Derivatives of amides, which are inhibitors of matrix metalloprotease, the pharmaceutical composition

 

(57) Abstract:

The compounds of formula 1, where dashed lines indicate optional double bonds, and, if n = 1, 2, or 3; m = 3 or 4, And denotes-CH2-; R1means (a) -CH2-R4where R4represents mercapto, acetylthio, carboxy, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, morpholino (C1-C4)alkoxycarbonyl, aryloxyalkyl, benzylaminocarbonyl or a residue of formula (i), where R6denotes China-2-yl; b) -CH(R7)-R8where R7denotes alkyl, hydroxy, amino, alkoxycarbonyl, aminocarbonyl or carboxy and R8denotes a carboxy, hydroxyaminobuteroyl, alkoxycarbonyl or arelaxation, in) -NH-CH(R9)-R10where R9denotes hydrogen or alkyl and R10denotes a carboxy, arelaxation; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl and R3denotes hydrogen, or, if n = 2 or 3; m = 3 or 4, And represents - N(R11)-, where R11denotes hydrogen or alkyl; and R1, R2and R3have the above values, as single stereoisomers or as mixtures thereof, or their pharmaceutically acceptable salts; suitable LASS="ptx2">

The invention relates to compounds and their pharmaceutically acceptable salts, having the ability to inhibit matrix metalloprotease, in particular interstitial collagenase, and therefore suitable for the treatment of painful conditions in mammals, facilitated by the inhibition of such matrix metalloprotease.

Matrix metalloprotease are a family of proteases responsible for the decomposition and the reconstruction of connective tissues. Representatives of this family of enzymes have numerous properties, including the zinc - and calcium-dependent secretion as proenzymes and 40-50% homologically amino acid sequence.

The family of matrix metalloprotease includes interstitial collagenase, derived from fibroblasts/macrophages and neutrophils, which catalyze the initial splitting and splitting with a limited speed of native collagen types I, II, III and X.

Collagen, the main structural protein in mammals is a major component of the extracellular matrix of many tissues, such as cartilage, bone, tissues, tendons and skin. Interstitial collagenase are very specificunitedunited at physiological temperatures and therefore become sensitive to the splitting of the less specific enzymes. Since splitting with collagenases leads to the loss of structural integrity of the target tissue, because this is essentially a reversal is possible, and therefore, we are talking about a good target for therapeutic intervention.

In addition to the interstitial collagenases, the family of matrix metalloprotease of enzymes includes two different, but very close gelatinase: enzyme 72 kDa secretory fibroblasts, and the enzyme 92 kDa released from mononuclear phagocytes. These gelatinase have the ability to degrade gelatin (denatured the collagens), native collagen types IV and V, fibronectin and insoluble elastin.

The family of matrix metalloprotease also includes stromelysin 1 and 2, which are able to cleave a wide range of matrix substrates, including laminin, fibronectin, proteoglycans and collagen types IV and IX in their nagelmodellage area.

Matrilysin (imaginary metalloprotease or MMP) is a recently open a representative of a family of matrix metalloprotease. Matrilysin has the ability to decompose a wide range of matrix substrates, including proteoglycans, gelatin, fibronectin, elastin, and laminin. His ex is.

It is believed that inhibitors of matrix metalloprotease suitable for the treatment of arthritis, diseases associated with bone resorption (such as osteoporosis), increased degradation of collagen associated with diabetes, periodontal diseases, ulcers on the cornea, ulcers on the skin and metastasis of tumors. The purpose and potential use of inhibitors of collagenases are described, for example, in J. Enzyme Inhibition (1987), I. 8, pages 1-22, and Drug News &. Prospectives (1990), I. 3, N 8, PP 453-458. Inhibitors of matrix metalloprotease are also the subject of various patents and patent applications, for example, US patents 5189178 (Galardy) and US 5183900 (Galardy), published applications, European patents EP 0438223 (Beecham) and EP 0276436 (F. Hoffmann-La Roche), International applications WO 92/21360 (Merck), WO 92/06966 (Beecham) and WO 92/09563 (Glycomed).

The object of the present invention are novel compounds which are suitable as inhibitors of matrix metalloprotease, in particular interstitial collagenases, which are effective in the treatment of painful conditions characterized by increased activity of matrix metalloprotease.

Thus, the present invention relates to derivatives of amides of General formula (I):

< / BR>
where the dashed lines indicate optional is;

(a)- (CH2-R4where R4represents mercapto, acetylthio, carboxy, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, morpholino(C1-C4)alkoxycarbonyl, aryloxyalkyl, benzylaminocarbonyl or

< / BR>
where R6denotes China-2-yl;

b) -CH(R7)-R8where R7denotes alkyl, hydroxy, amino, alkoxycarbonyl, aminocarbonyl or carboxy; and R8denotes a carboxy, hydroxyaminobuteroyl, alkoxycarbonyl or arelaxation;

in) -NH-CH(R9)-R10where R9denotes hydrogen or alkyl; and R10denotes a carboxy or arelaxation;

R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl;

R3denotes hydrogen;

or, if n is 2 or 3; m is 3 or 4; a represents-N(R11)-, where R11denotes hydrogen or alkyl; and

R1, R2and R3have the above values;

as individual stereoisomers or as mixtures thereof; or their pharmaceutically acceptable salts.

In addition videopreteen notation for R3, R4, R6, R9and R10in the compounds of formula (I) mentioned radicals may have the following dopolnitelnyekonsultatsii substituted aryl, where the aryl group denotes chinolin-2-yl, naphthas-1-yl, naphthas-2-yl, pyridyl or phenyl;

R9- aralkyl;

R10- alkoxycarbonyl, phosphonyl, dialkylphenol, methoxypropanol.

The present invention also describes a method of inhibiting the activity of matrix metalloprotease in mammals, including the appointment of 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 a mixture thereof; or its pharmaceutically acceptable salt.

Another object of the present invention is a pharmaceutical composition having inhibitory activity against matrix metalloprotease in mammals, comprising as active ingredient 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.

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

"VOS" oboznachaiushchaia N,N-dimethylformamide.

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

"HOBT" denotes 1-hydroxybenzotriazol.

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

"Halogen" denotes bromine, chlorine or fluorine.

"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 four carbon atoms, for example methyl, ethyl, n-propyl, 2-methylpropyl (isobutyl), 1-methylethyl (isopropyl), n-butyl and 1,1-dimethylethyl (tert.-butyl).

"Alkoxy" means a radical of the formula-ORawhere Rarefers to alkyl as defined above such as methoxy, ethoxy, n-propoxy, isopropoxy, 1 methylethoxy, n-butoxy, tert.-butoxy etc.

"Aryl" means phenyl or nattily 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, and Rbmeans aryl, as defined above, for example benzyl, phenylethylene, 3-phenylprop the AK defined above, and Rbmeans aryl, as defined above, for example benzyloxy or 3-naphthas-2-ylpropionic etc.

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

"Arelaxation" refers to a radical of the formula-C(O)Rcwhere Rcindicates arakaki, as defined above, such as benzyloxycarbonyl, naphthas-2-retexturing etc.

"Benzylaminocarbonyl" refers to a radical of the formula - C(O)NHCH2Rdwhere Rddenotes phenyl.

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

"Carboxy" refers to a radical-C(O)HE.

"Hydroxyamino" refers to the radical-NHOH.

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

"Mercapto" refers to the radical-SH.

"Sulfonyl" refers to the radical =S(O)2.

"Phosphonyl" refers to the radical-PO(OH)2.

"Optional" or "optionally" means that consistently describes the actions or circumstances may be or may not be, and that definition includes situations when the steps or discuss who appoints, what radical henol-2-yl may be substituted or may be unsubstituted, and that definition includes the radicals substituted henol-2-yl, and the radicals China-2-yl, without substitution.

"Optionally substituted aryl" denotes a radical henol-2-yl, naphthas-1-yl, naphthas-2-yl, pyridyl or phenyl, optionally substituted by one or more substituents, such as halogen, alkyl, alkoxy, hydroxy and nitro, for example 6-NITROPHENOL-2-yl, 6-fiorinal-2-yl, 6-hydroximino-2-yl, 6-methoxyindol-2-yl, 6-nitronate-1-yl, 6-Harnett-1-yl, 6-hydroximate-1-yl, 6-metaxilat-1-yl, 6-nitronate-2-yl, 6-Harnett-2-yl, 6-hydroximate-2-yl, 6-metaxilat-2-yl, 6-nitrophenyl, 6-chlorophenyl, 6-hydroxyphenyl, 6-methoxyphenyl, 3 - methylpyridyl, 4-ethylpyridine etc.

"Optionally substituted carbarnoyl" refers to a radical of carbamoyl, optionally substituted on the nitrogen atom by one or more substituents selected from the group comprising alkyl or aralkyl.

"Aminosidine group" as used in 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, Benz is dicarbonyl etc.

"Pharmaceutically acceptable salt" includes both pharmaceutically acceptable acid additive salts, and pharmaceutically acceptable salts accession grounds.

"Pharmaceutically acceptable acid additive salt" refers to such salts which retain the biological effectiveness and properties of the free bases, which are not undesirable biological or other reasons and which are formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and 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, methanesulfonate acid, econsultancy acid, para-toluensulfonate acid, salicylic acid, etc.

"Pharmaceutically acceptable salt accession grounds" means such salts which retain the biological effectiveness and properties of the free acids, which are not junk the definition of the base to the free acid. Salts formed from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., the Preferred inorganic salts are ammonium salts, sodium, potassium, calcium and magnesium. Salts formed from 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 ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-Diethylaminoethanol, tromethamine (trimethamin), dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine (hydrabamine, choline, betaine, Ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. are Particularly preferred organic bases are Isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

"Mammal" includes humans and all domestic and wild animals, including, but not limited to, cattle, horses, with whom icesto the compounds of formula (1), which, being assigned to a mammal, if necessary, is sufficient to effect the treatment, as defined below, disease States, facilitated by inhibiting the activity of matrix metalloprotease, in particular, the activity of interstitial collagenase. The amount of the compounds of formula (I), which constitutes a "therapeutically effective amount" is largely varies depending on the connection status of the disease and its severity, and the mammal undergoing treatment, but it can be defined as the accepted way an ordinary person skilled in the technical field, relying on his own knowledge and the description.

"Treatment" or "treat" as used in the present description, covers any treatment of a disease state in a mammal, especially humans, which is facilitated by inhibiting the activity of matrix metalloprotease, in particular activity of interstitial collagenase and so on; 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 has not yet established that tavoletta painful condition, i.e. regression of the disease condition.

"Stereoisomers" refers to compounds that have the same molecular formula and the nature or sequence of links, but differ in the orientation of their atoms in space. Used in the description of 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 phosphinic or alanovoy acids having critically Deputy. The compounds of formula (I) or their pharmaceutically acceptable salts have at least two asymmetric carbon atom, one carbon is a carbon that is attached to the substituent R2and the other carbon is a carbon that is attached indolylmethane group. The compounds of formula (I) and their pharmaceutically acceptable salts may also 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 this invention.

When the designation of the individual stereoisomers of compounds of formula (I) R or S mo the gold and Priloga.

For example, the following compound of formula (I), where n is 2; m is 3; And a represents-CH2-; R1denotes-CH2-R4where R4denotes-C(O)NHOH; R2denotes 2-methylpropyl and R3denotes hydrogen, i.e. the compound having the following formula:

< / BR>
named in the present description as (3R,10S)-N-hydroxy-5 - methyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.0of 13.18] endeca- 12(19),13(18),14,16-tetraen-10-ylcarbonyl) hexanamide.

The compounds of formula (I) useful as inhibitors of matrix metalloprotease mammals, in particular interstitial collagenases mammals, thus preventing the degradation of collagen in the body of a mammal. These compounds are also suitable for the treatment of painful conditions associated with increased activity of matrix metalloprotease, especially with increased activity of interstitial collagenase, such as arthritis and osteoarthritis, metastatic tumors, periodontal disease and ulcers of the cornea. See, for example, 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 I, (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.

The ability of compounds Genasi, can be demonstrated by various experiments in vitro and ex vivo, known to specialists in this field of technology. For example, the activity of individual metalloprotease can be demonstrated in in vitro experiments described in Anal.Biochem. (1985), I. 147, page 437, or their modifications. The physiological effect of inhibition of matrix metalloprotease can be demonstrated in ex vivo experiments on explanate bovine cartilage described in Methods of Enzymology (1987), T. 144, pages 412-419, or their modifications; or in the ex vivo experiments on the long bones of the embryo rats, described in Proc. Natl. Acad. Sci. USA (1988), I. 85, page 8761-8765, or modifications of, or in J. Clin. Invest. (1965), I. 44, pages 103-116, or their modifications.

Introduction compounds of formula (I) or their pharmaceutically acceptable salts, in pure form or in the form of a pharmaceutical acceptable composition can be carried out using any of the acceptable methods of appointment 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 or liquid dosage forms or dosage forms in the form of dried powder, such as tablets, suppositories, pills, me is the super in the form of standardized doses, suitable for simple introduction of precise doses. The composition may include a conventional pharmaceutical carrier or excipient and the compound of formula (I) as active substance and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

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

The preferred route of administration is oral, using the usual daily dosage regimen of medicines that can be adjusted depending on the complexity of the disease to be treated. For such oral administration of pharmaceutically acceptable composition comprising the compound(I) of the formula (I) or its pharmaceutically acceptable salt, get putuccasa, starch, pregelatinized starch, magnesium stearate, Nachrichten, talc, ether derivatives of cellulose, glucose, gelatin, sucrose, 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., disintegrator, such as nitrocresols or its derivatives; a lubricant such as magnesium stearate, etc.,; and 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 used in the form of a suppository, which includes from about 0.5% to about 50% active ingredient distributed in a slowly dissolving in the body of the carrier, for example, polyoxyethyleneglycol and polyethylene glycol (PEG) such as PEG 1000 (96%) and PEG 4000 (4%).

Liquid compositions for pharmaceutical purposes can, for example, be prepared by Rast acceptable salts and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to obtain a solution or suspension.

Optionally, the pharmaceutical composition according to the invention may also contain small amounts of additives, such as wetting or emulsifying agents, pH buffering 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). Appointed compositions in any case must contain a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salts for the treatment of diseases that may be alleviated by inhibiting matrix metalloprotease in accordance with the recommendations of this invention.

The compounds of formula (I) or their pharmaceutically acceptable salts should be administered in therapeutically effective amounts, which largely depends on various factors, blastia connection age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of a particular disease state 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 about 10 mg to about 1.0 g of the 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.

A preferred group of compounds of formula (I) according to the invention are those compounds in which n is 2 or 3; m is 3; And a represents - CH2-; R2denotes alkyl or aralkyl.

A preferred class of compounds of this group are those compounds is formylamino, alkoxycarbonyl, aryloxyalkyl or benzylaminocarbonyl; and R2denotes 2-methylpropyl.

A preferred subclass of compounds of this class are those compounds where n is 2 and R1denotes-CH2-C(O)HE or-CH2-C(O)NHOH.

From the specified subclass of preferred compounds of such individual stereoisomer of (3R, 10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid or (3R, 10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanamide.

Another preferred subclass of the above class of compounds are those compounds where n is 3 and R1denotes - CH2-C(O)NHOH.

In this preferred such individual stereoisomer of (3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo [11.6.1.014,19]eicosa-13(20), 14(19),15,17-tetraen-11 - ylcarbonyl)hexanamide.

In addition, a preferred subclass of the above class are compounds where n is 1 and R1denotes-CH2-C(O)HE or-CH2-C(O)NHOH.

While preferred specific stereoisomer, namely: (3R,9S)-5-methyl-3-(8-oxo-1,7-dimetyl-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12(17), 13,15-tetraen-9 - ylcarbonyl)hexanamide.

Another preferred class of compounds of the group are those compounds where R1denotes-CH2-R4where R4means mercapto or acetylthio.

In this preferred subclass of compounds where n is 2 and R1denotes-CH2SH or-CH2C(O)CH3.

From the specified subclass of preferred compounds: (10S)-2 - mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)pentanone; or (10S)-2-acetyltributyl-4-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10 - ylcarbonyl)pentanone.

Another preferred class of compounds of this group are compounds where R6denotes China-2-yl.

Thus preferably the connection, where n is equal to 2.

Particularly preferably the following compound: (10S)-[4-methyl-2-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18),14,16- tetraen-10-ylcarbonyl)pentyl]-(quinoline-2-altimeter)phosphinic acid.

Another preferred class of compounds of the group are those compounds where R1denotes XI, hydroxyaminobuteroyl, alkoxycarbonyl or arelaxation.

A preferred subclass of compounds of this class are those compounds where R7denotes methoxycarbonyl or methyl.

Especially preferred in this subclass are those compounds where R8denotes hydroxyaminobuteroyl.

In this particularly preferred subclass of an individual stereoisomer, where n is 2, namely (3R,10S)-N-hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18]endeca-12(19),13(18),14,16- tetraen-10-ylcarbonyl)hexanamide.

Another preferred class of compounds of the group are those compounds where R1denotes-NH-CH(R9)-R10where R9denotes hydrogen or alkyl; and R10denotes a carboxy or arelaxation.

While preferred are those compounds where R9denotes alkyl and R10represents carboxy.

Another preferred group of compounds of formula (I) are those compounds where n is 2 or 3; m is 4; And a represents - N(R11)-, where R11denotes hydrogen or alkyl; R2denotes alkyl.

A preferred class of this group are those with soedinenii compounds of this class are those compounds where R1denotes-CH2-R4where R4denotes a carboxy, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, aryloxyalkyl or benzylaminocarbonyl.

Especially preferred in this subclass are those compounds where n is 2 and R' denotes-CH2-C(O)NHOH.

The compounds of formula (I) as individual stereoisomers or as mixtures thereof, and their pharmaceutically acceptable salts are derived peptides, which can be obtained from the derivatives of the components of alpha-amino acids. The standard method of the formation of peptide bonds described in M. Bodanszky and others, The Practice of Peptide Synthesis (1984), Springer-Verlag; M. Bodanszky, Principles of Peptide Synthesis (1984), Springer-Verlag; J. P. Greenstein and others , Chemistry of the Amino Acids (1961), T. 1-3, John Wiley and Sons Inc.; G. R. Pettit, Synthetic Peptides (1970), T. 1-2, Van Nostrand Reinhold Company.

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 is consistent ether, such as nitrophenyloctyl ether. Usually spend amide combination of solution phase peptide fragments, or without them.

The choice of protective group for the terminal amino or carboxyl groups of the compounds used to produce compounds of formula (I), is determined partly by the specific conditions of amide or peptide combinations, and partly components of amino acids and/or peptide included in the combination. Usually used aminosidine groups include those well known in the art, such as benzyloxycarbonyl (carbobenzoxy), para-methoxybenzeneboronic, para-nitrobenzenesulfonyl, tert.-butoxycarbonyl (VOS), etc., it is Preferable to use either the WTP or benzyloxycarbonyl (CBZ) 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 catalytic hydrogenation.

Individual stereoisomers of compounds of formula (I) can be divided from each other by methods known to experts in the art, for example by selective crystallization or chromatography, and/or methods, prmy only in those cases if such combinations result in stable compounds.

The method of obtaining compounds of formula I includes the following stages.

A. Obtaining intermediates include compounds of formula (J)

Compounds of the following formula (J):

< / BR>
where R3denotes hydrogen, halogen, alkyl or alkoxy; and p is 5, 6, 7 or 8; used for obtaining the compounds of formula (I) and receive in accordance with reaction scheme 1 (see the end of the description), where R3denotes hydrogen, halogen, alkyl or alkoxy; p is 5, 6, 7 or 8; VOS denotes tert-butoxycarbonyl, and R13denotes hydrogen, mesyl or tosyl.

Compounds of formula (I) and (F) are commercially available, for example, are produced by firms Karl Industries, Inc. or Sigma, respectively, or can be obtained by methods known to experts in this field of technology.

Usually the compounds of formula (J) are obtained by a method that includes first etherification of the alcohol of formula (V) with acetic anhydride in the presence of a base, preferably pyridine, to form the compounds of formula (C), which is then restored in the presence of acetic anhydride to form a compound of formula (D). Connection fo the help of the formula (E), which is then subjected to the combination with the compound of the formula (F) under standard conditions of peptide combinations, for example, with EDCI in the presence HOBT in DMF, to form the compounds of formula (G), where R13denotes hydroxyl. This compound is then treated or mozillateam or methylchloride for the formation of compounds of formula (G), where R13indicates mesyl or tosyl. By cyclization of the thus obtained of tozilaty with an excess of NaH in an inert solvent, preferably THF, at a strong dilution and at room temperature produces the compounds of formula (H). The protective group in the compounds of formula (H) is removed in the acid environment, preferably in the presence of triperoxonane acid (TFA) to give the compounds of formula (J).

B. Obtaining compounds of formula (Ia), (Ib), (Ic) and (Id)

The compounds of formula (Ia) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-; R1denotes-CH2-R4where R4denotes tert-butoxycarbonyl; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (Ib) are compounds of fo is SUP>4represents carboxy; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (Ic) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-; R1denotes-CH2-R4where R4denotes benzylaminocarbonyl; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (Id) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-; R1denotes-CH2-R4where R4denotes hydroxyaminobuteroyl; R denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy.

Compounds of formula (Ia), (Ib), (Ic) and (Id) are obtained according to the following reaction scheme 2, where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy, R14denotes tert.-butyl or benzyl and R7adenotes hydrogen or alkoxycarbonyl.

Connect four is the leaves in this field of technology.

Typically, compounds of formula (Ia), (Ib) and (Ic) receive a first combination of the compounds of formula (J) with the compound of the formula (K) under standard conditions of peptide combination for the formation of compounds of formula (Ia). The protective group in the compound of formula (Ia) is then removed in a weakly acidic medium, receiving the compound of formula (Ib).

The compound of formula (Ib) is then subjected to the combination with O-benzylhydroxylamine under standard conditions of peptide combination for the formation of compounds of formula (Ic). Benzyl protective group in the compound of formula (Ic) is then removed under conditions of catalytic hydrogenation, receiving compound of formula (Id).

C. Obtaining compounds of formula (Ie) and (If)

The compounds of formula (Ie) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-; R1denotes - CH2-R4where R4indicates acetylthio; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen.

The compounds of formula (If) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-; R1denotes-CH2-R4where R4means mercapto; R2denotes ALK is (If) receive, in accordance with the following reaction scheme 3, where R2and R3have the above meanings and p is 5, 6, 7, or 8.

The compounds of formula (M) are commercially available or can be obtained by methods known to experts in this field of technology.

Typically, compounds of formula (Ie) and (If) receive a first combination of the compounds of formula (M) with the compound of the formula (J) under standard conditions of peptide combination for the formation of compounds of formula (Ie). By treating compounds of formula (Ie) concentrated NH4OH in methanol obtain the corresponding compounds of formula (If).

, Obtaining the individual stereoisomers of compounds of formula (K)

The compounds of formula (K):

< / BR>
where R14denotes a tert-butyl or benzyl and R7adenotes hydrogen, alkoxycarbonyl, hydroxycarbamoyl, carboxy or optionally substituted carbarnoyl, is used to produce compounds of formula (I)

Individual stereoisomers of compounds of formula (K) is used to produce individual stereoisomers of compounds of formula (I). In particular, the compounds of the following formula (Ka):

< / BR>
where R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R7bdenotes hydrogen, are the connected substituent R2.

The compounds of formula (Ka) receive, in accordance with the following reaction scheme 4, where R2and R7bhave the values specified above.

In a similar manner, but replacing sultam D-(-)-2,10-camphor on sultam L-(+)-2,10-camphor, obtained the appropriate individual isomers of S-configuration.

The compounds of formula (HH) 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 manufactured by Aldrich company.

Usually the compounds of formula (Ka) get first condensing a compound of formula (HH) with Sultana L-(+)-2,10-camphor and receiving the compound of formula (N). Using NaHMDS for the formation of the anion within hours, the reaction is then stopped by the addition of tert. -butylbromide to obtain the corresponding ester of formula (Q). Then remove the camphor group in an alkaline medium, receiving individual stereoisomer of the compounds of formula (Ka), where the carbon is attached to the substituent R2is in the (R)-configuration.

Connection formula alkoxycarbonyl,

also are the individual stereoisomers of compounds of formula (K) and receive them in accordance with the following reaction scheme 5, where R2and R7chave the values specified above.

Compounds of formula (R) and (T) are commercially available or can be obtained in accordance with methods known to experts in this field of technology.

Usually the compounds of formula (Kb) receive, first treating the compound of formula (R) Isobutanol and a catalytic amount of concentrated H2SO4in methylene chloride, followed by distillation to obtain the compounds of formula (S). The compound of formula (S) are then subjected to interaction with the compound of the formula (T) in the presence of tert.-butoxide potassium to obtain the compounds of formula (U). By hydrolysis of the compounds of formula (U) in an acidic medium, preferably with triperoxonane acid at room temperature, obtain the connection formula (Kb), where R7cdenotes alkoxycarbonyl.

The compounds of formula (K), where R7adenotes a carboxy, can be obtained from compounds of formula (Kb), where R7cdenotes alkoxycarbonyl, by methods known to experts in this field of technology.

7adenotes alkyl, can be obtained by treating compounds of formula (K), where R7adenotes hydrogen, in an aprotic solvent, such as THF, in the presence of NaN(tetramethylsilane)2with haloalkanes, preferably by iodomethane, to obtain the compounds of formula (K), where R7adenotes alkyl.

D. Obtaining compounds of formula (Ig)

The compounds of formula (Ig) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-; R1denotes-CH2-R4where R4does

< / BR>
where R6denotes optionally substituted aryl, and the aryl group denotes an henol-2-yl, naphthas-1-yl, naphthas-2-yl, pyridyl or phenyl; R2denotes alkyl and R3denotes hydrogen.

The compounds of formula (Ig) can be obtained in accordance with the following reaction scheme 6, where p is 5, 6, 7 or 8; R2, R3and R6have the above meanings and R12aindicates mesyl or tosyl.

The compounds of formula (W) can be obtained in accordance with methods known to experts in the art or can be obtained in accordance with the method, operatsii with ways, well-known specialists in this field of technology.

Usually the compounds of formula (Ig) receive, first treating the compound of formula (W) formamide to obtain the compounds of formula (X). The compound of formula (X) is then treated with chloride Totila or mesila in an alkaline medium to obtain the compounds of formula (Y). The compound of formula (Y) are then subjected to interaction with the salt of the compounds of formula (Z) (preferably sodium salt, obtained by the interaction of the compounds of formula (Z) with sodium hydride to obtain a compound of formula (AA). The compound of formula (AA) are then subjected to hydrolysis in an alkaline medium to obtain a compound of formula (BB). The compound of formula (BB) are combined with the compound of the formula (J) in the standard peptides conditions, preferably 1,1'-carbonyl diimidazol, to obtain the compounds of formula (Ig).

That is, the formation of compounds of formula (Ih), (Ii) and (Ij)

Compounds of formula (Ih), (Ii) and (Ij) are the compounds of formula (Ib), formula (Ic) and formula (Id), respectively, as described above in section B, where the indole ring is fully saturated. Get them in accordance with the following reaction scheme 7, where R2denotes alkyl, cycloalkyl, cycloalkyl is, 7 or 8.

Typically, compounds of formula (Ih), (Ii) and (Ij) receive, restoring the first compound of the formula (Ib) under conditions of catalytic hydrogenation to produce the compounds of formula (Ih). The compound of formula (Ih) are then subjected to the interaction with O-benzylhydroxylamine in terms of standard peptide combination, to obtain the compounds of formula (Ii). After that, from the compounds of formula (Ii) remove the benzyl protective group under conditions of catalytic hydrogenation to obtain the compounds of formula (Ij).

J. Obtaining compounds of formula (Ik), (Il), (Im) and (In)

The compounds of formula (Ik) are compounds of formula (I) with allyl bond, where n is 2 or 3; m is 4; And a represents - NR11where R11denotes hydrogen or alkyl; R1denotes-CH2-R4where R4denotes tert-butoxycarbonyl; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (II) are compounds of formula (I) with allyl bond, where n is 2 or 3; m is 4; And a represents-NR11where R11denotes hydrogen or alkyl; R1denotes-CH2-R4where R4is hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (Im) are compounds of formula (I) with allyl bond, where n is 2 or 3; m is 4; And a represents-NR11where R11denotes hydrogen or alkyl; R1denotes-CH2-R4where R4denotes benzylaminocarbonyl; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (In) are compounds of formula (I), where n is 2 or 3; m is 4; And a represents-NR11where R11denotes hydrogen or alkyl; R1denotes-CH2-R4where R4denotes hydroxyaminobuteroyl; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy.

Compounds of formula (Ik), (Il), (Im) and (In) are obtained in accordance with reaction scheme 8 (see end of description), where n is 2 or 3; R2and R11have the values indicated above; R14denotes tert.-butyl; R7adenotes hydrogen; and BOC represents tert.-butoxycarbonyl.

The compounds of formula (K) is obtained by methods known to experts in the field of technology, and the interaction of the compounds of formula (F) with diaminoalkanes or monoalkylammonium diaminoalkanes under standard conditions of peptide combinations, for example HOBT and EDCI, in an inert solvent, such as DMF, to produce the compounds of formula (DD). The compound of formula (DD) are then subjected to interaction with TRANS-1,4-dichlorobut-2-Yong in an alkaline environment for the formation of compounds of formula (IT). Aminosidine group of compounds of formula (IT) are removed in the acid environment, preferably with triperoxonane acid to form the compounds of formula (FF).

The compound of formula (FF) then subjected to the combination with the compound of the formula (K) under standard conditions of peptide combinations, for example with HOBT and EDCI, for the formation of compounds of formula (Ik). The protective group of the compounds of formula (Ik) are removed in the acid environment, preferably with triperoxonane acid to form the compounds of formula (Il). The compound of formula (II) is then treated On-benzylhydroxylamine under standard conditions of peptide combination, to obtain the compounds of formula (Im). The protective group of the compounds of formula (Im) is removed under conditions of catalytic hydrogenation to obtain the compounds of formula (In).

H. Obtaining compounds of formula (Io), (Ip)

The compounds of formula (Io) are compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-, R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy.

The compounds of formula (Ip) are the compounds of formula (I), where n is 1, 2 or 3; m is 3 or 4; And a represents-CH2-, R1denotes-NH-CH(R9)-R10, R9denotes hydrogen, alkyl or aralkyl and R10represents carboxy; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy.

Compounds of formula (Io), (Ip) receive, in accordance with the following reaction scheme 9, where p is 5, 6, 7 or 8; R2, R3and R9have the above values.

The compounds of formula (JJ) is obtained by methods known to experts in the art or as described below in example 36.

Usually the compounds of formula (Il) and (Im) are obtained first by treating compound of formula (JJ) anhydride of triftoratsetata, and then by treatment with a compound of formula (KK) in an alkaline medium to produce the compounds of formula (LL). Then the compound of formula (LL) is subjected to hydrolysis in acid medium, preferably with triperoxonane acid, for obrazovatelnyh conditions the peptide combination for the formation of compounds of formula (Io). Then, the compound (Io) remove the protective group for the formation of compounds of formula (Ip).

In addition, all the compounds of formula (I), existing in the form of a free base may be converted into their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic acid. Salts of compounds of formula (I) can also be transformed into the form of a free base or another salt.

In General, compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), which are all compounds of formula (I), is obtained by:

1. interaction of the compounds of formula (K), where R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R7adenotes hydrogen or alkoxycarbonyl; and R14denotes tert.-butyl or benzyl; with the compound of the formula (J), where p is 5, 6, 7, or 8; and R3denotes hydrogen, halogen, alkyl or alkoxy; to obtain the compounds of formula (Ia), where p, R2, R3, R7aand R14have the meanings specified for compounds of formula (K) and (J);

2. treatment of compounds of formula (Ia), where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkane the compounds of formula (Ib), where p, R2, R3and R7ahave the meanings specified for compounds of formula (Ia);

3. treatment of compounds of formula (Ib), where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy; and R7adenotes hydrogen or alkoxycarbonyl; with O-benzylhydroxylamine to obtain the compounds of formula (Ic), where p, R2, R3and R7ahave the meanings specified for compounds of formula (Ib);

4. treatment of compounds of formula (Ic), where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy; and R7adenotes hydrogen or alkoxycarbonyl; to obtain the compounds of formula (Id), where p, R2, R3and R7ahave the meanings specified for compounds of formula (Ic);

5. interaction of the compounds of formula (M), where R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; with a compound of formula (J), where p is 5, 6, 7, or 8; and R3denotes hydrogen, to obtain the compounds of formula (Ie), where p, R2and R3have the meanings specified for compounds of formula (M) and (J);

6. treatment of compounds of formula (Ie), where p rawd; to obtain the compounds of formula (If), where p, R2, R3have the meanings specified for compounds of formula (Ie);

7. interaction of the compounds of formula (BB), where R2denotes alkyl; and R6denotes optionally substituted aryl, and the aryl group denotes an henol-2-yl, naphthas-1-yl, naphthas-2-yl and phenyl; with the compound of the formula (J), where p is 5, 6, 7, or 8; and R3denotes hydrogen, to obtain the compounds of formula (Ig), where p, R2, R3and R6have the meanings specified for compounds of formula (BB) and (J);

8. treatment of compounds of formula (Ib), where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy; to obtain the compounds of formula (Ih), where p, R2and R3have the meanings specified for compounds of formula (Ib);

9. treatment of compounds of formula (Ih), where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy; to obtain the compounds of formula (Ii), where p, R2and R3have the meanings specified for compounds of formula (Ih);

10. treatment of compounds of formula (Ii), where p is 5, 6, 7 or 8; R2putting the; to obtain the compounds of formula (Ij), where p, R2and R3have the meanings specified for compounds of the formula (Ii);

11. interaction of the compounds of formula (FF), where n is 2 or 3; R3denotes hydrogen, halogen, alkyl or alkoxy; and R11denotes hydrogen or alkyl; with a compound of formula (K), where R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R7adenotes hydrogen; and R14denotes tert. -butyl; to obtain the compounds of formula (Ik), where n, R2, R3, R7a, R11and R14have the meanings specified for compounds of formula (FF) and (K);

12. treatment of compounds of formula (Ik), where n is 2 or 3; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy; R7adenotes hydrogen; R11denotes hydrogen or alkyl and R14denotes tert.-butyl; to obtain the compounds of formula (Il), where n, R2, R3, R7aand R11have the meanings specified for compounds of formula (Ik);

13. treatment of compounds of formula (Il), where n is 2 or 3; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy; R7athe formula (Im), where n, R2, R3, R7aand R11have the meanings specified for compounds of formula (Il);

14. treatment of compounds of formula (Im), where n is 2 or 3; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R3denotes hydrogen, halogen, alkyl or alkoxy; R7adenotes hydrogen; R11denotes hydrogen or alkyl; to obtain the compounds of formula (In), where n, R2, R3, R7aand R11have the meanings specified for compounds of formula (GG);

15. interaction of the compounds of formula (MM), where R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; and R9denotes hydrogen, alkyl or aralkyl; with a compound of formula (J), where p is 5, 6, 7, or 8; and R3denotes hydrogen, halogen, alkyl or alkoxy, to obtain the compounds of formula (Io), where p, R2, R3and R9have the meanings specified for compounds of formula (MM) and (J); and

16. treatment of compounds of formula (Io), where p is 5, 6, 7 or 8; R2denotes alkyl, cycloalkyl, cycloalkenyl or aralkyl; R3denotes hydrogen, halogen, alkyl or alkoxy; and R9denotes hydrogen, alkyl or aralkyl; to obtain the compounds of formula (Ip), where p, R2, R3and R9have s to implement the present invention in practice, and do not limit the scope of the invention.

Example 1

The compound of formula (E)

A. 6-Cyano-1-hexanol (7,1 g, 55.8 mmole) was dissolved in 30 ml of acetic anhydride in an argon atmosphere. To this material was added dropwise to 5.3 ml (65,4 mmole) of pyridine and the mixture was left to mix for 2 hours. The contents of the flask were then poured into a chemical beaker containing 50 ml of ice water, and the material was stirred for 15 minutes. Then the mixture was transferred into a separating funnel with a volume of 250 ml and added a simple ether (100 ml). After shaking the ether phase was isolated and the aqueous phase was twice washed with a simple ether (CH ml). The combined ethereal phase was washed with brine, dried (MgSO4) and filtered. By evaporation (rotary evaporator and vacuum pump) received 6-cyano-1-acetoxylation (compound of formula (C)), which is directly used in the next stage.

B. 6-Cyano-1-acetoxylation (55.8 mmole) was dissolved in approximately 100 ml of acetic anhydride in a reaction vessel Parra (500 ml). This was added acetic acid (0.5 ml), and then the platinum oxide (100 mg). The vessel was placed in hydrogenator Parra and missed gaseous hydrogen at a pressure of 40 lb/in2(2.8 kg/cm3). The material was shaken for 12 h, the pressure of 40 lb/inch2) and was shaken for 24 hours. The material was filtered through celite and all volatiles were removed under reduced pressure (rotary evaporator). Target 1-acetoxy-7-acetaminophen was sufficiently pure for use in the next stage (the output of 11.8 g).

Century 1-Acetoxy-7-acetaminophen (11.8 g, 54,3 mmole) was dissolved in 20 ml of methanol in a round bottom flask with a volume of 200 ml of this was added 50 ml of 40% aqueous hydrochloric acid and the mixture was heated under reflux for 60 hours. All volatile components were removed under reduced pressure. Target 7-amino-1 - heptanol received in the form of crystalline cleaners containing hydrochloride salt, melting point 74-81oC, MS: 131 (MH+).

Example 2

The compound of formula (G)

A. N-methylmorpholine (2.2 ml, 19.7 mmole) was added dropwise at room temperature to cleaners containing hydrochloride salt of 7-amino-1-heptanol (3,3 g, 19.7 mmole) in 50 ml dry DMF in an argon atmosphere with stirring. After stirring for 5 minutes was added to the following mixture: N-tert.-butoxycarbonyl-L-tryptophan (5 g, 16,45 mmole), 1-hydroxybenzotriazole (2,52 g, 16,45 mmole) and hydrochloride EDCI (4,73 g, 24.7 mmole). The mixture was stirred for 2 hours and then DMF was removed under reduced pressure. Onicescu phase was isolated and washed successively with cold 2,5% HCl (100 ml), and then with brine (100 ml). An ethyl acetate phase was dried (MgSO4), filtered and concentrated, obtaining N-tert.-butoxycarbonyl-L - tryptophan-N'-(7-hydroxyethyl)amide.

IR (net): 3300, 2921, 1685, 1645, 1490, 1356, 1157 cm-1.

1H-NMR (80 MHz, CDCl3): 0,98-of 1.62 (m, 10H, -(CH2)5-), 1,45 (s, 9H, tert. -butyl), 2,86-of 3.32 (m, 4H, CH-CH2, HN-CH2), 3,68 (t, 2H, J=5.6 Hz, -CH2IT), 4,22-4,55 (m, 1H, CH), 5,12-5,32 (broad d, 1H, NH-CH), 5,65-5,9 (broad t, 1H, NH-CH2), 6,98-a 7.92 (m, 5H, ArH), 8,63 (broad s, indole NH).

B. a Solution of N-tert. -butoxycarbonyl-L-tryptophan-N'-(7 - hydroxyethyl)amide (8,2 g) in 150 ml of anhydrous pyridine was cooled to 0oC (ice bath). Para-toluensulfonate (4.7 g) was added to the solution in one portion and the cooled mixture was left to mix for 7 hours. The reaction was stopped by adding 50 ml of ice water and removing all volatile components under reduced pressure. The product N-tert.-butoxycarbonyl-L-tryptophan-N'-[7-(4'-methylphen-1 ylsulphonyl)heptyl]amide was isolated using column chromatography on silica gel using as solvent for elution of a mixture of 10-40% ethyl acetate/hexane. This material crystallized upon standing, MS: 572 (MH+).

C. In another Varian is) and 1-hydroxybenzotriazole H2On (2,52 g, 16,45 mmole) in dry DMF (50 ml) at room temperature in an argon atmosphere was added EDCI (4,73 g, 24,68 mmole). After stirring over night DMF was removed under high vacuum. The residue was distributed between ethyl acetate (150 ml) and 1N HCl (75 ml). The organic layer is then washed with 1N HCl (75 ml), saturated sodium bicarbonate solution (g ml) and finally with brine (50 ml). The organic layer was dried (MgSO4) and evaporated to dryness, obtaining 6,45 g (97%) of N-tert.-butoxycarbonyl-L-tryptophan - N'-(6-hydroxyhexyl)amide as a white foam, MS: 404,3 (M+N)+. The purity of the product was confirmed by analysis using high-performance liquid chromatography.

, Continuing the process, N-tert.-butoxycarbonyl-L - tryptophan-N'-(6-hydroxyhexyl)amide (5.5 g, 13,64 mmole) in 150 ml dry pyridine at 0oC in argon atmosphere was added to 3.9 g (20,46 mmol) para-toluensulfonate. The homogeneous solution was stirred at this temperature overnight. The reaction was stopped by adding 25 ml of water and the excess pyridine was removed under reduced pressure. The residue was dissolved in ethyl acetate (120 ml) and washed with 1N HCl (g ml), a saturated solution of NaHCO3(50 ml) and with brine (50 ml). The organic layer was dried (MgSO4) is the form of a pale yellow oil (5,77 g, 76%), MS: 558,3 (M+N)+.

D. To 5-hydroxytryptophan (3.5 g, supplied by the company Sigma) and triethylamine (5.6 ml) in water (25 ml) and tetrahydrofuran (50 ml) was added BOC-ON [2-(tert. -butoxycarbonyloxyimino)-2 - phenylacetonitrile] . After 2.5 hours, the tetrahydrofuran was removed, was added 10% Na2CO3(20 ml) and the mixture was separated using a simple ether (50 ml). The aqueous fraction then was extracted with simple ether (20 ml) and then acidified with cold 10% HCl in a two-phase system containing ethyl acetate (100 ml). An ethyl acetate fraction was separated and washed with water (30 ml), with brine, dried over anhydrous MgSO4and concentrated to obtain a syrup. The syrup was subjected to interaction with 6-amino-1-hexanol manner similar to that described above in example 1B to obtain N-tert. - butoxycarbonyl-L-(5-hydroxy)tryptophan-N'-(6 - hydroxyhexyl)amide. Half of this product was extracted with 40 ml of DMF and was treated with K2CO3(5 g) and iodomethane (1.2 g) at room temperature over night. The reaction mixture is then distributed between water (50 ml) and ethyl acetate (80 ml), the organic fraction was then washed with water (2x20 ml), with brine, dried over anhydrous MgSO4and concentrated to obtain oil. Then Provotorov on silica gel;1H-NMR: CDCl3): 0,9-1,6 (m, CH2, 8H); 1,45 (s, N); 2,7-3,3 (m, 5H); 3.6 (t, 2H); 13,85 (s, 3H); of 4.35 (m, 1H); 5,3 (broad d, 1H); to 5.85 (broad t, 1H); 6.75 in to 8.3 (m, 4H); 8,73 (broad s, 1H).

E. in a Similar manner there were obtained the following compounds:

N-tert. -butoxycarbonyl-L-(5-ethoxy)tryptophan-N'-(6 - hydroxyhexyl)amide;

N-tert. -butoxycarbonyl-L-(5-propoxy)tryptophan-N'-(6 - hydroxyhexyl)amide;

N-tert. -butoxycarbonyl-L-(5-ethyl) - tryptophan-N'-(6 - hydroxyhexyl)amide; and

N-tert.-butoxycarbonyl-L-(4-methyl)tryptophan-N'-(6 - hydroxyhexyl)amide.

Example 3

The compounds of formula (H)

A. N-tert.-butoxycarbonyl-L-tryptophan-N'-[7-(4'-methylphen - 1 ylsulphonyl)heptyl] amide (of 6.78 g) portions was added to a solution of NaH (60% in oil, 1.9 g) in 1.1 liter of anhydrous tetrahydrofuran and left to mix overnight. The reaction mixture was concentrated and extracted with water (150 ml) and CH2Cl2(150 ml). The aqueous phase is slightly acidified with 2.5% HCl (pH 3-4) and the organic phase was isolated (g ml) and washed successively with cold 2,5% HCl (150 ml), 5% NaHCO3(150 ml) and with brine (150 ml). The organic phase was dried (MgSO4), filtered and concentrated, obtaining yellow-green semi-solid material. By cleaning using chromatogra), 14(19),15,17-tetraen with a melting point 208-209oC, MS: 400 (M+N)+.

B. In another embodiment, to N-tert.-butoxycarbonyl-L-tryptophan-N'- [6-(4'-methylphen-1 ylsulphonyl)hexyl] amide (5.0 g, 8,97 mmol) in one liter of dry THF at 0oC in argon atmosphere was added 4 equivalents of 60% NaH (1.44 g, 36 mmol) in small portions over 10 minutes. Then the mixture was stirred over night at room temperature. The yellow mixture was evaporated to ~ 200 ml) and then added 1 liter of distilled water. Then the mixture was acidified using 1N HCl under vigorous stirring. The yellow precipitate was collected by filtration and dried over P2ABOUT5in high vacuum over night. The dry crude product (8 g) was chromatographically on silica gel 60, elwira 30% ethyl acetate in CH2Cl2to obtain 1.2 g (35%) (10S)-10-N'- (benzyloxycarbonyl)amino-9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraene in the form of a white powder, MS: 386 (M+N)+, tPL222-223oC.

C. In another embodiment, to a solution of N-tert.-butoxycarbonyl-L - tryptophan-N'-[6-(4'-methylphen-1 ylsulphonyl)hexyl]amide (1,21 g, 2.17 mmol) in 45 ml of chemically pure methylene chloride was added 15 ml of 40% aqueous KOH and 0.3 equivalent of chloride Beenie night. The organic layer was separated and the aqueous layer was extracted with 25 ml of methylene chloride. The combined organic layer was washed with water (25 ml), dried (MgSO4) and evaporated to dryness. The residue was stirred in 10% ether in petroleum ether at 0oC for 15 minutes and filtered to obtain 792 mg (93%) (10S)-10-N'- (benzyloxycarbonyl)amino-9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18),14,16- tetraene in the form of a white powder.

Example 4

The compounds of formula (J)

A. (11S)-10-N'-(benzyloxycarbonyl)amino-10-oxo-1,9 - diazatricyclo[11.6.1.014,19]eicosa-13(20),14(19),15,17-tetraen (850 mg) was dissolved in 5 ml 10% triperoxonane acid in methylene chloride and was stirred for 1 hour. Volatile components were removed under reduced pressure. The residue was extracted with CH2Cl2(40 ml) and 1H NaOH (40 ml) and placed in a separating funnel. The organic phase was isolated and washed with brine, dried (MgSO4), filtered and concentrated to obtain 654 mg (11S)-10-amino-10-oxo-1,9-diazatricyclo[11.6.1.014,19]eicosa- 13(20),14(19),15,17-tetraen.

B. In another embodiment, (10S)-10-N'-(benzyloxycarbonyl)amino-9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18),14,16-tetraen (0.5 mmole, 193 mg) was stirred in 20% TFA is low pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with 1H HCl (25 ml), brine solution (10 ml) and dried (MgSO4). By evaporation to dryness received 140 mg (Nr.) (10S)-10-amino-9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18),14,16- tetraene in the form of a white foam, tPL157-160oC, MS: OF 286.2 (M+N)+.

Example 5

The compounds of formula (Ia)

A. To a stirred solution containing (11S)-10-amino-10 - oxo-1,9-diazatricyclo[11.6.1.014,19]eicosa-13(20),14(19),15,17- tetraen (654 mg) and racemic 4-methyl-2-(tert. - butoxycarbonylmethyl)pentane acid (800 mg) in 30 ml of anhydrous DMF, was added in an argon atmosphere 1-hydroxybenzotriazol (360 mg), and then EDCI (940 mg). The mixture was left to mix overnight and then DMF was removed under reduced pressure. The residue was extracted with a mixture containing CH2Cl2(100 ml) and 1.5% cold HCl (100 ml), and was placed in a separating funnel. The organic phase was isolated and washed sequentially with 1.5% HCl (100 ml), 5% NaHCO3(100 ml) and with brine (100 ml). Phase CH2Cl2dried (MgSO4), filtered and concentrated, receiving semi-crystalline product: tert.-butyl ether (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo [11.6.1.014,19]eicosa-13 (20),14 (19),15,17-tetraen-11 - ilkar is and the silica gel with ethyl acetate/hexane as solvent for elution. The less polar stereoisomer had a melting point 154-157oC []2D4= -43,9owith=23,8 mg/2 ml CHCl3whereas the more polar stereoisomer had a melting point 168-171oC []2D4=-19,1owith = up 11,86 mg/2 ml CHCl3.

B. In another embodiment, the solution containing (2R)-4-methyl-2- (tert.-butoxycarbonylmethyl)pentane acid, obtained as described above (2,39 g, 10.4 mmol), HOBT2About (2.5 g, 1 EQ.), N-methylmorpholine (2.3 ml, 2 EQ. and (10S)-10-amino-9-oxo - 1,8-diazatricyclo[10.6.1.0of 13.18]endeca-12(19), 13(18),14,16- tetraen (2,96 g, 1 EQ.) in dry DMF (200 ml) in an argon atmosphere was added EDCI (3,96 g, 2.0 EQ.). The resulting mixture was stirred overnight, then the next morning DMF was removed at 35oC in high vacuum. The residue was distributed between CH2Cl2(150 ml)/water (75 ml), then the organic layer was washed with 0.5 N HCl (g ml), saturated NaHCO3(G ml) and finally with brine (CH ml). After drying of the layer of CH2Cl2over Na2SO4it was filtered and evaporated to dryness. By purification using column chromatography (petroleum ether or a mixture of 30% ethyl acetate/petroleum ether) was obtained tert. -butyl ether (3R,10S)-5-methyl-3-(9-ASS="ptx2">

C. in a Similar manner there were obtained the following compounds of formula (Ia):

tert. -butyl ether (3R, 10S)-4-phenyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)butane acid, MS: 532 (M+N)+;

tert. -butyl ether (3R, 10S)-4-cyclohexyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18), 14,16- tetraen-10-ylcarbonyl)butane acid, MS: 538 (M+N)+;

tert. -butyl ether (3R, 10S)-6-phenyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13 (18), 14,16-tetraen-10 - ylcarbonyl)hexanoic acid, MS: 560 (M+N)+;

tert.-butyl ether (3R,10S)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid, MS: 484 (M+N)+;

benzyl ether of (3R,10S)-2-methoxycarbonyl-5-methyl-3-(9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18),14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS: 590 (M+N)+.

G. In another embodiment, to (2R)-4-methyl-2-(tert. - butoxycarbonylmethyl)pentanol acid (1 g, 4,34 mmole) in dry THF (100 ml) at -78oC in argon atmosphere was added dropwise NaN(tetramethylsilane was)2(1.0 M in THF, 10.9 ml, 2.5 EQ.) and the mixture was stirred for 1 hour. Added logmean (0.33 ml, 1.2 EQ.) and abreaction was stopped by adding water (100 ml). After extraction with ether (CH ml) the aqueous layer was combined with ethyl acetate and with stirring was added 4N HCl to pH 2. Also added to saturated sodium chloride and the aqueous layer was extracted with ethyl acetate (CH ml). The combined organic extracts were dried over Na2SO4was filtered and concentrated, obtaining (2R)-4-methyl-2- [(methyl)(tert.-butoxycarbonyl)methyl]pentane acid as a dark brown oil (1 g). To this crude reaction product (500 mg) and (10S)-10-amino-9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraene (399 mg, 0.7 EQ.) in dry DMF at 0oC in argon atmosphere was added HOBT2Of (1.1 EQ., 234 mg), and then EDCI (663 mg, 2.5 EQ). The resulting mixture was stirred overnight at a temperature of from 0oC to room. A large part of the DMF was removed by vacuum distillation at 65oC. Then the residue was distributed between CH2Cl2(150 ml)/water. After washing with 0.5 N HCl (g ml), saturated NaHCO3(G ml) and saline (CH ml) the organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified using instant column chromatography on silica, elwira 30% ethyl acetate in petroleum ether, the floor is-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19), 13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid and tert.-butyl ether (3R,10S)-5 - methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid. Further purification involves the selection of three compounds: tert. -butyl ether (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid (13 mg) as a white solid; 1:1-mixture of stereoisomers (5 mg) as white solids and less polar stereoisomer of tert. -butyl ether (3R,10S)-2-methyl-5 - methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca- 12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid (15 mg); 300 MHz,1H-NMR in CDCl3(less polar diastereoisomer): (-0,2)-(-0,05) (m, 1H); of 0.5-0.7 (m, 1H); 0,9 (dd, J= 4 Hz, J=6,7 Hz, 6N); to 1.15 (d, J=8,4 Hz, 3H); 1.18 to 1,4 (m, 3H); of 1.41 (s, N); 1,45-of 1.73 (m, 4H); about 1.75 to 1.8 (m, 2H); at 2.5-2.7 (m, 3H); 2,89 (dd, J=10,9 Hz, J= 15 Hz, 1H); 3,34 to 3.5 (m, 2H); 3.95 to a 4.1 (m, 1H); 4.25 in-4,4 (m, 1H); 4.72 in-4,82 (m, 1H); 5,22-to 5.3 (m, 1H); of 6.52 (d, J=7.5 Hz, 1H); 6,91 (s, 1H); 7,13 (dd, J= 6,7 Hz, J=8,4 Hz, 1H); 7,22 (dd, J=5 Hz, J=7,1 Hz, 1H); 7,34 (d, J= 8,4 Hz, 1H); to 7.84 (d,J=8,4 Hz, 1H).

Example 6

The compounds of formula (Ib)

A. In the less polar stereoisomer tert.-butyl ether (11S)- 5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19] acai acid in methylene chloride thus, to cover it, and left to mix. After 2.5 hours, thin layer chromatography showed that the reaction was completed. All volatile components were removed under reduced pressure. The residue was extracted with CH2Cl2(40 ml) was placed in a separating funnel, and gradually washed with 0.5% HCl (40 ml) and with brine (40 ml). The organic phase was dried (MgSO4), filtered and concentrated to obtain the less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9 - diazatricyclo[11.6.1.014,19]eicosa-13(20),14(19),15,17-tetraen-11 - ylcarbonyl)hexanoic acid.

B. in a Similar way the more polar stereoisomer of tert.- butyl ether (11S)-5-methyl-3-(10-oxo-1,9 - diazatricyclo[11.6.1.014,19] eicosa-13(20), 14(19), 15,17-tetraen-11 - ylcarbonyl)hexanoic acid was subjected to hydrolysis, getting more polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo [11.6.1.014,19] eicosa-13(20), 14(19), 15,17-tetraen-11 - ylcarbonyl)hexanoic acid.

C. In another embodiment, tert.-butyl ether (3R,10S)-5-methyl-3- (9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18),14,16-tetraen-10-ylcarbonyl)hexanoic acid (3,24 g, 6.5 mmole) was extracted with 95% TFA (aqueous) (30 ml) at 0oC, then was stirred for 20 minutes, removed, l is the Etat (250 ml) and washed with water (I ml). The organic layer was dried over Na2SO4, was filtered and was evaporated to dryness, obtaining individual stereoisomer (3R, 10S)-5-methyl-3-(9-oxo - 1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanoic acid as a white powder, 2.83 g (yield: 98.4 per cent); MS: 442 (M+N)+(connection 1).

Was a Similar manner, but replacing tert.-butyl ether (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid to the corresponding compound of formula (Ia), were obtained the following compounds of formula (Ib):

(3R, 10S)-4-phenyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19), 13(18), 14,16-tetraen-10 - ylcarbonyl)butane acid, MS: 474(M-H)-;

(3R, 10S)-4-cyclohexyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10 - ylcarbonyl)butane acid, MS: 482 (M+N)+;

(3R, 10S)-3-cyclohexyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10 - ylcarbonyl)propionic acid, MS: 468 (M+H)+;

(3R, 10S)-6-phenyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19), 13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid, MS: 502(M-H)-;

(3R, 10S)-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19 what KLO [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid, MS: 457 (M+N)+;

(3R, 10S)-2-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid, MS: 458 (M+N)+;

(3R, 9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)hexanoic acid.

D. (3R, 10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19), 13(18), 14,16-tetraen-10 - ylcarbonyl)hexanoic acid (183 g) was made in 40 ml of dry CH2Cl2and at 0oC was added ethanol (0.5 ml, 5 EQ.), and then N, N-dimethylaminopyridine (0.1 EQ., 5 mg), and finally, EDCI (209 mg, 5 EQ. ). The resulting solution was stirred overnight at a temperature in the range of 0oC to room. Additionally added CH2Cl2(100 ml) and the mixture was washed with 0.5 N HCl (g ml), saturated NaHCO3(G ml) and finally with brine (CH ml). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. By recrystallization from ethyl acetate and petroleum ether was obtained ethyl ester (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid as a white Omer tert.- butyl ether (3R,10S)-2-methyl-5-methyl-3- (9-oxo-1,8 - diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanoic acid obtained above in example 5G (15 mg) was added CH2Cl2(2.4 ml) and TFA (0.6 ml) and the resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure at 35oC. Then was added ethyl acetate and the solution washed with water (3x10 ml). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. By recrystallization from ethyl acetate/petroleum ether was obtained (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanoic acid as a white solid (7 mg), MS: 456,3 (M+N)+.

J. a Similar manner a mixture of 1:1 stereoisomers tert.- butyl ether (3R, 10S)-2-methyl-5-methyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanoic acid (obtained above in example 5G) (5 mg) is hydrolyzed, receiving 3 mg of a white solid;

300 MHz,1H-NMR in CDCl3: (-0,5)-(-0,3) (m, 1H); 0.6 to 0.8 (m, 1H); from 0.8 to 1.05 (m, 6N); of 1.05 to 1.22 (m, 2H); to 1.35 (3H, dd, J=9 Hz); 1,4-1,7 (m, 3H); 1.7 to 1,95 (m, 3H); 2,3-2,48 (m, 1H); 2,54-by 2.73 (m, 1H); 2.8 to 3.0 (m, 2H); 3,38-3,5 (m, 1H); 3,52-and 3.72 (m, 1H); 3,8-3,98 (m, 1H); 4,34 is 4.45 (m, 1H); 4,7-4,84 (m, 1H); 5,0-5,08 (m, 1H); to 6.8 (d, 1H); 7,15-arbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid, was extracted with ethanol (35 ml, required some heating) was added ammonium formate (1642 mg, 3 EQ.), and then added 10% Pd on activated charcoal (100 mg). After stirring in an argon atmosphere at room temperature for 3 hours the reaction was finished. The mixture was filtered under vacuum through a layer of celite 1 cm thick, then was concentrated, added MeOH and the resulting product was filtered through a cotton plug. After concentration the residue was added CH2Cl2and the resulting product was intensively stirred and then filtered. The filtrate was concentrated and recrystallized from ethyl acetate/petroleum ether, receiving (3R,10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18]endeca-12(19),13(18),14,16- tetraen-10-ylcarbonyl)hexanoic acid as a white solid (yield: 140 mg), MS: 500,3 (M+N)+.

I. (3R, 10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanoic acid was extracted with ethanol (25 ml) and then added dropwise 1H LiOH (0.3 ml, 3 EQ.). The obtained homogeneous solution was stirred at whom the eat was added with stirring, water (5 ml) and ethyl acetate (30 ml), added 4N HCl to obtain a pH of 2. An ethyl acetate layer was further washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Was purified by high performance liquid chromatography with reversed phase, receiving 47 mg of (3R,10S)-2-carboxy-5-methyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18]endeca-12(19),13(18),14,16- tetraen-10-ylcarbonyl)hexanoic acid as a white solid, MS: 484,5 (M-H)-.

Example 7

The compounds of formula (Ic)

A. a Solution of the less polar stereoisomer of (11S)-5-methyl-3-(10 - oxo-1,9-diazatricyclo[11.6.1.014,19] eicosa-13(20), 14(19),15,17- tetraen-11-ylcarbonyl)hexanoic acid (210 mg) and monohydrate 5-hydroxybenzotriazole (109 mg) in anhydrous DMF (20 ml) was cooled in an argon atmosphere to 0oC (ice bath). To this mixture was added EDCI (282 mg) and stirring was continued for 0.5 hour. Then to the solution was added O-benzylhydroxylamine (0,27 ml) and the reaction mixture is left to warm to room temperature over night. All volatile components were removed under reduced pressure. The residue was extracted with CH2Cl2(100 ml) and 20% HCl (100 ml) and placed in a separating funnel. The organic phase was isolated and the aqueous phase was washed (h ml) CH2Cl214,19]eicosa-13(20),14(19),15,17-tetraen-11 - ylcarbonyl)hexanamide in the form of a crystalline substance. The product was further purified by column chromatography on silica gel, and then by crystallization from a hot mixture of ethyl acetate/CH2Cl2got more polar stereoisomer of the compound, having a melting point 232-233oC, and the less polar stereoisomer of the compound, having a melting point 251-253oC.

B. In another embodiment, the solution containing (3R,10S)-5-methyl - 3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18),14,16-tetraen-10-ylcarbonyl)hexanoic acid (2.5 g, 5.82 mmol), HOBT2On (0,89 g, 1 EQ.) and About benzylhydroxylamine (2.2 ml, 3 EQ.) in 200 ml of DMF, at 0oC was added EDCI (2,77 g, 2.5 EQ.). The resulting mixture then was stirred overnight. DMF was removed by vacuum distillation at 65oC. To the residue was then added methanol (14 ml), then ether (140 ml). At 0oC and stirring was added 0.5 N HCl (140 ml), and then petroleum ether (140 ml). The mixture was stirred at 0oC for 15 minutes, then the white solid was filtered under vacuum and n is the Aquum (P2ABOUT5within 3 hours was obtained (3R,10S)-N-benzyloxy-5 - methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18),14,16-tetraen-10-ylcarbonyl)hexanamide in the form of a white solid (2.7 g, 84,9%).

C. in a Similar manner, but replacing (3R,10S)-5-methyl-3-(9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18),14,16-tetraen-10-ylcarbonyl)hexanoic acid on a suitable substituted compound of formula (Ib), were obtained the following compounds of formula (Ic):

(3R, 105)-N-benzyloxy-2-methoxycarbonyl-5-methyl-3-(9-oxo - 1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanamide, MS: 605,3 (M+N)+;

(3R,10S)-N-benzyloxy-6-phenyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanamide, MS: 609 (M+N)+;

(3R, 10S)-N-benzyloxy-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanamide, MS: 533 (M+N)+.

Example 8

Obtaining compounds of formula (Id)

A. To a solution of the more polar stereoisomer of (11S)-N - benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19] eicosa-13(20), 14(19), 15,17-tetraen-11-ylcarbonyl)hexanamide (90 mg) in a mixture of ethanol/tetrahydrofuran (350 ml; 2:1) was added 10% Pallady the second stream of gaseous hydrogen. After 3 hours, thin layer chromatography (10% CH3OH/CH2Cl2) showed that the reaction is complete. The material was filtered through a layer of celite (3 times) and concentrated under reduced pressure until almost dry residue. Added methylene chloride (15 ml) and the material was again concentrated under reduced pressure until almost dry residue and then repeated the procedure again. To the residue was added 3-4 drops of methanol, after this was added methylene chloride (15 ml). The material was stirred with cooling (ice bath) was added a simple ether (5 ml) and then hexane (2 ml). Slowly the resulting crystalline material was collected by filtration, receiving 50 mg of the more polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9 - diazatricyclo[11.6.1.014,19] eicosa-13(20), 14(19),15,17-tetraen-11 - ylcarbonyl)hexanamide with a melting point 197-201oC []2D3= -85,1o, (3.5 mg/1,0 l DMSO) (compound 2).

B. in a Similar manner, but replacing the more polar stereoisomer of (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9 - diazatricyclo[11.6.1.014,19] eicosa-13(20), 14(19),15,17-tetraen - 11-ylcarbonyl)hexanamide less polar, was obtained the less polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9 - diazatricyclo[11.6.1.014
3= -38,5o, (4,7 mg/1.0 ml CH3IT).

C. In another embodiment, (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo - 1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-ylcarbonyl)hexanamide (1.0 g, to 1.83 mmole) were extracted with a solution of 20% THF in ethanol (500 ml) and then portions was added Pd on activated charcoal (200 mg). The resulting suspension was stirred, passing through the solution slightly bubbling fluidised bed its gaseous H2. After 4 hours the reaction mixture was filtered under vacuum through a layer of celite (1.5 cm) and the filtrate was concentrated and then extracted with methanol (30 ml) and filtered through a cotton plug. By recrystallization from methanol/ethyl acetate/simple ether/petroleum ether was obtained (3R,10S)-N - hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanamide (768 mg, 92%), MS: 455 (M-H)+.

Was a Similar manner, but replacing (3R,10S)-N-benzyloxy-5 - methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18]endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanamide on the corresponding connection of the formula (Ic), were obtained the following compounds of formula (Id):

(3R, 10S)-N-hydroxy-2-methoxycarbonyl-5-methyl-3-(9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18co-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10 - ylcarbonyl)hexanamide, MS: 517(M-H)-;

(3R, 10S)-N-hydroxy-2-aminocarbonyl-5-methyl-3-(9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18), 14,16-tetraen-10-ylcarbonyl)hexanamide, MS: 483 (MH)+-H2O;

(3R, 10S)-N-hydroxy-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanamide, MS: 443(MH)+;

(3R,9S)-N-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17]octadeca-11 (18),12(17),13,15-tetraen-9-ylcarbonyl) hexanamide.

Example 9

The compounds of formula (Ie)

A. To a solution containing 4-methyl-2-acetylcyclopentanone acid (612 mg, 3 mmole), (10S)-10-amino-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen (427 mg, 1.5 mmole) and HOBT2Oh, (230 mg, 1.5 mmole) in dry DMF (30 ml) in an argon atmosphere at room temperature was added EDCI (863 mg, 4.5 mmole) in one portion. After stirring over night DMF was removed at 30oC in high vacuum, obtaining a yellowish semi-solid substance. It was dissolved in ethyl acetate (50 ml), washed with 1N HCl (30 ml), 5% solution of NaHCO3(30 ml) and finally with brine (30 ml). The organic layer was dried (MgSO4) and was evaporated to dryness. The resulting light-W-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10 - yl)pentahalide in the form of mixtures of the stereoisomers of 1:1. A mixture of the stereoisomers were separated using fast column chromatography (LPS-2), was suirable 20% ethyl acetate in petroleum ether, receiving less polar stereoisomer with a melting point of 226oC and the more polar stereoisomer with a melting point 220oC.

Example 10

The compounds of formula (If)

A. To a solution of the less polar stereoisomer of (10S)- 2-acetyltributyl-4-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-yl)pentanolide (50 mg, 0,106 mmole) in 10 ml of methanol at 0oC in argon atmosphere was added 0.5 ml of concentrated NH4OH. The reaction mixture was stirred at a temperature of from 0oC (ice bath was removed after addition of NH4OH) to room and then kept at room temperature for 1 hour. The excess methanol was removed under reduced pressure, obtaining a white solid residue. The residue was distributed between ethyl acetate (30 ml) and 0.1 N HCl (15 ml). The organic layer was washed with brine (15 ml), dried (MgSO4) and was evaporated to dryness. The solid residue was stirred in a mixture of 50% simple ether/petroleum ether and filtered, giving you better on etrain-10-yl)pentahalide in the form of a white powder, 41 mg (90%), melting point 224oC (compound 3).

Example 11

The compounds of formula (HH)

A. To 4-methylpentanoic acid (25 g, 0,215 mmole) in a water bath with a temperature of 25oC was slowly added thionyl chloride (20.4 ml, 1.3 g). The mixture is then kept at 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) with a boiling point 143oC.

B. in a Similar manner, but replacing 4-methylpentanol acid 5-phenylpentane acid (5 g), was obtained 5-phenylbutanoate (4.4 g) as a colourless liquid, boiling point 91-93oC.

Example 12

The compounds of formula (N)

A. To a suspension of 60% NaH (836 mg, 1.5 EQ.) in toluene (200 ml) at room temperature in an argon atmosphere was added in portions to sultam L-(+)-2,10-camphor (3.0 g, 3.9 mmole). The mixture was intensively stirred at room temperature for 1 hour. Then to a solution of caution was added dropwise 4-methylpentanoate at 0oC. After stirring the reaction mixture at room temperature for 3 hours the reaction was stopped by mixing with 10 ml of water and domla) and finally, the saline solution (g ml). The organic layer was dried over MgSO4, filtered and evaporated to dryness. By purification using column chromatography (mixture of 1: 6 ethyl acetate/petroleum ether as the solvent for elution) received sultam N-4-methylpentanol-L-(+)-2,10-camphor (3,39 g, 78%).

B. in a Similar manner, but replacing 4-methylpentanoate the corresponding chloride, were obtained the following compounds of formula (N):

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 (O)

A. To a solution of sultam N-4-methylpentanol-L-(+)-2,10-camphor (3,39 g, 10.8 mmole) in 75 ml of dry THF at -78oC in argon atmosphere was added dropwise over about 5 min NaN(tetramethylsilane was)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 tert.-butylbromide (5,2 ml, 3 EQ. ), and then in one portion was added 400 mg of iodide, Tetra-n - butylamine. The resulting solution was kept at -78oC in argon atmosphere overnight. The next utrennie ether layers were washed with brine, then was dried over Na2SO4, filtered and concentrated. By purification using column chromatography (with a ratio of ethyl acetate/petroleum ether 5:95 to 10:90 as eluent) received sultam N-(4-methyl-2-tert.- butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor (4 g, 86,5%).

B. in a Similar manner, but replacing sultam N-4-methylpentanol-L-(+)-2,10-camphor corresponding compound of formula (N), were obtained the following compounds of formula (Q):

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 (M+N)+;

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

Example 14

The compounds of formula (Ka)

A. 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 equiv.) then 30% H2ABOUT2(11.5 ml). Then the ice bath was removed and the resulting emulsion was stirred for 3 hours until, until it became transparent. A large part of the THF was removed under reduced Yes the add NaCl aqueous layer was again extracted with CH2Cl2(G ml). CH2Cl2was removed under reduced pressure at 35oC and then the residue was extracted with ethyl acetate (150 ml). This solution then was extracted with 5% K2CO3(G ml) and the combined extracts were washed with simple ether (50 ml). Then CH2Cl2added to the water layer, and when mixed with NaCl 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, yield quantitative).

B. in a Similar manner, but replacing sultam N-(4-methyl-2 - tert.-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor corresponding compound of formula (Q), obtained the following compounds of formula (Ka):

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

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

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

C. (2R)-3-phenyl-2-tert. -butoxycarbonylmethylene acid (55 mg) was extracted with glacial acetic acid (20 ml) and added PtO2(25 mg) in acetic who under the pressure of 100 lb/in2(7,03 kg/cm2). After stirring for 3 days the mixture was filtered under vacuum through a layer of celite thickness of 1 see the Filtrate is then concentrated, receiving (2R)-3-cyclohexyl-2 - tert.-butoxycarbonylmethylene acid (56 mg) as a yellow oil, MS: 269 (M-H)-.

Example 15

The compounds of formula (R)

To a solution of D-leucine (50 g, 0,381 mol) in 570 ml of 3H HBr (water.) at 0oC was added sodium nitrite (42 g, 1.6 EQ.) portions over 1 hour 15 minutes. Next, the reaction mixture was stirred for 3 hours at 0oC and then was extracted with simple ether (1000 ml). After washing the ether layer with water (2x500 stretch-forming press ml) was dried over MgSO4and concentrated. Red syrup is then evaporated with chloroform (CH ml) to remove the paint and then was aspirated receiving (2R)-2-bromo-4-methylpentanol acid in the form of a colourless oil with a constant weight 71,3,

Example 16

The compounds of formula (S)

In dichloromethane (80 ml) are condensed isobutane to double volume (-50oC CHCl3/dry ice). To this solution was added (2R)-2-bromo-4-methylpentanol acid (28 g, 143,6 mmole) and maintaining the temperature between -40oand -50oC, was added dropwise Connie 20 hours. Then the solution was concentrated before adding additional methylene chloride (300 ml), then successively washed with saturated NaHCO3(G ml) and then water (I ml). After drying over Na2SO4the organic layer was filtered and concentrated, obtaining a yellow oil. The material was distilled, receiving 23 g of tert.-butyl ether (2R)-2-bromo-4-methylpentanoic acid in the form of a colorless transparent oil.

Example 17

The compounds of formula (U)

To benzylmethylamine (2,13 ml, 1 EQ.) and tert.-the piperonyl potassium (1,36 g, 1 EQ. ) in dry DMF (100 ml) at 0oC was added dropwise within 1 hour of tert. -butyl ester (2R)-2-bromo-4 - methylpentanoic acid (2,89 g, 11.5 mmole) in 50 ml of DMF. The resulting solution was then stirred at 0oC for 3 days. Then the reaction mixture was distributed between the simple ether (150 ml) and saturated ammonium chloride (80 ml). The resulting mixture was filtered under vacuum through celite and separated the two phases. Then the aqueous layer was additionally extracted with simple ether (CH ml) and the combined ethereal extracts were washed with water (I ml). After drying over MgSO4the organic layer was filtered and evaporated to dryness. By cleaning with the help of instant Colo is -2[(1-methoxycarbonyl-1 - benzyloxycarbonyl)methyl]-4-methylpentanoic acid (2.55 g) as a clear colorless oil, MS: 322 (M-acetone)+.

Example 18

The compounds of formula (Kb)

Tert. -butyl ester (2R)-2[(1-methoxycarbonyl-1 - benzyloxycarbonyl)methyl]-4-methylpentanoic acid were placed in 5 ml of 80% TFA (water.) at room temperature and was stirred for 1.5 hours, monitoring by thin layer chromatography. The reaction was completed by only 30%, so I added an additional amount of TFA (10 ml). After 0.5 hours the reaction was completed. TFA was removed in high vacuum at 45oC and the residue was extracted with ethyl acetate and washed with water (5x30 ml). After drying over Na2SO4the ethyl acetate layer was filtered, concentrated and pumped out by receiving (2R)-2[(1-methoxycarbonyl-1 - benzyloxycarbonyl)methyl]-4-methylpentanol acid as a solid (1.68 g), MS: 322 (M+).

Example 19

The compounds of formula (W)

Crystal phosphinic acid (8,4 g of 0.13 mol) was stirred in pure triethyl-ortho-formate (22 ml of 0.20 mmole) for 90 minutes at room temperature. Then this mixture was injected through the cannula into the mixed solution containing utilitarianist (8 g, being 0.036 mol) and tetramethylguanidine (4,5 ml, being 0.036 mol), which was cooled to 0oC for 10 minutes. Ice bath acromiale 1N HCl (100 ml), water (ml) and with brine (100 ml) and dried over magnesium sulfate. By evaporation under reduced pressure received 8,15 g of ethyl ester of 2-(ethoxypropionate)- 4-methylpentanoic acid in the form of oil is pale-yellow, MS: 349 (M-H2O)+.

Example 20

The compounds of formula (X)

The crude ethyl ester of 2-(ethoxypropionate)-4 - methylpentanoic acid (26 g) was dissolved in 600 ml THF/CH2Cl2(50/50) and cooled to 0oC. Then the solution was added diisopropylethylamine (32 ml) and 90.8 ml of bis(trimethylsilyl)ndimethylacetamide and the resulting mixture was stirred for 20 minutes before adding para-formaldehyde (5.5 g). The solution was brought to room temperature and after heating to 37oC kept at this temperature 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, filtered and evaporated, receiving 19.3 g of ethyl ester of 2-[(ethoxy)(hydroxymethyl)phosphonomethyl] -4 - methylpentanoic acid in the form of a yellowish oil, MS: 281 (MH+).

Example 21

The compounds of formula (Y)

A. Ethyl ester 2-[(ethoxy)(HYDR is SUP>oC (with duplication). Methanesulfonamide (1.5 ml and triethylamine (3.0 ml) was added dropwise to the solution. After 15 minutes the bath was removed and the reaction mixture was left 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, filtered and evaporated, receiving 12.8 g (combined output) ethyl ester 2-[(ethoxy) (methanesulfonylaminoethyl)phosphonomethyl]-4-methylpentanoic acid.

B. in a Similar manner, but replacing methanesulfonanilide on pair-toluensulfonate received ethyl ester 2-[(ethoxy) (pair-toluensulfonate) phosphonomethyl] -4-methylpentanoic acid.

Example 22

The compounds of formula (AA)

Sodium hydride (1.52 g, (60%) and 6 g of 2-hinokitiol were mixed 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 h Then the mixture was cooled to 0oC and the cannula was added ethyl ester 2-[(ethoxy)(methanesulfonylaminoethyl)phosphonomethyl]-4 - methylpentanoic acid (12.8 g) in 10 ml DMF and the resulting mixture then was stirred for 18 hours, slowly warming up the room for the B>2About (2 times), brine solution (50 ml), dried over MgSO4and evaporated to a yellow semi-solid product. By cleaning with the help of instant chromatography using a mixture of 10%-80% ethyl acetate/hexane for elution received 10 g of ethyl ester of 2-[(ethoxy)(quinoline-2 - altimeter)phosphonomethyl]-4-methylpentanoic acid (Rf=0.35 in 80% ethyl acetate/hexane), MS: 424 (MH+).

B. in a Similar manner, but replacing 2-hinokitiol 1-naphthalenethiol, 2-naphthalenethiol or thiophenol receive the following compounds of formula (AA):

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

ethyl ester of 2-[(ethoxy)(naphthas-2 - altimeter)phosphonomethyl]-4-methylpentanoic acid; and

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

Example 23

The compounds of formula (BB)

A. Ethyl ester 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 a sufficient amount of methanol to obtain a homogeneous solution. After 18 hours, THF was removed by evaporation, the residue was dissolved in 50 ml of H2O and washed with 50 ml of ethyl acetate. The aqueous phase is then acidified Easily over MgSO4and evaporated, obtaining 3.8 g of 2-[(hydroxy)(quinoline-2-altimeter)phosphonomethyl]-4 - methylpentanoic acid as a yellow oil, MS: 368 (MH+).

B. in a Similar way received the following compounds of formula (BB):

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.

Example 24

Peptidase the compounds of formula (BB)

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 exposure at room temperature began to precipitate the salt. The flask was covered with foil and left to stand for 2 days. Then the salt was removed by filtration under vacuum and the filtrate was evaporated to condition yellow foam. Salt and filtrate, respectively, was dissolved in 100 ml ethyl acetate and washed sequentially with 1% HCl to remove cinchonidine, maintaining the pH above 4. Both solutions were dried separately over MgSO4and evaporated, obtaining 2.4 g of individual stereoisomer []2D4= +is 10.68ois tanoli (2 ml)).

Example 25

The compound of formula (Ig)

Individual stereoisomer of 2-[(hydroxy)(quinoline-2 - altimeter)phosphonomethyl] -4-methylpentanoic acid (300 mg, 0,81 mmole) and 1,1'-carbonyldiimidazole (174 mg, 1.0 mmol) was stirred at 0oC in 6 ml of THF over a period of 1.5 hours To the solution was added (10S)-10 - amino-9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18]endeca-12(19),13 (18),14,16-tetraen (270 mg, 0.95 mmole) and the resulting mixture was allowed to warm to room temperature and then was stirred for 18 hours. THF was removed by evaporation and the residue was dissolved in 60 ml of ethyl acetate. An ethyl acetate solution is washed with 10 ml of H2Oh, 10 ml of brine, dried over MgSO4and evaporated, receiving (10S)-[methyl-2-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18), 14,16-tetraen-10-ylcarbonyl)pentyl] - (quinoline-2-altimeter)phosphinic acid in the form of a yellow oil. Purification was performed by high performance liquid chromatography with reversed phase, using as solvents for elution gradient of acetonitrile and 50 ml of buffer NH4The OAc. The more polar stereoisomer of (30 mg) was isolated in 41% of acetonitrile, and the less polar stereoisomer (10 mg), with 43% of acetonitrile. Faction liofilizirovanny to obtain a white powder, MS is tricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid (200 mg, 0.45 mmole) was dissolved in 10 ml of glacial acetic acid and was first made when hydrogen pressure of 100 lb/in2in the presence of Pt2O (60 mg) in a Parr reactor at room temperature for 15 hours. Gaseous argon was barbotirovany the reaction mixture for 15 minutes, the catalyst (Pt2O) was filtered through a funnel with telicom). Transparent filtrate was evaporated to dryness and then conducted a double-evaporation with toluene, obtaining quantitative yield (3R, 10S)-5-methyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18]nonadecane-10-ylcarbonyl) hexanoic acid as a white solid, MS: 448 (M-H)+.

Example 27

The compound of formula (Ii)

(3R, 10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]nontechnically)hexanoic acid and O-benzylhydroxylamine (5 EQ., 2.25 mmole, 277 mg) in 10 ml dry DMF at room temperature was added 1-hydroxybenzotriazole2Oh (2 EQ. , 0.9 mmole, 122 mg) and EDCI (5 EQ., 2.25 mmole, 431 mg). The resulting clear reaction mixture was stirred at room temperature overnight. The solvent was removed in high vacuum at room temperature and estato yennie water extracts were podslushivaet with 4N NaOH to pH 10 and saturated NaCl and was extracted with CH2Cl2(G ml). United methylenchloride extract CH2Cl2dried (MgSO4), filtered and evaporated to dryness, receiving semi-solid product. This semi-solid product was stirred in a simple ether (10 ml) at 0oC for 30 minutes and filtered, receiving 85 mg (34%) of (3R, 10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18]nontechnically)hexanamide in the form of a white powder, MS: 555 (M+H)+< / BR>
Example 28

The compound of formula (Ij)

(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] nonadecane-10-ylcarbonyl)hexanamide (75 mg, is 0.135 mmole) was first made when the hydrogen pressure is 1 atmosphere in absolute ethanol (5 ml) in the presence of 10% Pd/C (35 mg) for 2 hours. Gaseous argon was barbotirovany the reaction mixture for 10 minutes and the reaction mixture was filtered through a funnel with telicom. Further, the catalyst for celite washed with 5 ml ethanol. The combined filtrate was evaporated to dryness before the formation of the solid residue. The solid residue was stirred in 10 ml of 5% MeOH in simple ether at 0oC for 30 minutes and after filtration was obtained 57 mg (91%) of (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo - 1,8-diazatricyclo[10.6.1.0of 13.18] nonadecane-10-ylcarbonyl)hexanamide as BELOVETH is ryptophan (3 mmole, 914 mg) and N-methylethanamine (3.6 mmole, 0.27 g, of 0.32 ml) in dry DMF (15 ml) was added 1-hydroxybenzotriazole2(3 mmole, 459 mg) and EDCI (4.5 mmole, 863 mg). The mixture was stirred at room temperature overnight in an argon atmosphere and the excess solvent (DMF) was removed in high vacuum at 35oC. the Residue was dissolved in ethyl acetate (40 ml) and the adduct was extracted with 1N HCl (g ml). The combined aqueous extract was podslushivaet solid K2CO3and were extracted with ethyl acetate (CH ml). The combined organic extract was washed with brine (30 ml) and dried (MgSO4). By evaporation to dryness received 920 mg (85%) purified by high performance liquid chromatography of the product, N'-tert. - butoxycarbonylmethyl-N-[(methyl)aminoethyl]amide as a white foam.

Example 30

The compound of formula (IT)

To intensively stirred solution of N'-tert - butoxycarbonylmethyl-N-[(methyl)aminoethyl] amide (2 g, of 5.55 mmole) and TRANS-1,4-dichlorobut-2-ene (8,32 mmole, 1.04 g, to 0.88 ml) in methylene chloride (75 ml) and 40% KOH (50 ml) was added 0.3 EQ. chloride of benzyltriethylammonium (of 1.66 mmole, 378 mg). After stirring at room temperature over night yellow organic layer was separated and the aqueous layer was then excile (MgSO4). The residue was dissolved in 10 ml MeOH and at 0oC was added with stirring 50 ml of a simple ester. The resulting yellow solid product was filtered. The filtrate was evaporated to dryness, obtaining 1.12 g purified by high performance liquid chromatography of the product 11-N'-(tert.-butoxycarbonyl)amino-10-oxo - 1,6,9-triaza-6-methyl-tricyclo[11.6.1.014,19]eicosa-3(4), 13(20), 14(19),15,17-pentene in the form of light yellow powder, MS: 413 (M+N)+.

Example 31

The compound of formula (FF)

11-N'-(tert. -butoxycarbonyl)amino-10-oxo-1,6,9-triaza-6 - methyltricyclo[11.6.1.014,19] eicosa-3(4),13(20),14(19),15,17- pentaen (414 mg, 1 mmol) was stirred in 40% TFA in CH2Cl2(10 ml) at room temperature for 1 hour. The excess TFA and solvent was removed under reduced pressure. The residue was dissolved in methylene chloride (30 ml) and washed with 5% solution of K2CO3(G ml) and with brine (15 ml). The organic layer was dried (MgSO4) and evaporated to obtain 240 mg (76%) as a pale yellow foam 11 - amino-10-oxo-1,6,9-triaza-6-methyltricyclo[11.6.1.014,19] eicosa-3(4), 13(20), 14(19), 15,17-pentene, MS: 313 (M+N)+.

Example 32

The compounds of formula (Ik)

11-Amino-10-oxo-1,6,9-triaza-6-methyltricyclo[11.6.1.014,19] eicosa-the I) was stirred in dry DMF (15 ml) in the presence of HOBT (0.7 mmole), EDCI (1.4 mmole, 268 mg) and N-methylmorpholine (1.4 mmole, 0.15 ml) in an argon atmosphere at room temperature overnight. Excess DMF was removed under reduced pressure. The residue was dissolved in methylene chloride (30 ml) and washed with water (30 ml). The aqueous fraction was extracted with CH2Cl2(30 ml). The combined methylene extract was dried (MgSO4) and evaporated to obtain a light brown oil. Light brown oil was purified by high performance liquid chromatography with reversed phase (C18-column; gradient CH3CN-50 MM NH4OH). The target fraction liofilizirovanny to obtain 148 mg (40%) of tert.-butyl ether (3R, 11S)-5-methyl-3-(10-oxo-1,6,9-triaza-6 - methyltricyclo[11.6.1.014,19] eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbonyl)hexanoic acid as a light yellow powder, MS: 525,2 (M+N)+.

Example 33

The compounds of formula (Il)

Tert. -butyl ether (3R, 11S)-5-methyl-3-(10-oxo-1,6,9-triaza - 6-methyl-tricyclo[11.6.1.014,19] eicosa-3(4), 13(20), 14(19),15,17- pentaen-11-ylcarbonyl)hexanoic acid (0,228 mmole, 120 mg) was stirred in 20% TFA in CH2Cl2(5 ml) at room temperature for 1 hour. The excess solvent was removed under reduced pressure (rotary evaporator at 30o3CN - NH4OAc in gradient conditions received 90 mg (75%) of the acid as a light yellow powder, MS: 469,1 (M+N)+.

Example 34

The compound of formula (Im)

(3R,11S)-5-methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo [11.6.1.014,19] eicosa-3(4),13(20),14(19),15,17-pentaen-11 - ylcarbonyl)hexanoic acid and O-benzylhydroxylamine (5 EQ., 2.5 mmole, 308 mg) was stirred in dry DMF (30 ml) in the presence of HOBT (2 EQ., 1 mmol, 135 mg), EDCI (5 EQ., 2.5 mmole, 479 mg) and N-methylmorpholine (10 EQ., 5 mmol, 0,55 ml) at room temperature in an argon atmosphere for 15 hours. The solvent was removed in high vacuum at room temperature. The residue was dissolved in distilled water (35 ml) and was extracted with 10% ethyl acetate in petroleum ether to remove less polar impurities. The target product was then extracted from the aqueous layer using CH2Cl2(G ml). The organic extract was washed with brine (25 ml), dried (MgSO4) and evaporated, receiving a yellow oil (330 mg). The crude product was purified by high performance liquid chromatography with reversed phase (buffer, CH3CN-NH414,19
]eicosa-3(4),13(20),14(19),15,17- pentaen-11-ylcarbonyl)hexanamide in the form of a whitish powder, MS: 572 (M-H)-.

Example 35

The compound of formula (In)

A mixture of (3R,11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,6,9-triaza-6 - methyltricyclo[11.6.1.014,19] eicosa-3(4), 13(20),14(19),15,17- pentaen-11-ylcarbonyl)hexanamide (40 mg, 0.07 mmole) and 10% Pd/C (10 mg) was stirred in a solution of 3% HCOOH in ethanol (5 ml) at room temperature for 1 hour. The mixture was filtered through a funnel with telicom and concentrated in vacuum. To the solid residue in 1 ml of 50% AcOH/MeOH with stirring was added in one portion to 5 ml of a simple ester. Whitish powder was then collected by filtration, receiving 26 mg (68%) of (3R,11S)-N-hydroxy-5-methyl-3-(10 - oxo-1,6,9-triaza-6-methyl-tricyclo[11.6.1.014,19] eicosa-3 (4), 13(20), 14(19), 15,17-pentaen-11-ylcarbonyl)hexanamide, MS: 488,5 (MH+).

Example 36

The compounds of formula (JJ)

A. To a solution of sodium salt of ()-2-hydroxybutanoic acid (2,54 g, 20.1 mmole) in dry DMF (30 ml) was added benzylbromide (2,9 ml, 1.2 EQ.) and anhydrous KI (330 mg, 0.1 EQ.). The suspension is kept at 100oC for 24 hours and DMF drove away under reduced pressure. The residue was extracted with simple ether, washed with water and saturated Na2S2OCibuconet in the form of a colorless oil, boiling point 95oC (0,45 Torr).

B. In another embodiment, to a cold (0oC) suspension of NaH (3.8 g 60% (by weight) dispersion in mineral oil, 95.0 mmol) in THF (50 ml) was added dropwise via cannula a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 ml). The resulting solution was heated to 25oC and concentrated in vacuum. The formed salt is suspended in DMF (100 ml) and was treated with KI (1,57 g, 0.1 EQ.) and benzylbromide (12.3 ml, 1.1 EQ). The mixture was stirred at 100oC for 23 hours in an atmosphere of argon and evaporated DMF. The residue was dissolved in a simple ether and washed with water, saturated Na2S2O3and with brine and dried over MgSO4. By distillation received benzylglycine (8.5 g, 54%) as a colourless oil, boiling point 85-87oC (0,5 Torr).

Example 37

The compounds of formula (LL)

A. To a cold (0oC) a solution of benzyl-()-2-hydroxybutanoic (1.75 g, 9,01 mmole) in CH2Cl2(50 ml) was added 2,6-lutidine (1.2 ml, 1.1 equiv.) then was added dropwise to the anhydride of triftoratsetata (1.7 ml, 1.1 EQ.). After 10 min dropwise at 0oC solution was added tert.-butyl ester of L-leucine (1.7 g, 1 EQ.) and diisopropylethylamine (1.7 ml, 1.1 EQ.) in CHAli saturated NaHCO3(50 ml). After drying (Na2SO4) and concentration in vacuo the remaining oil was subjected to instant chromatography (silica, 5% ethyl acetate/hexane) to separate the diastereomers. Less polar diastereoisomer tert. -butyl ether (1R)-N-(2 - benzyloxycarbonylamino)-L-leucine (Rf0,22; 5% ethyl acetate/hexane) and the more polar diastereoisomer of tert. -butyl ether (1S)-N-(2-benzyloxycarbonylamino)-L-leucine (Rf0,13), further purified separately using high-performance liquid chromatography (5% ethyl acetate/hexane) to obtain 1.1 g of the more polar diastereoisomer and 0.78 g of the less polar diastereoisomer, MS(BTA): 364 (MH+).

B. in a Similar way of benzylglycine (379 mg, 2.7 mmole), tert.-butyl ester of L-leucine (435 mg, 2.7 mmole), 2,6-lutidine (0.35 ml, 2.8 mmole), diisopropylethylamine (0,53 ml of 0.28 mmole) and anhydride of triftoratsetata (0.51 ml, 2.8 mmole) was received 383 mg (50%) of tert.-butyl ether N-benzyloxycarbonyl-L-leucine in the form of a colorless oil, MS(BTA): 336(MH+).

Example 38

The compounds of formula (Io)

A. To a solution of tert.-butyl ether (1S)-N-(2 - benzyloxycarbonylamino)-L-leucine (143 mg, 0,393 mmole) in CH2Cl2(3 ml) at 0oC dobavleniya salt (1S)-N-(2-benzyloxycarbonylamino)-L-leucine (compound of formula (MM)), which was then dissolved in DMF (3 ml) with (10S)-10-amino-9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13 (18), 14,16- tetraene (124 mg, 1.1 EQ.) and HOBT (80 mg, 1.5 EQ.). After cooling to 0oC was added N-methylmorpholine (60 ml, 1.5 EQ.) and EDCI (113 mg, 1.5 EQ.). After aging at 25oC for 18 hours the reaction mixture was diluted with 10 ml ethyl acetate, washed with saturated NaHCO3(3x10 ml) and water (2x10 ml), dried (Na2SO4) and concentrated. The residue was chromatographically instant chromatography (silica, 1% MeOH/CH2Cl2) and collected fractions with Rfof 0.5 (5% MeOH/CH2Cl2). By high-performance liquid chromatography with reversed-phase was obtained (2R,1'S,10S)-2-[N-(1 - benzyloxycarbonylamino)amino] -4-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10 - yl)pentanone (46 mg), MS(BTA): 575 (M+).

B. in a Similar manner, but replacing tert.-butyl ether (1S)- N-(2-benzyloxycarbonylamino)-L-leucine (270 mg) in tert.- butyl ether (1R)-N-(2-benzyloxycarbonylamino)-L-leucine was obtained (2R,1'R,10S)-2-[N-(1-benzyloxycarbonylamino)amino]-4 - methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18]endeca- 12(19),13(18),14,16-tetraen-10-yl)pentanone (175 mg), MS(BTA): 575 (MH+).

of 13.18] endeca-12(19),13(18), 14,16- tetraen-10-yl)pentanolide (46 mg) in THF/Meon (1:1, 2 ml) was added in argon atmosphere 1M barium hydroxide (0.3 ml). After aging at 25oC within 24 hours after the solution was passed WITH2and the resulting precipitate of barium carbonate was filtered. The solvent was removed under reduced pressure and the aqueous residue was brought to pH 5.5 with 1M HCl. After removal of water using high-performance liquid chromatography with reversed-phase was obtained (2R, 1'S,10S)- 2-[N'-(1-carboxypropyl)amino]-4-methyl-N-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18)14,16-tetraen-10 - yl)pentanone in the form of a white solid, MS(BTA): 483 (M-H)-(compound 5).

In a similar way received:

(2RS, 10S)-2-(carboxymethylamino)-2-cyclohexyl-N-(9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18),14,16- tetraen-10-yl)ndimethylacetamide, MS: 497 (M+N)+< / BR>
(2RS, 10S)-2-(carboxymethylamino)-3-methyl-N-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18),14,16- tetraen-10-yl)pentamid, MS: 471 (M+N)+;

(2RS, 10S)-2-(phosphorylethanolamine)-4-methyl-N-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18]endeca-12(19),13(18),14,16- tetraen-10-yl)pentamid.

B. in a Similar way from (2R,1'R,10S)-2-[N'-(1 - benzyloxycarbonylamino (2R,1'S,10S)-2-[N'-(1 - carboxypropyl)amino]-4-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10 - yl)pentanone (16 mg), MS(BTA): 483 (M-H)-.

C. In accordance with the above procedure for obtaining compounds of formula (Io) of tert. -butyl ether N-[(benzyloxycarbonyl)methyl]-L-leucine (156 mg, 0,465 mmole), HOBT (94 mg, 1.5 EQ.), EDCI (134 mg, 1.5 EQ. ), N-methylmorpholine (77 μl) and (10S)-10-amino-9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraene (133 mg, 1 EQ.) after instant chromatography (3% MeOH/CH2Cl2) received the crude benzyl ether. The crude benzyl ester was dissolved in THF/MeOH (1:1, 6 ml) and hydrolyzed with 1M barium hydroxide (0.9 ml) over night. After the solution was let in carbon dioxide and the resulting precipitate was filtered. The filtrate was concentrated and the aqueous residue was brought to pH 5.5 with 1M HCl. By high-performance liquid chromatography with reversed-phase was obtained (2R, 10S)-N'-(carboxymethyl)amino-4-methyl-N-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen - 10-yl)pentanone (17 mg) as a white solid, MS(BTA): 457 (MH+).

Example 40

4-Methyl-2-metilpentanovoyj acid

A. To clean utilizability (25 g, of 0.13 mol) at 0oC was slowly added ohlazhdenki, 37% aqueous formaldehyde). The mixture was stirred at 25oC for 3 days. Then the reaction mixture was treated with a solution containing 20 g2CO3in 40 ml of water, and was extracted with simple ether (CH ml). The ether extracts were combined, washed with brine, dried over MgSO4and concentrated under reduced pressure at 20oC. the Crude product, ethyl-4-methyl-2 - medienpartner containing a quantity of ether, was dissolved in absolute ethanol (250 ml) and treated with acetonitrile (250 ml), 1M LiOH (9.7 g in 250 ml of water, to 0.23 mole). After stirring overnight the organic solvents evaporated under reduced pressure and the aqueous residue was extracted with ethyl acetate (CH ml). The combined extracts were washed with brine, dried over MgSO4and concentrated under reduced pressure to obtain 10.5 g of 4-methyl-2-metilpentanovoyj acid as a colourless oil.

B. in a Similar way received the following connections:

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 41
oC for 8 hours. The reaction mixture was then divided between 50 ml of 1.0 N NaOH and 50 ml of diethyl ether. The aqueous fraction was separated, acidified to pH 3 with 10% HCl and washed with 50 ml of a simple ester. By ion-exchange chromatography (Dowex-50W) with elution with a mixture of 20% pyridine/water was obtained 2-(benzoyloxymethyl)-4-]methylpentanol acid.

300 MHz1H-NMR in CDCl3: 0,9-1,0 (dd, 6N, CH3); 1,25-1,35 (m, 1H, CH); 1,6-of 1.75 (m, 2H, CH2); the 2.8-2.9 (m, 1H, Calpha-H); 3,0-3,2 (ABq, 2H, CH2N); 4,7-4,75 (ABq, 2H, CH2O); 7.3 to 7.4 (m, 5H, Ph).

N. Formirovanie 2-(benzoyloxymethyl)-4-methylpentanoic acid were carried out in dichloromethane with a mixture of formic acid/acetic anhydride to obtain the N-formyl-2-(benzoyloxymethyl)-4 - methylpentanoic acid.

The combination with the compound of the formula (J): N-formyl-2- (benzoyloxymethyl)-4-methylpentanoic acid (175 mg) and the compound of formula (J) (230 mg) in a mixture of 5% pyridine/dichloromethane (30 ml) was added 4-dimethylaminopyridine (DMAP) (200 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) at room temperature. The reaction mixture was stirred for 8 hours and then concentrated and separated between 30 ml of ethyl acetate and 30 ml of 20% HCl. The organic fraction about the key on silica gel with elution with a mixture of 50% ethyl acetate/hexane received the product as a mixture of two isomers. By hydrogenolysis in methanol over 10% Pd/C was obtained (2R,10S)-2- (N-formyl-N-hydroxyquinolyl)-4-methyl-N-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16- tetraen-10-yl)pentamid in the form of a mixture of two isomers, MS: 455 (M-H)+(connection 6).

In a similar way received:

(2RS, 10S)-2-(isopropoxycarbonyl)-4-methyl-N-(9 - oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13 (18),14,16-tetraen-10-yl)pentamid, MS: 455 (M+N)+.

(2RS, 10S)-2-(morpholinoethoxy)-4-methyl-N-(9 - oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13 (18),14,16-tetraen-10-yl)pentamid, MS: 455 (M+H)+.

Example 42

This example illustrates the receive characteristic of the pharmaceutical compositions for oral administration containing a compound of the formula (I) or its pharmaceutically acceptable salt, such as (3R,10S)-2-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10 - ylcarbonyl)hexanamide:

A. Ingredients% weight

The compound of formula (I) - 20,0%

Lactose - 79.5% of

Magnesium stearate and 0.5%

The above ingredients are mixed and filled in a gelatin capsule with a hard shell containing 100 mg each, one capsule contains will bring the s (I) - 20,0%

Magnesium stearate was 0.9%

Starch - 8,6%

Lactose - 79.6% of

PVP (polyvinylpyrrolidine) - 0,9%

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

Century 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 an amount necessary to obtain a total solution volume of 100 ml, which is filtered and poured into bottles.

, Ingredients% weight

The compound of formula (I) - 20,0%

Peanut butter - 78,0%

Span 60 - 2,0%

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

Example 43

This example illustrates obtaining typical pharmaceutical composition for parenteral destination, containing the compound of formula (I) or it is a goat-13(20), 14(19), 15,17-tetraen-11 - ylcarbonyl)hexanamide:

Ingredients

The compound of formula (I) to 0.02 g

Propylene glycol - 20,0 g

The polyethylene glycol 400 - 20,0 g

Polysorbate 80 - 1.0 g

with 0.9% saline - q.s. 100 ml

The compound of formula (I) dissolved in propylene glycol, polyethylene glycol 400 and Polysorbate 80. Then add with stirring a 0.9% saline solution in a quantity sufficient to obtain 100 ml of solution for intravenous infusion, which is filtered through a membrane filter with a mesh size of 0.2 micron and packaged under sterile conditions.

Example 44

This example illustrates the receive characteristic of the pharmaceutical composition in the form of a suppository, containing the compound of formula (I) or its pharmaceutically acceptable salt, for example (10S)-2-mercaptomethyl-4-methyl-1-4-(9-oxo-1,8 - diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10 - ylcarbonyl)pentanone:

Ingredients% weight

The compound of formula (I) is 1.0%

Polyethylene glycol 1000 - 74,5%

Polyethylene glycol 4000 - 24,5%

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

Example 45

Dann the General formula (I) or its pharmaceutically acceptable salt, for example (10S)-4-methyl-2-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca- 12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)pentyl-(quinoline-2 - altimeter)phosphinic acid:

Ingredients% weight

Micronized compound of formula (I) is 1.0%

Micronized lactose - 99,0%

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

Example 46

This example illustrates the receive characteristic of the pharmaceutical composition in the not-inkind spray form containing a compound of the formula (I) or its pharmaceutically acceptable salt, such as (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo - 1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18), 14,16- tetraen-10-ylcarbonyl)hexanamide:

Ingredients% weight

The compound of formula (I) - 0,005%

Water - 89,995%

Ethanol - 10,000%

The compound of 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 47

This example illustrates the receive characteristic of the pharmaceutical composition in aerosol form containing a compound of the formula (I) or its pharmaceutically acceptable the 1-ylcarbonyl)hexanamide:

Ingredients% weight

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 is injected propellants. Then the mixture is poured into an aerosol container fitted with a metering valve.

Example 48

Analysis of in vitro

Collagenase type 1 fibroblast was purified from the non-serum media for culturing cells GMOO10A stimulated by PMA, using heparin and zinc-chelating separatrix columns and then using liquid chromatography quick resolution (column MONO S). The enzyme is activated by incubation with trypsin.

Collagenase type IV was purified from containing serum media for culturing fibroblast cells (GMOO10A) using zinc-chelating and gelatin-sepharose columns and then using liquid chromatography quick resolution (column MONO S). Electrophoresis in polyacrylamide gel with sodium dodecyl sulfate showed that the enzyme is homogeneous. The enzyme activated by incubation of 1 mmol ARMA for 1 h at 35-37oC.

The compound of formula (I) was dissolved in DMSO and added to a cuvette containing 0.2 Meazza DMSO 2%). Concentration of compounds of formula (I) was chosen so that for every 20% change activity to have at least one experimental point. The enzyme and the compound gave the opportunity to pass a preliminary 3-minute incubation at 37oC. to initiate the reaction, to each of 20 μm was added N-(7-dimethylamino-4-methyl)coumarinyl ("DACM") (firm Sigma) and dipeptide (Ac-Pro-Leu-Gly-S - Leu"-Leu-Gly-OEt, the company Bachem Bioscience Inc.). Fluorescence was detected at the wavelengths of excitation and emission 395 and 485 nm, respectively. Each experimental point was obtained by averaging over twice the experiment. 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 collagenase (see table).

Example 49

Analysis of in vitro

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

Small cartilage explants (3 mm in e 35S glycosaminoglycans (GAG) were in the medium for cultivation in response to the addition of rhIL-1 alpha induces the expression of chondrocyte matrix metalloprotease (MMP), including stromelysin and collagenase. To determine the percentage inhibition of labeled GAG has introduced a correction for spontaneous release in the absence of rhIL-1 alpha. The results for each group represent the average values of the standard error of five explanandum.

The compounds of formula (I) when tested by this method showed the ability to inhibit the exit labeled35S (GAG) of cartilaginous explantation.

Compound 2 (example 8) IC50= 40 μm

Compound 4 (example 25) IC50= 50 µm

Example 50

Analysis of in vitro

To study the in vitro effect of the compounds of formula (I) on bone resorption was used as a model of long bone rat embryos. To induce bone resorption in vitro used bovine PTH. Effect on bone resorption was expressed using the number of45Ca released into the environment for the cultivation of the pre-labeled by45Ca long bones rat embryos. Inhibitory effect of compounds of formula (I) in relation induced bovine PTH resorption of labeled45Ca long bones rat embryos (forearm) were cut and cultured in cups Linbro at 37oC during the night in BGJb medium, supplemented with 1 mg/ml bovine serum albumin (BSA). Each group used five pairs of bones. The compounds of formula (I) was first dissolved in ethanol, and then diluted to various concentrations and added simultaneously with bovine PTH (1-34) at a concentration of 110-8M on the first day. The concentration of ethanol solutions of compounds was less than 0.05%, which had no impact on the analysis. The analysis was completed on the sixth day of one-time replacement of the medium on the third day.

At the end of each substitution medium was counted45Ca present in the environment for cultivation. The remaining bones were dissolved using 0.1 N HCl and also counted the number of45Ca present in the product decomposition of the bone. The results were expressed as % relative to the total number of45Ca released from each pair of bones. Bovine PTH concentration 110-8M induces bone resorption to a maximum level, which is taken as 100%, and this concentration was used as standard. The level of bone resorption in the presence only of the environment took over the base is ncentrate, when the compound inhibits bone resorption by 50% was defined as IC50.

The compounds of formula (I) when tested by this method showed the ability to inhibit induced bovine PTH bone resorption.

Compound 3 (example 10) - IC50= 0.1 ám

Compound 4 (example 25) - IC50= 5 µm

Toxicology

In the above analyses, there was no serious Toxicological effects.

1. Derivatives of amides of General formula (I):

< / BR>
where the dashed lines indicate optional double bond, and when n = 1, 2, or 3; m = 3 or 4, And denotes-CH2-;

R1means (a) -CH2-R4where R4represents mercapto, acetylthio, carboxy, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, morpholino(C1-C4)alkoxycarbonyl, aryloxyalkyl, benzylaminocarbonyl or

< / BR>
where R6denotes China-2-yl;

b) -CH(R7)-R8where R7denotes alkyl, hydroxy, amino, alkoxycarbonyl, aminocarbonyl or carboxy and R8denotes a carboxy, hydroxyaminobuteroyl, alkoxycarbonyl or arelaxation;

in) -NH-CH(R9)-R10where R9denotes Voboril, cycloalkenyl or aralkyl;

R3denotes hydrogen;

or, if n = 2 or 3; m = 3 or 4, And represents-N(R11)-, where R11denotes hydrogen or alkyl;

and R1, R2and R3have the above values;

as individual stereoisomers or as mixtures thereof, or their pharmaceutically acceptable salts.

2. Connection on p. 1, where n = 1, 2, or 3; m = 3; And a represents-CH2-; R2denotes alkyl or aralkyl.

3. Connection on p. 2, where R1denotes-CH2-R4and R4denotes a carboxy, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, aryloxyalkyl or benzylaminocarbonyl, and R2denotes 2-methylpropyl.

4. Connection on p. 3, where n = 2 and R1denotes-CH2-C(O)OH or CH2-C(O)NHOH.

5. Individual stereoisomer compounds on p. 4, namely: (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid or (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanamide.

6. Connection on p. 3, where n = 3 and R1denotes CH2-C(O)NHOH.

7. Separate CTE is), 14(19),15,17-tetraen-11-ylcarbonyl)hexanamide.

8. Connection on p. 3, where n = 1 and R1denotes-CH2-C(O)OH or-CH2-C(O)NHOH.

9. Individual stereoisomer compounds on p. 8, namely: (3R,9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18), 12, (17), 13,15-tetraen-9-ylcarbonyl)hexanoic acid or (3R,9S)-N-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18), 12, (17), 13,15-tetraen-9-ylcarbonyl)hexanamide.

10. Connection on p. 2, where R1denotes-CH2-R4where R4means mercapto or acetylthio.

11. Connection on p. 10, where n = 2 and R1denotes CH2SH or CH2SC(O)CH3.

12. Connection on p. 11, namely: (10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)pentanone or (10S)-2-acetyltributyl-4-methyl-N-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)pentanone.

13. Connection on p. 2, R2denotes China-2-yl.

14. Connection on p. 13, where n = 2.

15. Connection on p. 14, namely: (10S)-[4-methyl-2-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)pentyl]-(quinoline-2-s R7denotes alkyl, alkoxycarbonyl or carboxy and R8denotes a carboxy, hydroxyaminobuteroyl, alkoxycarbonyl or arelaxation.

17. Connection on p. 16, where R7denotes methoxycarbonyl or methyl.

18. Connection on p. 17, where R8denotes hydroxyaminobuteroyl.

19. Individual stereoisomer compounds on p. 18, where n = 2, namely (3R, 10S)-N-hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14, -16-tetraen-10-ylcarbonyl)hexanamide.

20. Connection on p. 2, where R1denotes-NH-CH(R9)-R10where R9denotes hydrogen or alkyl and R10denotes a carboxy or arelaxation.

21. Connection on p. 20, where R9denotes alkyl and R10represents carboxy.

22. Connection on p. 1, where n = 2 or 3; m = 4; And a represents-N(R11)-, where R11denotes hydrogen or alkyl; R2denotes alkyl.

23. Connection on p. 22, where R2denotes 2-methylpropyl and R11denotes methyl.

24. Connection on p. 23, where R1denotes-CH2-R4where R4denotes a carboxy, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxy which means-CH2-C(O)NHOH.

26. Pharmaceutical composition having inhibitory activity against matrix metalloprotease in mammals comprising the active ingredient and pharmaceutically acceptable excipient, characterized in that the active substance contains a therapeutically effective amount of compounds of formula I.

 

Same patents:

The invention relates to a new protected bicyclic to amidines formula I, where a is chosen from the group

-CR1R2-CR3R4-CR5R6-; -CR1R2-CR3R4-CR5R6-CR7R8< / BR>
or

-CR1R2-CR3R4-CR5R6-CR7R8-CR9R10,

where the substituents in And respectively numbered, starting from a nitrogen atom;

In choosing from the group of CR11R12-CR13R14-, -CR11R12-CR15R16-CR17R18-CR13R14;

R1and R14respectively independently of one another denote hydrogen, C1-C4-alkyl;

R15-R18respectively independently of one another denote hydrogen, C1-C4-alkyl, or at least one of R15-R18means amino, C1-C4-alkylamino-, or substituted amino group or C1-C4-alkylaminocarbonyl C1-C4-alkyl;

and the way they are received

The invention relates to fungicidal compositions, a new derivative of triazolopyrimidine, method of production thereof and method of combating fungi

The invention relates to a derivative triazolopyridine and their salts, method of production thereof, intermediates and pharmaceuticals

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component

The invention relates to a condensed heterocyclic compounds or their salts and inhibitors of squalene synthetase containing these compounds as an effective component

-polyfluoroankyl-nitroaniline and method of production thereof" target="_blank">

The invention relates to organic chemistry, specifically to new chemical compounds- polyfluoroankyl-nitroanilines and their N-ACI-derivatives of the General formula 1

< / BR>
where (a) RF=CF3; C2F5; C3F7; C4F9; C6F13; H(CF2CF2)nwhere n=1,2,3;

R=H, alkyl (C1-C4Ph;

R1=H; C(O)R3where R3=H, alkyl (C1-C6Ph;

R2=H;

< / BR>
b) RF=C2F5; C3F7; C4F9; H(CF2CF2);nwhere n=1,2,3;

R1=HHCl;

R2=H

The invention relates to a derived indole of General formula (I)

< / BR>
or its physiologically acceptable salt, or metabolically labile ether complex, where R is chlorine in positions 4 and 6 of the indole ring, R2represents phenyl, possibly substituted by one or two groups selected from fluorine, trifloromethyl, lower alkyl, alkoxy, hydroxy and nitro group, X represents NH

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts
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