Bridge indoles as inhibitors of matrix metalloprotease

 

(57) Abstract:

The present invention describes compounds of formula (I) where the substituents have the values as individual stereoisomers or mixtures thereof and their pharmaceutically acceptable salts, which inhibit matrix metalloprotease, such as interstitial collagenase, and are suitable for the treatment of painful conditions in mammals, facilitated by the inhibition of such matrix metalloprotease, such as arthritis or diseases associated with bone resorption, such as osteoporosis. Describes obtaining pharmaceutical compositions containing as active substance a compound of the formula (I) and pharmaceutically acceptable additive. 2 c. and 21 C.p. f-crystals.

The technical field to which the invention relates

The present 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, making it easier for as a result of inhibition of such matrix metalloprotease.

The background to the image is the construction of connective tissue. Representatives of this family of enzymes have numerous properties, including the zinc - and calcium-dependent secretion as proenzymes and 40-50% homology to the sequence of amino acids.

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 matrix of many tissues, such as cartilage, bone, tissues, tendons and skin. Interstitial collagenase are very specific matrix metalloprotease that break down collagen with getting two fragments, which spontaneously denature at physiological temperatures and therefore become sensitive to the splitting of the less specific enzymes. Because cleavage by collagenase leads to the loss of structural integrity of the target tissue, it is an almost irreversible process and therefore is a good target for therapeutic intervention.

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 areas.

Matrilysin (imaginary metalloprotease or SNMP) 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 expression was detected in mononuclear phagocytes, explants of the uterus in rats and in isolated cases in tumors.

I believe 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 disease, ulceration, which the Directors of collagenases described, for example, in J. Enzyme Inhibition (1987), so 2, S. 1-22, and Drug News & Prospectives (1990), I. 3, 8, S. 453-458. Inhibitors of matrix metalloprotease are also the subject of various patents and applications for patents, for example U.S. patents 5189178 (name Galardy) and 5183900 (name Galardy), European applications 0438223 (name Beecham) and 0276436 (in the name of F. Hoffmann-La Roche), international applications WO 92/21360 (in the name of Merck), 92/06966 (name Beecham) and 92/09563 (in the name of Glycomed).

Summary of the invention

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

Thus, one subject of the invention relates to compounds of formula (I) in the form of a single stereoisomer or mixture of stereoisomers:

< / BR>
where m is 2, 3, 4, 5 or 6 and

n is 0, 1, 2, 3, or 4

moreover,

when m is 2, 3 or 4, n is 1,2,3 or 4 and

And denotes-CH2-, -O - or-NR11- where R11denotes hydrogen or alkyl,

R1does

(a)- (CH2-R4where R4represents mercapto, acetylthio, carboxypropyl, aminocarbonyl or group

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

b) -CHC(R7)-R8where R7denotes alkyl, hydroxy-, amino-, alkylamino, arylamino, alkylsulfonyl, aralkylamines, alkoxycarbonyl, aminocarbonyl, aralkyl or carboxypropyl or R7denotes-CH2Other, where R denotes hydrogen, alkyl, aryl, 2-benzoxazole, -SO2Ra, -SO2OTHERa, -SO2ORa, -C(O)Ra, -C(O)OTHERa-C(O)ORawhere Radenotes alkyl, trifluoromethyl, aryl, aralkyl, aralkyl or arylcarbamoyl, and R8denotes carboxypropyl, hydroxyaminobuteroyl, alkoxycarbonyl or arelaxation, or

in) -NH-CH(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R10denotes carboxypropyl, alkoxycarbonyl or arelaxation, phosphonyl, dialkylphenol or methoxypropanol,

R2denotes alkyl, alkenyl, triptorelin, cycloalkyl, cycloalkenyl, hydroxyalkyl, alkoxyalkyl, alcoxialchil, aryl, aryloxyalkyl or aralkyl and

R3denotes hydrogen, a hydroxy-group, halogen, ALK is 12 denotes carboxypropyl, alkoxycarbonyl or optionally substituted carbarnoyl and

R1, R2and R3have the meanings indicated above, or their pharmaceutically acceptable salts.

Another object of the invention relates to a method of inhibiting the activity of matrix metalloprotease in mammals, and these methods include administration to a mammal in need a therapeutic amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

Another object of the invention relates to pharmaceutical kompoziciyam suitable for inhibiting the activity of matrix metalloprotease in a mammal, which composition comprises a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salts, and pharmaceutically acceptable excipient.

The invention relates further to methods of producing the compounds of formula (I).

Detailed description of the invention

Definition

In the context of this invention and below the claims, unless otherwise specified, the following terms have the following values.

"VOS" means tertbutoxycarbonyl.

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

"HOBT" denotes 1-hydroxybenzotriazol.

"EtOAc" means ethyl acetate.

"THF" means tetrahydrofuran.

"DCC" means 1,3-dicyclohexylcarbodiimide.

"DMAP" refers to 4-dimethylaminopyridine.

"Pht" means phthalimid.

"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, having from one to six carbon atoms and not containing unsaturated bonds, such as methyl, ethyl, n-propyl, 2-methylpropyl (isobutyl), 1-methylethyl (isopropyl), 1,1-dimethylethyl (tertbutyl), etc.

"Alkenyl" refers to a radical with a straight or branched chain, containing at least one unsaturated bond, for example ethynyl, Penta-4-enyl etc.

"(Lower) alkyl" means a radical with a straight or branched chain containing 1 to 4-carbon atom.

"Alkylamino" refers to a radical of the formula-otherawhere Rarefers to alkyl as defined above, such as methylamino, ethylamino, n-propylamino etc.

"Alkylen" in the context of this description oboznachili, as methylene, ethylene, propylene, 2-methylpropyl, 1,2 - dimethylpropylene, hexylen etc.

"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, tributoxy, etc. that not necessarily substituted by hydroxy, alkoxygroup, aryl, amino, alkylamino, dialkylamino, dialkylaminoalkyl or N - methylpiperidin-3-yl.

"Aminocarbonyl" refers to a radical of the formula-C(O)-NH2where the amino group optionally may be substituted by one or two groups selected from a range that includes a hydroxy-group, aralkyl, urlcategory, acylaminoalkyl and dialkylaminoalkyl, such as hydroxyaminobuteroyl.

"Aryl" refers to monovalent unsaturated aromatic carbocyclic radical having one or two rings, such as phenyl, naphthyl, indanyl or biphenyl, or a monovalent unsaturated aromatic heterocyclic radical, such as chenail, dihydroisoxazole, furanyl, imidazolyl, pyridyl, phthalimido or thienyl, optionally substituted aryl, as defined above. Aryl can be mono-, di - or triamese, with substituents independently researched is Biloxi-, the amino, aryl, acetamido -, and/or cyano, for example 6-NITROPHENOL-2-yl, 6-fiorinal-2-yl, 6-hydroximino-2-yl, 6-methoxyindol-2-yl, 6-nitroav-1-yl, 6-Harnett-1-yl, 6 - hydroxine-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, biphenyl, 3-methylpyridyl, 4-ethylpyridine, 4-chlorophenyl, 4-phenoxyphenyl, 2-pyrrolidin-1 - elecoxiban, 4-tianfeng, naphthalen-2-yl, 4-hydroxy-3-were, etc.

"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 etc.

"Aralkyl" refers to a radical of the formula-RcRbwhere Rwithdenotes alkylene, as defined above, and Rbmeans aryl, as defined above, for example benzyl, phenylethylene, 3-phenylpropyl etc.

"Arakaki" refers to a radical of the formula-ORcRbwhere Rcdenotes alkylene, as defined above, and Rbmeans aryl, as defined above, for example benzyloxy, 3-naphthas-2-ylpropionic etc.

"Alkoxycarbonyl" refers to a radical of the formula-C(O)ORbwhere Rbdenotes alkyl, as defined by the example of methoxycarbonyl, etoxycarbonyl, tertbutoxycarbonyl, N-methylpiperid-4-jocstarbunny etc.

"Arelaxation" refers to a radical of the formula-C(O)Rdwhere Rddenotes urlcategory, as defined above, such as benzyloxycarbonyl, naphthyl-2-retexturing etc.

"Benzylaminocarbonyl" refers to a radical of the formula - C(O)NHOCH2Ph, where Ph denotes phenyl.

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

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

"Cycloalkyl" means a monovalent saturated carbocyclic radical containing no unsaturated bonds and having from three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

"Cycloalkenyl" refers to a radical of the formula -(CH2)pRewhere Redenotes cycloalkyl, as defined above, and p denotes an integer from 1 to 6, for example cyclopentylpropionyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl.

"Dialkylamino" refers to a radical of the formula-NRfRgwhere Rfand Rgindependently denote an alkyl, as defined above, or Rfand Rgtogether form a ring, such as morpholinyl, piperidinyl or means the radical-C(O)NHOH.

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

"Mercapto" refers to the radical-SH.

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

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

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

"Optionally substituted carbarnoyl" means carbamoyl radical, optionally substituted on the nitrogen atom by one or more substituents selected from the group consisting of alkyl, mono - and dialkylaminoalkyl and aralkyl.

"Aminosidine group" in the context of the present description refers to organic groups intended to protect nitrogen atoms against undesirable reactions during the synthesis process, and includes, but is not ogranichennodeesposobnymi, tertbutoxycarbonyl etc.

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

"Pharmaceutically acceptable acid additive salt" refers to such salts which retain the biological activity and properties of the free bases, which are not undesirable biological or other reasons and which are formed by adding to the free base of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, paratoluenesulfonyl acid, salicylic acid, etc..

"Pharmaceutically acceptable salt accession grounds" means such salts which retain the biological activity and properties of the free acids, the organic or organic base to the free acid. Salts formed with 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 ionoobmennye resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2 - Diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc. 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, pigs, sheep, Kozeny formula (I), which being optionally assigned to the mammal is sufficient to effect the treatment, as defined below, painful conditions, facilitated by the result of ingibirovaniya activity matrix metalloprotease, in particular activity of interstitial collagenase. The amount of the compounds of formula (I), which constitutes a "therapeutically effective amount" will vary depending on the connection status of the disease and its severity, and the mammal undergoing treatment, however, it may be determined in a conventional manner an ordinary specialist in the field of technology, relying on his own knowledge and the description.

The term "treatment" or "cure" in the context of the present description covers the treatment of painful conditions 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 have not established that such has occurred:

"Isomers are different compounds that have the same molecular formula.

"Stereoisomers are isomers that differ only in the orientation of their atoms in space.

"Enantiomers" are a pair of stereoisomers that are nesovmestimymi mirror images of each other. A mixture of 1:1 pair of enantiomers represents a "racemic" mixture.

"Diastereoisomers" are stereoisomers that are not mirror images of each other.

Used in the present description, the item basically is a modified form of the nomenclature of IUPAC (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 with tricyclic Deputy. The compounds of formula (I) have at least two asymmetric carbon atoms, namely, at the point of connection of the substituent R2and indolylmethane group. The compounds of formula (I) and their pharmaceutically acceptable salts can therefore things the ditch. All these separate stereoisomers, racemates, diastereoisomers and mixtures thereof are included in the scope of the present invention.

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

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

< / BR>
named in this description (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl) hexanamide.

Another example is the following compound of formula (I) in which m is 2, n is 2, represents oxygen, R1denotes-CH2-R4where R4denotes carboxypropyl, R denotes 3-(4 - pyridinyl)propyl and R3denotes hydrogen, i.e. the compound of the following formula:

< / BR>
that's called (3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbamate the formula (I) can be used as inhibitors of matrix metalloprotease mammals, in particular interstitial collagenases mammals, and, thus, prevents the decomposition of collagen in the body of a mammal. Therefore, the compound suitable for the treatment of painful conditions caused by increased activity of matrix metalloprotease, in particular increased activity of interstitial collagenase, such as arthritis and osteoarthritis, metastaz tumors, periodontal disease and ulceration of the cornea (see, for example, in Arthritis and Reumatism (1993), T. 36, 2, S. 181-189; Arthritis and Reumatism (1991), T. 34, 9, S. 1073-1075; Seminars in Arthritis and Reumatism (1990), T. 19, 4, Suplement 1 (February), S. 16-20; Drug of the Future (1990), T. 15, 5, S. 495-508; and J. Enzyme Inhibition (1987), so 2, S. 1-22).

B. Research

The ability of compounds of the formula (I) inhibit the activity of matrix metalloprotease, in particular the activity of interstitial collagenase, 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 the experiment in vitro, which is described in Anal. Biochem. (1985), I. 147, S. 437, or its modifications. Physiological effects resulting from inhibition of matrix metalloprotease can be prodemos is or with modifications, or by the method of ex vivo using rat long bones of the embryo, described in Proc. Natl. Acad. Sci. USA (1988), I. 85, S. 8761-8765, or with modifications, or in J. Clin. Invest. (1965), I. 44, S. 103-116, either through modifications to it.

The ability to inhibit the activity of collagenase-1,-2 and -3, stromelysin-1, gelatinase and matrilysin can be prodemonstrirovana methods described in the article MMP Enzymatic Assay (enzymatic analysis of MMP (matrix metalloprotease)) FEBS, 296, 263 (1992), or using their modifications. The ability of compounds of the formula (I) to inhibit mediasuite MMP processes in vivo can be studied by the method using stimulated by interleukin-1 in cartilage Explant and method using implanted cartilage pin.

C. General purpose

Introduction compounds of formula (I) or their pharmaceutically acceptable salts, in pure form or in the form of appropriate pharmaceutical compositions can be made by any acceptable route of administration or agents used for such purposes. Thus, the introduction can be effected, for example, oral, nazalnam, parenteral, local, transdermal or rectal route in the form of solid, semi-solid, is oppositely, pills, gelatin capsules, soft elastic or hard shell, powders, solutions, suspensions, or aerosols, etc., preferably in the form of a standardized dosage forms suitable for simple introduction with accurate dosage. The composition may include a conventional pharmaceutical carrier or excipient and the compound of formula (I) as active ingredient, as well as other drugs, pharmaceutical agents, carriers, adjuvants, etc.

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

The preferred route of administration is oral, using the usual daily dosage regimen which can be adjusted depending on the Serie is Yu song, containing the compound(I) of the formula (I) or its pharmaceutically acceptable (s) g(and), are obtained by incorporating any commonly used excipients, such as, for example, pharmaceutically pure mannitol, lactose, starch, pre-gelatinizing 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 should be in the form of capsules, drops or tablets and, therefore, should include a diluent, such as lactose, sucrose, calcium diphosphate, etc., the agent that promotes disintegration, such as nitrocresols or its derivatives, a lubricant such as magnesium stearate, etc., and a binder, such as starch, gum acacia, polyvinylpyrrolidone, gelatin, ether derivatives of cellulose, etc.

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

A liquid composition intended for pharmaceutical purposes, may, for example, be prepared by dissolving, dispersing, etc. of the compound (s) of formula (I) from about 0.5% to about 20%) or its pharmaceutically acceptable (s) salt (s) 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, sautereau pH agents, antioxidants, etc. such as, for example, citric acid, sorbitanoleat, triethanolamine, bottled hydroxytrol etc.

Practical methods for such dosage forms are known or obvious to a person skilled in the art, for example, see Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, Easton, Pennsylvania, 1990). The applied composition in any case must contain a therapeutically effective amount of the compounds of formula (I) or a pharmaceutically primnosti matrix metalloprotease in accordance with the recommendations of the present invention.

The compounds of formula (I) or their pharmaceutically acceptable salts are used in therapeutically effective amounts, which largely has to depend on various factors, including the specific activity of the applied compound, the metabolic stability and length of action of the compound, the age, body weight, General health condition, sex of the patient, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular painful condition and therapy, which is exposed to the patient. Typically, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day for the compounds of formula (I) or its pharmaceutically acceptable salt, preferably from about 0.7 mg to about 10 mg/kg of body weight per day and most preferably from about 1.4 mg to about 7.2 mg/kg body weight per day. For example, in the appointment of a person weighing 70 kg, the dose range may vary 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 predpochtitel inventions

A first preferred class of compounds of formula (I) are those in which n is 1, 2 or 3, m is 3 and a denotes-CH2-. A preferred subclass of compounds of this class are those compounds in which n is 1 or 2 and in which R1denotes-CH2-R4and R3denotes hydrogen, primarily in which R2denotes 2-methylpropyl, biphenyldiol, Tien-2-retil, cyclopentyl, cyclopropylmethyl or cyclopentylmethyl and R4indicates acetylthio, mercapto, carboxy, alkoxycarbonyl, N-hydroxyaminobuteroyl or N-hydroxypropylamino.

A preferred subgroup of compounds of this group are those compounds in which R2denotes 2-methylpropyl or cyclopentylmethyl and R4indicates acetylthio, mercapto, carboxy, N-hydroxyaminobuteroyl or N-hydroxypropylamino.

Another preferred subgroup includes those compounds in which R1does

< / BR>
where R6denotes optionally substituted aryl, and the aryl group denotes an henol-2-yl, naphthas-1-yl, naphthas-2-yl, pyridyl or phenyl. The preferred podclass compounds of this class are those compounds in which R6about the which R1denotes-CH(R7)-R8where R7denotes-CH2Other, where R is primarily denotes hydrogen, R2denotes 2-methylpropyl or cyclopentylmethyl, R3denotes hydrogen and R8denotes carboxypropyl. Especially preferred are such compounds in which R stands for methoxycarbonyl, methanesulfonyl or amiloride.

Another preferred subgroup of compounds are those compounds in which R1denotes-CH(R7)-R8-R8where R7denotes alkyl, alkoxycarbonyl or carboxypropyl, R2denotes 2-methylpropyl or cyclopentylmethyl, R3denotes hydrogen and R8denotes carboxypropyl or hydroxyaminobuteroyl. Especially preferred are such compounds in which R7denotes methoxycarbonyl.

Another preferred subgroup of compounds are those compounds in which R1denotes-NH-CH(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R denotes carboxypropyl, alkoxycarbonyl or arelaxation.

Another preferred class are those compounds in which n is 2 or 3, m is 4, And obet hydrogen. A preferred subclass of compounds of this class are those compounds in which n is 2, R2denotes 2-methylpropyl and R11denotes methyl.

Another preferred class are those compounds in which the type is both equal to 2, a represents oxygen, R4denotes carboxypropyl or hydroxyaminobuteroyl and R2denotes aryl, aralkyl or alcoxialchil.

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

(3R, 10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.13.18], endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanamide;

(3R, 11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.14.19] eicosa-13(20),14(19),15,17-tetraen-11-ylcarbonyl)hexanamide

(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;

(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;

(3R, 9S)-4-cyclopentyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0.12.17]octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(3R, 9S)-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12(17),13,15-tetraen-9-Hai>]octadeca-11(18),12(17), 13,15-tetraen-9-ylcarbonyl)6-pyridin-4-rexanna acid;

(3R, 9S)-4-(3-methoxy-4,5(R, S)-dihydroisoxazole-5-yl)-3-(8-oxo-1,7-diazatricyclo[9.6.1.12.17] octadeca-11(18), 12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(3R, 9S)-4-(3-hydroxy-4,5(R,S)-dihydroisoxazole-5-yl)-3-(8-oxo-1,7-diazatricyclo [9.6.1.012.17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(3R, 9S)-4-(3-bromo-4,5(R, S)-dihydroisoxazole-5-yl)-3-(8-oxo-1,7-diazatricyclo [9,6.1.012.17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(2S, 3R,9S)-2-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.12.17] octadeca-11(18), 12(17), 13,15-tetraen-9-ylcarbonyl)hexanoic acid;

(2R, 3R, 9S)-2-(ethoxycarbonylmethyl-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;

(3R, 9S)-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo [9.6.1.012.17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)hexanoic acid;

(2R, 3R, 9S)-2-(methanesulfonylaminoethyl)-4-cyclopentyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11(18), 12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1.8-diazatricyclo [10.6.1.013.18]endeca-12(19),13(18),14,16-tetraen-10-ilikai)pentyl] quinoline-2-altimeter)phosphinic acid;

(10S)-2-acetyltributyl-4-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.013.18]endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)pentanone;

(3R, 10S)-N-hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanamide;

(3S, 10S)-4-cyclopentyl-3-(9-oxo-1,8 - diazatricyclo [10.6.1.013.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)butane acid;

ethyl ester of (3R, 10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid;

1-(2-dimethylaminoethyl)amide(3R, 10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

1 methylpiperidin-4-silt ether (3R, 10S)-5-methyl-3-(9-oxo-1,8-10 diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-3-cyclopentyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.013.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl) propionic acid;

(3R,10S)-4-cyclopropyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18]endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)butane acid;

(3R,10S)-6-(biphenyl-4-yl) -3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18]endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexane is)pentane acid;

(3R,10S)-2-(aminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-N-hydroxy-N-formylamino-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-2-(methoxycarbonylamino)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-6-pyridin-4-yl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12,(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-2-(methanesulfonylaminoethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18]endeca-12,19,13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-2-(3-ailuridae)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-N-hydroxy-N-formylamino-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.013.18]endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl) hexylamine;

(2S, 3R, 9S)-N-hydroxy-2-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;

(3R,9S)-5-methyl-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexane Ki is carbarnoyl)succinamide acid;

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-5-Phenoxyethanol acid;

(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14, l6-tetraen-9-ylcarbonyl)pentane acid;

ethyl ester of (3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0.12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)pentanol acid;

ethyl ester of (3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0.12.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-5-Phenoxyethanol acid;

(3R, 9S)-6-(4-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid;

(3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rexanna acid;

(3R, 9S)-6-[4-(3-hydroxypropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11 (18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid;

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-5-(4-phenoxyphenyl)pentane acid;

(3R,9S)-6-[4-(2-hydroxyethoxy)phenyl] -3-(8-oxo-4-oxa-1,7 - diazatricyclo[9.6.1.0.12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexane-[4-(2-pyrrolidin-1 ylethoxy) phenyl] hexanoic acid;

(3R, 9S)-6-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0.12.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R, 9S)-6-[4-(2-methoxyethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-5-phenylpentane acid;

(3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-phenylhexanoic acid;

(3R,9S)-6-(3-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0.12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(3-piperidine-1-ylpropionic) phenyl]hexanoic acid;

(3R, 9S)-6-[4-(3-dimethylaminopropoxy)phenyl] -3-(8-oxo-4-oxa-1,7 - diazatricyclo[9.6.1.0.12.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R, 9S)-6-[4-(2-dimethylaminoethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0.12.17] octadeca-11, (18,12,14,16)tetraen-9-ylcarbonyl)hexanoic acid;

(3R, 9S)-6-(4-tianfeng)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17]octadeca-11(18),12,14,16-tetraen-9-DECA-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R,9S)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-(4-pyrrol-1-ylphenyl) hexanoic acid;

(3R,9S)-6-(4-hydroxy-3-were)-3-(8-oxo-4-oxa-1,7 - diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R, 9S)-6-(4-benzyloxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0.12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R, 9S)-6-[4-(4-aminobutoxy)phenyl] -3-(8-oxo-4-oxa-1,7 - diazatricyclo[9.6.1.0.12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanoic acid;

(3R,9S)-5-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)pentane acid;

(3R, 9S)-6-(4-AMINOPHENYL)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid;

(3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-14-(pyridine-4-ylethoxy) phenyl] hexanoic acid;

(3R, 9S)-6-(4-acetylaminophenol)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17]octadeca-11,(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid; and

ethyl ester of (3R, 9S)-6-[4-(3-hydroxypropoxy)phenyl]-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.0. 12.17] octadeca-e formula (I) are derived peptides which can be obtained from the derivative --of amino acids comprising these peptides.

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, in Chemistry of the Amino Acids (1961), T. 1-3, John Wiley and Sons Inc.; in G. R. Pettit in Synthetic Peptides (1970), T. 1-2, Van Nostrand Reinhold Company.

Amide combinations used for the formation of compounds of formula (I) is usually carried out using the carbodiimide method with reagents, as dicyclohexylcarbodiimide or N,-ethyl-N,-(3-dimethylene-npropyl)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 methods of synthesis using a carboxylic acid, acylated, mixed anhydride or activated complex ester, such as nitrophenyloctyl ether, but are not limited to them. Typically amide combination is carried out in solution phase peptide fragments, or without them.

The choice of protective group for the terminal amino or carboxyl groups in the compounds used to produce compounds of formula (I), partially op is or peptide, involved in combination. Usually used aminosidine groups include those well known in the art, as, for example, benzyloxycarbonyl (carbobenzoxy), paramethoxyamphetamine, paranitroaniline, tertbutoxycarbonyl (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 catalytic hydrogenation.

Individual stereoisomers of compounds of formula (I) can be separated from each other by methods known to experts in the art, for example, when R1denotes carboxypropyl, by separation (e.g. fractional crystallization, chromatography and/or by the methods described in the description) of the diastereomeric salts formed by interaction of the compounds of formula (I) with an optically active base at a temperature in the range of 0oWith up to the temperature of reflux distilled solvent used for fractionated crystallization. Examples of such optically active osnovii substituents and/or variables in the compounds of formula (I) valid only when such combinations result in stable compounds.

A. Obtaining intermediate compounds: the compounds of formula (J)

The compounds of formula (J):

< / BR>
in which R3has the values specified in section "Summary of the invention", and p is 5,6,7 or 8, is suitable for producing compounds of formula (I). The compounds of formula (J) are obtained according to reaction scheme 1, below, R3and R have the above values, VOS denotes tertbutoxycarbonyl and R13denotes hydrogen, mesyl or tosyl.

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

Usually the compounds of formula (J) receive a first esterification of the alcohol of formula (V) with acetic anhydride in the presence of a base, preferably pyridine, with the formation of the compounds of formula (C), which is then restored in the presence of acetic anhydride, receiving compound of formula (D). The compound of formula (D) is subjected to hydrolysis in an acidic medium, preferably in the presence of hydrochloric acid, with formation of compounds of Catania, for example, with EDCI in the presence HOBT in DMF, receiving the compound of formula (G), in which R13denotes a hydroxy-group. This connection can then be processed either by mozillateam or methylchloride with the formation of the compounds of formula (G), in which R13indicates mesyl or tosyl. 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 allows to obtain the compound of formula (H). In another embodiment, the cyclization of the thus obtained of tozilaty with concentrated sodium hydroxide in an inert solvent, preferably in CH2Cl2in the presence of a phase transfer catalyst, preferably hydrogen Tetra-(n-butyl)ammonium, allows to obtain the compounds of formula (H). The protective group in the compounds of formula (H) is removed in the acid medium, preferably in the presence of triperoxonane acid, obtaining 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) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4the seat is Britania".

The compounds of formula (Ib) are compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes carboxypropyl, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (Ic) are compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes benzylaminocarbonyl, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (Id) are compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes hydroxyaminobuteroyl, and R2and R3have the values specified in section "Summary of the invention".

Compounds of formula (Ia), (Ib), (Ic) and (Id) are obtained according to the following reaction scheme 2, where R is 5,6,7 or 8, R14denotes alkyl or benzyl, R7adenotes hydrogen or alkoxycarbonyl and R2and R3have ucaut ways, presented in the present description, or they can be obtained by methods known to experts 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 with the formation of the compounds of formula (Ia). The protective group in the compound of formula (Ia) is then removed in a slightly acidic environment, receiving compound of formula (Ib).

The compound of formula (Ib) is then subjected to a combination of 0-benzylhydroxylamine under standard conditions of peptide combinations, obtaining the compound 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 (Ia) are compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4indicates acetylthio, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (If) are compounds of formula (I) in which n rawnet mercaptopropyl, and R2and R3have the values specified in section "Summary of the invention".

Compounds of formula (Ie) and (If) are obtained according to the following reaction scheme 3, where R2and R3have the above values 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 with the formation of the compounds of formula (Ia). Treatment of compounds of formula (Ie) concentrated NH4OH in methanol allows to obtain the corresponding compounds of formula (If).

, Obtaining compounds of formula (K) and their individual stereoisomers

The compounds of formula (K):

< / BR>
in which R14denotes alkyl or benzyl and R denotes hydrogen, alkoxycarbonyl, hydroxycarbamoyl, carboxypropyl or optionally substituted carbarnoyl, is used to produce compounds of formula (I). Individual stereoisomers of compounds of formula (K) is used to obtain the corresponding stereos is SUP> denotes hydrogen, are stereoisomers of the compounds of formula (K), which have the R-configuration. The compounds of formula (Ka) are obtained according to the following reaction scheme 4, where R2has the above values

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

The compounds of formula (NN) 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, supplied by Aldrich company.

Usually the compounds of formula (Ka) are obtained by first condensing the compounds of formula (NN) with Sultana L-(+)-2,10-camphor with the formation of the compounds of formula (N). After you have added within one hour NaHMDS (hexamethyldisilazide sodium) for the formation of anion reaction stop using tributylphosphate with the formation of the corresponding complex ester of the formula (Q). Then remove the camphor group in an alkaline medium, receiving individual stereoisomer of the compound fo is ariante the compounds of formula (Ka) can be obtained in accordance with the following reaction scheme 4A.

The compound of formula (HH) is first condensed with the 4S-fenilmetilketenom under standard conditions, obtaining the corresponding compound of formula (aa). To the compound of formula (aa) add approximately equimolar amount hexamethyldisilazide sodium in an inert solvent, such as THF. The reaction proceeds at a temperature of from -70 to -95oC for approximately 15 minutes. To this mixture is added an excess of tributylphosphate and the solution is stirred for approximately 2 hours at a temperature of from -90 to -60oWith getting basically the only stereoisomer of formula (bb), which is purified using standard methods of organic chemistry. Oxazolidinone group of compounds of formula (bb) is removed in an alkaline medium, receiving individual stereoisomer of formula (Ka).

The compounds of formula (Kb):

< / BR>
in which R7cdenotes alkoxycarbonyl, can be obtained according to 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 amount of concentrated H2SO4in methylene chloride, followed by distillation and the receipt of the butyl ester of formula (S). The compound of formula (S) are then subjected to interaction with the compound of the formula (T) in the presence of tertbutoxide potassium, receiving the compound of formula (U). After hydrolysis of the compounds of formula (U) in an acidic medium, preferably in the presence of triperoxonane acid at room temperature, obtain the connection formula (Kb), in which R7cdenotes alkoxycarbonyl.

The compounds of formula (K), in which R7adenotes carboxypropyl, can be obtained from compounds of formula (Kb), in which R7cdenotes alkoxycarbonyl, by methods known to experts in the art, for example, by hydrolysis.

In addition to the above-described process for the production of isomers of compounds of formula (K), the compounds of formula (K), in which R7adenotes alkyl, can be obtained by treating compounds of formula (K), in which R7adenotes hydrogen, in an aprotic solvent, for example, THF, in the presence of NaN(tetramethylsilane)2, haloalkanes, preferably by iodomethane, obtaining the compounds of formula (K), in which R7adenotes alkyl.

D. Receipt is about 1,2 or 3, m is 3 or 4, 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) are obtained according to the following reaction scheme 6, where R is 5,6,7 or 8,R,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 described below in example 19. The compounds of formula (Z) are commercially available or can be obtained in accordance with methods known to experts in this field of technology.

Usually the compounds of formula (Ig) are obtained first by treating the compounds of formula (W) formamide with the formation of the compounds of formula (X). The compound of formula (X) is then treated with chloride Totila or mesila in an alkaline medium with the formation of the compounds of formula (Y). The compound of formula (Y) are then subjected to interaction with Sol the Oia formula (Z) with sodium hydride) to give the compounds of formula (AA). The compound of formula (AA) are then subjected to hydrolysis in an alkaline medium to obtain the compounds of formula (IV). The compound of formula (IV) is then subjected to the combination with the compound of the formula (J) in the standard peptides conditions, preferably from 1.1,-carbonyl diimidazol, receiving the compound 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, in which the indole ring is fully saturated. Get them according to the following reaction scheme 7, where R2and R3have the values specified in section "Summary of the invention", R7Adenotes hydrogen and R is 5,6,7 or 8.

Typically, compounds of formula (Ih), (Ii) and (Ij) are obtained first by restoring the compounds of formula (Ib) under conditions of catalytic hydrogenation with the formation of the compounds of formula (Ih). The compound of formula (Ih) are then subjected to the interaction with O-benzylhydroxylamine under standard conditions of peptide combinations, obtaining the compound of formula (Ii). Then, from the compounds of formula (Ii) remove the benzyl protective group in terms of catalyt)

The compounds of formula (Ik) are compounds of formula (I) with allyl coupling, in which n is 2 or 3, m is 4, And refers to-NR11where R11denotes hydrogen or alkyl, R1denotes-CH2-R4where R4denotes tertbutoxycarbonyl, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (Il) are compounds of formula (I) with allyl coupling, in which n is 2 or 3, m is 4,And refers to-NR11where R11denotes hydrogen or alkyl, R1denotes-CH2-R4where R4denotes carboxypropyl, and R2and R3- have the values specified in section "Summary of the invention".

The compounds of formula (Im) are compounds of formula (I) with allyl coupling, in which n is 2 or 3, m is 4,And refers to-NR11where R11denotes hydrogen or alkyl, R1denotes-CH2-R4where R4denotes benzylaminocarbonyl, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (In) are the compounds of formula denotes-CH2-R4where R4denotes hydroxyaminobuteroyl, and R2and R3have the values specified in section "Summary of the invention".

Compounds of formula (Ik), (Il), (Im) and (In) receive according to the following reaction scheme 8, where n is 2 or 3,R2,R3and R11have the above values, R14denotes alkyl or benzyl, R7adenotes hydrogen and VOS denotes tertbutoxycarbonyl.

The compounds of formula (F) are obtained by methods known to experts in the art or by the methods presented in this description.

Typically, compounds of formula (Ik), (II), (Im) and (In) receive a first interaction of the compounds of formula (F) with diaminoalkanes or monoalkylammonium diaminoalkanes under standard conditions of peptide combinations, for example, with HOBT and EDCI, in an inert solvent, for example, in DMF, to form compounds of formula (DD). The compound of formula (DD) are then subjected to interaction with TRANS-1,4-dichlorobut-2-Yong in an alkaline medium, receiving the compound of formula (IT). Aminosidine group of compounds of formula (IT) is then removed in a weakly acidic medium, preferably processing triperoxonane acid, receiving the connection Foch conditions of peptide combinations, for example, HOBT and EDCI, receiving the compound of formula (Ik). The protective group of the compounds of formula (Ik) then removed in weakly acidic medium, preferably processing triperoxonane acid, receiving the connection formula (Il). The compound of formula (Il) is then treated On-benzylhydroxylamine under standard conditions of peptide combinations, obtaining the compound of formula (Im). The protective group of the compounds of formula (Im) is then removed under conditions of catalytic hydrogenation, receiving compound of formula (In).

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

The compounds of formula (I) are compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-,R1denotes-NH-CH(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R10denotes arelaxation, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (IP) represent the connectivity of the formula (I) in which n is 1, 2 or 3, m is 3 or 4,a represents-CH2-, R1denotes-NH-CH-(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R10denotes carboxypropyl, and R2and R3and the) and (IP) are obtained according to the following reaction scheme 9, where R is 5,6,7 or 8, and R2,R3and R9have the above values.

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

Typically, compounds of formula (I) and (IP) receive first treatment of compounds of formula (JJ) Trifonova anhydride, and then by treating the compounds of formula (QC) in an alkaline medium with the formation of the compounds of formula (LL). Then the compound of formula (LL) is subjected to hydrolysis in acid medium, preferably processing triperoxonane acid, receiving the connection formulas (MM). Then the compound of formula (MM) is subjected to the combination with the compound of the formula (J) under standard conditions of peptide combinations, obtaining the compound of formula (O). Then, the compound (A) remove the protective group receiving compound of formula (IP).

I. Obtaining compounds of formula (Iq), (Ir)

The compounds of formula (Iq) are compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH(R7)-R8where R7denotes-CH2Other, where R is hydrogen and R8denotes carboxypropyl, benzyloxycarbonyl or alkoxy the ASS="ptx2">

The compounds of formula (Ir) are compounds of formula (I) in which n is 1, 2 or 3,m is 3 or 4,a represents-CH2-, R1denotes-CH(R7)-R8where R7denotes-CH2Other, where R is hydrogen and R8denotes carboxypropyl, and R, R2and R3have the values specified in section "Summary of the invention".

Compounds of formula (Iq) and (Ir) are obtained according to the following reaction scheme 10.

Compounds of formula (J) receives the following methods. The compounds of formula (NN) are obtained by methods well known to experts in the art, for example as described in EP 575844.

Typically, compounds of formula (PP) and (lq) receive first by combining the compounds of formula (J) compound of formula (NN) under standard conditions of peptide combinations, obtaining the compound of formula (PP). Phthalimido group of compounds of formula (PP) is then converted into the amine by standard methods, for example, by treatment with hydrazine, receiving compound of formula (Iq).

The compound of formula (Iq) can then be converted into a compound of formula (Ir) using reactions well known in the art. For example, vzaimodeystviya in the presence triperoxonane acid allows to obtain the compound of formula (Ir), in which R is alkylsulfonyl. Similarly, the interaction of the compounds of formula (Iq) with alkyl-, aryl - or aralkylamines allows to obtain the corresponding carbamate, interaction with allelochemical allows to obtain the corresponding amide, interaction with an appropriately substituted isocyanate allows to obtain the corresponding urea, etc.

K. Obtaining compounds of formula (I). in which R1denotes-CH-R4. where R4denotes the N-th hydroxypropylamino

To obtain the compounds of formula (I) in which R1denotes-CH2-R4where R4denotes the N-th hydroxypropylamino, the compound of formula (J) is first subjected to interaction in the conditions of peptide combinations described above, with the compound of the formula:

< / BR>
Such compounds can be obtained according to the description in U.S. patent 08/343158, full details of which are included in the present description by reference.

The product of this reaction combinations then dibenzyline manner similar to that described above in reaction scheme 2, receiving the compound of formula (I) in which R1denotes-CH2-R4where R4denotes the N-th hydroxypropylamino.

1denotes-CH2-R4where R4denotes tertbutyloxycarbonyl, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (It) are compounds of formula (I) in which m and n are both equal to 2,a represents oxygen, R1denotes-CH2-R4where R4denotes carboxypropyl, and R2and R3have the values specified in section "Summary of the invention".

The compounds of formula (Iu) are compounds of formula (I) in which m and n are both equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes alkoxycarbonyl, and R2and R3have the values specified in section "Summary of the invention".

Compounds of formula (Is), (It) or (Iu) are obtained according to the following reaction scheme 11.

The compounds of formula (Ka) can be obtained in accordance with this description. Obtaining compounds of formula (ff) is presented below.

Usually the compounds of formula (Is) are obtained first by combining the compounds of formula (Ka) with the compound of the formula is of the formula (Is) in a weakly acidic environment allows to obtain the corresponding compounds of formula (It).

The compounds of formula (Is) may also be converted into compounds of formula (Iu), in which R1denotes-CH2-R4where R4denotes alkoxycarbonyl other than tertbutyloxycarbonyl, by methods known in the art.

In addition, the compounds of formula (I) in which m and n equal to 2,a represents oxygen, R1denotes-CH2-R4where R4denotes hydroxyaminobuteroyl, and R2and R3have the values specified in section "Summary of the invention" can be obtained in accordance with the methodology described above to obtain compounds of formula (Id) from compounds of formula (IC).

M. Obtaining the compounds of formula (ff)

Obtaining the compounds of formula (ff)

< / BR>
shown in the following reaction scheme 12.

Compounds of formula (kk) and (ll) are commercially available, for example, are supplied by firms Sigma and Aldrich, respectively, or may be obtained by methods known to experts in this field of technology.

The compounds of formula (ll), shown in reaction scheme 12, is used to obtain the compounds of formula (I) in which m and n are both equal to 2. Obviously, the process shown in reaction CX is/SUB>)mOH, in which m and n have the meanings specified in section "Summary of the invention". These compounds are either commercially available or can be obtained by methods well known to specialists in this field of technology.

Typically, the compound of formula (ff) receive first by combining the compounds of formula (kk) with the compound of the formula (ll) under standard conditions of peptide combinations, for example, with DCC in the presence HOBT in DMF, to obtain the compound of formula (mm). This compound of formula (mm) is then treated with mozillateam, receiving the compound of formula (nn). For this reaction instead of tosylchloramide can also be used methylchloride. Cyclization of the thus obtained tosilata with an excess of NaH in an inert solvent, preferably THF, at a strong dilution and at room temperature allows to obtain a compound of the formula (ro). Alternatively, cyclization of the thus obtained tosilata with concentrated sodium hydroxide in an inert solvent, preferably in CH2CL2in the presence of a phase transfer catalyst, preferably hydrogen Tetra(n-butyl) ammonium, allows to obtain a compound of the formula (ro). Protective groupware, receiving the compound of formula (ff).

N. Obtaining compounds of formula (Iv)

The compounds of formula (Iv) are compounds of formula (I) in which m and n are both equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes carboxypropyl or alkoxycarbonyl, and R2denotes aralkyl, in which the chain alkylene represents -(CH2)3-, and R3has the values specified in section "Summary of the invention".

The compounds of formula (Iv) are obtained according to the following reaction scheme 13.

The compound of formula (ff) can be obtained according to the methods described in this description.

The compounds of formula (gg) can be obtained according to reaction scheme 4A with the replacement of the compounds of formula (NN) sootvetstvuyuschim allyl compound, in which the group denoted as R2in the formula (NN), is a prop-2-enyl.

Usually the compounds of formula (Iv) are obtained first by combining the compounds of formula (ff) with a compound of formula (gg) under standard conditions of peptide combinations, obtaining the compound of formula (hh).

The introduction of aryl groups R2in allyl chain by abalene of arylalkenes, preferably bromide or iodide, and aging the reaction mixture for about 2-4 hours, preferably 4 hours, at a temperature of about 100oWith obtaining the compounds of formula (ii). Catalytic hydrogenation (Pd/C) allyl compounds of the formula (ii) allows to obtain the corresponding compounds of formula (Iv').

The compounds of formula (Iv') can be converted into the corresponding compounds in which R1denotes-CH2-R4where R4denotes carboxypropyl or other alkoxycarbonyl group, using methods that are described for producing compounds of formula (It) or (Iu).

In another embodiment, atilirovanie can be carried out first for compounds of formula (gg) in the above-described methods, and the resulting compound of formula (Ka) is then subjected to the combination with the compound of the formula (ff).

Acting Obtaining compounds of formula (Iw)

The compounds of formula (Iw) are compounds of formula (I) in which R2denotes aralkyl, in which aryl substituted by alkoxygroup (aryl-O-R2and m, n, R1and R3have the values specified in section "Summary of the invention".

These compounds can be on oznachaet hydrogen.)

Salts of compounds of formula (I)

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

Thus, the compounds of formula (I) receive:

1) the interaction of the compounds of formula (K), in which R7adenotes hydrogen or alkoxycarbonyl, R14denotes alkyl or benzyl and R2has the values specified in section "Summary of the invention", with the compound of formula (J), where p is 5, 6, 7 or 8, and R3has the values specified in section "Summary of the invention", to obtain the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes alkoxycarbonyl, and R2and R3have the values specified in section "Summary of the invention", or

2) converting the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH22-, R is-CH2-R4where R4denotes carboxypropyl, and R2and R3have the values specified in section "Summary of the invention", or

3) treatment of compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R*denotes-CH2-R4where R4denotes carboxypropyl, and R2and R3have the values specified in section "Summary of the invention", O-protected hydroxylamine such as O-benzylhydroxylamine, obtaining the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes benzylaminocarbonyl, and R2and R3have the values specified in section "Summary of the invention", or

4) converting the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes benzylaminocarbonyl, and R2and R3have the values specified in section "Summary of the invention", UB>2-R4where R4denotes hydroxyaminobuteroyl, and R2and R3have the values specified in section "Summary of the invention", or

5) the interaction of the compounds of formula (M) in which R2has the values specified in section "Summary of the invention", with the compound of formula (J), where p is 5, 6, 7 or 8, and R3denotes hydrogen, to obtain the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4indicates acetylthio, and R2and R3have the values specified in section "Summary of the invention", or

6) the transformation of compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes acetylthiourea, and R2and R3have the values specified in section "Summary of the invention", in the compound of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH2-R4where R4denotes mercaptopropyl, and R2and R3have the values listed in the section "Summary of the su is Azania in the section "Summary of the invention", and R6denotes optionally substituted aryl, and the aryl group denotes an henol-2-yl, naphthas-1-yl, naphthas-2-yl, pyridyl or phenyl, with the compound of formula (J), where p is 5, 6, 7 or 8, and R has the values specified in section "Summary of the invention", to obtain the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, 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, and R2and R3have the values specified in section "Summary of the invention", or

8) the transformation of compounds of formula (Im), in which n is 2 or 3, m is 4, And refers to-NR11where R11denotes hydrogen or alkyl, R1denotes-CH2-R4where R4denotes benzylaminocarbonyl, R2and R3have the values specified in section "Summary of the invention", in the compound of formula (I) in which n is 2 or 3, m is 4, And refers to-NR11where R11denotes hydrogen or alkyl, R1denotes-CH2-R4where R4means of the invention", or

9) the interaction of the compounds of formula (MM), in which R9denotes hydrogen, alkyl or aralkyl and R2has the values specified in section "Summary of the invention", with the compound of formula (J), where p is 5, 6, 7 or 8, and R has the values specified in section "Summary of the invention", to obtain the compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes NH-CH(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R10denotes arelaxation, and R2and R3have the values specified in section "Summary of the invention", or

10) the transformation of compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes NH-CH(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R10denotes arelaxation, and R2and R3have the values specified in section "Summary of the invention", in the compound of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes NH-CH(R9)-R10where R9denotes hydrogen, alkyl or aralkyl and R10the STI of the invention", or

11) the transformation of compounds of formula (PP), where p is 5, 6, 7 or 8, R14denotes a hydroxy-group, benzyl or alkyl and R2and R3have the values specified in section "Summary of the invention", in the compound of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH(R7)-R8where R7denotes-CH2Other, where R is hydrogen and R8denotes carboxypropyl, benzyloxycarbonyl or alkoxycarbonyl, and R2and R3have the values specified in section "Summary of the invention", or

12) the transformation of compounds of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH(R7)-R8where R7denotes-CH2Other, where R is hydrogen and R8denotes benzyloxycarbonyl or alkoxycarbonyl, and R2and R3have the values specified in section "a Brief izlojeniem of the invention, in the compound of formula (I) in which n is 1, 2 or 3, m is 3 or 4, a represents-CH2-, R1denotes-CH(R7)-R8where R7denotes-CH2Other, where R is hydrogen and R8denotes carboxypropyl 13) the interaction of the compounds of formula (Ka), in which R2has the values specified in section "Summary of the invention", with the compound of formula (ff), in which R3has the values specified in section "Summary of the invention", to obtain the compounds of formula (I) in which m and n are both equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes tertbutyloxycarbonyl, and R2and R3have the values specified in section "a Brief izlozheniya of the invention", or

14) the hydrogenation of the compounds of formula (ii) in which R3has the values specified in section "Summary of the invention", to obtain the compounds of formula (I) in which m and n are both equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes tertbutoxycarbonyl, and R2denotes aralkyl (aryl-(CH2)3-), and R3- has the values specified in section "Summary of the invention", or

15) the transformation of compounds of formula (I) in which m and n are both equal to 2, a represents oxygen, R represents-CH2-R4where R4denotes tertbutyloxycarbonyl, and R2and R3have the values listed in the section "Brief izlozeni the means-CH2-R4where R4denotes carboxypropyl, and R2and R3have the values specified in section "Summary of the invention", or

16) the transformation of compounds of formula (I) in which m and n are both equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes carboxypropyl or tertbutyloxycarbonyl, and R2and R3have the values specified in section "Summary of the invention", in the compound of formula (I) in which m and n are both equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes alkoxycarbonyl other than tertbutyloxycarbonyl, and R2and R3have the values specified in section "Summary of the invention", or

17) the transformation of compounds of formula (I) in which R2denotes hydroxyarylalkyl, and m, n, R1and R3have the values specified in section "Summary of the invention", in the compound of formula (I), in which2denotes alkoxyalkyl and m, n, R1and R3have the values specified in section "Summary of the invention".

Below the invention is illustrated in the examples, which are not ogranichivaya in 30 ml of acetic anhydride in an argon atmosphere. To this product was added dropwise to 5.3 ml (65,4 mmole) of pyridine and the mixture was stirred for 2 hours. The contents of the flask were then poured into a chemical beaker containing 50 ml of ice water and the product was stirred for 15 minutes. 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. After evaporation (rotary evaporator and vacuum pump) received 6-cyan-1-acetoxylation (compound of formula (C), which is immediately used in the next stage.

B. 6-cyan-1-acetoxylation (55.8 mmole) was dissolved in approximately 100 ml of acetic anhydride in a reaction vessel Parra (500 ml). To this mixture was added acetic acid (0.5 ml), and then the platinum oxide (100 mg). The vessel was placed in an apparatus for the hydrogenation Parra and charged with gaseous hydrogen (40 psi). The product was shaken for 12 hours, filtered through celite to remove the catalyst) was charged fresh platinum oxide (100 mg) and hydrogen (40 psi) and shaken for 24 hours. The product was filtered through cetaminophen 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 200 ml round bottom flask. To this mixture was added 50 ml of 40% aqueous hydrochloric acid and the mixture is boiled under reflux for 60 hours. All volatile components were removed under reduced pressure. The desired 7-amino-1-heptanol received in the form of cleaners containing hydrochloride crystalline salt with tPL74-81oC, MS: 131 (MN+).

Example 2

The compounds of formula (G)

A. N-methylmorpholine (2.2 ml, 19.7 mmole) was added dropwise under stirring and at room temperature, the hydrochloride of 7-amino-1 - heptanol (3,3 g, 19.7 mmole) in 50 ml of anhydrous DMF in an argon atmosphere. After stirring for 5 minutes were added the following compounds: N-tertbutoxycarbonyl-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. The residue was dissolved in cold 2,5% Hcl (100 ml) and ethyl acetate (CH ml) and transferred into a separating funnel. The organic phase was isolated and then washed cold with 2.5% Hcl (100 ml) and then with brine (100 ml). An ethyl acetate phase was dried (MgSO4), filtered and koncentrere cm-1;

1H-NMR (80 MHz, D13): 0,98-of 1.62 (m, 10H, ), 1,45 (s, 9H, tertbutyl), 2,86-of 3.32 (m, 4H, CH - HN-), 3,68 (t, 2H, J=5.6 Hz, -), 4,22-4,55 (m, 1H, ), 5,12-5,32 (broad d, 1H, -CH), 5,65-5,9 (broad t, 1H, -CH2), 6,98-a 7.92 (m, 5H, ), 8,63 (broad s, indole ).

B. a Solution of N-tertbutoxycarbonyl-L-tryptophan-(7-hydroxyethyl)amide (8,2 g) in 150 ml of anhydrous pyridine was cooled at 0oC (ice bath). In one portion to the solution was added paratoluenesulfonyl (4.7 g) and cooled the 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-tertbutoxycarbonyl-L-tryptophan-(N'-(7-(4'-methylphen-1-yl)sulfonyloxy)heptyl)amide was isolated using column chromatography with silica gel, using as eluent from 10 to 40% ethyl acetate/hexane. This product crystallized upon maturation, MS: 572 (MN+).

C. In another embodiment, the solution containing N-tertbutoxycarbonyl-L-tryptophan (5.0 g, 16,45 mmole), 6-amino-1-hexanol (2,31 g to 19.74 mmole) and 1-hydroxybenzotriazole2On (2,52 g, 16,45 mmole) in anhydrous 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 the part was washed for 1H. HCl (75 ml), saturated sodium bicarbonate solution (g ml) and finally with brine (50 ml). The organic layer was dried (MgSO4) and was evaporated to dryness, obtaining 6,45 g (97%) of N-tertbutoxycarbonyl-L-tryptophan-N'-(6-hydroxyhexyl)amide as a white foam,

MS: 404,3 (M+N)+. The purity of the product was confirmed using analytical GHUR.

, Next to the N-tertbutoxycarbonyl-L-tryptophan-N'-(6-hydroxyhexyl)amide (5.5 g, 13,64 mmole) in 150 ml of anhydrous pyridine at 0oC in an atmosphere of argon was added to 3.9 g (20,46 mmol) paratoluenesulfonyl. 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 NaHCOg (50 ml) and with brine (50 ml). The organic layer was dried (MgSO4) and was evaporated, obtaining N-tertbutoxycarbonyl-L-tryptophan-(N'-(6-(4'-methylphen-1-yl)sulfonyloxy)hexyl)amide in the form of oil, pale yellow (5,77 g, 76%), MS: 558,3 (M+N)+.

D. To 5-hydroxytryptophan (3.5 g, postavleny firm Sigma), triethylamine (5.6 ml) in water (25 ml) and tetrahydrofuran (50 ml) was added BOC-ON (2- (tertbutoxycarbonyl) -2-Regaleali with 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, gaining syrup. The syrup was subjected to interaction with 6-amino-1-hexanol manner similar to that described above in example 1B, receiving N-tertbutoxycarbonyl-L-(5-hydroxy)tryptophan-N'-(6-hydroxyhexyl)amide. Half of this product was dissolved in 40 ml of DMF and treated at room temperature overnight TO2CO3(5 g) and iodomethane (1.2 g). Then the reaction mixture was 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, obtaining oil. Then the product, N-tertbutoxycarbonyl-L-(5-methoxy)tryptophan-N'-(6-hydroxyhexyl)amide was purified by chromatography on silica gel;

1H-NMR (D13): 0,9-1,6 (m, CH28H); 1,45 (s, 9H); 2,7-3,3 (m, 5H); 3.6 (t, 2H); 3,85 (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).

That is, the Same way received the following connections:

N-tertbutoxycarbonyl-L)amide;

N-tertbutoxycarbonyl-L-(5-ethyl) - tryptophan-N'-(6-hydroxyhexyl)amide; and

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

Example 3

The compounds of formula (H)

A. N-tertbutoxycarbonyl-L-tryptophan-(N'-(4'-methylphen-1-yl)sulfonyloxy)amide (of 6.78 g) was added in portions 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 dissolved in water (150 ml) and CH2CL2(150 ml). The aqueous phase is slightly acidified with 2.5% HCl (pH 3-4), 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, receiving semi-solid product is yellow-green. By purification using chromatography on silica gel was obtained (11S)-11-N'-(tertbutoxycarbonyl)amino-10-oxo-1,9-diazatricyclo[11.6.1.014.19] eicosa-13(20), 14(19), 15,17-tetraen, tPL208-209oC, MS: 400 (M+N)+.

B. In another embodiment, to N-tertbutoxycarbonyl-L-tryptophan-(N'-(6-(4'-methylphen-1-yl)sulfonyloxy)hexyl)amide (5 g, 8,97 mmole) in one liter of anhydrous THF at 0oC in an atmosphere of argon is whether over night at room temperature. The resulting mixture of yellow color was evaporated to -200 ml and then added to 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, was suirable 30% ethyl acetate in CH2Cl2receiving 1.2 g (35%) (10S)-10-N'-(tertbutyloxycarbonyl)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+H)+, tPL222-223oC.

C. In another embodiment, to a solution of N-tertbutoxycarbonyl-L-tryptophan-(N'-(6-(4'-methylphen-1-yl)sulfonyloxy)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 benzyltriethylammonium (0.65 mmole, 148 mg). A two-phase mixture was intensively stirred at room temperature overnight. 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 was evaporated to dryness. The residue was stirred in 10% simple ether in petroleum ether at 0oC for 15 minutes and Phi is and-12(19),13(18),14,16-tetraene in the form of white powder.

Example 4

The compounds of formula (J)

A. (11S)-11-N'-(tertbutyloxycarbonyl)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 (TFA) in methylene chloride and was stirred for 1 hour. Volatile components were removed under reduced pressure. The residue was dissolved in CH2CL2(40 ml) and 1N. NaOH (40 ml) and transferred into a separating funnel. The organic phase was isolated and washed with brine, dried (MgSO4), filtered and concentrated, getting 654 mg (11S)-11-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'-(tertbutyloxycarbonyl)amino-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen (0.5 mmole, 193 mg) was stirred in a mixture of 20% TFA/CH2CL2(10 ml) at room temperature for 2 hours. The excess TFA and solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml) and washed with 1N. HCl (25 ml), brine solution (10 ml) and dried (MgSO4). After evaporation to dryness received 140 mg (quantitative yield) (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraene in the form of a white foam, tPL157-160y contains (11S)-11-amino-(10-oxo-l, 9-diazatricyclo[11.6.1.014.19] eicosa-13(20), 14(19), 15,17-tetraen (654 mg) and racemic 4-methyl-2-tertbutoxycarbonyl acid (800 mg) in 30 ml of anhydrous DMF, was added in an argon atmosphere of 1-hydroxybenzotriazole (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 dissolved in a mixture consisting of CH2Cl2(100 ml) and 1.5% cold HCl (100 ml), and transferred into 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). CH2CL2phase was dried (MgSO4), filtered and concentrated, receiving semi-crystalline product, tributyl 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. Two individual stereoisomer of the compounds were separated using chromatography on silica gel with ethyl acetate/hexane as eluent. The less polar stereoisomer had a melting point 154-157oC []24D=-43,9owith=23,8 mg/2 ml CHCl3whereas the more polar stereoisomer had a melting point 168-171oS, 2R)-4-methyl-2-(tertbutoxycarbonyl)pentane acid, obtained by the above method, (2,39 g, 10.4 mmol), HOBtH2O (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 anhydrous DMF (200 ml) in an argon atmosphere, was added EDCI (3,96 g, 2.0 EQ.). The resulting mixture was stirred over night and then the next morning DMF was removed at 35oWith 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 Manso3(G ml) and finally with brine (CH ml). After drying, CH2CL2layer over Na2SO4it was filtered and evaporated to dryness. After purification using column chromatography (using only petroleum ether to a mixture of 30% ethyl acetate/petroleum ether) received tributyl ether (3R, 10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18]endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid (3,24 g, 62.7 percent).

C. in a Similar way received the following compounds of formula (Ia):

tributyl ether (3R,10S)-4-phenyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid, MS: 532 (M+N)+train-10-ylcarbonyl)butane acid, MS: 538 (M+N)+;

tributyl 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)+;

tributyl 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[10.6.1.013.18] endeca-12, (19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS: 590 (M+N)+;

tributyl ether (3R, 10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid;

methyl ester of (3R, 10S)-4-cyclopentyl-3-(9-oxo-1,8-district - lo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid, MS: 496 (M+N)+;

tributyl ether (3R, 10S)-4-cyclopropyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid;

ethyl ester of (3R,9S)-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

ethyl ester of (3R, 9S)-6-pyridin-4-yl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12(17),13,15-tetraen-9-alkarbala the ESA-11(18),12(17),13,15-tetraen-9-ylcarbonyl)pentanol acid;

tributyl 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;

ethyl ester 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;

isopropyl 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;

ethyl ester of (3R, 10S)-5-methyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

ethyl ester of (3R, 10S)-4-cyclopentyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid;

tributyl ether (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid; and

isopropyl ether (3R, 10S)-4-cyclopentyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid.

In a similar way received the following connection:

(3R, 10S)-N-benzyloxy-N-formyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-, 12(19), 13(18), 14,16-tetraen-10-ylcarbonyl) hexylamine.

the esters under the conditions described in example 56:

methyl ester of (3R,9S-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

methyl ester of (3R, 9S-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12(17),13,15-tetraen-9 ylcarbonyl)pentanol acid; and

methyl ester 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.

D. In another embodiment, to (2R)-4-methyl-2-(tertbutoxycarbonyl)pentanol acid (1 g, 4,34 mmole) in anhydrous THF (100 ml) at -78oC in an atmosphere of argon 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 the resulting mixture was stirred overnight at a temperature of from -78oWith up to room temperature. The next day the reaction was stopped by adding water (100 ml). After simple extraction with ether (CH ml) the aqueous layer was combined with an 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 concentracao color (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-tetraen (399 mg, 0.7 EQ. ) in anhydrous DMF at 0oC in an atmosphere of argon was added HOBT.N/ a) (1.1 EQ. , 234 mg), and then EDCI (663 mg, 2.5 EQ). The resulting mixture was stirred overnight at a temperature of from 0oWith up to room temperature. A large part of the DMF was removed by distillation under vacuum at 65oC. Then the residue was distributed between CH2Cl2(150 ml). After washing with 0.5 N. HCl (g ml), saturated Panso3(G ml) and saline (CH ml) the organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified using quick column chromatography on silica, elwira 30% ethyl acetate in petroleum ether to obtain a mixture of three compounds, two individual stereoisomers: butyl methyl ether (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid and butyl ether (3R, 105)-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 was divided three connections; tributyl ether (3R,Ty (13 mg) as white solids; a mixture of 1: 1 stereoisomers (5 mg) as white solids and less polar stereoisomer butyl ether (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] 12(19), 13(18), 14,16-tetraen-10 - ylcarbonyl)hexanoic acid (15 mg);1H NMR in D13, 300 MHz (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, 9H); 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); 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. To the less polar stereoisomer butyl ether (11S)-5-methyl-3-(10-oxo-l, 9-diazatricyclo[11.6.1.014.19] eicosa-13(20), 14(19), 15,17- tetraen-11-ylcarbonyl)hexanoic acid (300 mg) was added 5 ml of a solution containing a mixture of 10% triperoxonane acid/methylene chloride, and stirred. After 2.5 hours, the chromatography in thin layer (TLC) showed that the reaction was completed. All volatile components were removed under reduced pressure. The residue was dissolved in CH2Cl2(40 ml), transferred into a separating funnel and then washed with 0.5% HCl (40 ml) and with brine (40 ml). The organic phase sushi is cyclo[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 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, tributyl 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 (3,24 g, 6.5 mmole) was dissolved in 95% TFA (aqueous) (30 ml) at 0oAnd then was stirred for 20 minutes.

Then remove the ice bath and the mixture was stirred another hour. After concentration to obtain the oil residue was dissolved in ethyl acetate (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-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)+.

The Similar way is the ESA-10-ylcarbonyl)hexanoic acid to the corresponding compound of formula (Ia), received 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-N)-;

(3R, 10S)-4-cyclohexyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18]Nona-DECA-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)propanoic 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 - N)-;

(3R, 10S)-3-(9-oxo-1,8-diazatricyclo[10.6. l. 0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS:426 (M-N)-;

(3R,10S)-2-amino-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: 457 (M+N)+;

(3R, 10S)-2-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS: 458 (M+N)+;

(3R,10S)-2-aminomethyl-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;

(3R, 10S)-5-methyl-3-(15-methoxy-9-oxo-1,8-distril-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-2-carboxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(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;

(3R, 10S)-4-cyclopentyl-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: 509;

(3R,10S)-3-cyclopentyl-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: 454;

(3R,10S)-3-cyclopropyl-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: 439;

(3R, 10S)-6-(biphenyl-4-yl)-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: 579;

(3R, 10S)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)-5-(thiophene-2-yl)pentane acid, MS: 496,3 (M+N)+.

Similarly received:

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

(3R, 9S)-4-cyclobutyl-3-(8-oxo-1,7-d is hydrosocial-5-yl)-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(3R, 9S)-4-(3-hydroxy-4,5(RA)-dihydroisoxazole-5-yl)-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12(17),13,15-tetraen-9-ylcarbonyl)butane acid;

(3R, 9S)-4-(3-bromo-4,5(RS)-dihydroisoxazole-5-yl)-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12(17), 13,15-tetraen-9-ylcarbonyl)butane acid;

(3R, 9S)-5-(4-chlorophenoxy)-3-(8-oxo-l, 7-diazatricyclo [9.6.1.012'17] octadeca-11(18),12(17), 13,15-tetraen-9-ylcarbonyl)pentane acid;

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

(3R, 9S)-6-methoxy-3-(8-oxo-l, 7-diazatricyclo[9.6.1.012,17]octadeca-15 11(18),12(17),13,15-tetraen-9-ylcarbonyl)hexanoic acid;

(3R, 9S)-7-phenyl-3-(8-oxo-l, 7-diazatricyclo[9.6. l. 012,17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)heptane acid;

(3R, 10S)-3-(15-fluoro-9-oxo-1,8-diazatricyclo [10.6.1.0]endeca-11(19), 12(18),14,16-tetraen-10-ylcarbonyl)-5-methylhexanoic acid;

(3R, 10S)-phenyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.013,18] endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)pentane acid;

(3R, 10S)-3-cyclohexyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-11(19),12(18),14,16-tetraen-10-yl)succinamide acid is first acid;

(3R,10S)-3-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-11(19),12(18), 14,16-tetraen-10-ylcarbonyl)-5-metrex-5-envoy acid;

(3R, 10S)-2(R)-aminomethyl-3-(9-oxo-1,8-diazatricyclo[10.6. l.0of 13.18]endeca-11(19), 12(18), 14,16-tetraen-10-ylcarbonyl)-5-methylhexanoic acid;

(3R,10S)-3-(15-benzyloxy-9-oxo-1,8-diazatricyclo [10.6.1.of 13.18] endeca- 11(19),12(18),14,16-tetraen-10-ylcarbonyl)-5-methylhexanoic acid;

(3R 10S)-3-(15-hydroxy-9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)-5-methylhexanoic acid;

(3R, 10S)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-11(19), 12(18),14,16-tetraen-10-ylcarbonyl)octanoic acid;

(3R, 10S)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-11(19), 12(18),14,16-tetraen-10-ylcarbonyl)-7-hydroxygeraniol acid;

(3R,10S)-3-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-11(19),12(18), 14,16-tetraen-10-ylcarbonyl)-7-benzyloxyethanol acid;

(3R,10S)-4-(3-thiophenyl)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)butane acid;

(3R, 10S)-6-trifluoromethyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.013,8]endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R,10S)-5-(2-thiophenyl)-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] Nono [10.6.1.0of 13.18] endeca-11 (19), 12(18), 14,16-tetraen-10-ylcarbonyl)heptane acid;

(3R, 10S)-7-phenoxy-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18]endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)heptane acid;

(3R, 10S) (3-furanyl)-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-11(19), 12(18), 14,16-tetraen-10-ylcarbonyl)butane acid;

(3R, 10S)-6-(3-pyridyl)-3-(9-oxo-1,8-diazatricyclo.6.1.of 13.18] endeca-11(19), 12(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-6-(3-pyridyl)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R,10S)-3-(4-phenylimidazol-1-yl)-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-11(19), 12(18), 14,16-tetraen-10-yl) succinic acid;

(3R, 10S)-4-cyclobutyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.of 13.18]endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)butane acid; and

(3R, 10S)-4-benzyloxy-3-(9-oxo-1,8-diazatricyclo [10.6.1.of 13.18] endeca-11(19),12(18),14,16-tetraen-10-ylcarbonyl)butane 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 mg)was dissolved in 40 ml of anhydrous CH2Cl2and at 0oWith added ethanol (0.5 ml, 5 EQ. ), and then N,N-dimethylaminopyridine (0, is e 0oWith up to room temperature. Additionally added CH2CL2(100 ml) and the mixture was washed with 0.5 N. HCl (g ml), saturated Panso3(G ml) and finally with brine (CH ml). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. After 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 solid (yield: 108 mg, 55%), MS:470 (M+N)+.

Similarly received:

ethyl ester of (3R, 10S)-4-cyclopentyl-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:496 (M+N)+;

diethylcarbamoyl ether (3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo[9.6.1.12,17] octadeca-11(18), 12(17),13,15-tetraen-9-ylcarbonyl)pentanol acid;

indan-5-silt 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;

morpholinoethoxy ether (3R,10S)-5-methyl-3-(9-oxo-1,8-25 diazatricyclo[10.6.1.013,18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid;

1-methyl-4-piperidine canovai acid, MS: 539,51 (M+S+); and

1-methyl-3-piperidinylmethyl 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.

That is, In another embodiment less polar stereoisomer 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), obtained as described above in example 5G technique, was dissolved in 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 PA2SO4, filtered and evaporated to dryness. After 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 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-Il mg of white solids;1H NMR in Dl3, 300 MHz: (-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); 7,15-7,25 (m, 1H); 7,25-7,32 (m, 1H); to 7.35 (d, J=8,4 Hz, 1H); 7,88(d, J=8,4 Hz).

H. In another embodiment, a 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 was dissolved in ethanol (35 ml, required some heating) was added ammonium formate (1642 mg, 3 EQ. ), and then added 10% Pd on charcoal (100 mg). After stirring in an argon atmosphere at room temperature for 3 hours the reaction was completed. The mixture was filtered by vacuum filtration through a layer of celite (1 cm), then was concentrated, added the Meon and the obtained 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)hexabenzyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18]12(19) of endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl) hexanoic acid was dissolved in ethanol (25 ml) and then was added dropwise 1N. LiOH (0.3 ml, 3 EQ.). The resulting homogeneous solution was stirred at room temperature for 3 hours. A large part of the ethanol was removed under reduced pressure and at 30oC. Then, with stirring, was added water (5 ml) and ethyl acetate (30 ml) and was added 4n. HCl to obtain pH values of 2. Then an ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification via GHUR with reversed phase received 47 mg of (3R,10S)-2-1 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-N)-.

Example 7

A. a Mixture of dibenzyltoluene (5.3g, 0,018 mol) and 4-biphenyl-4-yl-1H-imidazole (3.94 g, 0,018 mol) was kept at a temperature of 110-115oC for 4 hours. Then the mixture was dissolved in simple ether and washed 0,05% HCl, 0.01 to N. NaOH and with brine and dried. After removal of ether, the crude product was purified by column chromatography (60% EtOAc/hexane) to give 5.75 g of dimensional ether 2-(4-bipheny is unity:

dimensiony ester 2-(4-phenylimidazol-1-yl) succinic acid;

dimensiony ester 2-(4-(4-methoxyphenyl)imidazol-1-yl)succinic acid; and

dimensiony ester 2-(4-(4-phenoxyphenyl)imidazol-1-yl)succinic acid.

B. Suspension of dimensional ether 2-(4-biphenyl-4-eliminator-1-yl) succinic acid (551 mg) in 10 ml of N2About boiled under reflux overnight and cooled to room temperature. The aqueous layer was removed and the remaining solids were dried on liofilizadora, receiving 4-benzyl ester 2-(4-biphenyl-4-eliminator-1-yl)succinic acid (437 mg), MS: 426 (M+).

Similarly received the following connections:

4-benzyl ester 2-(4-phenylimidazol-1-yl)succinic acid;

4-benzyl ester 2-(4-(4-methoxyphenyl)imidazol-1-yl)succinic acid; and

4-benzyl ester 2-(4-(4-phenoxyphenyl)imidazol-1-yl)succinic acid.

C. Mixture of 4-benzyl ester 2-(4-biphenyl-4-eliminator-1-yl)succinic acid (450 mg, 1.05 mmole), (10S)-10-amino-9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraene (284 mg, 0.95 mmole), EDCI (302 mg, 1.5 mmole), HOBT (142 mg, 1.05 mmole), N-methylmorpholine (0,14 ml) and DMAP (50 mg) in DMF (10 ml) was stirred at room temperature overnight. Dissolve is obtained after removal of solvents, was purified by column chromatography, obtaining the benzyl ether of (3RS,10S)-3-(4-biphenyl-4-eliminator-1-yl)-N-(9-oxo-1,8-diazatricyclo[10.6.1.013,1] endeca-12(19), 13(18), 14,16-tetraen-10-ilaclama acid.

Similarly received the following connections:

benzyl ether of (3RS, 10S)-3-(4-phenylimidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ilaclama acid;

benzyl ether of (3RS,10S)-3-(4-(4-methoxyphenyl)imidazol-1-yl)-N-(9-oxo-l, 8-diazatricyclo[10.6. l. 0of 13.18]endeca-12(19),13(18),14,16-tetraen-10-ilaclama acid; and

benzyl ether of (3RS,10S)-3-(4-(4-phenoxyphenyl)imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ilaclama acid.

G. a Solution of benzyl ether (3RS,10S)-3-(4-biphenyl-4-eliminator-1-yl)-N-(9-oxo-1,8-diazatricyclo[10.6. l. 0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ilaclama acid (190 mg) in THF/tO (5/1, 20 ml) was first made with 10% Pd/C (170 mg) for 8 hours, until TLC showed that the starting compound was reacted. The solution was filtered through a bed of celite. The filtrate was evaporated and recrystallized (THF/tO) to give 147 mg (3RS, 10S)-3-(4-biphenyl-4-eliminator-1-yl)-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] Nona is a logical way received the following connections:

(3RS,10S)-3-(4-phenylimidazol-1-yl)-N - (9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18) 14,16-tetraen-10-ilaclama acid, tPL: 184-187oC, MS: CONSISTS 528.3 (M+N)+;

(3RS, 10S)-3-(4-(4-methoxyphenyl)imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ilaclama acid tPL: 186 to 190oC, MS: 558,3 (M+N)+;

(3RS, 10S)-3-(4-(4-phenoxyphenyl)imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ilaclama acid, MS: 620,12 (M+N)+;

(3RS,10S)-3-(3-phenylpyrazol-1-yl)-N-(9-oxo-1,8-district-lo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ilaclama acid, MS: 568,4 (M+N)+.

Example 8

A. Carboxylic acid, obtained in accordance with example 6, in addition, can be converted into the corresponding amides by reacting the acid with the appropriate amines in the presence of the agents of the combination, such as EDCI and HOBT. These methods are well known to specialists in this field of technology.

In accordance with this received the following connections:

(3RS, 10S)-3(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10-icarbonell)-5-methylhexanoic; and

(3RS, 10S)-3-(9-oxo-1,8-diazatricyclo [10.6 P>.

B. In accordance with the method described in U.S. patent 4412994, received the following connection:

(3RS, 10S)-3(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-icarbonell)-5-methyl-N-hydroxy-N - morpholinylcarbonyl.

Example 9

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 continued for 0.5 h Then the solution was added O-benzylhydroxylamine (0,27 ml) and the reaction mixture was allowed to warm to room temperature over night. All volatile components were removed under reduced pressure. The residue was dissolved in CH2CL2(100 ml) and 20% Hcl (100 ml) and transferred into a separating funnel. The organic phase was isolated and the aqueous phase was washed CH2Cl2(G ml). Organic products are then washed sequentially with 5% NaHCO3, saline solution, dried (MgSO4), filtered and concentrated, obtaining (11S)-N-benzyloxy-5-methyl-3-(1o substances. The product was further purified by column chromatography with silica gel followed by crystallization from a hot mixture of ethyl acetate/CH2CL2getting more polar stereoisomer of the compound with a melting point 232-233oWith less polar stereoisomer of the compound with 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, of 5.82 mmole), HOBT2On (0,89 g, 1 EQ. ) and O-benzylhydroxylamine (2.2 ml, 3 EQ.) in DMF (200 ml), at 0oWith added EDCI (2,77 g, 2.5 EQ.). The resulting mixture then was stirred overnight. DMF was removed by distillation under vacuum at 65oC. To the residue was then added methanol (14 ml) and then a simple ether (140 ml). At 0oWith and with stirring was added to 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 by vacuum filtration and then washed with water (100 ml), and then a mixture of 1:1 simple ether/petroleum ether (100 ml). After drying under vacuum (P2ABOUT5within 3 hours was obtained (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-the substances (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 to the corresponding substituted compound of formula (Ib), were obtained the following compounds of formula (IC):

(3R, 10S)-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 [10.6.1.13'18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanamide, MS: 533 (M+N)+.

Was a Similar manner, but replacing O-benzylhydroxylamine 2-diethylaminoethylamine or 1-methyl-4-hydroxypiperidine received the following derivatives of the compounds of formula (I):

1-(2-dimethylaminoethyl)amide (3R,10S)-5-methyl-3-(9-oxo-l,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS: 512,49 (M+N)+;

1 methylpiperidin-4-silt 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)g is the target the more polar stereoisomer of (11S)-N-benzyloxy-5-methyl-3-(10-oxo-l, 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% palladium on coal (30 mg). The mixture was stirred, passing through her constant bubbling fluidised bed a stream of gaseous hydrogen. After 3 hours, TLC (10% CH3HE/CH2CL2) showed that the reaction is complete. The product was filtered three times through a layer of celite and concentrated under reduced pressure to obtain nearly dry residue. Added methylene chloride (15 ml) and the product was again concentrated under reduced pressure to obtain nearly dry residue and then repeated the procedure again. To the residue was added 3-4 drops of methanol, and then was added methylene chloride (15 ml). The product 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 197-201oWITH,

[]23D=- 85,1o, (3.5 mg/1.0 ml DMSO).

B. in a Similar manner, but replacing the more polar erased mail)hexanamide less polar, received less polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-l, 9-diazatricyclo[11.6.1.014,19] eicosa-13(20), 14(19), 15,17-tetraen-11-ylcarbonyl)hexanamide, tPL212-216oC []23D=-38,5o, (4,7 mg/1.0 ml of 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) was dissolved in 20% THF solution in ethanol (500 ml) and then the portions was added Pd on charcoal (200 mg). The resulting suspension was stirred, passing through the solution slightly bubbling fluidised bed its gaseous N2. After 4 hours the reaction mixture was filtered, vacuum-filtering through a layer of celite (1.5 cm), the filtrate was concentrated and then dissolved in methanol (30 ml) and filtered through a cotton plug. After recrystallization from methanol/ethyl acetate/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-N)+.

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 to meet the 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:515(M+N)+;

(3R, 10S)-N-hydroxy-6-phenyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanamide, MS:517(M-N)-;

(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)+-N2ABOUT;

(3R,10S)-N-hydroxy-3-(9-oxo-1,8-diazatricyclo[10.6.1.013'18] endeca- 12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanamide, MS: 443 (MN+);

(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;

(2S, 3R, 9S)-N-hydroxy-2-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;

(3RS, 10S)-N-hydroxy-N-formyl-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexylamine, MS: 455 (M-N)-;

(3R,9S)-N-hydroxy-6-pyridin-4-yl-3-(8-oxo-1,7-diazatricyclo [9.6.1.012'17]octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl)hexanamide;

(3R,9S)-N-hydroxy-2-hydroxy-5-methyl(8-oxo-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18),12(17),13,15-tetraen-9-ylcarbonyl) hexanamide;

(3R, 10S)-N-hydroxy-5-m(3R, 10S)-N-hydroxy-2-acetyl-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;

(3R, 10S)-N-hydroxy-6-phenyl-3-(9-oxo-1,8-district-lo[10.6.l.of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl) hexanamide;

(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;

(3R, 10S)-N-hydroxy-5-phenyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)pentanone;

(3S, 10R)-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;

(3R,10RS)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.l.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl) hexanamide;

(3R, 10RS)-N-hydroxy-5-methyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanamide; and

(3R, 10S)-N-hydroxy-2-aminocarbonyl-5-methyl-3-(15-fluoro-9-oxo-1,8-5 diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl) hexanamide.

Example 11

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 (atoi temperature in one portion was added EDCI (863 mg, 4.5 mmole). After stirring over night DMF was removed at 30oWith high-vacuum receiving a yellowish semi-solid substance. It was dissolved in ethyl acetate (50 ml), washed with 1N. HCl (30 ml), 5% solution Panso3(30 ml) and finally with brine (30 ml). The organic layer was dried (MgSO4) and was evaporated to dryness. The resulting oil is light yellow in color was stirred at 50% simple ether-petroleum ether (40 ml) to give 600 mg (85%) (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)pentahalide in the form of mixtures of the stereoisomers of 1: 1. A mixture of the stereoisomers were separated using fast column chromatography (type LPS-2), elwira 20% ethyl acetate in petroleum ether to obtain the less polar stereoisomer with tPL226oAnd the more polar stereoisomer with tPL220oC.

Example 12

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 [10.6.1.013,18] endeca-12(19),13(18), 14,16-tetraen-10-yl)pentanolide (50 mg, 0,106 mmole) in 10 ml of methanol at 0oC in an atmosphere of argon was added 0.5 ml of concentrated NH4HE. The reaction mixture was stirred at a temperature of ivali 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 G. of 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% ether/petroleum ether and filtered, getting more polar stereoisomer of (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-yl)pentahalide in the form of a white powder, 41 mg (90%), tPL224oC.

Example 13

The compounds of formula (NN)

A. To 4-methylpentanoic acid (25 g, 0,215 mmole) was slowly added in a water bath at 25oWith thionyl chloride (20.4 ml, 1.3 g). The mixture is then kept at 50oC in argon atmosphere for 3 hours (until then, until gas evolution ceased). The crude reaction mixture was distilled at atmospheric pressure, getting 4-methylpentanoate (25,3 g, 87.3 per cent), tKip143oC.

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,Kip91-93oC.

Example 14

The compounds of formula (N)
o
With added 4-methylpentanoate. After stirring the reaction mixture at room temperature for 3 hours the reaction was stopped with 10 ml of water was added 70 ml of a simple ester. The reaction mixture was first washed with 0.5 N. Hcl (g ml), then 5% TO2CO3(G ml) and finally with brine (CH ml). The organic layer was dried over MgSO4, filtered and evaporated to dryness. After purification using column chromatography (mixture of 1:6 ethyl acetate/petroleum ether as eluent) received sultam N-4-methylpentanol-L-(+)-2,10-camphor (3,39 g, 78%).

B. in a Similar manner, but replacing 4-methylpentanoate to 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 15

The compounds of formula (Q)

A. To a solution of sultam N-4-methylpentanol-L-(+)-2,10-camphor (3,39 g, 10.8 mmole) in 75 ml anhydrous THF at -78oIn an argon atmosphere of emiliania at -78oC for 1 hour to the mixture was added hexamethylphosphoramide (5 ml), then tertbutylbenzene (5,2 ml, 3 EQ. ), and then in one portion was added 400 mg of iodide, Tetra-n-butylamine. The resulting solution stood at -78oC in an atmosphere of argon overnight. The next morning the reaction was stopped by adding water (100 ml) and then was extracted with simple ether (CH ml). The combined ether layers were washed with brine, then dried over Na2SO4, filtered and concentrated. After purification using column chromatography (mixture of from 5: 95 ethyl acetate/petroleum ether 10:90 ethyl acetate/petroleum ether as eluent) received sultam N-(4-methyl-2-tertbutoxycarbonyl)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-tertbutoxycarbonyl)propanol-L-(+)-2,10-camphor, MS:461 M+;

sultam N-(5-phenyl-2-tertbutoxycarbonyl)pentanoyl-L-(+)-2,10-camphor, MS:490 (M+N)+and

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

Example 16

Connected)-2,10-camphor (of 5.45 g, 12.7 mmole) in 50% aqueous THF (150 ml) at 0oC in an atmosphere of argon was added crystals LiOHH2O (2.14 g, 4 equiv.) and then 30% N2ABOUT2(11.5 ml).

Then the ice bath was removed and the resulting emulsion was stirred for 3 hours until, until it becomes transparent. A large part of the THF was removed under reduced pressure at 35oC. Then was added CH2Cl2(150 ml) and with stirring was added 4n. HCl to obtain pH values of 2. After adding NaCl aqueous layer was again extracted with CH2CL2(G ml). CH2CL2was removed under reduced pressure and the 35oAnd then the residue was dissolved in ethyl acetate (150 ml). This solution then was extracted with 5% TO2CO3(G ml) and the combined extracts were washed with simple ether (50 ml). Then the aqueous layer was added CH2Cl2when mixing with NaCI aqueous layer was extracted with CH2Cl2(G ml) and the combined extracts were dried over Na2SO4was filtered and concentrated, obtaining (2R)-4-methyl-2-tertbutoxycarbonyl acid as a colourless oil (2,95 g, quantitative yield).

B. in a Similar manner, but replacing sultam N-(4-methyl-2-tertbutoxycarbonyl the crystals (SC):

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

(2R)-5-phenyl-2-tertbutoxycarbonyl acid, MS: 293 (M+N)+< / BR>
(2R)-2-tertbutoxycarbonyl acid (colorless oil, 1,09 g).

C. (2R)-3-phenyl - 2-tertbutoxycarbonyl acid (55 mg) was dissolved in glacial acetic acid (20 ml) and added PtO2(25 mg) in acetic acid. Then a chemical beaker was placed in a pressure vessel Parra, created a vacuum and charged H2under the pressure of 100 lbs/square inch. After stirring for 3 days the mixture was filtered by vacuum filtration through a layer of celite (1 cm). Then the filtrate was concentrated, receiving in the form of a yellow oil (2R-3-cyclohexyl-2-tertbutoxycarbonyl acid (56 mg), MS:269 (M-N)-.

Example 17

The compound of the formula (R)

To a solution of D-leucine (50 g, 0,381 mol) in 570 ml of 3h. NVG (water.) at 0oC for 1 hour and 15 minutes was added in portions sodium nitrite (42 g, 1.6 EQ.). Next, the reaction mixture was stirred for 3 hours at 0oWith, 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. Then this (2R)-2-bromo-4-methylpentanol acid in the form of a colourless oil with a constant weight 71,3,

Example 18

The compound of formula (S)

In dichloromethane (80 ml) are condensed isobutane to double volume (-50oWith, Cl3/dry ice). To this solution was added (2R)-2-bromo-4-methylpentanol acid (28 g, 143,6 mmole) and maintaining the temperature between -40 and -50oC, was added dropwise concentrated sulfuric acid (1 ml). The reaction mixture was then allowed to warm to room temperature for 20 hours. Then the solution was concentrated before adding additional portions of methylene chloride (300 ml) and then 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 product was distilled, receiving 23 g butyl ether (2R)-2-bromo-4-methylpentanoic acid in the form of a colorless transparent oil.

Example 19

The compound of formula (U)

To benzylmethylamine (2,13 ml, 1 EQ.) and tertbutoxide potassium (1,36 g, 1 EQ. ) in anhydrous DMF (100 ml) at 0oWith dropwise within 1 hour was added tributyl ether (2R)-2-bromo-4-methylpentanoic acid (2,89 g, 11.5 mmole) in 50 ml of DMF. The resulting solution is then stirred at 0oWith in 3 days. Next, the Xia and the mixture was filtered by vacuum filtration through celite and was divided in two phases. Then the aqueous layer was additionally extracted with simple ether (CH ml), and obyedinennye ether extracts were washed with water (I ml). After drying over MgSO4the organic layer was filtered and evaporated to dryness. After cleaning with fast column chromatography (elution with a mixture of 4:96 ethyl acetate/petroleum ether) received tributyl ether (2R)-2-[(1-methoxycarbonyl-1-benzyloxycarbonyl) methyl] -4-methylpentanoic acid (2.55 g) as a clear colorless oil, MS: 322 (M-acetone)+.

Example 20

The compound of the formula (Kb)

tributyl ether (2R)-2- [(1-methoxycarbonyl-1-benzyloxycarbonyl) methyl] -4-methylpentanoic acid was dissolved in 5 ml of 80% TFA (water.) at room temperature and was stirred for 1.5 h, monitoring by TLC. The reaction was completed by only 30%, so I added an additional portion of TFA (10 ml). After 0.5 h the reaction was complete. TFA was removed in high vacuum at 45oWith and the residue was dissolved in ethyl acetate and washed with water (5x30 ml). After drying over PA2SO4atrocity layer was filtered and concentrated under vacuum, obtaining (2R)-2-[(1-methoxycarbonyl-1-benzyloxycarbonyl)methyl]-4-methylpentanol acid in the form of a solid in the first acid (8,4 g, of 0.13 mol) was stirred in pure triethylorthoformate (22 ml of 0.20 ml) for 90 minutes at room temperature. Then this mixture was transferred via cannula to a stirred solution of utilizability (8 g, being 0.036 mol) and tetramethylguanidine (4,5 ml, being 0.036 mol), cooled to 0oC for 10 minutes. The ice bath was removed and the reaction mixture was stirred for 4 hours. The mixture was diluted with 200 ml diethyl ether, the solution washed with 1N. HCl (100 ml), water (4x100 ml), with brine (100 ml) and dried over magnesium sulfate. After evaporation under reduced pressure received 8,15 g of ethyl ester of 2-(ethoxy)-phosphonomethyl-4-methylpentanoic acid in the form of oil is light yellow in color, MS: 349 (M-N2O)+.

Example 22

The compound of formula (X)

The crude ethyl ester of 2-(ethoxy)-phosphonomethyl-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, after which was added paraformaldehyde (5.5 g). The temperature of the solution was brought to room temperature and kept at 37oC for 18 hours. The solvent was removed is 50 ml brine (2 times), dried over MgSO4, was filtered and was evaporated, receiving 19.3 g of ethyl ester of 2-(ethoxy)(hydroxymethyl)phosphonomethyl-4-methylpentanoic acid in the form of a yellowish oil, MS: 281 (MN+).

Example 23

The compounds of formula (Y)

A. Ethyl ester 2-(ethoxy)(hydroxymethyl)phosphonomethyl-4-methylpentanoic acid (5 g) was dissolved in 20 ml of CH2CL2and cooled to -20o(With duplication). To the solution was added dropwise methanesulfonamide (1.5 ml) and triethylamine (3.0 ml). After 15 minutes the bath was removed and the reaction mixture was stirred at room temperature for 3.5 hours. Then, each solution was washed with 10 ml of cold 2% HCl, 10 ml of NaHCO3(saturated), 10 ml of brine, dried over MgSO4, was filtered and was evaporated, receiving 12.8 g (combined output) ethyl ester 2- (ethoxy) (methanesulfonylaminoethyl)phosphonomethyl-4-methylpentanoic acid.

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

Example 24

The compounds of formula (AA)

Sodium hydride (1.52 g, (60%) and 6 g of 2-hinokitiol stirred matney temperature for 2.5 hours. Then the mixture was cooled to 0oWith and through 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 to room temperature. DMF was removed by evaporation, the residue was dissolved in 50 ml ethyl acetate and washed with 50 ml of N2About (2 times), brine solution (50 ml), dried over MgSO4and evaporated, receiving semi-solid substance is yellow. After cleaning with fast chromatography using elution mixture of 10% ethyl acetate/hexane to 80% ethyl acetate/hexane, received 10 g of ethyl ester of 2-(ethoxy) (quinoline-2-altimeter) phosphonomethyl-4-methylpentanoic acid (Rf=0.35 in a mixture of 80% ethyl acetate/hexane), MS:424(MN+).

B. in a Similar manner, but replacing 2-hinokitiol 1-naphthalenethiol, 2-naphthalenethiol or thiophenol received 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.

ethylpentane 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 N2O and washed with 50 ml of ethyl acetate. Then the aqueous phase was acidified to pH 4 and the product was extracted with 50 ml ethyl acetate (2 times). An ethyl acetate phase was washed with 20 ml brine, dried over MgSO4and evaporated, obtaining 3.8 g of 2-(hydroxy) (quinoline-2-altimeter)phosphonomethyl-4-methylpentanoic acid in the form of a yellow oil, MS:368(MN+).

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

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 26

Separation of 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 (abs.) and added to 4.2 g of (-)-cinchonidine. After 30 minutes at room temperature began to precipitate the salt. The flask was covered with foil and kept for 2 days. Then the salt was removed by vacuum filtration and fil is th HCl to remove cinchonidine, while maintaining the pH above 4. Both solutions were dried separately over MgSO4and evaporated, obtaining 2.4 g of one of the selected stereoisomer []24D=+is 10.68o(9,73 mg in methanol (2 ml) and 2.5 g of another selected stereoisomer []24D=-8,70o(9,88 mg in methanol (2 ml)).

Example 27

The compound of formula (Ig)

Dedicated 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 0oWith 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), 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 N2Oh, 10 ml of brine, dried over MgSO4and evaporated, receiving (10S)-[4-methyl-2-(9-oxo-1,8-diazatricyclo [10.6.1.013'18] 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 using GHUR with reversed phase, using brown 41% acetonitrile, and the less polar stereoisomer (10 mg) was isolated in 43% acetonitrile. Faction liofilizirovanny with obtaining a white powder, MS:635(MN+).

Example 28

The compound of formula (Ih)

(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 (200 mg, 0.45 mmole) was dissolved in 10 ml of glacial acetic acid and was first made at a pressure of H2100 psi in the presence of Pt2O (60 mg) in a Parr reactor at room temperature for 15 hours. The reaction mixture was barbotirovany gaseous argon for 15 minutes and was filtered catalyst (Pt2O) (through the funnel with telicom). Transparent filtrate was evaporated to dryness and then conducted a double-evaporation with toluene, receiving (3R,10S)-methyl-5-3(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] nonadecane-10-ylcarbonyl)hexanoic acid as a white solid, quantitative yield), MS: 448(M-N)-.

Example 29

The compound of formula (Ii)

(3R, 10S)-5-methyl-3-(9-oxo-1,8-districto [10.6.1,0of 13.18] nontechnically)hexanoic acid and O-benzylhydroxylamine (5 EQ., 2.25 mmole, 277 mg) in 10 ml of anhydrous DMF at room temperature was added 1 of hydroxybenzotriazole2Cl2(G ml). United CH2CL2the extract was dried (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[10.6.1.013,18] nontechnically)hexanamide, in the form of a white powder, MS:555(M+N)+.

Example 30

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 at a pressure of H21 ATM in absolute ethanol (5 ml) in the presence of 10% Pd/C (35 mg) for 2 hours. The reaction mixture was barbotirovany gaseous argon for 10 minutes and filytrovali through the funnel with telicom. Further, the catalyst for celite washed with 5 ml ethanol. The combined filtrate was evaporated to dryness, obtaining t and filtered, receiving 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 in the form of a whitish powder, MS: 465(M+N)+.

Example 31

The compound of formula (DD)

To N-tertbutoxycarbonyl (3 mmole, 914 mg) and N-methylethanamine (3.6 mmole, 0.27 g, of 0.32 ml) in anhydrous DMF (15 ml) was added 1-hydroxybenzotriazole2O (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 hard TO2CO3and were extracted with ethyl acetate (CH ml).

The combined organic extract was washed with brine (30 ml) and dried (MgSO4). After evaporation to dryness received 920 mg (85%) of pure according to GHUR product, namely, N-(methyl)aminoethyl)amide N,-tertbutoxycarbonyl in the form of a white foam.

Example 32

The compound of formula (IT)

To intensively mix the solution of N-((methyl)aminoethyl)amide N'-tertbutoxycarbonyl (2 g, of 5.55 mmole) and TRANS - 1,4-dichlorobut-2-ene (8,32 the La, 378 mg). After stirring at room temperature over night yellow organic layer was separated and the aqueous layer was then extracted with 30 ml of CH2Cl2. United methylenchloride the extract was washed with brine and dried (MgSO4). The residue was dissolved in 10 ml Meon 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 of pure according to GHUR product, namely, 11-N'-(tertbutoxycarbonyl)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 33

The compound of formula (FF)

11-N'-(tertbutoxycarbonyl)amino-10-oxo-1,6,9-triaza-6-methyl-tricyclo[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 was evaporated, receiving 240 mg (76%) of 11 - amino-10-oxo-1,6,9-triaza-6-methyl-trice the
The compounds of formula (Ik)

11-amino-10-oxo-1,6,9-triaza-6-methyltricyclo[11.6.1.014,19]eicosa-3(4), 13(20), 14(19), 15,17-pentaen (161 mg, 0.7 mmole) and (2R)-4-methyl-2-tertbutoxycarbonyl acid (220 mg, 0.7 mmole) was stirred in anhydrous 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 was evaporated, getting a light brown oil. It is pale brown oil was purified using GHUR with reversed phase (C18-column; gradient of CH3SP-50 mm NH4-OH). The desired fraction liofilizirovanny getting 148 mg (40%) butyl ether (3R,11S)-5-methyl-3-(10-oxo-1,6,9-triaza-6-methylbicyclo [11.6.1.014,19] -eicosa-3(4),13(20),14(19), 15,17-pentane-11-ylcarbonyl)hexanoic acid as a light yellow powder, MS:525,2(M+N)+.

Example 35

The compound of formula (Il)

tributyl 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-retenerte for 1 hour. The excess solvent was removed under reduced pressure (rotary evaporator at 30oC) receiving the crude (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 as a light brown oil. After purification using GHUR with reversed phase during elution in a gradient mixture of CH3SP-NH4SLA-buffer received 90 mg (75%) of the acid as a light yellow powder, MS: 469,1(M+N)+.

Example 36

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-alkarbala-yl)hexanoic acid and O-benzylhydroxylamine (5 EQ., 2.5 mmole, 308 mg) was stirred in anhydrous 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 expected product was then extracted from the aqueous layer using CH2Cl2(G ml). Organizatcionnii product was purified using GHUR with reversed phase gradient of CH3CN-NH4SLA-buffer) and liofilizirovanny, receiving 175 mg (61%) of (3R,11S)-N - benzyloxy-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-alkarbala-yl)hexanamide in the form of a whitish powder, MS: 572 (M-N)-.

Example 37

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 a mixture of 50% Asón/Meon with stirring in one portion was added 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(MN+).

In a similar way received the following connection:

(2S, 3R, 9S)-(N, 2)-dihydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanamide.

Example 38

The compounds of formula (JJ)

A. To R. the MFA (2,9 ml, 1,2 EQ. ) and anhydrous KI (330 mg, 0.1 EQ.). The suspension is kept at 100oWith in 24 hours and DMF drove away under reduced pressure. The residue was dissolved in a simple ether, washed with water and saturated PA2S2ABOUT3, dried (MgSO4) and concentrated. After distillation of the remaining oil was obtained 3.7 g (95%) of benzyl-()-2-hydroxybutanoic in the form of a colorless oil, tKip95oC (0,45 Torr).

B. In another embodiment, to a cold (0o(C) suspension of NaH (3.8 g, 60 wt.%-Naya dispersion in mineral oil, 95.0 mmol) in THF (50 ml) dropwise via cannula was added a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 ml). The resulting solution was heated to 25oWith 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 100oWith over 23 hours in an atmosphere of argon and evaporated DMF. The residue was dissolved in a simple ether, washed with water, saturated PA2S2ABOUT3and with brine and dried over MgSO4. After distillation received benzylglycine (8.5 g, 54%) as a colourless oil, tKip85-87oC (0,5 Torr).

Example 39

The compounds of formula (LL)

A. To holonomy (1.2 ml, 1.1 equiv.) then was added dropwise Trifonova anhydride (1.7 ml, 1.1 EQ.). After 10 minutes, dropwise at 0oC was added a solution of butyl ester of L-leucine (1.7 g, 1 EQ.) and diisopropylethylamine (1.7 ml, 1.1 EQ.) in CH2Cl2(30 ml). The solution was kept at 25oC for 36 hours, was diluted in CH2Cl2and washed with saturated Panso3(50 ml). After drying (Na2SO4) and concentration in vacuo the remaining oil was subjected to rapid chromatography (silica, 5% ethyl acetate/hexane) to separate the diastereomers. Less polar diastereomer tributyl ether (1R)-N-(2-benzyloxycarbonyl)propyl-L-leucine (Rf0,22; 5% ethyl acetate/hexane) and the more polar diastereomer tributyl ether (1S)-N-(2-benzyloxycarbonyl)propyl-L - leucine (Rf0,13) was further purified separately using GHUR (5% ethyl acetate/hexane) to give 1.1 g of the more polar diastereomer and 0.78 g of the less polar diastereomer, MS (FAB):364(MH+).

B. in a Similar way of benzylglycine (379 mg, 2.7 mmole), butyl ether 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 Trifonova anhydride (0.51 ml, 2.8 mmole) was received 383 mg (50%) of butyl ether is soedineniya formula (A)

A. To a solution of butyl ether (1S)-N-(2-benzyloxycarbonyl) propyl-L-leucine (143 mg, 0,393 mmole) in CH2CL2(3 ml) at 0oWith added TFA (0.5 ml). The solution was stirred at 25oC for 4 hours and then concentrated in vacuum, obtaining salt of (1S)-N-(2-benzyloxycarbonyl)propyl-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 0oWith added N-methylmorpholine (60 ml, 1.5 EQ.) and EDCI (113 ml, 1.5 EQ.). The reaction mixture was stirred at 25oC for 18 hours, then diluted with 10 ml ethyl acetate, washed with saturated Panso3(3x10 ml) and water (2x10 ml), dried (Na2SO4) and concentrated. The residue was chromatographically with fast chromatography (silica, 1% MeOH/CH2Cl2) and collected fractions with Rfof 0.5 (5% MeOH/CH2Cl2), Using GHUR with reversed-phase was obtained (2R, 1'S, 10S)-2- [N-(1-benzyloxycarbonyl)propylamino] -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 (FAB): 575 (MN+).

B. in a Similar manner, but replacing L-leucine, received (2R,1'R,10S)-2- [N-(1-benzyloxycarbonyl)propylamino]-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 (FAB):575(MN+).

Example 41

The compounds of formula (Ip)

A. To a solution of (2R,1S,10S)-2-[N-(1-benzyloxycarbonyl)propylamino]-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 (46 mg) in THF/Meon (1:1, 2 ml) in an argon atmosphere was added 1 M 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 pH value of an aqueous residue was brought to 5.5 with 1M HCl. After removal of water using GHUR with reversed-phase was obtained (2R,1'S,10S)-2- [N'-(1-carboxy)propylamino] -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 (FAB):483(M-N)-.

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)+;

(2RS, 10S)-2- [carboxymethylamino] -3-methyl-N-(9-oxo-1,8-diazatricyclo is but] -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-benzyloxycarbonyl)propylamino] -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 received (2R,1'S,10S)-2-[N'-(1-carboxy)propylamino]-4-methyl-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-l2(19), 13(18), 14,16-tetraen-10-yl)pentanone (16 mg), MS (FAB):483(M-N)-.

C. In accordance with the above-described method of obtaining the compounds of formula (I) of 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 a quick chromatography (3% MeOH/CH2Cl2) received the crude benzyl ether. The crude benzyl ester was dissolved in THF/Meon (1:1, 6 ml) and hydrolyzed with 1 M 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 pH value of an aqueous residue was brought to 5.5 with 1 M HCl. Using GHUR with reversed-phase was obtained (2R,10S)-N'-(carboxymethyl)amino-4 - methyl-N-(9-oxo-1,8-diazotize(MN+).

Example 42

The compounds of formula (6)

4-methyl-2-metilpentanovoyj acid

A. To clean utilizability (25 g, of 0.13 mol) at 0oWith was slowly added to a chilled on ice diethylamine (15.1 ml of 0.15 mol). After stirring for 15 minutes was added dropwise formalin (11,1 ml, 37% aqueous formaldehyde). The mixture was kept under stirring and 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 and at 20oC. the crude ethyl-4-methyl-2-medienpartner, containing a number of simple ether, was dissolved in absolute ethanol (250 ml) and treated with acetonitrile (250 ml) and 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, obtaining of 10.5 g of 4-methyl-2-metilpentanovoyj d):

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 43

The compound of formula (Id) (converted hydroxamate)

A. a Solution of 4-methyl-2-metilpentanovoyj acid (3.5 g) and O-benzylhydroxylamine kept at 120oC for 8 hours. The reaction mixture is then distributed 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. Using ion-exchange chromatography (model Dowex-50W) with elution 20% pyridine/water was obtained 2-(benzoyloxymethyl)-4-methylpentanol acid.

1H-NMR, Dl3, 300 MHz: 0.9 to 1.0 (dd, 6H, CH3); 1,25-1,35 (m, 1H, CH); 1,6-of 1.75 (m, 2H, CH2); 2,8-2,9 (m, 1H, CaN); 3,0-3,2 (ABq, 2H, CN2N); 4,7-of 4.75 (ABq, 2H, CH2O); 7.3 to 7.4 (m, 5H, Ph).

N. Formirovanie 2-(benzoyloxymethyl)-4-methylpentanoic acid was carried out in dichloromethane using a formic acid/acetic anhydride, receiving N-formyl-2-(benzoyloxymethyl)-4-methylpentanol acid.

The combination with the compound of the formula (J): N-formyl-2-(Benin (30 ml) at room temperature was added 4-dimethylaminopyridine (DMAP) (200 mg) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). The reaction mixture was stirred for 8 hours and then concentrated and distributed between 30 ml of ethyl acetate and 30 ml of 20% HCl. The organic fraction was washed with water (20 ml), 5% NaHCO3(20 ml) and with brine, dried over MgSO4and concentrated. After purification 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 using 10% Pd/C was obtained (2RS,10S)-2-[N-formyl,N-hydroxyquinolyl]-4-methyl-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,6-tetraen-10-yl)pentamid in the form of a mixture of two isomers, MS: 455(M-N)-(compound 6).

In a similar way received:

(2RS,10S)-2-isopropoxycarbonyl]-4-methyl-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,6-tetraen-10-yl)pentamid, MS: 455(M+N)+;

(2RS, 10S)-2- [morpholinoethoxy] -4-methyl-(9-oxo-1,8-diazatricyclo [10.6.1.013'18] endeca-12(19), 13(18), 14,6-tetraen-10-yl)pentamid, MS:555(M+N)+.

Example 44

The compound of formula (Iq)

A. Obtaining the compounds of formula (PP)

To a mixture containing tributyl ether 2-(phthalimid-2-ylmethyl)-3(R)-isobutylamino acid (3.4 g), N-methylmorpholin (1,92 ml), 1-hydroxybenzotriazole , the ri 0oC in an atmosphere of argon was added EDCI (3,34 g). The resulting mixture was stirred over night, the temperature gave a mixture to rise to ambient temperature and then the solvent was removed at 45oC in high vacuum. The residue was intensively stirred with a mixture of ethyl acetate (300 ml) and 0.5 G. hydrochloric acid (150 ml). The organic layer was washed with 0.5 N. HCl (g ml), saturated NaHCO4(G ml) and finally with brine (CH ml). After drying the organic layer over MgSO4it was filtered and evaporated to dryness. After purification of the residue using rapid column chromatography (mixture of 10% ethyl acetate/methylene chloride) received tributyl ether (3R, 10S)-2-(phthalimid-2-ylmethyl)-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 4.81 g). This compound was obtained as the less polar diastereoisomer (2,96 g), more polar diastereoisomer (1,05 g) and a mixture of both isomers (0.8 g).

B. Obtaining the compounds of formula (Iq)

To a solution of the less polar isomer of the compounds of formula (PP) (2,96 g) obtained according to example 42A, in methanol (50 ml) and methylene chloride (50 ml) at room temperature was added hydrazine (2.8 ml). The mixture is stirred during the course the tel was removed under reduced pressure, and the balance of silica gel, which was adsorbiroval product was loaded onto a column of silica gel and subjected to rapid chromatography. Elwira 4% methanol/methylene chloride, got 2,01 g butyl ether (3R,10S)-2-(aminomethyl)-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

Century through hydrolysis of the ester triperoxonane acid, as described below, was obtained (3R, 10S)-2-(aminomethyl)-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:471(MN+).

Example 45

The compound of formula (Ir)

A. To a solution of butyl ether (3R,10S)-2-(aminomethyl)-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 (363 mg) and triethylamine (0.54 ml) in anhydrous methylene chloride (20 ml) at 0oWith added methanesulfonamide (77 μl). The resulting mixture was stirred for 2 hours, the temperature of the mixture was allowed to rise to ambient temperature and then under vigorous stirring was added methylene chloride (100 ml) and 0.5 N. hydrochloric acid (50 ml). Then the aqueous layer was extracted with methylene chloride (CH ml), then combined believed and was evaporated to dryness. After purification of the residue using rapid column chromatography (mixture of from 10 to 30% ethyl acetate/methylene chloride) received tributyl ether (3R,10S)-2-(methylsulfonylamino)-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 (211 mg).

B. To a solution of compound (180 mg) obtained in paragraph a, in methylene chloride (4 ml) at 0oWith added triperoxonane acid (2 ml). The resulting mixture was stirred for 5 hours and the temperature of the mixture was allowed to rise to ambient temperature. The solvent was removed under reduced pressure, to the residue was added ethyl acetate and the solution washed with water (I ml). After drying the organic layer over MgSO4it was filtered and evaporated to dryness. After crystallization of the residue from methanol/ethyl acetate/hexane was obtained (3R, 10S)-2-(methylsulfonylamino)-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 (129 mg).

C. Similarly received the following compounds of formula (Ir):

(3R, 10S) -2- (methoxycarbonylamino) -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:TO 541.5 M-N+);

(3R, 10S)-2-(methanesulfonylaminoethyl)-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:549,2(M-N+);

(3R, 10S)-2-(acanaloniidae)-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:563(M-H+);

(3R, 10S)-2-(triftormetilfullerenov)-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:603,3(M-N+);

(3R, 10S)-2-(phenolsulfonphthalein)-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:611,1(M-N+);

(3R, 10S)-2-(benzylmaleimide)-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:625,2(M-N+);

(3R, 10S)-2- [5-(2-pyridyl)thiophene-2-ralfinamide]-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:692,4(M-N+);

(3R, 10S)-2-(Tien-2-ralfinamide)-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-1 is about-1.8 to diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS:637,6(M-N+);

(3R, 10S)-2-(1-Asanaliev-8-ralfinamide) -5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,18-tetraen-10-ylcarbonyl)hexanoic acid, MS:549,2(M-N+);

(3R, 10S)-2-(3-ailuridae)-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:542,34(M-N+); and

(3R, 10S)-2-(acetamidomethyl)-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:512(M-H+);

(3R, 10S)-2-(8-chinaandalbaniasigned)-5-methyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0l3,18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-2-(5-benzylaminopurine-2-yl)sulfoaluminate-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;

(3R, 10S)-2-(N-Mei-2-resultonline)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013, 18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid, MS:612,7(M-N)-;

(3R, 10S)-2-(5-pyridin-2-Illian-2-resultonline)-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] nonude tricyclo [10.6.1.0of 13.18]endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)hexanoic acid;

(3R, 10S)-2-(phthalimid-2-ylmethyl-4-cyclopentyl) -3-(9-oxo-1,8-diazatricyclo[10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)butane acid;

(3R, 10S)-2-(N-phthalimido-2-ylmethyl)-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;

(3R, 10S)-2-(methanesulfonylaminoethyl)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19),13(18),14,16-tetraen-10-ylcarbonyl)butane acid; and

(3R, 10S)-2-(phenylethylenediamine)-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.

Similarly received:

(3R,9S)-2-(methanesulfonylaminoethyl)-4-cyclopentyl-3-(8-oxo-diazatricyclo [9.6.1.013,15] tetraen-9-ylcarbonyl)butane acid.

Example 46

The compound of formula (mm)

To a solution containing N-tertbutoxycarbonyl-L-tryptophan (128 g of 0.42 mol), 2-(2-aminoethoxy)ethanol (46,42 g of 0.44 mol), 1-hydroxybenzo-resol (60,0, of 0.44 mol) in 700 ml of DMF, at 0oWith added DCC (100 g, of 0.48 mol). After stirring at oC for 15 minutes, the mixture was stirred at room temperature overnight. White solid fuel is varali simple ether and a small amount of EtOAc, washed with 1% HCl (g ml), saturated Panso3(G ml) and saline (CH ml). The organic layer was dried (MgSO4), filtered and concentrated, obtaining 2-(8)-tertbutoxycarbonyl-ylamino-N- [2-(2-hydroxyethoxy)ethyl] -3-(1H-indol-3-yl)propionamide, 150 g (yield 91%), MS:392,2(M+N)+.

Example 47

The compound of formula (nn)

To the compound obtained in example 46 (50 g, 0,128 mol), and N,N-dimethylpyridine (200 mg, 1%) in 250 ml of triethylamine/dichloromethane (1/4) at 0oWith added 29 grams (0.15 mole) of paratoluenesulfonyl. The mixture was stirred at 0oC for 4 hours. The solvent was removed at 0oC and under reduced pressure. The residue was dissolved in EtOAc and 1N. HCl and transferred into a separating funnel. The organic layer was isolated and washed with 2% HCl, repeating the procedure until the pH value of the aqueous layer became equal to approximately 2, and washed with saturated Panso3and salt solution, the organic phase was dried and evaporated, obtaining 60 g (86%) of 2-(S)-tert - butoxycarbonylamino-2-N-[2-(2-4,- methylphenylsulfonyl) is a K-si)ethyl] -3-(1H-indol-3-yl)propionamide, MS:545(M+).

Example 48

The compound of the formula (ro)

To the compound obtained in example 47 (30 g, by 0.055 mol) in CH212,17] octadeca-11(18), 12,14,16-tetraen-8-it, MS: 374(M+N)+, tPL177,5-178oC []D=-0,852 (Meon,=0,983 g/100 ml).

Example 49

The compound of formula (ff)

To the compound obtained in example 48 (15 g, of 0.04 mol) at 0oC was added a mixture of 40% TFA/CH2CL2(50 ml). The resulting mixture was stirred at room temperature for 3.5 hours, the Solvent was removed under reduced pressure. To the obtained residue was added toluene (50 ml) and the solvent was again removed. This procedure was repeated twice. The residue was dried in vacuum overnight and distributed between tO/1H. NaOH. Separated the two layers. The aqueous layer was extracted with EtOAc (g ml) and the combined tO phase was washed for 1H. NaOH (g ml) and saline (CH ml). The solution was dried (MgSO4) and was evaporated, receiving 11 g (100%) 9-(S)-amino-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-� anhydrous THF at -78oC was added Et3N (52,6 ml of 0.38 mol). Was added dropwise pivaloate (42,5 ml of 0.32 mol). When you are finished adding reactional the mixture was heated to 0oC and was stirred for a further 1 hour at 0oAnd then was cooled to -78oC. In a separating flask containing (S)-4-benzyl-2-oxazolidinone (43 g of 0.24 mol) in anhydrous THF (1 l) at -78oC was added triphenylmethane (20 mg) as an indicator. Was added dropwise a solution of n-utility in hexane (1.6 M) to obtain a stable yellow color. The solution was stirred for another 30 minutes. Then this solution was slowly added to the above mixed anhydride and stirred for 1 hour. The reaction was stopped by adding 500 ml of the diluted solution of NH4Cl. THF was removed and the remaining solution was extracted with simple ether (CH ml). The combined ether extracts were dried over MgSO4and focused, getting 64,9 g (S)-4-benzyl-3-Penta-4-tolocation-2-it, MS:259(M+).

B. (S)-4-benzyl-3-Penta-4-tolocation-2-ONU (64,9 g of 0.25 mol) in anhydrous THF (700 ml) at -78oC was added dropwise bis(trimetric-Lil)sodium amide in THF (1.0 M, 275 ml of 0.28 mol). After stirring for a further 1 hour at -78oC was added dropwise tretboot what omashu diluted solution of NH4Cl (200 ml). After removal of THF aqueous layer was extracted with simple ether (CH ml). The ether layers were washed with brine (200 ml), dried and evaporated, getting 109,7 g of the crude product. After purification using chromatography on columns (a mixture of 5% acetone/hexane) received a 41.3 g of pure butyl ether (R)-3-(S-4-benzyl-2-oxoacridine-3-carbonyl)Gex-5-ene acid, MS:373(M+).

Century, tributyl ether (R)-3-(3-4-benzyl-2-oxoacridine-3-carbonyl)Gex-5-ene acid (25 g, 0,067 mol) in 300 ml of THF/water (1/1) at 0oWith added lithium hydroxide (11.5g, 0,268 mole) and hydrogen peroxide (30%, and 31.1 ml, 0,268 mol). After stirring at 0oFor 20 minutes the reaction mixture was stirred at room temperature for 2 hours. THF was removed and the remaining solution was acidified to pH 2, saturated NaCl and was extracted with EtOAc (g ml). United tO extracts was extracted with 10% TO2CO3(G ml). United TO2CO3layers are washed with Et2O (g ml). The remaining K2CO3to the solution was added EtOAc (200 ml) and the solution at 0oWith acidified to pH 2. After saturation of NaCl two layers were separated. The aqueous layer was extracted with EtOAc (g ml). The combined EtOAc solutions were dried and BR> The compound of formula (hh)

To a solution containing tributyl ether 2-(R)-allinternal acid (5 g, 0,00234 mol) and 9-(S)-amino-4-oxa-,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-8-he (6,38 g, 0,00234 mol) in 50 ml of DMF, was added HOBT (3,47 g 0,026 mol), DMAP (80 mg), N-methylmorpholin (2,84 g 0,028 mol) and EDCI (6,69 g 0,035 mol). The mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with EtOAc (300 ml) and washed with brine (CH ml), saturated NaHCO3(G ml) and saline (CH ml) and dried (MgSO4). After removal of solvents was obtained 9 g of the crude product. After purification using column chromatography (mixture of 50% EtOAc/CH2Cl2) received 7.5 g of pure butyl ether (3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)Gex-5-ene acid, MS:469(M+).

Example 52

The compound of formula (ii)

The compound obtained in example 51 (1.5 g, 3.2 mmole), meta-itfinal (0,70 g, 3.2 mmole), NaHCO3(0,672 g, 8 mmol), n-tetrabutylammonium (0,89 g, 3.2 mmole) and PD(SLA)2(72 mg) in 10 ml of DMF kept at 90oC for 15 minutes. The solution was diluted with 50 ml EtOAc and washed with brine (4x25 ml), dried aluca 1.5 g butyl ether (3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-(3-hydroxyphenyl)Gex-5-ene acid, MS:562,4 (M+N)+.

Example 53

The compounds of formula (Iv')

Obtained in example 52 compound (1.5 g) in 40 ml tOH was first made with 1.4 g of Pd/C (10%) for 12 hours. The solution was filtered through a bed of celite and washed tO (10 ml). The filtrate was evaporated, receiving of 1.34 g (89%) of butyl ether (3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-(3-hydroxyphenyl) hexanoic acid, MS:564,2(M+N)+.

Example 54

The compounds of formula (Iv)

Obtained in example 53 compound (1,34 g, 0,0024 mol) and thioanisole (2.58 g, 0,024 mol) in 15 ml of a mixture of 30% TFA/CH2CL2was stirred at room temperature for 1.5 hours. The solvents were removed. To the obtained residue was added toluene (50 ml) which was then removed under reduced pressure. The procedure was repeated several times to remove all traces of TFA. The resulting solid residue was stirred in hot EtOAc (10 ml) for 10 minutes, cooled to room temperature, filtered and washed by a simple broadcast receiving 400 mg of pure (3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,1>/P>As described in the examples 51-54 techniques likewise received the following connections:

(3R,9S)-6-(4-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid, MS:562,2(M-N-);

(3R,9S)-6-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:520,1(M+);

(3R,9S)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012,17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(3-piperidine-1-ylpropionic)phenyl] hexanoic acid, MS:631,1(M-N+);

(3R, 9S)-6-[4-(3-dimethylaminopropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.12,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:TO $ 591.1(M-N+);

(3R, 9S)-6-[4-(2-dimethylaminoethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:577,1(M-N+);

(3R, 9S)-6-(4-tianfeng)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.0.12,17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS: 515,1(M-N+);

(3R,9S)-6-naphthalene-2-yl-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid, MS:USD 542.3(M+H+);

(3R, 9S) - Rev. Yu acid, MS:557(M+N+);

(3R, 9S) -6- (4-hydroxy-W-were) -3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl) hexanoic acid, MS:522,3(M+N+);

(3R,9S)-6-(4-AMINOPHENYL)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:505,1(M-N+);

(3R, 9S)-6-(4-acetylaminophenol)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid, MS:547,8(M-N-);

(3R, 9S)-6-[4-(2-hydroxyethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:550,1(M-N-); and

(3R,9S)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012,17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(2-pyrrolidin-1 ylethoxy)phenyl] hexanoic acid, MS:605,5(M+N+).

Example 55

Compounds of formula (Is) and (It)

To a solution containing 4-tributyl ether 2-(R)-isobutylamino acid (317 mg, of 1.45 mmole) and 9-amino-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-8-he (330 mg, 1,21 mmole) in 30 ml DMF, was added HOBT (163 mg, 1.2 mmole), DMAP (50 mg), N-methylmorpholine (0.16 ml, of 1.45 mmole) and EDCI (348 mg, 1.8 mmole). The mixture was stirred at room temperature for the practical layer was washed with brine (g ml) and saturated Panso3(G ml) and dried. After removal of the solvent thus obtained crude product was purified by column chromatography (mixture of from 30 to 50% EtOAc/CH2Cl2) to give 466 mg of pure butyl ether (3R,9S)-5-methyl-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid.

B. Obtained in the previous phase of tributyl ester (460 mg, 0.9 mmole) was stirred at room temperature overnight in 15 ml triperoxonane acid/methylene chloride. The solvents were removed. To the obtained residue were added methylene chloride, which was then removed. This procedure was repeated several times to remove any residual TFA. The resulting residue was led from t/CH2CL2/hexane (4:1:3) to give 100 mg (3R, 9S)-5-methyl-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl hexanoic acid, tPL193-194oC.

Similarly received the following connections:

(3R,9S)-3-cyclobutylmethyl-N-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-yl)succinamide acid, MS:456,2(M+N+);

(3R,9S)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012+17]octadeca-11 (the KSA-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)pentane acid, MS:526,3(M-N-);

(3R,9S)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012,17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rhexenor acid, tPL190-193oC.

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-5-phenylpentane acid, MS:478,3(M+H+);

(2R,9S)-3-(8-oxo-4-oxa-l,7-diazatricyclo[9.6.1.012,17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-phenylhexanoic acid, MS:492,3(M+N+); and

(3R,9S)-5-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)pentane acid, MS:508(M+N+).

Example 56

The compounds of formula (Iu)

tributyl ether (3R,9S)-6-[4-(3-hydroxypropoxy)phenyl]-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid (1.56 g, 2.5 mmole) was dissolved in 50 ml of EtOH saturated with HCl. The mixture was stirred at room temperature overnight. Then the solvent was removed and the crude product was purified by column chromatography (mixture of from 50 to 80% EtOAc/methylene chloride) to give 0.88 g (59%) of pure ethyl ester of (3R,9S)-6-[4-(3-hydroxypropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diastric is illogical received the following connections:

ethyl ester of (3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)pentanol acid, MS:556,3(M+); and

ethyl ester of (3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo [l9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-5-Phenoxyethanol acid, MS:521(M+).

Example 57

The compounds of formula (Iw)

A. To tributyl ether (3R,9S)-6-(4-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid (1.0 g, 1,72 mmole) in DMF (20 ml) at 0oWith added 3-improper (363 mg, 1,95 mmole) and cesium carbonate (636 mg, 1,95 mmole). Then the mixture was stirred at room temperature for 2.5 hours DMF was removed under reduced pressure. The obtained residue was dissolved in EtOAc (70 ml) and brine (40 ml). The EtOAc layer was washed with brine and dried (MgSO4). After removal of solvents was obtained pure tributyl ether (3R, 9S)-6-[4-(3-hydroxypropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl hexanoic acid (1.1 g, 100%), MS:622,4(M+N+).

B. the Compound obtained in the above stage are then transformed into the corresponding acid, and them who carbamoyl)hexanoic acid, according to the method described in example street, 55A. The compound obtained had MS:564,9(M-N-and 566,1(M+N+).

Similarly, received the following connections:

(3R,9S)-6-[4-(2-methoxyethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:564,2(M-N-);

(3R, 9S)-6-(4-benzyloxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, MS:598,3(M+N+);

(3R,9S)-6-[4-(4-aminobutoxy)phenyl]-3-(8-oxo-4-oxa-1,7-5 diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl) hexanoic acid, MS:579,3(M+N+); and

(3R, 9S)-3-(8-oxo-4-oxa-l, 7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(pyridine-4-ylethoxy)phenyl] hexanoic acid, MS:599,2(M+N+), tPL169, 5mm-171,2oC.

Example 58

The compounds of formula (I) in which m and n equal to 2, a represents oxygen, R1denotes-CH2-R4where R4denotes hydroxyaminobuteroyl

(3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rhexenor acid were subjected to combination with O-benzylhydroxylamine according to the method described in carbamoyl)-6-pyridin-4-rexanne. According to the method described in example 37, this compound was further converted to (3R,9S)-N-hydroxy-3-(8-oxo-4-oxa-1,7 - diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rexanne, MS:506(M+N+), tPL224-225oC.

Example 59

Salts of compounds of formula (I)

(3R, 9S)-3-oxo-4-oxa-and-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rhexenor acid was converted to the corresponding salt triperoxonane acid, stirring the compound in a mixture of 15% triperoxonane acid/methylene chloride for 10 minutes. The solvents were removed. To the residue was added methylene chloride. Then the solvent was removed. This procedure was repeated several times to remove any traces triperoxonane acid. The resulting product had a melting point of 158-160oC.

Similarly, received the following connections:

triptorelin (3R, 9S)-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-imagecanvas acid;

triptorelin (3R,10S)-3-(9-oxo-1,8-diazatricyclo [10.6.l.of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)-6-pyridin-3-imagecanvas acid; and

triptorelin (3R, 10S)-3-(9-oxo-1,8-diazatricyclo [1060

The conversion of salts of compounds of formula (I) into the corresponding free base

Hydrochloride, (3R,9S)-ethyl-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-Elecsnet was stirred in CH2Cl2/saturated Na2CO3within 10 minutes. The organic layer was separated, dried and evaporated. The crude product was led out of CH2CL2/hexane, receiving (3R,9S)-ethyl-3-(8-oxo-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-Elecsnet, tPL203-205oC.

Example 61

This example shows obtaining a representative pharmaceutical compositions for oral administration containing a compound of the formula (I) or its pharmaceutically acceptable salt, for example, (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:

A. the Ingredients wt.%

the compound of formula (I) - 20,0

lactose - 79,5

magnesium stearate and 0.5

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

starch - 8,6

lactose - 79,6

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 using the appropriate teletrauma machine is formed into tablets.

B. Ingredients - g

the compound of formula (I) 0,1

propylene glycol - 20,0

the polyethylene glycol 400 - 20,0

Polysorbate 80 - 1,0

water - q.s. to 100 ml

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

, Ingredients wt.%

the compound of formula (I) - 20,0

peanut butter - 78

Span 60 - 2,0

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

Example 62

This example shows obtaining a representative pharmaceutical composition for parenteral administration containing a compound of the formula (I) or its pharmaceutically acceptable salt, for example, (3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-1BR> the compound of formula (I) - 0.02

propylene glycol - 20,0

the polyethylene glycol 400 - 20,0

Polysorbate 80 - 1,0

a 0.9% saline solution - q.s. to 100 ml

The compound of formula (I) dissolved in propylene glycol, polyethylene glycol 400 and Polysorbate 80. Then with stirring, add 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 pore size of 0.2 μm and Packed in sterile conditions.

Example 63

This example shows obtaining a representative 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-N-(9-oxo-1,8-diazatricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)pentanone:

Ingredients wt.%

the compound of formula (I) - 1,0

polyethylene glycol 1000 - 74,5

polyethylene glycol 4000 is 24.5

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

Example 64

This example shows obtaining a representative pharmaceutical composition for insufflation, tricyclo [10.6.1.0of 13.18] endeca-12(19), 13(18),14,16-tetraen-10-ylcarbonyl)pencil(quinoline-2-altimeter)phosphinic acid:

Ingredients wt.%

micronized compound of formula I - 1,0

micronized lactose - 99,0

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

Example 65

This example shows obtaining a representative pharmaceutical composition for dispersion containing the compound of formula (I) or its pharmaceutically acceptable salt, for example, (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 wt.%

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 66

This example shows obtaining a representative pharmaceutical composition in aerosol form containing a compound of the formula (I) or its pharmaceutically acceptable salt, for example, (3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-l, 9-diazatricyclo[11.6. l. 014,19] eicosa-13(20), 14(19), 15,17-tetraen-11-ylcarbamate the I acid - 1,00

The compound of formula (I) is dispersed in oleic acid and repellent. Then the resulting mixture is poured into an aerosol container fitted with a measuring valve.

Example 67

Analysis of in vitro

Collagenase type I fibroblast was purified from serum-free media for culturing cells GM0010A stimulated formalparameterlist (FMA), using heparin and zinc-chelating separatrix columns with subsequent liquid Express chromatography of proteins (column type MONO S). The enzyme was activated by incubation with trypsin.

Collagenase type IV was purified from containing serum media for culturing fibroblast cells (GM0010A) using zinc-chelating and gelatin-sepharose columns with subsequent liquid Express chromatography of proteins (column type MONO S). Electrophoresis in polyacrylamide gel in the presence of sodium dodecyl sulfate (SDS page-ordinator) showed that the enzyme is homogeneous. The enzyme was activated by incubation with 1 mmol of aminophenylacetate mercury (AFAR) for 1 h at 35-37oC.

The compounds of formula (I) was dissolved in DMSO and added to a cuvette containing 0.2 μg collagenase type I or 0.03 μg collagenase type IV in 1 ml of TS buffer (20 mm Tris, 5 is m, so 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 nm 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.

Example 68

Analysis of in vitro

This analysis allows us to determine whether the compounds of formula (I) ability to inhibit the release of35S-labeled glycosaminoglycans (GAG) from cartilage explants.

Small cartilage explants (3 mm in diameter) were obtained from knee joints sieunarine bulls and were marked with35 the LLF, inducing the expression of chondrocyte matrix metalloprotease (MMP), including stromelysin and collagenase. The percentage inhibition of labeled GAG was adjusted 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 explants.

The compounds of formula (I) when tested by this method showed the ability to inhibit the release of35S-labeled GAG from cartilage explants.

Example 69

Analysis of in vitro

To study the in vitro effect of the compounds of formula (I) on bone resorption as the model used the long bone of the rat embryo. To induce bone resorption in vitro used bovine parathyroid hormone (PDH). Effect on bone resorption was determined by the number of45CA released into the medium from the pre45Sa-labeled rat long bones of embryos. The inhibitory activity of the compounds of formula (I) in relation to induced bullish PSG bone resorption was expressed as the average percent inhibition of root mean square error.

Previously45Sa-labeled rat long bones of embryos (forearm) has been cut off is used five pairs of bones. The compounds of formula (I) pre-dissolved in ethanol, and then diluted to various concentrations and added to the first day at a time with a bullish PSG (1-34) at a concentration of 1x10-8M on the first day. The concentration of ethanol solutions of compounds were below 0.05%, which had no impact on the analysis. The analysis was completed on the sixth day, with one replacing the medium on the third day.

At the end of each substitution medium was counted45Sa, which is present in the medium for cultivation. The remaining bone was dissolved with Hcl 0.1 N. and also counted the number of45Sa present in the product decomposition of the bone. The results were expressed as percent relative to the total number of 45CA released from each pair of bones. Bullish PSG at a concentration of 1x10-8M induces bone resorption to a maximum level, which is taken as 100%, and this concentration was used as standard. For 0% took level baseline bone resorption in the presence of only environment. All processed by the connection group compared with those treated bullish PSG (1-34) at a concentration of 1x10-8M Concentration at which the compound inhibited bone resorption by 50% was defined as IC5 is rblu bones, induced bullish PSG.

Example 70

Analysis of in vitro

A. Selection for MMP analysis

The catalytic domain of collagenase-1 person expressed as a fusion with the ubiquitin protein in E. coli (E. R. Gehring and others, J. Biol. Chem., 270, 22507, (1995)). After the removal of the fused protein catalytic domain of collagenase-1 fibroblast were isolated by treatment for 1 hour at 37oWith 1 mm aminophenylacetate mercury (AFAR) and purification of the zinc-chelating chromatography.

Collagenase-2 and gelatinase In person were isolated in active form from leukocyte films (Mookhtiar, K. A., and others, Biochemistry, 29, 10620, (1990)).

Propeptide and the site of the catalytic domain of collagenase-3 human expressed in E. coli as N-terminal protein, fused to ubiquitin. After purification of the catalytic domain were obtained using treatment for 1 hour at 37oWith 1 mm AFAR and purification of the zinc-chelating chromatography.

Collagenase-3 rats were purified in active form from the culture medium of the cells of the smooth muscle of the uterus (Roswit, W. T., and others, Arch. Biochem. Biophys., 225, 285-295, (1983)).

Catalytic and fibronectin-like part progelatinase And human expressed in E. coli protein, fused to ubiquitin. Experiments the keratinocytes, stimulated by interleukin-1 and activated by treatment for 1 hour at 37oWith 1 mm AFAR, followed by dialysis to remove excess AFAR.

Postremission-1 person was isolated from the culture medium synovial fibroblasts via affinity chromatography using immobilized monoclonal antibody. Zymogen activated by processing triaina (1.5 mcg/ml) for 1 hour at 23oC receives a mixture of species with a molecular mass of 45 and 28 kDa.

The catalytic domain stromelysin person was obtained by expression and allocation prostomariya-1 from E. coli and activation 1 mm AFAR for 1 hour at 37oC, followed by dialysis. Postremission-1 rats expressed in ovary cells Chinese hamster and was isolated from the culture medium. Its activated by 1 mm AFAR for 1 hour at 37oC and purified using zinc-chelating chromatography.

Promotility man was expressively and was isolated from the cells of the Chinese hamster ovary (Barnett J. and others, Prot. Expres. Pur., 5, 27, (1994)). Zymogen activated by processing 1 mm AFAR for 1 hour at 37oC and purified using zinc-chelating chromatography.

With the B. The method of analysis in vitro

Experiments were performed in buffer for analysis (50 mm Tricin, pH 7.5, 200 mm sodium chloride, 10 mm calcium chloride, 0.005% of the environment Brij-35) containing 2.5% dimethyl sulfoxide (DMSO), because it was dissolved substrate and inhibitor. Royal solutions of inhibitors were prepared in 100% DMSO.

Royal substrate solutions were prepared in 100% DMSO at a concentration of 2 mm.

The method of analysis was based on the hydrolysis of MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH2(company Bachem, Inc.) at 37o(Knight C. G., and others, FEBS, 296, 263-266, (1992)). Changes in fluorescence were measured using an LS-50B company Perkin-Elmer at a wavelength of 328 nm excitation and wavelength of 393 nm emission. Used in the experiments the concentration of substrate [S] was 10 μm. For the experiments the inhibitor was diluted from a solution in 100% DMSO and controls were replaced by an equal volume of DMSO so that the final concentration of DMSO, obtained using dilutions of inhibitor and substrate in all experiments was 2.5%.

Results inhibition was expressed as the concentration of inhibitor causing 50% inhibition (IC50) activity relative to control (neighborhool) reactions.

Connection - I50nm

A - 8,8

B - 4.2V

In - 0,6-tetraen-9-ylcarbonyl)-6-pyridin-4-rexanna acid;

B: (3R,9S)-3-(8-oxo-)1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rexanna acid;

In: (3R,9S)-6-[4-(2-methoxyethoxy)phenyl]-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid;

G: (3R, 9S)-6-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), l2,14,16-tetraen-9-ylcarbonyl)hexanoic acid;

D: (3R, 9S)-6- [4-(2-hydroxyethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid;

E: (3R, 9S)-6-[4-(3-hydroxypropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo [9. 6.1.012,17octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid.

Example 71

Analysis of in vitro

This analysis allows us to determine whether the compounds of formula (I) ability to inhibit decomposition of the collagen matrix (based on the release of hydroxyproline) and proteoglycan (based on data from the output-S - labeled glycosaminoglycans) from cartilage explants.

Small cartilage explants (3 mm in diameter) were obtained from knee joints viewpending bulls and were marked with35SO4.35S-meaningwise expression chondrocyte matrix metalloprotease (MMP), including stromelysin and collagenase. The percentage inhibition of hydroxyproline and released the GAG was adjusted for spontaneous release in the absence of rhIL-1 alpha.

The compounds of formula (I) when tested by this method showed the ability to inhibit the output as fragments of collagen and35S-labeled GAG from cartilage explants.

Example 72

Analysis of in vitro

Method based on the use of implantation of the cartilage pin allows to evaluate the degradation of the collagen matrix in cartilage pin implanted rat (Bishop J. and others, J. Pharm. Tox. Methods, 30, 19, (1993)).

Pre-frozen cartilage pins of the nasal region of a bull weighing approximately 20 mg was inserted into the polyvinyl sponge, impregnated Mycobacterium tuberculosis, and implanted subcutaneously to female rats Lewis. Introduction preparations began 9 days after implantatio and the pins were removed after about a week. Pins weighed, hydrolyzed and determined the content of hydroxyproline. Effectiveness was determined by comparing the group treated with the compound with the group treated control.

The compounds of formula (I) when tested by this method showed the ability inhibi what about the (3R, 9S)-3-(8-oxo-4-oxa-1,7-tricyclo [9.6.1.012,17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rhexenor acid in doses of 75 and 200 mg/kg/day for 10

With the introduction of any of these doses did not find any pathological changes associated with treatment.

1. The compound of formula (I) in the form of a single stereoisomer or mixture of stereoisomers:

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where a denotes-CH2-, -O - or-NR11- where R11denotes hydrogen or alkyl;

m is 2, 3 or 4;

n = 1,2,3 or 4;

R1means (a)-CH2-R4where R4represents mercapto, acetylthio, carboxypropyl, aminocarbonyl, hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl or group

< / BR>
where R6denotes China-2-yl; b)-CH(R7)-R8where R7denotes-CH2Other, where R denotes hydrogen, -SO2Rand-C(O)Randor-C(O)or SIGandwhere Randdenotes alkyl, trifluoromethyl, phenyl, benzyl, imidazolyl, thienyl, azonaphthalene or alkylaminocarbonyl;

R8denotes carboxypropyl or N-hydroxyaminobuteroyl;

R2denotes alkyl, cycloalkyl, cycloalkenyl, biphenylyl, program, or phenylalkyl, which phenyl group may be substituted by groups selected from hydroxy, alkoxy, alkyl, piperidinyloxy, dialkylaminoalkyl, cyano, amino, hydroxyalkoxy, pyrrolidinyloxy, alkoxyalkane, aminoethoxy, phenyl, substituted pyrrolidon, acetylamino, benzyloxy or pyridinylamino;

R3denotes hydrogen;

provided that when a represents-CH2or N(R11), R2does not denote alkyl, cycloalkyl or cycloalkenyl;

or its pharmaceutically acceptable salt.

2. Connection on p. 1, where a denotes oxygen, m = 2, n = 2.

3. Connection on p. 2, where R1denotes-CH2-R4and R3denotes hydrogen.

4. The compound or salt according to p. 3, where R2denotes alkyl or cycloalkyl.

5. Connection on p. 4, where R2represents isobutyl or cyclobutylmethyl and R4denotes carboxypropyl, namely (3R,9S)-5-methyl-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid and (3R, 9S)-3-cyclobutylmethyl-N-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-yl)succinamide acid, respectively, or their pharmaceutically p. 3, where R2denotes phenylalkyl, optionally independently substituted with phenyl, hydroxy, alkyl, alkoxy, amino or cyano.

7. Connection on p. 6, where R4denotes carboxypropyl or its pharmaceutically acceptable salt, such as acetate, triptorelin or hydrochloride.

8. Connection on p. 3, where R2denotes peroxyacyl.

9. Connection on p. 8, where R2denotes phenoxyethyl, 4-chlorophenoxide and R4denotes carboxypropyl, namely, respectively (3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo [9.6.1.012.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-5-Phenoxyethanol acid and (3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)pentane acid or their pharmaceutically acceptable salts such as acetate, triptorelin or hydrochloride.

10. Connection on p. 8, where R2denotes 4-chlorophenoxide or phenoxyethyl and R4means etoxycarbonyl, namely, respectively, ethyl ester (3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)-pentanol acid and ethyl ester of (3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17the, such as acetate, triptorelin or hydrochloride.

11. Connection on p. 3, where R2refers to 3-(4-hydroxyphenyl)propyl, 3-(4-pyridinyl)propyl, 3-[4-(3-hydroxypropoxy)phenyl] propyl, 3-[4-(2-hydroxyethoxy)phenyl] propyl, 3-[4-(2-pyrrolidin-1 ylethoxy)phenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-[4-(2-methoxyethoxy)phenyl]propyl, phenylethyl, 3-phenylpropyl, 3-(3-hydroxyphenyl)propyl, 3-[4-(3-piperidine-1-ylpropionic)phenyl] propyl, 3-[4-(3-dimethylaminopropoxy)phenyl]propyl, 3-[4-(2-dimethylaminoethoxy)phenyl] propyl, 3-(4-tianfeng)propyl, 3-(naphthalene-2-yl)propyl, 3-(4-pyrrol-1-ylphenyl)propyl, 3-(4-hydroxy-3-were)-propyl, 3-(4-benzyloxyphenyl)propyl, 3-(4-aminobutoxy)propyl, 4-methoxyphenylacetyl, 3-(4-AMINOPHENYL)propyl, 3-(4-pyridin-4-limitatively)propyl or 3-(4-acetylaminophenol)propyl and R4denotes carboxypropyl, namely

(3R,9S)-6-(4-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-rexanna acid,

(3R, 9S)-6-[4-(3-hydroxypropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanol,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(2-pyrrolidin-1 ylethoxy)phenyl] hexanoic acid,

(3R,9S)-6-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R, 9S)-6-[4-(2-methoxyethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-5-phenylpentane acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-phenylhexanoic acid,

(3R,9S)-6-(3-hydroxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(3-piperidine-1-ylpropionic)phenyl] hexanoic acid,

(3R, 9S)-6-[4-(3-dimethylaminopropoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R, 9S6-[4-(2-dimethylaminoethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(P>12.17
] octadeca-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-6-naphthalene-2-yl-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] OCTA-DECA-11(18),12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-(4-pyrrol-1-yl)hexanoic acid,

(3R, 9S)-6-(4-hydroxy-3-were)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R, 9S)-6-(4-benzyloxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R, 9S)-6-[4-(4-aminobutoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-5-(4-methoxyphenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)pentane acid,

(3R,9S)-6-(4-AMINOPHENYL)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(pyridine-4-ylethoxy)phenyl] hexanoic acid,

(3R, 9S)-6-(4-acetylaminophenol)-3-(8-oxo-4-o what about the

or their pharmaceutically acceptable salts such as acetate, triptorelin or hydrochloride.

12. Connection on p. 11, representing

acetate (3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17]octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-[4-(2-pyrrolidin-1 ylethoxy)phenyl]hexanoic acid, or

triptorelin (3R,9S)-6-[4-(3-dimethylaminopropoxy)phenyl]-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, or

triptorelin (3R, 9S)-6-[4-(2-dimethylaminoethoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, or

triptorelin (3R, 9S)-6-[4-aminobutoxy)phenyl] -3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)-hexanoic acid, or

acetate (3R, 9S)-6-(4-AMINOPHENYL)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid, or

triptorelin (3R, 9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl-6-[4-(pyridine-4-ylethoxy)phenyl]hexanoic acid.

13. Connection on p. 12, where R2denotes 3-[4-(3-hydroxypropoxy)phenyl] propyl Il is epoxy)phenyl]-3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] octadeca-11(18), 12,14,16-tetraen-9-ylcarbonyl)hexanoic acid,

ethyl ester of (3R,9S)- 3-(8-oxo-4-oxa-1,7-diazatricyclo[9.6.1.012.17] OCTA-DECA-11(18), 12,14,16-tetraen-9-ylcarbonyl)-6-pyridin-4-imagecanvas acid, respectively

or their pharmaceutically acceptable salts.

14. Pharmaceutically acceptable salt of the compound under item 13, which is the hydrochloride.

15. The compound or salt according to p. 1, where a denotes-CH2-, n = 1, 2, or 3; m = 2 or 3.

16. The compound or salt according to p. 15, where n = 2, R1denotes-CH2-R4, R3denotes hydrogen.

17. The compound or salt according to p. 16, where R2denotes optionally substituted phenylalkyl and R4denotes a carboxy, alkoxycarbonyl or N-hydroxyaminobuteroyl.

18. 3R, 10S-stereoisomer of the compound or salt according to p. 17, where R2denotes biphenyldiol and R4denotes carboxypropyl, namely (3R, 10S)-6-(biphenyl-4-yl)-3-(9-oxo-1,8-diazatricyclo [10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)hexanoic acid, where R2means Tien-2-retil and R4denotes carboxypropyl, namely (3R,10S)-3-(9-oxo-1,8-diazatricyclo[10.6.1.013.18] endeca-12(19), 13(18), 14,16-tetraen-10-ylcarbonyl)-5-R8where R7denotes-CH2Other.

20. Connection on p. 15, where R1denotes-CH(R7)-R8where R8denotes the N-hydroxyaminobuteroyl.

21. The compound or salt according to p. 1, where a represents-N(R11)-, where R11denotes hydrogen or alkyl, n = 2 or 3, m = 4, R3denotes hydrogen.

22. Connection on p. 21, where R1denotes-CH2-R4where R4denotes carboxypropyl, N-hydroxyaminobuteroyl, N-hydroxypropylamino, alkoxycarbonyl, aryloxyalkyl or benzylaminocarbonyl.

23. The pharmaceutical composition inhibiting matrix metalloprotease in mammals containing the active substance and one or more pharmaceutically acceptable additive, characterized in that the active substance is a compound of formula I in a therapeutically effective amount.

 

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