The compound, pharmaceutical composition and method of inhibiting hiv protease

 

(57) Abstract:

The compound of the formula I given in the text of the description, where Q3- aryl or S-aryl, possibly substituted with halogen, aryl is a carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue; And - carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, pyridine, pyridine-N-oxides, quinoline, isoquinoline, indole, indoline, thiazole-1,1-dioxide, thiophene or thiophene-1,1-dioxy; carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, including heteroatom of nitrogen, pyridylmethylene, octahydrate[3,2-C]pyridine or octahydrate[3,2-C] pyridine-1,1-dioxide; Q1, Q2independently represent a hydrogen atom or alkyl; Q4-8independently represent a hydrogen atom, hydroxyl, halogen, nitro, amino, sulfonylamino, alkylamino, alkyl, possibly substituted with halogen, alkoxyl, a group-O-J (where J is therelatively group) or a group of L6C(O)L4(where L6is a single bond or-O, a L4is alkyl or alkoxy); Y and G is an oxygen atom, D is a carbon atom or nitrogen, and the atom D is connected by a single bond with each of the adjacent ring atoms; E is a carbon atom; Q

The invention relates to a new series of chemical compounds useful as HIV protease inhibitors, and use of such compounds as antiviral agents.

Acquired immunodeficiency syndrome (AIDS) is a relatively recently recognized disease or condition. AIDS causes a gradual weakening of the human immune system, and progressive deterioration of the Central and peripheral nervous systems. Upon initial recognition in the early 1980s, AIDS has spread rapidly and has now reached epidemic dimensions among a relatively limited part of the population. Intensive research led to the discovery of the agent responsible for this disease, human T-lymphotropic retrovirus III (HTLV-III), now more commonly referred to as the human immunodeficiency virus or HIV.

HIV is a member of a class of viruses known as retroviruses. The retroviral genome is composed of RNA, which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into the chromosome of a host cell and using replicative processes of the host cell, produces a new retroviral particles and dissemination is citam, which play a vital role in the human immune system. HIV infection of these white blood cells exhaust their population. Eventually the immune system becomes inactive and ineffective in dealing with various concomitant diseases, such as pneumocystic carini pneumonia, Kaposi's sarcoma and cancer of the lymph system.

Although the exact mechanism of formation and work of the HIV virus is not installed, the identification of the virus has led to some progress in the management of the disease. For example, it was found that the drug of azidothymidine (AZT) is effective for inhibition of reverse transcription of the retroviral genome of the HIV virus, which allows to control the disease, but not to cure patients suffering from AIDS. The search for medicines that can cure or at least to provide an improved measure of control over the deadly HIV virus continues.

Retroviral replication usually involves post-translational processing of polyproteins. This processing is encoded in the virus by enzyme - HIV protease. As a result of processing formed the Mature polypeptides, subsequently helping inspire armaline production of HIV. Therefore, HIV protease inhibitors can act as antovic agents.

HIV protease is one of the translated products of the pol gene of HIV. This retroviral protease specific splits other structural polypeptides in separate sites, activating these newly synthesized structural proteins and enzymes and, thus, making the virion is capable of replication. Therefore, the inhibition of HIV protease potent compounds may prevent proviral integration in infected T-lymphocytes in the early phase of the life cycle of HIV-1 and to inhibit viral proteolytic processing in the later stage. Additional benefits of protease inhibitors may be more accessible, high duration on the virus and lower toxicity compared to currently available drugs, due to their specificity to the retroviral protease.

In accordance with the present invention a new class of chemical compounds able to inhibit and/or block the action of HIV protease, which helps the proliferation of HIV, pharmaceutical compositions containing these compounds, and use e the prescription of the following formula (1), and their pharmaceutically acceptable salts inhibit the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2). These compounds are useful in the treatment of infections caused by HIV, and acquired immunodeficiency syndrome (AIDS). Compounds, their pharmaceutically acceptable salts and pharmaceutical compositions provided by the invention can be used alone or in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. Compounds of the present invention, can also be used as prodrugs. Discusses methods of treatment, methods of treatment of HIV infection and methods of inhibiting HIV protease.

Compounds of the present invention are described by formula I

< / BR>
where Q3represents aryl or-S-aryl, possibly substituted with halogen, where aryl is a carbocyclic aromatic 5-14 - membered monocyclic or polycyclic residue;

A represents a carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue; pyridinyl, pyridinyl-N-oxide; chinoline; ethenolysis; indolyl: indolinyl; thiazolyl-1,1-dioxide; thienyl; or thienyl-1,1-dioxide;

B PR is sydeny 5-14-membered monocyclic or polycyclic residue, including the nitrogen heteroatom; pyridylmethylamine; octahydrate[3,2-c]pyridinyl; or octahydrate[3,2-c] pyridinyl-1,1-dioxide;

Q1and Q2independently represent a hydrogen atom or alkyl;

Q4-Q8independently represent a hydrogen atom, hydroxyl, halogen, nitro-, amino-, alkylsulfonate, alkylamino-, alkyl possibly substituted with halogen, alkoxyl, a group-O-J (where J denotes therelatively group) or a group of L6C(O)L4(where L6represents a simple bond or a-O, a L4denotes alkyl or alkoxy);

Y and G represent oxygen atoms;

D represents a carbon atom or nitrogen, and D is connected by a simple relationship with each of the adjacent atoms of the ring;

E represents a carbon atom;

Q9represents a hydrogen atom;

or its pharmaceutically acceptable salt.

Particularly preferred are those compounds of formula (I) in which Q3selected from substituted with halogen and unsubstituted phenyl, -S-phenyl, naphthyl and-S-naphthyl; or Q3selected from substituted with halogen and unsubstituted phenyl and S-phenyl; or Q3selected from substituted with halogen, and unsubstituted phenyl; or Q3selected the Dean of Q1and Q2is tert-bootrom; Q3denotes-S-phenyl or phenyl; and Q5denotes a hydroxyl group or a group-O-J, or a pharmaceutically acceptable salt of this compound; or one of Q1and Q2is tert-bootrom and the other is a hydrogen atom; Q3denotes-S-phenyl or phenyl; Q4denotes methyl; Q5denotes hydroxyl flu or a group-O-J; Q6, Q7and Q8denote hydrogen atoms; D represents a nitrogen atom; A represents phenyl; and B denotes

< / BR>
where M1and M2represent hydrogen atoms, or M1and M2can form part of a ring having up to 10 members; in particular M1and M2independently contain from zero to eight non-hydrogen atoms.

Also preferred compounds in which one of Q1and Q2is tert-bootrom and the other is a hydrogen atom; Q4denotes methyl; Q5denotes a hydroxyl group or-O-J; Q6, Q7and Q8denote hydrogen atoms; D represents a nitrogen atom; A represents phenyl; and B denotes decahydroquinoline or octahydrate[3,2-c] pyridinyl, or a pharmaceutically acceptable salt of this compound.

In this case what is tert-bootrom, and the other is a hydrogen atom; Q3denotes-S-aryl; D represents a nitrogen atom; B represents decahydroquinoline or octahydrate[3,2-c]pyridinyl.

More preferred compounds in which A represents a carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue; Q4denotes a hydroxyl group or alkoxyl or alkyl; and Q5denotes a hydroxyl group, a group-O-J or alkoxyl; or more specifically: A stands for phenyl; Q4denotes alkyl; and Q5denotes a hydroxyl group, or the group,- OPO(OH)2; Q3may be-S-phenyl.

Preferred are compounds in which at least one of Q1and Q2is alkyl; Q4-Q8independently selected from a hydrogen atom, hydroxyl, halogen, the group-O-J (where J denotes therelatively influenza), alkoxyl, amino, alkyl, possibly substituted with halogen, and a group of L6C(O)L4(where L6means downtime bond or-O, and L4denotes alkyl); D represents a nitrogen atom; A represents a carbocyclic aromatic 5-7-membered monocyclic or polycyclic residue; pyridinyl, peridiniaceae a rich 8-12-membered monocyclic or polycyclic residue, including the nitrogen heteroatom; pyridylmethylamine; octahydrate[3,2-c]pyridinyl; or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

More preferably, Q3was selected from substituted with halogen and unsubstituted phenyl, -S-phenyl, naphthyl and-S-naphthyl; or substituted with halogen, and unsubstituted phenyl and S-phenyl; or substituted with halogen, and unsubstituted phenyl; or substituted with halogen and unsubstituted-S-phenyl.

While it is preferable that one of Q1and Q2was the alkyl and the other is a hydrogen atom; Q4meant alkyl; Q5meant hydroxyl group or a group-O-J, where J is therelatively group, or alkoxyl or amino group; E is meant a carbon atom; A represents a carbocyclic aromatic 5-6 membered monocyclic or polycyclic residue; pyridinyl, pyridinyl-N-oxide; chinoline; ethenolysis; indolyl; indolinyl; thiazolyl-1,1-dioxide; thienyl; or thienyl-1,1-dioxy; B represents a saturated 8 to 10 membered monocyclic or polycyclic residue, including nitrogen heteroatom; pyridylmethylamine; octahydrate[3,2-c]pyridinyl; or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

Bole is; 5- hydroxyl group, amino group or the group-O-J, where J is therelatively group; A is phenyl; and B represents a saturated 9-10-membered bicyclic residue, including nitrogen heteroatom; octahydrate[3,2-c]pyridine; or octahydrate[3,2-c]pyridine-1,1-dioxide.

Still more preferably, when B is decahydroquinoline or octahydrate[3,2-c]pyridinyl.

Preferred are also compounds in which one of Q1and Q2is alkyl and the other is a hydrogen atom; Q4-Q8independently selected from a hydrogen atom, hydroxyl, halogen, the group-O-J (where J denotes therelatively group), alkoxyl, amino, alkyl, possibly substituted with halogen, and a group of L6C(O)L4(where L6means downtime bond or-O, and L4denotes alkyl or alkoxy); A represents a carbocyclic aromatic 5-7 membered monocyclic residue; pyridinyl, pyridinyl-N-oxide; thiazolyl-1,1-dioxide; thienyl; or thienyl-1,1-dioxide; B represents a saturated 8-10-membered polycyclic residue, including nitrogen heteroatom; octahydrate[3,2-c]pyridinyl; or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

And more specifically, B predstavljaetcja[3,2-c]pyridine; or octahydrate[3,2-c]pyridine-1,1-dioxide.

It is also possible that B meant

< / BR>
where M1and M2represent hydrogen atoms, or M1and M2can form part of a ring having up to 10 members.

All temperatures stated herein are in degrees Celsius (oC). All units used here are given in units of weight, in addition to liquids, which are measured in units of volume.

Used herein, the term "alkyl" refers to groups with linear or branched chain, preferably containing from one to eight, more preferably one to six, and most preferably from one to four carbon atoms. The term "C1-C6-alkyl" denotes a linear or branched alkyl chain containing from one to six carbon atoms. Typical C1-C6-alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, etc., the Term "C1-C4-alkyl" falls under the term "C1-C6-alkyl".

The term "cycloalkyl" refers to a saturated or partially saturated mono - or polycarbocyclic ring, PSIA from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Typical cycloalkyl is C5-C7-cycloalkyl, having a structure of a saturated hydrocarbon ring containing from five to seven carbon atoms.

The term "alkoxy" refers to-O-alkyl. An example of alkoxyl is C1-C6-alkoxy, which is a linear or branched alkyl chain containing from one to six carbon atoms connected with oxygen atom. Typical C1-C6-CNS group include methoxy, ethoxyl, propoxy, isopropoxy, butoxy, in-butoxyl, t-butoxyl, pentoksil, hexosyl, etc. C1-C4-alkoxyl falls under the definition of C1-C6-alkoxyl.

Used herein, the term "aryl" refers to a carbocyclic or heterocyclic aromatic 5-14-membered monocyclic or polycyclic ring. Typical arily include phenyl, naphthyl, antril, tenantry, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolin, furutani, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b] thienyl, oil[2,3-b]thianthrene, kinali, chenail, phthalazine, naphthyridine, honokalani, chinoline, benzothiazolyl, benzimidazolyl, tetrahydroquinoline, cinnoline, pteridine, carbazolyl, beta-carbolines, phenanthridines, acridines, pyrimidinyl, phenanthrolines, phenazines, phenothiazines and phenoxazines.

The term "aryloxy" refers to-O-aryl.

The term "therelatively group" means a group which, when attached to the oxygen atom forms an ether, capable of either hydrolyzed in vivo with the formation of hydroxyl groups. Typical therelatively group which may be substituted, include acyl groups, sulphonate and phosphate groups. For example, such therelatively groups include blocked or free amino acid, hemisuccinate and nicotinate remains.

The term "halogen atom" means a chlorine atoms, fluorine, bromine or iodine. The term "halo" refers to chlorine, fluorine, bromine - or iodine-.

The term "carbocycle" refers to an aromatic or saturated or partially saturated 5 to 14-membered monocyclic or polycyclic ring, e.g. 5-7-membered monocyclic or 7-10-membered bicyclic rings in which all ring atoms are carbon atoms.

The term "thioether includes S-aryl, for example, phenylthio and naphthylthiourea; S-heterocycle, and the heterocycle is saturated or partially saturated; S-(C5-C7-cycloalkyl; and S-alkyl, for example C1-C6-allylthiourea. In tiefere-aryl, -heterocycle, -cycloalkyl and-alkyl can be substituted. An example of tiefer is C1-C6-alkylthio", which is a linear or branched alkyl chain containing from one to six carbon atoms attached to a sulfur atom. Typical C1-C6-ancilliary include methylthio, ethylthio, propylthio, isopropylthio, butylthio-in-butylthio-, t-butylthio, pentylthio, vexillographer etc.

The term "mercapto" means-SH.

The term "amino" means-NL1L2where L1and L2preferably independently selected from oxygen atom, carbocycle, heterocycle, alkyl, sulfonyl and a hydrogen atom; or NC(O)L3where L3- preferably alkyl, alkoxyl, a hydrogen atom or - NL/SUB>-C4-alkylamino, which is a linear or branched alkyl chain containing from one to four carbon atoms attached to the amino group. Typical C1-C4-alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino-in-butylamino etc. Another example of an amino group is di(C1-C4)alkylamino representing two linear or branched alkyl chain, each of which contains from one to four carbon atoms, connected with the General amino group. Typical di(C1-C4)alkylamino include dimethylamino, ethylmethylamino, methylpropylamine, ethylisopropylamine, butylmethylamine-in-butylmethylamine, etc. an Example of an amino group is C1-C4-alkylsulfonamides having a linear or branched alkyl chain containing from one to four carbon atoms, with the United sulfonylamino part. Typical C1-C4-alkylsulfonamides include methylsulfonylamino, ethylsulfonyl, propylsulfonyl, isopropylbenzylamine, butylsulfonyl-in-butylsulfonyl-, t-butylsulfonyl, where L4- preferably alkyl, amino group, hydroxyl group, CNS group or a hydrogen atom. Alkyl and CNS group may be substituted. Typical acyl is C1-C4-alkoxycarbonyl representing a linear or branched CNS chain containing from one to four carbon atoms connected to the carbonyl part. Typical C1-C4-alkoxycarbonyl group include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, etc. Other typical acyl is carboxypropyl, characterized in that the L6represents a single bond, and L4- alkoxyl, a hydrogen atom or a hydroxyl group. The following typical acyl is N-(C1-C4)allylcarbamate (L6is a single bond, and L4- amino group), representing a linear or branched alkyl chain containing from one to four carbon atoms connected to the nitrogen atom carbamoyl part. Typical N-(C1-C4)alkylcarboxylic groups include N-methylcarbamoyl, N-ethylcarbazole, N-propellerblades, N-isopropylcarbamate, N-butylcarbamoyl, N-t-butylcarbamoyl etc. Another telcoline circuit, each of which contains from one to four carbon atoms connected to the nitrogen atom carbamoyl part. Typical N,N-di(C1-C4)alkylcarboxylic groups include N, N-dimethylcarbamoyl, N,N-ethylmethylamino, N,N-methylpropanol, N,N-ethylisopropylamine, N, N-butylmethylamine, N,N-second-butylacrylamide etc.

The term "sulfinil" means-SO-L5where L5- preferably alkyl, amino, aryl, cycloalkyl or heterocycle. Alkyl, aryl, cycloalkyl and heterocycle can be substituted.

The term "sulfonyl" means-SO2-L5where L5- preferably alkyl, aryl, cycloalkyl, heterocycle or amino group. Alkyl, aryl, cycloalkyl and heterocycle can be substituted. An example of sulfonyl is C1-C4-alkylsulfonyl, representing a linear or branched alkyl chain containing from one to four carbon atoms, the United sulfonyloxy part. Typical C1-C4-alkylsulfonyl groups include methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl, butylsulfonyl, butylsulfonyl, t-butylsulfonyl etc.

As noted above, many of the groups can be sidimote from if the valency of these groups such substitution, even if the determination of the chemical groups is not explicitly set zamestnanosti or nezamesnanosti groups. For example, if the group is simply defined as alkyl, this may be a substituted or unsubstituted alkyl. Examples of the substituents for alkyl and aryl include mercapto-, thioester, nitro-(NO2), an amino group, aryloxy, halogen atom, hydroxyl group, alkoxy and acyl, aryl, cycloalkyl and saturated and partially saturated heterocycles. Examples of substituents of the heterocycle and cycloalkyl include the same list above-mentioned substituents for alkyl and aryl, as well as themselves aryl and alkyl.

Typical substituted arily include phenyl or naphtalene ring, substituted by one or more substituents, preferably from one to three independently selected from halo, hydroxyl group, morpholino(C1-C4)alkoxycarbonyl, pyridyl(C1-C4)alkoxycarbonyl, halo(C1-C4)alkyl, C1-C4-alkyl, C1-C4-alkoxygroup, carboxypropyl, C1-C4-alkoxycarbonyl, carbamoyl, N-(C1-C4)allylcarbamate, amino, C1-C4-alkylamino-, di(C1-C1-C4-alkoxy, carboxypropyl, C1-C4-alkoxycarbonyl, amino group, carbamoyl, C1-C4-alkylamino - or di-(C1-C4)alkylaminocarbonyl.

Another substituted alkyl is halo(C1-C4)alkyl, which is linear or branched alkyl chain containing from one to four carbon atoms with 1 to 3 halogen atoms attached to it. Typical halo(C1-C4)alkyl groups include chloromethyl, 2-bromacil, 1-chloroisopropyl, 3-forproper, 2,3-dibromoethyl, 3-chloroisobutyl, iodine-t-butyl, trifluoromethyl, etc.,

Another substituted alkyl is hydroxy-(C1-C4)alkyl representing a linear or branched alkyl chain containing from one to four carbon atoms with attached hydroxyl groups. Typical hydroxy(C1-C4)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl etc.

Another substituted alkyl is C1-C4-alkylthio(C1-C4)alkyl representing a linear or branched C1-C4is an alkyl group attached to n is clucalc methylthiomethyl, ethylthiomethyl, propertyproxy, in-butylthioethyl etc.

Another typical substituted alkyl is a heterocycle(C1-C4)alkyl representing a linear or branched alkyl chain containing from one to four carbon atoms with attached heterocycle. Typical heterocycle(C1-C4)alkali include pyrrolidinyl, hyalinella, 1-indolicidin, 2-furiati, 3-Tien-2-ylpropyl, 1-imidazolidinyl, 4-triazolylmethyl etc.

Another substituted alkyl is aryl(C1-C4)alkyl representing a linear or branched alkyl chain containing from one to four carbon atoms with attached aryl group. Typical aryl(C1-C4)alkyl groups include phenylmethyl, 2-phenylethyl, 3-naftilamin, 1-naphthalenediol, 4-phenylbutyl etc.

The heterocycle may be substituted by 1, 2 or 3 substituents, independently selected from halogroup, halo(C1-C4)alkyl, C1-C4-alkyl, C1-C4-alkoxygroup, carboxypropyl, C1-C4-alkoxycarbonyl, carbamoyl, N-(C1-C4)allylcarbamate, amino, C1-C4-alkylamino-, di(C1-C41
-C4-CNS, carboxypropyl, C1-C4-alkoxycarbonyl, amino group, carbamoyl, C1-C4-alkylamino - or di(C1-C4)alkylaminocarbonyl.

Examples of substituted heterocycles include 3-N-t-botellaspetyderivados.com, 6-N-t-BUTYLCARBAMATE[3,2-c] -pyridinyl, 3-methylimidazole, 3-methoxypyridine, 4-chlorinolysis, 4-aminothiazolyl, 8-methylinosine, 6-chlorphenoxamine, 3-ethylpyridine, 6-methoxybenzimidazole, 4-hydroxyphenyl, 4-methylisoquinoline, 6,8-dibromononane, 4,8-dimethylallyl, 2-methyl-1,2,3,4-tetrahydroisoquinoline, N-methylinosine-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquinoline-7-yl, etc.

Typical heterocyclic ring system, represented by a or B include: (1) 5-membered monocyclic ring group type tanila, pyrrolyl, imidazolyl, pyrazolyl, furil, isothiazoline, furazane, isoxazolyl, thiazolyl and so on; (2) 6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and so on; and (3) polycyclic heterocyclic ring groups such as decahydroquinoline, octahydro-thieno[3,2-c] pyridinyl, benzo[b] teenie, oil[2,3-b]thianthrene, isobenzofuranyl, amesen 1, 2 or 3 substituents, independently selected from halogroup, halo(C1-C4)alkyl, C1-C4-alkyl, C1-C4-alkoxy, carboxypropyl, C1-C4-alkoxycarbonyl, carbamoyl, N-(C1-C4)allylcarbamate, amino , C1-C4-alkylamino-, di(C1-C4)alkylamino or group having the structure -(CH2)a-R7where a = 1, 2, 3 or 4 and R7is a hydroxyl group, a C1-C4-alkoxy, carboxypropyl, C1-C4-alkoxycarbonyl, amino group, carbamoyl, C1-C4-alkylamino - or di(C1-C4)alkylaminocarbonyl. Typical substituted cycloalkyl groups include 3-methylcyclopentene, 4-Toxicological, 5-carboxylicacid, 6-chlorcycloguanil etc.

Typical substituted therelatively groups include N-benzylglycine, N-Cbz-L-felling and N-methylnicotinate.

Compounds of the present invention have at least two asymmetric center represented by the asterisk in formula I

< / BR>
Consequently, the compounds of the present invention may exist in any of the possible stereoisomeric forms and can be used in the form of mixtures of stereoisomers, optionsdigital at least 95% purity. All asymmetric forms, individual stereoisomers and their combinations are the subject of the present invention.

Individual stereoisomers can be obtained from their respective predecessors methods described above, by separation of racemic mixtures or separation of diastereomers. The separation can be carried out in the presence of a separating agent, using chromatography, by recrystallization or some combination of these known in the art methods. Further details regarding methods of separation can be found in Jacques et. al. Enantiomers, Racemates and Resolutions. John Wiley & Sons, 1981 [1]. The preferred purity of the compounds according to the present invention exceeds 50%. More preferred is at least 75% purity. Even more preferred compounds with a purity of more than 90%. Even more preferred at least 95% purity, more preferred at least 97% purity and most preferred at least 99% purity.

As mentioned above, the invention includes pharmaceutically acceptable salts of compounds described by formula I. the Compound of the present invention may contain substantially acid, codestone organic bases, and inorganic and organic acids, forming a pharmaceutically acceptable salt.

Used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include salts derived from the reaction of the compounds of the present invention with a mineral or organic acid or inorganic base. The reactants in the General case are combined in a mutual solvent type diethyl ether or benzene for salts of acids or water or spirits of salts of the bases. Salt normally precipitates out of solution over a period of time ranging from about one hour to ten days and can be isolated by filtration or other conventional methods. Such salts are known as salts of acids and bases.

Acids which can be used for the formation of the corresponding salt is an inorganic acid type hydrochloric, Hydrobromic, Modesto-hydrogen, sulfuric, phosphoric acid, etc. and organic acids such as p-toluensulfonate, methanesulfonate, oxalic, p-bromophenylacetate, carbonic, succinic, citric, benzoic, acetic acid and the t, phosphate, one-deputizing phosphate, disubstituted phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, kaprilat, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, tabakat, fumarate, maleate, Butin-1,4-diet, hexyne-1,6-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, ecological, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate etc.

Preferred pharmaceutically acceptable salts of the acids are salts formed such mineral acids as hydrochloric and Hydrobromic acid, and salts formed such organic acids as maleic and methansulfonate acid.

Salts of the bases include those formed from inorganic and organic bases, such as ammonium or hydroxides, carbonates, bicarbonates, etc. of alkali or alkaline-earth metals. Such bases useful in obtaining salts of the compounds of the present invention, thus, include hidrock potassium, calcium hydroxide, calcium carbonate, etc., Particularly preferred are a form salts that contain potassium and sodium.

It should be recognized that individual counterion forming a part of any salt of the present invention, is not critical until the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired properties in the salt as a whole.

The compounds of formula I may be a prodrug. For example, compounds in which at least one of Q4-Q8is-O-J, as defined above, can be used as prodrugs with improved pharmaceutical properties, such as pharmacokinetic properties, namely improved bioavailability or solubility. Preparation of prodrugs may be carried out by the interaction of the compounds of formula I in which at least one of Q4-Q8is-O-H, for example, activated aminoaniline, phosphoryl or hemisuccinate derived.

The present invention also encompasses recipe of pharmaceutical preparations comprising an effective amount of the compounds of formula I or its pharmaceutically acceptable salt in combination with further encompasses a method of treating AIDS, including the introduction of the carrier of the virus or the patient, such as a Primate, an effective amount of the compounds of the present invention.

The present invention also covers a method of inhibiting HIV replication, including the introduction in HIV-infected cell, a cell susceptible to HIV infection, or virus carrier or patient, such as a Primate, an effective amount of the compounds of the present invention.

The present invention encompasses novel compounds falling under formula I, described above, which are useful for the treatment of HIV infection and/or AIDS.

Preferred implementations of the formula I are: [3S-(3R*,4aR*,8aR*, 2'S*,3'S*)] -2-[2'- hydroxy-3'-phenylthiomethyl - 4'-Aza-5'-oxo-5'-(2"- methyl-3"-hydroxyphenyl) pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE, and its pharmaceutically acceptable salts, especially salt methanesulfonic acid, and its proletarienne analogues, in which the 3"-hydroxyl group is converted to-O-J, as defined above, especially the one-deputizing hydrochloride phosphate; and [6S-(6R*, 3aS*, 7aR*,2'S*,3'S*)]- 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl methanesulfonic acid, and it proletarienne analogues, in which the 3"-hydroxyl group is converted to-O-J, as defined above.

The preferred compounds are: 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE:

< / BR>
< / BR>
where T2is a hydrogen atom or methyl;

Z1group having the structure:

< / BR>
< / BR>
where R7is a hydrogen atom, a C1-C4-alkyl, halo-, nitro-, amino-, hydroxyl group;

a = 1, 2, or 3;

c = 1;

or their pharmaceutically acceptable salt. Of these compounds, more preferred are those compounds where

< / BR>
R7is a hydrogen atom, methyl, ethyl, hydroxyl group, amino group, chlorine atom; R1- represents-S-phenyl, or-S-naphthas-2-yl, and R3represents-C(O)NR4R4or their pharmaceutically acceptable salt.

Particularly preferred of these compounds are those compounds where

< / BR>
where R7ais a hydrogen atom, methyl, ethyl, chlorine atoms, bromine or fluorine; R7bis a hydrogen atom, a hydroxyl group, a chlorine atom or amino group; R7cis a hydrogen atom, hydroxyl group or amino group; R3predstavlyayutsya: 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

< / BR>
2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE methanesulfonic acid salt

< / BR>
3"-odnogolosy phosphate 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza - 5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl] decahydroquinoline-3 - N-t-BUTYLCARBAMATE hydrochloride

< / BR>
2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl]-octahydro-thieno[3,2-c]pyridine-6-N-t-BUTYLCARBAMATE

< / BR>
and 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] -octahydro-thieno[3,2-c]pyridine-6-N-t-BUTYLCARBAMATE methanesulfonic acid salt

< / BR>
Each of these five formulas has five asymmetric centers and thus defines a compound selected from 32 individual stereoisomers or any mixture of two or more stereoisomers.

The preferred stereoisomers of these compounds: [3S-(3R*,4aR*,8aR*,2'S*, 3'S*)] - 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

< / BR>
[3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)]- 2-[2'-hydroxy-3'-phenylthiomethyl - 4'-Aza-5'-OK the ol

< / BR>
3"-one-deputizing phosphate [3S-(3R*, 4aR*, 8aR*, 2'S*,3'S*)]-2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'- oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl]decahydroquinoline-3-N - t-BUTYLCARBAMATE hydrochloride

< / BR>
[6S-(6R*, 3aS*, 7aR*, 2'S*,3'S*)]- 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE

< / BR>
and [6S-(6R*, 3aS*,7aR*,2'S*,3'S*)]- 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] octahydro-thieno[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE methanesulfonic acid salt

< / BR>
Other compounds of the present invention include: [3S-(3R*,4aR*,8aR*, 2'S*, 3'R*)] - 2-[2'-hydroxy-3'-phenylmethyl-4'- Aza-5'-oxo-5'-(2"-propyl-3 - hydroxyphenyl)pentyl] decahydroquinoline-3 - N-t-BUTYLCARBAMATE

< / BR>
[2S-(2R*, 2'S*, 3'S*)]-1-[2'-hydroxy-3'- phenylthiomethyl-4'-Aza-5'-oxo-5'-(3"-hydroxy-2"-were)pentyl] - 4-pyrid-3"-iletileri-2-N-t-BUTYLCARBAMATE

< / BR>
[3S-(3R*, 4aR*, 8aR*, 2'S*,3'S*)]- 2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(1", 2", 3",4"- tetrahydroquinolin-5"-yl)pentr>)]- 2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

< / BR>
[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-ethyl-3 - hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

< / BR>
[2'R-(2'R*, 3'S*)] -N-t-butyl-2-[2'-hydroxy-3'- naphthas-2-altimeter-4'-Aza-5'-oxo-5'-(1",2",3",4"-tetrahydroquinolin - 5"-yl)pentyl]benzamide;

[2'R-(2'R*, 3'S*)] -N-t-butyl-2-[2'-hydroxy-3'-naphthas-2 - altimeter-4'-Aza-5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl]benzamide;

[2'R-(2'R*, 3'S*)] -N-t-butyl-2-[2'-hydroxy-3'-naphthas-2 - altimeter-4'-Aza-5'-oxo-5'-(2"-methyl-3",5"-diaminophenyl)pentyl]benzamide;

[2'R-(2'R*, 3'S*)] -N-t-butyl-2-[2'-hydroxy-3'-naphthas - 2-altimeter-4'-Aza-5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl]-1 - naphthylamide; and

[2'R-(2'R*, 3'S*)] -N-t-butyl-2-[2'-hydroxy-3'- naphthas-2-altimeter-4'-Aza-5'-oxo-5'-(2"-chloro-3"-AMINOPHENYL)pentyl]-1 - naphthylamide, or pharmaceutically acceptable salt of any of the above preferred compounds.

The compounds of formula I can be obtained according to the following reaction I.

The reaction I

< / BR>
< / BR>
where indicated is a rule applied in the synthesis of amides or peptides, which is done through interaction with suitably substituted amine of formula IA with a suitably substituted carboxylic acid of the formula IB in an aprotic solvent or mixture of solvents. Usually, the reaction proceeds in the presence or absence of an activating agent, preferably in the presence of an activating agent, and in the presence of the binding reagent. Typical aprotic solvents for this reaction are tetrahydrofuran and dimethylformamide, or a mixture of such solvents. Usually the reaction is carried out at a temperature of from about -30oC to approximately 25oC. the Amine reactant mainly used in equimolar proportions relative to the carbon-acid reactant in the presence of equimolar amount or slight excess of the coupling reagent. Typical binding reagents include carbodiimides, such as dicyclohexylcarbodiimide (DCC) and N,N'-diethylcarbamoyl; imidazoles, such as carbonyldiimidazole; and such reagents as bis(2-oxo-3-oxazolidinyl)fatfingered (BOP-Cl) or N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Preferred binding reagent for this reaction is DCC. For carrying out this reaction, predpochtitelnye (HOBTH2O).

Upon completion of the reaction, the compound can be optionally selected using known in the art methods, such as crystallized and then collected by filtration, or the solvent used in the reaction may be removed by extraction, evaporation or decantation. If necessary, the compound may be further purified by means such as crystallization or chromatography on such solid carriers, as silica gel or aluminium oxide.

The initial compounds of formula IA can be obtained in accordance with the methods shown in reaction scheme A (see the end of the description).

The reaction scheme And is consistent reactions 1-7. At the end of each of the reaction intermediate connection can be optionally selected using known in the art methods, for example the compound may be crystallized and then collected by filtration or solvent used in the reaction may be removed by extraction, evaporation or decantation. If necessary, before carrying out the next stage of the reaction scheme, the intermediate compound may be further purified by means such as crystallization or gromoboi convert protected on the amino group of a carboxylic acid, having a structure

< / BR>
to the corresponding mixed anhydride under conditions known in the art. For example, protected on the amino group of a carboxylic acid can react with C1-C6-alkylchlorosilanes, such as isobutylparaben, preferably in the presence of an acid acceptor. Preferred acid acceptors are trialkylamine, preferably triethylamine. The reaction is typically performed in an aprotic solvent type ethyl acetate. The choice of solvent is not critical, while the used solvent inert to the proceeding of the reaction and the reactants enough solubilization to produce the desired reaction. The resulting mixed anhydride used in the reaction A. 2 mostly without any additional stages of separation or purification.

Reaction A. 2 is performed in two stages. First, the sodium hydroxide solution, covered with a layer of ether, preferably diethyl ether, is reacted with a large excess of N-methyl-N-nitro-N-nitrosoguanidine education diazomethane reactant. Sodium hydroxide is preferably used in aqueous solution with a concentration of approximately four to six mol/L. Upon completion of the reaction the organic layer vom, obtained in the reaction described above A. 1 with formation of the corresponding-diazocarbonyl compounds. Diazomethane reactant preferably used in this reaction without isolation or purification. The reaction is usually conducted at a temperature of from about -50oC to about -10oC, preferably at a temperature of about -20oC.

In reaction A. 3-diazocarbonyl compound obtained by the reaction of A. 2, interacts with the acid of the formula H-ZZ, where ZZ is holography, typically in an aprotic solvent, for example diethyl ether, education halocarbonyl connection. The preferred acid reactant is hydrochloric acid, acting as appropriate-chlorocarbonyl connection. The reaction is usually conducted at a temperature of from about -30oC to about 0oC. the Choice of solvent is not critical, while the applied solvent inert to the proceeding of the reaction and the reactants solubilization sufficient to implement the desired reaction. Acid reactant usually added in the form of an anhydrous gas in small portions to substantially complete the reaction. The course of the reaction can be controlled thin-layer foreseen in the well-known standard conditions with formation of the corresponding-chlorhydroxide connection. For example, the compound obtained in reaction A. 3, is mixed with the regenerating agent in the mixture of solvents. Typical reducing agents include sodium borohydride, lithium borohydride, zinc borohydride, diisobutylaluminum and bis(2-methoxyethoxy)alumoweld sodium. Preferred regenerating agent is sodium borohydride. A typical mixture of solvents include proton and aprotic mixture type tetrahydrofuran/water. The choice of solvent is not critical, while the used solvent inert to the proceeding of the reaction and the reactants enough solubilization to produce the desired reaction. The reaction is usually conducted at a temperature of approximately -10oC, preferably at a temperature of about 0oC.

In reaction A. 5-chlorhydroxide compound obtained in reaction A. 4, is treated with a strong base for the formation of the corresponding epoxide in a standard, well-known experts in the field conditions. For example-chlorhydroxide connection can communicate with a mixture of potassium hydroxide/ethanol in alcoholic solvent such as ethanol. Usually the reaction is carried out in the temperature range from approximately 0oC to temperature delegal is poxed, obtained in the reaction of A. 5, communicates with the heterocyclic reactant

< / BR>
usually in an alcohol solvent at a temperature in the range from approximately 20oC to 100oC. the Choice of solvent is not critical, while the applied solvent inert to the proceeding of the reaction and the reactants solubilization sufficient to implement the desired reaction. Typical solvents for this reaction include alcohols, preferably isopropanol or ethanol. Preferably the reaction is carried out at a temperature of about 80oC.

Reaction 7 A. standard reaction of removing the protection of the amino group using methods known to experts in this field, to obtain the corresponding amine, which is used in the above reaction I. This amine can be introduced into the reaction without purification, but it is preferable that at first he was cleansed.

The compounds of formula IA, where Q3represents an-S-aryl, usually get in the first interaction is protected on the amino group of serine with triphenylphosphine and diethylazodicarboxylate (DEAD) in an aprotic solvent at a temperature of from about -80oC and 0oC with the formation of the corresponding varnish is C to -50oC. Then reveal lactoovo ring, providing connection patterns

< / BR>
usually by reacting the lactone with a suitably substituted Chianina, having the structure-S-aryl. Toanyone connection is mainly obtained by interaction of the corresponding thiol with a strong base such as sodium hydride or potassium hydride. Typically this reaction is carried out in an aprotic solvent at a temperature of from about 0oC to approximately 40oC in an inert atmosphere, for example nitrogen. Typical solvents for this reaction are ethers, preferably tetrahydrofuran.

Alternatively the compounds of formula IA, where Q3represents an-S-aryl, can be obtained using methods described in detail in Photaki. JACS, 85, 1123 (1963) [2], Sasaki N. A. et. al. Tetrahedron Letters, 21, 6069, (1987) [3]. For example, the compounds can be obtained by reaction of the double-protected serine (protected carboxyl and amino groups) with toluensulfonate in the presence of dimethylaminopyridine (DMAP) and the acid acceptor type of pyridine in an aprotic solvent type methylene chloride with formation of the corresponding toluensulfonate, which can then react with about above, in the reaction of the appropriate thiol with a strong base. Carboxylamide group can be removed from the resulting double-protected arylthioureas under conditions well known to the experts.

Heterocyclic reactants of the formula

< / BR>
applied in reaction A. 6, can be obtained using methods known in the art. For example, they are usually obtained from the corresponding protected on the amino group of amino acids by acid activation with subsequent processing alkylamino. This reaction is usually carried out in the presence of an acid acceptor type N-methylmorpholine. After removal aminosidine groups standard chemical methods get the desired heterocyclic reactants. In particular, [3S-(3R*,4aR*,8aR*)]- decahydroquinoline-3-N-t-BUTYLCARBAMATE received using 2S-1,2,3,4-tetrahydro-3-ethanolammonium acid, in the following way:

1) protection of the amino group (t-Boc);

2) acid activation/interaction with t-butylamine;

3) catalytic hydrogenation;

4) removing the protection of the amino group.

Pieperazinove the reactants can be obtained by transformation with suitably substituted pirazinamida sedimentaries catalytic hydrogenation. For example, the hydrogenation can be performed by mixing pirazinamida reactant with the catalyst in a hydrogen atmosphere in an aprotic solvent at a temperature of from about 0oC to approximately the 60oC. Suitable catalysts are palladium on charcoal, platinum metal, platinum oxide, etc., the Preferred catalyst is platinum oxide. Typical solvents for this reaction include tetrahydrofuran, dimethylformamide or a mixture of tetrahydrofuran and dimethylformamide.

The nitrogen atom in the resulting piperazinovom reactance can be proaccelerin known in the art methods. For example, it may be a reaction between piperazinonyl reactants and halo(C1-C4)alkyl or kilometersregina, such as methyl iodide or chloromethylpyridine. The preferred halosubstituted are chlorine, bromine and iodine. The reaction is carried out at temperatures from about 0oC to 60oC in a mutually inert solvent and in the presence of an acid acceptor. The preferred acid acceptor is potassium carbonate. Typical solvents include a mixture of proton and aprotic solvents such as acetonitrile and water. The choice restore sufficient to implement the desired reaction.

Alternatively alkilirovanny pieperazinove reactant can be obtained using reductive amination. For example, it may be a reaction between the above piperazinonyl reactants and aldehyde (namely, 3-pyridylcarbonyl aldehyde, ethanal, propanal) or ketone in the presence of a reducing agent and acid. Usually, the reaction is carried out in an alcohol solvent such as methanol, ethanol or isopropanol. Typical reducing agents include sodium borohydride, Lamborghini lithium, Lamborghini sodium, etc. Preferred regenerating agent is Lamborghini sodium. Typical acids include any acid, such as hydrochloric, sulfuric, methansulfonate and acetic acid. The preferred acid is acetic acid.

Intermediate reactant

< / BR>
can also be obtained in the form of compounds of formula 2

< / BR>
where V0and V1is independently hydrogen, C1-C6-alkyl or hydroxy(C1-C6)alkyl;

V2is a hydrogen atom, aminosidine group, or a group of the formula

< / BR>
V3represents -(CH2)t-V3';

t = 0, 1, 2, 3 or 4;

each independently 0, 1 or 2; g and i each independently 0 or 1;

V5represents-CH2-, -CHV5'or CV5'V5'-;

V6represents-VH2-, -CHV6'or CV6'V6'-;

V7represents-CH2-, -CHV7'or CV7'V7'-;

each of the V5', V6'and V7'independently selected from halogroup, a hydroxyl group, a C1-C6of alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6-alkoxy, C1-C6-alkylthio-, amino - or cyanopropyl;

T and W is independently-S-, -S(O)-, -S(O)2-, -O-, -NH - or -(V9)-; and

V9represents a C1-C6is alkyl, aryl(C1-C6)alkyl, aryl or acyl;

with the conditions that:

g and i can't both be 0;

the sum of f, g, h, i and j must be 2, 3, 4 or 5;

if V5represents-CV5'V5'- V6should be-CH2or CHV6'-; V7should be-CH2or CHV7'-;

if V6represents-CV6'V6'- V5should be-CH2or CHV5'-; V7should be-CH2or CHV7'-;

if V7represents-CV7'V7'- V5is acceptable salt.

The compounds of formula 3 can be obtained in accordance with reaction scheme II (see below).

Reaction scheme II in succession to reactions 1-3 (or 1-5). At the end of each of the reaction intermediate connection can be optionally selected using known in the art methods, such as crystallized and then collected by filtration or solvent used in the reaction may be removed by extraction, evaporation or decantation. If necessary, before carrying out the next stage of the reaction scheme, the intermediate compound may be further purified by means of type crystallization or chromatography on such solid carriers, as silica gel or aluminium oxide.

Reaction II. 1 is usually carried out by activating carbon-acid part to use, such as DCC or mixed anhydride, such as isobutyl, followed by reaction with a primary or secondary amine having the formula NV0V1where V0and V1similar to the above-mentioned formula (2). Usually the reaction is carried out in a nonpolar aprotic solvent or mixture of solvents in the presence or absence of an acid acceptor when Rhodesia solvents for this reaction include ethers and chlorinated hydrocarbons, preferably diethyl ether, chloroform or methylene chloride. Preferably this reaction is carried out in the presence of an acid acceptor type tertiary amine, preferably triethylamine. Amide obtained in this reaction may be isolated or used in the next reaction as shown in reaction II.2.

Reaction II. 2 is usually carried out with the compound obtained in reaction II.1, using the methods described in detail Heteroatom Manipulation. In: Comprehensive Organic Synthesis. Vol. 6 (Barry M. Trost, ed.), pp. 736-746, (1991) [4] . In General, it is suitable substituted monocyclic ring reacts with the aldehyde, such as formaldehyde or trichloroacetaldehyde in the presence of acid. Acid can be used as the solvent. Typical acids include hydrochloric, Hydrobromic, sulfuric, acetic, triperoxonane, etc. To the reaction mixture may optionally be added as a co-solvent. The choice of co-solvent is not critical until the applicable co-solvent inert to the proceeding of the reaction and the reactants solubilization sufficient to implement the desired reaction. Typical solvents for this reaction include halogenated solvents such as methylene chloride, trichloroethane, carbon tetrachloride, etc. In alternatie.

In reaction II. 3 compound isolated after the reaction II.2, restore, as shown above, obtaining saturated heterocyclic compounds. The preferred method of recovery is by catalytic hydrogenation. Typical catalysts include catalysts based on palladium catalysts based on rhodium (for example rhodium on aluminum) and catalysts based on rhenium. The preferred catalysts are the catalysts as palladium on coal. Suitable solvents for this reaction include C1-C4-alcohols, tetrahydrofuran, acetic acid in alcohol, ethyl acetate, etc., the Preferred solvent is ethanol. The reaction is usually carried out in a hydrogen atmosphere at a pressure of from about 1000 to about 4000 psi, at a temperature of from about 25oC to approximately 150oC. Preferably the reaction is carried out in an atmosphere of hydrogen at a pressure in the range from 2000 to 3000 psi and a temperature in the range from 50oC to 100oC. the Catalyst is in General used in amounts lying in the range from about evimalar to about twelve excess (by weight) over reactants, preferably from six - to ten-fold excess (in the formula (3), which correspond to the compounds of the formula (2), where V2represents a group of the formula

< / BR>
and V3and V4defined as previously for formula (2), including definitions for V3'and t.

Reaction II. 4 is a standard reaction taken protection of amino groups using methods known in the art, leading to the corresponding amine, which is then used in reaction II. 5. Preferred are chemical methods for removal of protections. For example, the protective group from compounds selected after the reaction II. 3, can be removed using trimethylsilylacetamide (TMSI) in an aprotic solvent or mixture of solvents at a temperature of from about 10oC to 60oC, preferably at a temperature of from about 20oC to 40oC. Typical solvents include methylene chloride, acetonitrile, dichloromethane, etc.

In reaction II.5 epoxide obtained previously in reaction A. 5, in which the group Q3replaced by V3reacts with the compound obtained in reaction II.4, in an alcohol solvent at a temperature of from about 20oC to 100oC. the Choice of solvent is not critical, while the implementation of the desired reaction. Typical solvents for this reaction include alcohols, preferably isopropanol and ethanol. The reaction is preferably performed at a temperature of approximately 80oC.

With the compounds obtained in the reaction of II.5, may also be removed protective groups, which results in obtaining the compounds of formula (3), in which VAis a hydrogen atom.

The epoxide used in the reaction of II.5, can be synthesized using the aforementioned reaction scheme a in which Q3replaced by V3.

Carbon-acid reactant formula (IB)

< / BR>
used in reaction scheme I, is not always commercially available, may be obtained using known procedures. In particular, this reactant can be obtained by further substitution and/or by oxidation of commercially available carbocyclic or heterocyclic compounds. For example, carbocyclic, or heterocyclic compounds of the formula

< / BR>
can be oxidized using known in the art methods. More specifically, the compound of the formula

< / BR>
can interact with the oxidizing agent of the type of selenium dioxide or potassium permanganate at temperatures from arr"ptx2">

The second method of obtaining compounds of formula (IB) includes the protection of suitably substituted carboxypropanoyl carbocyclic or heterocyclic group with carboxyamide group, followed by substitution carbocyclic or heterocyclic group, known in the art methods. Carboxyamide group may then be removed by known methods to give the desired carbon-acid reactant formula (IB).

The term "carboxyamide group", introduced in specification terms, refers to an alternate carboxyl group, generally used to block or protection when carrying out reactions with other functional groups of the compounds. Examples of such carboxyamide groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzyl, 2,2', 4,4'-tetramethoxybenzene, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichlorethyl, b-(di(n-butyl)methylsilyl)ethyl, p-toluensulfonate method of protecting carboxyl groups, providing the requested their replacement, includes the transformation of the carboxylic part in the amide followed by reverse hydrolysis of the amide. Additional examples of such groups are present in E. Haslam Protective Groups in Organic Chemistry. J. G. W. McOmie, Ed., Plenum Press, New York, N. Y., 1973, Chapter 5 [5], Greene, T. W. Protective Groups in Organic Synthesis. John Wiley & Sons, New York, N. Y., 1981, Chapter 5 [6].

The preferred procedure for the protection of the carboxyl portion includes acid activation of the carboxyl part of the subsequent amide formation. For example carboxyl part can be turned into allalone, allanheld, alliegator, etc., preferably in the presence of an acid acceptor with the formation of the activated carboxyl groups. Commonly used commercially available acid chloride eliminates the need for further acid activation. Preferred acid acceptors are trialkylamine, preferably triethylamine. The reaction is usually carried out in an aprotic solvent type diethyl

ether, methylene chloride or other solvents. The preferred solvent is methylene chloride. The choice of solvent is not critical, while the applied solvent inert to the proceeding of the reaction and the reactants solubilization in sufficient tepenin2, for example, aniline, in an aprotic solvent, forming amide reactant

< / BR>
which can then be further substituted in accordance with known methods.

Amide reactant

< / BR>
may be further substituted by ortho-deprotonation group

< / BR>
to obtain the corresponding anion, followed by reaction with various reagents of type alkylhalogenide or Galaga - dominant agents of type bromine. Amide reactant in General deprotonated twice, using two equivalents of a strong base, type h-utility or in-utillity relatively amide reactant, optionally in the presence of the metal-coordinating agent type tetramethylethylenediamine (TMEDA). The reaction is usually carried out in an aprotic solvent, preferably ether type diethyl ether, tetrahydrofuran or similar solvent at a temperature from about -78oC to approximately 25oC.

The compound obtained may then be hydrolyzed using known in the art methods to obtain the desired substituted carbon-acid reactant formula (IB). For example, suitable hydrolysis includes the effect on the amide reactant strong is approximately 100oC to about 160oC. Typical acids that can be used in this reaction include Hydrobromic acid, acetic acid, hydrochloric acid, etc., Carrying out the reaction in a sealed tube can optionally be used to increase the rate of reaction.

The third method of obtaining substituted carbon-acidic reactant formula (IB) involves the diazotization of aniline followed by reaction (damping) of the resulting reactions of diazonium salts. More specifically, the amino group of aniline reactant turn into salt, page by reaction with nitrous acid. Nitrous acid can be obtained in situ by treatment of sodium nitrite in an aqueous solution of a strong acid type hydrochloric or sulfuric. This reaction is usually conducted at a temperature equal to or below the 5oC. Salt page then extinguished in the reaction with a suitable reagent to obtain the desired substituted aromatic system. Typical quenching reagents include water, cyanide, halide, aqueous sulfuric acid, etc., Usually to facilitate the reaction, the reaction mixture needs to be heated.

There is a large variety of reactions, known to specialists that can is H. For example, there is a wide variety of reactions of electrophilic and nucleophilic substitution in aromatic compounds J. March Advanced Organic Chemistry, 3rd. ed., Wiley 1985, Chapter 11, 13 [7].

In addition, the compounds of formula (IB) can be obtained by carboxylation suitably substituted carbocyclic or heterocyclic compounds. The carboxylation can be performed using a number of different reagents. For example, carbocyclic or heterocyclic reagents can react with phosgene, oxalicacid, urea hydrochloride or N, N-diethylcarbamoyl in the presence of catalysts of the Friedel -. A variation of this method includes the interaction carbocyclic or heterocyclic reagent with architekturforum (RSCOCl) or carbamoylation (H2NCOCl) to obtain, respectively, amide and thiol ether. Amide and thiol ester can then be hydrolyzed to obtain the desired carboxyl group March J. Advanced Organic Chemistry, 3rd. ed., Wiley 1985, p. 491 [8].

Examples of catalysts of the Friedel-include Lewis acid type aluminum bromide (AlBr3), aluminium chloride (AlCl3), ferric chloride (FeCl3), trichloride boron (BClry, Wiley, New York, 1973 [10].

Advanced carbon-acid reactants quinoline can be obtained as a result of interaction with suitably substituted aniline with glycerol using the reaction of Skroupa set forth in Bradford L. et. al. J. Chem. Soc. p. 437 (1947) [11]. For example, 3-aminobenzoic acid can react with glycerol in the presence of an oxidizing agent such as m-nitrobenzenesulfonic acid or m-nitrobenzenesulfonate sodium in 60-75% aqueous solution of sulfuric acid to give the desired carboxylester quinoline. The reaction is usually carried out at a temperature of from approximately 35oC to the temperature of reflux distilled within one to six hours, preferably at a temperature of from about 50oC to the temperature of reflux distilled from two to four hours.

The resulting reaction the reactants can then be restored or gidrirovanny using known procedures. Cm. for example, J. March, Advanced Organic Chemistry, 3rd ed., Wiley, 1985, page 700 [12]. The preferred procedure involves catalytic hydrogenation, for example by mixing hinolincarbonova acid reactant with gaseous hydrogen in the presence of a catalyst. The preferred catalyst is palladium on coal. Tipi is coy as ethyl acetate. The choice of solvent is not critical, while the applied solvent inert to the proceeding of the reaction. The reaction in the General case ends for about 1 to 24 hours, in the case where at a temperature in the range from approximately 25oC to about 100oC.

In accordance with another method, compounds of formula IA, in which Q3replaced by R1can be obtained according to reaction scheme B (see the end of the description).

Reaction scheme B is carried out by conducting reactions 1-6 in sequential order. At the end of each of the reaction intermediate connection can be optionally selected using known in the art methods, for example the compound may be crystallized and then collected by filtration or solvent used in the reaction may be removed by extraction, evaporation or decantation. If necessary, before carrying out the next stage of the reaction scheme, the intermediate compound may be further purified by means of type crystallization or chromatography on such solid carriers, as silica gel or aluminium oxide.

Reaction b 1 is usually carried out by activating, i.e., not the AI with thionyl chloride, tierbroker, trichloride phosphorus, tribromide phosphorus, pentabromide phosphorus or pentachloride phosphorus according to the known methods and conditions known in the art. Suitable connections

< / BR>
are commercially available or are obtained according to known standard methods.

In reaction B. 2 acylchlorides or Allbreed obtained in the reaction B. 1, normally reacts with ammonia or primary or secondary amine of the formula H-NR4R4< / BR>
< / BR>
or

< / BR>
where R4, R5, R6and p are defined as above for formula IB, in a nonpolar aprotic solvent or mixture of solvents in the presence or absence of an acid acceptor with the formation of the corresponding amide. The reaction is usually performed at a temperature of from about -20oC to approximately 25oC. Typical solvents for this reaction include ethers and hlorirovanii hydrocarbons, preferably diethyl ether, chloroform or methylene chloride. The reaction is preferably carried out in the presence of an acid acceptor type tertiary amine, preferably triethylamine.

In reaction B. 3 amide, obtained in the reaction B. 2, interacts with a strong Foundation in Pris is B. 4 with the Weinreb amidon, forming a ketone. Reaction b 3 is typically performed in an aprotic solvent at a temperature from about -78oC to about 0oC. Typical base used in the reaction B. 3 include amicitiae and alkyllithium base, preferably C1-C4-alkyllithium base and di(C1-C4)alkylamidoamines Foundation.

Typical solubilizers agents for reaction 3 are tetramethyl(C1-C4)alkylenediamine, preferably tetramethylethylenediamine. Reaction B. 4 usually carried out in an aprotic solvent at a temperature of from about -80oC to about -40oC. Typical solvents for reactions b 3 and b 4 include ethers, preferably tetrahydrofuran. In reaction B. 4 anion in the General case is used in a quantity lying in the range from about equimolar to about tremolando excess anion, it is preferable approximately dumesny excess of the anion relative to the amide reactant Weinreb.

In reaction B. 5 the ketone obtained in the reaction B. 3, reduced to the corresponding alcohol using a suitable reducing agent. The reaction is performed in proton solvent is for this reaction include sodium borohydride, borohydride lithium, diisobutylaluminum and bis(2-methoxyethoxy)alumoweld sodium. The preferred reducing agent is sodium borohydride. Typical proton solvents for this reaction include alcohols, preferably ethanol.

Reaction B. 6 - standard response taken protection from amino groups, using techniques and methods known in the art, the result of which is obtained the corresponding amine used in the reaction described above I. This amine can be used in the reaction without purification, but it is preferable that he was cleared.

Weinreb amide used as reactant in the reaction B. 4, usually obtained by reaction of the protected amino group of amino acids with N-methoxy-N-methylamine the presence of an activating agent, an acid acceptor and a binding agent. The reaction is usually carried out in an aprotic solvent or mixture of solvents at a temperature of from about -25oC to 25oC. the Preferred activating agent for this reaction is HOBTH2O. the Preferred acid acceptors - tertiary bonds alkylamines, preferably triethylamine or N-methylmorpholine. Preferred linking reagent hydrochloride tildelt the use in the reaction B. 4.

The compounds of formula IA, in which R1replaces Q3and R1represents an-S-aryl, get on the scheme B at the first stage in the reaction are protected on the amino group of serine with triphenylphosphine and diethylazodicarboxylate (DEAD) in an aprotic solvent at a temperature of from about -80oC and 0oC, with the formation of the corresponding-lactone. The reaction is usually carried out in the ether type of tetrahydrofuran at a temperature from about -80oC to 50oC. In the second stage lactoovo ring open, receiving the compound having the structure

< / BR>
the interaction of the lactone with a suitably substituted Chianina, having the structure-S-aryl. Dianion preferably get in the reaction of the appropriate thiol with a strong base type sodium hydride or potassium hydride. This reaction is usually carried out in an aprotic solvent at a temperature of from about 0oC to approximately 40oC in an atmosphere of inert gas, such as nitrogen. Typical solvents for this reaction include ethers, preferably tetrahydrofuran. The desired amide reactant then formed in the reaction of the obtained carbon-acid reactant with N-methoxy-N-methylamine in the presence of aktuna case, the compounds of formula (IA) in which R1replaces Q3and in which R1represents an-S-aryl, can be obtained according to scheme B using methods described in detail in [2, 3]. For example, these compounds can be obtained by reaction of the double-protected serine (protected carboxyl and amino groups) with toluensulfonate in the presence of dimethylaminopyridine (DMAP) and the acid acceptor type of pyridine in an aprotic solvent such as methylene chloride, with the formation of the corresponding toluensulfonate, which can then react with a suitably substituted Chianina, having the structure-S-aryl. Dianion, as described above, mainly get in the reaction of the appropriate thiol with a strong base. Carboxyamide group can then be removed from the resulting double-protected arylthioureas under conditions well known to the experts.

In some cases, an intermediate compound for producing compounds of the present invention was prepared as follows. The intermediate compound has the formula 4

< / BR>
where R1- aryl or-S-aryl;

R10is a hydrogen atom or aminosidine group;

R0represents a C1-C< / BR>
< / BR>
p = 4 or 5;

R4in each case independently a hydrogen atom, a C1-C6-alkyl or hydroxy(C1-C4)alkyl; and

R5and R6independently selected from a hydrogen atom, a hydroxyl group, a C1-C6-alkyl, C1-C6-alkoxygroup or hydroxy(C1-C4)alkyl;

or its pharmaceutically acceptable salt. Intermediate compound having the formula 4, are usually obtained in the process, including:

(a) restoring the compounds of formula

< / BR>
obtaining piperazinovogo connection;

(b) alkylation piperazinovogo connection with obtaining the compounds of formula

< / BR>
(C) interaction piperazinovogo compound obtained in step (b), with an epoxide of the formula

< / BR>
where Rb- aminosidine group;

in an alcohol solvent at a temperature of from about 20oC to 100oC with the formation of compounds of formula 4 in which R10represents aminosidine group; and (g) possible removal of aminosidine group, with the formation of compounds of formula 4 in which R10- the hydrogen atom.

The following preparations and examples illustrate aspects of the invention. These examples privaate for terms denoting the melting point, the spectra of nuclear magnetic resonance, electron-impact mass spectra, mass spectra with ionization, field desorption mass spectra with ionization fast atom, infrared spectra, ultraviolet spectra, elemental analysis, high performance liquid chromatography and thin-layer chromatography, respectively: etc., NMR, EIMS, mass spectrum (FD), mass spectrum (FAB), IR, UV, analysis, VGH and TLC. In addition, the absorption maxima are given for the IR spectra is not all of the observed peaks, but only those that are of interest.

In the NMR spectra used the following abbreviations: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), Quartet (q), multiplet (m), doublet of multiplets (dm), broad singlet (br.s), broad doublet (br. d), broad triplet (br.t) and a broad multiplet (br.m). J denotes the constant of spin-spin interaction, expressed in Hertz (Hz). Unless otherwise stated, NMR data refer to the free base of the compounds being considered.

NMR spectra were obtained at 270 MHz instrument (Bruker Corp. or 300 MHz instrument General Electric QE-300. Chemical shifts are expressed in units (ppm below from tetramethylsilane). Mass spectra (FD) obtained narci CEC 21-110 Consolidated Electrodynamics Corporation. Mass spectra (FAB) were obtained on a VG ZAB-3 Spectrometer. IR spectra were taken on the device model 281 company Perkin-Elmer. UV spectra were obtained on device model 118 firms Saga. TLC was performed on plates of silica gel firm E. Merck. The melting point miscorrection.

Preparation 1

A. [3S-(3R*, 4aR*,8aR*,2'S*,3'R*)]- 2-[3'-N-(Benzyloxycarbonyl)amino-2'-hydroxy-4'-phenyl] butyldeoxynojirimycin-3-N-t-BUTYLCARBAMATE

A solution of [1'S-(1'R*, 1R*)] -1-[1'-N-(benzyloxycarbonyl) amino-2-(phenyl)ethyl] oxirane and [3S-(3R*,4aR*,8aR*)]- decahydroquinoline-3-N-t-BUTYLCARBAMATE in absolute ethanol was heated at 80oC during the night. The reaction mixture was evaporated to dryness under reduced pressure, obtaining the remainder. This residue was purified using flash chromatography (eluting solution of 10-50% gradient of ethyl acetate in methylene chloride) to give 6,47 g of whitish foam.

Yield: 75%.

1H NMR (CDCl3): of 1.29 (s, 9H), 1.25 and was 2.05 (m, 2H), measuring 2.20 to 2.35 (m, 2H), 2,55-2,70 (m, 11H), 2,85-3,10 (m, 3H), 3,24 (br.s, 1H), 3,82 (br.s, 1H), 3,98 (br. s, 1H), 4,99 (br. s, 2H), 5,16-by 5.18 (m, 1H), 5,80 (br.s, 1H), 7,05-7,38 (m, 10H).

IR (CHCl3): 3600-3100 (br.), 3031, 2929, 1714, 1673, 1512, 1455, 1368, 1232, 1199, 1047 cm-1.

Mass spectrum (FD): m/e 536 (M+).

B. [3-N-t - BUTYLCARBAMATE

Quickly stir the suspension 6,37 g (11,91 mmol) of the named compound of preparation 1A and 1.2 g of 10% palladium on coal in 200 ml of absolute ethanol was placed in an atmosphere of hydrogen. After approximately 48 hours the reaction mixture was filtered through celite and evaporated to dryness under reduced pressure, getting 5,09 g of the desired named connection. This compound was used without further purification.

1H NMR (CDCl3): of 1.33 (s, 9H), 1,40-of 1.95 (m, 10H), 2,25-2,48 (m, 2H), 2,59 is 2.75 (m, 3H), 2,80 is 3.40 (m, 7H), 3.75 to 3,90 (m, 1H), to 6.19 (br.s, 1H), 7.18 in-7,35 (m, 5H).

IR (CHCl3): 3600-3100 (br.), 2929, 2865, 1671, 1515, 1455, 1367, 1245, 1047 cm-1.

Mass spectrum (FD): m/e 402 (M+, 100).

Preparation of 2

A. 2R-N(Benzyloxycarbonyl)amino-3-naphthas-2-indiaproperty acid

To a solution of 1.28 g (8,00 mmol) naphthalene-2-thiol in 30 ml of tetrahydrofuran was slowly added 1.77 g (8.16 mmol) of 60% sodium hydride under nitrogen atmosphere. After stirring for approximately 15 minutes to the mixture was slowly added a solution of N(benzyloxycarbonyl)serine-lactone in 20 ml of tetrahydrofuran. The reaction was carried out for about one hour at room temperature, after which the reaction mixture was evaporated under reduced pressure to obtain a residue. This OST is a PR. The resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure to obtain a residue. This residue was purified using flash chromatography, receiving of 2.08 g of pale yellow solid.

Yield: 68%.

1H NMR (CDCl3): 3,42-3,61 (br.m, 2H), of 5.53-5,76 (br.s, 1H), 4,85-5,08 (br.m, 2H), 5,54-5,76 (br.s, 1H), 7,06-of 7.97 (m, 12H).

[]D-55,72o(c=1,0, MeOH).

IR (KBr): 3348, 3048, 1746, 1715, 1674, 1560, 1550, 1269, 1200, 1060 cm-1.

Mass spectrum (FD): m/e 381 (M+), 381 (100).

Analysis for C20H19NO4S:

Calculation: C 66,12; H 5,02; N 3,67.

Found: C 66,22; H 5,04; N 3,86.

B. 3R-1-Diazo-2-oxo-3-N-(benzyloxycarbonyl)amino-4-(naphthas-2 - ylthio)Bhutan

To a cold solution (-30oC) 15,38 g (of 40.3 mmol) of the named compound of preparation 2A in 230 ml of ethyl acetate is added slowly using a syringe was added 5,62 ml (of 40.3 mmol) of triethylamine in a nitrogen atmosphere. To the resulting solution from a syringe was added to 7.84 ml (60,5 mmol) isobutylphthalate. In a separate flask 10 g of N - (methyl)-N - (nitro)-N(nitroso)guanidine was carefully added to a mixture of the two, consisting of 170 ml of diethyl ether and 170 ml of 5N. the sodium hydroxide solution, resulting in a rapidly highlighted is the reaction diazomethane education and accession repeated, using identical amounts of diethyl ether and sodium hydroxide and 30 g of N - (methyl)-N - (nitro)-N(nitroso)guanidine. Received diazomethane reactant was added to the solution of mixed anhydride prepared previously, and the reaction was carried out in the cold (-30oC) for about 20 minutes. Upon completion of the reaction according to TLC, to remove unreacted diazomethane through the solution propulsively nitrogen, using melted on the fire Pasteur pipette, and then the solution was evaporated under reduced pressure to obtain a residue. This residue was purified using flash chromatography (eluting solution - 10% ethyl acetate in methylene chloride) to give 13,62 g yellow oil.

Yield: 83%.

1H NMR (CDCl3): 3,32-of 3.46 (m, 2H), 4,40-of 4.67 (m, 1H), 5,00-5,09 (m, 2H), 5,44 (s, 1H), USD 5.76 (d, J = 7.8 Hz, 1H), 7,25-7,86 (m, 12H).

Century 3R-1-Chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4-(naphthas-2 - ylthio)Bhutan

Anhydrous hydrogen chloride (gas) was passed within about two seconds after a cold solution (-20oC) 13,62 g (33,59 mmol) of the named compound of preparation 2B in 230 ml of diethyl ether, resulting in the separated gas. This procedure was repeated, avoiding excess chloride-hydrogen acid. On sabarimala using flash chromatography (eluting solution 10% ethyl acetate in methylene chloride) to give a 12.05 g solids pale reddish-brown color.

Yield: 87%.

1H NMR (CDCl3): to 3.41 (dd, J = 12, 6 Hz, 1H), 3,53 (dd, J = 12, 6 Hz, 1H), 4,18 (AB q, J = 41,9 Hz, J = 15,9 Hz, 2H), 4,77 (dd, J = 9, 3 Hz, 1H), 5,04 (AB q, J = 12 Hz, J = 10.4 Hz, 2H), 5,59 (d, J = 7 Hz, 1H), 7.24 to a 7.85 (m, 12H).

[]D-80,00o(c = 1,0, MeOH).

IR (CHCl3): 3426, 3031, 3012, 1717, 1502, 1340, 1230, 1228, 1045 cm-1.

Mass spectrum (FD): m/e 413 (M+), 413 (100).

Analysis for C22H20NO3SCl:

Calculation: C, 63,84; H, to 4.87; N, 3,38;

Found: C, 64,12; H, Of 4.95; N, 3,54.

, [3R-(3R*4S*)]-1-Chloro-2-hydroxy-3-N- (benzyloxycarbonyl)amino-4-(naphthas-2-ylthio)Bhutan

To a cold solution (0oC) 530 mg (1.28 mmol) of the named compound of preparation 2B in 10 ml of tetrahydrofuran and 1 ml of water was added 73 mg (1.92 mmol) of sodium borohydride. Upon completion of the reaction according to TLC, the pH of the solution was brought to 3 using a 10 ml aqueous saturated solution of ammonium chloride and 500 μl of 5N. hydrochloric acid solution. The resulting solution was extracted twice with methylene chloride, the combined organic layers were washed with water, dried over sodium sulfate, filtered and then evaporated under reduced pressure to obtain about the 212 mg solid reddish-brown color.

Yield: 40%.

1H NMR (CDCl3): 3,40 (s, 2H), 3,61-3,71 (m, 2H), 3,97-to 3.99 (m, 2H), 4,99 (s, 2H), 5,16 (br.s, 1H), 7,21-7,83 (complex, 12H).

Mass spectrum (FD): m/e 415 (M+), 415 (100).

[]D-47,67o(c = 0,86, MeOH).

IR (CHCl3): 3630, 3412, 3011, 1720, 1502, 1236, 1044 cm-1.

Analysis for C22H22NO3ClS:

Calculation: C 63,53; H 5,33; N 3,37.

Found: C 63,72; H Ceiling Of 5.60; N 3,64.

D. [1'R-(1'R*, 1S*)]-1-[(1'-N-(Benzyloxycarbonyl)amino - 2'-(naphthas-2-ylthio)ethyl]oxirane

A solution of 31 mg (0.55 mmol) of potassium hydroxide in 1 ml of ethanol was added to a solution of 190 mg (0.46 mmol) of the named compound of preparation 2 G in 6 ml ethanol/acetate in a ratio of 1:2. Upon completion of the reaction according to TLC, the reaction mixture was poured into a mixture of water with methylene chloride. The resulting layers were separated, the organic layer was washed with water, dried over sodium sulfate, filtered and then evaporated under reduced pressure to obtain a residue. This residue was purified using radial chromatography (eluting solution - 10% ethyl acetate in methylene chloride) to give 172 mg of solid substances bright reddish-brown color.

Yield: 99%.

1H NMR (CDCl3): was 2.76 (br.s, 2H), 3,01 (br.s, 1H), and 3.31 (d, J = 5 Hz, 2H: m/e 379 (M+), 379 (100).

IR (CHCl3): 3640, 3022, 2976, 1720, 1502, 1235, 1045 cm-1.

Analysis for C22H21NO3S:

Calculation: C 69,63; H 5,58; N 3,69.

Found: C 69,41; H Of 5.53; N 3,64.

That is, [2S-(2R*,2'R*,3'S*)]-1-[2'-Hydroxy - 3'-(N-benzyloxycarbonyl)amino-4'-(naphthas-2-ylthio)butyl]piperidine-2 - N-(t-butyl)carboxamide

A solution of 0.51 g (of 1.34 mmol) of the named compound preparation of 2D and 0.26 g (of 1.41 mmol) of the named compound of preparation 4B in 25 ml of isopropanol was heated at 55oC for about forty-eight hours. The resulting reaction mixture was cooled and evaporated under reduced pressure, obtaining the crude material. This material was purified using radial chromatography (4 mm plate; an eluting solution of 10% acetone in methylene chloride) to give 104 mg of a white foam.

Yield: 14%.

1H NMR (CDCl3): of 1.29 (s, 9H), 1,44-to 1.82 (m, 6H), 2,19 (m, 1H), 2.40 a (m, 1H), 2,68 (m, 2H), to 3.09 (m, 1H), 3.46 in (m, 2H), 4.00 points (m, 2H), free 5.01 (s, 2H), 5,73 (d, 1H), 6,01 (br.s, 1H), 7.23 percent-7,34 (m, 5H), was 7.45 (m, 3H), 7,72-7,83 (m, 4H).

Mass spectrum (FD): m/e 563 (M+, 100).

J. [2S-(2R*,2'S*,3'S*)]-1-[2'-Hydroxy-3'- amino-4'-(naphthas-2-ylthio)butyl] piperidine-2-N-(t-butyl)carboxamide

The solution containing 1,05 g (0.18 mmol) named with the additional one hour. The reaction mixture was evaporated, azeotrope was distilled three times with toluene, pererestorani in methanol containing 4.5 ml of diethylamine and ammonium hydroxide, and then was evaporated under reduced pressure to obtain a residue. This residue was purified using radial chromatography (1 mm plate; an eluting solution - 3% methanol in methylene chloride containing 1% acetic acid) to give 64 mg of a white foam.

Yield: 80%.

1H NMR (CDCl3): of 1.29 (s, 9H), 1,52-of 1.73 (m, 6H), of 1.84 (m, 1H), 2,31 is 2.43 (m, 2H), 2,75 totaling 3.04 (m, 5H), 3,17 (m, 1H), 3,41 (m, 1H), 3,71 (m, 1H), 6.22 per (br.s, 1H), 7,47 (m, 3H), 7,73-of 7.82 (m, 4H).

Mass spectrum (FD): m/e 430 (M+, 100).

Preparation of 3

A. 2S-N-(Benzyloxycarbonyl)-2-pyrrolidinecarboxylic pentafluorophenyl ester

To a cold solution (0oC) 30 g (0.12 mole) of 2S-N-(benzyloxycarbonyl)-2-pyrrolidinecarboxylic acid and 25.8 g (0.14 mol) of pentafluorophenol in 450 ml of tetrahydrofuran was added in one portion to 27.7 g (0.14 mol) of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) followed by the addition of 150 ml of methylene chloride. The resulting reaction mixture was heated to room temperature and the reaction was carried out for approximately four hours. Upon completion of the reaction according to TLC, the reaction mixture was evaporated under ponie water, potassium carbonate, 1N. hydrochloric acid and brine, dried over sodium sulfate, filtered and then evaporated under reduced pressure to dryness, obtaining a solid substance. This solid was re-dissolved in hexane and washed with potassium carbonate, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, getting 45,95 g of the desired named connection.

Yield: 92%.

1H NMR (CDCl3): 1,95-2,15 (m, 2H), measuring 2.20 to 2.35 (m, 1H), 2,35-of 2.50 (m, 1H), 3,50-3,75 (m, 2H), 4,65-of 4.75 (m, 1H), 5,02-and 5.30 (m, 2H), 7,20 was 7.45 (m, 5H).

B. 2S-N-(Benzyloxycarbonyl)pyrrolidin-2-N(t-butyl)carboxamide

To a cold solution (0oC) 45,90 g (0,111 mmol) of the named compound of preparation 3A in 100 ml of anhydrous methylene chloride was slowly added 100 ml (0,952 mmol) of t-butylamine. The reaction mixture was heated to room temperature, the reaction was carried out for about one hour, after which the reaction mixture was diluted with 1000 ml of methylene chloride and then washed sequentially 1H. potassium carbonate, 1N. hydrochloric acid, 1N. potassium carbonate and brine, dried over sodium sulfate and then filtered through a tube, using 50% ethyl acetate in hexane, getting 37,74 g of the desired with the 4H), 3,30-of 3.60 (m, 2H), 4,10-4,30 (m, 1H), 4.95 points to 5.35 (m, 2H), 5,65 (br.s, 0.5 H), 6,55 (br.s, 1H), 7,20 is 7.50 (m, 5,5 H).

Century 2S-Pyrrolidin-2-N-(t-butyl)carboxamide

With the connection specified in the preparation 3B (2,71 g, 8.9 mmol) was filmed protection as described in preparation 1B using 500 mg of 10% palladium on coal and hydrogen gas (1 atmosphere) in 200 ml of ethanol.

Output: 1,53 g (100%).

1H NMR (CDCl3): of 1.35 (s, 9H), 1,60-1,75 m, 2H), 1,76-1,90 (m, 1H), 2.00 in to 2.15 (m, 1H), 2,58 (br.s, 1H), 2,80 was 3.05 (m, 2H), 3,55-the 3.65 (m, 1H), 7,45 (br.s, 1H).

, [2S-(2R*, 2'S*, 3'R*)]-1-[3'-N(Benzyloxycarbonyl)- amino-2'-hydroxy-4'-phenylbutyl]pyrrolidin-2-N-(t-butyl)carboxamide

The solution containing 122 mg (to 0.72 mmol) of the named compound of preparation 3 and 200 mg (of 0.68 mmol) of [1S-(1R*,1'R*)]- 1-[(1'-N-(benzyloxycarbonyl)amino-2'-phenyl)ethyl] oxirane in 10 ml of methanol was stirred over night. Upon completion of the reaction according to TLC, the reaction mixture was evaporated under reduced pressure. The desired compound was purified by column chromatography (eluting solution is 2-4% gradient of methanol in methylene chloride) to give 232,2 mg transparent amorphous solid.

Yield: 55%.

[]D-56,97o(c = a 0.27, MeOH).

1H NMR (CDCl3): of 1.33 (s , ,95 (m, 1H), 7,15-7,40 (m, 10H).

IR (CHCl3): 3700-3100 (br.), 3434, 3031, 2976, 1720, 1664, 1604, 1512, 1455, 1394, 1367, 1343, 1233, 1156, 1107, 1063, 1028, 911 cm-1.

Mass spectrum (FD): m/e 468 (M+, 100).

D. [2S-(2R*, 2'S*,3'R*)]-1-[3'-Amino-2'- hydroxy-4'-phenyl-butyl]pyrrolidin-2-N-(t-butyl)carboxamide

With the connection specified in the preparation 3G (222 mg, 0.47 mmol), filmed protection as described in preparation 1B using 67 mg of 10% palladium on coal and hydrogen gas (1 atmosphere) in 15 ml of ethanol. The desired compound was purified by column chromatography (eluting solution - 10% isopropanol in methylene chloride containing about 0.75% ammonium hydroxide) to give 80 mg of a whitish solid.

Yield: 51%.

[]D-55,26o(c = 0,23, MeOH).

1H NMR (CDCl3): 0,80-3,70 (m, 25H), 6,90-7,40 (m, 6H).

IR (CHCl3): 3692, 3600-3200 (br.), 2975, 1657, 1603, 1522, 1497, 1479, 1455, 1393, 1366, 1232, 1198, 1137, 1049, 882 cm-1.

Mass spectrum (FD): m/e 334 (M+, 100).

Preparation of 4

A. 2S-N-(t-Butoxycarbonyl)piperidine-2-carboxylic acid

A solution of 1.64 g of sodium carbonate in 15 ml of water was added to a cold solution (0oC) 2.0 g (15,5 mol) 2S-piperidinecarboxylic acid in 50 ml of dioxane. After was pauseinterval for about six hours, after which it was concentrated to one-fourth of the original volume and then acidified to pH 2 using 1 M one-deputizing sodium sulfate and ethyl acetate. The resulting layers were separated and the organic layers were washed with saturated salt solution, dried over sodium sulfate, filtered and then evaporated to dryness under reduced pressure, getting 2.67 g of a white crystalline solid.

Yield: 75%.

[]D-55,26o(c = 0,23, MeOH).

1H NMR (CDCl3): 1,20-1,80 (m, 15H), 2,15-of 2.30 (m, 1H), 2,85-3,10 (m, 1H), 3,90-4,10 (m, 2H), 4,70-5,00 (m, 1H).

IR (CHCl3): 3700-1800 (br.), 3025, 3018, 3011, 2980, 2947, 2865, 1716, 1685, 1449, 1394, 1368, 1280, 1252, 1162, 1147, 1129 cm-1.

Mass spectrum (FD): m/e 229 (M+, 100).

Analysis for C27H37N3O4:

Calculation: C 57,63; H 8,35; N 6,11.

Found: C 57,90; H 8,35; N Is 6.19.

B. 2S-N-(t-Butoxycarbonyl)piperidine-2-carboxylate, pentafluorophenyl ester

To a cold solution (0oC) 2,53 g (11,03 mol) of the named compound of preparation 4A and of 2.34 g (12.7 mol) pentafluorobenzoic acid in 50 ml of tetrahydrofuran was added to 2.42 g (12.7 mol) of EDC. The resulting reaction mixture was heated to room temperature and the reaction was conducted in a period when the substance was re-dissolved in methylene chloride and the solution was washed successively with potassium carbonate and brine, dried over sodium sulfate, filtered and then evaporated to dryness under reduced pressure, obtaining of 3.85 g of a clear oil, which solidify upon standing.

Yield: 88%.

1H NMR (CDCl3): 1,20-1,90 (m, 15H), 2,30-to 2.40 (m, 1H), 2,90 is 3.15 (m, 1H), 3,90-to 4.15 (m, 1H), of 5.05 to 5.35 (m, 1H).

Century 2S-N-(t-Butoxycarbonyl)piperidine-2-N-t-BUTYLCARBAMATE

To a cold solution (0oC) 3.8 g (9.6 mmol) of the named compound of preparation 4B in 200 ml of methylene chloride was slowly added 2,53 ml (24,0 mmol) of t-butylamine. The reaction mixture was worked for about four hours, after which it was evaporated under reduced pressure to obtain a residue. This residue was re-dissolved in methylene chloride and then washed sequentially 1 M potassium carbonate and brine, dried over sodium sulfate, was filtered and was purified by column chromatography (eluting solution is 10-20% gradient of ethyl acetate in hexane) to give 2,52 g of a white solid.

Yield: 92%.

[]D-41,47o(c = 0,506, MeOH).

1H NMR (CDCl3): 1,10-1,70 (m, 15H), of 2.20 to 2.35 (m, 1H), 2,65-2,82 (m, 1H), 3,90-4,10 (m, 1H), 4,62 (br.s, 1H).

IR (CHCl3): 3600-3300 (br.), 2978, 2945, 2869, 1677, 1512, 1455, 1413, 1394, 1367, 1317, 1280, 1255, 1162, 1144, 112B>2
O3:

Calculation: C 63,35; H 9,92; N 9,85.

Found: C 63,10; H 9,66; N 9,92.

, 2S-piperidine-2-N-T-BUTYLCARBAMATE

A solution containing 1.0 g (3.5 mol) of the named compound of preparation 4 (C) and 3.5 ml triperoxonane acid in 25 ml of methylene chloride, stirred at room temperature for about two hours. The reaction mixture was concentrated and once azeotrope was distilled with toluene. The reaction mixture is then distributed between methylene chloride and sodium bicarbonate. The resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, getting 641 mg of the named compound.

Yield: 99%.

[]D-22,45o(C = 0.95, and MeOH).

1H NMR (CDCl3): 1,20-1,50 (m, 12H), 1,51-of 1.62 (m, 1H), 1,64 (s, 1H), 1,75-of 1.88 (m, 1H), 1,90-2,00 (m, 1H), 2,60-of 2.72 (m, 1H), 2,98-3,10 (m, 2H), 6,63 (br.s, 1H).

IR (CHCl3): 3363, 3002, 2969, 2940, 2860, 1738, 1660, 1522, 1480, 1455, 1398, 1367, 1324, 1295, 1230, 1129, 1110, 852 cm-1.

Mass spectrum (FD): m/e 184 (M+, 100).

D. [2S-(2R*, 2'S*,3'R*)]-N-[3'-(N - Benzyloxycarbonyl)-amino-2'-hydroxy-4'-phenyl]butylpiperazine-2-N-t - BUTYLCARBAMATE

The solution containing 195 mg (1.06 mmol) poimena who yl)ethyl]oxirane in 10 ml of isopropanol, was stirred at 55oC for about forty-eight hours. Upon completion of the reaction according to TLC, the reaction mixture was concentrated under reduced pressure. The desired compound was purified using column chromatography (eluting solution of 1-5% gradient of isopropanol in methylene chloride).

Output: 395 mg (81%).

[]D-55,64o(c = 0,22, MeOH).

1H NMR (CDCl3): of 1.32 (s, 9H), 1,45-1,90 (m, 6H), 2,25-2,50 (m, 2H), 2,70-3,20 (m, 5H), 3,30 is 3.40 (m, 1H), 3.75 to of 4.05 (m, 2H), 4,95-5,10 (m, 3H), x 6.15 (br.s, 1H), 7.18 in-7,40 (m, 10H).

IR (CHCl3): 3700-3100 (br.), 3623, 3021, 2976, 1668, 1603, 1511, 1456, 1313, 1047, 878 cm-1.

Mass spectrum (FD): m/e 482 (M+, 100).

That is, [2S-(2R*, 2'S*,3'R*)]-N-[3'-amino-2'- hydroxy-4'-phenyl]butylpiperazine-2-N-t-BUTYLCARBAMATE

With the connection specified in the preparation of 4D (371 mg, 0.77 mmol), filmed protection as described in preparation 1B using 110 mg of 10% palladium on coal and hydrogen gas in 20 ml of ethanol and getting 260 mg of a white foam.

Yield: 97%.

[]D-64,92o(c = 0,39, MeOH).

1H NMR (CDCl3): of 1.35 (s, 9H), 1,45-1,90 (m, 6H), of 2.25 to 2.35 (m, 1H), 2,50-2,90 (m, 5H), 3.00 and is 3.40 (m, 3H), 3,85-3,98 (m, 1H), 6,29 (s, 1H), 7,15-7,38 (m, 5H).

IR (CHCl3): 3693, 3650-3100 (br.), 2943, 2862, 1671, 1603, 1517, 1497, 1455, Razin-2-N-(t-butyl)carboxamide

To a suspension of 50 g (0,403 mol) pyrazin-2-carboxylic acid in 600 ml of tetrahydrofuran and 100 ml of dimethylformamide was added 65.9 g (0,407 mol) of carbonyldiimidazole. The reaction mixture is worked at the 50oC until until gas evolution ceased. After cooling the reaction mixture to it was slowly added of 73.5 g (1.00 mol) of butylamine. The reaction was carried out for about thirty minutes, after which the reaction mixture was evaporated under reduced pressure, pererestorani in 500 ml of methylene chloride and then washed successively with water, hydrochloric acid (pH 2), saturated sodium bicarbonate, water, 1 M potassium hydroxide and brine, dried over sodium sulfate and concentrated, receiving and 68.5 g of a white solid.

Yield: 95%.

1H NMR (CDCl3): is 1.51 (s, 9H), 7,73 (br.s, 1H), 8,49 (m, 1H), 8,72 (m, 1H), 9,38 (s, 1H).

B. (+/-)-Piperazine-2-N-(t-butyl)carboxamide

Mix and 68.5 g (0,382 mol) of the named compound of preparation 5A and 70 g (0,308 mol) of platinum oxide in 186 ml of ethanol was heated overnight at 40oC in an atmosphere of hydrogen (60 psi). The crude material was filtered and the filtrate was concentrated, receiving 65 g of a white solid.

Output:camid

To a solution of 5.0 g (or 0.027 mol) of the named compound of preparation 5B in 160 ml of a mixture of water and acetonitrile in the ratio of 1:1 was added 18,65 g (is 0.135 mol) of potassium carbonate. The resulting mixture was vigorously stirred while adding 4,43 g (or 0.027 mol) of the hydrochloride of 3-chloromethylpyridine and the reaction was carried out for the night. The reaction mixture was concentrated under reduced pressure, suspended in a solution of 20% isopropanol in chloroform, washed successively with water and brine, dried over sodium sulfate, filtered and then concentrated to obtain the residue. This residue was purified using flash chromatography (eluting solution of 5% methanol in methylene chloride containing 1% ammonium hydroxide), receiving of 1.34 g of clear yellow oil.

Yield: 18%.

1H NMR (CDCl3): 1,10 (s, 9H), 1,89 is 2.01 (m, 2H), 2,35 (m, 1H), 2.57 m-to 2.74 (m, 4H), to 3.09 (m, 1H), 3.27 to (s, 2H), of 6.71 (br.s, 1H), 7,03 (m, 1H), 7,44 (m, 1H) compared to 8.26 (m, 2H).

IR (KBr): 3691, 3611, 3366, 2974, 1666, 1602, 1521, 1479, 1456, 1427, 1393, 1366, 1324, 1139, 1047, 839 cm-1.

Mass spectrum (FD): m/e 276 (M+, 100).

, [2S-(2R*,2'S*,3'R*)]-1-[2'-Hydroxy-3'- (N-benzyloxycarbonyl)amino-4'-phenylbutyl] -4-(pyrid-3"-ylmethyl) piperazine-2-N-(t-butyl)carboxamide

The solution containing 0,377 g (1,27 µm) [is soedineniya training 5V in 12 ml of isopropanol, interacted at 45oC for about forty-eight hours. The reaction mixture was cooled and then evaporated under reduced pressure, obtaining the crude material. This material was purified using radial chromatography (6 mm plate; an eluting solution of 5-10% gradient of isopropanol in methylene chloride) to give 120 mg of isomer a and 68 mg of isomer B.

Output: total 26%.

Isomer A:

1H NMR (CDCl3): of 1.33 (s, 9H), 2.26 and-2,89 (m, 13H), 3,29 (m, 1H), 3.45 points (s, 2H), 2,79-3,95 (m, 3H), 4,73 (br.s, 1H), equal to 4.97 (br.s, 2H), 5,20 (m, 1H), 7,14-7,29 (m, 6H) EUR 7.57 (m, 1H), 7,82 (br.s, 1H), 8,53 (m, 2H).

IR (KBr): 3692, 3434, 2970, 2829, 1714, 1661, 1604, 1579, 1512, 1455, 1427, 1393, 1365, 1231, 1149, 1029, 909 cm-1.

Mass spectrum (FD): m/e 573 (M+, 100).

D. [2S-(2R*, 2'S*, 3'R*)] -1-[2'-Hydroxy-3'-amino - 4'-phenyl]butyl-4-(pyrid-3"-ylmethyl)piperazine-2-N-(t-butyl)carboxamide

The solution containing 0,062 g (0.11 mmol) of the named compound of preparation 5 G (isomer A), was stirred for approximately ninety minutes in 1.5 ml of 30% Hydrobromic acid in acetic acid. The mixture was concentrated, azeotrope was distilled three times with toluene, and re-dissolved in methanol containing 1 ml of diethylamine and ammonium hydroxide, and then was evaporated latina; an eluting solution 15-25% gradient of methanol in methylene chloride containing 1% ammonium hydroxide) to give 13 mg of a white solid.

Yield: 28%.

1H NMR (CDCl3): of 1.33 (s, 9H), 2,36-is 3.21 (m, 15H), 3,47 (d, 2H, in), 3.75 (m, 1H), 7,19-7,30 (m, 6H), EUR 7.57 (m, 2H), charged 8.52 (m, 2H).

Mass spectrum (FD): m/e 440 (M+, 100).

Preparation of 6

A. [2S-(2R*, 2'S*, 3'S*)]-1-[3'-N- (Benzyloxycarbonyl)amino-2'-hydroxy-4'-phenylthiomethyl] -4-[pyrid-3"- ylmethyl]piperazine-2-N-t-BUTYLCARBAMATE [isomer B]

The solution 596 mg (1,81 mmol) of [1S-(1R*,1'S*)]-1- [1'-N-(benzyloxycarbonyl)amino-2'-(phenylthio)ethyl] oxirane and 500 mg (of 1.81 mmol) of the named compound of preparation 5B in 15 ml of isopropanol was heated at 43oC for about forty-eight hours. The reaction was monitored using TLC (10% isopropanol in methylene chloride containing 1% ammonium hydroxide; isomer And Rf) = 0,7; isomer B Rfor = 0.6). Upon completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a residue. This residue was purified using radial chromatography (6 mm plate; an eluting solution of 5-15% gradient of isopropanol in methylene chloride containing 1% ammonium hydroxide) to give 200 mg of the isomer in the form of friable foam rusty-the Mrs (CDCl3): of 1.31 (s, 9H), 2,25-2,62 (m, 7H), 2,78-2,95 (m, 2H), 2,98-is 3.08 (m, 1H), 3,10-of 3.25 (m, 2H), 3,40-3,55 (m, 2H), 3.72 points-of 3.85 (m, 1H), 3,90-4,00 (m, 1H), of 5.05 (s, 2H), 7,01 (br.s, 1H), 7,10-7,40 (m, 11H), a 7.62 (d, J = 7.8 Hz, 1H), 8,49 (s, 2H).

Mass spectrum (FD): m/e 606 (M+, 100).

Analysis for C33H43N5O4S:

Calculation: C, 65.42 Per; H 7,15; N To 11.56.

Found: C, Compared With 65.38; H 7,27; N 11,36.

Isomer B:

Yield: 11%.

1H NMR (CDCl3): of 1.33 (s, 9H), 2,25-to 2.85 (m, 8H), 3,20-of 3.32 (m, 3H), 3,47 (s, 2H), 3,78-3,95 (m, 2H), is 5.06 (s, 2H), 5,30 is 5.38 (m, 1H), 7,10-7,42 (m, 12H), 7,55-a 7.85 (m, 2H), 8,50 at 8.60 (m, 2H).

Mass spectrum (FD): m/e 606 (M) 497 (100).

HR Mass spectrum (FAB) for C33H44N5O4S:

Calculation: 606,3114.

Found: 606,3141.

B. [2S-(2R*, 2'S*,3'S*)]-1-[2'-Hydroxy-3'- amino-4'-phenylthiomethyl]-4-[pyrid-3"-ylmethyl]piperazine-2-N-t-BUTYLCARBAMATE

A solution of 110 mg (0.18 mmol) of isomer B of preparation 6A in 5 ml of 30% Hydrobromic acid in acetic acid was stirred at room temperature for about 1 hour. The reaction mixture was evaporated under reduced pressure to obtain a residue. This residue pererestorani in 4 ml of ammonium hydroxide. The resulting solution was extracted four times with 10 ml of a solution of 10% isopropanol in chloroform. United org balance. This residue was purified using radial chromatography (2 mm plate; an eluting solution of 10-30% gradient of methanol in methylene chloride containing 1% ammonium hydroxide) to give 65 mg of loose yellow foam.

Yield: 72%.

1H NMR (CDCl3): a 1.25 (s, 9H), 2,25-2,78 (m, 7H), 3.00 and-of 3.32 (m, 4H), 3,47 (s, 2H), 3,60 of 3.75 (m, 1H), 4,18 is 4.35 (m, 1H), 6.90 to-the 7.65 (m, 9H), 8,40 at 8.60 (m, 2H).

Mass spectrum (FD): m/e 473 (M+, 100).

Preparation of 7

A. [3S-(3R*,4aR*,8aR*,2'S*,3'S*)]- 2-[3'-N-(Benzyloxycarbonyl) amino-2'-hydroxy-4'-(naphthas-2-ylthio)]butyldeoxynojirimycin-3 - N-(t-butyl)carboxamide

Preparing a solution containing 165 mg (0.40 mmol) named intermediate training 2D and 94 mg (0.43 mmol) of 3-(1-N-(t-butyl)amino-1-oxoethyl)octahydro-(2H)-isoquinoline in 5 ml of ethanol. The reaction was carried out at 80oC for approximately 19 hours. The solution is then cooled to room temperature and evaporated under reduced pressure to obtain a residue. This residue was purified using radial chromatography (eluting solution - 10% ethyl acetate in methylene chloride) to give 103 mg of whitish foam.

Yield: 42%.

1H NMR (CDCl3): 1,10-of 1.73 (m, 20H), 2,13-2,31 (m, 2H), 2,44 of $ 2.53 (m, 1H), 2,56 of 2.68 (m, 1H), 2,86-of 2.97 (m, 1H), 3,52 (br.s, 2H), 4.0 D-92,45o(c = 1,06, MeOH).

IR (CHCl3): 3429, 3010, 2929, 1713, 1670, 1514, 1455, 1047 cm-1.

Analysis for C35H47N3O4S:

Calculation: C 69,98; H To 7.67; N 6,80.

Found: C 69,86; H 7,78; N 6,58.

B [3S-(3R*,4aR*,8aR*,2'S*,3'S*)]- 2-[3'-amino-2'-hydroxy-4'-(naphthas-2-ylthio)]butyldeoxynojirimycin-3-N- (t-butyl)carboxamide

Preparing a solution containing 50 mg (of 0.081 mmol) named intermediate compound of preparation 7A and 1 ml of 38% aqueous solution of Hydrobromic acid in acetic acid. The reaction was carried out at room temperature for about 1 hour, after which the reaction mixture was evaporated under reduced pressure to obtain a residue. The residue is suspended in toluene and then evaporated under reduced pressure, receiving 61 mg of the desired named intermediate compounds. The compound obtained was used without purification in example 9.

1H NMR (CDCl3): 1,14 (s, 1H), 1,17-2,07 (complex, 15H), 2,66-2,87 (m, 2H), 3,21-of 3.25 (m, 2H, in), 3.75 (d, J = 12 Hz, 1H), 3,85 (d, J = 6 Hz, 1H), 4,36-4,47 (m, 1H), 6.73 x (s, 1H), 7,39-of 7.90 (complex, 7H).

Mass spectrum (FD): 483 (M+), 483 (100).

Preparation 8

A. 2R-2-N(Benzyloxycarbonyl)amino-3-phenylthiourea acid

what about the described in preparation 2A, using of 13.1 ml (127 mmol) of thiophenol, 4.6 g (117 mmol) of a 60% solution of sodium hydride and 25.6 g (116 mmol) of L-N(benzyloxycarbonyl)serine-lactone in 450 ml of tetrahydrofuran. This residue was purified using flash chromatography (eluting solution - 0-2% gradient of acetic acid in a mixture of methylene chloride/ethyl acetate in the ratio 4:1) to give 27.9 g of a white solid.

Yield: 72%.

1H NMR (CDCl3): 7,55-to 7.18 (m, 10H), of 5.55 (d, J = 7 Hz, 1H), to 5.08 (s, 2H), 4,73-4,60 (m, 1H), 3,55-3,30 (m, 2H).

IR (KBr): 3304, 3035, 1687, 1532, 736 cm-1.

Mass spectrum (FD): m/e 332, 288, 271, 181.

Analysis for C17H17NO4S:

Calculation: C 61,61; H 5,17; N To 4.23.

Found: C 61,69; H 5,22; N 4,47.

B. 3S-1-Diazo-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthiazole

The desired named compound was obtained as a residue in accordance with the method described in preparation 2B, using 12.1 g (37 mmol) of the named compound of preparation 8A, 5,09 ml (37 mmol) of triethylamine, 7,13 ml (55 mmol) of isobutylacetate, 146 mmol solution diazomethane. The solution diazomethane was prepared using 100 ml of diethyl ether, 150 ml of 5N. solution of sodium hydroxide and 21 g (146 mmol) N(methyl)-N - (nitro)-N(nitroso)guanidine as described in preparation 2B. Polyceridae), getting a yellow oil.

Yield: 73%.

1H NMR (CDCl3): 7,50-7,19 (m, 10H), 5,62 (d, J = 7 Hz, 1H), vs. 5.47 (br. s, 1H), 5,11 (s, 2H), 4,50-4,32 (m, 1H), 3,33 (d, J = 6 Hz, 1H).

IR (KBr): 3012, 2115, 1720, 1501, 1367, 1228 cm-1.

Mass spectrum (FD): m/e 356, 328, 242.

Century 3R-1-Chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4-phenylthiazole

The desired named compound was obtained in accordance with the method described in preparation 2B, using 22,3 g (63 mmol) of the named compound preparation 8B and small amounts of hydrogen chloride (gas) in 400 ml of diethyl ether, getting 21 grams of white solids. This solid was used without further purification.

1H NMR (CDCl3): 7,50-to 7.15 (m, 10H), to 5.56 (dd, J = 26,7 Hz, 1H), 5,11 (s, 2H), 4,78-of 4.67 (m, 1H), 4,20 (d, J = 15,9 Hz, 1H), 4,12 (d, J = 15,9 Hz, 1H), 3,48 is 3.23 (m, 2H).

IR (KBr): 3349, 1732, 1684, 1515, 1266 cm-1.

Mass spectrum (FD): m/e 363 (M+).

Analysis for C18H18NO3SCl:

Calculation: C 59,42; H 4,99; N 3,85.

Found: C 59,57; H 5,09; N 4,13.

, [2S-(2R*, 3S*)] -1-Chloro-2-hydroxy-3 - N(benzyloxycarbonyl)amino-4-phenylthiazole

The desired named compound was obtained in accordance with the method described in preparation 2, isophorone. The obtained residue was purified using flash chromatography (eluting solution - 0-2% gradient of methanol in methylene chloride) and subsequent flash chromatography (eluting solution - 0-2% gradient of ethyl acetate in chloroform) and then recrystallized from methylene chloride at -78oC, receiving of 8.3 g of the named compound.

Yield: 39%.

1H NMR (CDCl3): 7,47-7,19 (m, 10H), 5,22-to 5.03 (m, 1H), 5,09 (s, 2H), 4,01-to 3.89 (m, 2H), 3.75 to to 3.58 (m, 2H), 3,32 (d, J = 4 Hz, 2H).

IR (KBr): 3321, 2951, 1688, 1542, 1246, 738 cm-1.

Mass spectrum (FD): m/e 366 (M+), 119.

Analysis for C18H20NO3SCl:

Calculation: C 59,09; H 5,51; N 3,83.

Found: C 59,03; H 5,50; N 3,96.

D. [1'R-(1'R*, 1S*)] -1-((1'-N-(Benzyloxycarbonyl) amino-2'- phenylthio)heteroxylan

The desired named compound was obtained in accordance with the methodology described in detail in the preparation of 2D, using 8,3 g (23 mmol) of the named compound of preparation 8G, 1.4 g (25 mmol) of potassium hydroxide in 400 ml of ethanol. The obtained residue was purified using flash chromatography (eluting solution - 0-2% gradient of ethyl acetate in methylene chloride) to give 6.4 g of a white solid.

Yield: 85%.

1H NMR (CDCl3): 7,45-to 7.15 (m, 10H), 5,12 (s,P> Mass spectrum (FD) m/e 329.

Analysis for C32H45N3O4S:

Calculation: C 65,63; H Of 5.81; N, 4.25 In.

Found: C 65,48; H Of 5.82; N 4,29.

That is [3S-(3R*, 4aR*,8aR*,2'S*,3'S*)]- 2-[3'-N-(benzyloxycarbonyl)amino-2'-hydroxy-4'-(phenyl)thio) butyldeoxynojirimycin-3-N-t-BUTYLCARBAMATE

The desired named compound was obtained in accordance with the method described in preparation 2, using 6.3 g (19 mmol) of the named compound of preparation 8, 5 g (21 mmol) of (3S-(3R*,4aR*,8aR*))-decahydroquinoline - 3-N-t-BUTYLCARBAMATE in 300 ml of ethanol. The obtained residue was purified using flash chromatography (eluting solution 0-20% gradient of ethyl acetate in methylene chloride) to give 4.3 g of a white solid.

Yield: 40%.

1H NMR (CDCl3): 7,41-7,11 (m, 10H), 5,90 (d, J = 5 Hz, 1H), 5,64 (s, 1H), of 5.05 (d, J = 4 Hz, 2H), 4,08-3,90 (m, 2H), 3,40 (d, J = 6, 2H), 3,05 (s, 1H), 2,95-to 2.85 (m, 1H), 2,62 at 2.45 (m, 2H), 2,28-of 2.15 (m, 2H), 2,05-of 1.88 (m, 2H), 1,78-1,10 (m, 7H), of 1.29 (s, 9H).

IR (KBr): 3330, 2925, 2862, 1706, 1661, 1520, 1454, 1246, 738, 694 cm-1.

Mass spectrum (FD): m/e 568 (M+), 467.

Analysis for C32H45N3O4S:

Calculation: C 67,69; H 7,99; N 7,40.

Found: C 67,64; H 8,20; N 7,45.

J. [3S-(3R- t-BUTYLCARBAMATE

The desired named compound was obtained in accordance with the methodology described in detail in the preparation 2ZH, using 1 g (1.8 mmol) of the named compound of preparation 8 and 40 ml of 30% Hydrobromic acid in acetic acid solution, except that the crude material was dissolved in 30 ml of methanol. To the resulting solution were added 2 ml of diethylamine and 2 ml of concentrated ammonium hydroxide and then the mixture was evaporated under reduced pressure to obtain a residue. This residue was re-dissolved in water and ethyl acetate. The resulting layers were separated and the organic layer was washed sequentially with an aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, filtered and then evaporated to dryness under reduced pressure to obtain a residue. This residue was purified using flash chromatography (eluting solution 0-10% gradient of methanol in chloroform containing 3 drops of ammonium hydroxide in 1000 ml of chloroform) to give 0.54 g of a white foam.

Yield: 71%.

1H NMR (CDCl3): 7,41-7,16 (m, 5H), 6,07 (s, 1H), 3,78-3,70 (m, 1H), 3.45 points-to 3.38 (m, 1H), 3,03-2,84 (m, 3H), 2,38-of 2.20 (m, 3H), a 2.0 to 1.05 (m, 12H), of 1.33 (s, 9H).

IR (KBr): 2924, 2862, 1660, 1517, 1454, 1439, 737, 691 cm-1.

Mass spectrum (FD): m/e 434 (a 30.7 ml of triethylamine was slowly added to the solution, containing a 25.1 g (147 mmol) of 3-methoxybenzylamine in methylene chloride. The reaction was carried out for about thirty minutes, after which the reaction mixture was diluted with 1N. bicarbonate of sodium. The resulting layers were separated and the organic layer was washed successively with water, 1 M sodium hydroxide and then brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, obtaining of 31.6 g of a whitish solid.

Yield: 95%

B. 3-Methoxy-2-methyl-N-phenylbenzene

To a cold solution (-70oC) of 4.54 g (20 mmol) of the named compound of preparation 9A and of 5.11 g (44 mmol) of TMEDA in 70 ml of anhydrous tetrahydrofuran, was added to 26.9 ml of 1.56 M solution of n-utility in hexane. The resulting reaction mixture was heated to - 15oC and was stirred for approximately 45 minutes, receiving a yellow suspension. This suspension was re-cooled to -70oC and to it was added 2,89 g (20 mmol) of methyl iodide, which led to the formation of a white precipitate. The reaction mixture was stirred over night at room temperature, the reaction was stopped with saturated ammonium chloride and the reaction mixture was diluted with diethyl ether. The resulting layers were separated and Oriya and saline. The organic extracts were then dried over sodium sulfate and concentrated, obtaining white solid, which was purified by recrystallization from a solution in ethyl acetate/hexane in the ratio 2:1, receiving of 4.00 g of needle crystals.

Yield: 99%.

1H NMR (CDCl3): a 2.36 (s, 3H), 3,88 (s, 3H), 3,89 (s, 1H), 6.90 to-of 7.70 (m, 8H).

IR (CHCl3): 3424, 3013, 2963, 2943, 2840, 1678, 1597, 1585, 1519, 1463, 1438, 1383, 1321, 1264, 1240, 1178, 1083, 1069 cm-1.

Mass spectrum (FD): m/e 241 (M+, 100).

Analysis for C15H15NO2:

Calculation: C 74,67; H 6,27; N 5,80.

Found: C 74,65; H 6,29; N Of 5.82.

Century 3-Hydroxy-2-methylbenzoic acid

A mixture of 1.21 g (5.00 mmol) of the named compound of preparation 9B, 35 ml of 5N. hydrochloric acid and 20 ml of 30% solution of Hydrobromic acid in acetic acid was boiled under reflux for 24 hours. After cooling, the reaction mixture was diluted with 100 ml ethyl acetate and 100 ml of water. The resulting layers were separated, and the organic layer was washed once with water and then podslushivaet to pH 11 using a 0.5 n sodium hydroxide; the resulting layers were separated and the aqueous layer was acidified to pH 1 with 5N. hydrochloric acid. The desired compound was extracted from this water trevali and then concentrated to obtain a residue, formed after two pariani from hexane 750 mg of a white solid.

Yield: 98%.

1H NMR (DMSO-d6): of 2.26 (s, 3H), 6,98 (d, J = 8,03 Hz, 1H), 7,02 (t, J = of 7.69 Hz, 1H), 7,15 (d, J = 7,37 Hz, 1H), of 9.55 (br.s, 1H).

IR (CHCl3): 3600-2100 (br.), 3602, 2983, 1696, 1588, 1462, 1406, 1338, 1279, 1174, 1154, 1075, 1038, 920, 892, 854, 816 cm-1.

Mass spectrum (FD): m/e 152 (M+, 100).

Analysis for C8H8O3:

Calculation: C 63,15; H 5,30.

Found: C 63,18; H To 5.21.

In the alternative, if desired named compound was obtained by adding small portions of 22.6 g (0.33 mol) of sodium nitrite to a cooled solution (-10oC) 45 g (0.30 mol) of 3-amino-2-methylbenzoic acid and 106 g (58 ml; at 1.08 mol) of concentrated sulfuric acid in 400 ml of water while maintaining the temperature below 7oC. the resulting reaction mixture was stirred for approximately 30 minutes at -10oC, was poured into the solution containing 240 ml of concentrated sulfuric acid in 1.2 l of water, and then slowly heated up to 80oC (rapid outgassing occurs between the temperatures of 40-60oC). When the evolution of gas has ended, the reaction mixture was cooled to room temperature and named compound was extracted with pattr the ATA sodium. The resulting layers were separated and the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid. The named compound was then extracted using ethyl acetate (500 ml) and the combined organic phases are washed with saline, dried over sodium sulfate, filtered and then evaporated under reduced pressure, obtaining the crude material. This material was purified using two precrystallization from a mixture of ethyl acetate/chloroform, receiving of 23.2 g of loose orange powder.

Yield: 52%.

Preparation 10

A. 2-Ethyl-3-methoxy-N-phenylbenzene

Named compound was obtained in accordance with the methodology described in detail in the preparation of 9B, using a 13.5 ml (21 mmol) of 1.56 M n-utility, and 2.27 g (10.0 mmol) of the named compound of preparation 9A, of 2.56 g (22,0 mmol) of TMEDA and 1.56 g (10.0 mmol) of ethyl iodide in 50 ml anhydrous tetrahydrofuran. The crude material was purified by recrystallization from a solution in ethyl acetate/hexane in the ratio of 3:1, receiving of 1.57 g of needle crystals.

Yield: 62%.

1H NMR (CDCl3): 1,22 (t, J = 7.4 Hz, 3H), of 2.81 (q, J = 7,4 Hz, 2H), 3,88 (s, 3H), of 6.96 (d, J = 8,2 Hz, 1H), 7,05 (d, J = 7,6 Hz, 1H), 7,10 was 7.45 (m, 4H), to 7.50 (s, 1H), 7.62mm (d, J = 7,95 Hz, 1H).

Mass spectrum (FD): m/e 255 (M+

B. 2-Ethyl-3-hydroxybenzoic acid

A solution containing 180 mg (0.71 mmol) of the named compound of preparation 10A, 3 ml of 5N. hydrochloric acid and 3 ml of 30% Hydrobromic acid in acetic acid was heated at 155oC for 20 hours in a sealed tube. After cooling, the reaction mixture was diluted with ethyl acetate and water. The resulting layers were separated, and the organic layer was extracted once with water and then podslushivaet to pH 11 using a 0.5 n sodium hydroxide. The resulting layers were separated and the aqueous layer was acidified to pH 1 with 5N. hydrochloric acid. The desired compound was extracted from this aqueous layer with ethyl acetate. An ethyl acetate extracts were washed with saline, dried over sodium sulfate, filtered and then concentrated, gaining 103 mg solids pale red color.

Yield: 88%.

1H NMR (acetone-d6): of 1.16 (t, J = 7.4 Hz, 3H), 2,98 (q, J = 7,4 Hz, 2H), 7,00-to 7.15 (m, 2H), to 7.32 and 7.36 (m, 1H), 8,48 (br.s, 1H).

Mass spectrum (FD): m/e 166 (M+, 100).

Preparation 11

A. 2-Fluoro-3-methoxy-N-phenylbenzene

The desired named compound was obtained in accordance with the methodology described in detail in the preparation of 9B, DOB mmol) of 1.56 M n-utility, of 2.27 g (10.0 mmol) of the named compound of preparation 9A and of 2.56 g (22,0 mmol) of TMEDA in 50 ml of anhydrous tetrahydrofuran. The crude material is recrystallized twice from a solution in ethyl acetate/hexane in the ratio of 2:1 and then was further purified using radial chromatography (6 mm, 0.5% ethyl acetate in methylene chloride) to give 540 mg whitish solid.

Yield: 22%.

1H NMR (CDCl3): of 3.94 (s, 3H), 7,05-7,80 (m, 8H), 8,35-of 8.50 (m, 1H).

Mass spectrum (FD): m/e 245 (M+, 100).

B. 2-Fluoro-3-hydroxybenzoic acid

Named compound was obtained in accordance with the methodology described in detail in the preparation of 9B, using a solution of 255 mg (1,02 mmol) of the named compound of preparation 11A, 3 ml of 5N. hydrochloric acid and 5 ml of 30% solution of Hydrobromic acid in acetic acid and receiving 134 mg of a white solid.

Yield: 86%.

1H NMR (acetone-d6): 7,05 is 7.50 (m, 5H).

Mass spectrum (FD): m/e 156 (M+, 100).

Preparation 12

A. 4-N-(Phenyl)carbamoylation

A solution of 22.8 ml (250 mmol) of aniline in 104,5 ml (750 mmol) of triethylamine was slowly added to a solution of 44.5 g (250 mmol) of 4-chlororespiration hydrochloride in 500 ml of chloroform. Obtained after cooling the reaction mixture was diluted with 600 ml of water, the result was the formation of a precipitate. After adding to the mixture of 200 ml of isopropanol resulting layers were separated and the organic layer was washed sequentially with 0.1 N. sodium hydroxide, water and then brine, dried over sodium sulfate, filtered and evaporated under reduced pressure at 70oC, getting a white solid with a brown tint. This solid is washed with 200 ml of ethyl acetate, receiving of 38.9 g of the desired named connection.

Yield: 78%.

B. 4-N-(Phenyl)carbamoylation N-oxide

To a hot solution (85-90oC) to 19.8 g (100 mmol) of the named compound of preparation 12A in 60 ml of glacial acetic acid, placed behind a protective screen, was slowly added 51 ml of hydrogen peroxide. The resulting reaction mixture was worked for about four hours at 90oC, after which it was cooled to room temperature, diluted with approximately 60 ml of a mixture of isopropanol and chloroform and then podslushivaet to pH 12. The resulting layers were separated and the combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure, obtaining a solid pale yellow color. This is STV.

Yield: 75%.

Century 2-Chloro-4-N-(phenyl)carbamoylation

To a solution containing 20.2 g (97,0 mmol) pentachloride phosphorus in 27 ml (289 mmol) of phosphorus oxychloride was added to 14.4 g (67.2 per mmol) of the named compound preparation 12B. The resulting reaction mixture was slowly heated to 130oC and the reaction was carried out for about 40 minutes. The reaction mixture was cooled to room temperature and then was evaporated under reduced pressure to obtain a residue. This residue was re-dissolved in 80 ml of water and diluted with 80 ml of aqueous potassium carbonate, which resulted in a yellow precipitate. The precipitate was separated by filtration, was dissolved in 250 ml of hot ethanol and filtered in hot condition, receiving a dark yellow solution. This solution was evaporated under reduced pressure to approximately the volume of 160 ml, and then again filtered in hot condition before adding approximately 50-60 ml of water. The resulting solution was cooled and the desired compound was isolated by recrystallization, receiving 8.0 g of needle crystals pale yellow and white color.

Yield: 51%.

Year 2-Methoxy-4-N-(phenyl)carbamoylation

To a suspension containing 4.09 g (18.0 mmol) of the named compound in the under reflux for about eighteen hours, was cooled and evaporated under reduced pressure, obtaining a solid substance. This solid is washed with water and triturated with cold benzene, obtaining 1.8 g of solid substance. Analysis of this solid showed that the reaction was not complete, so to the obtained substance in methanol was further added to 10.01 g (144 mmol) of sodium methoxide. The reaction mixture was boiled in methanol under reflux for fifteen hours and treated in the same way as before, receiving 300 mg of solids. This solid was purified using radial chromatography (2 mm plate; an eluting solution - 40% ethyl acetate in hexane) followed by recrystallization from hot hexane, receiving 140 mg of the desired compound.

Output: 3%.

D. 2-Methoxy-3-methyl-4-N-(phenyl)carbamoylation

Named compound was obtained according to the procedure described in preparation 9B, using 260 mg (1,17 mmol) of the named compound preparation 12G, 404 ml (2.68 mmol) of TMEDA, of 1.78 ml (2.68 mmol) of n-utility and 329 ml (5,61 mmol) of methyl iodide in 2 ml of tetrahydrofuran. The crude material was purified using radial chromatography (2 mm plate; an eluting solution 4 is consistent connection.

E. 3-Methyl-2-pyridone-4-carboxylic acid

The suspension containing 150 mg (0,598 mmol) of the named compound preparation D in 4 ml of 5N. hydrochloric acid (water), boiled under reflux for about five hours. After cooling, the reaction mixture was evaporated under reduced pressure, obtaining a yellow oil. This oil was dissolved in 15 ml of water and the pH of the resulting solution was brought to 8 by using potassium hydroxide, after which it was diluted with 10 ml toluene. The resulting layers were separated and the aqueous layer was acidified to pH 3.5 using 5N. hydrochloric acid was evaporated under reduced pressure, obtaining a solid yellow color. The obtained solid is suspended in 2 ml of hot ethanol and filtered through cotton stuffing. The filtrate was evaporated to dryness under reduced pressure, receiving 130 mg solids. This solid is washed with 5 ml of hot 10% acetic acid in ethyl acetate, receiving 17 mg of solid, which was led from ethanol, getting to 6.8 mg of the desired named connection.

Yield: 6%.

Preparation 13

2,6-Dichloro-3-hydroxybenzoic acid

Chlorine gas (20 g, 282 mmol) slowly propulsively through a cold solution (-70oC. the Reaction mixture was re-cooled, and after about thirty minutes of gaseous chlorine was replaced with nitrogen. The reaction mixture was heated to room temperature and diluted with 100 ml of water. The desired titled compound was isolated by recrystallization, getting a solid white color. This solid was purified by recrystallization from 90 ml of water followed by recrystallization from 250 ml of benzene containing 10 ml of acetone, receiving 4.8 g of the desired titled compound.

Yield: 16%.

Preparation 14

2-Chloro-3-hydroxybenzoic acid

Chlorine gas (10.3 g; 147 mmol) slowly propulsively through a cold solution of 20 g (145 mmol) of 3-hydroxybenzoic acid in 100 ml of methanol in a nitrogen atmosphere, maintaining the temperature below -60oC. after About thirty minutes of gaseous chlorine was replaced with nitrogen, the reaction mixture was left to warm to room temperature and diluted with 100 ml of water. The desired named in the title compound was isolated by recrystallization, getting a white solid. This solid was purified by recrystallization from 50 ml of water followed by recrystallization from 130 ml of benzene containing 10 ml of acetone, receiving the initial broadcast

Suspension 306 mg (2.00 mmol) of the named compound of preparation 9C, the 1.06 ml (20.0 mmol) under the conditions and 1.38 g (10.0 mmol) of potassium carbonate in 8 ml of acetone was heated under reflux for about 3 hours. Because the reaction has not gone to the end, to the reaction mixture was further added 2 ml of 37.7 mmol) under the conditions, 2 g (14.5 mmol) of potassium carbonate and 10 ml of acetone. After boiling the mixture under reflux for about sixteen hours the mixture was filtered. The filtrate is then concentrated under reduced pressure to obtain a residue. This residue was dissolved in ethyl acetate, washed with water and then evaporated to dryness under reduced pressure, getting 188 mg of material, which contained 88% of the desired product.

B. 2-Methyl-3-methoxy benzoic acid

A solution of 116 mg (a 4.86 mmol) of lithium hydroxide in 1 ml of water was added to a solution of 175 mg (0.97 mmol) of the named compound of preparation 15A in 3 ml of tetrahydrofuran. The resulting reaction mixture was intensively stirred. Upon completion of the reaction according to TLC, the reaction mixture was concentrated under reduced pressure to obtain a residue. This residue was re-dissolved in 10 ml of hexane, 25 ml of water and 3 ml of 1N. of sodium hydroxide. Education is islote. The resulting layers were separated and an ethyl acetate layer was washed with saline, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, receiving 73 mg of the desired named in the connection header.

Preparation 16

A. 2-Butyl-3-methoxy-N-phenylbenzene

The desired named in the title compound was obtained in accordance with the methodology described in detail in the preparation of 9B, using 11,95 ml 1,51 M n-utility in hexane (18,04 mmol), 1,95 g (of 8.95 mmol) of the named compound of preparation 9A, 2,19 g (rate 18.89 mmol) of TMEDA and 1.60 g (of 9.45 mmol) butylated in 30 ml of anhydrous tetrahydrofuran. The crude material was purified using radial chromatography (4 mm plate; an eluting solution 15% ethyl acetate in hexane) to give 83 mg of a clear, colorless oil.

Output: 3,5%.

1H NMR (CDCl3): to 0.89 (t, J=7,27 Hz, 3H), of 1.36 (m, 2H), and 1.56 (m, 2H), 2,78 (m, 2H), of 3.84 (s, 3H), 6,92 (d, J=7,98 Hz, 1H), 7,00 (d, J=of 7.36 Hz, 1H), 7,11-7,22 (m, 2H), 7,35 (t, 2H), to 7.59 (m, 2H).

IR (CHCl3): 3691, 3619, 3424, 3024, 3010, 2963, 2874, 1677, 1602, 1580, 1517, 1459, 1437, 1315, 1265, 1177, 1055, 877 cm-1.

Macc-spectrum (FD): m/e 283 (M+, 100).

B. 2-Butyl-3-hydroxybenzoic acid

The desired named in the title soedinenie connection preparation 16A in 2 ml of 5N. hydrochloric acid and 2 ml of 30% Hydrobromic acid in acetic acid, receiving 44 mg of the crude material, which was used without further purification.

Yield: 60% (according to1H NMR).

1H NNR (CDCl3): to 0.96 (t, J=8,09 Hz, H), of 1.44 (m, 2H), 1,59 (m, 2H), 3,03 (m, 2H), 6,99 (d, J=8,03 Hz, 1H), 7,15 (t, J=to 7.77 Hz, 1H), to 7.59 (d, J= 6.85 Hz, 1H).

Preparation 17

A. 3-Methoxy-2-propyl-N-phenylbenzene

The desired named in the title compound was obtained in accordance with the methodology described in detail in the preparation of 9B, using 2.5 g (11.0 mmol) of the named compound of preparation 9A, of 2.81 g (or 24.2 mmol) TMEDA, 15,23 ml (23,13 mmol) n-utility and of 1.33 g (11.0 mmol) allylbromide in 30 ml of tetrahydrofuran, receiving 2.5 g of crude material. This material was dissolved in 30 ml of absolute stanol in the presence of 0.5 g of 10% palladium on coal, after which the mixture is reacted in hydrogen atmosphere for approximately twelve hours. The mixture was then filtered through celite and the filtrate was concentrated under reduced pressure, obtaining an orange oil. This oil was purified using radial chromatography (6 mm plate; an eluting solution of 10% ethyl acetate in hexane) to give 438 mg of a white foam.

Yield: 15%.

1H NMR (CDCl3"ptx2">

B. 3-Hydroxy-2-propylbenzene acid

The desired named in the title compound was obtained in accordance with the methodology described in detail in the preparation of 10B using 438 mg (of 1.62 mmol) of the named compound preparation 17A in 7 ml of 5N. hydrochloric acid and 7 ml of 30% Hydrobromic acid in acetic acid, getting a solid reddish-brown color. This solid was purified by recrystallization from hot toluene, receiving 84 mg solid reddish-brown color.

Yield: 29%.

1H NMR (CDCl3): a 1.01 (t, J=7,33 Hz, 3H), and 1.63 (m, 2H), 2,98 (m, 2H), 6,98 (d, J=7,97 Hz, 1H), 7,14 (t, J=7,86 Hz, 1H), EUR 7.57 (d, J= 7,28 Hz, 1H).

IR (KBr): 3383, 3047, 2962, 2872, 2641, 1698, 1458, 1412, 1341, 1296, 1278, 1223, 1174, 1086, 929, 815, 752 cm-1.

Macc-spectrum (FD): m/e 180 (M+, 100).

Preparation 18

A. 2-Isopropyl-3-methoxybenzonitrile

To a mixture of 2.76 g (0,115 mol) of magnesium in 75 ml diethyl ether was slowly added 24,31 g (0,143 mol) of Isopropylamine. The resulting reaction mixture was allowed to react until then, until all the magnesium was not used. Then within ninety minutes to the mixture was added a solution of 15.0 g (to 0.92 mol) of 2,3-dimethoxybenzonitrile in 75 ml diethyl ether. The resulting reaction mixture had been four hours. The reaction mixture then was cooled to 0oC, and the upper layer decantation in a saturated ammonium chloride in ice. The resulting layers were separated and the organic layer was washed successively with dilute sodium hydroxide solution, water and dilute hydrochloric acid, dried over sodium sulfate, filtered and then concentrated, getting an orange oil. This oil was distilled under reduced pressure (5 inch vigreux column; 0.2 mm Hg) to give 6.25 g of orange oil.

Yield: 39%.

1H NMR (CDCl3): 1.37 (d, J=6,47 Hz, 6H), 3,55 (m, 1H), 3,83 (s, 3H),? 7.04 baby mortality (d, J=7,79 Hz, 1H), 7,18 (m, 2H).

IR (CDCl3): 3690, 3617, 3019, 2968, 2939, 2841, 2228, 1577, 1470, 1457, 1440, 1387, 1363, 1265, 1100, 1070, 1045, 878 cm-1.

Mass spectrum (FD): m/e 175 (M+, 100).

B. 3-Hydroxy-2-isopropylbenzoic acid

The desired named in the title compound was obtained in accordance with the methodology described in detail in the preparation of 10B, using 330 mg (1.88 mmol) of the named compound of preparation 18A in 2 ml of 5N. hydrochloric acid and 30% Hydrobromic acid in acetic acid. The crude product was purified using radial chromatography (2 mm plate; an eluting solution - 3% methanol in methylene chloride>/P>1H NMR (CDCl3): of 1.40 (d, J=6,92 Hz, 6H), 3,62 (m, 1H), 6,83 (d, J=7,86 Hz, 1H), 7,06 (t, J=7,89 Hz, 1H), 7,24 (d, J=at 7.55 Hz, 1H).

IR (CHCl3): 3599, 3025, 2965, 2876, 1695, 1603, 1584, 1466, 1454, 1404, 1360, 1275, 1234, 1166, 1148, 1086, 1057, 926 cm-1.

Macc-spectrum (FD): m/e 180 (M+, 100).

Analysis for C10H12O3:

Calculation: C 66,65; H Of 6.71.

Found: C 66,53; H 6,84.

Preparation 19

3-Methylethanolamine acid

To a hot solution (155oC) 10.7 g (0.1 mol) of 3,4-lutidine in 100 ml of diphenyl ether was added in portions 18 g (0.16 mol) of selenium dioxide. After approximately 20 minutes the reaction mixture was heated to 185oC and the reaction was carried out for about thirty minutes. After cooling, the reaction mixture was diluted with water and filtered. The filtrate was extracted with chloroform and the chloroform extracts were then concentrated under reduced pressure, obtaining 6.0 g solids pale brown color.

Yield: 44%.

1H NMR (CDCl3): 2,43 (s, 3H), to 7.61 (d, J=4,98 Hz, 1H), 8,49 (d, J=4,99 Hz, 1H), 8,53 (s, 1H).

13C NMR (CDCl3): 17,91, 123,21, 132,81, 138,15, 148,12, 152,71, 167,89 ppm.

IR (KBr): 3425, 2418, 1724, 1606, 1445, 1387, 1303, 1278, 1235, 1100, 1072, 850 cm-1.

Macc-specto (FD): m/e 138 (M+, 100).

oC, acidified to pH 5 with glacial acetic acid (15 ml) and filtered, obtaining a brown solid. This solid was boiled in 300 ml of water containing 10 ml of acetic acid, and filtered in hot condition, receiving raw material. This material was purified using recrystallization from boiling acetic acid, getting 6,1 g solids pale brown color.

Yield: 32%.

1H NMR (CDCl3): a 7.62 (m, 1H), 7,81 (t, J=of 7.82 Hz, 1H), to 8.20 (m, 2H), 8,93 (d, J=3,79 Hz, 1H), 9,24 (d, J=8,58 Hz, 1H).

IR (KBr): 2772, 2431, 1906, 1708, 1610, 1589, 1507, 1363, 1323, 1269, 1235, 1211, 1141, 1076, 1034, 999, 866, 807 cm-1.

Mass spectrum (FD): m/e 173 (M+, 100).

Preparation 21

1,2,3,4-Tetrahydro-5-quinoline-carboxylic acid

A solution containing of 1.03 g (5,95 mmol) of the compound of preparation 20, of 1.87 g (29,77 mmol) of ammonium formate in 100 ml ational the mixture was heated to 65oC. After about three hours the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to obtain a residue. This residue was distributed between water (pH=4) and a solution of 10% isopropanol in chloroform. The resulting layers were separated and the organic layer was washed with water (pH=4), dried over sodium sulfate, filtered and concentrated, obtaining the crude material. This material was purified using radial chromatography (2 mm plate; an eluting solution of 5-10% gradient of methanol in methylene chloride containing 1% acetic acid) to give 87 mg of solid reddish-brown color.

Output: 8%.

1H NMR (CDCl3): 1,04 (m, 2H), 2,16 (t, 2H), 2.40 a (m, 2H), of 5.81 (d, J= 8,05 Hz, 1H), 6,09 (t, J=7,78 Hz, 1H), 6,23 (d, J=of 7.96 Hz, 1H).

IR (KBr): 3296, 2965, 2929, 1691, 1597, 1474, 1461, 1443, 1350, 1305, 1279, 1236, 1184, 1159, 1106, 1073, 1022, 827 cm-1.

Macc-spectrum (FD): m/e 177 (M+, 100).

Analysis for C10H11NO2:

Calculation: C 67,78; H Of 6.26; N Of 7.90.

Found: C 67,96; H 6,10; N 7,88.

Preparation 22

A. 3-Amino-2-methylbenzoate methyl ester

A solution of 10 g (66,2 mmol) 3-amino-2-methylbenzoic acid and 20 g of p-toluensulfonate acid monohydrate in 400 ml of methanol boil ovaries layers were cooled and separated. The organic layer was washed successively 1 M potassium carbonate and brine, dried over sodium sulfate, filtered and concentrated, obtaining 9,23 g orange oil.

Yield: 85%.

1H NMR (CDCl3): of 2.34 (s, 3H), of 3.73 (br.s, 2H), 3,88 (s, 3H), for 6.81 (d, J=of 7.96 Hz, 1H), 7,05 (t, J=7,78 Hz, 1H), 7,19-7,30 (m, 1H).

IR (CDCl3): 3406, 3027, 3012, 2978, 2953, 1718, 1621, 1467, 1435, 1315, 1301, 1265, 1196, 1159, 1108, 1066, 1045, 810 cm-1.

Mass spectrum (FD): m/e 165 (M+, 100).

B. 3-N-(Methylsulphonyl)amino-2-methylbenzoate methyl ester

To a cold solution (0oC) 1.07 g (6,48 mmol) of the named compound preparation 22A in 50 ml of anhydrous methylene-chloride was added 1.18 g (to 6.80 mmol) of methylsulfonic anhydride.

The resulting reaction mixture was reacted overnight at room temperature, after which it was diluted with 100 ml of methylene chloride, washed twice with sodium bicarbonate solution, dried over sodium sulfate, filtered, concentrated, pererestorani in hexane and then concentrated to obtain a residue. This residue was thrice washed in hexane, then was evaporated to dryness under reduced pressure, obtaining of 1.46 g of solid pink color. This solid is then PE is SUP>1
H NMR (DMSO-d6): 2,25-of 2.45 (m, 4,5 H) of 2.97 (s, 1,5 H) of 3.80 (s, 3H), 7.23 percent-7,63 (m, 3H), 9,24 (s, 1H).

IR (KBr): 3900-2400 (br. ), 3298, 1713, 1466, 1320, 1290, 1265, 1248, 1210, 1183, 1156, 1047, 971, 964, 752, 563, 519 cm-1.

Macc-spectrum (FD): m/e 243 (M+, 100).

Analysis for C10H13NO4S:

Calculation: C 49,37; H 5,39; N 5,76.

Found: C 49,15; H 5,54; N 5,80.

Century 3-N-(Methylsulphonyl)amino-2-methylbenzoic acid

The desired named in the title compound was obtained in accordance with the method described in preparation 15B, using 400 mg (1,64 mmol) compound named in the heading of preparation 22B and 118 mg (4,93 mmol) of lithium hydroxide in 20 ml of tetrahydrofuran and 8 ml of water, getting 206 mg of a white solid.

Yield: 55%.

1H NMR (DMSO-d6): 2,43 (s, 3H), of 2.97 (s, 3H), 7,26 (t, J=7.87 in Hz, 1H), 7,43 (d, J=7,79 Hz, 1H), 7,60 (d, J=7,17 Hz, 1H).

IR (KBr): 3800-2200 (br. ), 3252, 1685, 1404, 1334, 1309, 1277, 1149, 982, 965, 914, 780, 763, 748, 632, 518, 498 cm-1.

Macc-spectrum (FD): m/e 243 (M+, 100).

Preparation 23

A. 3-methoxy-M-phenylbenzene

A solution of 13.4 ml (147 mmol) of aniline in a 30.7 ml of triethylamine was slowly added to a solution containing a 25.1 g (147 mmol) of 3-methoxybenzylamine in methylene chloride. The resulting reaction mixture reagirovali were separated and the organic layer was washed successively with water, 1 M sodium hydroxide and then brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, obtaining of 31.6 g of a whitish solid.

Yield: 95%.

B. 3-Methoxy-2-methyl-N-phenylbenzene

To a cold solution (-70oC) of 4.54 g (20 mmol) of the compound named in the heading preparation 23A and of 5.11 g (44 mmol) of TMEDA in 70 ml of anhydrous tetrahydrofuran was added to 26.9 ml of 1.56 M n-utility in hexane. The resulting reaction mixture was heated to -15oC and was stirred for approximately 45 minutes, receiving a yellow suspension. The slurry is then re-cooled to -70oC and to it was added 2,89 g (20 mmol) under the conditions, resulting white precipitate was formed. The reaction mixture was stirred over night at room temperature, the reaction was stopped by adding saturated ammonium chloride, and the contents of the reaction mixture was diluted with diethyl ether. The resulting layers were separated and the organic phase was washed sequentially with saturated ammonium chloride, water, saturated sodium bicarbonate and saline. The organic extracts were then dried over sodium sulfate and concentrated, obtaining a white solid prophetic is atih crystals.

Yield: 99%.

1H NMR (CDCl3): a 2.36 (s, 3H), 3,88 (s, 3H), 3,89 (s, 1H), 6.90 to-of 7.70 (m, 8H).

IR (CHCl3): 3424, 3013, 2963, 2943, 2840, 1678, 1597, 1585, 1519, 1463, 1438, 1383, 1321, 1264, 1240, 1178, 1083, 1069 cm-1.

Mass spectrum (FD): m/e 241 (M+, 100).

Analysis for C15H15NO2:

Calculation: C 74,67; H 6,27; N 5,80.

Found: C 74,65; H 6,29; N Of 5.82.

Century 2-Methyl-3-hydroxybenzoic acid

A mixture of 1.21 g (5.00 mmol) of the named compound preparation 23B, 35 ml of 5N. hydrochloric acid and 20 ml of 30% solution of Hydrobromic acid in acetic acid was boiled under reflux for 24 hours. After cooling, the reaction mixture was diluted by adding 100 ml of ethyl acetate and 100 ml of water. The resulting layers were separated and the organic layer was washed once with water and then the pH was brought to 11, using a 0.5 n sodium hydroxide solution. The resulting layers were separated and the pH of the aqueous layer was brought to 1, using 5N. hydrochloric acid. The desired compound was then extracted from this aqueous layer using ethyl acetate. An ethyl acetate extract is then washed with saline, dried over sodium sulfate, filtered and evaporated to obtain the residue, which after two pariani from hexane Yes what,03 Hz, 1H), 7,02 (t, J= of 7.69 Hz, 1H), 7,15 (d, J=7,37 Hz, 1H), of 9.55 (br.s, 1H).

IR (CHCl3): 3600-2100 (br.), 3602, 2983, 1696, 1588, 1462, 1406, 1338, 1279, 1174, 1154, 1075, 1038, 920, 892, 854, 816 cm-1.

Mass spectrum (FD): m/e 152 (M+, 100).

Analysis for C8H8O3:

Calculation: C 63,15; H 5,30.

Found: C 63,18; H To 5.21.

Alternative preparation to obtain 2-methyl-3-hydroxybenzoic acid

To a cold suspension (0oC) of 0.54 g (3.3 mmol) of 2-methyl-3 - aminobenzoic acid in 5 ml of water containing 0,65 ml of concentrated sulfuric acid, was added 0.25 g (3.6 mmol) of solid sodium nitrite. After about 15 minutes the reaction mixture was poured into 20 ml of warm water containing 4 ml of concentrated sulfuric acid. The resulting reaction mixture was slowly heated to 90oC, which was allocated gas. After the gas evolution, the solution was cooled to room temperature and was extracted with ethyl acetate. The organic layers were combined, washed with 0.5 G. hydrochloric acid, dried and concentrated under reduced pressure. The crude residue was purified by rapid filtration through silica gel (eluting solution of 5% methanol in methylene chloride) to give 350 mg of a white solid substance (tn), 6,93 (d, J=7.9 Hz, 1H), 2,46 (s, 3H).

Analysis for C8H8O3:

Calculation: C 63,15; H Of 5.29.

Found: C 63,32; H Are 5.36.

Preparation 24

A. N-(t-butyl)-2-methylbenzamide

To a cold solution (0oC) 139,2 g (0.9 mol) of the chloride of o toluoyl in 1200 ml of methylene chloride at 25oC in nitrogen atmosphere was slowly added 180,0 g (1.8 mol) of triethylamine followed by the addition dropwise of a solution containing 73,14 g (1.0 mol) of t-butylamine in 200 ml of methylene chloride. The resulting reaction mixture was heated to room temperature and left to react for 2.5 hours. After the reaction mixture was diluted with 1800 ml of water. The resulting organic and aqueous layers were separated and the organic layer was washed sequentially 2n. sodium hydroxide, 1,0 N. hydrochloric acid and brine, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure, getting 167,6 g of the desired named connection in the form of a whitish solid (i.e. 77-78oC).

Yield: 97%.

1H NMR (CDCl3): of 1.41 (s, 9H), is 2.41 (s, 3H), 5,54 (br.s, 1H), 7,13-7,30 (m, 4H).

IR (CHCl3): 3430, 3011, 2971, 2932, 1661, 1510, 1484, 1452, 1393, 1366, 1304, 1216, 876 cm-1.

Mass spec is obnarujeno: C 75,10; H 9,11; N 7,20.

B. S-N-t-Butyl-2-(3-(N-benzyloxycarbonyl)amino-2-oxo-4 - phenylbutyl)benzamide

To a solution of 7.0 g (to 36.5 mmol) of the named compound preparation 24A in 200 ml of anhydrous tetrahydrofuran from a syringe was added to 12.1 ml (80,3 mmol) N, N,N',N'-tetramethylethylenediamine (TMEDA). The resulting solution was cooled to -78oC, then thereto is added dropwise from a syringe was added to 55.9 ml-utility, maintaining the temperature of the reaction mixture below -60oC. the Resulting reaction solution was then stirred for approximately 1 hour at -78oC, before adding, using a cannula, a solution containing of 5.00 g (14.6 mmol) of S-N-methoxy-N - methyl-2-(N-benzyloxycarbonyl)amino-3-phenylpropanamide in 50 ml of anhydrous tetrahydrofuran, maintaining the temperature of the reaction mixture below -65oC. the Resulting reaction mixture was heated to -20oC, the reaction was stopped using 20 ml saturated ammonium chloride and then diluted with 200 ml dietrologia ether. Organic and aqueous layers were separated and the organic layer was washed successively with water, 0,2 N. one-deputizing sodium sulfate and brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure, getting bestv is ideal), getting between 6.08 g of a colorless foam.

Yield: 88%.

[]D-289,26o(C=0,12, MeOH).

1H NMR (CDCl3): to 1.38 (s, 9H), 2,99 (dd, J=15 and 6 Hz, 1H), 3,24 (dd, J= 15 and 6 Hz, 1H), 3,89 (d, J=18 Hz, 1H), 4.16 the (d, J=18 Hz, 1H), 4.72 in (dd, J=15, 6 Hz, 1H), 5,00-5,09 (m, 2H), 5.56mm (d, J=6 Hz, 1H), 5,93 (br.s, 1H), 7.03 is-7,40 (m, 14H).

IR (CHCl3): 3431, 3027, 3012, 2973, 1713, 1658, 1511, 1454, 1383, 1366, 1307, 1231, 1046 cm-1.

Macc-spectrum (FD): m/e 472 (M+), 218 (100).

Analysis for C29H32N2O4:

Calculation: C 73,70; H 6,82; N 5,93.

Found: C 73,41; H 6,98; N Of 5.83.

Century, [2R-(2R*, 3S*)] -N-t-Butyl-2-(3-(N-benzyloxycarbonyl) amino-2-hydroxy-4-phenylbutyl)benzamide

To a solution of 6.96 g (14.7 mmol) of the named compound preparation 24B in 200 ml of absolute ethanol under nitrogen atmosphere was added 2,78 g (of 73.5 mmol) of sodium borohydride. Upon completion of the reaction, according to thin-layer chromatography (TLC), the reaction mixture was diluted with 200 ml ethyl acetate and the reaction was stopped by adding dropwise 20 ml of saturated ammonium chloride. Organic and aqueous layers were then separated and the organic layer was washed sequentially 1H. hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated, s (eluting solution 2-10% gradient of methylene chloride in ethyl acetate), obtaining 5,12 g of the named compound.

Yield: 74%.

[]D+10,38o(=to 0.10, MeOH).

1H NMR (CDCl3): of 1.40 (s, 9H), and 2.79 (dd, J=12, 3 Hz, 1H), 2,90 are 2.98 (m, 2H), 3.04 from (44, J=12, 3 Hz, 1H), 3,70-3,81 (m, 1H), 3,97 (m, 1H), 4,96-5,08 (m, 2H), 5,10 (d, J=9 Hz, 1H), 5,88 (d, J=6 Hz, 1H), to 5.93 (s, 1H), 7,13-7,42 (m, 14H).

IR (CHCl3): 3431, 3028, 3012, 2971, 1773, 1643, 1515, 1454, 1367, 1229, 1028 cm-1.

Macc-spectrum (FD): m/e 475 (M+), 475 (100).

Analysis for C29H34N2O4:

Calculation: C 73,39; H 7,22; N 5,99.

Found: C 73,12; H Of 7.48; N 5,62.

, [2R-(2R*,3S*) 1-N-t-Butyl-2-(3-amino-2-hydroxy-4-phenylbutyl)benzamide

Preparing a suspension containing 41,0 g (120 mmol) poimenovano compound of preparation 24 and 500 kg of 10% palladium on coal in 150 ml of absolute ethanol. This suspension was shaken in a hydrogen atmosphere under a pressure of 60 psi in a Parr apparatus. The catalyst is 10 % palladium on coal was removed by filtration. The filtrate was evaporated to dryness under reduced pressure, getting 31.1 g of a light yellow foam. This compound was used without further purification.

Yield: 96%.

[]D+34,68o(C=1,0, MeOH).

1H NMR (CDCl3): of 1.46 (s, 9H), 2,71 (dd, J=13,7; 9.5 Hz, 1H), 2,84 (dd, J= 13.3-inch; of 2.51 Hz, 1H3 cm-1.

Macc-spectrum (FD): m/e 341 (M+), 341 (100).

Preparation 25

A. 2R-2-N(t-Butoxycarbonyl)amino-3-naphthas-indiaproperty acid

To a solution of 2.14 g (a 13.4 mmol) 2-naphthalenethiol in 40 ml of anhydrous tetrahydrofuran at room temperature was added a suspension of 0.54 g (13.5 mmol) of sodium hydride in mineral oil. After about 15 minutes, to the mixture was added dropwise a solution of 2.5 g (13,4 mmol) S-N-butoxycarbonyl)-serine-b in 30 ml of tetrahydrofuran. The mixture was reacted for about one hour, after which it was concentrated under reduced pressure, getting sticky solid. It was purified using flash chromatography (eluting solution 1% methanol in ethyl acetate) to give 4.35 g of a white solid.

Yield: 94%.

1H NMR (CDCl3): of 10.25 (s, 1H), 7,89 (s, 1H), 1,78 (m, 3H), 7,46 (m, 3H), of 5.39 (d, 1H), br4.61 (m, 1H), 3,49 (m, 2H), of 1.37 (s, 9H).

B. 2R-N - (Methoxy)-N(methyl)[2-N(t-butoxycarbonyl)amino - 3-naphthas-2-ylthio] propanamide

To a cold solution (0oC) containing 4.3 g (12.4 mmol) named intermediate compound of preparation 25A, 1,58 g (16,15 mmol) N,O-dimethylhydroxylamine hydrochloride, 2,18 g (16,15 mmol) of 1-hydroxybenzotriazole monohydrate (HOBT H2O) of 2.24 ml (16,15 mmol) of t is propyl)-3-ethylcarbodiimide hydrochloride (EDC). The resulting reaction mixture was allowed to react at room temperature over night. The reaction mixture was diluted with 100 ml of hexane, washed sequentially with 200 ml saturated sodium bicarbonate solution and 200 ml of saline solution. The resulting layers were separated and the organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure, obtaining a transparent yellow oil.

1H NMR (CDCl3): of 7.90 (s, 1H), 7,80 (m, 3H), 7,49 (m, 3H), 5,41 (d, 1H), 4.92 in (m, 1H) and 3.59 (S, 3H), 3,18-of 3.46 (m, 2H), 3,05 (s, 3H), of 1.42 (s, 9H).

Mass spectrum (FD): m/e 391 (M+), 390 (100).

Century 3R-N(t-Butyl)-2-[2'-oxo-3'-N(t-butoxycarbonyl)amino -4'-naphthas-2-ylthio]butylbenzamide

To a cold solution (-78oC) containing at 8.60 g (45 mmol) of the named compound of preparation 24 and 14.2 ml (95 mmol) of TMEDA in 100 ml of anhydrous tetrahydrofuran in an atmosphere of inert gas was slowly added 111 ml (95 mmol) of 0.85 M solution in-utility in hexane, using a syringe. For the internal temperature of the reaction vessel was monitored during the addition of in-utility, providing not exceed -57oC. After the reaction for about one hour at -78oC to the reaction mixture was added dropwise a solution of 7.90 g (20 m is I the reaction mixture was heated to -20oC, after which the reaction was stopped by adding a saturated solution of ammonium chloride. The mixture was then diluted with 600 ml of diethyl ether. The resulting layers were separated and the organic layer was washed successively 1 M solution of sodium bisulfate and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure, obtaining a yellow oil. This oil was purified using flash chromatography (eluting solution of 10-50% gradient of ethyl acetate in hexane) to give 8.5 g of the desired named intermediate compounds.

Yield: 82%.

1H NMR (CDCl3): of 7.90 (s, 1H), 7,79 (t, 3H), of 7.48 (m, 3H), 7,40 (d, 1H), 7,29 (m, 2H), 7,05 (d, 1H), 5,94 (br. s, 1H), 5,65 (m, 1H) and 4.65 (d, 1H), 4,24 (d, J=17 Hz, 1H), 3,86 (d, J=17 Hz, 1H), 3,66 (m, 1H), 3,40 (m, 1H), of 1.42 (s, 9H), of 1.39 (s, 9H).

Mass spectrum (FD): m/e 521 (M+), 521 (100).

G [(2R-(2R*3R*)] - N(t-Butyl)-2-[2'-hydroxy-3'-N-(t-butoxycarbonyl)amino-4' -naphthas-2-ylthio]butylbenzamide

To a solution 3,49 g (6.7 mmol) named intermediate training 25V in 150 ml of absolute ethanol was added 0.51 g (13 mmol) of sodium borohydride and the resulting reaction mixture was allowed to react overnight at room temperature. The reaction mixture is then klidarithmos 550 ml of methylene chloride. The resulting layers were separated and the organic layer was washed sequentially 1H. hydrochloric acid, 2n. sodium hydroxide and brine, dried over sodium sulfate, filtered and then evaporated under reduced pressure, obtaining a colorless foam. This foam was purified using flash chromatography (eluting solution 10-25% gradient of hexane in ethyl acetate), obtaining 2,78 g of the desired named intermediate compounds.

Yield: 78%.

1H NMR (CDCl3): to 7.84 (s, 1H), 7,73 (m, 3H), 7,41 (m, 3H), 7,29 (t, 2H), 7,16 (t, 2H), 6,53 (s, 1H), 5,32 (d, 1H), 3,86 (m, 2H), 3.33 and (m, 2H), and 2.83 (m, 2H), 1,40 (s, 9H).

Mass spectrum (FD): m/e 523 (M+), 522 (100).

Analysis for C30H38N2O4S:

Calculation: C 68,94; H 7,33; N Are 5.36.

Found: C 68,65; H 7,34; N 5,15.

D. [(2R-(2R*,3R*)]-N(t-Butyl)-2-[2'-hydroxy - 3'-amino-4'-naphthas-2-ylthio] butylbenzamide

To a cold solution (0oC) 2,89 g (of 5.53 mmol) named intermediate training 25G in 100 ml of methylene chloride was added 18 ml triperoxonane acid. The resulting reaction mixture was allowed to react for approximately one hour. The reaction mixture is then evaporated; at reduced pressure, obtaining a foam. It was suspensively in t (eluting solution 5% methanol in methylene chloride) to give 1,71 g of white foam.

Yield: 74%.

1H NMR (CDCl3): 7,75-a 7.85 (m, 4H), 7.24 to 7,51 (m, 7H), the 6.06 (s, 1H, in), 3.75 (m, 1H), 3,61 (m, 1H), of 3.07 (m, 2H), 2.95 and (m, 2H), 1,47 (s, 9H).

Mass spectrum (FD): m/e 423 (M+), 422 (100).

Preparation 26

A. N-t-Butyl-2-methyl-1-naphthylamide

The desired named in the title compound was obtained in accordance with the method described in preparation 24. The crude material was purified by recrystallization from hexane/ethyl acetate, getting 20,99 g of colorless needle-like crystals (I. p. 124-126oC).

Yield: 68%.

1H NMR (CDCl3): and 1.54 (s, 9H), of 2.50 (s, 3H), 5,50-the 5.65 (br.s, 1H), 7.23 percent-rate of 7.54 (m, 3H), 7,74 (d, J=10 Hz, 1H), 7,78 (d, J=10 Hz, 1H), 7,87 (d, J= 10 Hz, 1H).

IR (CHCl3): 3424, 3010, 2969, 1660, 1512, 1503, 1454, 1366, 1291, 1263, 1221 cm-1.

Mass spectrum (FD): m/e 241 (M+), 241(100).

Analysis for C16H19NO:

Calculation: C 79,63; H 7,94; N 5,80.

Found: C 79,90; H 8,11; N 5,76.

B. S-N-T-Butyl-2-(3-(N-benzyloxycarbonyl)amino-4-phenyl-2-oxobutyl)-1-naphthylamide

The desired named in the title compound was obtained in accordance with the method described in preparation 24. The residue was purified using flash chromatography (gluerule solution of 1.86o(=to 0.10, MeOH).

1H NMR (CDCl3): 1,45 (s, 9H), 3,03 (dd, J=15, 8 Hz, 1H), 3,18 (dd, J= 15, 5 Hz, 1H), 3,91 (d, J=16 Hz, 1H), Android 4.04 (d, J= 16 Hz, 1H), 4,70-4,80 (m, 1H), 4,94-of 5.06 (m, 2H), 5,41 (d, J= 8 Hz, 1H), 6,12-of 6.20 (br.s, 1H), 7,10-7,38 (m, 11H), 7,42-7,58 (m, 2H), 7,76-a 7.85 (m, 2H), to 7.93 (s, J=9 Hz, 1H).

IR (CHCl3): 3420, 3029, 3012, 2970, 1713, 1658, 1505, 1455, 1367, 1232, 1045 cm-1.

Mass spectrum (FD): m/e 522 (M+), 522 (100).

Analysis for C33H34N2O4:

Calculation: C 75,84; H 6,56; N Are 5.36.

Found: C 75,56; H 6,74; N 5,17.

Century, [2R-(2R*, 3S*)] -N-t-Butyl-2-(3-(N-benzyloxycarbonyl) amino-3-(phenylmethyl-hydroxypropyl)-1-naphthylamide

The desired named in the title compound was obtained in accordance with the method described in preparation 24. The material was purified using flash chromatography (eluting solution of 2-10% gradient of ethyl acetate in methylene chloride) to give 5.50 g of colorless foam.

Yield: 74%.

[]D+11,55o(C=0,20, MeOH).

1H NMR (CDCl3): and 1.54 (s, 9H), 2,85 is 3.15 (m, 4H), 3,85 - 3,95 (m, 1H), 4,00-4,13 (m, 2H), 4,90-of 5.34 (m, 3H), 5,85-5,95 (m, 1H), 7,05-of 7.60 (m, 15H), 7,81 (d, J=9 Hz, 2H), to $ 7.91 (d, J=9 Hz, 2H).

IR (CHCl3): 3420, 3012, 2970, 1713, 1643, 1515, 1454, 1367, 1219, 1209, 1028 cm-1.

Mass spectrum (FD): m/e 524 (M+), 524 (100).

Analysis for C33H363S*)] -N-t-Butyl-2-(3-amino-2-hydroxypropyl)-1-naphthylamide

The desired named in the title compound was obtained in accordance with the methodology described in detail in the preparation of 24G. The crude filtrate was concentrated, obtaining of 1.30 g of a colorless foam, which was used without any further purification.

Yield: 92%.

Preparation 27

A. 2-Iodine-4-hydroxymetoprolol

To a solution of 5.0 g (19,1 mmol) 2-iodine-3-methylbenzoic acid in 50 ml of anhydrous tetrahydrofuran was slowly added 22 ml of 1 M solution of borane in tetrahydrofuran. The reaction proceeded for about ninety minutes, after which it was stopped by the addition of ethanol, causing the release of gaseous hydrogen. The mixture was diluted with ethyl acetate. The resulting layers were separated and the organic layer was washed successively with sodium bicarbonate and brine, dried over sodium sulfate, was filtered and was led from a mixture of hexane/ethyl acetate, receiving 120 mg of the desired named connection.

Century 2-Methyl-5-hydroxymethylbenzene acid

A mixture of 142 mg (of 5.92 mmol) of lithium hydroxide and 249 mg (1.48 mmol) of the named compound preparation 27A in a mixture of tetrahydrofuran/water in the ratio of 3: 1 the second mixture was evaporated under reduced pressure and acidified using 1N. the hydrochloric acid. The mixture was diluted with ethyl acetate and the resulting layers were separated. The organic layer was washed with saline, dried over sodium sulfate, filtered and evaporated to dryness, receiving 70 mg of the desired named in the connection header.

Preparation 28

2-Methyl-3-methylaminomethyl acid

To a solution of 500 mg (2.5 mmol) of the methyl ester of 2-methyl-3 - aminobenzoate in 5 ml of dimethylformamide was added 387 mg (2.7 mmol) of methyl iodide and 700 mg (5.4 mmol) of diisopropylethylamine. The reaction mixture was heated to 70oC for about two hours and then was poured into 10 ml of 1N. potassium hydroxide. After about sixteen hours the mixture podkalyvali 2n. hydrochloric acid to pH 6. The desired named in the title compound was extracted into ethyl acetate, dried and evaporated to dryness under reduced pressure, getting 343 mg of a white solid substance (i.e. 165-167oC).

Yield: 84%.

1H NMR (CDCl3): to 12.52 (br.s, 1H), 7,38 (d, J=7.8 Hz, 1H), 7,25 (t, J= 7.9 Hz, 1H), 6,93 (d, J=7.8 Hz, 1H), 2,92 (s, 3H), of 2.21 (s, 3H).

Analysis for C9H11NO2:

Calculation: C 65,44; H Of 6.71; N 8,48.

Found: C 65,62; H 6,84; N Compared To 8.26.

Preparation 29

A. 2-Methyl-5-aminobenzoic the slot, using a mixture of tin with hydrochloric acid (T. p. 142-144oC).

Yield: 75%.

1H NMR (DMSO-d6): 12,67 (br.s, 1H), 7.23 percent (s, 1H),? 7.04 baby mortality (d, J=8,2 Hz, 1H), PC 6.82 (d, J=7.9 Hz, 1H), 3,25 (s, 2H), 2.40 a (s, 3H).

Analysis for C8H9NO2:

Calculation: C 63,57; H 6,00; N 9,27.

Found: C Expenses 63.81; H 6,24; N 9,06.

B. 2-Methyl-5-hydroxybenzoic acid

The desired named in the title compound was obtained in accordance with the methodology described in detail in the alternative preparation 23C using the connection preparation 29A.

Yield: 65% (i.e. 136-139oC).

1H NMR (DMSO): 12,77 (br.S, 1H), 9,46 (br. s, 1H), 7,26 (s, 1H), 7,12 (d, J=8,3 Hz, 1H), 6,85 (d, J=8,l Hz, 1H), 2,41 (s, 3H).

Analysis for C8H8O3:

Calculation: C 63,15; H Of 5.29.

Found: C 63,27; H 5,22.

Preparation 30

A. 5-Zaniskari

To a cold solution (0oC) 10.0 g (61,4 mmol) 5-amino-isoquinoline in 288 ml of 1.5 N. hydrochloric acid was added 15 ml of 5.2 M solution of sodium nitrite in water. After about 5 minutes the reaction mixture was added a cooled saturated solution of sodium bicarbonate until then, while the reaction solution showed a negative reaction in the test using iodide and starch paper. Rastgoo of 8.4 g (177 mmol) of sodium cyanide and 7.6 g (85 mmol) of copper cyanide. The resulting reaction mixture was heated to room temperature and the reaction was conducted for about 1 hour, then the reaction mixture was diluted with a mixture of ethyl acetate and water. The resulting layers were separated and the organic phase was dried over sodium sulfate, filtered and then evaporated to dryness under reduced pressure, obtaining 5.9 g of a yellow solid.

Yield: 56%.

1H NMR (CDCl3): 9,38 (s, 1H), 8,76 (d, J=of 5.89 Hz, 1H), 8,25 (d, J=8,29 Hz, 1H), 8,13 (d, J=8,30 Hz, 1H), 8,03 (d, J= 8,59 Hz, 1H), 7,71 (t, J=7,78 Hz, 1H).

IR (KBr): 3433, 3090, 3026, 2924, 2226, 1618, 1574, 1495, 1433, 1373, 1277, 1225, 1034, 829, 766, 714.

B. 5-Carboxyethyl

A solution of 6.5 g (42 mmol) of the named compound preparation 30A in 55 ml of concentrated hydrochloric acid was heated to 155oC in a sealed tube for 5.5 hours, cooled to room temperature and was evaporated to dryness, obtaining a solid substance. This solid was re-dissolved in 300 ml of water and the pH was brought to 6 by using a dilute solution of ammonium hydroxide, resulting precipitated brown solid residue. This precipitate was separated by filtration, azeotrope was distilled with benzene and then dried under reduced pressure at 130oC for o
C).

Yield: 78%.

1H NMR (DMSO): 13,4 (dr. s, 1H), 8,69 (d, 1H, J=6,00 Hz), 8,58 (d, 1H, J=4,6 Hz), 8,40 (d, 1H, J=7,37 Hz), at 8.36 (d, 1H, J=8,12 Hz), 7,74 (t, 1H, J= 7,76).

IR (KBr): 3460, 3014, 2930, 2851, 2777, 2405, 1912, 1711, 1622, 1574, 1493, 1427, 1375, 1264, 1211, 1152, 1044.

Century 5-Carboxymethylaminomethyl ether

To a cold solution (0oC) of 1.53 g (7,39 mmol) of 1,3 - dicyclohexylcarbodiimide (DCC) in 60 ml of ethyl acetate was added 1.28 g (7,39 mmol) of the named compound preparation 30B and 4,08 g (22,17 mmol) pentafluorophenol in 30 ml of ethyl acetate. The reaction mixture is reacted for about 6 hours at 0oC, after which it was filtered through celite. The filtrate was washed successively 1H. sodium hydroxide, water and brine and then evaporated under reduced pressure, obtaining a white solid. This solid was purified using column chromatography (silica; an eluting solution 33% ethyl acetate in hexane) to give 1.80 g of the desired named compounds (T. p. 142-144oC).

Yield 72%.

1H NMR (CDCl3): 9,38 (s, 1H), total of 8.74 (m, 3H), to 8.34 (d, J=8,1 Hz, 1H), 7,78 (t, J=7.7 Hz, 1H).

IR (KBr): 3422, 3021, 2089, 1752, 1622, 1522, 1215, 758.

Analysis for C16H6NO2F50,3 CH2Cl2:

Calculation: C enjoy ether

The desired named in the title compound was obtained in accordance with the method described in preparation 30B using 0,236 g (1,36 mmol) 5-carboxyaniline, 0,746 g (of 4.05 mmol) pentafluorophenol and 0,571 g (was 2.76 mmol) DCC in 25 ml of ethyl acetate, except that the reaction was carried out for 48 hours. The crude material was purified using column chromatography, obtaining 0.40 g of a white solid.

Yield 87%.

1H NMR (CDCl3): was 9.33 (d, J=8,54 Hz, 1H), 9,03 (dd, J=4,16, of 1.28 Hz, 1H), 8,63 (d, J=7,25 Hz, 1H), of 8.47 (d, J=8.53 Hz, 1H); 7,87 (t, J=of 7.96 Hz, 1H), to 7.61 (dd, J=8,76, 4,18 Hz, 1H).

IR (KBr): 3472, 2667, 2461, 1749, 1520, 1319, 1259, 1182, 1145, 1105, 1005, 947, 812.

Preparation 32

1H-Indolin-4-carboxylic acid

To a cold solution (10oC) containing 100 mg (of 0.62 mmol) of indolin-4-carboxylic acid in 5 ml of acetic acid was added 390 mg (6.2 mmol) of solid laborgerate sodium. The resulting mixture was reacted for approximately 16 hours at room temperature, after which it was diluted with water. The desired compound was extracted from this solution with methylene chloride and the organic extracts were dried over sodium sulfate and filtered. The crude material was purified using column chromium is I (etc. 97-98oC).

Output: 12%.

1H NMR (CDCl3): of 7.48 (d, J=8,8 Hz, 1H), 7,34 (t, J=8.6 Hz, 1H), to 6.88 (d, J=8,8 Hz, 1H) and 3.59 (m, 4H).

Analysis for C9H9NO2:

Calculation: C 66,25; H 5,56; N 8,58.

Found: C Collected 66.36; H Of 5.82; N 8,42.

Preparation 33

A. 2,3-Dimethoxy-6-chlorotoluene

To a mixture of 25 g (0.16 mmol) 1-methyl-2,3-dimethoxybenzene in 25 ml of acetic acid was slowly added to 26.4 g (0.33 mmol) of 1 - chloromethylmethylether ether. The resulting reaction mixture was reacted overnight at 30oC, after which it was diluted with cold water, which led to the formation of a precipitate. The residue was purified by recrystallization from hot hexane and then evaporated to dryness under reduced pressure, obtaining a 20.3 g of a white solid substance (i.e. 69-70oC).

Yield: 62%.

1H NMR (CDCl3): 7,01 (d, J=6,1 Hz, 1H), 6.75 in (d), to 4.62 (s, 2H), 3,85 (s, 3H), 3,76 (s, 3H), is 2.37 (s, 3H).

Analysis for C10H13O2Cl:

Calculation: C 59,93; H 6,54.

Found: C 59,87; H To 6.43.

B. 2-Methyl-3,4-dimethoxybenzoic acid

To a mixture of 3.0 g (15 mmol) of the named compound preparation 33A in 150 ml of water was added 3.2 g (20 mmol) of solid potassium permanganate and 3.0 g (36 mmol) of sodium carbonate. The reaction mixture was naked was filtered and diluted with ethyl acetate. The resulting layers were separated and the aqueous layer was acidified using 2n. hydrochloric acid, which led to the formation of a precipitate. This precipitate was separated by filtration and washed with cold hexane, obtaining 1.7 g of a white solid substance (i.e. 179-180oC).

Yield: 58%.

1H NMR (DMSO-d6): 12,49 (br.s, 1H), 7,71 (br.s, 1H) 6,99 (br.s, 1H), with 3.89 (s, 3H), of 3.77 (s, 3H), of 2.45 (s, 3H).

Analysis for C10H12O4:

Calculation: C 61,28; H 6,17.

Found: C 61,36; H 6,24.

Century 2-Methyl-3,4-dihydroxybenzoic acid

To a cold mixture (0oC) 250 ml (1.3 mmol) of the named compound of preparation 33 B in 5 ml of methylene chloride, was added to 6.4 ml, 6.4 mmol/1.0 M solution tribromide boron in methylene chloride. The reaction mixture is reacted for about 90 minutes, after which it was diluted with 25 ml of 2n. of hydrochloric acid. The desired compound was extracted using ethyl acetate, and the organic extracts were dried over sodium sulfate, filtered and evaporated, getting 197 mg solid reddish-brown color (similar 200-201oC).

Yield: 92%.

1H NMR (DMSO): 12,14 (br.s, 1H), 9,96 (br.s, 1H), 8.34 per (dr.s, 1H), 7,27 (d, J=7,0 Hz, 1H), to 6.67 (d, J=6,7 Hz, 1H), is 2.37 (s, 3H).

Analysis for C8H8O>8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2" -fluoro-3 ' hydroxyphenyl) pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE

To a cold solution (-10oC) containing 80 mg (0.20 mmol) of the named compound of preparation 1B, 31 mg (0.20 mmol) of preparation 11B and 27 mg (0.20 mmol) of 1-hydroxybenzotriazole monohydrate (HOBTH2O) in 3 ml of anhydrous tetrahydrofuran, was added 41 mg (0.20 mmol) of 1,3-dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred for 36 hours at room temperature and then was evaporated under reduced pressure. The resulting residue was re-dissolved in ethyl acetate, filtered through celite, washed sequentially with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified using radial chromatography (1 mm plate; an eluting solution of 2-5% gradient of methanol in methylene chloride) to give 79 mg of a white foam.

Yield: 73%.

[]D-90,80o(=of 0.333, MeOH).

1H NMR (CDCl3): 1,24 (s, 9H), 1,16-of 2.05 (m, 14H), 2,20-2,40 (m, 2H), 2,55-2,70 (m, 2H), 2,90 totaling 3.04 (m, 2H), 3,10-of 3.25 (m, 1H), 4,03 (br.s, 1H), 4,51 (dr.s, 1H), 6,01 (s, 1H), 6.90 to-7,35 (m, 9H).

IR (CHCl3): 3580, 3550-3100 (br.), 2929, 2865, 1662, 1596, 1521, 14FAB): m/e for C31H43N3O4F:

Calculation: 540,3238.

Found: 540,3228.

Example 2

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]-2- [2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-chloropyridin - 3"-yl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 80 mg (0.20 mmol) of the named compound of preparation 1B, 31 mg (0.20 mmol) of 2-chloronicotinic acid, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2About 3 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution - 0-5% gradient of methanol in methylene chloride) to give 58 mg of whitish foam.

Yield: 54%.

[]D-70,64o(c=0,224, MeOH).

1H NMR (CDCl3): of 1.16 (s, 9H), 1,17 is 2.10 (m, 12H), 2,25-is 2.37 (m, 2H), 2,52-2,70 (m, 2H), 2,97-of 3.06 (m, 2H), 3,44-of 3.53 (m, 2H), 4,05 (br.s, 1H), 4,60-4,70 (m, 1H), 5,64 (s, 1H), 7.18 in-7,38 (m, 7H), 7,60-7,63 (m, 1H), scored 8.38-to 8.40 (m, 1H).

IR (CHCl3): 3618, 3428, 3650-3100 (br.), 2929, 1667, 1583, 1515, 1455, 1401, 1368, 1247, 1071, 1046, 877 cm-1.

Macc-spectrum (FD): m/e 541 (M+), 440 (100).

Analysis for C30H41N4O3Cl:

Calculation: C 66,59; H Of 7.64; N 10,35; Cl 6,55.

Found: C 66,60; H 7,58; lmutil-4'-Aza-5'-oxo-5'-(2"-ethyl-3 - hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 80 mg (0.20 mmol) of the named compound of preparation 1B, 35 mg (0.21 mmol) of the named compound preparation 10B, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2About 3 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution of 3-5% gradient of methanol in methylene chloride) to give 71 mg of whitish foam.

Yield: 65%.

[]D: -76,29o(c=0,291, MeOH).

1H NMR (CDCl3): of 1.03 (t, J=7,42 Hz, 3H), of 1.21 (s, 9H), 1,22-2,10 (m, 11H), 2,24 to 2.35 (m, 2H), 2,44-2,70 (m, 4H), 2,96 -3,05 (m, 2H), 3,26 is 3.40 (m, 1H), 3.96 points-to 4.23 (m, 2H), 4,53 (br. s, 1H), 5,80 (s, 1H), 6.30-in-6,56 (m, 3H), 6,77 (d, J=to 7.77 Hz, 1 H), to 6.88 (t, J=7,75 Hz, 1H), 7,19-7,39 (m, 5H).

IR (CHCl3): 3700-3100 (br.), 3429, 3327, 3011, 2971, 2930, 2867, 1662, 1604, 1585, 1514, 1455, 1394, 1368, 1278, 1155, 1087, 1046, 910 cm-1.

NS (FD): m/e 550 (M+, 100).

HR Mass spectrum (FAB): m/e for C33H48N3O4:

Calculation: 550,3645.

Found: 550,3664.

Example 4

[2S-(2R*, 2'S*, 3'R*)]-1-[2'-Hydroxy-3'- phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl) pentyl]pyrrolidin-2-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with IU the (0.16 mmol) of the named compound of preparation 9B, 33 mg (0.16 mmol) of DCC and 22 mg (0.16 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution 4-8% gradient of methanol in methylene chloride) to give 52 mg of a white solid.

Yield: 69%.

[]D: -72,15o(c=0,211, MeOH).

1H NMR (CD3OD): of 1.33 (s, 9H), 1,70-1,90 (m, 4H), 2.06 to of 2.20 (m, 1H), 2,45-3,30 (m, 8H), 3,60-3,70 (m, 1H), 4,25-to 4.38 (m, 1H), 6.48 in (d, J=8,8 Hz, 1H), 6,74 (d, J=7.7 Hz, 1H), 6,93 (t, J=7.7 Hz, 1H), 7,15-to 7.32 (m, 5H).

IR (CHCl3): 3600-2700 (br.), 3450, 3255, 2968, 2928, 1653, 1632, 1588, 1513, 1454, 1364, 1291, 1233, 1064, 884, 836 cm-1.

Mass spectrum (FD): m/e 468 (M+, 100).

Analysis for C27H37N3O4:

Calculation: C 69,35; H 7,98; N 8,99.

Found: C 69,54; H 8,10; N 9,19.

Example 5

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(pyrid-3"-yl-N - oxides)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 80 mg (0.20 mmol) of the named compound of preparation 1B, 28 mg (0.20 mmol) of N-oxide, nicotinic acid, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2About 3 ml of anhydrous tetragon - 5-10% gradient of methanol in methylene chloride) to give 81 mg of a white foam.

Yield: 76%.

[]D: -104,39o(C=0,213, MeOH).

1H NMR (DMSO-d6): to 1.19 (s, 9H), 1,19 is 2.10 (m, 14H), 2,50-2,60 (m, 1H), 2,65-and 2.79 (m, 1H), 2.95 and - 3,10 (m, 2H), 3,83 (br.s, 1H), 4,22-4,32 (m, 1H), 4,87 (d, J=5.5 Hz, 1H), 7,06-7,11 (m, 1H), 7,17-7,22 (m, 2H), 7,33-7,44 (m, 3H), EUR 7.57 (d, J=8.0 Hz, 1H), compared to 8.26 (d, J=6,4 Hz, 1H), 8,44-8,48 (m, 2H).

IR (CHCl3): 3600-3100 (br.), 3428, 2930, 2864, 1669, 1603, 1515, 1479, 1455, 1432, 1394, 1368, 1300, 1279, 1245, 1135, 1083, 1046, 1017 cm-1.

Macc-spectrum (FD): m/e 522 (M+, 100).

Example 6.

[2S-(2R*, 2'S*, 3'R*)]-1-[2'-Hydroxy-3'- phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl] piperidine-2-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 100 mg (0.29 mmol) of the named compound preparation 4E, 44 mg (0.29 mmol) of the named compound of preparation 9B, 59 mg (0.29 mmol) of DCC and 39 mg (0.29 mmol) HOBTH2About 5 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution of 1.5-7% gradient of methanol in methylene chloride) to give 57 mg of whitish foam.

Yield: 41%.

[]D: -58,90o(c=0,163, MeOH).

1H NMR (CD(d, J=7,29 Hz, 1H), 6.75 in (d, J=7,83 Hz, 1H), 6.90 to-of 6.96 (m, 1H), 7,15-to 7.35 (m, 5H).

IR (CDCl3): 3601, 3600-3100 (br.), 3428, 3340, 3008, 2941, 2861, 1661, 1601, 1587, 1514, 1455, 1394, 1367, 1284, 1156, 1086, 1047, 832 cm-1.

Mass spectrum (FD): m/e 482 (M+, 100).

Analysis for C28H39N3O4:

Calculation: C 69,83; H 8,16; N 8,72.

Found: C 69,84; H 8,46; N 8,50.

Example 7

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]-2- [2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'- (2"-methyl-3"- forfinal)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 80 mg (0.20 mmol) of the named compound of preparation 1B, 31 mg (0.20 mmol) of 3-fluoro-2-methylbenzoic acid, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2About 3 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution to 1.5-3% gradient of methanol in methylene chloride) to give 40 mg of a white foam.

Yield: 37%.

[]D: -80,10o(C=0,132, MeOH).

1H NMR (CDCl3): of 1.13 (s, 9H), 1,13-2,10 (m, 16H), of 2.20 to 2.35 (m, 2H), 2,50-2,70 (m, 2H), 2.95 and was 3.05 (m, 2H), 3,53-to 3.58 (m, 1H), 3,98 (s, 1H), 4,03-4,10 (m, 1H), of 5.68 (s, 1H), 6,83-7,07 (m, 3H), 7,10-7,40 (m, 5H).

IR (CHCl3): 3650 CLASS="ptx2">

HR Mass spectrum (FAB): m/e for C32H45N3O3F:

Calculation: 538,3445.

Found: 538,3469.

Example 8

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-chloro-3", 5"- dihydroxyphenyl)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 100 mg (0.25 mmol) of the named compound of preparation 1B, 47 mg (0.25 mmol) of 2-chloro-3,5-dihydroxybenzoic acid, 51 mg (0.25 mmol) of DCC and 34 mg (0.25 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (2 mm plate; an eluting solution of 2-10% gradient of methanol in methylene chloride) to give 47 mg of a white solid.

Yield: 33%.

[]D: -53,79o(c=0,097, MeOH).

1H NMR (CDCl3): 0,5-3,10 (m, 32H), 3,70-4,60 (m, 2H), 6,00 is 7.50 (m, 8H).

IR (CHCl3): 3700-3100 (br.), 2930, 2865, 1658, 1604, 1521, 1455, 1368, 1246, 1156, 1047, 1014, 856 cm-1.

Macc-spectrum (FD): 572 (M+, 100).

Analysis for C31H42N3O5Cl:

Calculation: C 65,08; H 7,40; N 7,34.

Found: C 65,30; H 7,35; N 7,43.

Example 9

[3S-(3R*the Nile)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 100 mg (0.25 mmol) of the named compound of preparation 1B, 41 mg (0.25 mmol) of 3,5-diamino-2-methylbenzoic acid, 51 mg (0.25 mmol) of DCC and 34 mg (0.25 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran and 0.5 ml of dimethylformamide. The crude product was purified using radial chromatography (1 mm plate; an eluting solution, 1 to 10% gradient of methanol in methylene chloride) to give 30 mg of loose orange foam.

Yield: 22%.

[]D-89,27o(c=0,137, MeOH).

1H NMR (CDCl3): to 1.21 (s, 9H), 1.30 and 2,02 (m, 16H), 2,19 to 2.35 (m, 2H), 2,48-2,70 (m, 2H), 2,90-of 3.07 (m, 2H), 3,10-of 3.23 (m, 1H), 3,50 (br.s, 4H), of 3.94 (br. s, 1H), 4,40 - 4,50 (m, 1H), 5,70 (s, 1H), of 5.89-5,95 (m, 2H), 6,30 (d, J=8,4 Hz, 1H), 7,15-7,33 (m, 5H).

IR (CHCl3): 3600-3100 (br.), 3029, 3005, 2928, 2865, 1664, 1621, 1513, 1455, 1392, 1367, 1276, 1244, 1171, 1047, 841 cm-1.

Mass spectrum (FD): m/e 550 (M+, 100).

HR Mass spectrum (FAB): m/e for C32H48N5O3:

Calculation: 550,3757.

Found: 550,3762.

Example 10

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3", 5"-dinitrophenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

Named Severnogo compound of preparation 1B, 56 mg (0.25 mmol) of 3,5-dinitro-2-methylbenzoic acid, 51 mg (0.25 mmol) of DCC and 34 mg (0.25 mmol) HOBTH2About 3 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution - 0-3% gradient of methanol in methylene chloride) to give 61 mg of whitish foam.

Yield: 41%.

[]D105,96o(c=0,302, MeOH).

1H NMR (CDCl3): of 1.02 (s, 9H), 1,02 - 2,60 (m, 20H), 2,90 -3,06 (m, 2H), 3,21 (br. s, 1H), 3,60 of 3.75 (m, 1H), 4,05-4,20 (m, 1H), 4,65-4,80 (m, 1H), vs. 5.47 (s, 1H), 7,20 is 7.50 (m, 5H), 8,00-to 8.20 (m, 2H), 8,56 (s, 1H).

IR (CHCl3): 3621, 3500-3100 (br.), 3428, 3024, 2977, 2931, 1665, 1615, 1539, 1455, 1347, 1278, 1245, 1047, 878 cm-1.

Macc-spectrum (FD): me 610 (M+, 100).

HR Mass spectrum (FAB): m/e for C32H44N5O7:

Calculation: 610,3241.

Found: 610,3240.

Example 11

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-chloro-3"- hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 116 mg (0.29 mmol) of the named compound of preparation 1B, 50 mg (0.29 mmol) of the titled compound of preparation 14, 60 mg (0.29 mmol) of DCC and 39 mg (0.29 mmol) what the photo (1 mm plate; an eluting solution of 2.5 - 5% gradient of methanol in methylene chloride) to give 83 mg of a white solid.

Yield: 51%.

[]D-74,29o(c=0,140, MeOH).

1H NMR (CDCl3): to 1.19 (s,9H), 1,19 is 2.80 (m, 16H), 2,90 is 3.15 (m, 2H), 3,35 (br. s, 1H), 4,06 (br.s, 1H), 4,56 (br.s, 1H), 5,85 (dr.s, 1H), 6,60-6,70 (m, 1H), 6.90 to-7,35 (m, 8H).

IR (CHCl3): 3621, 3600-3100 (br), 3429, 2977, 2929,1 1671, 1584, 1515, 1445, 1394, 1368, 1292, 1182, 1046, 878, 823 cm-1.

Mass spectrum (FD): m/e 556 (M+, 100).

Analysis for C31H42N3O4Cl:

Calculation: C 66,95; H To 7.61; N 7,56.

Found: C 66,76; H 7,72; N 7,69.

Example 12

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3" -hydroxyphenyl)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 261 mg (of 0.65 mmol) of the named compound of preparation 1B, 100 mg (of 0.65 mmol) of the named compound of preparation 9B, 134 mg (of 0.65 mmol) DCC and 88 mg (of 0.65 mmol) HOBTH2About 6 ml of anhydrous tetrahydrofuran and 0.2 ml of anhydrous dimethylformamide. The crude product was purified using radial chromatography (2 mm plate; an eluting solution of 1-5% gradient meta is UP>o
(C=0,200, MeOH).

1H NMR (CDCl3): of 1.18 (s, 9H), 1,19-of 2.05 (m, 18H), of 2.20 to 2.35 (m, 2H), 2,50-2,70 (m, 2H), 2,90 was 3.05 (m, 2H), 3,22-to 3.35 (m, 1H), 3.96 points-of 4.05 (m, 1H), 4,45-4,55 (m, 1H), 5,77 (s, 1H), 6,53 (d, J=7,4 Hz, 2H), 6.75 in (d, J=7.8 Hz, 1H), 6,85-of 6.90 (m, 1H), 7,15-7,35 (m, 6H).

IR (CHCl3): 3606, 3600-3100 (br), 3429, 3011, 2929, 2865, 1663, 1604, 1587, 1514, 1455, 1367, 1277, 1200, 1156, 1046, 910 cm-1.

Mass spectrum (FD): m/e 537 (M+, 100).

HR Mass spectrum (FAB): m/e for C32H46N3O4:

Calculation: 536,3488.

Found: 536,3488.

Example 13

[3S-(3R*, 4aR*, 8aR*,2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl - 4'-Aza-5'-oxo-5'-(2"-methyl-3"-methoxyphenyl)pentyl] decahydroquinoline - 3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 80 mg (0.20 mmol) of the named compound of preparation 1B, 33 mg (0.20 mmol) of the named compound preparation 15B, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (2 mm plate; an eluting solution of 2.5% methanol in methylene chloride) to give 93 mg of a white foam.

Exit; 84%.

1H NMR (CDCl3): of 1.17 (s, 9H), 1,17-of 2.05 (m, 12H), was 2.05 (s, 3H), 2,25 - of 2.38 (m, 2H), 2,50-2,75 (m (t, J= 7,0 Hz, 1H), 7,15 was 7.45 (m, 5H).

Analysis for C33H47N3O4:

Calculation: C 72,10; H 8,62; N Of 7.64.

Found: C 71,84; H 8,49: N To 7.67.

Example 14

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2", 3" -dichlorophenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 80 mg (0.20 mmol) of the named compound of preparation 1B, 38 mg (0.20 mmol) of 2,3-dichlorobenzoyl acid, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2O in 3 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (2 ml plate; an eluting solution of 2.5 - 5% gradient of methanol in methylene chloride) to give 95 mg of a white foam.

Yield: 84%.

1H NMR (CDCl3): of 1.16 (s, 9H), 1,17-of 2.05 (m, 12H), 2,20 - of 2.38 (m, 2H), 2,50-2,75 (m, 2H), 2.95 and-3,10 (m, 2H), 3,40-3,55 (m, 1H), 3,69 (s, 1H), 4,00-4,10 (m, 1H), 4,58-4,72 (m, 1H), 5,77 (s, 1H), 6,98-7,47 (m, 9H).

Mass spectrum (FD): m/e 574 (M+), 473 (100).

Example 15

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"- triptoreline)pentyl]decahydroquinoline-3-N-t - BUTYLCARBAMATE

Nezapomenutelneho compound of preparation 1B, 38 mg (0.20 mmol) 2-triftorperasin acid, 41 mg (0.20 mmol) of DCC and 27 mg (0.20 mmol) HOBTH2About 3 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (2 mm plate; an eluting solution of 2.5 - 5% gradient of methanol in methylene chloride) to give 72 mg of a white foam.

Yield: 63%.

1H NMR (CDCl3): 1,10 (s, 9H), 1,16-of 2.05 (m, 14H), of 2.15 to 2.35 (m, 2H), 2,45-2,70 (m, 2H), 2,92 was 3.05 (m, 2H), 3,38 - 3,55 (m, 1H), 3,70 (br.s, 1H), 3,98-4,10 (m, 1H), 4,58-4,70 (m, 1H), 5,90 (s, 1H), 7,00-the 7.65 (m, 10H).

Mass spectrum (FD): m/e 573 (M+, 100).

Analysis for C32H42N3O3F3:

Calculation: C 67,00; H 7,38; N 7,32.

Found: C 67,11; H To 7.09; N 7,10.

Example 16

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-oxo-3 - methylpiperid-4"-yl)pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 14,7 mg (0,037 mmol) of the named compound of preparation 1B, 5.6 mg (0,037 mmol) of the named compound of preparation 12 and 7.6 mg (0,037 mmol) DCC and 4.9 mg (0,037 mmol) HOBTH2About 1.3 ml of anhydrous dimethylformamide. The crude product was purified using radial, chromatographi the ptx2">

Yield: 34%.

1H NMR (CDCl3): 1,00 is 3.40 (m, 32H), 4,00-4,70 (m, 3H), 5,90-6,10 (m, 1H), 6.90 to-7,40 (m, 8H).

Mass spectrum (FD): m/e 537 (M+, 100).

Example 17

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'- (2",6"-dichloro-3 - hydroxyphenyl)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 48 mg (0.12 mmol) of the named compound of preparation 1B, 25 mg (0.12 mmol) of the named compound of preparation 13, 2.5 mg (0.12 mmol) of DCC and 16 mg (0.12 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran. The crude product was purified using radial chromatography (1 mm plate; an eluting solution of 2-5% gradient of methanol in methylene chloride) to give 14 mg of the desired titled compound.

1H NMR (CDCl3): 0,9-of 2.15 (m, 23H), 2,22-to 2.85 (m, 4H), 2.95 and - 3,10 (m, 2H), 3,30-to 3.58 (m, 1H), 3,98-4,12 (m, 1H), 4,56 - of 4.75 (m, 1H), ceiling of 5.60-of 5.82 (m, 1H), 6,60-6,79 (m, 1H), 6.90 to-7,40 (m, 6H).

IR (CHCl3): 3010, 2937, 1644, 1606, 1605, 1497, 1474, 1454, 1433, 1417, 1341, 1313, 1274, 1252, 1161, 1093, 1074, 1027, 991 cm-1.

Mass spectrum (FD): m/e 590 (M+, 100).

Example 18

[3S-(3R*, 4aR*, 8aR*,2'S*,3'R*)]- 2-[2'-Hydroxy-3'- phenylmethy inania received in accordance with the methodology described in detail in example 1, using 100 mg (0.25 mmol) of the named compound of preparation 1B, 38 mg (0.25 mmol) 3-amino-2-methylbenzoic acid, 34 mg (0.25 mmol) HOBTH2Oh, 52 mg (0.25 mmol) of DCC in 3 ml of anhydrous tetrahydrofuran, except that the reaction was carried out in the presence of 76 mg (0.75 mmol) of triethylamine. The substance resulting from the reaction was purified using radial chromatography (2 mm plate; an eluting solution of 2-5% gradient of methanol in methylene chloride) to give 78 mg of whitish foam.

Yield: 58%.

1H NMR (CDCl3): to 1.19 (s, 9H), 1,20-of 2.08 (m, 15H), of 2.20 to 2.35 (m, 2H), 2,50-2,70 (m, 2H), 2,92 was 3.05 (m, 2H), 3,28-to 3.38 (m, 1H), 3,61 (br.s, 1H), 3,93-4,20 (m, 2H), 4,45-4,58 (m, 1H), 5,80 (s, 1H), 6,44 (d, J=7.5 Hz, 2H), 6,63 (d, J=7.9 Hz, 1H), 6.90 to (t, J=7.7 Hz, 1H), 7,17 and 7.36 (m, 6H).

Mass spectrum (FD): m/e 535 (M+, 100).

Example 19

[2S-(2R*, 2'S*, 3'S*)]-1-[2'- Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(3"-hydroxy-2"- were)pentyl]-4-pyrid-3"-iletileri-2-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 50 mg (0.11 mmol) of the named compound of preparation 6B, 16 mg (0.11 mmol) of the named compound preparation 9V, 14 mg (0.11 mmol), HOBT H2Oh and 22 mg (0.11 mmol what the function chromatography (1 mm plate; an eluting solution of 5-10 % gradient of methanol in methylene chloride) to give 35 mg of whitish foam.

Yield: 55%.

1H NMR (CDCl2): of 1.29 (s, 9H), to 2.18 (s, 3H), 2,23 is 2.33 (m, 1H), 2,45-to 2.85 (m, 7H), 3,20-to 3.35 (m, 3H), of 3.45 (s, 1H), 4,00-4,10 (m, 1H), 4,25 is 4.35 (m, 1H), 5,00-of 5.40 (br.s, 1H), is 6.61 (d, J=7,6 Hz, 1H), 6,76-to 6.80 (m, 2H), 6,92 (t, J= 7.7 Hz, 1H), 7,12-the 7.43 (m, 7H), EUR 7.57 to 7.62 (m, 1H), 7,78 (br.s, 1H), 8,48-8,58 (m, 2H).

Mass spectrum (FD): m/e 606 (M+, 100).

Example 20

[3S-(3R*, 4aR*,8aR*,2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4-Aza-5'-oxo-5'-(2-isopropyl-3 - hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 55 mg (0,137 mmol) of the named compound of preparation 1B, to 24.7 mg (0,137 mmol) of the named compound preparation 18B, 28,25 mg (0,137 mmol) DCC and 18.5 mg (0,137 mmol) HOBTH2About 8 ml of tetrahydrofuran. The crude substance, the resulting reaction was purified using radial chromatography (1 mm plate; an eluting solution - 3% methanol in methylene chloride) to give 46 mg of a white foam.

Yield: 60%.

[]D-84,61o(C=2,60, MeOH).

1H NMR (CDCl3): 1,19 (d, J=3,7 Hz, 3H) to 1.21 (d, J=3.75 Hz, 3H), of 1.23 (s, 9H), 1,27-is 1.51 (m, 7H), 1,61 is 2.00 (m, 6H), 2,267,17 Hz, 1H), 6,86 (t, J=7,74 Hz, 1H), 7,21-7,31 (m, 5H).

IR (CDC[3): 3427, 3322, 3028, 3008, 2930, 2868, 1660, 1603, 1582, 1513, 1455, 1393, 1366, 1304, 1278, 1245, 1088, 1059 cm-1.

Mass spectrum (FD): m/e 564 (M+, 100).

Analysis for C34H49N3O4:

Calculation: C 72,43; H 8,76; N 7,45.

Found: C 72,13; H Cent To 8.85; N 7,30.

Example 21

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"- butyl-3"-hydroxyphenyl)pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 91 mg (0,227 mmol) of the named compound of preparation 1B, 44 mg (0,227 mmol) of the named compound preparation 16B, to 46.7 mg (0,227 mmol) DCC and 30.6 mg (0,227 mmol) HOBTH2About 10 ml of tetrahydrofuran. The crude substance, the resulting reaction was purified using radial chromatography (1 mm plate; an eluting solution 4-7% gradient of methanol in methylene chloride) to give 72 mg of a white foam.

Yield: 55%.

[]D-77,36o(C=0,36, MeOH).

1H NMR (CDCl3): 0,84 (t, J=7.2 Hz, 3H), of 1.20 (s, 9H), 1,29-2,00 (m, 18H), and 2.27 (m, 2H), 2,48-2,69 (m, 4H), 2,99 (m, 2H), 3,29 (m, 1H), 3,99 (m, 1H), 4,49 (m, 1H), to 5.85 (s, 1H), 6,45 (m, 2H), 6.75 in (d, J=7,19 Hz, 1H), 6,86 (t, J=/P> Mass spectrum (FD): m/e 578 (M+, 100).

HR Mass spectrum (FAB): m/e for C35H51N3O4:

Calculation: 578,3958.

Found: 578,3962.

Example 22

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-propyl-3 - hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 67 mg (0,167 mmol) of the named compound of preparation 1B, 30 mg (0,167 mmol) of the named compound preparation 17B, 34 mg (0,167 mmol) DCC and 23 mg (0,167 mmol) HOBTH2About 4 ml of tetrahydrofuran. The crude substance, the resulting reaction was purified using radial chromatography (1 mm plate; an eluting solution - 3% methanol in methylene chloride) to give 75 mg of a white foam.

Yield: 80%.

[]D-43,75 (c=0,160, MeOH).

1H NMR (CDCl3): of 0.87 (t, 3H), of 1.18 (s, 9H), 1,21-2,04 (m, 15H), 2,24 is 2.33 (m, 2H), 2,49 - of 2.58 (m, 3H), of 2.66 (m, 1H), 2,98 (m, 2H), 3,37 (m, 1H), 3,99 (m, 1H), to 4.52 (m, 1H), 5,07 (m, 1H), 5,70 (s, 1H), gold 6.43 (d, J=8,32 Hz, 1H), 6,56 (d, J=7,32 Hz, 1H), 6,76 (d, J=7,12 Hz, 1H), 6,95 (t, J=7,78 Hz, 1 H), 7,20-7,33 (m, 5H).

IR (KBr): 3287 (br.), 3086, 2932, 2868, 1681, 1558, 1456, 1368, 1334, 1291, 1261, 1218, 1169, 1101, 1042, 776, 734, 552 cm-1.

Macc-SPE,3801.

Found: 564,3789.

Example 23

[3S-(3R*, 4aR*,8aR*,2'S*,3'S*)]- 2-[2'-Hydroxy-3-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"- methyl-3"oksifenil)pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 70 mg (0.16 mmol) of the named compound preparation G, 24.6 mg (0.16 mmol) of the named compound of preparation 9C, 33 mg (0.16 mmol) of DCC and 22 mg (0.16 mmol) HOBTH2O in 4 ml of tetrahydrofuran. The crude substance, the resulting reaction was purified using radial chromatography (1 mm plate; an eluting solution - 3% methanol in methylene chloride) to give 54 mg of a white foam.

Yield: 60%.

[]D-119,23o(=of 0.26, MeOH).

1H NMR (CDCl3): of 1.09 (s, 9H), 1,12-to 1.79 (m, 12H), 1.93 and-2,02 (m, 2H), 2,17-of 2.30 (m, 2H), 2,31 (s, 3H), 2,43-2,61 (m, 2 H), 2.91 in (m, 1H), 3,42 (m, 1H), 3,78 (m, 1H), 4,07 (m, 1H), 4,47 (m, 1H), lower than the 5.37 (m, 1H), 5,51 (br.s, 1H), 6,84 (m, 1H), 7,06 (m, 2H), 7,17-to 7.32 (m, 4H), 7,45 (m, 2H).

IR (KBr): 3297, 2925, 2862, 1627, 1586, 1530, 1482, 1466, 1439, 1366, 1287, 1221, 1156, 1119, 1026, 801, 735, 689 cm-1.

Macc-spectrum (FD): m/e 568 (M+, 100).

HR Mass spectrum (FAB) for C32H46N3O4S:

Calculation: 568,3209.

Found: 568,3182.

At-5'- (2" -methyl-3"-hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 70 mg (0,145 mmol) of the named compound preparation 7B, 22 mg (0,145 mmol) of the named compound of preparation 9C, 29 mg (0,145 mmol) DCC and 19 mg (0,145 mmol) HOBTH2About 4 ml of tetrahydrofuran. The crude substance, the resulting reaction was purified using flash chromatography (eluting solution is 5 to 15% gradient of acetone in methylene chloride) to give 65 mg of a white solid.

Yield: 73%.

[]D-112,00o(C=0,25, MeOH).

1H NMR (CDCl3): 1,10 (s, 9H), 1,15-of 1.80 (m, 12H), 1.93 and e 2.06 (m, 1H), 2,17-of 2.28 (m, 2H), to 2.29 (s, 3H), 2,42-2,61 (m, 2 H), to 2.94 (d, 1H), 3,51 (m, 1H), 3,83-to 3.92 (m, 1H), 4,10 (m, 1H), are 5.36 (br.s, 1H), of 5.53 (br.s, 1H), 6,79 (m, 1H), 6,93 (m, 2H), 7,21 (d, J=8,83 Hz, 1H), 7,40-7,53 (m, 3H), 7,73 (m, 3H), of 7.90 (s, 1H).

IR (KBr): 3427, 3311 (br), 2929, 2864, 1703, 1661, 1587, 1514, 1456, 1393, 1366, 1276, 1200, 1177, 1146, 1119, 1070, 1042 cm-1.

Macc-spectrum (FD): m/e 618 (M+, 100).

Analysis for C34H49N3O4:

Calculation: C 69,98; H To 7.67; N 6,80.

Found: C 69,92; H 7,72; N 6,75.

Example 25

[2S-(2R*, 2'S*,3'S*)]-1-[2'-Hydroxy-3'- (naphthas-2-altimeter)-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] piperidine-2-N-t-BUTYLCARBAMATE

Named the United compounds of preparation 2ZH, 10 mg (0,065 mmol) of the named compound of preparation 9C, 13.5 mg (0,065 mmol) DCC and 9 mg (0,065 mmol) HOBTH2About 2 ml of tetrahydrofuran. The crude substance, the resulting reaction was purified using radial chromatography (1 mm plate; an eluting solution - 2% methanol in methylene chloride) to give 23 mg of a white foam.

Yield: 63%.

[]D-233,33o(C=0,09, MeOH).

1H NMR (CDCl3): of 1.17 (s, 9H), 1.26 in (m, 1H), 1.56 to at 1.73 (m, 6H), 2,19-of 2.23 (m, 2H, in), 2.25 (s, 3H), 2,42 (m, 1H), 2,62-by 2.73 (m, 2H), 3,11-3,19 (m, 1H), 3,50-and 3.72 (m, 2H), 4,10 (m, 1H), 4,45 (m, 1H), of 5.89 (s, 1H), 6,77-6,87 (m, 3H), 7,00 (d, J=8,65 Hz, 1H), 7,43 - 7,51 (m, 3H), 7,72-7,80 (m, 3H), 7,88 (s, 1H).

IR (KBr): 3329, 2934, 2857, 1646, 1586, 1522, 1457, 1364, 1284, 1223, 1133, 1072, 944, 835, 811, 744, 474 cm-1.

Mass spectrum (FD): m/e 564 (M+, 100).

HR Mass spectrum (FAB) for C32H42N3O4S:

Calculation: 564,2896.

Found: 564,2916.

Example 26

[2S-(2R*, 2'S*,3'R*)]-1- [2'-Hydroxy-3'-phenylmethyl-4'-Aza - 5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl] -4-(pyrid-3"'- ylmethyl)piperazine-2-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 65 mg (0,148 mmol) of the named compound preparation 5D, 22,5 mg (0,148 mmol) named with the society, the resulting reaction was purified using radial chromatography (1 mm plate; an eluting solution - 3% methanol in methylene chloride) to give 64 mg of a white foam.

Yield: 75%.

1H NMR (CDCl3): of 1.33 (s, 9H), to 1.86 (s, 3H), 2,30 (m, 1H), 2,49-of 2.58 (m, 11H), to 3.33 (m, 1H), 3.46 in (m, 1H), was 4.02 (m, 1H), 4,46 (m, 1H), 6,29 (d, J-9,16 Hz, 1H), 6,46 (d, J=7.23 percent Hz, 1H), 6.73 x (d, J=7,79 Hz, 1H), 6,83 (t, J= 7,84 Hz, 1H), 7,17-7,31 (m, 7H), 7,60 (m, 1H), 7,95 (br.s, 1H), 8,50-8,55 (m, 2H).

Mass spectrum (FD): m/e 574 (M+, 100).

HR Mass spectrum (FAB): m/e for C33H44N5O4:

Calculation: 574,3393.

Found: 574,3373.

Example 27

[3S-(3R*, 4aR*, 8aR*,2'S*,3'R*)]- 2-[2'- Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"- ethyl-3-hydroxyphenyl)pentyl]decahydroquinoline-3 - N-t-BUTYLCARBAMATE monomethylamine salt

To a cold solution (0oC) of 35.1 mg (0,064 mmol) of the titled compound of Example 3 in 2 μl of anhydrous methylene chloride was added dropwise 134 ml (0,067 mmol) of 0.5 M solution methanesulfonic acid in methylene chloride. The resulting reaction product was evaporated to dryness under reduced pressure (0,2 - 0,1 Torr) to give 38 mg of light yellow (untreated) foam.

Yield: 90%.

1H NMR (CD3OD): of 0.91 (t, J=7,39, 3H), of 1.29 (s, 9H), 1.30 and 3,20 m,aR*, 8aR*, 2'S*,3'R*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE monomethylamine salt

The named compound was obtained in accordance with the method described in example 27, using 125 mg (0.23 mmol) of the titled compound of Example 13 in 5 ml of anhydrous methylene chloride and 240 μl (0.24 mmol) of 1.0 M solution methanesulfonic acid in methylene chloride, getting 136 mg whitish (untreated) foam.

Yield: 95%.

1H NMR (CD3OD): 1,12 (s, 9H), 1,10-2,20 (m, 16H), 2,60-of 2.75 (m, 4H), 3,10-to 3.50 (m, 6H), 3,60-3,70 (m, 1H), 3,90-4,30 (m, 3H), 6,53 (d, J=7,35 Hz, 1H), 6,55 (t, J=7.87 in Hz, 1H), 6.89 in (t, J=of 7.82 Hz, 1H).

Example 29

[3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)]- 2-[2'- Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2" -methyl-phenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 15 mg (0,034 mmol) of the named compound preparation I, 4,7 mg (0,034 mmol) o-Truelove acid, 7,13 mg (0,034 mmol) DCC and 4.7 mg (0,034 mmol) HOBTH2About 2.5 ml of tetrahydrofuran. The substance resulting from the reaction was purified using radial chromatography (1 mm square>/P>[]D-80,00o(c=0,15).

1H NMR (CDCl3): the 1.04 (s, 9H), 1,08 and 1.80 (m, 11H), of 1.93 (m, 3H), 2,22 (m, 4H), 2,44 (m, 1H), 2.49 USD (s, 3H), 2,58 (m, 1H), equal to 2.94 (m, 1H), 3,47 (m, 1H), 3,84 (m, 1H), a 4.03 (m, 1H), 4,50 (m, 1H), the 5.45 (br.s, 1H), 7,12-to 7.32 (m, 7H), was 7.45 (m, 2H), 7,51 (d, J=7,51 Hz, 1H).

IR (KBr): 3327, 2928, 2852, 1627, 1574, 1535, 1481, 1364, 1311, 1275, 1225, 1088, 737 cm-1.

HR Mass spectrum (FAB) for C32H46N3O3S:

Calculation: 552,3260.

Found: 552,3272.

Example 30

[3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)]- 2-[2'-Hydroxy-3'- phenylthiomethyl-4'-Aza-5'-oxo-5'-[3"-methylpiperid-4"-yl)] pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 15 mg (0,034 mmol) of the named compound preparation I, 6,69 mg (0,048 mmol) of the titled compound of preparation 19, 7,13 mg (0,034 mmol) DCC and 4.7 mg (0,034 mmol) HOBTH2About 1.5 ml of tetrahydrofuran and 1 ml of dimethylformamide. The substance resulting from the reaction was purified using radial chromatography (1 mm plate; an eluting solution is a gradient of 3-5% methanol in methylene chloride) to give 10 mg of a white foam.

Yield: 52%.

[]D-95,65o(c=0,115).

1H NMR (CDCl3): of 1.00 (s, 9H), 1,20-to 1.77 (m, 12H), 1,

IR (KBr): 3307, 2925, 2860, 1653, 1542, 1481, 1439, 1391, 1365, 1281, 1224, 1058, 1041, 738, 691, 669 cm-1.

HR Mass spectrum (FAB) for C31H45N4O3S:

Calculation: 553,3212.

Found: 553,3222.

Example 31

[3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)]- 2-[2'- Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(quinoline - 5"-yl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 15 mg (0,034 mmol) of the named compound preparation G, 6.0 mg (0,034 mmol) of the titled compound of preparation 20, 7,13 mg (0,034 mmol) DCC and 4.7 mg (0,034 mmol) HOBTH2O in 2 ml of tetrahydrofuran. The substance resulting from the reaction was purified using radial chromatography (1 mm plate; an eluting solution of 3-5% gradient of methanol in methylene chloride) to give 15 mg of a white foam.

Yield: 74%.

[]D-99,50o(C=0, 201).

1H NMR (CDCl3): 0,74 (s, 9H), 1,15-to 1.79 (m, 12H) of 1.97 (m, 1H), 2,17 (m, 2H), a 2.36 (m, 1H), 2,54 (m, 1H), 2,90 (m, 1H), of 3.45 (m, 1H), 3,99 (m, 1H), 4,16 (m, 1H), to 4.62 (m, 1H), from 5.29 (s, 1H), 7.18 in-7,32 (m, 3H), 7,40-to 7.50 (m, 3H), of 7.70 (m, 1 H), 7,89 (m, 2H), 8,17 (m, 1H), 8,91 (m, 2H).

IR (KBr): 3299, 2923, 2862, 1644, 1546, 1481, 1439, 1390, 1327, 1279, 1222, 1207, 1037, 810, 735, 689 cm-1.

HR Mass spectrum (FAB2

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'S*)]- 2-[2'-Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'- (1", 2", 3",4"-tetrahydroquinolin-5"-yl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 18 mg (0.04 mmol) of the named compound preparation I, 7,38 mg (0.04 mmol) of the titled compound of preparation 21, 8,56 mg (0.04 mmol) of DCC and 5,61 mg (0.04 mmol) HOBTH2About 2 ml of tetrahydrofuran. The substance resulting from the reaction was purified using radial chromatography (1 mm plate; an eluting solution of 3-5% gradient of methanol in methylene chloride) to give 12 mg of a white foam.

Yield: 50%.

[]D-98,59o(c=0,142).

1H NMR (CDCl3): of 1.13 (s, 9H), 1,14-2,04 (m, 15H), 2,19 (m, 2H), 2,45 (m, 1H), 2.57 m (m, 1H), 2,75 (m, 1H), 2,90-to 3.09 (m, 2H), 3,26 (m, 2H), 3,44 (m, 2H, in), 3.75 (m, 1H), 4,01-to 4.14 (m, 2H), 4,42 (m, 1H), 5.56mm (s, 1H), of 6.49 (d, J= of 7.96 Hz, 1H), 6,80 (d, J=7,40 Hz, 1H), 6,93 (t, J=7,72 Hz, 1H), was 7.08 (d, J=8,39 Hz, 1H), 7,18 (m, 1H), 7,27 (m, 2H), 7,42 (d, 2H).

IR (KBr): 3327, 2928, 2852, 1629, 1590, 1519, 1481, 1449, 1364, 1310, 1275, 1229, 1087, 738, 690 cm-1.

Mass spectrum (FAB) for C34H49N4O3S:

Calculation: 593,3525.

Found: 593,3552.

Example 33

[2S-(2R*, 2'S*, 3'S*)]-1-Azin-2-N-t-BUTYLCARBAMATE

To a cooled solution (-10oC) containing 45 mg (0.10 mmol) of the named compound of preparation 6B, 18 mg (0.10 mmol) of 1,2,3,4-tetrahydroquinolin-5-carboxylic acid, 30 mg (0.30 mmol) of triethylamine and 14 mg (0.10 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran, was added 22 mg (0.11 mmol) of DCC. The resulting reaction mixture was stirred for approximately 24 hours at room temperature and then was evaporated under reduced pressure to obtain a residue. This residue was re-dissolved in ethyl acetate and filtered through celite. The filtrate was then extracted sequentially with saturated sodium bicarbonate (twice) and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified using radial chromatography (1 mm plate; an eluting solution of 2.5 - 5% gradient of methanol in methylene chloride) to give 33 mg of whitish foam.

Yield: 62%.

1H NMR (CDCl3): of 1.29 (s, 9H), 1,79-of 1.97 (m, 2H), 2.26 and-3,00 (m, 11H), 3,20-3,50 (m, 9H), 3.95 to of 4.05 (m, 1H), 4,23 - of 4.35 (m, 1H), to 6.43-6,62 (m, 2H), 6.89 in (t, J=7.8 Hz, 1H), 7,12 - 7,35 (m, 6H), 7,41 (d, J=7.7 Hz, 2H), EUR 7.57-of 7.70 (m, 2H), 8,50 - 8,58 (m, 2H).

Mass spectrum (FD): m/e 631 (M+, 100).

Example 34

[2S-(2R*, 2'S*, 3'S*)]-1-[2'-Hydroc is/BR> The named compound was obtained from example 33.

Yield: 13 mg whitish foam.

1H NMR (CDCl3): of 1.18 (s, 9H), 2,27-2,90 (m, 9H), 3,17-of 3.60 (m, 5H), 4,07-4,19 (m, 1H), 4,40-4,55 (m, 1H), 4.75 V-of 4.95 (m, 1H), 6.90 to-to 7.68 (m, 11H), 8,16 (d, J=8.1 Hz, 1H), 8,48 -8,60 (m, 2H), 8,80 (d, J=8,4 Hz, 1H), 8,89-8,97 (m, 1H).

Mass spectrum (FD): m/e 527 (M+, 100).

Example 35

[2S-(2R*, 2'S*, 3'S*)]-1-[2'-Hydroxy-3'- phenylthiomethyl-4'-Aza-5'-oxo-5'-[3"-methylpiperid-4"- yl)] pentyl]-4-(pyrid-3"'-ylmethyl)piperazine-2-N-t - BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using a 20.3 mg (0,148 mmol) of the titled compound of preparation 19, 70 mg (0,148 mmol) of the named compound of preparation 19, 31 mg (0,148 mmol) DCC and 20 mg (0,148 mmol) HOBTH2About in tetrahydrofuran containing 62 ml of triethylamine. The substance resulting from the reaction was purified using radial chromatography (2 mm plate; an eluting solution of 2.5 - 15% gradient of methanol in methylene chloride) to give 48 mg of a white foam.

Yield: 55%.

1H NMR (CDCl3): of 1.23 (s, 9H), 2,30-2,90 (m, 12H), 3,16-to 3.50 (m, 5H), was 4.02-4,10 (m, 1H), 4,30-4,42,41 (m, 1H), 4,85 (br.s, 1H), 6.90 to-7,60 (m, 10H), scored 8.38-to 8.57 (m, 3H).

Mass spectrum (FAB): m/e 591,4 (M+, 100).

Example 36

[3S-(3R*, 4aR*
The named compound was obtained in accordance with the methodology described in detail in example 1, using 70 mg (0,17 mmol) of the named compound of preparation 1B, 40 mg (0,17 mmol) of the titled compound of preparation 22, 35 mg (0,17 mmol) DCC and 123 mg (0,17 mmol) HOBTH2About 2 ml of anhydrous tetrahydrofuran. The substance resulting from the reaction was purified using radial chromatography (2 mm plate; an eluting solution of 1-5% gradient of methanol in methylene chloride) to give 72 mg whitish solid.

Yield: 69%.

1H NMR (CDCl3): to 1.14 (s, 9H), 1,19-of 2.38 (m, 19H), 2,50 - 2,70 (m, 2H), 2,92-of 3.06 (m, 4H), 3,43-3,55 (m, 1H), 4,01-4,10 (m, 1H), 4,58-4,70 (m, 1H), to 5.66 (s, 1H), 6,37 (br.s, 1H), 6,82-6,93 (m, 2H), 7,10-7,39 (m, 6H), of 7.48 (d, J=8,16 Hz, 1H).

IR (KBr): 3691, 3600-3300 (br.), 2929, 2866, 1672, 1603, 1513, 1455, 1393, 1368, 1327, 1277, 1154, 1047, 972, 909, 877 cm-1.

Mass spectrum (FD): m/e (M+, 100).

Example 37

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'S*)]- 2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-[(1",2",3",4"- tetrahydroquinolin-5"-yl)]pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 18,5 mg (0.046 mmol) of the named compound of preparation 1B, 8,14 mg (0.046 mmol) of naturana. The substance resulting from the reaction was purified using radial chromatography (1 mm plate; an eluting solution of 2-5% gradient of methanol in methylene chloride) to give 11 mg of foam.

Yield: 43%.

1H NMR (CDCl3): of 1.20 (s, 9H), 1,25-2,02 (m, 15H), 2,28 (m, 2H), 2,46-2,70 (m, 4H), 2,99 (m, 2H), 3,21 (m, 1H), 3,35 (m, 1H), 3,98 (m, 1H), 4,49 (m, 1H), 5,75 (br.s, 1H), 6,38 (m, 3H), 6,83 (t, 1H), 7,21-7,33 (m, 5H).

Example 38

[3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)]- 2-[2'- Hydroxy-3'-phenyl-thiomethyl-4'-Aza-5'-oxo-5'-[6" -methyl-(1", 2",3",4"-tetrahydroquinolin-5"-yl)]pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 15 mg (0.035 mmol) of the named compound preparation I, 6,5 mg (0.035 mmol) of 6 - methyl-1,2,3,4-tetrahydro-5-quinoline-carboxylic acid, 7,15 mg (0.035 mmol) of DCC and 4.7 mg (0.035 mmol) HOBTH2About 2 ml of tetrahydrofuran and 1 ml of dimethylformamide. The substance resulting from the reaction was purified using radial chromatography (1 mm plate; an eluting solution of 3-5% gradient of methanol in methylene chloride) to give 12.5 mg of white solid.

Yield: 60%.

HR Mass spectrum (FAB) for C35H47N4O3S:

The Calculations Of The P>*
)]- 2-[2'-Hydroxy-3'-phenyl-thiomethyl-4'-Aza-5'-oxo-5'-[2",6" -dimethyl-3-hydroxyphenyl]pentyl)decahydroquinoline-3 - N-t-BUTYLCARBAMATE

The named compound was obtained in accordance with the methodology described in detail in example 1, using 20 mg (0.046 mmol) of the named compound preparation I, 11,53 mg (0,0694 mmol) of 2,6-dimethyl-3-hydroxybenzoic acid, 9,54 mg (0.046 mmol) of DCC and 6.25 mg (0.046 mmol) HOBTH2About 3 ml of tetrahydrofuran. The substance resulting from the reaction was purified using radial chromatography (1 mm plate; eluting a solution of 4% methanol in methylene chloride) to give 14 mg of a white solid.

Yield: 52%.

HR Mass spectrum (FAB) for C33H48N3O4S:

Calculation: 582,3375.

Found: 582,3373.

Example 40

[2R'-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"-hydroxyphenyl)pentyl] benzamide

The named compound was obtained in accordance with the method described in example 40, using 100 mg (0.29 mmol) of the named compound preparation 24G, 44 mg (0.29 mmol) of the named compound preparation 23C, 60 mg (0.29 mmol) of DCC and 39 mg (0.29 mmol) of 1-hydroxybenzotriazole monohydrate (HOBTH2Oh) 4 is on; an eluting solution of 2-5% gradient of methanol in methylene chloride) to give 58 mg of white powder.

Yield: 42%.

[]D2,34 (=3,4, MeOH).

1H NMR (CD3OD): to 1.47 (s, 9H), of 1.88 (s, 3H), 2.70 height is 2.80 (m, 1H), 2.95 and-3,10 (m, 3H), 3.25 to 3.30 is (m, 1H), 3,85-3,95 (m, 1H), 4,35 is 4.45 (m, 1H), 4,84 (s, 1H), 6,55 return of 6.58 (m, 1H), 6,74 (d, J=8.0 Hz, 1H), 6,94 (t, J=7.8 Hz, 1H), 7,15 was 7.45 (m, 11H).

IR (CHCl3): 3580, 3550-3100 (br.), 2929, 2865, 1662, 1596, 1521, 1472, 1455, 1394, 1368, 1293, 1157, 1047, 879, 839 cm-1.

Macc-spectrum (FD): 475 (M+, 100).

HR Mass spectrum (FAB): m/e for C29H35N2O4:

Calculation: 475,2597.

Found: 475,2610.

Example 41

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-5 ' - hydroxymethylene)pentyl]benzamide

The named compound was obtained in accordance with the method described in example 40, using 95 mg (0.28 mmol) of the named compound preparation 24G, 65 mg (0.28 mmol) of the named compound preparation B, 58 mg (0.28 mmol) of DCC and 38 mg (0.28 mmol) HOBTH2O in 2 ml of tetrahydrofuran containing 0.2 ml of dimethylformamide. The crude product was purified using radial chromatography (2 mm plate; eluting a solution of 4% methanol in methylene chloride) to give a 64.6 mg of the desired titled connected is to 1.98 (s, 3H), 2,70-to 2.85 (m, 1H), 3.00 and-of 3.12 (m, 2H), of 3.25 to 3.35 (m, 1H), 3,85 - of 3.97 (m, 1H), 4,00-4,10 (m, 2H), 4,35-to 4.46 (m, 1H), 4,50 (s, 2H), 6,98 - the 7.43 (m, 11H), 8,06-8,18 (m, 1H).

Mass spectrum (FD): m/e (M++1, 490).

Analysis for C30H36N2O4:

Calculation: C 73,74; H 7,43; N 5,52.

Found: C 74,00; H 7,49; N 5,68.

Example 42

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3" -AMINOPHENYL)pentyl]benzamide

To a cold solution (0oC) 50 mg (0.12 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide was added 22 mg (0.14 mmol) of 2-methyl-3-aminobenzoic acid, 16 mg (0.12 mmol) of HOBT, 22 mg (0.12 mmol) of EDC And of 0.081 ml (of 0.58 mmol) of triethylamine. The resulting reaction mixture was stirred at 0oC for about one hour and then for sixteen hours at room temperature. The reaction was stopped by addition of water and the reaction mixture was extracted with ethyl acetate. The resulting layers were separated and the organic layer was dried, filtered and evaporated under reduced pressure to obtain a crude residue. This residue was purified using flash chromatography (eluting solution - 3% methanol in methylene chloride) to give 52 mg of a white solid substance (i.e. 105 - 106oC).<, ,51 (m, 1H), was 4.02 (m, 1H), 3,68 (br.s, 2H), 3,51 (m, 3H), of 3.12 (s, 2H), 3.04 from (dd, J=13,4, 10.1 Hz, 1H), 2,92 (dd, J=13,4, 3.3 Hz, 1H), of 2.23 (s, 3H), of 1.50 (s, 9H).

IR (KBr): 3304, 3068, 1633, 1516, 1321, 1221, 1076, 746 cm-1.

Analysis for C33H37N3O3S:

Calculation: C 71,32; H Of 6.71; N 7,56.

Found: C 71,54; H 6,83; N 7,32.

Example 43

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- N(methyl)AMINOPHENYL)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 100 mg (0.23 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 42 mg (0.26 mmol) of the titled compound of preparation 28, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution - 2% methanol in methylene chloride) to give 102 mg of a white solid substance (i.e. 111 -113oC).

Yield: 76%.

1H NMR (CDCl3): 7,89 (s, 1H), to 7.75 (m, 2H), 7,52-7,21 (m, 9H), 7,00 (t, J=7.9 Hz, 1H), 6,62 (t, J=7,4 Hz, 1H), 6,41 (d, J=9.1 Hz, 1H), 6,09 (d, J= 5.8 Hz, 1H), 5,91 (s, 1H), 4,48 (m, 1H), 4,01 (m, 1H), 3,69 (s, 1H), to 3.50 (m, 2H), 3,01 (m, 2H), 2,85 (s, 3H), of 2.15 (s, 3H), 1,45 (s, 9H).

Analysis for C34H49N3O3S:

Calculation: C 71,67; H 6,89; N 7,37.

-thiomethyl-4'-Aza-5'-oxo-5'-(2"-chloro-3" -AMINOPHENYL)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 100 mg (0.23 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 48 mg (0.28 mmol) of 2-chloro-3-aminobenzoic acid, 32 mg (0.23 mmol) NOWT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution - 2% methanol in methylene chloride) to give 97 mg of a white solid substance (i.e. 107 - 108oC).

Yield: 72%.

1H NMR (CDCl3): 7,89 (s, 1H), 7,78 (m, 2H), to 7.61-of 7.23 (m, 9H), to 6.95 (t, J=7.8 Hz, 1H), 6,78 (m, 1H), of 6.52 (d, J=7.9 Hz, 1H), equal to 6.05 (d, J=6.0 Hz, 1H), of 5.92 (s, 1H), 4,51 (m, 1H), is 4.21 (s, 2H), 4.16 the (m, 1H), 3,51 (m, 2H), 3,01 (m, 3H), 1,49 (s, 9H).

Analysis for C32H34ClN3O3S:

Calculation: C 66,71; H 5,95; N 7,29.

Found: C 66,85; H The 6.06; N 7,42.

Example 45

[2'R-(2'R*, 3'S*)]-N-Butyl-2-[2'-hydroxy - 3'-naphthas-2-altimeter-4'-Aza-5'-oxo-5'-(2"-bromo-3" -AMINOPHENYL)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 100 mg (0.23 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 61 mg (0.28 mmol) of 2-bromo-3-aminobenzoic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol what milenaria), getting 102 mg of a white solid substance (i.e. 110 - 112oC).

Yield: 71%.

1H NMR (CDCl3): 7,88 (s, 1H), 7,78 (m, 2H), 7,60 - 7,25 (m, 9H), to 6.95 (t, J= 7.8 Hz, 1H), 6,78 (m, 1H), of 6.52 (d, J=7.9 Hz, 1H), 6,1 (d, J=6,1 Hz, 1H), 5,90 (s, 1H), to 4.52 (m, 1H), is 4.21 (s, 2H), 4,15 (m, 1H), 3,50 (m, 2H), 3,00 (m, 3H), 1,49 (s, 9H).

Analysis for C32H34BrN3O3S:

Calculation: C 61,93; H 5,52; N 6,77.

Found: C 61,82; H Of 5.83; N 6,63.

Example 46

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3" -hydroxyphenyl)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 75 mg (0.18 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 32 mg (0.21 mmol) of the named compound preparation 23C, 24 mg (0.18 mmol) HOBT, 34 mg (0.18 mmol) of EDC and 0.12 ml (0.88 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution 1% methanol in methylene chloride) to give 52 mg of a white solid substance (i.e. 119 - 120oC).

Yield: 53%.

IR (KBr): 3297, 1636, 1518, 1284, 1221, 1073, 746 cm-1.

1H NMR (CDCl3): of 7.90 (s, 1H), 7,76 (m, 3H), of 7.48 (m, 6H), 6,79 (m, 4H), of 6.52 (d, J=9,2 Hz, 1H), 6,23 (s, 1H), of 5.92 (s, 1H), 4,50 (m, 1H), was 4.02 (m, 1H), 3,49 (m, 3H), 3,03 (dd, J =13,4, 10.2 G is C 71,19; H OF 6.52; N 5,03.

Found: C 70,95; H 6,59; N 4,87.

Example 47

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl - 5-AMINOPHENYL)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 100 mg (0.23 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 44 mg (0.28 mmol) of the titled compound of preparation 29, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution - 2% methanol in methylene chloride) to give 101 mg of a white solid substance (i.e. 106 - 107oC).

Yield: 79%.

1H NMR (CDCl3): 7,89 (s, 1H), 7,76 (m, 3H), 7,40-7,25 (m, 7H), 6,85 (t, J=9.0 Hz, 1H), 6,62 (d, J=7.7 Hz, 1H), gold 6.43 (d, J=9.0 Hz, 1H), between 6.08 (d, J= 5.8 Hz, 1H), of 5.89 (s, 1H), 4,51 (m, 1H), was 4.02 (m, 1H), 3,70 (br.s, 2H), 3,50 (m, 3H), 3.04 from (dd, J=13.3-inch, 10.1 Hz, 1H), 2,92 (dd, J=13.3-inch, 3.2 Hz, 1H), of 2.21 (s, 3H), of 1.50 (s, 9H).

Analysis for C33H37N3O3S:

Calculation: C 71,32; H Of 6.71; N 7,56.

Found: C 71,64; H 6,93; N 7,45.

Example 48

[2'R-(2'R*,3'S*)]-N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl - thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- hydroxyphenyl)pentyl]-1-naphthylamide

A named connection p is soedineniya training 26G in 2.0 ml of dimethylformamide, 35 mg (0.23 mmol) of the named compound preparation 23C, 29 mg (0.21 mmol) of HOBT and 40 mg (0.21 mmol) of EDC and 0.15 ml (1.10 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution of 1.5% methanol in methylene chloride) to give 106 mg of a white solid substance (i.e. 115-117oC).

Yield: 82%.

1H NMR (CDCl3): of 7.90 (s, 1H), 7,76 (m, 2H), 7,53-7,24 (m, 11H), 6,85 (t, J=7,6 Hz, 1H), 6.73 x (m, 1H), 6,63 (d, J=5.7 Hz, 1H), 6,51 (d, J=9,2 Hz, 1H), 6,10 (s, 1H), 5,90 (s, 1H), 4,50 (m, 1H), 4.09 to (m, 1H), 2,48 (m, 2H), 3,10 (dd, J=12,9, 9.7 Hz, 1H), 2,88 (dd, J=12,9, and 3.2 Hz, 1H), 2,13 (s, 3H), of 1.46 (s, 9H).

Analysis for C37H38N2O4S:

Calculation: C 73,24; H Of 6.31; N 4,62.

Found: C 73,46; H 6,70; N 4,35.

Example 49

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-chloro-3"- AMINOPHENYL)pentyl]-1-naphthylamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 100 mg (0.21 mmol) of the named compound preparation 26G in 2.0 ml of dimethylformamide, 39 mg (0.23 mmol) of 2-chloro-3-aminobenzoic acid, 29 mg (0.21 mmol) of HOBT and 40 mg (0.21 mmol) of EDC and 0.15 ml (1.10 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution of 1.5% methanol in methylene chloride), produces (s, 1H), 7,81 (m, 4H), 7,75-7,21 (m, 9H), to 6.95 (t, J=7.8 HZ, 1H), 6.75 in (m, 1H), 6,51 (d, J=8,2 Hz, 1H), 6,12 (d, J=5,9 Hz, 1H), 5,95 (s, 1H), 4,50 (m, 1H), is 4.21 (s, 2H), 4,15 (m, 1H), 3,51 (m, 2H), 3,00 (m, 3H), 1,49 (s, 9H).

Analysis for C36H36ClN3O3S:

Calculation: C 69,05; H 5,79; N Of 6.71.

Found: C 69,21; H Of 5.85; N 6,54.

Example 50

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(3"- AMINOPHENYL)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 100 mg (0.23 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 38 mg (0.28 mmol) of 3-aminobenzoic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution - 2% methanol in methylene chloride) to give 90 mg of a white solid substance (i.e. 101-102oC).

Yield: 72%.

1H NMR (CDCl3): 7,87 (s, 1H), 7,78 (m, 2H) to 7.61-7,22 (m, 10H), of 6.96 (c, J=7.7 Hz, 1H), 6,76 (m, 1H), of 6.52 (d, J=7.8 Hz, 1H), 6,04 (d, J=6,1 Hz, 1H), 5,91 (s, 1H), and 4.5 (m, 1H), 4,20 (s, 2H), 4,15 (m, 1H), 3,50 (m, 2H), 3,01 (m, 3H), 1,49 (s, 9H).

Analysis for C32H35N3O3S:

Calculation: C 70,95; H 6,51; N 7,76.

Found: C 71,21; H 6,72; N 7,72.

Example 51

[2'R-(2'R*, 3'S*the second compound was obtained in accordance with the methodology described in detail in example 42, using 50 mg (0.12 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 20 mg (0.14 mmol) of 3-hydroxybenzoic acid, 16 mg (0.12 mmol) of HOBT, 22 mg (0.12 mmol) of EDC and of 0.081 ml (of 0.58 mmol) of triethylamine. The crude residue was purified using flash chromatography (eluting solution - 50% ethyl acetate in hexane) to give 36 mg of a white solid substance (i.e. 125-128oC).

Yield: 57%.

1H NMR (CDCl3): 7,87 (s, 1H), 7,73 (m, 3H), 7,20 is 7.50 (m, 7H), 6,95-to 7.15 (m, 4H), to 6.80 (m, 1H), 6,80 (m, 1H), 6,50 (s, 1H), 6.30-in (m, 1H), 5,95 (s, 1H), 4.53-in (m, 1H), 4,10 (m, 1H), of 3.45 (m, 2H), 3,03 (dd, J=13,4, the 10.5 Hz, 1H), 2,90 (dd, J=13,4, 3.5 Hz, 1H), of 1.46 (s, 9H).

HR Mass spectrum for C32H34N2O4S:

Calculation: m/e 675,1294.

Found: m/e 675,1311.

Example 52

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"- were)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 50 mg (0.12 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 19 mg (0.14 mmol) of 2-methylbenzoic acid, 16 mg (0.12 mmol) of HOBT, 22 mg (0.12 mmol) of EDC and of 0.081 ml (of 0.58 mmol) of triethylamine. The crude residue was purified using flash chromatography (e Yield: 52%.

1H NMR (CDCl3): 7,89 (d, J=1.0 Hz, 1H), 7,76 (m, 3H), 7,15-7,52 (m, 11H), 7,02 (t, J= 7,4 Hz, 1H), 6.48 in (d, J=9.0 Hz, 1H), between 6.08 (d, J=6,1 Hz, 1H), of 5.89 (s, 1H), 4.53-in (m, 1H), was 4.02 (m, 1H), 3,48 (d, J=6,8 Hz, 2H), of 3.00 (dd, J=13,4, 10,2 Hz, 1H), 2,92 (dd, J=13,4, 3.6 Hz, 1H), 2,46 (s, 3H), 1,45 (s, 9H).

HR Mass spectrum for C33H36N2O3S:

Calculation: m/e 673,1501.

Found: m/e 673,1504.

Example 53

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'- hydroxy-3'-naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3",5"-diaminophenyl)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 50 mg (0.12 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide, 23 mg (0.14 mmol) of 2-methyl-3,5-diaminobenzoic acid, 16 mg (0.12 mmol) of HOBT, 22 mg (0.12 mmol) of EDC and of 0.081 ml (of 0.58 mmol) of triethylamine. The crude oil was purified flash chromatography (eluting solution of 5% methanol in methylene chloride) to give 28 mg of white powder (similar 125-128oC).

Yield: 42%.

1H NMR (CDCl3): of 7.90 (d, J=1.2 Hz, 1H), to 7.77 (m, 3H), 7,20-7,53 (m, 10H), 6.35mm (d, J= 9,3 Hz, 1H), x 6.15 (br.m, 1H), 6,01 (d, J=2.1 Hz, 1H), of 5.92 (s, 1H), of 5.83 (d, J=2.1 Hz, 1H), 4,50 (m, 1H), 3.96 points (m, 1H), 3,50 (m, 4H), 3,03 (dd, J=13,4, 10,2 Hz, 1H), only 2.91 (dd, J=13,4, 3.5 Hz, 1H), 2,10 (s, 3H), of 1.47 (s, 9H).

HR Mass spectrum for C33H38N4O3S:
The named compound was obtained in accordance with the procedure detailed in example 42, using 75 mg (0.18 mmol) of the named compound preparation 25D in 1.0 ml of dimethylformamide, 40 mg (0.21 mmol) of 2,3-dichlorobenzoyl acid, 24 mg (0.18 mmol) HOBT, 34 mg (0.18 mmol) of EDC and 0.12 ml (0.88 mmol) of triethylamine. The crude oil was purified using flash chromatography (eluting solution 25-50% gradient of ethyl acetate in hexane) to give 75 mg of a white solid substance (I. p. 116-119oC).

Yield: 74%.

1H NMR (CDCl3): of 7.90 (s, 1H), to 7.75 (m, 3H), 7,20-7,52 (m, 9H), 7,13 (dd, J= 7,9, 1.2 Hz, 1H), 7,00 (t, J=7.8 Hz, 1H), only 6.64 (d, J=9.9 Hz, 1H), 5,88 (br. s, 1H), to 4.52 (m, 1H), a 4.03 (m, 1H), 3,50 (d, J=6.0 Hz, 2H), 3,00 (m, 2H), of 1.44 (s, 9H).

Analysis for C32H32Cl2N2O3S:

Calculation: C 64,53; H 5,42; N 4,70.

Found: 64,54; H 5,50; N 4,73.

Example 55

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-chloro-5-AMINOPHENYL)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 75 mg (0.18 mmol) of the named compound preparation 25D in 1.0 ml of dimethylformamide, 36 mg (0.21 mmol) of the titled compound of preparation 29, 24 mg (0.18 mmol) HOBT, 34 mg (0.18 mmol) of EDC and 0,ethyl acetate in hexane), receiving 90 mg of a white solid substance (i.e. 109-110oC).

Yield: 90%.

1H NMR (CDCl3): 7,89 (s, 1H), to 7.75 (m, 3H), 7,21-7,52 (m, 10H),? 7.04 baby mortality (d, J= 8,3 Hz, 1H), 6.73 x (m, 1H), 6,55 (m, 2H), of 5.92 (br.s, 1H), 4,50 (m, 1H), 3,99 (m, 1H), 3,52 (d, J=5.6 Hz, 2H), to 3.02 (m, 2H), 1,45 (s, 9H).

Analysis for C32H34ClN3O3S:

Calculation: C 66,71; H 5,95; N 7,29.

Found: C 66,94; H 6,34; N 6,92.

Example 56

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'- (2"-chloro-3" -hydroxyphenyl)pectel]benzamide

The named compound was obtained in accordance with the procedure detailed in example 42, using 75 kg (0.18 mmol) of the named compound preparation 25D in 1.0 ml of dimethylformamide, 36 mg (0.21 mmol) of the titled compound of preparation 14, 24 mg (0.18 mmol) HOBT, 34 mg (0.18 mmol) of EDC and 0.12 ml (0.88 mmol) of triethylamine. The crude oil was purified using flash chromatography (eluting solution 25-50% gradient of ethyl acetate in hexane) to give 71 mg of a white solid substance (i.e. 104-105oC).

Yield: 71%.

1H NMR (CDCl3): of 7.90 (d, J=1.0 Hz, 1H), and 7.7 (m, 3H), 7,19-7,52 (m, 8H), 7,00 (m, 2H), 6.87 in (m, 1H), only 6.64 (d, J=9.1 Hz, 1H), of 5.89 (s, 1H), to 4.52 (m, 1H), Android 4.04 (m, 1H), 3,50 (d, J= 6,1 Hz, 1H), 3,05 (dd, J=13,4, 10,2 Hz, 2H), equal to 2.94 (dd, J=13,4, 3.6 Hz, 1H), 1,45 (s, 9H).

Analysis for C32
[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(isoquinoline-5"- yl)pentyl]benzamide

To a solution of 0.40 g (0.95 mmol) of the named compound preparation 25D and 134 μl (1,22 mmol) N-methylmorpholine in 15 ml of tetrahydrofuran was added 0.45 g (of 1.33 mmol) of the named compound preparation 30B. The reaction was conducted for approximately 8 hours, after which the reaction mixture was diluted with ethyl acetate. The resulting layers were separated and the organic layer was washed successively with water and brine and then concentrated, receiving raw material. This crude material was purified using flash chromatography (silica; eluting a solution of 4% methanol in methylene chloride), receiving of 0.53 g of a white solid substance (i.e. 109-112oC).

Yield: 97%.

1H NMR (CDCl3): 9,19 (s, 1H), and 8.50 (d, J=4,6 Hz, 1H), 8,23 (d, J=5,9 Hz, 1H), 7,92 (m, 2H), 7,76 (m, 3H), 7,56 (m, 3 H), the 7.43 (m, 3H), 7,32 (m, 2H), 7,24 (m, 1H), to 6.88 (d, J=9.0 Hz, 1H), equal to 6.05 (br.s, 1H), to 5.93 (s, 1H), with 4.64 (m, 1H), 4,12 (m, 1H), 3,51 (d, J=6.3 Hz, 2H), 3,01 (m, 2H), 1,40 (s, 9H).

IR (neat, thin layer): 3428, 3019, 2978, 1647, 1514, 1215, 758 cm-1.

HR Mass spectrum for C35H36N3O3S (MH+):

Calculation: 578,2477.

Found: 578,2468.

Who Found: C 71,35; H 6,00; N 7,09; S 5,44.

Example 58

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3' -naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(1",2",3",4" -tetrahydroisoquinoline-5"-yl)pentyl]benzamide

To a solution of 0.15 g (0.26 mmol) of the titled compound of Example 57 in 6 ml of acetic acid was added 0.08 g (1,27 mmol) laborgerate sodium. The reaction was carried out for approximately 1 hour, after which it was stopped by the addition of saturated sodium bicarbonate solution. The desired compound was then extracted using ethyl acetate, and the organic extracts were washed successively with water and brine and then evaporated under reduced pressure to obtain a foam. This foam was purified using flash chromatography (silica; eluting a solution of 4% methanol in methylene chloride) to give 0.10 g of a white amorphous solid (i.e. 197-199oC).

Yield: 66%.

1H NMR (CDCl3): a 7.85 (s, 1H), to 7.75 (m, 3H), 7,50-7,20 (m, 7H), 7,06 (m, 1H), 6,95 (m, 2H), 6,59 (d, J=9.1 Hz, 1H); of 6.02 (s, 1H), 4,48 (br.s, 1H), 4.00 points (br.s, 1H), 3,98 (s, 2H), of 3.45 (m, 2H), 3,01 (s, 1H), 2,98 (d, J= 6.0 Hz, 3H), 2,89 (m, 3H), of 1.44 (s, 9H), OH not observed.

IR (neat, thin layer): 3418, 3281, 3019, 1632, 1516, 1215, 756.

HR Mass spectrum for C35H40N3O3S:

Calculation: 582,2790.

About the 85; H OF 6.65; N 7,05; S 5,38.

Found: C 70,85; H 6,74; N 7,16; S 5,42.

Example 59

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'- hydroxy-3'-naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-[2-N (methyl)-1", 2", 3", 4"-tetrahydroisoquinoline-5"- yl)pentyl]benzamide

To a hot solution (60oC) 0.11 g (0,19 mmol) of the above compound of example 57 in 3 ml of tetrahydrofuran was added 53 mg (1,40 mmol) sodium borohydride and 75 μl of formic acid. After approximately 1 hour the reaction was stopped by adding a saturated solution of sodium bicarbonate. The desired compound was extracted using ethyl acetate, and the organic extracts were washed successively with water and brine and then concentrated, receiving the foam. This foam was purified using flash chromatography (silica; an eluting solution of 5% methanol in methylene chloride) to give 0.05 g of a white amorphous solid (T. p. 110-113oC).

Yield: 44%.

1H NMR (CDCl3): 7,86 (s, 1H), to 7.75 (m, 3H), 7,50-7,20 (m, 7H), 7,00 (m, 3H), 6,46 (d, J=9.0 Hz, 1H), 6,13 (d, J=5.0 Hz, 1H), 5,96 (s, 1H), 4,45 (m, 1H), 3,97 (m, 1H), 3,54 (S, 2H), 3.46 in (m, 2H), 3,20-2,90 (m, 4H), 2,60 (t, J=5,9 Hz, 2H), 2.40 a (s, 3H), of 1.44 (s, 9H).

IR (neat, thin layer): 3432, 3019, 2976, 1645, 1516, 1215, 756 cm-1.

HR Mass spectrum for C36H42N3O3O3S0,32CH2Cl2:

Calculation: C 70,02; H 6,74; N 6,75; S 5,15.

Found: C 70,03; H 6,74; For 6.81 N; S 5,24.

Example 60

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy - 3'-phenylmethyl-4'-Aza-5'-oxo-5'-(1",2",3",4" -tetrahydroisoquinoline-5"-yl)pentyl]benzamide

The named compound was obtained in accordance with the method described in example 58.

1H NMR (CDCl3): 7,42 (m, 10H) to 7.00 (m, 3H), 6,28 (d, J =9.4 Hz, 1H), 5,95 (s, 1H), 4,60 (m, 1H), 3,95 (bs, 3H), 2,80-3,20 (m, 7H), 2,62 (m, 1H), 1,47 (s, 9H).

Analysis for C31H37N3O3MeOH:

Calculation: C 72,29; H To 7.77; N Of 7.90.

Found: C 72,61; H 7,58; N To 7.61.

Example 61

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(naphthas-1"-yl)pentyl]benzamide

To a cold solution (0oC) 100 mg (0.23 mmol) of the named compound preparation 25D in 2.0 ml of dimethylformamide was added 45 mg (0.26 mmol) naphthalene-1-carboxylic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine. The reaction was carried out for approximately 1 hour at 0oC and 16 hours at room temperature, after which the reaction mixture was diluted with 10 ml of ethyl acetate. The resulting mixture was washed with water, dried over sodium sulfate, filter is matography (eluting solution 1% methanol in methylene chloride) to give 82 mg of a white solid substance (i.e. 92-95oC).

Exit 63%.

1H NMR (CDCl3): 8,35 (br.s, 1H), 7.95 is-to 7.68 (m, 7H), 7,62-7,30 (1m, 10H), of 6.71 (d, J=8,9 Hz, 1H), 6,10 (d, J=6.2 Hz, 1 H), of 5.89 (s, 1H), br4.61 (m, 1H), 4.26 deaths (m, 1H), 3,51 (d, J= 8,9 Hz, 2H), 3.0 a (m, 2H) and 1.51 (s, 9H).

Analysis for C36H36N2O3S:

Calculation: C 74,97; H 6,29; N 4,86.

Found: C 75,13; H 6,45; N 4,49.

Example 62

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(indol-4"-yl)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the compound of preparation 25D, 42 mg (0.26 mmol) of the titled compound of preparation 32, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution 1% methanol in methylene chloride) to give 43 mg of a white solid substance (i.e. 109-110oC).

Yield: 35%.

1H NMR (CDCl3): to 8.45 (br.s, 1H), of 7.90 (s, 1H), 7,76 (m, 3H), EUR 7.57-of 7.23 (m, 10H), 7,19-6,89 (m, 3H), 6,24 (d, J=6.2 Hz, 1H), 5,97 (s, 1H), 4,63 (m, 1H), 4,13 (m, 1H), 3,51 (m, 2H), 3,01 (m, 2H), 1,49 (s, 9H).

Analysis for C34H36N3O3S:

Calculation: C is l-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(quinoline-5"-yl) pentyl]benzamide

The named compound was obtained in accordance with the method described in example 57 using to 0.060 g (0.15 mmol) of the named compound preparation 25D, 42 μl (0.38 mmol) N-methylmorpholine and 0,074 g (0.38 mmol) of the titled compound of preparation 31 in 2 ml of tetrahydrofuran, getting 0,045 g of a white solid.

Yield: 54%.

1H NMR (CDCl3): cent to 8.85 (m, 1H), up 8.75 (m, 1H), up 8.75 (d, J= 8,21 Hz, 1H), 8,07 (m, 2H), 7,95 (s, 1H), 7,76 (m, 3H), of 7.64 (m, 2H), 7,54 (m, 2H), 7,44 (m, 2H), 7,38 (m, 3H), 7,25 (m, 1H), 4,88 (s, 2H), of 4.45 (m, 1H), of 4.05 (m, 1H), 3,69 (dd, J=14, 3,09 Hz, 1H) 3,23 (m, 1H), 3,05 (m, 2H), 1,32 (s, 9H).

IR (KBr): 3485, 3429, 3279, 3061, 2964, 1638, 1543, 1454, 1364, 1319, 1219, 1072, 806, 746 cm-1.

HR Mass spectrum for C35H36N3O3S (MH+):

Calculation: 578,2477.

Found: 578,2491.

Analysis for C35H35N3O3S0,6H2O:

Calculation: C 71,42; H 6,20; N 7,14; S The 5.45.

Found: C 71,44; H 6,16; N 7,19; S 5,41.

Example 64

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(1",2",3",4"- tetrahydroquinolin-5"-yl)pentyl]benzamide

The named compound was obtained in accordance with the method described in example 58, using 0,023 g (0.36 mmol) of laborgerate sodium 0,041 g (0.07 mmol), the above link is="ptx2">

1H NMR (CDCl3): 7,88 (s, 1H), to 7.75 (m, 3H), 7,42 (m, 6H), 6,79 (t, J= 7,73 Hz, 1H), is 6.54 (d, J=7,28 Hz, 1H), 6,44 (d, J=8,15 Hz, 2H), 6,10 (br. 1H), 5,91 (br.s, 1H), 4,45 (m, 1H), of 4.05 (m, 1H), 3,48 (m, 2H), 3,24 (t, J= 5.50 Hz, 2H), 2,89 (m, 4H) of 1.85 (m, 2H), of 1.46 (s, 9H).

IR (KBr): 3450, 2972, 1638, 1618, 1591, 1512, 1454, 1309, 1119, 1134, 1086, 814, 698, 621 cm-1.

HR Mass spectrum for C35H40N3O3S (MH+):

Calculation: 582,2790.

Found: 582,2792.

Example 65

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(indolin-4"-yl)pentyl] benzamide

The named compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 42 mg (0.26 mmol) of the titled compound of preparation 32, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution of 1.5% methanol in methylene chloride) to give 12 mg of a white solid substance (i.e. 83-84oC).

Yield: 9%.

1H NMR (CDCl3): to 7.99 (s, 1H), 7,76 (m, 3H), 7,69-of 7.23 (m, 10H), 7,10 (d, J=8,8 Hz, 1H), 6,60 (d, J=8,9 Hz, 1H), of 5.99 (d, J=6.2 Hz, 1H), of 5.89 (s, 1H), 4.53-in (m, 1H), 4,11 (m, 1 H), 3,44 (m, 6H), 3,01 (m, 2H), for 1.49 (s, 9H).

Analysis for C34H37N3O3*
)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(quinoline-4"- yl)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 45 mg (0.26 mmol) quinoline-4-carboxylic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution of 1.5% methanol in methylene chloride) to give 42 mg of a white solid substance (i.e. 88-92oC).

Yield: 32%.

1H NMR (CDCl3): 8,59 (s, 1H), with 8.33 (d, J=7.9 Hz, 1H), of 8.09 (d, J=8,4 Hz, 1H), to 7.93 (s, 1H), 7,80-7,71 (m, 4H), 7,69 - 7,25 (m, 8H), to 7.15 (s, 1H), to 6.88 (d, J=8,4 Hz, 1H), of 5.99 (s, 1H), to 5.85 (s, 1H), 4,63 (m, 1H), is 4.21 (m, 1H), 3,51 (d, 6.2 Hz, 2H), to 3.02 (m, 2H), 1.39 in (s, 9H).

Analysis for C35H35N3O3S:

Calculation: C 72,76; H 611; N 7,27.

Found: C 72,91; H 6,33; N Of 7.36.

Example 67

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3-nitrophenyl]pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 47 mg (0,26 multiformed. The crude residue was purified using flash chromatography (eluting solution 1% methanol in methylene chloride) to give 100 mg of a white solid substance (i.e. 80-81oC).

Yield: 74%.

1H NMR (CDCl3): 7,89 (s, 1H), to 7.75 (m, 3H), 7,65-7,25 (m, 9H), 7,10 (d, J= 7.9 Hz, 1H), 6,63 (d, J=8,9 Hz, 1H), 5,97 (d, J=6.0 Hz, 1H), by 5.87 (s, 1H), 4.53-in (m, 1H), 4,11 (m, 1H), 3,44 (m, J=6.3 Hz, 2H), 3,03 (dd, J=13,3, 10,2 Hz, 1H), 2,28 (dd, J=13,5, 2.8 Hz, 1H), 2,53 (s, 3H), of 1.47 (s, 9H).

Analysis for C33H35N3O5S:

Calculation: C 67,67; H Of 6.02; N 7,17.

Found: C 67,83; H To 5.93; N 7,05.

Example 68

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(3"-nitro-6" -were)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 47 mg (0.26 mmol) of 2 - methyl-5-nitrobenzoic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution 1% methanol in methylene chloride) to give 102 mg of a white solid substance (i.e. 85-88oC).

Yield: 75%.

1H NMR (CDCl3): 8,17 (s, 1H), 8,07 (d, J=8,4 Hz, 1H), 7,78 (m, 2H) who, 1H), to 2.55 (s, 3H), USD 1.43 (s, 9H).

Analysis for C33H35N3O5S:

Calculation: C 67,67; H Of 6.02; N 7,17.

Found: C 67,92; H 6,22; N 7,02.

Example 69

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(1"-N(methyl)indol - 4"-yl)pentyl]benzamide

The named compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 46 mg (0.26 mmol) of 1-N - methyl-4-carbonbearing indoline, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution 1% methanol in methylene chloride) to give 42 mg of a white solid substance (i.e. 86-89oC).

Yield: 31%.

1H NMR (CDCl3): 7,88 (s, 1H), 7,79-the 7.65 (m, 3H), 7,53-to 6.95 (m, 13H), to 6.22 (d, J=6.3 Hz, 1H), of 5.99 (s, 1H), 4,67 (m, 1H), 4,13 (m, 1H, in), 3.75 (s, 3H), 3,51 (m, 2H), 3,03 (m, 2H), 1,49 (s, 9H).

Analysis for C35H35N3O3S:

Calculation: C 72,51; H To 6.43; N 7,25.

Found: C 72,83; H 6,51; N 7,15.

Example 70

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3", 4"-dihydroxyphenyl)pentyl]benzamide

Nsundomanager connection preparation 25D, 44 mg (0.26 mmol) of the named compound preparation 33B, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution of 2.5% methanol in methylene chloride) to give 76 mg of a white solid substance (i.e. 121-123oC).

Yield: 58%.

1H NMR (CDCl3): 7,89 (s, 1H), to 7.75 (m, 2H), 7,55 - 7,22 (m, 10H), 6,85 (t, J=7.9 Hz, 1H), 6,72 (m, 2H), is 6.61 (d, J=5.7 Hz, 1H), 6,50 (d, J=9.4 Hz, 1H), 6,13 (s, 1H), of 5.92 (s, 1H), 4,51 (m, 1H), 4.09 to (m, 1H), 3,51 (m, 2H), 3,12 (dd, J=13,1, 10 Hz, 1H), 2,87, (dd, J=13,l, 3.1 Hz, 1H), 2,13 (s, 3H), of 1.46 (s, 9H).

Analysis for C33H36N2O5S:

Calculation: C 69,21; H 6,34; N 4,89.

Found: C 69,43; H 6,72; N 4,72.

Example 71

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(3"- hydroxyphenyl)pentyl]benzamide

The desired titled compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 45 mg (0.26 mmol) of 2-chloro-4-aminobenzoic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution - 2% methanol in 1H NMR (CDCl3): 7,88 (s, 1H), to 7.77 (m, 2H), to 7.61-of 7.23 (m, 9H), to 6.95 (t, J=7.7 Hz, 1H), 6.75 in (m, 1H), 6,51 (d, J=7.8 Hz, 1H), the 6.06 (d, J=6,l Hz, 1H), 5,90 (s, 1H), 4,51 (m, 1H), 4,20 (s, 2H), 4,12 (m, 1H), to 3.50 (m, 2H), 3,01 (m, 3H), of 1.48 (s, 9H).

Analysis for C32H34ClN3O3S:

Calculation: C 66,71; H 5,95; N 7,29.

Found: C 66,92; H 5,97; N 7,16.

Example 72

[2'R-(2'R*, 3'S*)] -N-t-Butyl-2-[2'-hydroxy-3'- naphthas-2-yl-thiomethyl-4'-Aza-5'-oxo-5'-(2"-methyl-5 ' - hydroxyphenyl)pentyl]benzamide

The desired titled compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 47 mg (0.26 mmol) of the named compound preparation 29B, 32 mg (0.23 mmol) of HOBT and 40 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution - 3% methanol in methylene chloride) to give 86 mg of a white solid substance (i.e. 104-106oC).

Yield: 67%.

1H NMR (CDCl3): a 7.85 (s, 1H), 7,72 (m, 3H), 7,60-7,22 (m, 9H), 6,92 (t, J=7.5 Hz, 1H), 6,72 (m, 1H), 6,50 (d, J=7,6 Hz, 1H), 5,96 (s, 1H), 5,90 (s, 1H), 4,50 (m, 1H), 4,15 (m, 1H), was 4.02 (m, 1H), of 2.51 (m, 2H), a 3.01 (m, 3H), of 2.36 (s, 3H), 1,45 (s, 9H).

Analysis for C33H37N3O3S:

Calculation: C 71,32; H Of 6.71; N 7,56.

Found-Aza-5'-oxo-5'-(3"-hydroxy-4" -AMINOPHENYL)pentyl]benzamide

The desired titled compound was obtained in accordance with the procedure detailed in example 61, using 100 mg (0.23 mmol) of the named compound preparation 25D, 40 mg (0.26 mmol) of 3-hydroxy-4-aminobenzoic acid, 32 mg (0.23 mmol) of HOBT, 45 mg (0.23 mmol) of EDC, and 0.16 ml (1.20 mmol) of triethylamine in 2.0 ml of dimethylformamide. The crude residue was purified using flash chromatography (eluting solution - 3% methanol in methylene chloride) to give 43 mg of a white solid substance (i.e. 119-122oC).

Yield: 34%.

1H NMR (CDCl3): to $ 7.91 (s, 1H), to 7.75 (m, 2H) 7,60-7,20 (m, 10H), of 6.96 (t, J= 7.9 Hz, 1H), 6.75 in (m, 1H), 6,55 (d, J=7.8 Hz, 1H), 6,1 (s, 1H), 5,95 (s, 1H), 4,51 (m, 1H), 4,23 (s, 2H), 4,12 (m, 1H), 3,52 (m, 2H), 3,00 (m, 3H), of 1.48 (s, 9H).

Analysis for C32H35N3O4S:

Calculation: C 68,92; H 6,33; N 7,53.

Found: C 69,12; H To 6.57; N 7,32.

Reaction scheme III (see below) shows the structure of the compounds in the following examples 74(A - M).

Example 74

An example of A

N-(Benzyloxycarbonyl-3-(2-thienyl)-D,L-alanine

In a flask with a capacity of 500 ml was placed 3.0 g of 3-(2-thienyl)-D, L-alanine (optically active material in an L-shape is produced by firms Aldrich or SIGMA and can be used to obtain optically active product) in the mixture, cocoamphodiacetate. The mixture was rapidly stirred for 1 hour. TLC (21/7/7/9, EtOAc/AcOH/ CH3CN/H2O) showed that the starting material of the reaction are exhausted. Witnessed the emergence of a new product with higher Rf value. The dioxane was evaporated and the aqueous layer was washed with Et2O (75 ml). The aqueous layer was mixed with CH2Cl2(150 ml) and the value of its pH was brought to 2.0 with 5N. HCl. The desired N-(benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine was extracted with CH2Cl2. The organic layer was separated, dried over Na2SO4was filtered and concentrated, obtaining of 5.05 g of the desired N-(benzyloxycarbonyl)-3-(2-thienyl)-D,L-alanine (yield 98 %).

1H NMR (300 MHz, CDCl3): 7,37 (m, 5H), 7,18 (d, J=4 Hz, 1H), 6,95 (m, 1H), 6,83 (m, 1H), 5,35 (d, J=8 Hz, 1H), further 5.15 (s, 2H), 4,7 (m, 1H) and 3.4 (m, 2H).

Example B

N-(Benzyloxycarbonyl)-3-(2-thienyl)-L-alanine-t-butylamide

In a flask with a capacity of 500 ml was placed 8.06 g of the named compound a, N-(benzyloxycarbonyl)-3-(2-thienyl)-L - alanine in 130 ml of THF. The connection was cooled to 0oC. To the flask was added N-methylmorpholine (4,23 ml) followed by the addition over a two minute isobutylphthalate (Android 4.04 ml). The mixture was stirred for 15-20 minutes, and then thereto was added 3,74 ml of t-butylamine. The cooling was removed and Smeaton was dissolved in ethyl acetate. The residue was washed successively H2O, HCl and a saturated solution of NaHCO3. The organic phase was separated, dried over Na2SO4, filtered and concentrated to a oil. The oil was dissolved in 100 ml of hot hexane and cooled in the refrigerator over night, getting solid. Hexane decantation, after which the precipitate was dried, obtaining a 9.25 g of solid N-(carbobenzoxy)-3-(2-thienyl)-L - alanine-t-butylamide (yield 97%).

1H NMR (300 MHz, CDCl3): 7,37 (s, 5H), 7,2 (d, J=4 Hz, 1H), 6,95 (dd, J= 4 Hz, 8 Hz, 1H), 6.87 in (d, J=4 Hz, 1H), 5,52 (m, 2H), 5,12 (s, 2H), 4,27 (m, 1H), 3.27 to (m, 2H) and of 1.23 (s, 9H).

The example IN

N-t-Butyl-5-benzyloxycarbonyl-(4,5,6,7)- tetrahydro-thieno [3,2-c] pyridine-6S-N - t-BUTYLCARBAMATE

In a flask with a capacity of 50 ml was placed 500 mg of the named compound of example B, N-(benzyloxycarbonyl)-3-(2-thienyl)-L - alanine-t-butylamide in 12 ml of 1,1,2-trichloroethane. The contents of the flask were added 2 ml of TFA, followed by adding 2 ml of dimethoxymethane. The mixture was boiled under reflux, controlling the passage of the reaction using TLC every five minutes. After 15 minutes, TLC showed that the starting material of the reaction are exhausted. Upon receipt mostly the desired product, the heat was removed and the contents of the flask you is inuu funnel, the organic phase was separated, dried over Na2SO4, filtered and concentrated to a oil. The product was purified flash chromatography using 25 g (SiO2and 3% EtOAc/CH2Cl2. As a result received 357 mg of N-t-butyl-5-benzyloxycarbonyl (4,5,6,7)-tetrahydro-thieno [3,2-c]pyridine-6S-N-t-BUTYLCARBAMATE (yield 69%).

Compliance with the time interval of fifteen minutes from the start of reflux distilled to remove a heating source and immediate subsequent mixing is very important to avoid adverse reactions.

1H NMR (300 MHz, d6DMSO): 7,35 (m, 7H), 6,83 (m, 1H), 5,15 (m, 2H), to 4.98 (m, 1H), 4,35 (m, 2H), 3,10 (m, 2H) and 1,10 (s, 9H).

Mass spectrum: m/e 372 (M+).

Example D

[6S-(6R*,3aS*,7aR*)]-N-(Benzyloxycarbonyl)- octahydro-thieno[3,2-c]pyridine-6-N-t-BUTYLCARBAMATE

In the vessel for hydrogenation under high pressure was placed named the compound of example, N-t-butyl-5-benzyloxycarbonyl- (4,5,6,7)-tetrahydro-thieno[3,2-C] pyridine-6S-N-t - BUTYLCARBAMATE (10.5 g), and 105 g of 5% palladium on coal in 1100 ml of THF and 525 ml of EtOH. The mixture was placed in an atmosphere of H2(3000 psi) at 80oC for 24 hours. The reaction mixture was cooled, the catalyst was filtered and washed with 20% MeOH/CHCl3. The organic Fergal flash chromatography on 250 g (SiO2), elwira 2% MeOH/CH2Cl2. The desired CIS-isomer (major) in the chromatography obtained in purified form with a small admixture of a minor isomer. This mixture was recrystallized by dissolving in 1.5 ml MeOH, adding 20 ml of Et2O, followed by addition of 120 ml of hexane, after which the mixture was placed in a refrigerator overnight. The obtained crystals were separated by filtration, washed with cold hexane and dried under vacuum, obtaining of 2.54 g of the CIS isomer of [6S-(6R*,3aS*,7aR*)]-N- (benzyloxycarbonyl) octahydro-thieno[3,2,-C] pyridine-6-N-t - BUTYLCARBAMATE (yield 24%).

1H NMR (300 MHz, CDCl3): 7,37 (s, 5H), of 6.0 and 5.5 (br.s, 1H), 5,18 (br. s, 2H), 4,22 (m, 2H), 3,40 (m, 1H), 2,87 (m, 3H), 2,48 (m, 1H), 2,15 (m, 2H), 1.70 to (m, 1H), and 1.15 (br.s, 9H).

Mass spectrum: m/e 377 (M++1).

Example D

[6S-(6R*,3aS*,7aR*)] -Octahydrate[3,2-c]pyridine-6-N - t-BUTYLCARBAMATE

In a flask with a capacity of 100 ml were placed to 2.41 g of the named compound of example G, [6S-(6R*, 3aS*,7aR*)] -T(benzyloxycarbonyl)- octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE in 12 ml of a mixture 1:1 CH3CN/CH2Cl2. To the solution was added to the first portion of trimethylsilylacetamide (TMSI) (1.9 ml) and was stirred for 10 minutes. Then it is time to relax is within 30 minutes. TLC (5% EtOAc/CH2Cl2) showed that the starting material of the reaction are exhausted. The reaction mixture was diluted with 30 ml of diethyl ether, 40 ml of H2O and 6 ml of 1N. HCl. The ether layer was separated and washed with 15 ml of 0.1 G. of HCl. The combined ether layers were discarded, and the aqueous washings were combined. Thereto was added a saturated solution of NaHCO3to summarize the pH of the aqueous layer to 8. The aqueous layer was extracted with twice 200 ml of CH2Cl2organic layers were combined and dried over Na2SO4. The solution was filtered and concentrated, obtaining 1.3 g (yield 84%) of the desired [6S-(6R*,3aS*,7aR*)]-octahydrate[3,2-C] pyridine-6-N-t-BUTYLCARBAMATE.

1H NMR (300 MHz, CDC13): to 6.43 (s, 1H), up 3.22 (m, 2H), 2.95 and (m, 4H), 2,17 (m, 3H), 2,0 (m, 1H), 1.55V (m, 2H) and of 1.32 (s, 9H).

[]D(EtOH) = -179,1o(25oC).

Example E

[6S-(6R*,3aS*,7aR*, 2'S*,3'S*)]-5-[2-Hydroxy-4 - phenylthio-3-(menthoxycarbonyl)-aminobutyl] -octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE

In a flask with a capacity of 100 ml were placed 1.45 g [1'R-(1'R*,1S*)]-1-[(1' -N-(benzyloxycarbonyl)amino-2'-(phenylthio)ethyl] oxirane (obtained after preparation 8, [1'R-(1'R*, 1S*)] -1-[(1'-N (benzyloxycarbonyl)amino-2'-(phenylthio)ethyl]oxera is SUP>,3aS*, 7aR*)] octahydrate[3,2-C] pyridine-6-N-t-BUTYLCARBAMATE in 30 ml of EtOH and the mixture was heated to 65oC for 60 hours. The reaction mixture was concentrated to a foam and purified on chromatotron (4000 micron plate), elwira 1% MeOH/CH2Cl2. The desired fractions were concentrated, obtaining 1.8 g of the desired [6S-(6R*, 3aS*,7aR*,2'S*,3'S*)]-5-[2-hydroxy-4 - phenylthio-3-(menthoxycarbonyl)- aminobutyl] -octahydrate[3,2-C] pyridine-6-N-t-butyl carboxamide. Several factions at the beginning of the separation, containing a mixture of substances, United, getting 326 mg of the mixture, which was again purified chromatographically in the same conditions on a 2000 micron plate. The result has been additional 228 mg of the desired [6S-(6R*,3aS*,7aR*,2'S*, 3'S*)]-5-[2-hydroxy-4 - phenylthio-3-(menthoxycarbonyl)-aminobutyl]octahydrate[3,2 - C]pyridine-6-N-t-BUTYLCARBAMATE. The total yield obtained [6S-(6R*,3aS*,7aR*,2'S*, 3'S*)] -5-[2-hydroxy-4-phenylthio-3-(menthoxycarbonyl)aminobutyl] -octahydrate[3,2-c]pyridine-6-N-t-BUTYLCARBAMATE amounted to 80.5 per cent.

1H NMR (300 MHz, CDCl3): 7,30 (m, 10H) 5,80 (m, 2H), 5,08 (AB, 2H), 3,95 (m, 2H), 3,42 (m, 2H), 3,17 (m, 3H), 2,90 (m, 2H), to 2.67 (m, 1H), 2,58 (m, 1H), 2,48 (m, 1H), 2,35 (m,C-4 phenylthio-3-aminobutyl] -octahydrate[3,2-c]pyridine-6-N-t - BUTYLCARBAMATE

In a flask with a capacity of 100 ml were placed 1.8 g of the named compound of example E, [6S-(6R*,3aS*,7aR*,2'S*,3'S*)] -5-[2-hydroxy-4-phenylthio-3-(menthoxycarbonyl)-aminobutyl] octahydrate [3,2-C] pyridine-6-N-t-BUTYLCARBAMATE in 10 ml each of CH2Cl2and CH3CN. To the solution was added to the first portion (TMSI) (1,14 ml) and was stirred for 10 minutes. Then add the second portion of TMSI (0,72 ml) and was stirred for 10 minutes. Added a third portion TMSI (0,24 ml) and was stirred for 15 minutes. The reaction mixture was diluted with 40 ml Et2O and poured into 30 ml of 0.1 G. of HCl and 60 ml of Et2O. Ethanol layer was separated and discarded. The aqueous layer was podslushivaet a saturated solution of NaHCO3and was extracted with CH2Cl2(2 X 100 ml). The organic phase was separated, dried over Na2SO4was filtered and concentrated, gaining 1.18 g [6S-(6R*, 3aS*,7aR*,2'S*,3'S*)] -5-[2-hydroxy-4-phenylthio-3-aminobutyl]octahydrate[3,2 - C]pyridine-6-N-t-BUTYLCARBAMATE (86% yield) as a white solid.

1H NMR (300 MHz, CDCl3): 7,38 (m, 2H); 7,28 (m, 2H); 7,20 (m, 1H); 6,23 (s, 2H); the 3.65 (s, 1H); or 3.28 (m, 3H); 2,90 (m, 4H); 2,70 (m, 2H); of 2.58 (m, 1H); 2,43 (m, 1H); of 2.34 (m, 1H); is 2.05 (m, 4H); of 1.80 (m, 3H) and of 1.32 (s, 9H).

IR (CHCl3): 3430; 300P>, 3aS*, 7aR*, 2'S*,3'S*)] -2-[2'-Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"- methyl-3"-hydroxy-phenyl)pentyl] -octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE

In a flask with a capacity of 25 ml was placed 40 mg of the named compound of example G, [6S-(6R*,3aS*,7aR*,2'S*,3'S*)] -5-[2-hydroxy-4-phenylthio-3-aminobutyl]-octahydrate[3,2-C] pyridine - 6-N-t-BUTYLCARBAMATE, 14 mg of 3-hydroxy-2-methylbenzoic acid and 12.6 mg of HOBT in 2 ml of THF and the reaction mixture was cooled to -10oC. To the mixture was added DCC (18.7 mg) was heated to room temperature and was stirred for 85 hours. The reaction mixture was diluted with 2 ml of Et2O and filtered through cotton stuffing, the filtrate was concentrated and the residue was suirable on chromatotron (2000 micron plate) using 3% MeOH/CHCl3. The desired fractions were concentrated, receiving 44 mg [6S-(6R*,3aS*, 7aR*, 2'S*, 3'S*)] -2-[2'-hydroxy-3'-phenylthiomethyl - 4'-Aza-5'-oxo-5' -(2"-methyl-3"-hydroxyphenyl) pentyl] -octahydrate [3,2-c]pyridine-6-N-t - BUTYLCARBAMATE (yield 85%).

Example

[6S-(6R*, 3aS*, 7aR*, 2'S*,3'S*)] -2-[2'-Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3"-hydroxyphenyl)pentyl] -octahydrate[3,2 - C] povinnogo compound of example 3, [6S-(6R*,3aS*,7aR*,2'S*,3'S*)] -2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3"-hydroxyphenyl)pentyl] -octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE in a mixture of CH2Cl2/CH2CN (4 ml/2 ml), and thereto using micrometry a syringe was added to 37.5 ml MeSO3H. the Mixture became opaque. It was diluted in 1 ml of CH2Cl2added Et2O and hexane and concentrated. The residue with hexane and concentrated twice, getting 385 mg of the desired salt methanesulfonic acid [6S-(6R*,3aS*,7aR*,2'S*,3'S*)] -2-(2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"- methyl-3"hydroxyphenyl)pentyl] -octahydrate[3,2-C] pyridine-6 - N-t-BUTYLCARBAMATE (yield 100%).

Example TO

[6S-(6R*,3aS*,7aR*,2'S*,3'R*)] -5-[2-Hydroxy - 4-phenyl-3-(menthoxycarbonyl)-aminobutyl] -octahydrate[3,2 - c] pyridine-6-T-t-BUTYLCARBAMATE

In a flask with a capacity of 50 ml was placed 145 mg [1'S-(1'R*,1R*)]-1-[(1'-N-(benzyloxycarbonyl)amino-2'- (phenyl)ethyl] oxirane (can be obtained as in reaction scheme a, steps 1 to 5) below) and 118 mg of the named compound of example D, [6S-(6R*, 3aS*,7aR*)]-octahydrate[3,2-C] pyridine - 6-N-the temperature for 20 hours. Next, the reaction mixture was concentrated and the crude residue was purified using chromatotron 2000 micron plate, elwira 1% MeOH/CHCl3and getting 98 mg [6S-(6R*,3aS*,7aR*,2'S*,3'R*)] -5-[2-hydroxy-4-phenyl-3- (menthoxycarbonyl)-aminobutyl] octahydrate[3,2-c]pyridine - 6-N-t-BUTYLCARBAMATE (yield 37%) and 109 mg of diastereoisomer [6S-(6R*,3aS*,7aR*, 2'S*, 3'R*)] -5-[2-hydroxy-4-phenyl-3- (menthoxycarbonyl)-aminobutyl]octahydrate[3,2-c]pyridine-6-N-t-BUTYLCARBAMATE.

The use of substantially enantiomerically pure (6S-(6R*,3aS*,7aR*)]-octahydrate[3,2-C] pyridine - 6-N-t-BUTYLCARBAMATE instead of [6S-(6R*,3aS*, 7aR*)] -octahydrate[3,2 - C] pyridine-6-N-t-BUTYLCARBAMATE in the form of a mixture of enantiomers should lead to higher output [6S-(6R*,3aS*,7aR*, 2'S*,3'R*)] -5-[2-hydroxy-4-phenyl-3-(menthoxycarbonyl)-aminobutyl]- octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE (see, for example, example E above).

Example L

[6S-(6R*, 3aS*,7aR*,2'S*,3'R*)] -5-[2-Hydroxy-4 - phenyl-3-aminobutyl]-octahydrate[3,2-C]pyridine-6-N-t - BUTYLCARBAMATE

In a flask with a capacity of 25 ml were placed 85 mg momsaxurebis)-aminobutyl] octahydrate [3,2-C] pyridine-6-N-t-BUTYLCARBAMATE in a mixture of CH3CN/CH2Cl2. To a solution of portions 56, 34 and 11 microliters respectively every ten minutes was added TMSI and was stirred for 1.5 hours. The mixture was diluted with Et2O (5 ml) and poured into 15 ml of 1N. HCl and Et2O (20 ml). The organic phase was separated and discarded. The aqueous layer was treated with 30 ml of a saturated solution of NaHCO3and was extracted with CH2Cl2(2 X 50 ml). The organic phase was dried over Na2SO4, filtered and concentrated to a oil, which was led by receiving 64 mg [6S-(6R*,3aS*, 7aR*,2'S*,3'R*)] -5-[2-hydroxy-4-phenyl-3-aminobutyl]-octahydrate [3,2-C] pyridine-6-N-t-BUTYLCARBAMATE (yield 100%).

1H NMR (300 MHz, CDCl3): 7,28 (m, 5H), 6,38 (s, 1H, in), 3.75 (m, 1H), 3,32 (m, 2H), 3,12 (m, 1H), 2,93 (m, 2H), 2,78 (m, 2H), 2,58 (m, 3H), of 2.38 (m, 1H), 2,12 (m, 5H) and 1.83 (m, 2H) and 1.35 (s, 9H).

Example M

[6S-(6R*, 3aS*, 7aR*, 2'S*,3'R*)] -2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'- (2"- methyl-3"-hydroxyphenyl)pentyl] -octahydrate[3,2 - c] pyridine-6-N-t-BUTYLCARBAMATE

In a flask with a capacity of 25 ml were placed 64 mg of the named compound of example L, [6S-(6R*, 3aS*,7aR*,2'S*,3'R*)] -5-[2-hydroxy-4-phenyl-3-aminobutyl]-octahydrate[3,2-C] pyridine-6 - N-t-Buti is H2O in 2 ml of THF and the mixture was cooled to -10oC. thereafter, to the mixture was added DCC (32 mg), the mixture was heated to room temperature and was stirred for 60 hours. The reaction mixture was diluted with 2 ml of Et2O, filtered through cotton stuffing, the filtrate was concentrated and the residue was suirable on chromatotron (2000 micron plate) with a gradient of 1.5% MeOH/CHCl3up to 4% MeOH/CHCl3. The desired fractions were concentrated, receiving 72 mg [6S-(6R*,3aS*, 7aR*, 2'S*, 3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5' -(2"-methyl-3"-hydroxyphenyl)pentyl] - octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE (yield 85%).

Example 75

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'S*)] -2-[2'-Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3"-hydroxyphenyl)pentyl]-decahydroquinoline-3-N-t - BUTYLCARBAMATE salt methanesulfonic acid

This compound was obtained in the same way as in example 23, except that the points of preparation 8A and 8D were changed as set forth below in paragraph (1) and, in addition, was added below the stage of formation of the salt (2).

(1). In a flask with a capacity of 2 l was added to Ph3P (109,6 g) in 500 ml of CH2Cl2and the mixture was cooled to -70oC. To the mixture dropwise in TechTV for 45 minutes was added a solution of N-carbobenzoxy-L-serine (100 g) in 400 ml of THF and allowed the mixture to be heated in a water bath to room temperature for two hours. Then to the mixture was added 150 ml of THF. In another flask a solution of thiophenol (46 g) in 1 l of THF was cooled in an ice bath to 0oC and were processed by the crushed portions NaH (10 g) to give a viscous solution. After one hour the solution tialata for 30 minutes was added dropwise using an addition funnel, the crude solution of the lactone. After 12 hours, a white precipitate was filtered, washed with THF. The solids were dissolved in 0.4 N. NaHSO4and EtOAc, separated phase and the organic layer was washed with saline, dried and evaporated, receiving 85 g 2R-2-N-(benzyloxycarbonyl)amino-3-phenylthiophene acid in the form of a viscous oil.

Originally obtained solid substance, apparently, is the sodium salt of the desired product. Thus, the yield of the reaction and the ease of selection can be improved by separating the sodium salt directly.

The crude chlorcon 3R-1-chloro-2-oxo-3-N-(benzyloxycarbonyl)amino-4 - phenylthiazole (16,87 g of 46.4 mmol) was added to 1 l of absolute EtOH and 200 ml of THF and the solution was cooled in CO2-acetone bath (TNR= -78oC), and then thereto was added dropwise over 1 hour a solution of NaBH4(2,63 g of 69.5 mmol) in 200 ml absolute EtOH (TNR3with stirring, which was caused by the evolution of gas. The resulting mixture was evaporated under reduced pressure to remove most of EtOH and added an additional amount of water. The mixture was extracted with ether, the combined organic layers washed with saturated aqueous NaHCO3and brine, dried (Na2SO4) and concentrated, obtaining a 15.7 g of a whitish solid. This material was ground into powder with boiling hexane (300 ml) and hexane carefully decantation in a hot condition. This procedure was repeated 10 times (each time in a 300 ml), receiving 10,35 g of a whitish solid (one pure isomer according to TLC). The hexane filtrate was concentrated, receiving 6 g of white solid, which was postponed. Powdered solid substance was heated in 50 ml of CH2Cl2and about 6 ml of hexane and filtered hot. The transparent solution was allowed to cool to 25oC, after which it was placed in the freezer. The obtained solid was filtered and washed with hexane, getting 7,157 g of a white solid. The filtrate was combined with hexa experiments (500 mg source of ketone in each) and the combined material was chromatographically on SiO2(solvent system 2:1 hexane-ether to 1: 1 hexane-ether, saturated CH2Cl2), receiving additional 2,62 g of the product. The total number of received pure isomer [2S-(2R*,3S*)] -1-chloro - 2-hydroxy-3-N-(benzyloxycarbonyl)amino-4-phenylthiophene was 10,31 g (yield 50% based on the acid).

[]D-63,6o(C=1, MeOH).

(2). Education salt

[3S-(3R*, 4aR*,8aR*,2'S*,3'S*)] -2-[2'-Hydroxy - 3'-phenylthiomethyl-4'-Aza -5'-oxo-5'-(2"-methyl -3 - hydroxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE (3,34 g) was dissolved in 30 ml of MeOH and 30 ml of CH2Cl2to the solution was added dropwise a solution of methanesulfonic acid (596 mg) in 10 ml of CH2Cl2. After 10 minutes the reaction mixture was concentrated to a foam. The crude salt was dissolved in 5 ml of THF and slowly added to a mixture of 175 ml of ethyl ether and 25 ml of hexane, with stirring, to obtain a fine suspension. The suspension was cooled in the freezer, filtered cold and washed several times with ethyl ether, followed by drying in a vacuum oven, receiving 3.75 g (96%) salt methansulfonate sour the - hydroxyphenyl) pentyl]-decahydroquinoline-3-N-t-BUTYLCARBAMATE in the form of a white powder.

Example 76

3-[Bisbenzamidoximes)hydroxy-2-methylbenzoic acid

< / BR>
To a cooled (0oC) stir the solution containing 706 mg (4,67 mmol) 3-hydroxy-2-methylbenzoic acid in 30 ml of pyridine was added dropwise within 5 minutes 10.3 ml (of 10.21 mmol) of 1.0 M solution hexamethyldisilazide lithium. After stirring for 5 minutes, to the mixture in one portion was added 3.0 g (5,57 mmol) tetraethylpyrophosphate and the reaction mixture was heated to room temperature within 30 minutes. The reaction mixture was concentrated and the residue was distributed between 2.5 N. HCl (200 ml) and the mixture is a 50/50 ethyl acetate/hexane (200 ml). The layers were separated and the aqueous layer was extracted twice with a mixture of ethyl acetate/hexane in the ratio of 50/50. The organic layers were combined, washed with brine and dried over sodium sulfate. Purification of the crude product flash chromatography (elution gradient 50 to 70% ethyl acetate/hexane/2% acetic acid) gave 910 mg of light yellow oil, which is 3- (bisbenzamidoximes)hydroxy-2-methylbenzoic acid.

Yield: 47%.

1H NMR (CDCl3): 2,49 (s, 3H), 5,14 (d, J=at 8.60 Hz, 4H), 7,10 - 7,40 (m, 11H), of 7.48 (d, J=8,09 Hz, 1H), 7,81 (d, J=7,80 Hz, 1H).

IR (CHCl3): 3700-2350 (br), 1700, 1457, 1382, 1273, 1240,S-(3R*, 4aR*,8aR*,2'S*,3'R*)] -2-[2'-Hydroxy-3' -phenylmethyl-4'- Aza-5'-oxo-5'-(2"-methyl-3" -(bisbenzamidoximes)oxyphenyl) pentyl]decahydroquinoline-3 - N-t-BUTYLCARBAMATE

< / BR>
To a cooled (-10oC) a solution containing 95 mg (0.23 mmol) of the named compound of example 76, 3-(bisbenzamidoximes) hydroxy-2-methylbenzoic acid 92 mg (0.23 mmol) of [3S-(3R*,4aR*,8aR*,2'S*,3'R*)] -2-(3'-amino-2'-hydroxy-4'- phenyl] butyldeoxynojirimycin-3-N-t-BUTYLCARBAMATE (see for example the preparation 1B) and 31 mg (0.23 mmol) of HOBT in 5 ml of anhydrous THF was added in one portion 48 mg (0.23 mmol) of DCC. After stirring for 3 days at room temperature the reaction mixture was diluted with ethyl acetate and filtered through cotton stuffing. The obtained filtrate was extracted twice with saturated sodium carbonate, washed with brine and dried over sodium sulfate. Purification of the product by radial chromatography (2 mm plate; an eluting solution of 2.5 - 5% gradient of methanol in methylene chloride) gave a 1.00 mg of a white foam, which is [3S-(3R*,4aR*,8aR*,2'S*, 3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3" -(bisbenzamidoximes)oxyphenyl)pentyl]-d is 2.10 (m, 15H), 2,23 - of 2.36 (m, 2H), 2,50-2,70 (m, 2H), 2,92 was 3.05 (m, 2H), 3,39-to 3.50 (m, 1H), 3,80 - 4,10 (m, 2H), to 4.52-to 4.62 (m, 1H), 5,03-5,13 (m, 4 H), the 5.65 (s, 1H), 6,62 (d, J=8,51 Hz, 1H), 6,83 (d, J=7,60 Hz, 1H), 7,02 (t, J=8,10 Hz, 1H).

IR (CHCl3): 3690, 3600-3100 (br), 3009, 2929, 2866, 1672, 1603, 1513, 1456, 1368, 1277, 1239, 1182, 1037, 1023, 1001, 967, 880 cm-1.

Mass spectrum (FD): m/e 796 (M+, 100).

Analysis for C46H58N3O7P1:

Calculation: C 69,41; H 7,34; N 5,28.

Found: C 69,57; H 7,33; N 5,20.

Example 78

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)] -2-[2'-Hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3" -hydroxyphenyl)pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE

3"-one-deputizing phosphate

< / BR>
A mixture of 86 mg (to 0.108 mmol) of the named compound of example 77, [3S-(3R*, 4aR*, 8aR*,2'S*,3'R*)] -2-(2'-hydroxy-3'- phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3" -(bisbenzamidoximes)oxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE and 23 mg of 10% palladium on coal in 16 ml of methanol was stirred under one atmosphere of hydrogen for 1 hour. The reaction mixture was filtered through celite and concentrated, gaining 61 mg of a white solid, which is a 3"-one-deputizing phosphate [3S-(3R*, 4aR*, 8aR*,2'S*,3'R*

Yield: 96%.

1H NMR (Methanol-d6): of 1.32 (s, 9H), 1,33-of 2.21 (m, 14H), 2,60, to 2.75 (m, 1H), 3,18-to 3.49 (m, 5H), 3,56 - 3,70 (m, 1H), 3.95 to of 4.35 (m, 3H), vs. 5.47 (s, 1H), of 6.71 (d, J=7,26 Hz, 1H), 7,02 (t, J=8,24 Hz, 1H), 7,15-to 7.35 (m, 5H), 7,40 (d, J=8,18 Hz, 1H).

IR (KBr): 3800-2400 (br), 1673, 1545, 1456, 1395, 1368, 1222, 1185, 1077, 942, 857, 792 cm-1.

Mass spectrum (FAB): m/e 616,3 (M+, 100).

Example 79

[3S-(3R*, 4aR*, 8aR*, 2'S*,3'S*)] -2-[2'-Hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3"-(bisbenzamidoximes)oxyphenyl)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE

< / BR>
To a cooled (0oC) stir the solution containing 478 mg (1,16 mmol) of the named compound of example 76, 3- (bisbenzamidoximes)hydroxy-2-methylbenzoic acid, 500 mg (1,16 mmol) of [3S-(3R*,4aR*,8aR*,2'S*,3'S*)] -2-[3'-amino-2'-hydroxy-4'-(phenyl)thio] butyldeoxynojirimycin-3-N-t-BUTYLCARBAMATE (see , for example, training G or training G with modifications of preparation 8A and 8D as in example 75), 352 mg (3,48 mmol), triethylamine and 166 mg (1,23 mmol) HOBT in 8 ml of anhydrous THF was added in one portion 254 mg (1,23 mmol) of DCC. After stirring over night at room temperature the reaction mixture was concentrated, to the residue was added ethyl acetate and filtered by the saline solution, and dried over sodium sulfate. Purification of the product by radial chromatography (6 mm plate; an eluting solution to 30% gradient of ethyl acetate in hexane) gave 644 mg of a white foam, which is [3S-(3R*,4aR*,8aR*,2'S*, 3'S*)] -2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(2"- methyl-3" -(bisbenzamidoximes)oxyphenyl)pentyl]decahydroquinoline - 3-N-t-BUTYLCARBAMATE.

Yield: 67%.

1H NMR (CDCl3): the 1.04 (s, 9H), 1,15-2,61 (m, 19H), 2,89 - 3,00 (m, 1H), 3,39-to 3.50 (m, 1H), 3,67 (s, 1H), 3.75 to of 3.85 (m, 1 H), a 4.03-to 4.15 (m, 1H), 4,43-4,58 (m, 1H), 5,00-5,20 (m, 4H), vs. 5.47 (s, 1H), 7,10 - of 7.55 (m, 19H).

IR (CHCl3): 3600-3150 (br), 3010, 2975, 2929, 2867, 1670, 1517, 1457, 1440, 1368, 1277, 1239, 1082, 1035, 1025, 1001, 968, 879 cm-1.

Mass spectrum (FAB): 828,4 (M+, 100).

Analysis for C46H58N3O7S1P1:

Calculation: C 66,73; H 7,06; N 5,07; S A 3.87.

Found: C 66,56; H 7,29; N 4,82; S 3,62.

Example 80

[3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)] -2-[2'-Hydroxy-3'-phenylthiomethyl-4' -Aza-5'-oxo-5'-2"- methyl-3"-hydroxyphenyl)pentyl] decahydroquinoline-3-N-t - BUTYLCARBAMATE

3"-odnozameshchenny phosphate hydrochloride

< / BR>
A mixture containing 505 mg (0.61 mmol) of the named compound of example 79, [3S-(3R*, 4aR*, 8aR*,2'S*,3'S*)] -2-[2'-GN-3-N-t-BUTYLCARBAMATE and 500 mg of 10% palladium on coal in 20 ml of methanol was stirred under one atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through celite and concentrated, gaining 380 mg of the crude product, which was purified using VIH (column Waters Nova pack C18 RCM (about 40 x 10 cm); flow rate 40 ml/min; eluting solution 45% (1% HCl) water, 15% acetonitrile, 40% methanol) to give 230 mg of a white foam, which is a 3"-one-deputizing phosphate [3S-(3R*,4aR*,8aR*, 2'S*, 3'S*)] -2-[2'-hydroxy-3'- phenylthiomethyl-4'-Aza-5'-oxo-5' -(2"-methyl-3"- hydroxyphenyl)pentyl] decahydroquinoline-3 - N-t - BUTYLCARBAMATE.

Yield: 58%.

1H NMR (Methanol-d4): 1,10-2,30 (m, 25H), 2,39 (s, 3H), 2.95 and - the 3.65 (m, 4H), 3,90-of 4.25 (m, 3H), 7,15-to 7.50 (m, 8H), to 7.99 (s, 1H).

IR (KBr): 3700-2100 (br), 1674, 1547, 1458, 1440, 1395, 1368, 1241, 1182, 1074, 1025, 966, 867 cm-1.

Mass spectrum (FAB): m/e 648,3 (M++1, 100).

Analysis for C32H41N3O9S1Cl1P1:

Calculation: C 53,37; H 7,14; N Of 5.83.

Found: C 53,44; H 6,76; N Of 5.84.

Example 81

3-(Acetyl)hydroxy-2-methylbenzoic acid

< / BR>
For the heterogeneous solution containing a 3.06 g (30 mmol) of acetic anhydride and 1.53 g (10 mmol) 3-hydroxy-2-methylbenzoic acid was added one drop of concentrated sulfuric acid. The mixture was heated using a heat gun for 2 Menomonie, washed twice with water and dried overnight in a vacuum oven. Recrystallization from 20% ethyl acetate/hexane (7 ml) gave 595 mg of a white solid substance representing 3-(acetyl) hydroxy-2-methylbenzoic acid.

Yield: 31%.

IR (CHCl3): 3700-2300 (br), 1765, 1698, 1460, 1404, 1372, 1299, 1273, 1172, 1081, 1041, 1012, 933, 913, 865, 823 cm-1.

Mass spectrum (FD): m/e 194 (M+, 100).

Example 82

[3S-(3R*, 4aR*, 8aR*,2'S*,3'R*)] -2-[2'-Hydroxy-3'- phenylmethyl-4'-Aza-5'-oxo-5'-(2"-methyl-3"- (acetyl)hydroxyphenyl) pentyl]decahydroquinoline-3 - N-t - BUTYLCARBAMATE

< / BR>
To a cooled (-10oC) stir the solution containing 34 mg (0,174 mmol) of the named compound of example 81, 3-(acetyl)hydroxy-2-methylbenzoic acid, 70 mg (0,174 mmol) of [3S-(3R*,4aR*,8aR*,2'S*,3'R*)] -2-[3'-amino-2'-hydroxy-4'-phenyl] butyldeoxynojirimycin-3-N-t - BUTYLCARBAMATE and 24 mg (0,174 mmol) HOBT in 3 ml of anhydrous THF was added in one portion 36 mg (0,174 mmol) of DCC. After stirring for 2 days at room temperature, the reaction mixture was diluted with ethyl acetate and filtered through cotton stuffing. The obtained filtrate was extracted once with saturated carbon is Noah chromatography (1 mm plate; an eluting solution - 0-5% gradient of methanol/methylene chloride) gave 65 mg of a white foam, which represents [3S-(3R*,4aR*,8aR*,2'S*,3'R*)] -2-[2'-hydroxy-3'-phenylethyl-4'-Aza'-oxo-5'-(2"-methyl-3" -(acetyl)hydroxyphenyl)pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE.

Yield: 65%.

1H NMR (CDCl3): to 1.15 (s, 9H) 1,16-is 2.37 (m, 21H) 2,50-2,70 (m, 2H), 2.93 which was 3.05 (m, 2H), 3,39-to 3.50 (m, 1H), 3,99-4,10 (s, 1H), 4.53-in with 4.64 (m, 1H), 3,99-4,10 (m, 1H), 4.53-in - of 4.54 (m, 1H), 5,69 (s, 1H), only 6.64 (d, J=8,45 Hz, 1H), 6,91 (d, J=7,47 Hz, 1H), 7,00 (d, J=EUR 7.57 Hz, 1H), 7,11 (t, J=7,75 Hz, 1H), 7,19-7,40 (m, 5H).

IR (CHCl3): 3700-3100 (br), 3008, 2929, 2865, 1762, 1671, 1604, 1514, 1455, 1394, 1368, 1303, 1277, 1175, 1121, 1082, 1047, 910 cm-1.

Mass spectrum (FD): m/e 578 (M+, 100).

Example 83

< / BR>
To a cold solution (0oC) containing 35 mg (0.061 mmol) of the named compound of example 82, [3S-(3R*,4aR*,8aR*,2'S*,3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3"-(acetyl)hydroxyphenyl)pentyl]-decahydroquinoline - 3-N-t-BUTYLCARBAMATE in 2 ml of anhydrous methylene chloride, was added dropwise 128 microlitres (0,064 mmol) of 0.5 M solution methanesulfonic acid in methylene chloride. The resulting reaction mixture was evaporated to dryness under reduced pressure (0,2-0,1 Torr), receiving 40.5 mg light yellow is *
,3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5' -oxo-5'-(2"-methyl-3"-(acetyl)hydroxyphenyl) pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE.

Yield: 98%.

Example 84

< / BR>
N-BOC-4-thio-L-Proline (can be obtained from the company Sigma) (1.5 g) was dissolved in 3 ml of methanol and cooled to 0oC in an ice bath. In a separate flask was dissolved 5.8 g "OXONE" in 5 ml of H2O and the resulting solution was added dropwise to the reaction mixture. After 30 minutes the reaction mixture was left to warm to room temperature and was stirred overnight, then diluted with CHCl3/H2O, shared phase was extracted with CHCl3(3 X 100 ml). The organic layers were combined, dried over Na2SO4and concentrated in vacuum, obtaining the compound of the above formula (700 mg, yield 41%) as a white solid.

Example 85

< / BR>
The compound of the formula shown in example 84, and [3S-(3R*,4aR*,8aR*,2'S*, 3'S*)] -2-[3'-amino-2'-hydroxy-4'- (phenyl)thio]butyldeoxynojirimycin-3-N-t-BUTYLCARBAMATE was made in accordance with the procedure described above in example 79. The crude material was purified flash chromatography (3% MeOH/CH2Cl2) to give 40 mg (Oh in example 85 (20 mg), was dissolved in 1 ml of CH2Cl2and was treated with 1 ml triperoxonane acid. After 30 minutes at room temperature the reaction product was evaporated in vacuum, obtaining the compound of the above formula representing [3S-(3R*,4aR*,8aR*, 2'S*, 3'S*, 4"S)] - 2-[2'-hydroxy-3'-phenylthiomethyl-4' -Aza-5'-oxo-5'-(thiazoline-4"- yl-1", 1 ' -dioxide)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE.

Pandex IC50= 244 ng/ml

Example 87

< / BR>
3-Carbonbearing thiophene (can be obtained from the firm Aldrich) and [3S-(3R*, 4aR*, 8aR*, 2'S*, 3'R*)] -2-[3'-amino - 2'-hydroxy-4'-phenyl]butyldeoxynojirimycin-3-N-t - BUTYLCARBAMATE was made in accordance with the procedure described above in example 77. The crude material was purified flash chromatography (2% MeOH/CH2Cl2) to give 70 mg (yield 63%) of the compounds of the above formula representing [3S-(3R*,4aR*,8aR*,2'S*,3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(thieno-3"-yl) pentyl]decahydroquinoline-3-N-t-BUTYLCARBAMATE.

Pandex IC50= 25% at 1,000 ng/ml

Example 88

< / BR>
3-Carbonbearing the tetrahydrothiophene-1,1-dioxide and [3S-(3R*, 4aR*,8aRwhat if in accordance with the methodology described above in example 77. The crude material was purified flash chromatography (3% MeOH/CH2Cl2), receiving 50 mg (42% yield) compound of the above formula [3S-(3R*, 4aR*, 8aR*, 2'S*,3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4' -Aza-5'-oxo-5'-(tetrahydrothieno-3"-yl-1", 1 ' - dioxide)pentyl] decahydroquinoline-3-N-t-BUTYLCARBAMATE, in the form of a mixture of diastereoisomers.

Pandex IC50= 28% at 20 ng/ml

Example 89

< / BR>
3-Carbonbearing the tetrahydrothiophene-1,1-dioxide and [6S-(6R*, 3aS*,7aR*, 2'S*, 3'S*)] -5-[2-hydroxy-4-phenylthio-3- (menthoxycarbonyl)aminobutyl] octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE was made in accordance with the methods described above in examples 74 W and H. the Crude material was purified flash chromatography (3-4% MeOH/CH2Cl2) to give 30 mg (yield 57%) [6S-(6R*, 3aS*, 7aR*,2'S*,3'S*)] -2-[2'-hydroxy-3'- phenylthiomethyl-4'-Aza-5'-oxo-5'-(tetrahydrothieno-3" -yl-1", 1 ' -dioxide)pentyl]octahydrate[3,2-c]pyridine - 6-N-t-BUTYLCARBAMATE in the form of a mixture of diastereoisomers.

CEM IC95= 98 nm.

Pandex IC50= 50 ng/ml (0,9).

Example 90

< / BR>
3-Methyl-2-carbonbearing thiophene and [3S-(3R*,4aR*,Ivali in accordance with the methodology described above in example 79, receiving 39 mg (yield 76 %) of the compound of the above formula representing [3S-(3R*, 4aR*,8aR*,2'S*,3'S*)] -2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo-5'-(3" -methyl-thieno-2"-yl)pentyl] -decahydroquinoline-3-N-t-BUTYLCARBAMATE.

Example 91

< / BR>
[6S-(6R*, 3aS*, 7aR*, 2'S*,3'R*)] -2-[2'-hydroxy-3'-phenylmethyl-4'-Aza-5'-oxo-5'-(2" -methyl-3'-hydroxyphenyl)pentyl] -octahydrate[3,2-c] pyridine-6-N-t-BUTYLCARBAMATE (see, for example, example 74 M) (30,5 mg) was dissolved in 2 ml of MeOH. In another flask "OXONE" (51 mg) was dissolved in 1 ml of water and the prepared solution was added to the contents of the first flask. After 6 hours stirring was added the second portion of "OXONE" (17 mg) and the reaction mixture was stirred for 42 hours. The reaction mixture was diluted with CH2Cl2and washed with water. The organic layer was dried over Na2SO2, filtered and concentrated. The crude residue was purified by radial chromatography (1000 micron plate; 3-9% MeOH/CH2Cl2), receiving 5 mg [6S-(6R*,3aS*,7aR*,2'S*, 3'R*)] -2-[2'-hydroxy-3'-phenylthiomethyl-4'-Aza-5'-oxo - 5'-(2" -methyl-3"- hydroxyphenyl)pentyl] - octahydrate[3,2-C]pyridine-1,1-dioxide-6 - SUP>*
,2'S*,3'R*)] -2-[2'-hydroxy-3'- (4"'-fluoro)-phenylthiomethyl-4'- Aza-5'-oxo-5'-(2" -methyl-3"-hydroxyphenyl)pentyl] decahydroquinoline-3 - N-t-BUTYLCARBAMATE were obtained using methods similar to that shown in example 23, except that thiophenol was replaced by 4-portifino in the Preparation of 8A.

The product used is similar to using the product of Preparation 8A, shown in example 23.

Example 93

< / BR>
The above compound salt methanesulfonic acid [3S-(3R*, 4aR*, 8aR*, 2'S*, 3'R*)] -2-[2'-hydroxy-3'-(4"'- fluoro)-phenylthiomethyl-4'-Aza-5'- oxo-5'-(2"-methyl-3" -hydroxyphenyl)pentyl] decahydroquinoline-3-N-t - butocarboxim, received by a method similar to the above example 75 (step 2).

As noted above, the compounds of the present invention are useful as inhibitors of HIV protease, an enzyme that is associated with the formation and Assembly of viral components. An essential component of the present invention is a method of treating HIV infection, which consists in the introduction of the carrier of the virus or the patient, such as primates, the effective amount of the compounds of formula (1) or its pharmaceutically acceptable the research Institute of the carrier of the virus or to the patient an effective amount of the compounds of formula (1) or its pharmaceutically acceptable salt. The next essential component of the present invention is a method of inhibiting HIV protease, which consists in the introduction of HIV-infected cells or virus carrier or patient, such as primates infected with the HIV virus, an effective amount of the compounds of formula (1) or its pharmaceutically acceptable salt.

The term "effective amount" means that amount of the compounds of formula (1) or its pharmaceutically acceptable salt which is effective for the inhibition mediated by the protease of HIV education and Assembly of viral components. The specific dose of a compound, administered according to the present invention to obtain therapeutic or inhibitory influences, will, of course, be determined by the specific circumstances related disease, including, for example, a particular input connection, the route of administration, the condition of the patient treated and the individual characteristics of treated infected person or patient. Estimated daily dose (injected once or a single dose is from about 0.01 mg to 50 mg of the compounds according to the invention per kg of body weight. Preferred daily doses generally approximately from 0.05 Yu can be entered in a variety of ways, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular ways and through the nasal hole. Compounds according to the invention is preferably introduced into the composition of the medicinal product before use. Therefore, another essential component of the present invention is a pharmaceutical composition or prescription drugs, containing an effective amount of the compounds of formula (1) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier such as a diluent or excipient.

The content of the active ingredient is preferably from 0.1% to 99.9% by weight of the drug. The term "pharmaceutically acceptable" is meant that the carrier, such as a diluent or excipient is compatible with other ingredients of the medicinal product and is not harmful to the infected person or patient.

Pharmaceutical drugs can be prepared from compounds provided by the invention, by means of known methods that use readily available ingredients. In the preparation of the compositions according to the present invention the active ingredient is usually some capsules, cachet, paper or other suitable container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a filler, excipient or medium for the active ingredient. Thus the compositions can be made in the form of tablets, pills, powders, pellets, wafers, starch capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid sulfur), ointments containing for example up to 10% of active compound by weight), soft or hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, etc.

The following examples of inventories is provided only to illustrate and not limit the scope of the invention. The term "active ingredient" means a compound represented by the formula (1), or pharmaceutically acceptable salt of this compound.

Division 1

Preparation of hard gelatin capsules containing the following ingredients mg/capsule:

Active ingredient: 250

Starch dried 200

Magnesium stearate - 10

Total, mg - 460

Division 2

Preparation of tablets using given the>/BR>White soot - 10

Stearic acid - 5

Total, mg - 665

The components are mixed and pressed to form tablets weighing 665 mg each.

Recipe 3

Preparation of the solution of aerosol using the following ingredients, wt.%:

Active ingredient - 0,25

Ethanol - 25,75

Propellant 22

(Chlorodifluoromethane) - 74,00

Total - 100,00

The active compound is mixed with ethanol, the mixture was added to portions of propellant 22, cooled to -30oC and transferred to a filling device. Then the required amount of the mixture to fill the stainless steel container and diluted with the remainder of propellant. Further, in the container, set the valve elements.

Recipe 4

Tablets containing 60 mg of active ingredient each prepared as follows:

Composition mg/tablet

Active ingredient - 60

Starch - 45

Microcrystalline cellulose - 35

Polyvinylpyrrolidone

(in the form of a 10% aqueous solution) - 4

Sodium salt of carboxymethyl amylum - 4,5

Magnesium stearate and 0.5

Talc - 1

Total - 150

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and mix thoroughly. An aqueous solution containing the thus granules are dried at 50oC and passed through sieve No. 18 mesh U.S. Sodium salt of carboxymethyl amylum, magnesium stearate and talc, previously passed through sieve # 60 mesh U. S., added to the granules which, after mixing is pressed on the machine to prepare tablets, receiving tablets weighing 150 mg each.

Division 5

Capsules containing 80 mg of active ingredient each prepared as follows:

Composition mg/capsule

Active ingredient - 80

Starch - 59

Microcrystalline cellulose - 59

Magnesium stearate - 2

Total - 200

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through sieve No. 45 mesh U.S. and this mixture in an amount of 200 mg fill hard gelatin capsules.

Division 6

Suppositories containing 225 mg of active ingredient, are prepared as follows:

Part - number mg

Active ingredient: 225

Glycerides of saturated fatty acids - 2000

Total - 2225

The active ingredient is passed through sieve # 60 mesh U. S. and suspended in the glycerides of saturated fatty acids, previously melted using the minimum required amount of heat. The mixture is then poured into supositorio FD is 50 mg of active ingredient per 5 ml dose of each, prepared as follows:

The active ingredient, mg - 50

Sodium salt of carboxymethylcellulose, mg - 50

Syrup, ml - 1,25

A solution of benzoic acid, ml - 0,10

Flavor - q.v.

Dye - q.v.

Purified water to total volume, ml - 5

The active ingredient is passed through a sieve No. 45 mesh U.S. and mix with the sodium salt of carboxymethyl cellulose and syrup to form a homogeneous paste. A solution of benzoic acid, flavoring and coloring diluted with part water and add with stirring. Then add the remaining water to obtain the desired volume.

Division 8.

Drugs for intravenous infusion is prepared as follows:

The active ingredient, mg - 100

Isotonic saline solution, ml - 1000

The solution of the above ingredients is usually administered to the subject intravenously at a rate of 1 ml per minute.

Screening activity

To study the biological activity of compounds inhibiting HIV protease, used a series of tests. For example, used the tests for velocity analysis of proteolytic inhibition, and antiviral activity in HIV-infected cell lines. Metodipaketti in the above examples.

I. Primary screening of drugs antovic connections made in the southern research Institute (SRI) (the results are listed in table 1, labeled "SRI CEM (ng/ml) or SRI MT2 (ng/ml)")

A. the Principle of MTT analysis:

SRI has established a program for the primary anti-virus analysis of compounds through microtiter-analyses, which measure the ability of selected compounds to inhibit the death of HIV-induced cells. This analysis consists in making tetrazolium dye MTT to a colored formosanus product under the action of mitochondrial enzymes in metabolically active cells. This analytical system is used in SRI to check over 30,000 connections per year. Briefly, this analysis is infected CEM or MT2 cells in round-bottom 96-well plates. The interesting connection is added immediately before infection. After 6 days of incubation at 37oC tablets dye MTT. The results of the analysis determined quantitatively by spectrophotometric apparatus for reading plates (Molecular Devices Vmax). Data analyzed by the method of linear regression, using its own program to calculate the antiviral activity (ICPrimary anti-virus tests are usually carried out on a CEM or MT2 cells. In SRI, it was found that all active connections are manifested in CEM cells, while in the experiments performed on the MT2 cell line, a small part of the active compounds does not show its effect.

B. Standard screening tests for CEM and MT2 cells

1. Breeding compounds and their application for tablets

Drugs are dissolved in a suitable solvent, such as distilled water or, if necessary, DHS. Latex gloves, laboratory clothing and masks used in all stages of the implementation process to prevent contact with potentially harmful agents. The drug is prepared at the desired concentration and stored at -20oC to use in the screening laboratory. The first dilution of each connection do in vitro for cultivation with the environment in such a way as to obtain a concentration two times higher than the highest tested concentration. Then use sterile tubes for titration, producing consistent semi-log cultivation of each connection. After that, the diluted compound added to the corresponding well of 96-hole tablet for micrometrology. On AAMI, including controls on a cell, virus, toxicity, color, drug, control environment and control on plastic tablet (background). If you analyze only six dilutions, on one tablet titration is possible to analyze two drugs. Drugs applied to the tablet in a final volume of 100 μl.

2. Cells and virus

While preparing for dilution, the cells are washed and counted. The viability of control by exclusion dye tripan blue and testing is not carried out if the viability drops below 90%. The support cells in the exponential growth phase and split 1:2 on the day prior to analysis to ensure exponential growth rate.

For primary screening using cell lines CEM and MT2. If not specifically listed, then use the medium RPMI 1640 with 10% solution thermoinactivation fetal calf serum (FBS), glutamine and antibiotics.

Cells are grown at 37oC in an atmosphere of 5% CO2in the air. The virus used in this work, is an HIV-1 isolates W and/or RF obtained by an acute infectious process.

Briefly, virus-infected cells daily FDS is in the culture. To identify pools with the largest amount of virus used for measurement of activity of the reverse transcriptase and method P24 ELISA.

These 24-hour fees cells unite, filtered and frozen at -90oC. Infectious pool of virus octarepeat on all available cell lines before it is used in the analysis to determine the amount of virus required for virus analysis.

Pools typically obtained by the method of acute infection, require the addition of one microliter of infectious virus per well, resulting in screening of drugs multiplicity of infection of 0.01. This way, prepare and freeze the virus in sufficient quantity to fill more than one thousand tablets for titration, allowing to test up to two thousand connections from a single line of infectious virus. Use one line of the virus over a long period of testing has a very favorable influence on the reproducibility of the measuring systems.

Viral infection of the CEM and MT2 cells with anti-virus analysis is performed in the process of infection in volume. The required number of cells required for assistme, equal 1-2 ál.

After 4-hour incubation the infected cells lead to the desired end concentration of 5104cells / ml with fresh nutrient media for tissue culture and add 100 ál to wells corresponding to the experiment and control the virus. Uninfected cells in the same concentration placed on pads for controls on toxicity and controls on the cells. You can also perform the analysis using the method of infection in the hole. In this case, the drug, the cells and the virus is added to the wells individually. In each case, MY pick to get the complete destruction of cells in the wells of the control to the virus on the sixth day.

3. Evaluation of the CPE-inhibition

After the addition of cells and drugs in tablet for micrometrology last incubated for 6 days at 37oC. Experience has shown that incubation for longer periods of time (7-8 days) or the use of higher initial amounts of cells (1104) leads to a significant reduction in cell viability control and to a narrowing of the differences in optical density between cell and virus controls when staining with MTT.

The presence of the metabolic activity of viable cells in culture leads to the appearance of the colored reaction product, which is measured spectrophotometrically in the apparatus for reading plates (Molecular Devices Vmax) at 570 nm. The value of optical density (O. D.) is a function of the number formisano product, which is proportional to the number of viable cells.

Apparatus for reading tablet is connected to the set in the screening laboratory microcomputer, which evaluates and calculates the data obtained with tablets. The report received on tablets results represent a summary of all relevant to the case information, including raw values O. D., calculated values of O. D. and percentage reduction in viral CPE, as well as calculations involving TC50IC50anti-virus index and the index of specificity. Finally, the results include a graph that visually displays the influence of the compounds on uninfected cells (toxicity) and the effect of protection or nesesity connection infected cells.

II. Screening of whole cells ant the TKA IC90nm")

A. Purpose and materials

Objective: to determine the IC50and CC50for connections:

Reagents and materials

Environment AND

Medium [1% DMSO] (100 μl DMSO + 9,9 ml of medium)

SN 123 is used to infect cells (15 ml 6 tablets) (10 ml 4 tablet)

CEM cells @ [1104] cells/ml (4 tablet = 40 ml) (6 tablets = 60 ml)

DMSO (need 5 ml)

35V in [10 mm] (requires 70 µl of each connection)

A-D in [10 mm] in 100% DMSO

4 or 6 96-well plate with a u-shaped bottom

4 96-well plate with flat bottom for dilutions

8-10 boxes of sterile costar tips

Approximately 10 trays of chemicals

Costar 12-channel pipette

Auxiliary info:

1000 cells/well = 1104cells/ml = 1000 ál

200 µl = total volume in the hole

The final concentration of DMSO = 0,25%

The final dilution Sn123 = 1:64

Serially diluted compounds 35V, A-D, 1:3

B. Methodology

1. Preparation of cells and applying them to the tablets, the environment and the environment And (1% DMSO)

A. Number 96-well plate for tissue culture for each test compound, one tablet for control and one for the control connection.

Tablet # - Described the cells on hemocytometer and resuspending them in 40 ml or 80 ml of Medium And the concentration of [1104] cells/ml.

Counting cells on hemocytometer:

Mark two nunc tubes with a capacity of 1.8 ml of labels 1 and 2.

Place 0.5 ml of well mixed CEM cells (growth phase) in test tube 1.

Place 50 ál of PBS and 40 μl of tripan blue in the tube 2.

Mix well cells in vitro 1, then take 10 ál of the cells and place them in a test tube 2.

Stir well the contents of the tubes 2, then take 10 μl of stained cells and place them in hemocytometer.

Count the number of cells in the Central square of hemocytometer under a microscope at magnification of 10X.

The concentration of the initial suspension CEM expressed in cells/ml is defined as follows:

The number of counted cells 1105= Concentration of CEM in [cells/ml].

C. Add 200 ál medium As in:

A1 tablet 2-6.

It is forms.

A4-H4 tablet 1.

It is forms.

, Add 5 ál of the environment And to all wells of rows A-D tablets 2-6 except wells A1 (upper half of each tablet).

D. Add 50 ál of medium in wells A1-D3 tablet 1 (upper half of the tablet).

that is, Add 50 ál of medium [1% DMSO] ancheta 1 and all wells (except for A1, which is the form of the other tablets. This makes 1000 cells per well.

C. Place the plates in the incubator at the time of preparation of dilutions of the drug.

2. Preparation of control and test drug

(a) Preparing serial dilutions (35V, A-D) 1:3 tablet with 100% DMSO.

(1) Place 60 ál of DMSO in all wells of columns 2-12, rows A-E.

(2) Place 70 ál 35B [10 mm] in 100% DMSO in well A1.

(3) Place 70 μl of A [10 mm] in 100% DMSO to well B1.

(4) Place 70 ál B [10 mm] in 100% DMSO into the hole C1.

(5) Place 70 ál C [10 mm] in 100% DMSO into the hole D1.

(6) Put 70 ál D [10 mm] in 100% DMSO in well E1.

(7) Serially dilute (35B, A-D) 1:3 to column 12, transferring 30 ál from column 1 to column 2, then column 2 to column 3 and so on up to column 12. Change pipette tips prior to each breeding.

(b) Preparation of tablet for cultivation of 1:10 in medium A:

(1) In rows A-E another tablet do some for the first dilution 1: 10 so that it matches the row containing 100% DMSO for each connection.

35B in a row for A first dilution of 1:10.

A number B for the first dilution of 1:10.poison E for the first dilution of 1:10.

(2) Place 180 μl of medium A to all wells of rows A-E, corresponding to the rows containing 100% DMSO. To prepare each series, it is necessary to 2.5 ml of medium.

(3) Collect 20 µl from all wells of each row in the rows containing 100% DMSO, and drag them into the appropriate rows for cultivation of 1:10.

(C) Preparation of tablet for cultivation of 1:100 in Medium A:

(1) Prepare a tablet for every 3 of the studied compounds.

(2) Place 225 μl of medium A to all wells of rows A, B, D, E, G and H, leaving the ranks of C and F is empty. Use 20 ml of medium on A tablet.

(3) Transfer 25 ál of each connection from a number of breeding 1:10 into the corresponding two rows on the tablet to dilution 1:100, changing tips before each transfer (see table 4).

3. Adding virus Sn123 in tablets

A. Defrost Sn123 in a water bath at 37oC for approximately 10 minutes,

B. Dilute Sn123 in the ratio of 1:16, adding 1 ml Sn123 to 15 ml of medium A.

C. Add 50 ál Sn123 [1:16] wells E1-H12 tablets 2-6 and in wells E1-H3 on the tablet 1.

4. Adding drugs in tablets

A. Add 50 ál of the control and test drug from the tablets with a dilution of 1:100 is set 1:100 will get 4 rows on the target plate. Leave the hole A1 is empty.

B. Incubate all tablets up to 7 days at 37oC in 5% CO2.

C. Follow Templ Protocol on day 7 as follows.

G. Preparation Xt-t/PMS solution:

(4 tablet = 20 ml)

(6 tablets = 30 ml)

(1) Recipe 2 mm PMS:

15.3 mg PMS + 0.5 ml PBS = PMS in conc. [100 mm]

100 ál [100 mm] PMS +4,9 ml PBS = PMS] concentration [2 mm]

(2) Warm up 500 ml of H2O in a microwave oven for 5 minutes.

(3) Place 20 or 30 ml of phenol red RPMI to a centrifuge tube, with a capacity of 50 ml.

(4) Place RPMI in a beaker with hot water.

(5) Add 20 or 30 mg Templ heated to RPMI. The final concentration Templ = [1 mg/ml].

(6) Wait until dissolved Templ, then add 200 ál of [2 mm] PMS in 10 ml Templ.

D. Adding Templ/PMS in the tablet:

(1) Add 50 μl of solution Templ/PMS to all wells of all plates.

(2) Close the tablets and incubate for 4 hours at 37oC in 5% CO2.

(3) Remove the tablets from the incubator and replace the lid on the plastic protective coating for tablets.

(4) Stir the contents of the tablets.

(5) Read the tablets at the test wavelength of 450 nm and etaliban HIV protease (results, listed in table 1, labeled "Pandex (ng/ml)")

Used abbreviations are defined as follows:

BSA - bovine serum albumin

BOC - t-butoxycarbonyl

BrZ - 2-bromobenzyloxycarbonyl

2-ClZ - 2-chlorobenzenesulfonyl

DCC - dicyclohexylcarbodiimide

DIEA - diisopropylethylamine

DTT - dithiothreitol

EDTA - ethylenediaminetetraacetic acid

FITC - fluorescein isotianil

HEPES - 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

MES - 4-morpholinepropanesulfonic acid

RAM phenylacetamide

TAPS - 3-[Tris(hydroxymethyl)methyl]amino-1-sulfonic acid

TRIS - Tris(hydroxymethyl)aminomethan

TOS - p-toluensulfonyl (tosyl)

A. Preparation by and GAG-fractions

1. Culture of E. coli K12 L507/pHP10D

Liofilizovannye culture of E. coli K12 L507/pHP10D were obtained from the Northern Regional research laboratory, Peoria, Illinois 61604, under catalogue number NRRL B-18560 (strain deposited on November 14, 1989). Liofilizovannye bacterial cells decantation in tubes containing 10 ml LB-medium (10 g bacteriophora, 5 g backdragging extract and 10 g of aqueous sodium chloride per liter), brought the pH to 7.5 and incu is m (LB medium with 15 g/l of baktagir), containing 12.5 micrograms/ml tetracycline order to obtain isolated colonies of E. coli K12 L507/pHP10D. Received a separate colony was inoculable in 10 ml LB-medium containing 12.5 micrograms/ml tetracycline, and incubated overnight at 32oC with vigorous shaking. 10 ml overnight culture was inoculable in LB-medium containing 12.5 micrograms/ml tetracycline, and incubated at 32oC with vigorous shaking until the mid-logarithmic phase of growth.

2. Culture of E. coli K12 L507/pHGAG

Liofilizovannye culture of E. coli K12 L507/pHGAG were obtained from the NRRL under the catalog number NRRL B - 18561 (strain deposited on November 14, 1989). Purified colony of E. coli K12 L507/pHGAG was isolated and used as seed material for culture, which was grown to mid-logarithmic phase of growth in full compliance with the above in section a methodology for the strain of E. coli K12 L507/pHP10D.

3. Preparation by fractions

Culture of E. coli K12 L507/pHP10D were grown to mid-logarithmic phase at the 32oC in LB-medium containing 12.5 micrograms/ml tetracycline. The cultivation temperature was quickly raised to 40oC with the intention of inducing the expression of genes and cells have remained by centrifugation and the cell sediment resuspendable in 20 ml of 50 mm MES buffer (pH 6,0), containing 1 mmol EDTA, 1 mmol DTT, 1 mmol PMSF and 10% glycerol (Buffer A). Cells were literally ultrasound using cell disintegrator (Model 300, Fischer) and a probe with micromechanical. After centrifugation at 27000xg the supernatant was diluted with Buffer A to a final volume of 60 ml and was applied on a column of QAE-separate size 2,h cm (1 ml/min, 4oC), which was balanced with Buffer A. the Column was washed isocrate for 180 min and then was suirable gradient of 0-1,0 M aqueous solution of sodium chloride in Buffer a for 120 min Enzymatic activity was measured using VIH using the synthetic peptide Ser-Gln-Asn-Tyr-Pro-Ile-Val, as described in [13]; measured the formation of pl-peptide (Ser-Gln-Asn-Tyr).

Active fractions were pooled, brought to pH 1,2...M... in ammonium sulfate and applied to column 2,h cm with exelerate, equilibrated with Buffer A, containing 1.2 M ammonium sulfate. The sample was applied at a flow rate of 1 ml/min and 4oC, washed with equilibrating buffer for 240 min (1 ml/min) and then was suirable using a reverse linear gradient of ammonium sulfate 1,2 - 0 M in Buffer a for 120 min at the same flow rate. The column was then washed isocrate Buffer a for 120 minutes

Active fractions were combined and concentrated to 200 microlitres using cell sorting (Amicon) and the membrane YM-10, and then applied on a column of Superose 6 gel filtration, equilibrated with Buffer A containing 0.1 M aqueous solution of sodium chloride. The column was washed isocrate this buffer at a flow rate of 0.5 ml/min and HIV-protease was suirable as a single peak.

QAE-sepharose and hexyl-agarose were purchased from Sigma chemical company. Superose 6 and MonoS were purchased from Pharmacia. Buffers and reagents were obtained from Sigma.

4. Preparation GAG-fractions

In a similar way the culture of E. coli K12 507/pHGAG were grown to mid-logarithmic phase at the 32oC, then the temperature was raised to 40oC for about 4-5 hours. The culture was cooled in ice and centrifuged, the OS is IP-HCl (pH 7.8), 5 mm EDTA, 1 mm DTT, 100 mm NaCl, 1 micrograms/ml E and 2 micrograms/ml Aprotinin. The culture is incubated from about 30 to 60 minutes at 4oC, then quickly literally ultrasound using a cell disintegrator (Branson @) at 60% power three 20-second pulses with cooling before each pulse. After this culture besieged by centrifugation at 15000xg. The supernatant, containing reprezentirovanii gag protein was partially purified by gel-filtration on a column of Sephadex G-50 and stored at -20oC in 50% glycerol and lyse buffer.

B. Preparation of substrate: Na-Biotin-Gly-Ser-Gln-Asn-Tyr - Pro-Ile-Val-Gly-Lys(Ne-FITC)-OH

(a = alpha, e = Epsilon)

1. Preparation of peptide, biotinylated on aminobenzo

The resin containing the protected peptide, Na-Boc-Gly-Ser-Gln-Asn-Tyr(BrZ) -Pro-Ile-Val-Gly-Lys (2-ClZ) -OCH2-PAM-resin was synthesized on a peptide synthesizer (Advanced Chemtech Model 200) in an amount of 1.5 mmol, using the standard algorithm double bind. Aminobenzene t-Boc group was removed with 50% triperoxonane acid in methylene chloride and the resulting resin was neutralized with 5% diisopropylethylamine (DIEA) in methylene chloride. Then to the peptide resin was added 1.1 g (4.5 mmol) of Biotin in 20 ml Dimenna the reaction mixture was diluted to a final volume of 40 ml, using 1.1 ml of methylene chloride, after which the reaction was conducted for about 5 hours. The reaction solution was concentrated, the resin was washed sequentially dimethylsulfoxide, dimethylformamide and methylene chloride and then neutralized with 5% DIEA in methylene chloride. This reaction was repeated twice, increasing the reaction time up to 12 hours. Analysis of the resin by using ninhydrin testified to the completion of the reaction of Biotin with the amino group of glycine. The resulting peptide resin was intensively washed with dimethylformamide and methylene chloride and dried, obtaining 4.3 g of resin (yield 98%).

2. Removing protection

With peptide filmed protection, and separated him from the resin by processing 50 ml fluoride-hydrogen acid/m-cresol at 0oC for 1 hour. After removal of fluoride-hydrogen acid by vacuum distillation m-cresol was extracted from the reaction mixture using 100 ml of diethyl ether. Then the peptide was solubilizers in 50% aqueous acetic acid, frozen and freeze-dried, receiving 2.14 g of the peptide.

3. Clean

The crude peptide, biotinylated at the terminal amino group was dissolved in 200 ml of 5% aqueous solution of acetonitrile containing 0.1% triperoxonane C column with octadecyl-silica (Vydac C-18), equilibrated with the same buffer. The peptide was suirable using 855-minute linear gradient of 7.5-25% acetonitrile, at a flow rate of 2 ml/min, producing a collection of fractions. These fractions were analyzed using analytical VGH. VIH performed at 4,h mm column (Vydac C-18 in similar conditions on the buffer. The fractions containing the desired material were combined, frozen and freeze-dried, receiving 1,206 g peptide (yield 62%).

Amino acid analysis of the biotinylated peptide showed the following results corresponding to theoretically calculated: Asn 1,1; Ser 0,96; Gln 1,1; Pro 1,1; Gly 2,1; Val 0,80; Ile 0,78; Tyr 1,1; Lys 1,1. FAB-mass spectrometry gave the mass of the molecular ion is equal 1288, which corresponds to theoretically calculated.

4. Introduction tag

Purified biotinylated peptide was then labeled with fluorescent marker C-terminal group for use in Pandex-analysis. First, biotinylated peptide (1,206 g, 0,936 mmol) was dissolved in 100 ml of 0.1 M sodium borate, pH of 9.5. Then it was added in ten equal portions over two hours in a solution containing 3 g (7.7 mmol) fluoresceinisothiocyanate in 15 ml of dimethylsulfoxide. The reaction was carried out for one hour after the last is the one that removed by centrifugation.

Then the pH of the peptide solution was brought to a value of 7.8, using 5N. sodium hydroxide, after which the solution was diluted to 200 ml by adding 0.1 M ammonium acetate, pH 7.5. The resulting solution was filtered through a 0,22 micron filter and applied on 2,h cm column of Vydac C-18, equilibrated with 5% acetonitrile in 0.1 M ammonium acetate (pH 7.5). The peptide was suirable with speakers using 855-minute linear gradient of 5-25% acetonitrile, at a flow rate of 2 ml/min with collection of fractions. For analysis of the fractions used analytical VGH. The fractions containing the desired product were combined, frozen and freeze-dried, receiving 190,2 mg of peptide (12%).

Amino acid analysis of the purified peptide showed the following results corresponding to theoretically calculated: Asn 1,1; Ser 1,0; Gln 1,1; Pro 1,1; Gly 2,1; Val 0,8; Ile 0,8; Tyr 1,1; Lys and 1.0. FAB-mass spectrometry gave the mass of the molecular ion is equal to 1678, which corresponds to theoretically calculated.

5. Fluorescence analysis on the inhibition of HIV protease-1

The following buffers and solutions used in fluorescence analysis on the inhibition of HIV-1 protease:

MES-ALB buffer:

0.05 M 4-mortality

sulfonic acid, pH 5.5

of 0.02 M NaCl

OF 0.002 M EDTA

0.001 M DTT

0.1% solution Fluoricon videnovic test particles (avidin conjugated with solid polystyrene beads with a diameter of 0.6-0.8 μm in TBSA buffer)

The enzyme solution:

27 IU/ml of purified HIV-1 protease in MES-ALB buffer (1 IU corresponds to the amount of enzyme required to hydrolyze 1 µmol of substrate per minute at 37oC)

To each well of round-bottom 96-well tablet add 20 μl of an enzyme solution, followed by adding 10 ál of the test compound in 20% aqueous solution of dimethyl sulfoxide. Purified HIV-1 protease was obtained as described above. The resulting solution was incubated for one hour at room temperature, after which each well was added 20 μl of a solution containing the substrate, prepared previously, in MES-ALB buffer (1,5 µl). The solutions are then incubated for 16 hours at room temperature, after which the contents of each well was diluted with 150 μl of MES-ALB buffer.

To each well of the second round-bottom 96-well Pandex tablet add 25 ál of the solution is covered with Avidya balls. Then to each well was added 25 μl of the previously prepared diluted incubation solutions. The solutions are thoroughly mixed and tablets are placed in Pandex machine, promiseyou as a result epifluorescence at 535 nm.

The results of the IC50received in fluorescence analysis for compounds of the present invention are listed in tables 1, 2 and 3. All values were assigned to the positive control, which is [1S-(1R*,4R*,5S*)]-N-(1-(2-amino-2 - oxoethyl)-2-oxo-3-Aza-4-phenylmethyl-5-hydroxy-6-(2-(1-t-butylamino - 1-oxoethyl)phenyl)hexyl)-2-chinainternational.

Illustrative data on the activity of the compounds covered by this invention, are presented in tables 1, 2 and 3 and in the previous Examples. The results given in parentheses are for Example 1 of the published application for the European patent 0526009 A1 = 35B in same assay.

1. The compound of the formula I

< / BR>
where Q3- aryl or-S-aryl, possibly substituted with halogen, where aryl is a carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue;

A - carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, pyridinyl, pyridinyl-N-oxide, chinoline, ethenolysis, indolyl, indolinyl, thiazolyl-1,1-dioxide, thienyl, or thienyl-1,1-dioxide;

In - carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, nasyshennaya, octahydrate[3,2-C]pyridinyl or octahydrate[3,2-C]pyridinyl-1,1-dioxide;

Q1and Q2independently a hydrogen atom or alkyl;

Q4- Q8independently a hydrogen atom, hydroxyl, halogen, nitro-, amino-, alkylsulfonate, alkylamino-, alkyl possibly substituted with halogen, alkoxyl, the group-O-I (where I denotes therelatively group) or a group of L6C(O)L4(where L6represents a simple bond or - O, and L4is alkyl or alkoxy);

Y and G - atoms of oxygen;

D is a carbon atom or nitrogen, and D is connected by a simple relationship with each of the adjacent atoms of the ring;

E is a carbon atom;

Q9is a hydrogen atom;

or its pharmaceutically acceptable salt.

2. The compound or pharmaceutically acceptable salt p. 1, where Q3selected from substituted with halogen and unsubstituted phenyl, -S-phenyl, naphthyl and-S-naphthyl.

3. The compound or pharmaceutically acceptable salt p. 1, where Q3selected from substituted with halogen and unsubstituted phenyl and-S-phenyl.

4. The compound or pharmaceutically acceptable salt p. 1, where Q3selected from Samusenko halogen and unsubstituted phenyl.

5. The compound or pharmaceutically acceptable what about p. 1, where one of Q1and Q2is tert-bootrom, Q3-S-phenyl or phenyl, and Q5is hydroxyl or a group-O-I, or pharmaceutically acceptable salt of this compound.

7. Connection on p. 1, where one of Q1and Q2is tert-bootrom and the other is a hydrogen atom, Q3-S-phenyl or phenyl, Q4is methyl, Q5is hydroxyl or a group-O-I, Q6- Q8- hydrogen atoms, D is a nitrogen atom And the phenyl and represents

< / BR>
where M1and M2- hydrogen atoms, or M1and M2can form part of a ring having up to 10 members,

or pharmaceutically acceptable salt of this compound.

8. Connection on p. 7, where M1and M2independently contain from zero to eight non-hydrogen atoms, or pharmaceutically acceptable salt of this compound.

9. Connection on p. 1, where one of Q1and Q2is tert-bootrom and the other is a hydrogen atom, Q4is methyl, Q5is hydroxyl or a group-O-I; Q6- Q8hydrogen atoms, D is a nitrogen atom And the phenyl and decahydroquinoline or octahydrate[3,2-c] pyridinyl, or a pharmaceutically acceptable salt of this compound.

10. Connection on p. 9, where Q3- -S-aryl, or pharmaceutical is tert-bootrom, and the other is a hydrogen atom, Q3- -S-aryl, D is a nitrogen atom, In - decahydroquinoline or octahydrate[3,2-c]pyridinyl, or a pharmaceutically acceptable salt of this compound.

12. Connection on p. 11, where a is a carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, Q4is hydroxyl, alkoxyl or alkyl possibly substituted with halogen, and Q5the hydroxyl group-O-I or alkoxy, or pharmaceutically acceptable salt of this compound.

13. Connection on p. 12, where a is phenyl, Q4- alkyl and Q5is hydroxyl or a group - ORO(OH)2or pharmaceutically acceptable salt of this compound.

14. Connection on p. 11, where Q3- -S-phenyl, or a pharmaceutically acceptable salt of this compound.

15. The compound or pharmaceutically acceptable salt p. 1, where at least one of Q1and Q2is alkyl, Q4- Q8independently selected from a hydrogen atom, hydroxyl, halogen, a group-O-I (where I denotes therelatively group), alkoxyl, amino, alkyl, possibly substituted with halogen, and a group of L6C(O)L4(where L6represents a simple bond or-O, and L4- alkyl), D is a nitrogen atom, And - carbocycles the sludge, ethenolysis, indolyl, indolinyl, thiazolyl-1,1-dioxide, thienyl or thienyl-1,1-dioxide; In - rich 8 - to 12-membered monocyclic or polycyclic residue, including heteroatom of nitrogen, pyridylmethylamine, octahydrate[3,2-c] pyridinyl or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

16. The compound or pharmaceutically acceptable salt according to p. 15, where Q3selected from substituted with halogen and unsubstituted phenyl, -S-phenyl, naphthyl and-S-naphthyl.

17. The compound or pharmaceutically acceptable salt according to p. 15, where Q3selected from substituted halogeno and unsubstituted phenyl and-S-phenyl.

18. The compound or pharmaceutically acceptable salt according to p. 15, where Q3selected from substituted with halogen, and unsubstituted phenyl.

19. The compound or pharmaceutically acceptable salt according to p. 15, where Q3selected from substituted with halogen and unsubstituted-S-phenyl.

20. The compound or pharmaceutically acceptable salt according to p. 15, where one of Q1and Q2is alkyl and the other is a hydrogen atom, Q4- alkyl, Q5is hydroxyl or a group-O-I (where I denotes therelatively group), or alkoxy, or amino-, E - carbon atom, And is a carbocyclic aromatic 5 or 6 members of the Lil, indolinyl, thiazolyl-1,1-dioxide, thienyl or thienyl-1,1-dioxide, saturated 8 - to 10-membered monocyclic or polycyclic residue, including heteroatom of nitrogen, pyridylmethylamine, octahydrate[3,2-c] pyridinyl or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

21.The compound or pharmaceutically acceptable salt according to p. 20, where Q3selected from substituted with halogen and unsubstituted phenyl, -S-phenyl, naphthyl and-S-naphthyl.

22. The compound or pharmaceutically acceptable salt according to p. 20, where Q3selected from substituted with halogen and unsubstituted phenyl and-S-phenyl.

23. The compound or pharmaceutically acceptable salt according to p. 20, where Q3selected from substituted with halogen, and unsubstituted phenyl.

24. The compound or pharmaceutically acceptable salt according to p. 20, where Q3selected from substituted with halogen and unsubstituted-S-phenyl.

25. The compound or pharmaceutically acceptable salt according to p. 20, where one of Q1and Q2- tertiary alkyl, and the other is a hydrogen atom, Q4is methyl, Q5is hydroxyl, amino or the group-O-I (where I denotes therelatively group) And phenyl and a saturated 9 - or 10-membered bicyclic residue comprising heteroatom of nitrogen, octahedrally salt p. 25, where Q3selected from substituted with halogen and unsubstituted phenyl, -S-phenyl, naphthyl and-S-naphthyl.

27. The compound or pharmaceutically acceptable salt p. 25, where Q3selected from substituted with halogen and unsubstituted phenyl and-S-phenyl.

28. The compound or pharmaceutically acceptable salt p. 25, where Q3selected from substituted with halogen, and unsubstituted phenyl.

29. The compound or pharmaceutically acceptable salt p. 25, where Q3selected from substituted with halogen and unsubstituted-S-phenyl.

30. The compound or pharmaceutically acceptable salt p. 25, where In - decahydroquinoline or octahydrate[3,2-c]pyridinyl.

31. The compound or pharmaceutically acceptable salt p. 1, where one of Q1and Q2- alkyl and the other is a hydrogen atom, Q4- Q8independently selected from a hydrogen atom, hydroxyl, halogen, the group-O-I (where I denotes therelatively group), alkoxyl, amino, alkyl, possibly substituted with halogen, and a group of L6C(O)L4(where L6represents a simple bond or-O, and L4is alkyl or alkoxyl), And is a carbocyclic aromatic 5-7 membered monocyclic residue, pyridinyl, pyridinyl-N-oxide; thiazolyl-1,1-is m nitrogen, octahydrate[3,2-c]pyridinyl or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

32. The compound or pharmaceutically acceptable salt p. 31, where In - rich 9-10-membered bicyclic residue comprising heteroatom of nitrogen, pyridylmethylamine, octahydrate[3,2-c] pyridinyl or octahydrate[3,2-c]pyridinyl-1,1-dioxide.

33. The compound or pharmaceutically acceptable salt p. 32, where In denotes

< / BR>
where M1and M2- hydrogen atoms, or M1and M2can form part of a ring having up to 10 members.

34. The connection formulas

< / BR>
or its prodrug, or pharmaceutically acceptable salt.

35. Connection on p. 34, characterized in that it is a stereoisomer and has the formula

< / BR>
or its prodrug, or pharmaceutically acceptable salt.

36. Substantially pure stereoisomer, prodrug or salt of p. 35.

37. Stereoisomer by p. 36, characterized in that it is substantially pure.

38. The connection formulas

< / BR>
39. Connection on p. 38, characterized in that it is a stereoisomer and has the formula

< / BR>
40. Connection on p. 39, characterized in that it is pie in p. 41, characterized in that it is a stereoisomer and has the formula

< / BR>
43. Substantially pure stereoisomer by p. 42.

44. The connection formulas

< / BR>
45. Connection on p. 44, characterized in that it is a stereoisomer and has the formula

< / BR>
46. Connection on p. 45, characterized in that it is a substantially pure stereoisomer.

47. The connection formulas

< / BR>
or its prodrug, or pharmaceutically acceptable salt.

48. Connection on p. 47, characterized in that it is a stereoisomer and has the formula

< / BR>
or its prodrug, or pharmaceutically acceptable salt.

49. Connection on p. 48, characterized in that it is a substantially pure stereoisomer, prodrug or salt.

50. Connection on p. 49, characterized in that it is a substantially pure stereoisomer.

51. The pharmaceutical composition inhibiting HIV protease, containing an effective amount of the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is a compound according to any one of paragraphs.1 - 50.

52. is inane formula I

< / BR>
where Q3- aryl or-S-aryl, possibly substituted with halogen, where aryl is a carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue;

A - carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, pyridinyl, pyridinyl-N-oxide, chinoline, ethenolysis, indolyl, indolinyl, thiazolyl-1,1-dioxide, thienyl or thienyl-1,1-dioxide;

In - carbocyclic aromatic 5-14-membered monocyclic or polycyclic residue, a saturated 5 to 14-membered monocyclic or polycyclic residue, including heteroatom of nitrogen, pyridylmethylamine, octahydrate[3,2-c] pyridinyl, or octahydrate[3,2-c]pyridinyl-1,1-dioxide,

Q1and Q2independently a hydrogen atom or alkyl;

Q4- Q8independently a hydrogen atom, hydroxyl, halogen, nitro, amino, alkylsulfonyl, alkylamino-, alkyl possibly substituted with halogen, alkoxyl, a group-O-I (where I denotes therelatively group) or a group of L6C(O)L4(where L6represents a simple bond or-O, and L4is alkyl or alkoxy);

Y and G - atoms of oxygen;

D is a carbon atom or nitrogen, and D is connected by a simple relationship with each of the adjacent th salt.

Priority points:

02.02.94 when In - octahydrate[3,2-c] pyridine and octahydrate[3,2-c]pyridine-1,1-dioxide, p. 1-33, 38-50, 51 and 52.

07.10.93 other signs, PP.1 - 33, 34-37, 51 and 52.

 

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