can be obtained in accordance with the method described below in example 1. The compounds of formula (Ed) are commercially available or can be obtained in accordance with methods known to experts in this field of technology.

Formula (Eb): Typically, the compounds of formula (E) are obtained first by treating compound of formula (Ea) paraformaldehyde in an aprotic solvent, preferably tetrahydrofuran and methylene chloride at 0-15oC, preferably at 0oC in the presence of the Yat to 25-37oC, preferably up to 37oC for 18 hours. Then the alcohol of formula (Eb) was isolated using standard methods, preferably by evaporation of the solvent, extraction and filtering.

Formula (Ec): Then the alcohol of formula (Eb) in an aprotic solvent, preferably methylene chloride, cooled to a temperature in the range -20oWith up to approximately 0oC, preferably to about -20oC, and then subjected to esterification by standard processing of alcohol or methylchloride or mozillateam in an amount of at least stoichiometric to about 100% excess. The etherification

exercise during the first period of time (preferably within 15 minutes) at -20oC, and then during the second period of time (preferably within 3.5 hours) at room temperature. Then ester of the formula (EU) was isolated from the reaction mixture using standard methods, preferably by extraction, filtration and evaporation.

Formula (Ee): Then ester of formula (Ec) in an aprotic solvent, preferably DMF, is subjected to the interaction with the salt of the compounds of formula (Ed) (preferably sodium salt, Les, preferably DMF) for about 16-20 hours, preferably for 18 hours, when the initial temperature of approximately 0oC and slow warming to room temperature. The resulting mercapto-compound of formula (Ee) was isolated from the reaction mixture using standard techniques such as extraction, evaporation and fast chromatography.

Formula (E): Then, the compound of formula (Ee) is subjected to hydrolysis under alkaline conditions, preferably in the presence of sodium hydroxide, to obtain the compounds of formula (E), which is separated from the reaction mixture using standard methods.

Obtaining compounds of formula (Ia)

The compounds of formula (Ia) are compounds of formula (I) in which R1denotes a group of the formula

< / BR>
(where, if R6denotes aryl, it is preferably a naphthas-1-yl, naphthas-2-yl or phenyl, and, if R6denotes heteroaryl, it preferably represents a pyridyl or China-2-yl; R2preferably denotes alkyl; and R5preferably denotes hydrogen) are obtained in accordance with reaction scheme 2.

Original products

Amino acid with a protected nitrogen atom ways, well-known specialists in this field of technology. The compounds of formula (E) are obtained in accordance with reaction scheme 1.

Formula (C): Typically, the compounds of formula (1a) are obtained first by combining the compounds of formula (A) with the compound of the formula (I) [or with another compound of the formula H2N-(CH2)p-R7] in the standard conditions amide combination, receiving compound of formula (C). For example, to a cold (0-5oC) a solution of the compounds of formula (a) and excess molar amount HOBT in DMF add excess molar amount of EDCI. The resulting solution is stirred for from about 1 to about 2 hours, preferably for about 1 hour at 0-5oC, preferably at 0oC. Then to the cold solution was added a solution containing equimolar amounts of compounds of formula (I), in the presence of a base, preferably of DMAP. The resulting mixture is stirred for a period of time from 12 to 24 hours, preferably within 24 hours, at room temperature, preferably at 25oC. Then compound of formula (C) is recovered from the reaction mixture using techniques standard in the field of peptide chemistry.

in the presence of triperoxonane acid, receiving the compound of formula (D).

Alternative methods of producing compounds of the formula (D)

Another method of obtaining the compounds of formula (D), in particular, when R3represents tert-butyl and the other branched side chain amino acids, or cyclohexyl, p is 0 and R7denotes aryl or heteroaryl, includes the use of intermediate product (a-1), the receipt of which is shown in reaction scheme 2A. Another alternative method of obtaining the compounds of formula (D), in particular, when R3denotes 1-hydroxyisopropyl, or other hydroxy-side chain amino acids and R7denotes aryl or heteroaryl shown in reaction scheme 2B.

As shown in reaction scheme 2A, the compound of formula (A) will powerhaul combination with approximately 1 molar equivalent of N - hydroxysuccinimide in acetonitrile at 0oC in the presence of DCC. The reaction is carried out with stirring and at a temperature of from 0oC to 25oC for 8-16 hours to obtain the corresponding N - hydroxysuccinimide ether of the formula (a-1). Then this ester is subjected to interaction with the compound of the formula (V) or with another compound of the formula H2N-(CH2)p-R7in Indesit and remove the protective group, receiving the compound of formula (D) in accordance with the above reaction scheme 2.

As shown in reaction scheme 2, the compound of the formula (s - 1) in an inert anhydrous solvent such as THF, stirred with n-butyllithium at temperatures below 10oC, preferably at 0oC, for about 1 hour, then cooled to approximately -70oC and subjected to interaction with 3 molar equivalents of acetone. The compound of the formula (C-2) in the form of a racemic mixture is isolated and purified using standard methods. After removal of the protective group CBT using hydrogenolysis get compound of formula (D-1).

Formula (Ia) As shown in reaction scheme 2, the compound of formula (D) are combined with the compound of the formula (E) under standard conditions of peptide combinations. For example, to a cold (0-5oC, preferably 0oC) a solution of the compounds of formula (D) in an inert solvent, preferably THF, add 1,1'-carbonyldiimidazole. The resulting mixture is stirred for a period of time from 60 to 90 minutes, preferably for 75 minutes at 0-5oC, preferably at 0oC, and then subjected to interaction with the compound of the formula (the General formula (Ia) is then isolated from the reaction mixture using techniques the standard in the field of peptide chemistry, for example, by extraction and GHUR with reversed phase.

Obtaining compounds of formula (F)

The compounds of formula (F)

< / BR>
where R8represents tert-butyl, are intermediates for producing compounds of formula (I) in accordance with the following reaction scheme 4. The compounds of formula (F) are obtained in accordance with reaction scheme 3.

Original products

The compounds of formula (Fa) are commercially available or can be obtained in accordance with methods known to experts in the art, for example, by the method described below in example 11. Sultam L-(+)- 2,10-camphor and sultam D-(-)-2,10-camphor are commercially available, for example, they are manufactured by Aldrich company.

Formula (Fb): Typically, the compounds of formula (F) (the diagram shows one of the two isomers obtained by this synthesis) receive first the condensation of the compounds of formula (Fa) [where R2includes the group "X" of formula (I) and may represent, for example, biphenylphosphine or fortiprotect group] Sultana L-(+)-2,10-camphor with the formation of the compounds of formula (Fb).

Formula (Fc): Use matrikelstyrelsen corresponding complex ester of the formula (Fc).

Formula (F): Then remove the camphor group in an alkaline environment, such as lithium hydroperoxide (obtained in situ from lithium hydroxide and hydrogen peroxide), first at low temperature (preferably at 0oC) for 15 minutes, then warmed to room temperature for 2 hours. The mixture is again cooled to 0oC and added dropwise with stirring an aqueous mixture of sodium sulfite and sodium bicarbonate, after which the mixture is allowed to warm to room temperature and adjusted the pH to neutral, receiving individual stereoisomer of formula (F), in which the carbon attached to the group-X-R2is in the (R) -configuration. On a similar methodology, but substituting sultam D-(-)-2,10-camphor on Sultana L-(+)-2,10-camphor, you can get a corresponding individual stereoisomer (S) -configuration.

An alternative method of preparing compounds of formula (F)

Another way to obtain stereoisomers of formula (F) based on the use of commercially available chiral compounds, namely, 4S-perimeterisation, as shown below in reaction scheme 3A [following after paragraph of "Original products", where it retrieves compounds used will ecobotanical-O-CH2-CH2- receive in accordance with the reaction scheme 3A-1.

Commercially available alcohol (a) is subjected to interaction with ethyl-4-bromocrotonate (b) in the presence of stoichiometric amount of sodium hydride in a solvent such as DMF, at a temperature of from 0oC to room, or in the case of phenol (a) by boiling for several hours under reflux of the compound (b) in acetone in the presence of excess potassium carbonate. The resulting unsaturated ester (C) turn the hydrogenation in the presence of platinum at an angle in a saturated ester (d), which is then amyraut aqueous sodium hydroxide in ethanol to acid (e). Acid (e) is transformed into the acid chloride (Fa'-1) by treatment with oxalylamino in the temperature range from room temperature up to 50oC.

The compounds of formula (Fa'), in which X represents-S-CH2-CH2- receive in accordance with the reaction scheme 3A-2.

Commercially available thiol (f) is subjected to interact within a few hours with lithium hydride in DMF at room temperature with the formation of thiolate lithium. Add excess butyrolactone (g) and heated to boiling point under reflux in an argon atmosphere, paranee.

The compounds of formula (Fa') where X denotes-CH2-CH2"Oh, get in accordance with the reaction scheme 3A-3.

Compounds of formulas (l) and (k) in many cases are commercially available. Otherwise, they receive the following way. The compounds of formula (j), in which R2denotes aryl or heteroaryl into alkenes (k) processing within a few hours vinyltrimethylsilane (which is issued by the company Aldrich Chemical Co.) in the presence of tetrakis(triphenylphosphine) palladium as a catalyst at the temperature of reflux distilled toluene. In addition, alkenes (k) can be converted into alcohols (l) by hydroabrasive borane in THF at a temperature from 0oC to room within a few hours, followed by oxidation with alkaline hydrogen peroxide. Alcohols (l) and turn them into acids (m) processing Chloroacetic acid and an excess of sodium hydride in DMF at elevated temperature, preferably at 60oC. Acid (m) is transformed into the acid chlorides (Fa'-3) by treatment with oxalylamino, as described earlier.

The compounds of formula (Fa') where X denotes-CH2-CH2-S, receive in accordance with the reaction scheme 3A-4.

Alcohols (l) is transformed into the one in THF at 0oC. Thioacetate (n) is transformed into acids (b) by treatment with potassium carbonate in methanol in the presence of Chloroacetic acid. Acid (R) is transformed into the acid chlorides (Fa'-4) treatment oxalylamino, as described earlier.

Formula (Fb'): First, the compound of formula (Fa') condense under standard conditions with the 4S-fenilmetilketenom to obtain the corresponding compounds of formula (Fb').

Formula (Fc'): Approximately equimolar amount hexamethyldisilazide sodium added to the compound of formula (Fb') in an inert solvent, such as THF. The reaction is carried out at a temperature of from -80oC to -95oC for about 15 minutes.

To this mixture is added an excess of tert-butylbromide and the solution is stirred for approximately 2 hours at a temperature of from -90oC to -60oC, receiving individual stereoisomer of formula (Fc'), which is cleaned by standard organic chemistry methods.

The formula (F'): Group oxazolidinone the compounds of formula (Fc') is removed in the basic conditions to receive individual stereoisomer of formula (F'), for example, in accordance with the method of obtaining the compounds of formula (F) shown in reaction seminatural method of obtaining compounds of formula (F)

The compounds of formula (F) can also be obtained in accordance with the method represented by reaction scheme 3B.

Original products

The compound designated as compound of formula (Fc) can be obtained in a manner analogous to the method of obtaining the compounds of formula (Fc') shown in reaction scheme 3A, by replacing the compounds of formula (Fa') on the corresponding lilinoe connection, in which the group denoted by X is a prop-2-enyl, a R2denotes H.

Formula (Fc -1): Atilirovanie or heteroarylboronic the compounds of formula (Fc") is carried out in the presence of a base and a palladium catalyst by the addition of aryl - or heteroarylboronic, preferably bromide or iodide, and aging the reaction mixture for 2-4 hours, preferably 4 hours, at a temperature of approximately 100oC with the formation of the compounds of formula (Fc -1).

Formula (Fc"-2): Catalytic hydrogenation (Pd/C) allyl compounds of formula (Fc -1) leads to the corresponding alkyl compounds of formula (Fc"-2).

Formula (F): Compound of formula (Fc"-2) is treated in an alkaline environment, such as lithium hydroperoxide (obtained in situ from the hydroxide is chickpeas and then warmed to room temperature for 2 hours. The mixture is again cooled to 0oC and added dropwise with stirring an aqueous mixture of sodium sulfite and sodium bicarbonate, after which the mixture is allowed to warm to room temperature, the pH adjusted to neutral, receiving compound of formula (F) using standard extraction methods.

Obtaining compounds of formula (Ib), (Ic), (Id) and (Ie)

Compounds of formula (Ib), (Ic), (Id) and (Ie), each of which is a subclass of compounds of formula (I), in which the substituent R1has different meanings, receive consistently in accordance with reaction scheme 4, where R8represents tert-butyl. In the compounds of formula (Ib), R1denotes alkoxycarbonyl or arelaxation. In the compounds of formula (Ic) R1represents carboxy. In the compounds of formula (Id) R1indicates benzyloxycarbonyl. In the compounds of formula (Ie)1indicates hydroxycarbamoyl.

Original products

The compounds of formula (D) are obtained in accordance with reaction schemes 2, 2A and 2B. The compounds of formula (F) are obtained in accordance with reaction schemes 3 and 3A. O - benzylhydroxylamine is commercially available, for example, in the form of cleaners containing hydrochloride salt, manufactured by Aldrich Chemical Co.

Formitalia, receiving the compound of formula (Ib). For example, to a solution of the compounds of formula (F) in an aprotic solvent, preferably DMF) containing a slight excess molar amount of HOBT add excess molar amount of EDCI. The resulting mixture is stirred for 1-2 hours (preferably 1 hour) at 0-5oC (preferably at 0oC). Then to the cold solution was added an equimolar amount of the compounds of formula (D) in the presence of a base, preferably of DMAP. The resulting mixture was then stirred for 12-24 hours (preferably within 24 hours) at room temperature (preferably at 25oC). Then the compound of formula (Ib) is recovered from the reaction mixture using techniques standard in the field of peptide chemistry, for example, by evaporation of solvents, extraction, fast chromatography and/or GHUR.

Formula Ic: Compound of formula (Ib) is subjected to hydrolysis in a weakly acidic conditions, preferably in the presence of triperoxonane acid, receiving the connection formula (Ic).

Formula Id: Compound of formula (Ic) is then treated with O - benzylhydroxylamine under standard conditions amide combination, receiving compound of formula (Id). NDMP, handle excess molar amount of EDCI. After stirring the resulting mixture for 0.5-1 h at 0-5oC (preferably at 0oC) add an equimolar amount of O-benzylhydroxylamine. The reaction mixture is allowed to warm and incubated at room temperature overnight (8-16 hours). The compound of formula (Id) is then isolated from the reaction mixture using standard methods, for example, extraction and fast chromatography.

The formula Ie: Hydroxyamino group (benzyl) compounds of formula (Id) are removed under conditions of catalytic hydrogenation (Pd/C), obtaining the compound of formula (Ie).

An alternative method of preparing compounds of formula (Ie)

An alternative method of preparing compounds of formula (Ie) (in which R4means, in particular, structurai fragment, such as alkylsulfonyl) is the treatment of the corresponding compounds of formula (Ic) hydroxylamine-hydrochloride and peptide reagent combinations, preferably benzotriazol -1 - yloxy - Tris (dimethylamino) phosphodiesterases, in the presence of a tertiary amine base, such as N-methylmorpholine, in a solvent such as DMF. The resulting compound of formula (Ie): what="ptx2">

An alternative method of preparing compounds of formula (Ib)

The most preferred method of preparing compounds of formula (Ib) where R2denotes aryl or heteroaryl and where X (not shown) denotes propane-1,3-diyl, and p (not shown) is 0, is shown in reaction scheme 4A.

Original products

The compound designated as compound of formula (Fc) can be obtained in a manner analogous to the method of obtaining the compounds of formula (Fc') shown in reaction scheme 3A, by replacing the compounds of formula (Fa') on the corresponding lilinoe connection, in which R2denotes prop-2-enyl. The compound of formula (D') is a compound of formula (D) and can be obtained in accordance with reaction scheme 2. Halodrol or haloalkaline reagents used to obtain the compounds of formula (D'-2), are commercially available or can be obtained in accordance with methods known to experts in the art, for example, according to example 41C.

The compound of formula (F) is obtained by alkaline hydrolysis oxazolidinone group of compounds of formula (Fc"). After a standard selection methods compound of formula (Fc"), subject to the OI scheme 2, receiving the compound of formula (D'-1). Atilirovanie or heteroarylboronic the compounds of formula (D'-1) carried out by adding the aryl - or heteroarylboronic (preferably aryl - or heteroarylboronic, iodide or triflate) and maintaining the reaction mixture for about 2 hours at a temperature of approximately 100oC obtaining the compounds of formula (D'-2). By catalytic hydrogenation (Pd/C) compounds of the formula (D'-2) are compound of the formula (Ib').

Obtaining compounds of formula (G)

The compounds of formula (G)

< / BR>
are intermediates for producing compounds of formula (I), the receipt of which is shown below in reaction scheme 6. The compounds of formula (G) are obtained in accordance with reaction scheme 5.

Original products

The compounds of formula (Ga) and teoksessa acid are commercially available, for example, they are produced by firms TCI America Organic Chemicals and Aldrich Company, respectively.

Formula (Gb): Compound of formula (Ga) is subjected to hydrolysis with an equimolar amount of base, such as potassium hydroxide, obtaining the compound of formula (Gb).

Formula (Gc): Compound of formula (Gb) subjected to deprotonation in basic conditions, for example, p is Maldegem with subsequent treatment of the water base, preferably potassium carbonate, receiving the compound of formula (Gc), which is separated from the reaction mixture using standard methods.

The formula (Gd): Compound of formula (Gc) is subjected to hydrolysis in basic conditions, preferably in the presence of lithium hydroxide, obtaining the compound of the formula (Gd).

Formula (G): Compound of the formula (Gd) are then subjected to interaction with an excess molar amount teoksessa acid at 90 - 100oC (preferably at 95oC), in the atmosphere of inert gas. Then the compound of formula (G) was isolated from the reaction mixture using standard methods, for example, by extraction and evaporation.

Obtaining compounds of formula (If) and (lg)

Compounds of formula (If) and (Ig), each of which is a subclass of compounds of formula I, where Deputy1means structurae connection, receive consistently in accordance with reaction scheme 6. In the compounds of formula (If) R1indicates acetylthio. In the compounds of formula (Ig) R1means mercapto.

Formula (If): Compound of formula (G) are combined with the compound of the formula (D) under standard conditions amide combination, receiving compound of formula (If). Such is offered by the molar number of EDCI. Then add the compound of formula (D) and the resulting mixture is stirred over night at room temperature. After that, the formed compound of formula (If) is recovered from the reaction mixture using standard methods, for example by evaporation of the solvent, extraction and fast chromatography.

Formula (Ig): Compound of formula (If) is subjected to hydrolysis under alkaline conditions, preferably in proton solvent such as methanol, in the presence of ammonium hydroxide, obtaining the compound of formula (Ig).

Obtaining compounds of formula (Ih)

The compounds of formula (Ih) are a subclass of compounds of formula (I) in which R1denotes the N-th hydroxypropylamino, and receive them in accordance with reaction scheme 7.

Original products

The compound designated as compound of formula (Fb) can be obtained in a manner analogous to the method of obtaining the compounds of formula (Fb') shown in reaction scheme 3A, by replacing the compounds of formula (Fa') on the corresponding lilinoe connection, in which R2denotes prop-2-enyl.

Formula (P-1): Compound of formula (Fb") are hydroxymethylpropane by incubation with tetrachloro predpochtitelno within 1 hour with the subsequent addition of S-trioxane and titanium tetrachloride and with continued incubation at 0oC for 3-5 hours, preferably 4 hours. The compound of the formula (R-1) then allocate standard methods, for example, by extraction and chromatography columns.

Formula (P-2): Compound of the formula (R-1) is subjected to interaction with an excess molar amount of O - benzylhydroxylamine and trimethylaluminum at a low temperature, preferably at 0oC. the Reaction allowed to proceed under stirring for 5-7 hours, preferably 6 hours, and at 0oC in argon atmosphere. The resulting compound of the formula (R-2) was isolated by standard methods.

Formula (P-3): Excess methylchloride subjected to interaction with the compound of the formula (P-2) in pyridine at 0oC for several hours, preferably for 3 hours. The reaction mixture is cooled on ice, extracted with an organic solvent and concentrated. The concentrated extract was refluxed in an alkaline environment within a few hours, preferably for 3 hours, thus obtaining azetidinone compound of the formula (R-3), which is purified by standard methods.

group (for example, aryl - or heteroarylboronic, preferably bromide or iodide) in an inert solvent in the presence of a base such as triethylamine and a palladium catalyst, preferably formed from palladium (II) acetate and about two molar equivalents of tri-ortho-tolylphosphino. After holding the reaction mixture for 15 to 20 hours, preferably for 18 hours at 100oC corresponding compound of formula (R-4) was isolated and purified by standard methods.

Formula (P-5): Splitting azetidinone ring compounds of the formula (R-4) is carried out in basic conditions at room temperature for 1-3 hours, preferably 1 hour. The resulting compound is extracted with an organic solvent, concentrated, re-dissolved in containing the base solvent (e.g. pyridine) and carboxylic formic anhydride at low temperature, preferably atoC, for 30 minutes, obtaining the corresponding compound of formula (R-5), which produce standard ways.

Formula (P-6): Compound of the formula (R-5) are combined with the compound of the formula (D') under standard conditions amide combin the tx2">

Formula (Ih): Catalytic hydrogenation of the compounds of formula (P-6) using Pd/C, followed by removal of the catalyst by filtration allows to obtain the corresponding compound of formula (Ih).

Obtaining salts

All the compounds of formula (I), which exist either in the form of free acid or free base form, in addition, can be converted into their pharmaceutically acceptable salts by treatment of the corresponding inorganic or organic base or the corresponding inorganic or organic acid, respectively. Salts of compounds of formula (I) can also be converted into the free acid or free base or into another salt. For example, the compound of formula (I), with a fragment of the carboxylic acid may be converted into the carboxylate adding 1 equivalent of NaOH or KOH in ethanol solvent, followed by evaporation of the solvent. The compound of formula (I) in free base form may be converted into a chloride salt, for example, by adding 1 equivalent of HCl in an organic solvent, followed by concentration.

Preferred methods of synthesis and final stage

In General, compounds of formula (I) receive the UP> denotes alkoxycarbonyl, arelaxation, aryl - or heteroarylboronic or acetylthio; in the presence of a base and amide reagent combination to obtain the corresponding compounds of formula (I); or

(B) catalytic hydrogenation of the corresponding compounds where X and R2together denote an optionally aryl - or heteroarylboronic of alkenyl; or

(C) processing the compounds of formula (I), where R1denotes alkoxycarbonyl or arelaxation, in acid medium to obtain the corresponding compounds of formula (I), where R1represents carboxy; or

(G) interaction of the compounds of formula (I), where R1denotes a carboxy, O-benzylhydroxylamine with obtaining the compounds of formula (I), where R1indicates benzyloxycarbonyl; or

(D) catalytic hydrogenation of the compounds of formula (I), where R1indicates benzyloxycarbonyl, to obtain the corresponding compounds of formula (I), where R1indicates hydroxycarbamoyl; or

(E) interaction of the compounds of formula (I), where R1denotes a carboxy, with hydroxylamine to obtain the corresponding compounds of formula (I), where R1indicates hydroxycarbamoyl; or1denotes the N-th hydroxypropylamino; or

(C) interaction of the compounds of formula (I), where R1indicates acetylthio, with ammonium hydroxide in proton solvent to obtain the corresponding compounds of formula (I), where R1means mercapto.

A preferred method of preparing compounds of formula (I), where R1denotes the N-th hydroxypropylamino, includes the transformation of the compounds of formula (P-4)

< / BR>
where R2denotes aryl or heteroaryl by alkaline hydrolysis with subsequent formirovanie with obtaining the compounds of formula (P-5)

< / BR>
interaction of the compounds of formula (P-5) with the compound of the formula (D) obtaining the compounds of formula (P-6)

< / BR>
and catalytic hydrogenation of the compounds of formula (P-6).

Compounds obtained by the above method according to the invention, can be identified by the presence of detectable amounts of one or more compounds of the formula (R-3), (P-4) or (R-6). Although, as it is well known that pharmaceuticals must meet Pharmacopoeia standards prior to their approval and/or sale, and the purity of the reagents for synthesis (such as O-benzylhydroxylamine) or predshestvennika the connection, obtained by the method according to the present invention may contain small, but detectable amounts of these products present, for example, in concentrations of 50 ppm million or below. Such concentration of the compound of formula (R-3) can be detected, for example, using GC-MS, the compounds of formula (P-4) can be detected, for example, using GHUR-MS or GHUR with fluorescent detection, the compounds of formula (P-6) can be detected, for example, using GHUR with fluorescent detection. Because it is important to control the purity of pharmaceutical compounds for the presence of these substances, then the scope of the invention also includes a method of detection used in the implementation of the method according to the present invention.

Examples

The following methods of preparation, composition, and examples are intended for a more detailed explanation of the essence of the present invention, which should ensure the possibility of practical implementation of the present invention by experts in the field of technology. These examples should not be construed as limiting the scope of invention, and they are only illustrative and representative.

Example 1

The compounds of formula (Ea)oC for 10 minutes. The ice bath was removed and the reaction mixture was stirred for 4 hours. The mixture was diluted with 200 ml diethyl ether and the solution was washed for 1H. HCl (100 ml), water (4x100 ml), with brine (100 ml) and dried over magnesium sulfate. This product was evaporated using a rotary evaporator, getting 8,15 g of ethyl ester of 2- (ethoxy)phosphonomethyl-4-methylpentanoic acid in the form of a slightly yellowish oil, MS: 349 (M-H2O)+.

1B. In a similar way received the following compounds of formula (Ea):

ethyl ester of 2-(ethoxy)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2-(ethoxy)phosphonomethyl-4-phenylbutanoate acid;

ethyl ester of 2-(ethoxy)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2-(ethoxy)phosphonomethyl-3-cyclohexylpropionic acid; and

ethyl ester of 2-((ethoxy)phosphonomethyl)pentanol acid.

Example 2

The compounds of formula (Eb)

2A. The crude ethyl ester of 2- (ethoxy)phosphonomethyl-4-methylpentanoic acid (26 g) was dissolved in 600 ml of T is rimacillin)ndimethylacetamide and the resulting mixture was stirred for 20 minutes followed by the addition of paraformaldehyde (5.5 g). The temperature of the solution was brought to room temperature and kept at 37oC for 18 hours. The solvent was removed by evaporation and the resulting oil was dissolved in 200 ml of ethyl acetate. The solution was washed with 50 ml 1N. HCl (2 times), 50 ml brine (2 times), dried over MgSO4, was filtered and was evaporated, receiving 19.3 g of ethyl ester of 2-(ethoxy) (hydroxymethyl)phosphonomethyl-4-methylpentanoic acid in the form of a pale yellow oil, MS: 281,2 (MN+).

2B. In a similar way received the following compounds of formula (Eb):

ethyl ester of 2- (ethoxy)(hydroxymethyl)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2-(ethoxy)(hydroxymethyl)phosphonomethyl-4 - phenylbutanoate acid;

ethyl ester of 2- (ethoxy)(hydroxymethyl)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2-(ethoxy)(hydroxymethyl)phosphonomethyl-3 - cyclohexylpropionic acid; and

ethyl ester of 2- ((ethoxy)(hydroxymethyl)phosphonomethyl)pentanol acid.

Example 3

The compounds of formula (Ec)

3A. Ethyl ester of 2- (ethoxy)(hydroxymethyl)phosphonomethyl-4-methylpentanoic acid (5 g) was dissolved in 20 ml of CH2Cl2and cooled to -20oC (with duplication). To the solution of tablestable at room temperature for 3.5 hours. Then, each solution was washed with 10 ml of cold 2% HCl, 10 ml of NaHCO3(saturated), 10 ml of brine, dried over MgSO4, was filtered and was evaporated, receiving 12.8 g (combined output) ethyl ester 2-(ethoxy) (methanesulfonylaminoethyl)phosphonomethyl-4-methylpentanoic acid.

3B. In a similar manner, but replacing methanesulfonanilide on pair-toluensulfonate received ethyl ester 2-(ethoxy)(pair - toluensulfonate)phosphonomethyl-4-methylpentanoic acid.

3V. In a similar way received the following compounds of formula (Ec):

ethyl ester of 2- (ethoxy)(methanesulfonylaminoethyl)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2- (ethoxy)(methanesulfonylaminoethyl)phosphonomethyl-4-phenylbutanoate acid;

ethyl ester of 2- (ethoxy)(methanesulfonylaminoethyl)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2- (ethoxy)(methanesulfonylaminoethyl)phosphonomethyl-3 - cyclohexylpropionic acid;

ethyl ester of 2- ((ethoxy)(methanesulfonylaminoethyl)phosphonomethyl)pentanol acid;

ethyl ester of 2-(ethoxy)(pair - toluensulfonate)phosphinoyl-methyl-5-phenylpentane acid;

ethyl ester of 2-(Atara-toluensulfonate)phosphonomethyl - 3 - phenylpropane acid;

ethyl ester of 2- (ethoxy)(pair-toluensulfonate)phosphonomethyl-3 - cyclohexylpropionic acid; and

ethyl ester of 2-((ethoxy)(pair - toluensulfonate)phosphonomethyl)pentanol acid.

Example 4

The compounds of formula (Ee)

4A. Sodium hydride (1.52 g, (60%) and 2-hinokitiol (6 g) was stirred together at 0oC in 50 ml of DMF. After the termination of the initial allocation of H2the mixture was stirred at room temperature for 2.5 hours. Then the mixture was cooled to 0oC and added via cannula ethyl ester 2-(ethoxy)(methanesulfonylaminoethyl)phosphinoyl-methyl-4 - methylpentanoic acid (12.8 g) in 10 ml of DMF, after which the resulting mixture was stirred for 18 hours, slowly warming to room temperature. DMF was removed by evaporation, the residue was dissolved in 50 ml ethyl acetate and washed with 50 ml of H2About (2 times), brine solution (50 ml), dried over MgSO4and was evaporated to a yellow semi-solid product. By cleaning with fast chromatography using elution of a mixture of from 10% to 80% ethyl acetate/hexane received 10 g of ethyl ester of 2- (ethoxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol is but replacing 2-hinokitiol 1-naphthalenethiol, 2-naphthalenyl or thiophenol received the following compounds of formula (Ee):

ethyl ester of 2-(ethoxy) (naphthas-1 - altimeter)phosphonomethyl-4-methylpentanoic acid;

ethyl ester of 2-(ethoxy) (naphthas-2-altimeter)phosphonomethyl-4-methylpentanoic acid

ethyl ester of 2-(ethoxy)(phenylthiomethyl)phosphonomethyl - 4-methylpentanoic acid.

4B. In a similar way received the following compounds of formula (Ee):

ethyl ester of 2-(ethoxy) (quinoline-2-altimeter)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2-(ethoxy)(quinoline-2-altimeter)phosphonomethyl-4 - phenylbutanoate acid;

ethyl ester of 2-(ethoxy)(quinoline-2 - altimeter)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2-(ethoxy)(quinoline-2 - altimeter)phosphonomethyl-3-cyclohexylpropionic acid;

ethyl ester of 2-((ethoxy)(quinoline-2-altimeter)phosphonomethyl)pentanol acid;

ethyl ester of 2-(ethoxy)(naphthas-1 - altimeter)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2-(ethoxy)(naphthas-1-altimeter)phosphonomethyl-4-phenylbutanoate acid;

ethyl ester of 2-(ethoxy)(naphthas-1 - altimeter)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2-(ethoxy)(naphthas-1-altimeter)fo the l)pentanol acid;

ethyl ester of 2- (ethoxy)(naphthas-2-altimeter)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2-(ethoxy)(naphthas-2 - altimeter)phosphonomethyl-4-phenylbutanoate acid;

ethyl ester of 2-(ethoxy)(naphthas-2-altimeter)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2-(ethoxy)(naphthas-2 - altimeter)phosphonomethyl-3-cyclohexylpropionic acid;

ethyl ester of 2-((ethoxy)(naphthas-2-altimeter)phosphonomethyl)pentanol acid;

ethyl ester of 2- (ethoxy)(phenylthiomethyl)phosphonomethyl-5-phenylpentane acid;

ethyl ester of 2-(ethoxy)(phenylthiomethyl)phosphonomethyl-4 - phenylbutanoate acid;

ethyl ester of 2- (ethoxy)(phenylthiomethyl)phosphonomethyl-3-phenylpropane acid;

ethyl ester of 2-(ethoxy)(phenylthiomethyl)phosphonomethyl-3 - cyclohexylpropionic acid and

ethyl ester of 2- ((ethoxy)(phenylthiomethyl)phosphonomethyl)pentanol acid.

Example 5

The compounds of Formula (E)

5A. Ethyl ester of 2-(ethoxy)(quinoline-2 - altimeter)phosphonomethyl-4-methylpentanoic acid (4.5 g) was dissolved in 100 ml of THF and was added to 12.5 ml of 2n. NaOH together with methanol in a quantity sufficient to obtain a homogeneous solution. After 18 hours, THF was removed by vyparivayte was extracted with 50 ml ethyl acetate (2 times). An ethyl acetate fraction was washed with 20 ml brine, dried over MgSO4and evaporated, obtaining 3.8 g of 2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanoic acid as a yellow oil, MS: 368 (MN+).

5B. In a similar way received the following compounds of formula (E):

2-(hydroxy)(naphthas-1-altimeter)phosphonomethyl-4-methylpentanol acid;

2-(hydroxy)(naphthas-2-altimeter)phosphonomethyl-4-methylpentanol acid and

2-(hydroxy)(phenylthiomethyl)phosphonomethyl-4 - methylpentanol acid.

5V. In a similar way we obtain the following compounds of formula (E):

2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-5-phenylpentane acid;

2-(hydroxy) (quinoline-2-altimeter)phosphonomethyl-4-phenylbutanoate acid;

2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-3-phenylpropane acid;

2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-3-cyclohexylpropionic acid;

2-((hydroxy) (quinoline-2-altimeter)phosphonomethyl)pentane acid;

2-(hydroxy)(naphthas-1-altimeter)phosphonomethyl-5 - phenylpentane acid;

2-(hydroxy)(naphthas-1 - altimeter)phosphonomethyl-4-phenylbutanoate acid;

2-(hydroxy)(naphthas-1-altimeter) is openbuy acid;

2-((hydroxy)(naphthas-1-altimeter) phosphonomethyl)pentane acid;

2-(hydroxy)(naphthas-2 - altimeter)phosphonomethyl-5-phenylpentane acid;

2-(hydroxy)(naphthas-2-altimeter)phosphonomethyl-4-phenylbutanoate acid;

2-(hydroxy)(naphthas-2-altimeter)phosphonomethyl-3-phenylpropane acid;

2-(hydroxy)(naphthas-2-altimeter)phosphonomethyl-3 - cyclohexylpropionic acid;

2-((hydroxy)(naphthas-2 - altimeter)phosphonomethyl)pentane acid;

2-(hydroxy)(phenylthiomethyl)phosphonomethyl-5-phenylpentane acid;

2-(hydroxy)(phenylthiomethyl)phosphonomethyl-4-phenylbutanoate acid;

2-(hydroxy)(phenylthiomethyl)phosphonomethyl-3-phenylpropane acid;

2-(hydroxy)(phenylthiomethyl)phosphonomethyl-3 - cyclohexylpropionic acid and

2-((hydroxy)(phenylthiomethyl)phosphonomethyl)pentane acid.

Example 6

Separation of the compounds of formula (E)

2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol acid (5.3 g) was dissolved in 50 ml of warm ethanol (absolute) was added to 4.2 g of (-)-cinchonidine.

After 30 minutes at room temperature began to precipitate the salt. The flask was covered with foil and kept for 2 days. Then castoral in 100 ml ethyl acetate and washed successively 1% HCl to remove cinchonidine, while maintaining the pH above 4. Both solutions were dried separately over MgSO4and evaporated, obtaining 2.4 g of individual stereoisomer []2D4= +is 10.68o(9,73 mg in methanol (2 ml) and 2.5 g of another individual stereoisomer []2D4= - 8,70o(9,88 mg in methanol (2 ml)).

Example 7

The compounds of formula (IN)

7A. To a cold (0oC) suspension of 4-acetamidobenzenesulfonyl (4.0 g, 17 mmol) in CH2Cl2(40 ml) was added pyridine (1.7 ml, 20 mmol) and DMAP (209 mg, 1.7 mmole). (Which resulted in formation of a clear solution). Anhydrous methylamine was barbotirovany in the solution for 1 hour at 0oC, and then the solution was left to stir at 25oC for 2 hours. The solution was extracted with 1M NaOH (g ml) and the combined extracts were brought to pH 6 withoC with 3M HCl. The product which has precipitated in the form of fluffy white crystals were filtered and washed with cold water, obtaining 3.2 g (82%) of 4-acetamido-N-methylbenzenesulfonamide;1H-NMR (300 MHz, MeOH) to 2.35 (s,3H), 2,70 (s,3H), of 7.96 (s,4H).

7B. A mixture of 4-acetamido-N-methylbenzenesulfonamide (3.2 g, 14 mmol) and 100 ml of 1M HCl was kept at the boiling point under reflux in an argon atmosphere for the power of 1M NaOH atoC. the Aqueous phase was separated and was extracted with CH2Cl2(G ml). The combined organic phases were washed with brine (10 ml), dried (Na2SO4) and concentrated, obtaining 1.5 g (58%) of the compounds of formula (V), where R4denotes the N - methylsulfonate, in the form of a colourless solid;1H-NMR (300 MHz, MeOH) to 2.46 (s,3H), 6,67-6,72 (AA1part from AA1XX1,2H), OF 7.48-7,52 (XX1part from AA1XX1,2H).

Example 8

The compounds of formula (C)

8A. To a cold (0oC) a solution of N-tert-butoxycarbonyl-L-leucine (1.4 g, 6.3 mmole) and HOBT (1.5 g, 9.8 mmole) in DMF (30 ml) portions was added EDCI (2.5 g, 14 mmol). The solution formed after stirring for 1 hour at 0oC, was treated with methyl-4-aminobenzoate (1,09 ml, 6.8 mmole) and DMAP (0.32 g, 2.6 mmole). After stirring for 24 hours at 25oC DMF was removed under vacuum. The residue was dissolved in CH2Cl2and washed with saturated solution of NaHCO31M HCl (twice) and with brine. After drying over Na2SO4and concentration under vacuum was obtained the crude product, which was purified using fast chromatography on SiO2(20% ethyl acetate/hexane as solvent for elution). In re the spent solids, MS (BTA): 363 (M-N)-.

8B. In a similar way received the following compounds of formula (C):

N-tert-butoxycarbonyl-L-tryptophan-N'-fenilatilmalonamid;

N-tert-butoxycarbonyl-L-tryptophan-N'-phenolcarboxylic;

N-tert-butoxycarbonyl-L-tryptophan-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-tryptophan-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(4- (N-methylaminomethyl)phenyl)carboxamide;

N-tert-butoxycarbonyl-L-alanine-N'-(4-ethoxycarbonylphenyl) carboxamide;

N-tert-butoxycarbonyl-L-methionine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L - leucine-N'-(3-ethoxycarbonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(2-ethoxycarbonylphenyl) carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(4-(1 - methylethylacetate)phenyl)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(aminosulphonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'- (4-methoxycarbonylmethylene)carboxamide;

N-tert-butoxycarbonyl - L-pyridin-3-ylalanine-N'-(4-ethoxycarbonylphenyl) carboxamide;

N-tert-butoxycarbonyl-L-cyclohexylglycine-N'- (4-ethoxycarbonylphenyl)carboxamide;

siltronic-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-tert-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(4-tianfeng)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(4-(N-(2 - dimethylaminoethyl)carbarnoyl)phenyl)carboxamide and

N-tert-butoxycarbonyl-L-leucine-N'-(4- (N-(3-dimethylaminopropyl)carbarnoyl)phenyl)carboxamide.

8B. In a similar way received the following compounds of formula (C):

N-tert-butoxycarbonyl-L-tryptophan-N'- (4-nitrophenyl)carboxamide;

N-tert-butoxycarbonyl-L-tryptophan-N'- (4-AMINOPHENYL)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'- (4-methylsulfinylphenyl)carboxamide;

N-tert-butoxycarbonyl-L-leucine-N'-(4-ethylsulfonyl) carboxamid and

N-tert-butoxycarbonyl-L - leucine-N'-(4-tetrazolyl)carboxamide.

Example 9

The compounds of formula (D)

9A. To a cold (0oC) a solution of N-tert-butoxycarbonyl-L-leucine-N'-phenylcarbamate (3.4 g, 11 mmol) in anhydrous CH2Cl2(10 ml) was added TFA (2 ml). The solution was left to stir at 25oC for 6 hours and then concentrated under vacuum. The residue was distributed between CH2Cl2and H2O and the aqueous layer was podslushivaet a saturated solution of K2CO3the organic layers were washed with brine and dried over Na2SO4. By concentrating the received L-leucine-N'-phenolcarboxylic.

9B. In a similar way received the following connections:

L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-tryptophan-N'-fenilatilmalonamid;

L-tryptophan-N'-phenolcarboxylic;

L-tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-leucine-N'-(4-(N-methylaminomethyl)phenyl)carboxamide;

L-alanine-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-methionine-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-leucine-N'-(3-ethoxycarbonylphenyl)carboxamide;

L-leucine-N'-(2-ethoxycarbonylphenyl)carboxamide;

L-leucine-N'-(4-(1-methylethylacetate)phenyl)carboxamide;

L-leucine-N'-(aminosulphonylphenyl)carboxamide;

L-leucine-N'-(4-methoxycarbonylmethylene)carboxamide;

L-pyridine-3-ylalanine-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-spirocyclopentane-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-cyclohexylglycine-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-isoleucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-O-benzylation-N'-(4-ethoxycarbonylphenyl)carboxamide;

L-tert-leucine-N'-(4-ethoxycarbonylphenyl carb is backslid and

L-leucine-N'-(4-(N-(3 - dimethylaminopropyl)carbarnoyl)phenyl)carboxamide.

9B. In a similar way received the following compounds of formula (D):

L-tryptophan-N'-(4-nitrophenyl)carboxamide;

L-tryptophan-N'-(4-AMINOPHENYL)carboxamide;

L-leucine-N'-(4-methylsulfinylphenyl)carboxamide;

L-leucine-N'-(4-ethylsulfonyl)carboxamid and

L-leucine-N'-(4-tetrazolyl)carboxamide.

Example 10

The compounds of formula (Ia)

10A. To a cold (0oC) solution of 2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanoic acid (0.20 g, 0.54 mmole) in THF (6 ml) was added 1,1'-carbonyldiimidazole (0.12 g, 0.7 mmole). The mixture was stirred for 75 minutes at 0oC and then was treated with L-tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamido (0,22 g, of 0.62 mmole) and stirred at 25oC for 15 hours. THF is evaporated and the residue was dissolved in ethyl acetate (60 ml). The solution was washed H2About (10 ml), brine solution (10 ml) and dried over MgSO4. By concentration using GHUR with reversed phase using a gradient of acetonitrile and 50 mm buffer NH4OAc received 30 mg of N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol)-L - tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamide ate way received the following compounds of formula (Ia):

N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4 - methylpentanol)-L-tryptophan-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 687 (M+N)+;

N-(2-(hydroxy) (quinoline-2-altimeter)phosphonomethyl-4 - methylpentanol)-L-alanine-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 572 (M+N)+;

N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4 - methylpentanol)-L-methionine-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 632 (M+N)+;

N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4 - methylpentanol)-L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 614 (M+N)+;

N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol)- L-leucine-N'-(3-ethoxycarbonylphenyl)carboxamide,1H-NMR (300 MHz, MeOH) 0,73-a 1.01 (m, 12H), 1,28-2,00 (m,14H), 2,4-3,61 (m,2H), 4,27 is 4.45 (m,3H), 7.23 percent-7,44 (m,3H), 7,65-7,98 (m,6H), 8,29 (s,0,5 H), and 8.50 (s,0,5 H);

N-(2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-4-methylpentanol)-L-leucine-N'-(2 - ethoxycarbonylphenyl)carboxamide,1H-NMR (300 MHz, MeOH) 0,78 is 0.99 (m, 13H), 1,3-2,4 (m,7H), 2,90 was 3.05 (m,1H), 3,5-of 3.75 (m,2H), 3,89, 3,90, 3,94 (3s,3H full.), 4,35-to 3.50 (m,1H), 7,05 - 8,10 (m,11H), 8,32, 8,55, at 8.60 (3d, J=8,7,1 H);

N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol)- L-leucine-N'-(4-(1,1-dimethylethoxysilane)phenyl)carboxamide, MS (BTA): 642 (MN)+;

N-(is, d, 1H-NMR (300 MHz, MeOH) 0,76 (d, J=6,5, 3H), 0,81 (d, J=6,5, 3H), 0,85-1,1 (m,7H), 1,2-2,1 (m,7H), 2,92-2,95 (m,1H), 3,45 - 3,70 (m,2H), 4,35 is 4.45 (m,1H), 7,28 (d, J=8,7, 1H), 7,45 (t, J=8,7, 1H), to 7.68 (t,J=8,7,1 H) of 7.7 to 7.8 (m,3H), 7,87 (d, J=8,7, 1H), 7.95 is to 8.1 (m,3H);

N-(2-(hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol) -L-leucine-N'-(4-methoxycarbonylmethylene)carboxamide, MS (BTA): 628 (MN)+.

10V. In a similar way received the following compounds of formula (Ia):

N-(2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-5-phenylpentane)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-4-phenylbutane)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-3-phenylpropenoyl)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-3-cyclohexylpropionic)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-((hydroxy)(quinoline-2 - altimeter)phosphonomethyl)pentanoyl)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(naphthas-1 - altimeter)phosphonomethyl-5-phenylpentane)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(naphthas-1 - altimeter)phosphonomethyl-4-phenylbutane)-L-leucine-N'-(4 - methoxycarbonylbenzyl)carboxamide;

N-(2-(hydroxy)(naphthas-1 - altimeter)phosphonomethyl-3-cyclohexylpropionic)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(2-((hydroxy)(naphthas-1 - altimeter)phosphonomethyl)pentanoyl)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(naphthas-2 - altimeter)phosphonomethyl-5-phenylpentane)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(naphthas-2 - altimeter)phosphonomethyl-4-phenylbutane)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(naphthas-2 - altimeter)phosphonomethyl-3-phenylpropenoyl)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(naphthas-2 - altimeter)phosphonomethyl-3-cyclohexylpropionic)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(2-((hydroxy)(naphthas-2 - altimeter)phosphonomethyl)pentanoyl)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(penicillinate)phosphonomethyl-5 - phenylpentane)-L-leucine-N'-(4-ethoxycarbonylphenyl) carboxamide;

N-(2-(hydroxy)(penicillinate)phosphonomethyl-4 - phenylbutane)-L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(penicillinate)phosphonomethyl-3-phenylpropenoyl)-L - leucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(2-(hydroxy)(feniltiometilindol)phosphonomethyl)pentanoyl) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide.

10G. A solution of N-(2-(hydroxy) (quinoline-2-altimeter)phosphonomethyl-4-methylpentanol)-L - tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamide in THF (2 ml) and 1M NaOH (1 ml) was stirred for 24 hours at 25oC. the Organic solvents were evaporated and the residue was dissolved in ethyl acetate/H2O. the Aqueous phase was acidified with 1M HCl and the separated aqueous phase was twice extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to obtain 27 mg of N-(2- (hydroxy)(quinoline-2-altimeter)phosphonomethyl-4-methylpentanol)-L - tryptophan-N'-(4-carboxyphenyl)carboxamide as a yellow powder.

10D. In a similar way, but using as starting material N-(2-(hydroxy)(quinoline-2 - altimeter)phosphonomethyl-4-methylpentanol)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide (30 mg, 0,048 mmole), after trituration with ethyl acetate was given 10 mg of N-(2-(hydroxy)(quinoline - 2-altimeter)phosphonomethyl-4-methylpentanol)-L-leucine-N'-(4 - carboxyphenyl)carboxamide in the form of a semi-solid product;1H-NMR (300 MHz, MeOH) 0,81-of 1.02 (m, 12H), 1,1-2,3 (m,10H), 2,82-3,00 (m,1H), 3,49, 3,56, (2s,2H), 3,53 to 3.8 (m, 2H), 4,45-4,55 (m,1H), to 7.09 (d,J=8,2,1 H), 7,19 (d,J=8,2,1 H), was 7.45 (t, J= 8,2,1 H), 7,45-to 7.6 (m,3H), 7,65-7,80 (m,1H), 7,82-7,98 (m,2H), 8,10-to 8.20 (m,1H).

When/SUP>C was slowly added thionyl chloride (20.4 ml, 1.3 g). The mixture was heated to 50oC in argon atmosphere for 3 hours (until gas evolution ceased). The crude reaction mixture was distilled at atmospheric pressure, getting 4-methylpentanoate (25,3 g, 87.3 per cent), tKip143oC.

11 B. a Similar manner, but replacing 4-methylpentanol acid 5-phenylpentane acid (5 g), was obtained 5 - phenylbutanoate (4.4 g) as a colourless liquid, tKip91-93oC.

Example 12

The compounds of formula (Fb)

12A. To a suspension of 60% NaH (836 mg, 1.5 EQ.) in toluene (200 ml) at room temperature in an argon atmosphere portions were added to sultam L-(+)- 2,10-camphor (3.0 g, 13.9 mmole). The mixture was intensively stirred at room temperature for 1 hour. Then the solution is carefully added dropwise at 0oC was added 4-methylpentanoate. After stirring the reaction mixture at room temperature for 3 hours the reaction was stopped by mixing with 10 ml of chilled water and was added 70 ml of a simple ester. The reaction mixture was washed first with 0.5 N. HCl (g ml), then 5% TO2CO3(G ml) and finally with brine (CH ml). The organic layer was dried over MgSO4that filtered the solvent for elution) received sultam N-4-methylpentanol-L-(+)-2,10-camphor (3,39 g, 78%).

12B. In a similar manner, but replacing 4-methylpentanoate the corresponding chloride, were obtained the following compounds of formula (Fb):

sultam N-3-phenylpropenoyl-L-(+)-2,10-camphor, MS: 347 (M+);

sultam N-5-phenylpentane-L-(+)-2,10-camphor, MS: 375 M+;

sultam N-pentanoyl-L-(+)-2,10-camphor, MS: 300 (M+N)+.

Example 13

The compounds of formula (Fc)

13A. To a solution of sultam N-4-methylpentanol-L-(+)-2,10-camphor (3,39 g, 10.8 mmole) in 75 ml anhydrous THF at -78oC in argon atmosphere is added dropwise within 5 minutes was added NaN(TMS)2[NaN(trimethylsilane)2] (1.0 M in THF, 11,34 ml of 1.05 EQ.). After stirring at -78oC for 1 hour to the mixture was added hexamethylphosphoramide (5 ml), then tertbutylbenzene (5,2 ml, 3 EQ. ), and then in one portion was added 400 mg of Tetra-n-butylammonium. The resulting solution was kept at -78oC in argon atmosphere overnight. The next morning the reaction was stopped by mixing with cooling water (100 ml) and then was extracted with simple ether (CH ml). The combined ether layers were washed with brine, then dried over Na2SO4, filtered and concentrated. By purification using chromatography on colonography) received sultam N-(4 - methyl-2-tert-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor (4.0 g, 86,5%).

13B. In a similar manner, but replacing sultam N - 4-methylpentanol-L-(+)-2,10-camphor corresponding compound of formula (Fb), were obtained the following compounds of formula (Fc):

sultam N-(3-phenyl-2-tert-butoxycarbonylmethyl)propanol-L- (+)-2,10-camphor, MS: 461 (M)+;

sultam N-(5-phenyl-2-tert - butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor, MS: 490,1 (M+N)+;

sultam N-(2-tert-butoxycarbonylmethyl)pentanoyl-L- (+)-2,10-camphor, MS: 414 (M+N)+.

Example 14

The compounds of formula (F)

14A. To a stirred solution of sultam N-(4-methyl-2-tert-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor (of 5.45 g, 12.7 mmole) in 50% aqueous THF (150 ml) at 0oC in argon atmosphere was added crystals LiOHH2O (2.14 g, 4 EQ. ), and then 30% H2ABOUT2(11.5 ml). Then the ice bath was removed and the resulting emulsion was stirred for 3 hours, until it became transparent. A large part of the THF was removed under reduced pressure at 35oC. Then was added CH2Cl2(150 ml) and with stirring was added 4n. HCl to pH 2. After adding NaCl aqueous layer was extracted with CH2Cl2(G ml). Under reduced pressure and the 35oC delete CH2Cl2and then the residue was dissolved in the washed simple ether (50 ml). To the aqueous layer was added CH2Cl2and then, with stirring, was added NaCl, the aqueous layer was extracted with CH2Cl2(G ml) and the combined extracts were dried over Na2SO4was filtered and concentrated, obtaining (2R)-4-methyl-2-tert - butoxycarbonylmethylene acid as a colourless oil (2,95 g, quantitative yield).

14B. In a similar manner, but replacing sultam N-(4-methyl-2-tert-butoxycarbonylmethyl)pentanoyl-L-(+) -2,10-camphor corresponding compound of formula (Fc), were obtained the following compounds of formula (F):

(2R)-3-phenyl-2-tert-butoxycarbonylmethylene acid, MS: 265(M+N)+;

(2R)-5-phenyl-2-tert-butoxycarbonylmethylene acid, MS: 293,1 (M+N)+;

(2R)-2-tert-butoxycarbonylmethylene acid (colorless oil, 1,09 g).

14C. (2R)-3-phenyl-2-tert-butoxycarbonylmethylene acid (55 mg) was dissolved in glacial acetic acid (20 ml) and added PtO2(25 mg) in acetic acid. Then a chemical beaker was placed in a vessel Parr high pressure, pumped out the air and gave H2at a pressure of 100 pounds per square inch. After stirring for 3 days the mixture was filtered under vacuum through a layer of celite 1 see Then the filtrate to the SLA, MS: 269,5 (M-N)-.

Example 15

The compounds of formula (Ib)

15A. To a solution of 4-methyl-2-tert-butoxycarbonylmethylene acid (0.28 g, 1.2 mmole) in DMF (5 ml) containing HOBT (0,22 g, 1.8 mmole), was added EDCI (0.31 g, 1.8 mmole). The mixture was stirred at 0oC for 1 hour and then treated with L-cyclohexylglycine-N'-(4-ethoxycarbonylphenyl)carboxamide (1.2 mmole) and DMAP (27 mg, 0.24 mmole). Stirring was continued for 24 hours at 25oC and then evaporated DMF. The residue was dissolved in CH2Cl2(20 ml) and the solution washed with 1M HCl (10 ml), saturated NaHCO3(10 ml), brine solution (10 ml) and dried over Na2SO4. After concentration under vacuum was obtained an oil which was purified using fast chromatography on SiO2using as solvent for elution of 20% ethyl acetate/hexane. Thus received 0,22 g (22%) of N-(4-methyl-2-tert-butoxycarbonylmethylene) -L-cyclohexylglycine-N'-(4-ethoxycarbonylphenyl)carboxamide in the form of a solid product, MS (BTA): 503 (M+N)+.

15B. In a similar way received the following connections:

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-pyridin-3-ylalanine-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(4-what-methyl-2-tert-butoxycarbonylmethylene)-L-isoleucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-tert-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-leucine-N'- (4-tianfeng)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-leucine-N'-(4-(N-(3-dimethylaminopropyl)carbarnoyl)phenyl)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L - leucine-N'-(4-(N-(2-dimethylaminoethyl)carbarnoyl)phenyl)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-leucine-N'- (4-aminosulphonylphenyl)carboxamide;

N-(4-methyl-2-tert-butoxycarbonylmethylene)-L-leucine-N'- (4-methylaminoethanol)carboxamide;

N-(2-tert-butoxycarbonylmethylene)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(3-phenyl-2-tert-butoxycarbonylmethylene)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(3-cyclohexyl-2-tert - butoxycarbonylmethylene)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(4-phenyl-2-tert - butoxycarbonylmethylene)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamid and

N-(5-phenyl-2-tert-butoxycarbonylmethylene)-L-leucine is the solution (0oC) N-(4-methyl-2-tert - butoxycarbonyl-methylpentanol)-L-cyclohexylglycine-N'-(4 - ethoxycarbonylphenyl)carboxamide (70 mg, of 0.14 mmole) in CH2Cl2(2 ml) was added TFA (0.5 ml). After stirring for 5 hours at 25oC the solution was concentrated under vacuum and the product was purified using GHUR with reversed phase using a gradient of acetonitrile and 50 mm NH4OAc buffer, receiving 44 mg (71%) of N-(4-methyl-2-carboxymethylamino)-L-cyclohexylglycine-N'-(4 - ethoxycarbonylphenyl)carboxamide as a white solid, MS (BTA): 445 (M-N)-.

16B. In a similar way received the following connections:

N-(4-methyl-2-carboxymethylamino) -L-isoleucine-N'-(4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 419 (M-N)-;

N-(4-methyl-2-carboxymethylamino)-L-leucine - N'-(4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 419 (M-N)-;

N-(4-methyl-2-carboxymethylamino)-L-tert-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-carboxymethylamino)-L-leucine-N'-(4-tianfeng) carboxamide,1H-NMR (300 MHz, MeOH) 0,84 is 0.99 (m,12H), 1,15-to 1.82 (m,6H), 2,36-to 2.41 (m, 1H), 2,52-to 2.65 (m,1H), 2,8-2,95 (m,1H), 4,49-of 4.54 (m,1H), and 7.4 to 7.9 (m,4H);

N-(4-methyl-2-carboxymethylamino)-L-leucine-N'- (4-aminosulphonylphenyl)carboxamide,1H-Yl)-L-leucine-N'-(4-methylaminoethanol) carboxamide, MS (BTA): 459 (M-N)-;

N-(2-carboxymethylamino)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 405 (M-N)-;

N-(3-phenyl-2-carboxymethylamino)-L-leucine-N'-(4-ethoxycarbonylphenyl) carboxamide, MS (BTA): 455 (M+N)+;

N-(3-cyclohexyl-2-carboxymethylamino)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 459 (M-N)-;

N-(4-phenyl-2-carboxymethylamino)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 467 (M-N)-;

N-(4-phenyl-2-carboxymethylamino)-L-cyclohexylglycine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(4-phenyl-2-carboxymethylamino)-L-tert-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(5-phenyl-2-carboxymethylamino)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 481 (M-N)-and

N-(4-methyl-2-carboxymethylamino)-L-O-benzylation-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 497 (M-N)-.

16B. In a similar way, but by trituration of the crude product with simple ether and subsequent desantirovaniya ether were obtained the following compounds as TFA salts:

N-(4-methyl-2-carboxymethylamino)-L-pyridin-3-ylalanine - N'-(4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 456 (M+N)+;
+< / BR>
and

N-(4-methyl-2-carboxymethylamino)-L-leucine-N'-(4- (N-(2-dimethylaminoethyl)carbarnoyl)phenyl)carboxamide, MS (BTA): 491 (M+N)+.

16G. A mixture of N-(4-methyl-2-tert - butoxycarbonylmethylene)-L-O-benzylation-N'-(4 - ethoxycarbonylphenyl)carboxamide (60 mg) and Pd/C in ethyl acetate/THF (1:1.25 ml) was first made during the night at a pressure of 1 ATM. By filtration through celite, concentration of the filtrate and trituration of the residue with ether/hexane was obtained N-(4 - methyl-2-tert-butoxycarbonylmethylene)-L-threonine-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 407 (M-N)-.

16D. Similar to the method described in section a, but replacing N-(4-methyl-2-tert-butoxycarbonylmethylene) -L-cyclohexylglycine-N'-(4-ethoxycarbonylphenyl)carboxamid on the following connections:

N-(2R-(tert-butoxycarbonyl)methyl-5- (bifen-4-yl)pentanoyl)-L-lysine-N'-(4-(etoxycarbonyl)phenyl) carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5- (phenyl)pentanoyl)-L-lysine-N'-(4-(etoxycarbonyl)phenyl) carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5- (bifen-4-yl)pentanoyl)-L-(N-isopropyl)lysine-N'-(4 - (etoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-4-(phenyl)butanoyl)-L - cyclohexylglycine-N'-(4-(N",N"-dimethylbiguanide)lysine-N'-(4- (etoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L-tert - leucine-N'-(4-(methylthio)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L-tert - leucine-N'-(3-(2-hydroxyethyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4 - yl)pentanoyl) -L-S-((4-tianfeng)methyl)penicillamine-N'- (phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen - 4-yl)pentanoyl)-L-cyclohexylglycine-N'-(2-(4 - aminosulfonyl)phenylethyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L - cyclohexylglycine-N'-(3-(morpholine-4-yl)propyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L - tert-leucine-N'-(4-(methylaminomethyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L - cyclohexylglycine-N'-(4-((2-hydroxyethyl)aminosulfonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L - cyclohexylglycine-N'-(4-(N",N"-dimethylbenzenesulfonyl) phenyl)carboxamide and

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L - tert-leucine-N'-(4-((3-(morpholine-4 - yl)propyl)aminosulfonyl)phenyl)carboxamide,

received

N-(2R, S)-(N"-formyl-N"-hydroxyamino)methyl-4- (methyl)pentanoyl)-L-leucine-N'-(4-(meth shall anoil) -D, L-Norvaline-N'-(4-((2-(dimethylamino)ethyl)carbarnoyl)phenyl)carboxamide: MS: 478(M+N)+;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-lysine-N'-(4- (etoxycarbonyl)phenyl)carboxamide: MS: 588,3 (M+N)+;

N-(2R-carboxymethyl-5-(phenyl)pentanoyl)-L-lysine-N'-(4- (etoxycarbonyl)phenyl)carboxamide: MS: 512,3 (M+N)+;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L- (N - isopropyl)lysine-N'-(4-(etoxycarbonyl)phenyl)carboxamide: MS: 630 (M+N)+;

N-(2R-carboxymethyl-4-(phenyl)butanoyl)-L - cyclohexylglycine-N'-(4-(N", N"- dimethylbenzenesulfonyl)phenyl)carboxamide: MS: 586 (M+N)+;

N-(2R-carboxymethyl-5-(phenyl)pentanoyl)-L- (N, N'-dietilamida)lysine-N'-(4-(etoxycarbonyl)phenyl)carboxamide: MS: 610,4 (M+N)+;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert - leucine-N'-(4-(methylthio)phenyl)carboxamide: MS-BT (M+Na)+: designed 569,2450; received 569,2461;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N' -(3-(2-hydroxyethyl)phenyl)carboxamide: MS-BT (M+N)+: designed 545,3015; received 545,3021;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-S-((4-tianfeng)methyl) penicillamine-N'-(phenyl)carboxamide: MS-BT (M+N)+: designed 634,2740; received 634,2749;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-qi is e 634,2963;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-cyclohexylglycine-N'- (3-(morpholine-4-yl)propyl)carboxamide: MS-BT (M+N)+: designed 578,3594; received 578,3583;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'-(4- (methylaminomethyl)phenyl)carboxamide;1H-NMR (300 MHz, acetone-d6) 9,73 (br, s, 1H), to $ 7.91 (d, 2H, J=9 Hz), 7,79 (d, 2H, J=9 Hz), 7,56 (d, 2H, J=8 Hz), 7,25 was 7.45 (m,6H), 7,19 (d, 2H, J=8 Hz), 4,48 (d, 1H, J=9 Hz), 2,38-3,00 (m, 9H), 1,43-1,72 (m,4H), the 1.04 (s,9H);

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-cyclohexylglycine-N'-(4-((2 - hydroxyethyl)aminosulfonyl)phenyl)carboxamide: MS-BT (M+Cs)+: designed 782,1876; received 782,1896;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl) -L-cyclohexylglycine-N'-(4-((2-dimethylamino)ethyl)aminosulfonyl)phenyl) carboxamide: MS-BT (M+Cs)+: designed 809,2349; received 809,2369 and

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert - leucine-N'-(4-((3-(morpholine-4-yl)propyl)aminosulfonyl)phenyl)carboxamide: MS-BT (M+N)+: designed 707,3478; received 707,3489.

Example 17

The compounds of formula (Id)

17A. A solution of N-(4-methyl-2-carboxymethylamino)-L - leucine-N'-(4-ethoxycarbonylphenyl)carboxamide (0.28 g, of 0.66 mmole) and HOBT (0.12 g) in anhydrous DMF (20 ml) was cooled to 0oC and processed EDCI (0.32 g). After re is the promise to the 25oC during the night. DMF drove under vacuum and the residue was dissolved in CH2Cl2off , washed with a mixture of 5% HCl/5% NaHCO3and the saline solution and the solution was dried over Na2SO4. After concentration the product was purified using fast chromatography (SiO2, Rfor = 0.6, 10% MeOH/CH2Cl2). The fractions containing the product was further purified by rubbing with CH2Cl2receiving N-(4-methyl-2-(N"-benzyloxycarbonyl)methylpentanol)-L-leucine - N'-(4-ethoxycarbonylphenyl)carboxamide in the form of a solid substance with tPL198-199oC.

17B. In a similar way received the following connections:

N-(2-(N"-benzyloxycarbonyl)methylpentanol)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(4-phenyl-2-(N"-benzyloxycarbonyl)methylbutanoyl)-L-leucine-N ' -(4 - ethoxycarbonylphenyl)carboxamid and

N-(4-phenyl-2-(N"-benzyloxycarbonyl)methylpentanol)-L-tryptophan-N'- (4-ethoxycarbonylphenyl)carboxamide.

17V. N-(4-methyl-2-(N"-benzyloxycarbonyl)methylpentanol) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide (210 mg) was subjected to hydrolysis with 1M NaOH (1.4 ml) at 50-60oC for 2 hours in THF (20 ml) and MeOH (5 ml). Organic solvents were evaporated and the residue was dissolved in 10 ml of Hthe acetate (3x10 ml). The combined extracts were washed with brine, dried over Na2SO4and concentrated, obtaining N-(4-methyl-2-(N"- benzyloxycarbonyl)methylpentanol)-L-leucine-N'-(4 - carboxyphenyl)carboxamide (110 mg).

Example 18

The compounds of formula (Ie)

18A. To a solution of N-(4-phenyl-2-(N"- benzyloxycarbonyl)methylbutanoyl)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide (25 mg) in 20 ml of MeOH and 10 ml of THF was added 10% Pd/C (20 mg). The suspension was first made for 1 hour and then filtered under vacuum through celite. The resulting concentration of the product was purified on silica (2.5% of MeOH/CH2Cl2), receiving 8 mg of N-(4-phenyl-2-(N"-hydroxycarbamoyl)methylbutanoyl) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 482 (M-N)-.

18B. In a similar way received the following connections:

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanol) -L-leucine-N'-(4-carboxyphenyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanol)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 436 (M+N)+;

N-(2-(N"-hydroxycarbamoyl)methylpentanol)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide, MS (BTA): 420 (M-N)-;

N-(4-phenyl-2-(N"-hydroxycarbamoyl)methylbutanoyl) -L-tert-Lil-glycine-N'-(4-ethoxycarbonylphenyl)carboxamid

N-(4-phenyl-2-(N"-hydroxycarbamoyl)methylbutanoyl) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-(N"-hydroxycarbamoyl)methylpentanol) -L-tert-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(4-methyl-2-(N"- hydroxycarbamoyl)methylpentanol) -L-tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamide, MS (BTA): 507 (M-N)-and

N-(4-phenyl-2-(N"-hydroxycarbamoyl)methylbutanoyl) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide.

18V. In a similar way received the following connections:

N-(3-phenyl-2-(N"-hydroxycarbamoyl)methylpropanoyl)-L - leucine-N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(5-phenyl-2-(N"-hydroxycarbamoyl)methylpentanol) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamid and

N-(3-cyclohexyl-2-(N"- hydroxycarbamoyl)methylpropanoyl) -L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide.

Example 19

The compounds of formula (Gb)

19A. To a cold (0oC) the solution diethylethanolamine (21,6 g of 0.1 mol) in 150 ml of ethanol slowly for 30 minutes was added a solution of KOH (of 5.89 g of 0.1 mol). A clear solution was stirred at 25oC for 60 hours. The ethanol was removed under reduced pressure and the solid residue was dissolved in 50 ml of N2O. the Aqueous solution was acidified deepali, getting 19,0 g (100%) ethylisopropylamine in the form of a colorless oil.

19B. In a similar way received the following compounds of formula (Gb):

ethyl-tert-butylmalonate;

ethylpropylamine;

ethylbenzylamine and

ethylcyclohexylamine.

Example 20

Compounds of formula (Gc) and (Gd)

20A. To clean utilizability (25 g, of 0.13 mol) at 0oC was slowly added to a chilled on ice diethylamine (15.1 ml of 0.15 mol). After stirring for 15 minutes was added dropwise formalin (11,1 ml of 37% aqueous formaldehyde) and the mixture was left for stirring at 25oC for 3 days. The reaction mixture was treated with a solution containing 20 g2CO3in 40 ml of H2Oh, and was extracted with simple ether (CH ml). The combined ether layers were washed with brine, dried over MgSO4and was evaporated at 20oC on a rotary evaporator. The crude product, namely, ethyl-4-methyl-2-medienpartner (containing some ether) was dissolved in 250 ml of absolute ethanol and treated with acetonitrile (250 ml), IM LiOH (9.7 g in 250 ml of H2Oh, to 0.23 mole). After stirring overnight the organic solvents are evaporated and the aqueous residue was extracted with is the learn of 10.5 g of 4-methyl-2-metilpentanovoyj acid as a colourless oil.

20B. In a similar way received the following compounds of formula (Gd):

4-phenyl-2-metilenovuju acid;

3-cyclohexyl-2-metilpropanova acid;

5-phenyl-2-medienpartner acid;

2-medienpartner acid and

3,3-dimethyl-2 - metilenovuju acid.

Example 21

The compounds of formula (G)

A mixture of 4-methyl-2-metilpentanovoyj acid (5.0 g) and teoksessa acid (25 ml) kept at 95oC in argon atmosphere for 3 days. Excess teoksessa acid is evaporated and the remaining oil was dissolved in ethyl acetate (40 ml) and was extracted with saturated NaHCO3(G ml). United NaHCO3the extracts were combined and acidified to pH 2 at 0oC with 1M HCl. The aqueous layer was extracted with CH2Cl2(G ml), the combined organic phases were dried (MgSO4) and was evaporated, obtaining 3.0 g of 4-methyl-2-acetylcyclopentanone acid;1H-NMR (80 MHz, CDCl3) of 0.95 (d, J=8.0 Hz, 6H), 1,20-1,90 (m,4H), to 2.35 (s,3H), 2,50-3,20 (m,3H), 6,7 (br s,1H).

Example 22

The compounds of formula (If)

22A. To a solution of 4-methyl-2-acetylcyclopentanone acid (204 mg, 1.0 mmol) in anhydrous DMF (15 ml) containing HOBT (92 mg, 0.6 mmole) and L-leucine-N'-(4-ethoxycarbonylphenyl)carboxamide (0,6 mol), we use the ATOC was dissolved in ethyl acetate (35 ml) and washed with 1M HCl, 1M NaOH and with brine. After drying over MgSO4and evaporation was received semi-solid product, which was subjected to rapid chromatography on silica gel (ethyl acetate/petroleum ether 1:2) to give N-(4 - methyl-2-acetylcyclopentanone)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide (190 mg) as a white solid.

22B. In a similar way received the following compounds of formula (If):

N-(5-phenyl-2-acetylcyclopentanone)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(4-phenyl-2-acetyldeoxynivalenol)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(3-phenyl-2-acetylthiocholine)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(3-cyclohexyl-2-acetylthiocholine)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(2-acetylcyclopentanone)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(5-phenyl-2-acetylcyclopentanone)-L-leucine-N'- (4-aminosulphonylphenyl)carboxamide;

N-(4-phenyl-2-acetyldeoxynivalenol)-L-leucine-N'- (4-carboxyphenyl)carboxamide;

N-(3-phenyl-2-acetylthiocholine)-L-leucine-N'- (4-methylsulfinylphenyl)carboxamide;

N-(3-cyclohexyl-2-acetylthiocholine)-L-leucine-N'- (4-carbamoylphenoxy)carboxamide;

N-(2-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(4-phenyl-2-acetyldeoxynivalenol)-L-tryptophan-N'- (4-ethoxycarbonylphenyl)carboxamide;

N-(3-phenyl-2-acetylthiocholine)-L-tryptophan-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(3-cyclohexyl-2-acetylthiocholine)-L-tryptophan-N'- (4-ethoxycarbonylphenyl)carboxamid and

N-(2-acetylcyclopentanone)-L-tryptophan-N'-(4 - ethoxycarbonylphenyl)carboxamide.

Example 23

The compounds of formula (Ig)

23A. To a solution of N-(4-methyl-2-acetylcyclopentanone)-L - leucine-N'-(4-ethoxycarbonylphenyl)carboxamide (85 mg, 0,19 mmole) in MeOH (8 ml) at 0oC was added concentrated HN4OH (0.4 ml). After stirring at 0oC for 5 hours, the methanol evaporated and added a simple ether (30 ml). The ether solution was washed with 0.5 M HCl, brine solution and dried over MgSO4. By concentrating the received N-(4-methyl-2-mercaptoethanol)-L-leucine-N'- (4-ethoxycarbonylphenyl)carboxamide in the form of a white foam in quantitative yield, MS (BTA): 407 (M-H)-.

23 B. Similarly received the following compounds of formula (Ig):

N-(5-phenyl-2-mercaptoethanol)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(4-phenyl-2-mercaptoethanol)-L-leucine-N'- (4-N-(3-cyclohexyl-2-mercaptoethanol)-L-leucine-N' -(4-ethoxycarbonylphenyl) carboxamide;

N-(2-mercaptoethanol)-L-leucine-N'-(4 - ethoxycarbonylphenyl)carboxamide;

N-(5-phenyl-2-mercaptoethanol)-L-leucine-N'-(4-aminosulphonylphenyl) carboxamide;

N-(4-phenyl-2-mercaptoethanol)-L-leucine-N'-(4 - carboxyphenyl)carboxamide;

N-(3-phenyl-2-mercaptoethanol) -L-leucine-N'-(4-methylsulfinylphenyl)carboxamide;

N-(3-cyclohexyl-2-mercaptoethanol)-L-leucine-N'-(4 - carbamoylphenoxy)carboxamide;

N-(2-mercaptoethanol)-L - leucine-N'-(4-tianfeng)carboxamide;

N-(5-phenyl-2-mercaptoethanol)-L-tryptophan-N'-(4-ethoxycarbonylphenyl) carboxamide;

N-(4-phenyl-2-mercaptoethanol)-L-tryptophan - N'-(4-ethoxycarbonylphenyl)carboxamide;

N-(3-phenyl-2-mercaptoethanol)-L-tryptophan-N'- (4-ethoxycarbonylphenyl) carboxamide;

N-(3-cyclohexyl-2-mercaptoethanol)-L - tryptophan-N'-(4-ethoxycarbonylphenyl)carboxamid and

N-(2-mercaptoethanol)-L-tryptophan-N'- (4-ethoxycarbonylphenyl)carboxamide.

Example 24

The compounds of formula (Fc)

To mix the solution containing 6,48 g (25.0 mmol) of N-(4-pentanoyl)-4S-phenylmethyl-2-oxazolidinone in 50 ml of anhydrous THF in an argon atmosphere at -95oC with a syringe was added 27.5 ml (of 27.5 mmole) who -75oC. After 15 minutes at a temperature of from -80oC to -95oC via syringe over 1 minute was added to the 5.65 ml (6,83 g, 35 mmol) of tert-butylbromide, which previously just before use filtered through basic alumina. The solution was stirred at a temperature of from -90oC to -60oC for 2 h and then distributed between hexane (100 ml) and dilute aqueous NaHSO4. The organic layer was washed with saturated aqueous NaCl, containing a small amount of 1M phosphate buffer (pH 7), dried over Na2SO4and concentrated. The residue was recrystallized from 75 ml of hexane, getting to 5.56 g (60%) of N-(2R-(tert - butoxycarbonyl)methyl-4-pentenyl)-4S-phenylmethyl-2-oxazolidinone in the form of light yellow needle crystals: tPL75-76oC. Elemental analysis: calculated for C21H27NO5: 67,54; H 7,29; N of 3.75; found: 67,76; H 7,34; N a 3.87.

Example 25

The compounds of formula (Fc -1), in which R2denotes the biphenyl

To a solution containing of 4.75 g (12.7 mmole) of N-(2R-(tert - butoxycarbonyl)methyl-4-pentenyl)-4S-phenylmethyl-2 - oxazolidinone, of 3.73 g (16.0 mmol) of 4-bromobiphenyl, 0,234 g (0.77 mmole) of tri-ortho-tolylphosphino and 2,22 ml of 1.62 g, 16.0 mmol) of triethylamine in 10 ml besod is within 4 h, was cooled to room temperature and was diluted with ethyl acetate. The precipitate was removed by filtration and the filtrate was distributed between 150 ml of ethyl acetate:hexane (2:1) and 50 ml of phosphate buffer pH 7 (0.5 M) containing a small amount of sodium sulfate. The organic layer was washed with 0.2 N. aqueous sodium bisulfate and saline/phosphate buffer with pH 7, dried over sodium sulfate and concentrated. The residue was dissolved in 50 ml of ethyl acetate, diluted with 250 ml of isooctane and contributed to several seed crystals of the product. The solid was removed by filtration and recrystallization from 250 ml of isooctane:ethyl acetate (4:1) received 4,20 g (63%) of product, namely, N-(2R-(tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)-4 - pentenyl)-4S-phenylmethyl-2-oxazolidinone, in the form of fine white needle-shaped crystals: tPL118-119oC;1H-NMR (300 MHz, CDCl3) 7,25-of 7.60 (m, 14H), 6,47 (d, 1H, J=16 Hz), and 6.25 (dt, 1H, J=16 and 8 Hz), 4,65-4,70 (m, 1H), 4,34-of 4.44 (m, 1H), 4,11 (dd, 1H, J=9 and 2 Hz), 4,01 (t, 1H, J=8 Hz), to 3.33 (dd, 1H, J=14 and 3 Hz), 2,89 (dd, 1H, J=17 and 11 Hz), was 2.76 (dd, 1H, J=14 and 10 Hz), 2,40-to 2.57 (m, 3H), USD 1.43 (s, 9H). Elemental analysis: calculated for C33H35NO5: 75,40; H 6,77; N 2,66; found: 75,17; H 6,84; N 2,58.

Example 26

The compounds of formula (Fc"-2), in which R2denotes the biphenyl

Realigion in 50 ml of ethyl acetate, was first made when hydrogen pressure of 1 ATM in the presence of 500 mg of 10% Pd/C for 2 h at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated to approximately 20 ml, and then diluted to approximately 75 ml of isooctane. In the solution for starters made a few crystals of the product and the mixture was concentrated to approximately 50 ml, and then cooled to -20oC. After filtration, the precipitate was received 4,91 g (94%) of N-(2R-(tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanoyl) -4S-phenylmethyl-2-oxazolidinone in the form of a white powder: tPL75-76oC; 1H-NMR (300 MHz, CDCl3) 7,22-to 7.59 (m, 14H), br4.61-4,70 (m, 1H), 4,18-4,24 (m, 1H), 4,14 (d, 2H, J=5 Hz) to 3.34 (dd, 1H, J=13 and 3 Hz), 2.57 m-2,89 (m, 4H), 2,48 (dd, 1H, J=13 and 5 Hz), 1,65 of-1.83 (m, 3H), 1,50-1,60 (m, 1H), 1,42 (s, 9H). Elemental analysis: calculated for C33H37NO5: 75,11; H 7,07; N 2,65; found: 75,34; H 7,11; N 2,69.

Example 27

The compounds of formula (F), in which R2denotes the biphenyl

To a solution containing as 4.02 g (7,62 mmole) N - (2R-(tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanoyl) - 4S-phenylmethyl-2-oxazolidinone in 60 ml of THF, at 0oC was added to 2.8 ml of 30% aqueous hydrogen peroxide, and then to 8.0 ml of 2n. aqueous lithium hydroxide. The mixture was intensively stirred at 0oC in aslali 20 ml of 2n. aqueous sodium sulfite and 30 ml saturated aqueous sodium bicarbonate solution. After exposure for 10 minutes at 0oC the mixture was additionally stirred for 1 h at room temperature and then was poured into 1M phosphate buffer with pH 7. The aqueous phase was acidified to pH 6 by adding solid sodium bisulfate, and then the mixture was extracted with ethyl acetate:hexane (1:1) (200 ml).

The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographically on 125 g of silica gel,

elwira 20-30% ethyl acetate:hexane containing 0.5% acetic acid. The fractions containing the product were concentrated and then repeatedly subjected to azeotropic distillation with toluene, receiving of 2.93 g (> 100%) of product, namely, 2R-(tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanol acid, in the form of a thick syrup which slowly hardened when stored at -20oC: tPL44-45oC (after drying, the solid product under vacuum);1H-NMR (300 MHz, CDCl3) 7,22-to 7.59 (m, 9H), 2,82-2,90 (m, 1H), 2,59 is 2.75 (m, 3H), 2.40 a (dd, 1H, J=14 and 5 Hz), 1.55V and 1.80 (m, 4H), of 1.42 (s, 9H). Elemental analysis: calculated for C23H28O4: 74,97; H 7,66; found: 75,08; H 7,76.

Example 28

Connection formprocessing in 40 ml of acetonitrile, at 0oC was added dropwise a solution containing 4.12 g (20 mmol) of dicyclohexylcarbodiimide in 40 ml of acetonitrile. The mixture was stirred at a temperature of from 0oC to room during the night, and then the mixture was filtered to remove precipitated dicyclohexylphosphino. The filtrate was concentrated and the residue triturated with ethyl acetate/dichloromethane, receiving of 5.06 g (80%) N - hydroxysuccinimide ester of N-(tert-butoxycarbonyl)-L-tert - leucine as a white solid product: tPL136 - 137oC;1H-NMR (300 MHz, CDCl3) 5,07 (br d, 1H), 4,43 (d, 1H, J=10 Hz), 2,84 (s, 4H), of 1.46 (s, 9H), 1,10 (s, 9H).

Example 29

The compounds of formula (C), in which R3represents tert-butyl and R7represents a 4-pyridine (instead of the shown phenyl group)

A solution containing 2.00 g (6,32 mmole) N - hydroxysuccinimide ester of N-(tert-butoxycarbonyl)-L-tert-leucine and 2,98 g (of 31.6 mmole) of 4-aminopyridine in 20 ml of dioxane and kept at 100oC for 3 hours the Reaction mixture was cooled to room temperature and concentrated. The residue was purified by chromatography on silica gel, elwira 5-10% methanol in dichloromethane and receiving 1.06 g (54%) of N-(tert-butoxycarbonyl) -L-tert-leucine-N'-(pyrid-4-yl)carboxamide as a white solid(s, 9H). MS-BT (M+H)+: designed 308,1974 received 308,1970.

Example 30

30A. The compounds of formula (D), in which R3represents tert-butyl and R7represents a 4-pyridine (instead of the shown phenyl group)

To a solution containing 132 mg (0.43 mmole) of L-(tert-butoxycarbonyl)-L-tert-leucine-N'-(pyrid-4-yl)carboxamide in 2 ml of dichloromethane was added 1 ml triperoxonane acid. After soaking for 1 h at room temperature the solution was diluted with about 5 ml of toluene and concentrated. By re-dissolving in toluene/dichloromethane/methanol and concentration was obtained 190 mg (100%) of L-tert-leucine-N'- (pyrid-4-yl)carboxamides(triptoreline) as white solids:1H-NMR (300 MHz, DMCO-d6) 11,58 (br s, 1H), 8,68 (d, 2H, J=6 Hz), 8,35 (br s, 2H), to $ 7.91 (d, 2H, J= 6 Hz), 3,81 (s, 1H), was 1.04 (s, 9H). MS-BT (M+N)+: designed 208,1500 received 208,1496.

30B. The compounds of formula (D), in which R3represents tert - butyl and R7refers to 4-(methylthio)phenyl

By the way, is similar to that described in section a received L-tert-leucine-N'-(4-(methylthio)phenyl)carboxamide: 1H-NMR (300 MHz, CDCl3) of 9.02 (s, 1H), 7,49 (d, 2H, J=6.5 Hz), of 7.23 (d, 2H, J=6.5 Hz), 3,23 (s, 2H), 2,44 (s, 3H), of 1.03 (s, 9H).

Example 31

>denote tert-butyl and R7represents a 4-pyridine (instead of the shown phenyl group)

To a solution containing 357 mg (0.97 mmole) of 2R-(tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanol acid, 422 mg (0.97 mmole) of L-tert-leucine-N'-(4-(pyrid-4-yl))carboxamide(triptoreline) and 0.50 ml (3.6 mmole) of triethylamine in 5 ml of DMF, was added 442 mg (1.00 mmol) benzotriazol-1-yl - Tris(dimethylamino)fosfodiesterasa. After 4 h the reaction mixture was distributed between ethyl acetate and water. The aqueous layer was twice extracted with ethyl acetate and the combined organic layers were washed with water and with brine, dried over sodium sulfate and concentrated. After purification of the residue by chromatography on silica gel with elution 25-75% ethyl acetate in hexane received 360 mg (66%) of N-(2R-(tert - butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanoyl)-L-tert-leucine - N'-(pyrid-4-yl)carboxamide:1H-NMR (300 MHz, CDCl3) charged 8.52 (s, 1H), 8,42 (d, 2H, J=6 Hz), 7,54 (d, 2H, J=7 Hz), 7,40-of 7.48 (m, 6H), 7,32 (t, 1H, J=7 Hz), 7,13 (d, 2H, J=8 Hz), 6,62 (d, 1H, J= 9 Hz), 4,35 (d, 1H, J=9 Hz), 2,58 of 2.68 (m, 4H), is 2.40 (dd, 1H, J=16 and 3 Hz), 1,40-1,75 (s over m, indoor H2Oh, 13H), a 1.08 (s, 9H).

31B. The compounds of formula (Ib) with different values of R7< / BR>
Similar to the method described in section a, substituting L-tert-is setil)aminosulfonyl)phenyl)carboxamide;

L-tert-leucine-N'-(4-(methylthio)phenyl)carboxamide;

received

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(4-((2-hydroxyethyl)aminosulfonyl)phenyl) carboxamide: tPL89-92oC;1H-NMR (300 MHz, methanol-d4) 7,80 (s, 4H), 7,51 (d, 2H, J=7 Hz), 7,41 (d, 2H, J=7 Hz), was 7.36 (d, 2H, J=8 Hz), 7,28 (t, 1H, J=7 Hz), 7,14 (d, 2H, J=8 Hz), 4,47 (s, 1H), 3,47 (t, 2H, J=6 Hz), 2,85-2,95 (t, overlapping m, 3H), 2,52-2,62 (m, 3H), 2,32 (dd, 1H, J=16.5 and 5 Hz), 1,48-of 1.62 (m, 4H), of 1.41 (s, 9H), of 1.09 (s, 9H); elemental analysis: calculated for C37H49N3O7S: 65,37; H 7,26; N 6,18; S 4,72; found: 65,13; H 7,33; N 6,22; S 4,63 and

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4 - yl)pentanoyl)-L-tert-leucine-N'-(4-(methylthio)phenyl)carboxamide: 1H-NMR (300 MHz, CDCl3) 7,79 (s, 1H), 7,53 (d, 2H, J=7 Hz), 7,31-7,44 (m, 7H), 7,19 (d, 2H, J=9 Hz), 7,13 (d, 2H, J=8 Hz), to 6.58 (d, 1H, J=9 Hz), 4,36 (d, 1H, J=9 Hz), 2,55-to 2.67 (m, 4H), 2,34-2,40 (s overlapping m, 4H), 1,38 is 1.75 (s overlapping m, 13H), of 1.07 (s, 9H); elemental analysis: calculated for C36H46NO4S0,25 H2About: With 71,19; H 7,72; N Br4.61; S 5,28; found: 71,20; H 7,78; N 4,58; S 5,28.

Example 32

32A. The compounds of formula (Ic) in which R2means biphenyl (and X denotes propane-1,3-diyl), R3represents tert-butyl and R7represents a 4-pyridine (instead of the shown phenyl group)

pyrid-4-yl)carboxamide in 4 ml of dichloromethane, added 2 ml triperoxonane acid. After soaking for 1 h at room temperature the solution was diluted with toluene and concentrated. The residue was dissolved in ethyl acetate (15 ml) and washed with 0.5 M citrate buffer pH 4 (g ml). The combined aqueous layers were extracted with ethyl acetate (CH ml) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue is triturated with ethyl acetate/hexane, getting 230 mg (71%) of N-(2R-carboxymethyl - 5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'-(pyridine-4-yl) carboxamide as a white solid: tPL198-201oC; 1H-NMR (300 MHz, MeOH-d4) 8,32 (d, 2H, J=7 Hz), to 7.64 (d, 2H, J=5 Hz), was 7.45 (d, 2H, J=7 Hz), 7.24 to 7,38 (m, 7H), 7,10 (d, 2H, J=8 Hz), 4,42 (s, 1H), 2,85-3,00 (m, 1H), 2,33-to 2.65 (m, 4H), 1,40-of 1.62 (m, 4H), of 1.02 (s, 9H). Elemental analysis: calculated for C30H36N3O40.5 H2O0,5 ethyl acetate (MES): 69,29; H 7,27; N 7,58; found: 69,46; H to 7.09; N 7,55.

32B. The compounds of formula (Ic) with different values of R7< / BR>
Similar to the method described in section a, substituting N-(2R-(tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(pyrid-4-yl)carboxamide on the following connections:

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L-tert - Le is enthanol) -L-tert-leucine-N'-(4R/S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(fluoren-2 - yl)pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl) phenyl) carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(7- (glycyl)aminofluorene-2-yl)pentanoyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5- (4-(pyrid-4-yl)phenyl)pentanoyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L- -hydroxylamin-N'-(phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(4-(methylsulphonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(4- (2-hydroxyethyl)phenyl)pentanoyl)-N'- leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(4'-hydroxyben-4-yl)pentanoyl)-L-leucine-N-(4- (methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(4'-tianbian-4-yl)pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(4'(2-aminoethoxy)bifen-4-yl) pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide

N-(2R-(tert-butoxycarbonyl)methyl-5-(4-(pyridin-4-intoxicaton)methyl-5-(bifen-4 - yl)pentanoyl)-L-threonine-N'-(4S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(2-forbiden-4-yl)pentanoyl)-L-leucine - N'-(4-(methoxycarbonyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-4-((bifen-4-yl)thio)butanoyl)-L-tert - leucine-N'-(pyridine-4-yl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(4- (2-aminopyridine-5-yl)phenyl)pentanoyl)-L-threonine-N'-(4S- (methylsulfinyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(2-hydroxyben-4 - yl)pentanoyl)-L-threonine-N'-(4S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(4'-tianbian-4-yl)pentanoyl) - L-(TRANS-4-hydroxycyclohexyl)glycine-N'-(4S-(methylsulfinyl)phenyl) carboxamide;

N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4 - yl)pentanoyl)-L-(4-hydroxyethylamino-4-yl)glycine-N'-(4S- (methylsulfinyl)phenyl) carboxamide and

N-(2R-(tert-butoxycarbonyl)methyl-5-(2R/S-hydroxy-3,3,3 - cryptochromes)phenyl)pentanoyl)-L-(cyclohexyl)glycine-N'-(4S- (4-((2-hydroxyethyl)aminosulfonyl)phenyl) carboxamide,

received

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(4- ((2-hydroxyethyl)aminosulfonyl)phenyl)carboxamide:1H-NMR (300 MHz, Meon-d4) 7,80 (s, 4H), to 7.50 (d, 2H, J=7 Hz), 7,25-7,42 (m, 5H), to 7.15 (d, 1H, J=8 Hz), 4,47 (s, 1H), 3,47 (t, 2H, J=6 Hz), 2,89-3,00 (m, 1H), 2,87 (t, 2H, J=6 Hz), 2,49-2,70 (m, 3H), 2,39 (dd, 1H, J=16 and 5 Hz), 1,46-to 1.67 (m, S 5,07; found: 62,61; H to 6.80; N OF 6.31; S equal to 4.97;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L - tert-leucine-N'-(4R/S-(methylsulfinyl)phenyl)carboxamide: 1H-NMR (300 MHz, MeOH-d4) 8,03 (d, 1H, J= 9 Hz), 7,76 (d, 2H, J=9 Hz), EUR 7.57 (dd, 2H, J=9 and 2 Hz), 7,44 (d, 2H, J=7 Hz), was 7.36 (t, 2H, J=7 Hz), 7.23 percent-7,28 (m, 3H), 7,10 (d, 2H, J=8 Hz), of 4.45 (d, 1H, J=9 Hz), 2,85 are 2.98 (m, 1H, J=8 Hz), 2,44-of 2.64 (m, 7H), 2,35 (dd, 1H, J= 16 and 5 Hz), 1,43-of 1.62 (m, 4H), of 1.03 (s, 9H);

N-(2R-carboxymethyl-5-(fluoren-2-yl)pentanoyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide: tPL188-190oC;1H-NMR (300 MHz, CDCl3) 12,06 (s, 1H), 10.30 a.m. (s, 1H), 8,19 (d, 1H, J=8 Hz), 7,86 (d, 2H, J=9 Hz), 7.68 per-to 7.77 (m, 3H), a 7.62 (d, 1H, J=8 Hz), of 7.48 (d, IH, J=7 Hz), 7,20-7,35 (m, 3H), 7,10 (d, 1H, J=7 Hz), 4,48 (m, 1H), 3,76 (s, 3H), 3,70 (s, 2H), 2,15-of 2.75 (m, 5H), of 1.35 and 1.75 (m, 5H), 0,90 is 0.99 (m, 4H); elemental analysis: calculated for C34H38N2O6: 71,56; H of 6.71; N 4,91; found: 71,51; H 6,97; N 4,84;

N-(2R-carboxymethyl-5-(7-(glycyl)aminofluorene-2-yl)pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide: tPL222-224oC; MS-BT (M+N)+: calculated for C40H51N4O7: 699,3758; received 699,3770;

N-(2R-carboxymethyl-5-(4-(pyrid-4-yl)phenyl)pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide:1H-NMR (300 MHz, d4-MeOH) charged 8.52 (d, 2H, J=5.5 Hz), 7,92 (d, 2H, J=9,19 Hz), to 7.67 (d, 2H, J=8,82 Hz), 7,58 (d, 2H, J= 6.25 Hz), 7,46 (d, 2H, J=to 8.45 Hz), 7,20 (d, 2H, J=8,46 Hz), 4,6-4,4 shall tanjil)-L- - hydroxylamin-N'-(phenyl)carboxamide:1H-NMR (300 MHz, CDCl3) 8,73 (s, 1H), 8,07 (d, 1H, J= 8,09 Hz), 7,52-7,25 (m, 11H), 7,10 (t, 1H, J=7,54 Hz), 6,97 (d, 2H, J=8,08 Hz) to 4.41 (d, IH, J=to 8.45 Hz), 3,02-3,00 (m, 1H), 2,75 (dd, 1H, J= 16,55 and to 8.45 Hz), 2,53 is 2.51 (m, 2H), of 2.44 (dd, 1H, J=17.1 to and 4.6 Hz), 1.85 to about 1.47 (m, 4H), 1,45 (s, 3H), 1,21 (s, 3H); elemental analysis: calculated for C3H3N4O4: 71,69; H 6,82; N to 5.57; found: 71,65; H 6,86; N OF 5.53;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'-(4- (methylsulphonyl)phenyl)carboxamide:1H-NMR (300 MHz, MeOH - d4) 8,10 (d, 1H, J=9 Hz), 7,81 (s, 4H), 7,47 (d, 2H, J=8 Hz), 7,25-7,40 (m, 5H), 7,13 (d, 2H, J= 8 Hz), 4,48 (d, 1H, J=9 Hz), 2.95 and (s, 3H), 2,44-2,70 (m, 4H), of 2.36 (dd, 1H, J=16 and 5 Hz), 1,47-to 1.63 (m, 4H), of 1.06 (s, 9H);

N-(2R-carboxymethyl-5-(4-(2-hydroxyethyl)phenyl)pentanoyl)-L-leucine - N'-(4-(methoxycarbonyl)phenyl)carboxamide:1H-NMR (300 MHz, d4-MeOH) to $ 7.91 (d, 2H, J=9 Hz), to 7.64 (d, 2H, J=9 Hz), of 6.96 (s, 4H), 4,47-4,51 (m, 1H) 3,84 (s, 3H), 3,63 (t, 2H, J=7 Hz), 2,68 (t, 2H, J=7 Hz), 2,46 is 2.75 (m, 4H), 2,37 (dd, 1H, J=16 and 5 Hz), 1,51 - of 1.73 (m, 7H), 0,89 0,93 and (2d, 6H, J=7 Hz);

N-(2R-carboxymethyl-5-(4'-hydroxyben-4 - yl)pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide: tPL195-197oC; MS-BT (M+H): calculated 575,2757; received 595,2750;

N-(2R-carboxymethyl-5-(4'-tianbian-4-yl)pentanoyl)-L - leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide:1H-NMR (300 MHz, MeOH-d4) 10,02 (s, 1H), of 8.37 (d, 1H, J=7 Hz), 7,87 1,46-1,72 (m, 7H), 0.88 and 0.90 (2d, 2H, J=7 Hz);

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide: tPL191-193oC;

N-(2R-carboxymethyl-5- (4'-(2-aminoethoxy)bifen-4-yl)pentanoyl)-L - leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide: MS-BT (M+H): calculated 618,3179; received 618,3189;

N-(2R-carboxymethyl-5-(4-(pyridin-4-yl)phenyl)pentanoyl)-L - cyclohexylglycine-N'-(4- ((2-hydroxyethyl)aminosulfonyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-threonine-N'-(4S- (methylsulfinyl) phenyl) carboxamide;

N-(2R-carboxymethyl-5-(2 - forbiden-4-yl)pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl) phenyl) carboxamide;

N-(2R-carboxymethyl-4-((bifen-4 - yl)thio)butanoyl)-L-tert-leucine-N'-(pyridine-4-yl)carboxamide;

N-(2R-carboxymethyl-5-(4-(2-aminopyridine-5-yl)phenyl)pentanoyl)-L - threonine-N'-(4S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(2-hydroxyben-4-yl)pentanoyl)-L-threonine-N'-(4S- (methylsulfinyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5- (4'-tianbian-4-yl)pentanoyl)-L-(TRANS-4 - hydroxycyclohexyl)glycine-N'-(4S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L- (4-hydroxylate-gidropony-4-yl)glycine-N'-(4S- (methylsulfinyl)phenyl)carboxamide and

N-(aminosulfonyl) phenyl) carboxamide.

Example 33

33A. The compounds of formula (Ie), in which R denotes biphenyl (and X denotes propane-1,3-diyl), R2represents tert-butyl and R3represents a 4-pyridine (instead of the shown phenyl group)

To a solution containing 127,4 mg (0.200 mmole) of N-(2R - carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'- (pyridine-4-yl)carboxamide and 40 μl of N-methylmorpholine in 1.0 ml DMF at room temperature was added 115 mg (0,26 mmole) benzotriazol-1-yl-Tris(dimethylamino)fosfodiesterasa. After 15 minutes in one portion was added 42 mg (0.60 mmole) of hydroxylamine hydrochloride, and then an additional 70 μl of N - methylmorpholine. The mixture was stirred for 24 h at room temperature, and then distributed between 30 ml of ethyl acetate and 25 ml of 0.5 M aqueous sodium bicarbonate. The organic layer was washed with additional portions of aqueous sodium bicarbonate and saline solution/buffer with pH 7, dried over sodium sulfate and concentrated. After recrystallization from ethyl acetate received 42.2 mg of N-(2R-(N-hydroxycarbamoyl)methyl-5-(bifen-4 - yl)pentanoyl)-L-tert-leucine-N'-(pyrid-4-yl)carboxamide. By concentrating the filtrate and purification using radial chromatography (plate 1 mm, 5-10% ethanol:dichloromethane) the fork to 63.1 mg (61%) of N-(2R-(N-hydroxycarbamoyl)methyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'- (pyrid-4-yl)carboxamide as a white powder:1H-NMR (300 MHz, DMSO-d6) 10,45 (s, 1H), 10,34 (s, 1H), 8,68 (s, 1H), scored 8.38 (d, 2H, J=7 Hz), of 8.04 (d, 1H, J=9 Hz), 7,25-of 7.60 (m, 9H), 7,12 (d, 2H, J=7 Hz), 4,39 (d, 1H, J=9 Hz), 2,86-of 2.97 (m, 1H), 2,36-2,60 (m, 2H, indoor resonance from DMSO-d5), and 2.14 (dd, 1H, J=15 and 7 Hz), 2,02 (dd, IH, J=15 and 8 Hz), 1.30 and of 1.53 (m, 4H), were 0.94 (s, 9H). Elemental analysis: calculated for C30H36N4ABOUT40,25 H2O: 69,14; H 7,06; N is 10.75; found: 69,15; H of 7.23; N 10,56.

33B. The compounds of formula (Ie) with different values of R2, R3and R7< / BR>
Similar to the method described in section a, substituting N-(2R - carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-tert-leucine-N'- (pyridine-4-yl)carboxamide on the following connections:

N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L-threonine-N'- (4-S-(methylsulfinyl)phenyl) carboxamide;

N-(2R-carboxymethyl-5-(4-(pyridin-4-yl)phenyl)pentanoyl)-L - hydroxy)valine-N'-(4S-(methylsulfinyl)phenyl)carboxamide and

N-(2R-(carboxymethyl-4-methylpentanol)-L-tert-leucine-N'- (pyridine-4-yl)carboxamide;

N-(2R-(carboxymethyl-(5-(4-(2S - hydroxypropyl)phenyl)pentanoyl)-L-(TRANS-4 - hydroxycyclohexyl)glycine-N'-(pyridine-4-yl)carboxamide;

N-(2R-(carboxymethyl-5-(4-(2-methylthiazole-4-yl)phenyl)pentanoyl)-L- (-hydroxy)valine-N'-(pyridine-4-yl)carboxamide and

N-(2R-carboxymethyl-5-(4-(2R/S-hydroxy-3,3,3-cryptochromes)phenyl)bifen-4-yl)pentanoyl)-L-threonine-N'- (4S-(methylsulfinyl)phenyl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-5-(4-(pyridin-4-yl)phenyl)pentanoyl) -L-(-hydroxy)valine-N'-(4S-(methylsulfinyl)phenyl) carboxamide;

N (2R-(N-hydroxycarbamoyl)methyl-4 - methylpentanol)-L-tert-leucine-N'-(pyridine-4-yl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-(5-(4-(2S-hydroxypropyl)phenyl) pentanoyl)-L-(TRANS-4-hydroxycyclohexyl)glycine-N'- (pyridine-4-yl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-5-(4-(2-methylthiazole-4-yl)phenyl)pentanoyl) -L- (-hydroxy)valine-N'-(pyridine-4-yl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-5-(4-(2R/S - hydroxy-3,3,3 - cryptochromes)phenyl)pentanoyl)-L-(-hydroxy)valine-N'-(pyridine-4-yl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-(5-(4-(2S-hydroxypropyl)phenyl) pentanoyl)-L-(TRANS-4-hydroxycyclohexyl)glycine - N'-(pyridine-4-yl)carboxamide;

N-(2R-(N-hydroxycarbamoyl)methyl-5-(4-(2-methylthiazole-4 - yl)phenyl)pentanoyl)-L-(-hydroxy)valine-N'-(pyridine - 4-yl)carboxamide and

N-(2R-(N-hydroxycarbamoyl)methyl-5-(4-(2R/S - hydroxy-3,3,3-cryptochromes)phenyl)pentanoyl)-L-(-hydroxy)valine-N'-(pyridine-4-yl)carboxamide.

Example 34

34A. The compounds of formula (C), in which R3represents tert-butyl, a R4and R5denote H

A solution containing 2.00 g (6,32 mmole) N-hydroxysuccinimide ether N-(tre is for 30 minutes. The mixture was allowed to cool to room temperature and diluted with 40 ml ethyl acetate. The solution was washed for 1H. aqueous sodium bisulfate (4x50 ml) and the combined aqueous layers were extracted with 25 ml ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (2-10% ethyl acetate in dichloromethane) to give 1,36 g (74%) of N-(tert-butoxycarbonyl)-L - tert-leucine-N'-phenylcarbamate in the form of a white solid product:1H-NMR (300 MHz, CDCl3) 7,49 (d, 2H, J=8 Hz), 7,31 (t, 2H, J=8 Hz), 7,11 (t, 1H, J=7 Hz), and 5.30 and 5.36 (m, 1H), 3,95 (d, 1H, J=9 Hz), the 1.44 (s, 9H), of 1.07 (s, 9H).

34B. The compounds of formula (C), in which R3represents tert - butyl, R4denotes 4-methylthio and R5denote H

Similar to the method described in section a, received N-(tert-butoxycarbonyl)-L-tert-leucine-N'-(4- (methylthio)phenyl)carboxamide:1H-NMR (300 MHz, CDCl3) the 7.65 (br s, 1H), 7,42 (d, 2H, J=8.5 Hz), 7,21 (d, 2H, J=8.5 Hz), 5,32 (br d, 1H), 3,95 (d, 1H, J=8.5 Hz), a 2.45 (s, 3H), of 1.44 (s, 9H), of 1.06 (s, 9H). Elemental analysis: calculated for C18H23N2ABOUT3S: 61,33; H 8,01; N 7,95; S a 9.09; found: 61,34; H of 8.06; N 8,00; S 9,18.

Example 35

The compounds of formula (C) With trifluoracetyl protecting group, to the mole) of N-(tert-butoxycarbonyl)-L-tert-leucine-N'-phenylcarbamate in 10 ml of dichloromethane, added 5 ml triperoxonane acid. After holding for 45 minutes at room temperature the solution was diluted with toluene and concentrated. The residue is twice more concentrated from toluene to remove excess triperoxonane acid, and then dried under vacuum (about 1 mm RT.cent.). Then the residue was dissolved in 15 ml dichloromethane and successively treated with pyridine (0,90 ml, 11 mmol) and triperoxonane anhydride (0,70 ml, 4,84 mmole). After 30 minutes the mixture was distributed between dichloromethane (25 ml) and 1N. aqueous sodium bisulfate. The organic layer was washed with additional portions of aqueous sodium bisulfate, brine solution, dried over sodium sulfate and concentrated, gaining 1.22 g (91%) of N-(TRIFLUOROACETYL)-L-tert-leucine-N'-phenylcarbamate in the form of a white solid product: tPL201-203oC;1H-NMR (300 MHz, CDCl3) to 7.50 (d, 2H, J=8 Hz), was 7.36 (t, 2H, J=8 Hz), 7,17 (t, 1H, J=7 Hz), 4,43 (d, 1H, J=9 Hz), 1,10 (s, 9H). Elemental analysis: calculated for C14H17F3N2O2: 55,62; H 5,67; N 9,27; found: 55,57; H ceiling of 5.60; N 9,18.

Example 36

The compounds of formula (C) With trifluoracetyl protective group, in which R3represents tert-butyl, R4denotes 4-(2 - hydroxyethyl)aminosulfonyl and xamiga in 5 ml of chloroform, added 0.4 ml (6 mmol) of chlorosulfonic acid. The mixture was boiled under reflux for 35 minutes and then cooled to 0oC and was diluted with ethyl acetate. Added ethanolamine (1.5 ml) and the mixture was stirred at 0oC for 15 minutes. The mixture was distributed between water and ethyl acetate and the organic layer was washed for 1H. aqueous sodium bisulfate, dried over sodium sulfate and concentrated, receiving 140 mg (40%) of N- (TRIFLUOROACETYL)-L-tert-leucine-N'-(4-((2 - hydroxyethyl)aminosulfonyl)phenyl)carboxamide:1H-NMR (300 MHz, CDCl3) to 7.93 (s, 1H), to 7.84 (d, 2H, J=9 Hz), to 7.67 (d, 2H, J=9 Hz), 7,15 (br d, 1H), 4,90 (br t, 1H), 4,49 (d, 1H, J=9 Hz), 3,70 (t, 2H, J=5 Hz), 3,11 (q, 2H, J=5 Hz), of 1.12 (s, 9H).

Example 37

The compounds of formula (D), in which R3represents tert-butyl, R4denotes 4-(2-hydroxyethyl)aminosulfonyl and R5denote H

To a solution containing 257 mg (0.6 mmole) of N-(TRIFLUOROACETYL)-L-tert - leucine-N'-(4-((2-hydroxyethyl)aminosulfonyl)phenyl)carboxamide in 8 ml of ethanol, was added 227 mg (6 mmol) of sodium borohydride. The mixture was heated to 55oC for 15 minutes, allowed to cool to room temperature and the reaction was stopped chilled 10% ammonium hydroxide in methanol. After aging for 20 hours at room temperature the Ana to a mixture of dichloromethane:methanol:ammonium hydroxide 90:9:1) was obtained 110 mg (56%) of L-tert-leucine-N'-(4-((2-hydroxyethyl)aminosulfonyl)phenyl) carboxamide in the form of oil:1H-NMR (300 MHz, CDCl3) 9,48 (br s, 1H), 7,81 (d, 2H, J=9 Hz), 7,72 (d, 2H, J=9 Hz), to 3.67 (t, 2H, J=5 Hz), 3,30 (s, 1H), is 3.08 (q, 2H, J=5 Hz), of 1.06 (s, 9H). MS-BT (M+N)+: designed 330,1488 received 330,1480.

Example 38

The compounds of formula (Ib) in which R2means biphenyl (X denotes propane-1,3-diyl), R3represents tert-butyl, R4indicates 4R/S-methylsulfinyl and R5denote H

To a solution containing of 60.3 mg (0,100 mmole) of N-(2R-(tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl) -L-tert-leucine-N'-(4-(methylthio)phenyl)carboxamide in 2 ml of dichloromethane at -78oC was added a solution containing 26 mg (0.15 mmole) of meta-chloroperbenzoic acid in 1 ml of dichloromethane. The reaction mixture was stirred at -78oC for 50 minutes and then was added 0.2 ml of dimethyl sulfide. The mixture was allowed to warm to room temperature and then was distributed between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated, getting to 59.6 mg (96%) of N-(2R- (tert-butoxycarbonyl)methyl-5-(bifen-4-yl)pentanoyl)-L-tert - leucine-N'-(4R/S-methylsulfinyl)phenyl)carboxamide as a white solid:1H-NMR (300 MHz, CDCl3) 8,46 (br s, 1H), 7,32-to 7.68 (m, 11H), 7,14 (d, jinene formula (F")

To a solution containing 2,779 g (7,50 mmole) of N-(2R-(tert-butoxycarbonyl)methyl-4-pentenyl) -4S-phenylmethyl-2-oxazolidinone in 30 ml of THF, at 0oC was added 2.55 ml (22.5 mmole) of 30% aqueous hydrogen peroxide, and then added 7.5 ml (15 mmol) of 2,N. aqueous lithium hydroxide. The mixture was stirred for 2 h at 0oC and then for 0.5 h at room temperature. After re-cooling the mixture to 0oC was added 15 ml of 2M aqueous sodium sulfite and 23 ml of saturated aqueous sodium bicarbonate. The mixture was stirred additionally for 30 minutes at 0oC and then a large part of the THF was removed by concentration under vacuum. The residue was distributed between CH2Cl2and H2O and the aqueous layer was extracted with an additional portion of CH2Cl2. The combined organic layers were extracted with aqueous sodium bicarbonate and water then the organic layers were acidified to pH 2 with sodium bisulfate. The resulting mixture was extracted twice with ethyl acetate and the combined organic layers were washed with saturated aqueous NaCl, diluted with 0.25 volume of hexane, dried over Na2SO4and concentrated, obtaining 1.47 g (92%) of 2R-(tert-butoxycarbonyl) methyl-4-pentenol acid as a colorless oil:what measures 40

The compounds of formula (D'-1) in which R3represents tert-butyl and R7denotes 4-(methoxycarbonyl) phenyl

Similar to the method described in example 31, substituting 2R-(tert - butoxycarbonyl)methyl-(5-(bifen-4-yl)pentane acid on 2R- (tert-butoxycarbonyl)methyl-4-pontenova acid, and substituting L-tert-leucine-N'-(4-(pyrid-4-yl)carboxamide on L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide received N-(2R-(tert - butoxycarbonyl)methyl-4-pentenyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide: tPL118 - 119oC (cyclohexane); 1H-NMR (300 MHz, CDCl3) 8,96 (s, 1H), 7,95 (d, 2H, J=9 Hz), EUR 7.57 (d, 2H,J=9 Hz), 6,32 (d, 1H, J=7 Hz), 5,63 is 5.77 (m, 1H), 4,95-5,08 (m, 2H), to 4.52-4,60 (m, 1H), 3,88 (s, 3H), 2,36-2,77 (m, 4H), 2,14-of 2.27 (m, 1H), 1,60-to 1.87 (m, 3H), 1,45 (s, 9H), of 0.97 (d, 3H,J=7 Hz), of 0.91 (d, 3H, J=7 Hz). Elemental analysis: calculated for C25H36N2O6: 65,20; H 7,88; N between 6.08; found: 65,04; H 7,80; N 6,06.

Example 41

41A. The compounds of formula (D'-2), in which R2denotes fluoren-2-yl (X denotes propane-1.3-diyl), R3represents tert-butyl and R7denotes 4-(methoxycarbonyl) phenyl

To a solution containing 167 mg (0,36 mmole) of N-(2R-(tert-butoxycarbonyl)methyl-4-pentenyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide, 108 mg (of 0.44 mmole) 2-bromofluorene, 21 mg (0,07 is(0.035 mmole) of palladium diacetate. The solution is kept at 100oC for 2 h, cooled to room temperature and then was distributed between ethyl acetate: hexane (3:1) and water. The organic layer was washed for 1H. aqueous sodium bisulfate and brine solution/buffer with pH 7, dried over sodium sulfate and concentrated. After cleaning with fast chromatography (20 g silica, 5-10% tert-butyl methyl ether in dichloromethane) received 185 mg (82%) of product as a solid substance containing according to TLC trace amounts of impurities. After recrystallization from tertbutylamine ether/isooctane received 115 mg (51%) of N-(2R- (tert-butoxycarbonyl)methyl-5-(fluoren-2-yl)-4E-pentanoyl)-L - leucine-N'-(4-(methoxycarbonyl) phenyl) carboxamide in the form of fine white needle-shaped crystals: tPL189-192oC;1H-NMR (300 MHz, CDCl3) 8,32 (s, 1H), 7,79 (d, 2H, J=8 Hz), 7,72 (d, 1H, J=8 Hz), EUR 7.57 (d, 1H, J=8 Hz), 7,45-7,53 (m, 3H), of 7.36 (t, 1H, J= 7.5 Hz), 7,25-to 7.32 (m, 2H), 7,17 (d, 1H, J=7 Hz), to 4.52-4,60 (m, 1H, in), 3.75 (s, 5H), 2,33-2,87 (m, 5H), 1.60-to 1,90 (m, 3H), 1,45 (s, 9H), 0,92 (apparent t, 6H). Elemental analysis: calculated for C38H44ABOUT60.5 H2About: With 72,01; H 7,16; N was 4.42; found: 71,87; H 7,07; N 4,32.

41B. The compounds of formula (D'-2), in which R2denotes 7-(N-(benzyloxycarbonyl)glycyl)aminofluorene-2-yl (X hereafter Toro, containing 600 mg (2,31 mmole) of 2-amino-7-bromofluorene and 483 mg (2,31 mmole) of N- (benzyloxycarbonyl)glycine in 10 ml of anhydrous pyridine, was added 442 mg (2,31 mmole) of the hydrochloride ED. The reaction mixture was stirred at 60oC for 4 days and then the solution was concentrated. The residue was distributed between ethyl acetate and 1N. aqueous hydrochloric acid and the organic layer was washed saturated aqueous sodium bicarbonate and with brine, dried over magnesium sulfate and concentrated, obtaining 813 mg (78%) of N- (benzyloxycarbonyl)glycine-N'-(7-bromofluorene-2-yl)carboxamide in the form of a yellowish-brown solid: tPL194-195oC.

Similar to the method described in section a, replacing 2-bromofluorene N-(benzyloxycarbonyl)glycine-N'-(7-bromofluorene-2 - yl)carboxamide received N-(2R-(tert-butoxycarbonyl)methyl-5- (7-(N-(benzyloxycarbonyl)glycyl)aminofluorene-2-yl)-4E-pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide: tPL213-214; MS-BT (M+Cs)+: calculated for C48H54N4O9Cs 963,2945; received 963,2960. Elemental analysis: calculated for C47H54N4O9: 69,40; H 6,51; N is 6.75; found: 69,47; H 6,51; N 6,70.

41C. The compounds of formula (D'-2), in which R2O4- (methoxycarbonyl) phenyl

To a suspension containing 400 mg (2.0 mmole) of 4-bromopyridine in 2 ml of benzene, was added aqueous 2M sodium carbonate (3 ml) to obtain two distinguishable phases and the mixture was barbotirovany with argon for several minutes followed by the addition of 115 mg (0.10 mmole) tetrakis(triphenylphosphine) palladium. To the resulting mixture was added a solution containing 200 mg (1.00 mmol) 4 - brompheniramine acid in 1 ml of ethanol, and the mixture is boiled under reflux for 4 hours After cooling to room temperature, the mixture was distributed between ethyl acetate (25 ml) and water (25 ml). The organic layer was dried over sodium sulfate and concentrated. After purification of the residue by chromatography on silica gel with elution of 25-50% ethyl acetate in hexane received 193 mg (82%) of 4-(4-brave-nil)pyridine as a white solid: tPL124-126oC;

Similar to the method described in section a, replacing 2-bromofluorene 4-(4-bromophenyl)pyridine was obtained N-(2R- (tert-butoxycarbonyl)methyl-5-(4-(pyrid-4-yl)phenyl) -4E-pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide: 1H-NMR (300 MHz, CDCl3) 8,80 (s, 1H), 8,64 (d, 2H, J=6 Hz), a 7.85 (d, 2H, J=8.5 Hz), 7,49 (d, 2H,J=9 Hz), was 7.45 (d, 2H, J= 6 Hz), 7,19 (d, 2H, J=8 Hz), 6,40 (d, 1H,J=16 Hz), 6,33 (d, 1H,J=8 Hz), 6,09-of 6.17 (m, 1H), 4,54-of 4.57 (m, 1H), 3,80 (s, 3H), 2,38-2,81 (mP> denotes fluoren-2-yl (X denotes propane-1,3-diyl), R3represents tert-butyl and R7denotes 4-(methoxycarbonyl) phenyl

The solution containing 111 mg (0,177 mmole) of N-(2R-(tert-butoxycarbonyl)methyl-5-(fluoren-2-yl)-4-pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide in 7 ml of ethyl acetate:ethanol (4:3) was first made when hydrogen pressure of 1 ATM in the presence of 30 mg of 10% palladium on coal for 3 hours, the Catalyst was removed by filtering through celite and the filtrate was concentrated. By trituration with tert - butylmethylamine ether was obtained 110 mg (99%) of N-(2R-(tert - butoxycarbonyl)methyl-5-(fluoren-2-yl)pentanoyl)-L-leucine-N'- (4-(methoxycarbonyl)phenyl)carboxamide as a white solid: tPL166-167oC (softening at 161oC). Elemental analysis: calculated for C37H46N2ABOUT6: 72,29; H rate of 7.54; N 4,56; found: 72,32; H rate of 7.54; N 4,62.

42B. The compounds of formula (Ib') with different values of R2< / BR>
Similar to the method described in section a, substituting N-(2R-(tert-butoxycarbonyl)methyl-5-(fluoren-2-yl)-4-pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl) carboxamide on:

N-(2R-(tert-butoxycarbonyl)methyl-5-(7-(N- (benzyloxycarbonyl)glycyl)aminofluorene-2-yl)-4E-pentanoyl) -L-lazy the oil)-L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide, received:

N-(2R-(tert-butoxycarbonyl)methyl-5-(7 - glycyl)aminofluorene-2-yl)pentanoyl)-L-leucine-N'-(4- (methoxycarbonyl)phenyl)carboxamide: MS-BT (M+N)+: calculated for C40H51N4O7: 699,3758; received 699,3770 and

N-(2R-(tert-butoxycarbonyl)methyl-5-(4- (pyrid-4-yl)phenyl)pentanoyl)-L - leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide: tPL174-176oC;1H-NMR (300 MHz, CDCl3) cent to 8.85 (s, 1H), 8,63 (d, 2H, J=5 Hz), 7,95 (d, 2H, J=8 Hz), EUR 7.57 (d, 2H, J=9 Hz), 7,41-7,47 (m, 4H), 7,07 (d, 2H, J=8 Hz), to 6.19 (d, 1H, J=7 Hz), 4.53-in-4,56 (m, 1H), 3,85 (s, 3H), 2,37-of 2.66 (m, 5H), 1,45 of-1.83 (m, 7H), of 1.42 (s, 9H), of 0.91 and 0.95 (2d, 6H, J=7 Hz).

Example 43

The compounds of formula (C-1), in which R4and R5denote H

To a stirred suspension containing 4,18 g (20.0 mmol) of N-(benzyloxycarbonyl)glycine, 2,73 ml (2,79 g, 30.0 mmol) of aniline and 110 mg (1.0 mmol) of 4-dimethylaminopyridine in 55 ml of dichloromethane, at 0oC was added in one portion 6,53 g (22 mmole) of methiodide EDC. The mixture was stirred for 18 h at room temperature and then distributed between 200 ml of ethyl acetate: hexane (3:1) and water. The organic layer was washed for 1H. aqueous sodium bisulfate, saturated aqueous sodium bicarbonate and finally saline/phosphate buffer with pH 7, dried over sodium sulfate and conatin-N'-phenylcarbamate: tPL143-144oC.

Example 44

The compounds of formula (C-2), in which R4and R5denote H

To mix the solution containing 1.42 g (5.00 mmol) of N-(benzyloxycarbonyl)glycine-N'-phenylcarbamate in 35 ml of anhydrous THF at -5oC with a syringe was added 6,15 ml (16.0 mmol) of 2.6 M n-utility in hexane with such a rate as to maintain the temperature of the reaction mixture below 10oC. After adding approximately 2/3 of the total number of n-utility appeared stable yellow color, the addition was stopped for about 10 minutes and then started to add dropwise so as to maintain the temperature of the reaction mixture at about 0oC. Upon completion of addition of the orange solution was stirred at 0oC for about 45 minutes and then cooled to -70oC. using a syringe was added acetone (1,10 ml, 15 mmol) in one portion. After 10 minutes the reaction mixture was distributed between 1M phosphate buffer with pH 7 and ethyl acetate:hexane (3: 1). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on 75 g of silica, elwira 40% ethyl acetate glycinamide (pool 2). The residue pool N2 recrystallized from ethyl acetate: isooctane, receiving almost pure starting material in the form of a solid product and the mother liquor solutions containing mainly the product. The residue after concentration of the fallopian solution was purified using radial chromatography (plate 4 mm, 30% ethyl acetate:hexane) and the fraction of the product was combined with a pool of 1, after receiving rubbing a resinous residue with hexane/tert-butylmethylamine ether 423 mg (25%) N-(benzyloxycarbonyl)-DL- -hydroxylamin - N'-(phenyl)carboxamide as a pale yellow solid: tPL128-129oC;1H-NMR (300 MHz, CDCl3) 8,30 (br s, 1H), 7,39 (d, 2H, J=8 Hz), 7.18 in-7,28 (m, 7H), 7,06 (t, 1H, J=7 Hz), of 5.83 (br d, 1H), of 5.05 (s, 2H), Android 4.04 (d, IH, J=9 Hz) of 3.73 (s, 1H), 1,33 (s, 3H), of 1.16 (s, 3H). Elemental analysis: calculated for C19H22N2O4: 66,65; H 6,48; N 8,18; found: 66,66; H to 6.57; N 8,14.

Example 45

The compounds of formula (C-2), in which R4and R5denote H

A solution containing 400 mg (1,17 mmole) of N-(benzyloxycarbonyl)-DL- -hydroxylamin-N'-(phenyl)carboxamide in 10 ml of ethyl acetate, was first made at the hydrogen pressure of 1 ATM in the presence of 50 mg of 10% palladium on coal for 1.5 hours, the Catalyst was removed by filtering through celite and the C additional purification; tPL97-99oC. Elemental analysis: calculated for C11H16N2O2: 63,44; H 7,74; N 13,45; found: 63,52; H 7,79; N 13,40.

Example 46

The compounds of formula (Ib) in which R2denotes bisphenol, R3denotes hydroxy-tert-butyl, a R4and R5denote H

To a solution containing 203 mg (0.55 mmole) of 2R-(tert - butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanol acid, 104 mg (0,50 mmole) DL- -hydroxylamin-N'-(phenyl)carboxamide and 90 μl (0.65 mmole) of triethylamine in 2.5 ml DMF, was added 265 mg (0.60 mmole) benzotriazol-1-iltis(dimethylamino)fosfodiesterasa. After 24 h the reaction mixture was distributed between ethyl acetate:hexane (3:1) and about 0.2 N. aqueous sodium bicarbonate. The organic layer was washed for 1H. aqueous sodium bisulfate and brine solution/buffer with pH 7, dried over sodium sulfate and concentrated. The residue was purified using radial chromatography (plate 4 mm), elwira 25-30% ethyl acetate in hexane. First loirevalley 121 mg (43%) of N-(2R- (tert-butoxycarbonyl)methyl-(5-(bifen-4-yl)pentanoyl)-D- -hydroxylamin-N'-(phenyl)carboxamide (diastereoisomer), and then 140 mg (50%) of N-(2R-(tert - butoxycarbonyl)methyl- (5-(bifen-4-yl)pentanoyl)-L- -hydroxylamin-N'- (phenyl)ka is part 1 mol - equivalent of isooctane (solvent, which was the final concentrated sample):1H-NMR (300 MHz, CDCl3) 8,77 (s, 1H), 7.24 to 7,56 (m, 11H), 7,03-7,14 (m, 3H), 6.89 in (d, 1H, J=8.5 Hz), 4,46 (d, 1H, J= 8.5 Hz), 4,17 (s, 1H), 2,52-2,70 (m, 4H), 2,36 (br d, 1H, J=12,5 Hz), 1,50-1,70 (m, 4H), USD 1.43 (s, 3H), of 1.40 (s, 9H), 1,25 (s, 3H).

Example 47

The compounds of formula (P-1)

To a solution containing 510 mg (1.97 mmole) of N-(4-pentanoyl)-4S-phenylmethyl-2 - oxazolidinone in 8 ml of dichloromethane, at 0oC was added 2.2 ml (2.2 mmole) of 1M titanium tetrachloride in dichloromethane. After 15 minutes to a thick emulsion was added at 0.42 ml (2.4 mmole) of diisopropylethylamine getting the solution dark red. After soaking for 1 h at 0oC via cannula was added 216 mg (2.4 mmole) of s-trioxane in 2 ml of dichloromethane, and then further added 2.2 ml of 1M titanium tetrachloride in dichloromethane. After exposure for 4 h at 0oC the solution was distributed between aqueous ammonium chloride and dichloromethane. The organic layer was washed for 1H. aqueous HCl, brine solution containing phosphate buffer with pH 7, dried over sodium sulfate and concentrated. The residue was purified by chromatography on 20 g silica, elwira 30-40% ethyl acetate in hexane. After recrystallization of the purified product of tert-butyl methyl ether/isooctane received 4 CDCl3) 7,22-7,37 (m, 5H), 5,78 (dddd, J=10, 7, 4 and 3 Hz), 5,03 - of 5.15 (m, 2H), 4,69 (dddd, 1H, J=10, 6, 4 and 3 Hz), 4,17-4,24 (m, 2H), was 4.02-4,10 (m, 1H), 3,85-3,91 (m, 2H), 3,29 (dd, 1H, J=4 and 3 Hz), 2,82 (dd, 1H, J=14 and 10 Hz), 2,44 (dt, 1H, J=14 and 7 Hz), 2,31 (dd, 1H, J=14 and 7 Hz), 2,17 (br s, 1H).

Example 48

The compounds of formula (P-2)

To a suspension containing 4.0 g (25,1 mmole) of the hydrochloride of O-benzylhydroxylamine in 50 ml of THF, at 0oC in argon atmosphere was added and 11.4 ml (22,8 mmole) of 2M trimethylaluminum in toluene. Upon completion of addition the solution was allowed to warm to room temperature. After 15 minutes the solution at 0oC in argon atmosphere was added via cannula to a solution containing 2,40 g (8,30 mmole) of N-(2R-hydroxymethyl-4 - pentanoyl)-4S-phenylmethyl-2-oxazolidinone in 100 ml of THF. The reaction mixture was stirred for 6 h at 0oC and then distributed between 1N. HCl/saline solution and ethyl acetate/diethyl ether. The organic layer with 1 M phosphate buffer with pH 7 with hydrochloric solution was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica, elwira 35-45% ethyl acetate in hexane, after receiving elution 4S-phenylmethyl-2-oxazolidinone 2,01 g of the product. After recrystallization from ethyl acetate: isooctane received 1,90 g (97%) of N-benzyloxy-2R-hydroxide is (m, 1H), 5,03-of 5.06 (m, 1H), 4,91 (dd, 1H, J=16 and 12 Hz), to 3.73 (m, 1H), measuring 2.20 (m, 2H). Elemental analysis: calculated for C13H17NO3: Collected 66.36; H 7,28; N 5,95; found: 66,15; H 7,32; N 5,99.

Example 49

The compounds of formula (P-3)

To a solution containing 1.92 g (8,17 mmole) of N-benzyloxy-2R-hydroxymethyl-4-pentanolide in 10 ml of anhydrous pyridine, at 0oC was added to 1.24 ml (16.3 mmole) of methylchloride. After 3 h the reaction mixture was poured into ice and the mixture was distributed between ethyl acetate and 1N. aqueous sodium bisulfate. The organic layer is washed with an additional portion of sodium bisulfate and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The remaining oil was dissolved in 30 ml of acetone and added to 3.38 g of powdered potassium carbonate. The mixture was boiled under reflux for 3 h and then cooled to room temperature. The precipitate was removed by filtering through celite and the filter cake was thoroughly washed with ethyl acetate. The filtrate was concentrated and the residue was purified by chromatography on silica, elwira 25% ethyl acetate in hexane and receiving 1.64 g (93%) of N-benzyloxy-3R-(2-propen-1-yl)-2-azetidinone in the form of a pale orange oil is 0-2,28 (m, 1H). Elemental analysis: calculated for C13H15NO2: 71,86; H of 6.96; N of 6.45; found: 71,59; H 6,88; N 6,37.

Example 50

The compounds of formula (P-4) in which R2denotes the biphenyl

The solution containing 434 mg (2.00 mmole) of N-benzyloxy-3R-(2-propen-1-yl)-2-azetidinone, 583 mg (2.5 mmole) of 4-bromobiphenyl, 0,34 ml (2.5 mmole) of triethylamine, 35 mg (0.11 mmole) of tri-(ortho - tolyl)phosphine and 14 mg (0.06 mmole) of palladium diacetate in 7 ml of DMF, was kept at 100oC for 18 hours the Reaction solution was cooled to room temperature and distributed between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was chromatographically on silicon dioxide, elwira 25% ethyl acetate in hexane and receiving the product with a small amount of impurities, which was recrystallized from ethyl acetate/isooctane to obtain 315 mg (43%) of N-benzyloxy-3R-(3-(bifen-4-yl)-2 - propen-1-yl)-2-azetidinone in the form of small white flakes:PL109-110oC;1H-NMR (300 MHz, CDCl3) 7,31-to 7.61 (m, 14H), to 6.43 (d, 1H, J=15 Hz), 6,18 (ddd, 1H, J=15, 9 and 7 Hz), 4,94 (s, 2H), 3,36 (dd, 1H, J=10 and 5 Hz), 3.00 and totaling 3.04 (m, 2H), 2,60-of 2.75 (m, 1H), 2,20-of 2.50 (m, 1H). Elemental analysis: calculated for C25H23NO2: 81,27; H 6,28; N 3,79; found: 81,09; H of 6.31; N 3 is the reception solution, containing 62,0 mg (has 0.168 mmole) of N - benzyloxy-3R-(3-(bifen-4-yl)-2-propen-1-yl)-2-azetidinone in 5 ml of THF:ethanol (4: 1), was added 2 ml of 1N. aqueous lithium hydroxide. The mixture was intensively stirred for 1 h at room temperature and diluted with 10 ml of 0.5 M citrate buffer with a pH of 4. The mixture was distributed between 20 ml tert-butyl methyl ether and the salt solution and the organic layer after dilution of approximately 5 ml of hexane was dried over sodium sulfate and concentrated to a glassy residue. This residue was immediately dissolved in 5 ml dichloromethane, cooled to 0oWith, and was added 0.10 ml of pyridine, and then was added 1.2 ml of a solution of formic anhydride in dichloromethane, which was received as a result of interaction at 0oC for 15 minutes 297 mg (1.00 mmol) of methiodide EDC and 80 μl (2.00 mmole) of formic acid in 5 ml of dichloromethane. After 30 minutes the reaction mixture was distributed between dichloromethane and 0.5 M citrate buffer with a pH of 3. The organic layer was dried over sodium sulfate and concentrated. After chromatography of the residue on a 5 g silica, elwira in a gradient from 5% to 10% ethanol in dichloromethane, was obtained 58 mg (83%) of N-((N"-formyl-N"- benzylamino)methyl-5-(bifen-4-yl)-4-pentenol acid in the vitreous washes the century

Example 52

The compounds of formula (P-6), in which R2means biphenyl, R3represents tert-butyl, R7represents 4-pyridyl and p is 0

To a solution containing a 99.6 mg (0.24 mmole) of N-((N"-formyl-N"- benzylamino)methyl-5-(bifen-4-yl)-4-pentenol acid, 125 mg (in 0.288 mmole) of L-tert-leucine-N'-(pyridine-4-yl)carboxamide - bis(triptoreline) and 0.125 ml (0,90 mmole) of triethylamine in 4 ml of DMF, was added 133 mg (0.30 mmole) benzotriazol-1-yl - Tris(dimethylamino)fosfodiesterasa. After exposure for 16 h at room temperature the reaction mixture was distributed between ethyl acetate and approximately 0.5 M aqueous sodium bicarbonate. The organic layer is washed with 1M phosphate buffer with pH 7 and with brine, dried over sodium sulfate and concentrated. After purification of the residue by chromatography with elution 40-75% ethyl acetate in hexane and subsequent recrystallization from ethyl acetate/isooctane received 97,4 mg (67%) of N-((N"-formyl-N"- benzylamino)methyl-5-(bifen-4-yl)-4-pentanoyl)-L-tert - leucine-N'-(pyridine-4-yl)carboxamide: tPL215-216oC.

Example 53

53A. The compounds of formula (Ih) in which R2means biphenyl, R3represents tert-butyl, R7denotes 4-pyridi who yl)-L-tert-leucine-N'- (pyridine-4-yl)carboxamide in 5 ml of ethyl acetate/ethanol (3:2), was first made in the presence of 25 mg of 10% palladium on coal at a pressure of 1 ATM hydrogen for 6 hours, the Catalyst was removed by filtration through celite and the filtrate was concentrated. After recrystallization of the residue from ethyl acetate were received of 59.0 mg (80%) of N-((N"-formyl-N"-hydroxyamino)methyl-5-(bifen-4-yl)pentanoyl)-L - tert-leucine-N'-(pyridine-4-yl)carboxamide as a white powder: tPL190-191oC;1H-NMR (300 MHz, DMSO-d6) 10,52 (br s, 1H), (becomes 9.97 (br s, 1H), at 9.53 (br s, 1H), scored 8.38 (d, 2H, J=7 Hz), 7,20 (br s, 1H), 7,14 (br d, 1H, J=8 Hz), 7.23 percent-of 7.60 (m, 9H), 7,12 (d, 2H, J=7 Hz), to 4.41 (d, 1H, J=9 Hz), 3,40-3,62 (m, 2H), 2,90-3,10 (m, 1H), 2,4-2,6 (m, 2H, partially closed resonance from DMSO-d5), 1,28-of 1.52 (m, 4H), were 0.94 (s, 9H). Elemental analysis: calculated for C30H36N4O40.5 H2O: 68,55; H 7,10; N 10,66; found: 68,48; H? 7.04 baby mortality; N 10,63.

53B. The compounds of formula (Ih) with different values of R2, R3and R7< / BR>
Similar to the methods described in the examples 50-52, received the following compounds of formula (P-6):

N-(2R-(N"-formyl-N"-benzylamino)methyl-5-(4-(2RS-hydroxy-3,3,3 - cryptochromes)phenyl)-4-pentanoyl)-L-tert-leucine-N'-(pyridine-4-yl) carboxamide;

N-(2R-(N"-formyl-N"-benzylamino)methyl-5-(4- (imidazol-4-yl)phenyl)-4-pentanoyl)-L-threonine-N'-((4S - methylsulfinyl)phenyl)carboxamide;

N-(2-4-yl) carboxamide;

N-(2R-(N"-formyl-N"-benzylamino)methyl-5-(4- (imidazol-4-yl)phenyl)-4-pentanoyl)- L-threonine-N'-((4S-methylsulfinyl)phenyl)carboxamide;

N-(2R-(N"-formyl-N"-benzylamino)methyl-5-(4-(pyridin-4-yl) phenyl)-4-pentanoyl)-L-tert-leucine-N'-(4-((2-hydroxyethyl)aminosulfonyl) phenyl)carboxamide;

N-(2R-(N"-formyl-N"-benzylamino)methyl-5- (4-(pyridin-4-yl)phenyl)-4-pentanoyl)-L- (-hydroxy)valine-N'- (4S-methylsulfinyl)phenyl)carboxamide;

N-(2R, S-(N"-formyl-N"-benzylamino)methyl-(4-(methyl)-4-pentanoyl) -L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide and

N-(2R-(N"-formyl-N"-benzylamino)methyl-5- (bifen-4-yl)pentanoyl)-L-cyclohexylglycine-N'-(4-((2- (dimethylamino)ethyl)aminosulfonyl)phenyl)carboxamide, when replacing which N-((N"-formyl-N"-benzylamino)methyl-5- (bifen-4-yl)pentanoyl)-L-tert-leucine-N'-(pyridine-4-yl)carboxamide in the method of example 53A have obtained the following respective compounds:

N-(2R-(N"-formyl-N"-hydroxyamino)methyl-5-(4- (4-(2RS-hydroxy-3,3,3-cryptochromes)phenyl) pentanoyl)-L-tert-leucine-N'-(pyridine-4-yl)carboxamide;

N-(2R-(N"-formyl-N"-hydroxyamino)methyl-5-(4-(imidazol-4-yl) phenyl)pentanoyl)-L-threonine-N'-((4S-methylsulfinyl) phenyl) carboxamide;

N-(2R-(N"-formyl-N"-hydroxyamino)methyl-5- (4- (pyrid-4-yl) phenyl) pentanoyl)-L-t is-(4-(pyrid-4 - yl)phenyl)pentanoyl)-L-(-hydroxy)valine-N'-(4S-methylsulfinyl) phenyl)carboxamide;

N-(2R, S-(N"-formyl-N"-hydroxyamino)methyl-(4-(methyl) pentanoyl)-L-leucine-N'-(4-(methoxycarbonyl)phenyl)carboxamide; MS (M-N)-: 434,2; (M-CO, H2): 388 and

N-(2R-(N"-formyl-N"-hydroxyamino)methyl-5-(bifen-4 - yl)pentanoyl)-L-cyclohexylglycine-N'-(4-((2- (dimethylamino)ethyl)aminosulfonyl)phenyl)carboxamide.

Examples 54-59

In these examples illustrates the obtaining of a representative pharmaceutical compositions containing as active ingredient the compounds of formula (I), for example, N-(2R-carboxymethyl-5-(bifen-4-yl)pentanoyl)-L- -hydroxylamin-N'-(phenyl)carboxamide or its pharmaceutically acceptable salt. In the manufacture of the compositions in these examples as active ingredient can be applied to other compounds of formula (I).

Example 54

This example illustrates the obtaining of a representative pharmaceutical compositions for oral administration.

Option a

Ingredients, wt.%:

The compound of formula (I) - 20,0

Lactose - 79,5

Magnesium stearate and 0.5

The above ingredients are mixed and filled them gelatine capsules with a hard shell, each of which contains 100 mg of the composition, and one capsule should include approximately peat magnesium - 0,9

Starch - 8,6

Lactose is 69.6

PVP(polyvinylpyrrolidine) - 0,9

The above ingredients, except magnesium stearate, unite and granularit, using water as a fluid granulation. Then the composition is dried, mixed with magnesium stearate and using the appropriate teletrauma machine is formed into tablets.

Option

Ingredients

The compound of formula (I) 0.1 g

Propylene glycol - 20,0 g

The polyethylene glycol 400 - 20,0 g

Polysorbate 80 - 1.0 g

Water - q.s. to 100 ml

The compound of formula (I) dissolved in propylene glycol, polyethylene glycol 400 and Polysorbate 80. Then, under stirring, water is added in a quantity sufficient to obtain 100 ml of solution, which is filtered and poured into bottles.

Option G

Ingredients, wt.%:

The compound of formula (I) - 20,0

Peanut oil - 78,0

Span 60 - 2,0

The above ingredients are melted, mix and fill them soft elastic capsules.

Example 55

This example illustrates the obtaining of a representative pharmaceutical composition for parenteral administration.

Ingredients

The compound of formula (I) to 0.02 g

Profiling to 100 ml

The compound of formula (I) dissolved in propylene glycol, polyethylene glycol 400 and Polysorbate 80. Then added with stirring a 0.9% saline solution in a quantity sufficient to obtain 100 ml intravenous solution, which is filtered through a membrane filter with a pore size of 0.2 μm and Packed in sterile conditions.

Example 56

This example illustrates the obtaining of a representative pharmaceutical composition in the form of a suppository.

Ingredients, wt.%:

The compound of formula (I) - 1,0

Polyethylene glycol 1000 - 74,5

Polyethylene glycol 4000 is 24.5

The ingredients are melted together and mixed in a steam bath, and then poured into molds containing 2.5 g total weight.

Example 57

This example illustrates the obtaining of a representative pharmaceutical composition for insufflation.

Ingredients, wt.%:

Micronized compound of formula I - 1,0

Micronized lactose - 99,0

The ingredients are ground, mixed and Packed in insufflator, fitted with a metering pump.

Example 58

This example illustrates the obtaining of a representative pharmaceutical composition in the sprayed voudintie formula (I) is dissolved in ethanol and mixed with water. Then the composition is packaged in a spray bottle fitted with a metering pump.

Example 59

This example illustrates the obtaining of a representative pharmaceutical composition in aerosol form.

Ingredients, wt.%:

The compound of formula (I) 0,10

Propellant 11/12 - 98,90

Oleic acid - 1,00

The compound of formula (I) is dispersed in oleic acid and propellants. Then the resulting mixture is poured into an aerosol packaging, equipped with a measuring valve.

Example 60

Study of in vitro activity against matrilysin

Matrilysin from cloned culture of mammalian cells was purified using the blue sepharose and zinc-chelating sepharose column with subsequent rapid liquid chromatography of proteins on a column of type MONO S. the Enzyme was activated by incubation with 1 mmol ARMA for 1 h at 35-37oC.

The compounds of formula (I) was dissolved in DMSO and added to a cuvette containing 0.4 µg matrilysin in 1 ml of TS buffer (20 mm Tris, 5 mm CaCl2, pH 7.5) (final concentration of DMSO 2%). Concentration of compounds of formula (I) was chosen so that for every 20% change activity to have at least one experimental the>. To initiate the reaction to each of 20 μm was added N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimid ("DACM") (firm Sigma) and dipeptide (Ac-Pro-Leu-Gly-S-Leu"-Leu-Gly-OEt, the company Bachem Bioscience Inc.). The increase in fluorescence was detected at the wavelengths of excitation and emission 395 and 485 nm, respectively. Each experimental point was obtained by averaging over repeated twice experiments. To determine the value IC50using the program Enzfitter used at least six experimental points, showing the dependence of a change in fluorescence per minute from the concentration of the compound.

This analysis confirms that the compounds of formula (I) possess the ability to inhibit matrilysin.

Example 61

Analysis of in vitro

This analysis allows us to determine whether the compounds of formula (I) ability to inhibit the exit labeled35S glycosaminoglycans (GAG) from cartilage explants.

Small cartilage explants (3 mm in diameter) were obtained from knee joints viewpending bulls and were marked with35SO4. Marked by 35S glycosaminoglycans (GAG) are released into the medium in response to the addition of rhIL-1 alpha induces the expression of chondrocyte mA is chirawan taking into account the spontaneous release in the absence of rhIL-1 alpha. The results for each group represent the average values of the standard error of five explants.

The compounds of formula (I) when tested by this method showed the ability to inhibit the exit labeled35's GAG from cartilage explants.

Example 62

Analysis of in vitro

To study the in vitro effect of the compounds of formula (I) on bone resorption as the model used the long bone of the rat embryo. To induce bone resorption in vitro used bovine parathyroid hormone (PDH). Effect on bone resorption was determined by the number of45Ca released into the medium from the pre-labeled by45Ca long bones rat embryos. The inhibitory activity of the compounds of formula (I) in relation to induced bullish PSG bone resorption was expressed as the average percent inhibition of root mean square error.

Pre-labeled by45Ca long bones rat embryos (forearm) were cut and cultured in cups Linbro at 37oC during the night in BGJb medium with addition of 1 mg/ml BSA. Each group used 5 pairs of bones. The compounds of formula (I) pre-dissolved in ethanol, then bit>-8
M. the Concentration of ethanol solutions of compounds were below 0.05%, which does not affect the analysis. The experience was finished on the sixth day, with one replacing the medium on the third day.

At the end of each substitution medium was counted45Ca present in the environment for cultivation. The remaining bone was dissolved with HCl 0.1 N. and also counted the number of3Ca present in the product decomposition of the bone. The results were expressed as percent relative to the total number of45Ca released from each pair of bones. Bullish PSG at a concentration of 110-8M induces bone resorption to a maximum level, which is taken as 100%, and this concentration was used as standard. For 0% took level baseline bone resorption in the presence of only environment. All processed by the connection group compared with those treated bullish PSG (1-34) at a concentration of 110-8M Concentration at which the compound inhibited bone resorption by 50% was defined as IC50.

The compounds of formula (Ia) when tested by this method showed the ability to inhibit bone resorption induced bullish PSG.

Example 63

Study of in vitro activity in the analysis of energy transfer in terms of resonance using a peptide substrate MCA: 7 - methoxycoumarin-4-ylacetic-pro-leu-gly-leu-3-(2,4 - dinitrophenyl) -L-2,3-diaminopropionic-ala-arg-NH2. Cleavage of the substrate for connection gly-leu leads to loss of energy transfer in the resonance conditions for 2,4-dinitroaniline the group and to increase the fluorescence of MCA (7-methoxycoumarin-4-ratetylenol) group.

The analysis was carried out at 37oC in buffer containing 50 mm Tricin, pH 7.5, 10 mm CCl2, 200 mm NaCl, 1% DMSO and 1.4 nm stromelysin. The substrate concentration ISA was 10 or 20 μm in a final volume of 1.6 ml In the absence of compounds tested for inhibitory activity, or in the presence of rapidly communicating inhibitors fluorescence was measured using spectrofluorimetric LS-5B and LS-50B company Perkin-Elmer at wavelengthsexcitation= 328 nm andissue= 393 nm for 3 -5 minutes and data was approximatively a straight line. For the slow-binding inhibitors data on the inhibition was recorded during the period of time from 45 minutes to 1 hour. The stationary rate of change of fluorescence was evaluated on the basis of a curve approximation equation for a simple exponential decay, containing linear phase, as well as obtained on the basis of the approximation is linear phase fixed speed.

Explored the compounds of formula (I), and found that they periments when using other matrix metalloprotease, such as matrilysin or gelatinase And by replacing stromelysin on 0,063 nm matrilysin or 0,030 nm gelatinase A (PL.1).

Although the present invention is described on the example of a specific variants of its implementation, specialists in the art should be obvious that can be done various modifications and equivalent substitutions, without departing from the scope of invention.

Special work on the toxicity of selected compounds according to the invention was conducted. However, when conducting the primary screening of some substances serious Toxicological effects were observed.

He was not found in the above analyses.

1. Carboxamide formula

< / BR>
where R1represents mercapto, acetylthio, carboxy, hydroxycarbamoyl, N-hydroxypropylamino, alkoxycarbonyl with 1 to 10 carbon atoms, aryloxyalkyl, arelaxation, benzyloxycarbonyl or a group of the formula

< / BR>
where R6denotes aryl or heteroaryl;

R2denotes alkyl with 1 to 10 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl, heteroseksualci or heteroaryl;

R3denotes alkyl with 1 to 10 carbon atoms, recloak loukil;

X denotes a group of the formula -(CH2)m-Y-(CH2)n- where

Y represents O, S or a simple link,

m denotes an integer from 0 to 4,

n denotes an integer from 0 to 4 and m + n represents an integer from 0 to 4;

p denotes an integer from 0 to 4, provided that R2X denotes biphenylyl when p is not equal to 0, and R2-X is not alkyl, aralkyl or cycloalkylation, if p is 0 and R7is phenyl;

or their pharmaceutically acceptable salts.

2. Carboxamide or salt p. 1, where R1represents carboxy; R3denotes cyclohexyl; R7denotes optionally substituted phenyl or N-morpholino; X denotes propane-1,3-diyl and p is 2 or 3.

3. Carboxamide or salt p. 2, where R7denotes 4-(aminosulfonyl)phenyl or N-morpholino.

4. Carboxamide or salt p. 1, where R2denotes alkyl with 1 to 10 carbon atoms, optionally substituted phenyl or a group of the formula

< / BR>
where a denotes CH2, O, NH, S, CH2-CH2or NH-CH2;

R10denotes H, alkyl, alkoxy, alkylamino or acylamino;

R11denotes H or halogen;

R7denotes a 4-pyridyl or AAT carboxy, hydroxycarbamoyl or N-hydroxypropylamino; R2denotes phenyl, biphenyl, 4-(pyridyl)phenyl or 2-methylpropyl; R3represents tert-butyl, 4-aminobutyl, dimethylaminomethyl, 4-(N, N'-dietilamida)butyl, propyl, 2-methylpropyl, 1-hydroxyisopropyl, 1-hydroxyethyl or cyclohexyl and X represents a simple bond, ethylene or propane-1,3-diyl.

6. Carboxamide or salt p. 4, where R2denotes the biphenyl.

7. Carboxamide or salt p. 6, where R1denotes a carboxy, N-hydroxypropylamino or hydroxycarbamoyl; R3denotes alkyl with 1 to 10 carbon atoms and R7represents 4-pyridyl.

8. Carboxamide or salt p. 7, where R3represents tert-butyl and X represents propan-1,3-diyl.

9. Carboxamide or salt p. 8, where R1denotes a carboxy, N-hydroxypropylamino or hydroxycarbamoyl.

10. Carboxamide or salt p. 4, where R2denotes a group of the formula

< / BR>
where a denotes CH2;

R10denotes H or acylamino;

R11denotes H;

R7denotes optionally substituted phenyl;

X denotes propane-1,3-diyl.

11. Carboxamide or salt p. 10, where R1means carbocylic.

12. Carboxamide or salt on p. 11, where R1represents carboxy; R3denotes 2-methylpropyl and R7denotes 4-(methoxycarbonyl)phenyl.

13. Carboxamide or salt p. 6, where R7denotes optionally substituted phenyl.

14. Carboxamide or salt p. 13, where R1represents carboxy; R3denotes alkyl with 1 to 10 carbon atoms or cycloalkyl with 5 to 7 carbon atoms and X denotes propane-1,3-diyl.

15. Carboxamide or salt p. 14, where R3denotes cyclohexyl and R7denotes 4-(hydroxyethylaminomethyl)phenyl or 4-(dimethylbenzenesulfonyl)phenyl; or R3denotes 4-(amino)butyl or 4-(isopropylamino)butyl and R7denotes 4-(etoxycarbonyl)phenyl; or R3denotes 1-hydroxyisopropyl and R7denotes phenyl; or R3represents tert-butyl.

16. Carboxamide or salt p. 15, where R7refers to 4-(N-morpholinepropanesulfonic)phenyl, 4-(methylaminomethyl)phenyl, 4-(hydroxyethylaminomethyl)phenyl or 4-(methylsulfinyl)phenyl.

17. Carboxamide or salt p. 4, where R1represents carboxy; R2denotes phenyl; R3denotes alkyl with 1 to 10 carbon atoms and oxamide or salt p. 17, where R3denotes 4-(amino)butyl; R7denotes 4-(etoxycarbonyl)phenyl, and X denotes propane-1,3-diyl; or R3denotes the (N,N'-dietilamida)-N-butyl; R7denotes 4-(etoxycarbonyl)phenyl, and X denotes propylene; or R3denotes cyclohexyl; R7refers to 4-(N",N"-dimethylbenzenesulfonyl)phenyl and X represents ethylene.

19. Carboxamide or salt p. 4, where R1represents mercapto, carboxy, hydroxycarbamoyl or N-hydroxypropylamino; R2denotes 2-methylpropyl; R3denotes alkyl with 1 to 10 carbon atoms, cycloalkyl with 5 to 7 carbon atoms or heteroalkyl; R7denotes optionally substituted phenyl, and X represents a simple bond.

20. Carboxamide or salt according to p. 19, where R1indicates hydroxycarbamoyl, R3denotes propyl, 2-methylpropyl, cyclohexyl, or 3-methylindole, R7denotes 4-(methoxy)phenyl, 4-(carboxy)phenyl, 4-(methoxycarbonyl)phenyl or 4-(dimethylaminoethanol)phenyl.

21. Carboxamide or salt according to p. 20, where R7denotes 4-(dimethylaminoethanol)phenyl, or R7denotes 4-(methoxycarbonyl)phenyl.

22. Carboxamide or salt according to p. 19, where R1indicates1represents carboxy; R3represents cyclohexyl or 2-methylpropyl and R7denotes 4-(methoxycarbonyl)phenyl; or R1means mercapto; R3denotes 2-methylpropyl and R7denotes 4-(methoxycarbonyl)phenyl.

23. Carboxamide or salt p. 4, where R1represents carboxy; R2denotes 4-(2-hydroxyethyl)phenyl, 4-(2-hydroxypropyl)phenyl, 4-(2-hydroxybutyl)phenyl, 4-pyridylethyl, biphenyl, 4'-(aminoethoxy)biphenyl, 4'-(cyan)biphenyl or 4'-(hydroxy)biphenyl; R3denotes 2-methylpropyl; R7denotes 4-(methoxycarbonyl)phenyl, and X denotes propane-1,3-diyl.

24. Carboxamide or salt p. 23, where R2denotes 4-(pyridyl)phenyl.

25. Pharmaceutical composition having the ability to inhibit the activity of matrix metalloprotease containing the active ingredient and pharmaceutically acceptable excipient, characterized in that the active substance it contains a connection on p. 1 or its salt in an effective amount.

26. The method of producing carboxamido formula I

< / BR>
where R1represents mercapto, acetylthio, carboxy, hydroxycarbamoyl, N-hydroxypropylamino, alkoxycarbonyl with 1 to 10 atoms which uly

< / BR>
where R6denotes aryl or heteroaryl;

R2denotes alkyl with 1 to 10 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl, heteroseksualci or heteroaryl;

R3denotes alkyl with 1 to 10 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aralkyl or heteroalkyl;

R7denotes aryl, heteroaryl or heteroseksualci;

X denotes a group of the formula -(CH2)m-Y-(CH2)n- where

Y represents O, S or a simple link, m represents an integer from 0 to 4, n represents an integer from 0 to 4 and m + n represents an integer from 0 to 4;

p denotes an integer from 0 to 4, provided that R2X denotes biphenylyl when p is not equal to 0, and R2-X is not alkyl, aralkyl or cycloalkylation, if p is 0 and R7is phenyl;

or their pharmaceutically acceptable salts, characterized in that the compound of formula D

< / BR>
subjected to interaction with the compound of the formula F

< / BR>
where R1denotes alkoxycarbonyl with 1 to 10 carbon atoms, arelaxation, aryl - or heteroarylboronic or acetylthio,

in the presence of a base and amide reagent combination with obtaining the appropriate SOER>1denotes alkoxycarbonyl with 1 to 10 carbon atoms or arelaxation, in acid medium to obtain the corresponding compounds of formula I, where R1denotes carboxypropyl, which, if necessary, or subjected to interaction with O-benzylhydroxylamine with obtaining the compounds of formula I, where R1indicates benzyloxycarbonyl, followed, if necessary, by catalytic hydrogenation to obtain the corresponding compounds of formula I, where R1indicates hydroxycarbamoyl, or subjected to interaction with hydroxylamine to obtain the corresponding compounds of formula I, where R1indicates hydroxycarbamoyl, or followed, if necessary, treatment of compounds of formula I, where R1denotes acetylthiourea, hydroxyl ammonium proton solvent to obtain the corresponding compounds of formula I, where R1denotes mercaptopropyl.

 

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< / BR>
where R1, R2, R3, R4, R5and "n" and "m" have the following meanings:

R1, R2denote hydrogen, linear or branched (C1-C8)-alkyl;

(C3-C8-cycloalkyl as cyclohexyl; phenyl, which can be single or twofold substituted linear (C1-C4)-alkyl, (C1-C2-alkoxyl, halogen, cyano group, nitro group, trifluoromethyl or acylamino group; phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and a phenyl ring, which may be single or twofold substituted stands, methoxy group, halogen, nitro group, cyano group or acylamino-group;

< / BR>
denotes a morpholine or piperidine which may be substituted by one or twice (C1-C2)-alkyl group or a group

< / BR>
where R6may denote H, NHCО2CH2CH3;

R3does

< / BR>
represents piperidine or morpholine

n = 1-5;

m = 2-4;

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