Inhibitors of hiv protease

 

(57) Abstract:

Describes new compounds of formula (I) or pharmaceutically acceptable salt of such a compound, which is a sustainable 8-10 membered bicyclic a heterocycle, each of the rings which may be saturated or unsaturated, and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from the group consisting of N, S or O, and the heterocycle may be unsubstituted or substituted with halogen or lower C1-4the alkyl, provided that is not the groups (A). The compounds are inhibitors of the protease encoded by human immunodeficiency virus. Also describes a pharmaceutical composition based on compounds of the formula (I) and a method of inhibiting HIV protease. 3 S. and 11 C.p. f-crystals.

The invention is a partial continuation of application Merck A, filed December 15, 1993, the Present invention relates to the application Merck 18996 with U. S-S-N. 08/059038 may 7, 1993, which is partially continued application claims Merck V, which in turn is partially continued application claims Merck A, which is a partial continued application of application U.S. serial number 07/7895 08 8 noaptea 1990 (case Merck 18236); the application U.S. serial number 746460 from August 16, 1991 (case Merck 18466); the application Merck filed on 23 October 1991, and the application Merck 18416.

The invention relates to compounds which inhibit the protease encoded by human immunodeficiency virus, or their pharmaceutically acceptable salts, and such compounds are used for the prevention of infection by HIV, treating infection by HIV and the treatment of acquired as a result immunodeficiency syndrome (AIDS). The present invention also relates to pharmaceutical compositions containing such compounds, and method of application of the present compounds and other agents for the treatment of AIDS and viral infection is HIV.

The technical field to which the invention relates.

Retrovirus, designated as the human immunodeficiency virus (HIV) is the etiological agent of the complex disease that is progressive destruction of the immune system (acquired immune deficiency syndrome) and degeneration of the Central and peripheral nervous system. This virus was previously known as LAV, HTLV-111 or ARY. A common feature of retrovirus replication is the extensive post-translational processing polyproteins-preceded the bill to the Assembly and functioning of the virus. Inhibition of this process prevents the formation of infectious under normal conditions the virus. For example, Kohl, N. E. al., in Proc. Natl Acad. Sci.. 85, 4686 (1988) showed that genetic inactivation of protease, encoded by HIV, results in the formation of immature, noninfectious viral particles. These results indicate that the inhibition of HIV protease is a viable method for the treatment of AIDS and the prevention or treatment of HIV infection.

The nucleotide sequence of the HIV detects the presence a gene in one open reading frame (Rather, Z, al., Nature, 313, 277 (1985)). Homology of amino acid sequences provides evidence that the pol sequence encodes reverse transcriptase, endonuclease and HIV protease (Toh, H. with al., EMBO J. 4, 1267 (1985); Power, M. D, with TCS. , Science, 231, 1567 (1986); Pearl, L. H. with al., Nature, 329, 351, (1987)). Applicants have demonstrated the fact that the compounds of the present invention are inhibitors of HIV protease.

Summary of the invention.

The compounds of formula I mentioned in the descriptive text that can be used for inhibition of HIV protease, the prevention of infection by HIV, treating infection by HIV and for the treatment of AlDS, price composition, optional in combination with other antiviral agents, immunomodulators, antibiotics or vaccines. Disclosed are also methods of treating AIDS, ways of prevention of HIV infection and treatment of HIV infection.

In the application abbreviations may be used, provided at the end of the description.

Description of the invention and preferred implementations.

The invention relates to compounds of the formula I, their compounds or their pharmaceutically acceptable salts, intended for the inhibition of HIV protease, the prevention or treatment of HIV infection and treatment acquired as a result immunodeficiency syndrome (AIDS). The compounds of formula I are defined as follows:

< / BR>
or their pharmaceutically acceptable salts

where is a steady 8-10-membered ring of the bicyclic heterocycle, each of the rings which may be saturated or unsaturated, and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from the group consisting of N, S or O, and the heterocycle may be unsubstituted or substituted by OH, halogen, C1-4the alkyl, exography;

provided that is not the following groups:

< / BR>
< / BR>
< / BR>
Oemleria salt, in which represents a steady 8-10-membered ring of the bicyclic heterocycle, any of the rings which may be saturated or unsaturated, and said heterocycle comprises carbon atoms and 2 heteroatoms selected from the group consisting of N or O, whereby the heteroatoms are in different rings.

The second implementation of the invention is a compound of formula I, which is limited to values:

< / BR>
< / BR>
X represents O or S,

or their pharmaceutically acceptable salts.

The third implementation of the invention is a compound of formula I, in which limited value:

< / BR>
or their pharmaceutically acceptable salts.

Another embodiment of the present invention is a compound A:

< / BR>
which is N-(2(R)-hydroxy-1(S)-indanyl)- 2(R)-phenylmethyl-4(S)-hydroxy-5(1-(4-(3-furo[2.3-b] pyridyl - methyl)-2(S)-N'-(tert. -BUTYLCARBAMATE)piperazinil)pentanone, or its pharmaceutically acceptable salt.

Compounds of the present invention have chiral centers, and exist as racemates, racemic mixtures and individual diastereomers or enantiomers, with all isomeric forms are included in this is.

In the case when any variable (for example ) occurs more than one time in any constituent part of compounds or formula I, its designation in each case does not depend on the symbols in any other case. In addition, combinations of substituents and/or variables of fragments permitted only in those cases where such combinations provide a permanent connection.

Used in the text of the description, the term "alkyl", unless otherwise specified, includes both branched and primocane (normal structure) saturated aliphatic hydrocarbon groups containing the indicated number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); used in the text, the term "halogen" denotes fluorine, chlorine, bromine and iodine.

Pharmaceutically acceptable salts of compounds of the formula I (in the form of a water - or oil-soluble or dispersible products) include the conventional nontoxic salts or Quaternary ammonium salt, which receive, for example, from inorganic or organic acids or bases. Examples of such salts accession acids include acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, fumarate, glucoheptonate, glutamate, glycerol, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy - econsultant, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate. Basic salts include ammonium salts, such salts of alkali metals as sodium and potassium; salts of alkaline earth metals as calcium salts and magnesium salts, salts with organic bases, such as salts dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc. additionally, basic nitrogen containing groups may be Quaternary, using such agents as lower alkylhalogenide, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; such diallylsulfide as dimethyl-, diethyl-, dibutil and dimycolate such long chain halides as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, such aralkylated as benzyl and phenetermine, etc., Other pharmaceutically acceptable salts include athanassoula and sulfate salts.

Schemes I-II (see the end of the description) for the schemes to specific compounds.

Reaction of amide combinations used to obtain the compounds of the present invention, typically through carbodiimide method using such reagents as dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Other methods of obtaining an amide or peptide bond include; but are not limited to, synthetic routes via the acid chloride of the acid azide, mixed anhydride or activated ester. Usually carry out a liquid-phase reaction of amide combinations, however, can be used instead of solid-phase synthesis using the classical method of Merrifield. Attaching or removing one or more protective groups is an accepted procedure.

Additional related information entity synthetic methods contained in EPO 0337714 and EPO 0541168.

One method of preparing compounds of formula I are represented by Scheme I. Dihydro-5(S)-(tert. -butyldimethylsilyloxy)- 3(2H)-furanone (compound 1 below) are obtained by standard methods known in this field, from commercially available dihydro-5(S)-(hydroxymethyl)-2(3H)-furanone. After alkylation of compound 1 with the formation of compound 2 protective group of the lactone 2 is wirhout transformation in such a leaving group, as mesilate, toilet or triflate, in the treatment of alcohol chloride sulfonium or (preferably) sulphuric anhydride, for example an anhydride of triftoratsetata, in the presence of such a difficult amine base like triethylamine, diethylethanolamine or 2,6-lutidine, obtaining such compounds as Compound 4. Leaving group of Compound 4 as opposed to Amin 5, such as 4-(1,1 - dimethylethylenediamine)-piperazine-2(S)-carboxamide, in a solvent such as DMF or xylene, with the receipt of such connection, as the connection 6. Tripterocalyx group can substitute for amine at room temperature in a solvent such as isopropanol or methylene chloride, in the treatment with N,N - diisopropylethylamine.

Connection 6 hydrolyzing with aqueous solution of lithium hydroxide or sodium, and the resulting hydroxy acid 7 in turn protected hydroxy acid 8. Hydroxyl group to protect facilities such standard silyl-protecting group as tert.-butyldimethylsilyl or tert-butyldiphenylsilyl.

Protected hydroxy acid 8 further combine with the desired R12Amin with the formation of compound 9, and silyl protective groups which is the synthesis of epoxide 12 by the reaction of 11 in the presence of a strong base. As strong bases can be used metallsoderjasimi base, and the reaction is carried out in an environment of such inert anhydrous organic solvent, such as cyclic or acyclic hydrocarbons, including hexane, pentane, cyclohexane, etc., Suitable strong bases include: LiN/(CH3)3Si/2, KN(CH3)3Si/2, NaN/(CH3)3Si/2, n-utility (n-BuLi), Deut.-BuLi, tert.-BuLi, tert.-butyl potassium, diisopropylamide lithium (LDA), isopropylcyclohexane lithium, pyrrolidin lithium, tetramethylpiperidine lithium finality, chloride Isopropylamine, chloride isobutylene, and other similar strong bases known in the field. Preferred strong bases are n-BuLi, sec. -BuLi, LiN/(CH3)3Si/2 and LDA, and n-BuLi and LiN/(CH3)3Si/2 are the most preferred.

Preferably 1 molar equivalent of compound (11) used 1-2 molar equivalents of a strong base.

The connection 13 to receive the reaction of compound 12 with N-tert.- butyl-4-(1, 1 dimethylethylenediamine)piperazine-2(S) carboxamide (5). Preferably 1-3 molar equivalent of the amine (5) is used in molar equivalent of epoxide 12, and b is but carried out in any suitable solvent, for example in a solvent selected from hydrocarbons such as toluene, such ethers like diethyl ether, alcohols such as methanol, ethanol or isopropanol, NITRILES such as acetonitrile, and such esters as ethyl acetate, or combinations thereof, and alcohols are the most preferred solvents, isopropanol is the preferred solvent. The reaction temperature can be maintained in the range of from ambient to the temperature of reflux distilled solvent used, but it is preferable to conduct the reaction at elevated temperature, for example in the range of 80 - 90oC, most preferably at 83-85oC.

Activated glycidol can be obtained by methods known in this field, as described, for example, in the article J. Klunder with al., J. Org. Chem., 1989, 54, 1295-1304, and in the references cited in this work.

Amide compounds such as compound 11 can be obtained according to standard techniques known to experts in this field, for example by the method of example 10, using the appropriate starting materials.

Protective group, for example a nitrogen protecting group, can be used when it is necessary Samid piperazine may be protected by such a group, as BOC, CBZ, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, triptorelin, trialkylsilyl, and other groups known in this field.

The compound of formula 15

< / BR>
in which P is a nitrogen protecting group, such as BOC or CBZ,

also receive according to the method described in Scheme I, preferably using a 5-triftoratsetilatsetonom analogue of lactone 4.

The compound of formula 16

< / BR>
can be obtained from compound 14

< / BR>
which is obtained after removal of the nitrogen protecting group from compound 15 using methods that are well known in this field, for example by catalytic hydrogenation to remove the CBZ group or treatment trimethylsilyltriflate and 2,6 - lutidine at 0oC in a solvent such as CH2Cl2or by treatment with 6 N HCl in isopropanol in order to remove the BOC group.

The nitrogen in position 4 piperazinil in connection 14 may be proaccelerin compound of formula R1-X in a solvent such as DMF in the presence of Et3N, at room temperature, in the case where X represents Cl, Br or I. Methods such procedures are well known to the specialist in dovedennogo below.

Compounds of the present invention is useful for preparation and conduct of tests for screening of antiviral compounds. For example, the compounds of the present invention is very useful for highlighting enzyme mutants, which are excellent screening tools for more powerful anti-virus connection. In addition, the compounds of the present invention can be used for establishing or determining the binding site of other antiviral agents HIV protease, for example by the method of competitive inhibition. Thus, the compounds of the present invention are commercial products sold for such purposes.

Compounds of the present invention can be used for inhibition of HIV protease, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the subsequent treatment of such pathological conditions as AIDS. The AIDS treatment or prevention, or treatment of HIV infection includes, but is not limited to, treatment of a large number of States of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic nature, as well as acute or potential exposure to HIV action. For example, loadindependent action HIV, for example, through blood transfusion, organ transplant, the replacement of the liquid environment of the body for any signs of bites, accidental needle stick, or exposure to the blood of the patient during surgery.

For these purposes, the compounds of the present invention can be used orally, parenterally (including subcutaneous injections, intravenous, intramuscular, vnutrigodovye injection or infusion), by inhalation spray or rectally in formulations of a single dose, including conventional non-toxic pharmaceutically acceptable carriers, stimulants and auxiliary agents.

Thus, in accordance with the present invention additionally provides a method of treatment and pharmaceutical compositions for the treatment of HIV infection and AIDS. This treatment involves administering to a patient in need of such treatment, a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt.

Such pharmaceutical compositions can be produced in the form of orally applied suspensions or tablets; nasal spree; sterile preparations the ri oral application in the form of suspensions such compositions are prepared according to methods widely known in the field of preparation of pharmaceutical formulation and may contain microcrystalline cellulose for maintenance of weight, alginic acid or sodium alginate as a suspending agent, methylcellulose as an amplifier viscosity and sweetening agents and/or fragrances, known in this area. In the form of tablets immediate allocation of such compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrators, diluents and lubricants known in this field.

When applied as nasal aerosols or by inhalation, such compositions are prepared by methods well known in the field of pharmaceutical formulations, and they can be produced as solutions in saline, using benzyl alcohol or other suitable preservatives, promoters adsorption to enhance bioremediate, fluorocarbons, and/or other solubilizing or dispersing agents known in this field.

Solutions or suspensions for injection can be formulated according to known methods, with the use of the l, water, ringer's solution or isotonic sodium chloride solution or suitable dispersing or wetting and suspendida agents, such as sterile, soft, sustainable oils, including synthetic mono - or diglycerides or fatty acids, including oleic acid.

At rectal administration in the form of candles such compositions can be prepared by mixing the drug with such a non-irritating excipients as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but sigalda and/or dissolve in the rectal cavity emitting medicines.

The dosage levels of the order of 0.02 to 5.0 or 10.0 g/day can be used for treatment or prevention of the above conditions, and oral dosage is 2-5 times higher. For example, HIV infection is effectively treated by the application of 1.0 to 50 mg of compound per kilogram of body weight when taking medications 1-4 times a day. According to one preferred modes of treatment, the dosage is 100-400 mg every 6 hours was applied orally to each patient. However, it should be borne in mind that a particular level of dosage and frequency of medication for each cancro connection the metabolic stability and length of action of this compound, the patient's age, body weight, General health, sex, type and time of administration, rate of excretion, drug combination, the severity of the particular painful condition and the owner, subject therapy.

The present invention also relates to combinations of compounds inhibiting HIV protease, one or more agents used to treat AIDS. For example, the compounds of the present invention can be effectively used as pre-exposure and post-exposure, in combination with effective amounts of the AIDS antiviral agents, immunomodulators, disinfecting agents or vaccines, known to specialists in this field.

It should be borne in mind that the scope of combinations of the compounds of the present invention with AIDS antiviral agents, immunomodulators, anti-infective agents or vaccines is not limited to the list given in the lists at the end of the table, but in principle any combination with any pharmaceutical composition intended for the treatment of AIDS.

Some compounds shown in the table, predstavleniya-2(1H)-he;

Compound C is a(-)-6-chloro-4(S)-trifluoromethyl - 1,2-dihydro-4(H)-3,1-benzoxazin-2-he;

nevirapine is an N-cyclopropyl-5,11-dihydro-4 - methyl-6H-dipyrido/3,2-b:2',3'-e//1,4/diazepin-6-he.

Compounds B and C were synthesized according to the methods of EP 0569083, the contents of which are referenced in this description. Nevirapine synthesized J. M. Klunder with al., Med. Chem., 35, 1887 (1992); argrave K. D. al., J. Med. Chem. , 34, 2231 (1991); Cohen K. A. al., J. Biol. Chem., 260, 14670 (1991), all three works referred to in the present description.

Preferred combinations simultaneously and alternately used in the treatment of inhibitor of HIV protease and non-nucleoside HIV reverse transcriptase inhibitors. An optional third component in combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddC or ddI. A preferred inhibitor of HIV protease is the connection A. the Preferred non-nucleoside HIV reverse transcriptase inhibitors include the connection, the connection C or nevirapine. Such combinations may yield synergistic effects on the spread of HIV. Preferred combinations include:

(1) connection A, together with the preferred non-nucleoside inheritanoe of AZT, ddI or ddC.

Analysis of the inhibition mikrobielle expressed HIV protease

The study of inhibition of the reaction the expression of proteases in Eschericia coli in the presence of peptide substrate (Val - Ser-Gln - Asn-(betanaphthol)Ala-Pro-Ile-Val, 0.5 mg/ml during the initiation of the reaction) was performed in 50 mm Na acetate, pH 5.5 at 30oC for 1 hour. Various concentrations of inhibitor in 1.0 μl of DMSO was added to 25 µl of the peptide solution in water. The reaction was initiated by adding 15 μl of 0.33 nm protease (0.11 ng) in a solution of 0.133 M Na acetate, pH 5.5 and 0.1% bovine serum albumin. The reaction was stopped with 160 ál of 5% phosphoric acid. The reaction products were separated by HPLC method (VVDAC, broad porous, 5 cm C-18 reversible phase, the combined acetonitrile gradient in 0.1% phosphoric acid). The degree of inhibition of the reaction was determined from the peak heights of the products. HPLC independently synthesized products, serving quantitative standards, confirmed the composition of the products. Compound a had the value of the IC50order of 0.27 nm.

Analysis on the distribution of cells

The inhibition of the spread of HIV in cell culture was measured according to the method Nunberg J. H, al., J. Virol. 65, 4887 (1991). B the analysis of the MT-4 T-lymphoma cells infected HIV-1 (wild type, ERUs within 24 hours. By this time, 1% of the cells were positive according to the indirect immunofluorescence assay. The cells are then carefully washed and distributed in the cups for crops with a 96-Yu recesses. In deepening added a serial twofold dilution of the inhibitor and the culture was kept for another 3 days. 4 days after infection, 100% of the cells in the control culture were found to be infected. The accumulation of HIV P24 directly correlated with the spread of the virus. Inhibitory concentration of cell culture was defined as the concentration of inhibitor, expressed in nanomole/liter, which reduces the spread of infection, at least 95%, or it was called CIC95. The CIC value95for compound A was 25 nm.

Inhibition of the spread of the virus.

A. Preparation of suspension cells MT-4, infected with HIV.

MT cells were infected on day 0 with a concentration of 250,000/ ml 1:1000 dilution of HIV-1 strain line IIIb (final concentration 125 PG p24/ml, which is sufficient for the formation of a 1% infected cells on day 1 and 25-100% on day 4). Cells were infected and were grown in the following medium: RPMI (Whittaker Bio-products), 10% inactivated fetal calf serum, 4 mm glutamine (Flexible labs.) 1:100E, containing 5% CO2.

B. Processing inhibitors.

Preparing a matrix of nanomolar concentration range of pairwise combinations. In day 1 of the aliquots in 125 μl of inhibitors were added to equal volumes of HIV-infected MT-4 cells (50,000 per deepening) in micrometrically plate for cell culture 96-Yu recesses. Incubation was continued for 3 days at 37oC in an atmosphere containing 5% CO2.

C. Measuring the spread of the virus.

Using a multichannel pipette precipitated cells resuspendable and 125 µl were collected in separate micrometrically plate. The supernatant was analyzed for the presence of HIV P24 antigen.

The concentration of HIV P24 antigen was measured using enzyme immunoassay described below. Aliquots R24, should be changed, added to microglobuline, coated with a monoclonal antibody specific to the antigen shell HIV. This and other subsequent relevant stages of microglobuline washed. Then added biotinylated HIV-specific antibody, after which was added to the conjugate streptavidin - horseradish peroxidase. When adding hydrogen peroxide and tetramethylbenzidine substrate proceeded printing synergy or enhanced inhibition.

In the presence of a synergistic effect of paired combinations of inhibitors, as was found, show a clearly increased inhibition of the spread of the virus in comparison with the effect of each inhibitor separately or in comparison with a simple additive inhibition of each inhibitor.

The obtained data were processed as follows: fractional inhibitory concentration (FIC) was calculated according to article Elion with TCS. , J. Biol, Chem., 208, 477 (1954). The minimum amount FIC, showing the maximum synergistic effect was determined for different paired combinations. The smaller the number, the higher synergistic effect.

Example 1. Obtaining N-(2(R)-hydroxy-1(S)-indanyl)- 2(R)-phenylmethyl-4(S)-hydroxy)-5-(1-(2(S)-N-(tert. -butyl - carboxamido)piperazinil)-pentanolide, the Connection 14

Stage 1: Getting dihydro-5-(S)-((tert.-butyldiphenylsilyl)- oxymethyl)-3(R)phenylmethyl-3(2H)-furanone.

The solution diisopropylamide lithium (LDA) was obtained by addition of 1.55 ml n-BuLi (2.5 M in hexane) of 0.55 ml (39 mmole) of Diisopropylamine in 10 ml of THF at -78oC. After 30 minutes was added dihydro-5-(S)-((tert.-butyldiphenylsilyl)-oxymethyl)- 3(2H)-furanone (1,38 g, to 3.89 mmole) in 5 ml of THF. After another 30 minutes AC the action was stopped by adding 10% aqueous citric acid solution. The solution was extracted with ethyl acetate (2 x 50 ml), which was subjected to the backwash brine, dried, filtered and concentrated to obtain oil. The product was purified by chromatography (SiO2, 20% EtOAc/ hexane) to give the target compound.

Stage 2: Getting dihydro-5(S)-(hydroxymethyl)-3(R)- phenylmethyl-3(2H)-furanone.

To of 5.26 g of dihydro-5(S)-((tert.-butyldiphenylsilyl)oxymethyl - 3(R)phenylmethyl-3(2H)-furanone in 40 ml of acetonitrile was added to 1.34 ml of 49% aqueous HF. After 18 hours at room temperature the reaction mixture was concentrated to dryness and the residue was distributed between water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with brine, dried, filtered and concentrated to obtain the product as a yellowish brown solid (so pl. 69-72oC).

Stage 3: Getting dihydro-5(S)-((trifloromethyl)- oxymethyl)-3(R)-phenylmethyl-3(2H)-furanone.

To a solution of 18.4 g (89,2 mmole) of dihydro-5(S)-(hydroxymethyl) -3(R)-phenylmethyl-3(2H)-furanone in 350 ml of methylene chloride, cooled to 0oC, was added 13,51 ml of 2,6-lutidine (115,98 mmole), and then bury 16,51 ml triftormetilfullerenov anhydride (98,1 mmole). After 1.5 hours at 0oC reactionable methylene chloride (3 x 150 ml), the organic layers were washed with 10% HCl (2 x 75 ml), saturated NaHCO3(100 ml), water (100 ml), dried over MgSO4, filtered and concentrated to obtain a solid residue. In the purification by chromatography single evaporation (column 120 x 150 mm, gradient elution with mixtures hexane: EtOAc, 4:1-3:1) received the target connection, so pl. 53-54oC.

Stage 4: Obtain 4-(1,1-dimethylethylenediamine)-1- (phenylethylenediamine)-piperazine-2S-carboxylic acid

The target compound was obtained by following the procedure described Bigge, C. F., Hays S. J., Novak, P. M., Drummond, J. T., Johnson Y., Bobovski, T., Tetrahedron Lett, 1989, 30, 5193; using as starting compound 2(S)-piperazinylcarbonyl acid (see E. Felder, Maffei, S., Pietra, S., D. Pitre, Helv, Chim. Acta, 1960, 117, 888.

Stage 5: Obtain N-tert. -butyl-4-(1,1 - dimethylethoxysilane-amino)-1-(phenylethylenediamine) piperazine-2(S)-carboxamide.

To 9.90 g (27,16 mmole) of the product from step 4,dissolved in 75 ml DMF and cooled to 0oC, was added 5.73 g (29,88 mmole) EDS, a 4.03 g (29,88 mmole) HOBt, 3,14 ml (29,88 mmole) of tert.-of butylamine and, finally, to 4.16 ml (29,88 mmole) of triethylamine. The reaction mixture was stirred for 18 hours and the reaction volume was concentrated by half. Then the mixture was diluted with 600 ml E4 and concentrated to obtain a solid substance. This solid was treated with a mixture of EtOAc:hexane (1:2) and filtered to obtain the target compound as white solids; so pl. 134-135oC.

Step 6: Obtain N-tert. -butyl-4-(1,1 - dimethylethylenediamine)piperazine-2(S)-carboxamide.

To 1.20 g (2.86 mmole) of N-tert.-butyl-4-(1,1 - dimethylethylenediamine)-1-(phenylethylenediamine)piperazine-2-(S) - carboxamide and 1.1 g (0,086 mmole) and 10% Pd/C was added 15 ml of methanol. Into a reaction vessel were introduced hydrogen and the reaction mixture was stirred for 2 hours, filtered through celite and washed with ethanol. The solvents were removed in vacuo to obtain the desired product in the form of foam.

Range1H-NMR (300 MHz, CDCl3) : of 6.65 (broad band, 1H), 4.10 (multiplet, 1H), 3.81 (broad band, 1H), 3.21 (double doublet, J = 18 and 7 Hz), 3.02-2.70 (multiplet, 4H), 2.10-2.0 (broad, 1H), 1.50 (singlet, 9H), 1.41 (singlet, 9H).

Stage 7: Getting dihydro-5(S)-(4-(1,1 - dimethylethylenediamine)-2(S)-N-(tert. -BUTYLCARBAMATE) -piperazinil)methyl)-3(R)-phenylmethyl-3(2H)-furanone.

To a solution of 22,40 g (0,0662 mol) of dihydro-5(S)- ((trifloromethyl)oxymethyl)-3-(R)-phenylmethyl-3(2H)-furanone (obtained in stage 3) and 18,0 is propanol, added 11,53 ml (0,062 mole) of N,N-diisopropylethylamine. After 2.5 hours, was added to 1.2 g of dihydro-5(S)-(trifloromethyl)oxymethyl)-3(R)- phenylmethyl-3(2H)-furanone. The reaction mixture was analyzed by thin layer chromatography (TLC) after 3.5 hours and concentrated to state a thick oil. As a result of processing a mixture of EtOAc/hexane (1:2, 200 ml) was obtained white solid, which was filtered and discarded. The oil was purified by the method of column chromatography flash evaporation (column h mm, gradient elution with mixture of EtOAc/hexane 1:1, 2:1, 3:1 up to 100% of the contents EtOAc) to give the target compound.

Range1H-NMR (400 MHz, CDCl3) : 7.34-7.17 (multiplet, 5H), 6.31 (broad singlet, 1H), 4.38 (broad multiplet, 1H), 3.96-3.92 (multiplet, 1H), 3.79 (broad multiplet, 1H), 3.16 (double doublet, J = 13,6 and 4.4 Hz, 1H), 3.08-2.99 (multiplet, 3H), 2.90-2.82 (multiplet, 1H), 2.80 (double doublet, J=13.5 and 8.9 Hz, 1H), 2.78 (multiplet, 1H), 2.67-2.61 (multiplet, 1H), 2.58-2.49 (multiplet, 1H), 2.38-2.32 (multiplet, 1H), 2.32-2.04 (multiplet, 1H), 1.99-1.92 (multiplet, 1H), 1.45 (singlet, M), 1.29 (singlet, 9H).

Step 8: Obtain 2(R)-phenylmethyl-4(S)-(tert.- butyldimethylsilyloxy)-5-(1-(4-(1,1-di methylethanolamine)))-2(S)-N-(tert. - BUTYLCARBAMATE)-piperazinil)-Pintado)piperazinyl)-methyl-3(R)-phenylmethyl-3(2H)- furanone, dissolved in 120 ml of DMF, cooled to 0oC, the solution was added 60 ml of water and 1,512 g (63,01 mmole) of lithium hydroxide. After 0.5 hours the reaction was stopped by adding 10% HCl to pH 6 and the solution was concentrated in vacuum. The residue was dissolved in 50 ml of water and was extracted with EtOAc (4 x 75 ml) and the organic layers were washed with water (1 x 20 ml), brine (1 x 20 ml). The aqueous layer was subjected to back extraction with EtOAc (2 x 75 ml) and the combined organic layers were dried over MgSO4and concentrated to obtain a yellow solid. This crude product was dissolved in 100 ml of DMF and added 17,87 g (0,262 mole) of imidazole, was cooled to 0oC and then added 31,50 g (of 0.21 mol) chloride, tert.- butyldimethylsilyl. The resulting mixture was stirred for one hour at 0oC and then heated to room temperature. After 20 hours the reaction was stopped with 10 ml of methanol and the reaction mixture was concentrated to half volume. Added 100 ml of buffered water with a pH of 7 and the aqueous layer was extracted with EtOAc (4 x 100 ml), the combined organic layers were washed with 10% HCl (2 x 50 ml), water (3 x 75 ml) and brine (1 x 50 ml), dried over MgSO4and concentrated to obtain the target compounds. The resulting material was directly used for the next stud is-(4-(1,1 - dimethylethylenediamine)))-2(S)-N-(tert.-BUTYLCARBAMATE) -piperazinil)-pentanolide.

To 27,0 g (0,0446 mole) of the crude material from step 6, dissolved in 180 ml of DMF and cooled to 0oC, was added 8,98 g (0,0468 mole) of EDC, 6,32 g (0,0468 mol) and HOBt 7,31 g (0,049 mole) of aminohydrocinnamic. Was added triethylamine (6,52 ml, 0,0468 mol) and the reaction mixture was stirred for 2 hours at 0oC, at room temperature for 16 hours, and the reaction was stopped by diluting 500 ml of EtOAc. The organic layer was washed with 10% HCl (2 x 100 ml), saturated NaHCO3(1 x 100 ml), water (3 x 150 ml), brine (1 x 75 ml), dried over MgSO4and concentrated to obtain the target compound as a white foam.

1H-NMR (400 MHz, CDCl3) : 7.4-7.17 (multiplet, 9H), 6.51 (broad singlet, 1H), 5.79 (broad singlet, 1H), 5.23 (multiplet, 1H), 4.23 (broad singlet, 1H), 4.06 (multiplet, 1H), 3.96-3.84 (multiplet, 2H), 3.07-2.78 (multiplet, 8H), 3.65 (double doublet, J= 9.6 and 4.1 Hz, 1H), 2.56-2.44 (multiplet, 2H), 2.29 (double doublet, J=12.0 and 4.5 Hz, 1H), 2.17-2.09 (multiplet, 1H), 1.79 (broad singlet, 1H), 1.44 (singlet, 9H), 1.35 (singlet, 9H), 1.10 (singlet, 2H), 0.84 (singlet, 9H), 0.12 (singlet, 3H), 0.08 singlet, 3H).

Step 10: Obtain N-(2(R)-hydroxy-1(S)-indanyl)- 2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(4-(1,1-dimethyl - ethoxycarbonyl)))-2(S)-N-(tert. -BUTYLCARBAMATE) piperazinil)-pentanolide.

To 32,20 Ebonyline))-2(S)-N-(tert. -BUTYLCARBAMATE)- piperazinil))-pentanolide added 437 ml (0,437 mole) tetrabutylammonium fluoride (1.0 M solution in THF, Aldrich). The reaction mixture was stirred for 18 hours and then concentrated to a volume of 200 ml and diluted with 700 ml of EtOAc. The resulting solution was washed with water (2 x 100 ml), brine (1 x 50 ml) and the aqueous layers were subjected to back extraction with EtOAc (2 x 200 ml). The combined organic layers were dried over MgSO4and concentrated to a oil. In the purification by chromatography flash evaporation (column h mm, gradient elution with a mixture of CH2Cl2:CHCl3rich mixture of NH3:methanol, with increasing amounts of methanol in the range of 1%, 1,5%, 2%) was obtained target compound as a white foam.

Range1H-NMR (400 MHz, CDCl3) : 7.31-7.11 (multiplet, 9H), 6.41 (broad singlet, 1H), 6.23 (doublet, J=8.6 Hz, 1H), 5.25 (double doublet, J= 8.6 and 4.7 Hz, 1H), 4.21 (multiplet, 1H), 3.83-3.82 (multiplet, 2H), 3.78-3.61 (multiplet, 2H), 3.22-3.19 (multiplet, 2H), 3.03-2.78 (multiplet, 8H), 2.62-2.58 (multiplet, 1H), 2.41-2.35 (multiplet, 2H), 2.04-2.02 (multiplet, 1H), 1.57-1.50 (multiplet, 1H), 1.45 (singlet, 9H), 1.32 (singlet, 9H).

Stage 11: Obtain N-(2(R)-hydroxy-1(S)-indanyl)- 2(R)-phenylmethyl-4(S)-(hydroxy)-5-(1-(2(S)-N-(tert. - butylcarbamoyl-4(S)-(hydroxy)-5-(1-(4-(1,1-dimethylmethoxy - carbylamine))-2(S)-N-(tert.-BUTYLCARBAMATE)- piperazinil))-pentanolide, dissolved in 350 ml of methylene chloride and cooled to 0oC, was added 22,43 ml (0,204 mole) of 2,6-lutidine and then 32,85 ml (0,170 mole) of trimethylsilyltriflate within 5 minutes. After 0.5 hours the reaction was stopped with 10% HCl (80 ml) and the resulting mixture was stirred for 0.5 hour. To the mixture was added 100 ml of saturated NaHCO3and then solid NaHCO3to pH 8. Then the aqueous layer was extracted with EtOAc (4 x 100 ml) and the combined organic layers were washed with water (1 x 50 ml), brine (1 x 75 ml), dried over MgSO4and concentrated. The residue was purified by the method of column chromatography (CH mm, gradient elution with a mixture of CH2Cl2:CHCl3rich mixture of NH3:MeOH, slowly increasing the concentration of methanol in the range of 2%, 3%, 4%, 5%, 6% and up to 10%). The result is received, the target product as a white foam.

Range1H-NMR (400 MHz, CDCl3) : 7.53 (singlet, 1H), 7.29-7.09 (multiplet, 9H), 6.52 (doublet, J=1.83 Hz, 1H), 5.24 (double doublet, J=1.82 and 4.9 Hz, 1H), 4.23 (double doublet, J= 4.7 and 4.03 Hz, 1H), 4.25-4.00 (broad singlet, 1H), 3.83-3.81 (multiplet, 1H), 3.03-2.88 (multiplet, 4H), 2.82-2.73 (multiplet, 7H), 2.50 - 1.60 (broad singlet, 2H), 2.45 (doublet, J= 6.2 Hz, 2H), 2.32-2.29 (multiplet, 1H), 1.98 (multiplet, 1H), 1.51 (multiplet, 1H), 1.33 (singlet, 9H).

Example 2. Proximodo) - piperazinil))-pentanolide

Stage 1: Receive (furo[2,3-b]-piperidin-2,5 - dicarboxylic acid

< / BR>
To the solution is known (H. R. Snyder, F. F. Ebetino, J. Het. Chem., 1, 202-205 are (1966) diethyl-(furo-[2,3-b] pyridine-2,5-in primary forms (1.22 g, 4,923 mmole) in 10 ml of 95% ethanol was added a solution of potassium hydroxide (0.66 g, 11,81 mmole) in 10 ml of water. The reaction mixture was heated for 3 hours to 80oC, cooled to room temperature and filtered. Dvuhkletevogo salt was dissolved in water and acidified with 10% HCl to pH 2. The precipitate was filtered and dried in vacuum to obtain 850 mg of a white solid.

Range 1H-NMR (400 MHz, (CD3)2SO) : 8.98 (doublet, J=2.2 Hz), 8.76 (doublet, J=2.2 Hz), 7.69 (singlet, 1H), 4.25 (broad singlet, 3H).

Stage 2: Getting furo[2,3-b]pyridine-5-carboxylic acid

< / BR>
To a suspension of furo[2,3-b]pyridine-2,5-dicarboxylic acid (0.36 g, 1,484 mmole) in 3 ml of quinoline, in an atmosphere of Ar was added powdered copper (180 mg, 2,82 mmole) and the reaction mixture was heated for 1.5 hours to 210oC. the Reaction mixture was cooled to room temperature and diluted with 50 ml methylene chloride and filtered through celite. The organic layer was extracted with a saturated solution (2 x 40 ml) Na2CO3acidified to pH 3 with the Vali with a mixture of ether/methanol (85/15) (x ml) and washed with brine (1 x 10 ml), dried over MgSO4was filtered and concentrated to obtain 35 mg of the product.

Range1H-NMR (400 MHz, CD3OD) 8.89 (singlet, 1H), 8.67 (doublet, J=2.0 Hz, 1H), 7.97 (doublet, J=2.5 Hz, 1H), 7.01 (doublet, J=2.4 Hz, 1H).

Stage 3: Obtaining methyl-furo-[2,3-b]pyridine-5 - carboxylate.

< / BR>
To furo-[2,3-b] pyridine-5-carboxylic acid (3.0 g, is 18.40 mmole), dissolved in 40 ml of methanol, was added 160 ml of chloroform and then was slowly added trimethylsilyldiazomethane (42 ml, 10% solution of hexene). After 0.5 hours was added 4 drops of glacial acetic acid and the reaction mixture was concentrated. The result has been 3,20 g of a white solid.

Range 1H-NMR (400 MHz, CDCl3) / : 9.02 (doublet, J=2.0 Hz, 1H), 8.60 (doublet, J=2.0 Hz, 1H), 7.9 (doublet, J= 2.5 Hz, 1H), 6.87 (doublet, J=2.5 Hz, 1H), 3.98 (singlet, 3H).

Stage 4: Getting 5-hydroxymethyl-furo[2.3-b]pyridine.

< / BR>
In a flame-dried 500 ml round bottom flask was loaded methyl-furo-[2,3-b] pyridine-5-carboxylate (3,20 g, 18,08 mmole), dissolved in THF and cooled to 0oC. To the resulting solution was added diisobutylaluminium hydride (46 ml 46,1 mmole, 1 M solution in hexano) for 10 minutes and the cooling bath was removed. After 4 hours the reaction mixture kladny layer was extracted with ethyl acetate (4 x 40 ml). The combined organic layers were washed with brine (1 x 20 ml), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography flash evaporation (column h mm, gradient elution CH2Cl2:CHCl3filled with a mixture of NH3:MeOH ratio 60-39-1,0 (1000 ml), 60:38:2 (1000 ml), 60-37-3 (1000 ml), 60-36-4 (1000 ml). The result obtained 2.16 g of a white solid.

Range1H-NMR (400 MHz, CDCl3) : 8.19 (doublet, J=2.0 Hz, 1H), 7.92 (doublet, J= 2.0 Hz, 1H), 7.64 (doublet, J= 2.5 Hz, 1H), 6.69 (doublet, J=2.4 Hz, 1H), 4.78 (doublet, J=3.8 Hz, 2H), 4.69 (broad singlet, 1H).

Stage 5: obtain the hydrochloride of 3-chloromethyl-furo[2,3-b] pyridine.

< / BR>
To a solution of 5-hydroxymethyl-furo[2,3-b] pyridine, dissolved in 9 ml of methylene chloride, cooled to 0oC, was added chloride thionyl (to 4.23 ml, 57,99 mmole). The ice bath was removed and after 1 hour the reaction mixture was concentrated to obtain 2.86 g of white solid.

Range1H-NMR (400 MHz, CDCl3) : 8.40 (doublet, J=2.0 Hz, 1H), 8.13 Doublet, J= 2.2 Hz,1E), 7.80 (doublet, J=2.4 Hz, 1H), 6.86 (doublet, J=2.4 Hz, 1H), 4.74 (singlet, 2H).

Step 6: Obtain N-(2(R)-hydroxy-1(S)-indanyl)-2(R)- phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-furo[2,3-b] pyridylmethyl) - 2(S)-N'-(tert.-butyl - 4(S)-hydroxy-5(-2(S)-N'-(tert.-BUTYLCARBAMATE)-piperazinil - pentanolide (6.50 g, 12,48 mmole), dissolved in 12 ml of dimethylformamide in an argon atmosphere, was added 3-chloromethylene [2.3-b]pyridine hydrochloride (2,80 g, 13,72 mmole) and triethylamine (total of 5.21 ml, 38.44 mmole). After 18 hours the reaction mixture was diluted with 400 ml ethyl acetate and washed with saturated NaHCO3(1 x 25 ml), water (5 x 20 ml) and brine (1 x 25 ml).

The resulting solution was dried over MgSO4, filtered and concentrated to a oil. The residue was purified by chromatography flash evaporation (column h ml, gradient elution with a mixture of CH2Cl2:CH2Cl2rich mixture of NH3:MeOH in a ratio of 60:39:1 (1000 ml), 60:38:2 (1000 ml), 60:37:3 (1500 ml), 60:36:4 (1500 ml). The resulting foam was treated with ethyl acetate and the desired product was filtered and dried overnight in high vacuum at 65oC to obtain 5.30 g of a white crystalline solid. Mixed fractions from the chromatographic column can be combined and subjected to repeated cleaning with additional quantity of the product, so pl. 183,5-184,5oC.

Range1H-NMR (400 MHz, CDCl3) : 8.25 (doublet, J=2.2 Hz, 1H), 7.85 (doublet, J= 2.0 Hz, 1H), 7.5 (singlet, 1H), 7.73 (doublet, J=2.4 Hz, 1H), 7.32-7.10 (multiplet, 9H),6.75 (doublet, J=2.4 Hz, 1H), 5.95 (Dubl.51 (singlet, 2H), 3.29 (double doublet, J=17.5 and 4.0 Hz, 1H), 3.16 (double doublet, J= 3.36 and 3.48 Hz, 1H), 3.15 (double doublet, J=6.6 and 5.1 Hz, 1H), 2.94-2.50 (multiplet, 11H), 2.36-2.34 (multiplet, 1H), 1.66 (singlet, 1H), 1.62-1.47 (multiplet, 1H), 1.35 (singlet, 9H).

Elemental analysis: calculated for C38H47N5O5< / BR>
C 69.81, H 7.25. N 10.71;

Found: C, 69.46, H 7.22, N, 10.69.

Example 3.

Using almost the same technique as described in example 2, but carrying out the reaction between N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(2(S)-N'-(tert. BUTYLCARBAMATE)piperazinil))-pentanediol used in this example (compound (1), see below), and an alkylating agent (11) below, instead of the alkylating agent used in stage 6, received the following products of formula (III), see the end of the description.

Example 4. Getting amide I (see the end of the description).

A solution of (-)-CIS-1-aminoindan-2-ol (884 g, to 5.93 mol) 17.8 l dry THF (KF= 55 mg/ml) (KF denotes the titration of water by Karl-Fischer) and triethylamine (868 ml, 6.22 per mole) in 50 l round bottom flask, equipped with a pocket for a thermocouple, a mechanical stirrer, a device for input of nitrogen and bubbler, was cooled to 15oC. Then, in the course of 75 minutes was added 3-phenylpropylamine (1000 g, 5,93 mol ice water. After complete addition, the mixture was allowed to age at 18-20oC for 30 minutes and using the analysis method HPLC tested disappearance (2)-CIS-1-aminoindan-2-ol.

The reaction course was monitored by chromatography high resolution: 25 cm column DuPont C8-RX 60-40 acetonitrile/10 mm (KH2PO4/K2HPO4), 1.0 ml/min, injected volume = 20 ml, detection = 200 nm, sample preparation: dilute 500 times. The approximate retention times:

< / BR>
The reaction mixture was treated with p-toluensulfonate pyridinium (241 g of 0.96 mol, 0.16 equivalents) and stirred for 10 minutes (pH of the mixture after diluting 1 ml of the sample an equal volume of water was $ 4.3 to 4.6). Then added 2-methoxypropene (1,27 l, 13,24 mol, 2.2 equivalents) and the reaction mixture was heated to 38-40oC for 2 hours. The reaction mixture was cooled to 20oC and distributed between ethyl acetate (12 l) and 5% aqueous solution of NaHCO3(10 l). The mixture was stirred and the layers were separated. An ethyl acetate extract washed with 5% aqueous solution of NaHCO3(10 l) and water (4 l). An ethyl acetate extract was dried by distillation at atmospheric pressure, and the solvent was changed to cyclohexane (total volume ~ 30 l). After the end of the distillation and concentration (volume what izala of the reaction product. The resulting suspension was further cooled to 10oC and gave her age. The reaction product was isolated by filtration and the wet precipitate on the filter was washed with cold (10oC) cyclohexane (2 x 800 ml). The washed precipitate on the filter was dried under vacuum (26" H; approximately 66 mm RT.CT.) when 40oC obtaining 1.65kg acetonide 1 (86,4%, 98% of the area, according to HPLC).

Range 1H-NMR (300.13 MHz, CDCl3the main rotamer) : 7.36-7.14 (multiplet, 9H), 5.03 (doublet, J=4.4 Hz, 1H), 4.66 multiplet, 1H), 3.15 (multiplet, 2H), 3.06 (broad singlet, 2H), 2.97 (multiplet, 2H): 1.62 (singlet, 3H), 1.37 (singlet, 3H);

13C-NMR (75.5 MHz, CDCl3the main rotamer)c: 168.8, 140.9, 140.8, 140.6,128.6, 128.5, 128.4,127.1, 126.3, 125.8, 124.1, 96.5, 78.6, 65.9, 38.4, 36.2, 31.9, 26.5, 24.1.

Elemental analysis: calculated for C21H23NO2< / BR>
C 78.47, H 7.21, N 4.36;

Found; 78.65, H 7.24, N 4.40.

Example 5. Getting epoxide 3

< / BR>
A solution of acetonide 1 (1000 g, 3,11 mole) and 2(S)-glycidylmethacrylate 2 (853 g, 3,74 mol, 1.2 equivalents) in 15.6 liters THF (KF=22 mg/ml) in 50 l chetyrehkolkoy round bottom flask equipped with a thermocouple, mechanical stirrer, addition funnel and adapter for input of nitrogen, three degirolami, creating a vacuum and by purging with nitrogen, and the resulting cm is i/2) (2.6 liters, to 1.38 mol, 1.15 equivalents), supporting adding the temperature inside the flask in the range of -50 - -45oC. Then the reaction mixture was stirred for 1 hour at -45 to -40oC and gave it to warm to -25oC for 1 hour. The mixture was stirred for 4 hours at -25 to -22oC (or until until the original acetonide was not to 3.0% of the area).

Over the course of the reaction was monitored using HPLC analysis: column ZORBAX silicon Oxide, size 25 cm x 4,6 nm, 20% ethyl acetate in hexane, 2.0 ml/min, injected volume = 20 ml, detection = 254 nm, sample preparation = 100-fold dilution. The approximate retention times:

Retention time (min) - Identification

5,5 - amide 1

6,5 - glycidylether 2

13,5 - epoxide 3

The reaction mixture was treated with deionized water (6.7 l) at -15oC and was treated with ethyl acetate (10 l). The mixture was stirred and the layers were separated. An ethyl acetate extract was washed with a mixture of 1% aqueous solution of NaHCO3(5 l) and saturated NaCl solution (0.5 l). An ethyl acetate extract (28.3 l) was concentrated by vacuum distillation (28" Hg; 71,1 mm RT.CT.) and added an additional amount of ethyl acetate to replace ethyl acetate solvent to the (final volume = 11,7 l). In an ethyl acetate to echnolo the volume of 3.2 liters Remaining an ethyl acetate solvent was removed by loading 10 l of methanol and collecting 10 l of distillate. The resulting suspension was stirred for 1 hour at 22oC, then cooled to 5oC and has been aging for 0.5 hours. The product was isolated by filtration and the wet precipitate on the filter was washed with cold methanol (2 x 250 ml). The washed precipitate on the filter was dried under vacuum (26" of Hg; about 66 mm RT.CT.) at 25oC with getting 727 g of epoxide 3 (61,2%, 98.7 per cent of the area of the main epoxide, according to HPLC).

13C NMR (300 MHz, CDCl3) : 171.1, 140.6, 140.5, 139.6, 129.6, 128.8, 128.2, 127.2, 126.8, 125.6, 124.1, 96.8, 79.2, 65.8, 50.0, 48.0, 44.8, 39.2, 37.4, 36.2, 26.6, 24.1

Example 6. Getting penultimate 6 (see the end of the description).

A suspension of 2(S)-tert. -BUTYLCARBAMATE-4-N-BOC-piperazine 4 (1950. g, 6,83 mole, > 99.5%of EE) (ee = enantiomeric excess) and epoxide 3 (2456 g, the mixture ratio of 97.5: 2.5 epoxides 4 S/R, 6,51 mole) in isopropanol (2-propanol, 18,6 l), placed in a 72 l round bottom flask with four inlet holes, equipped with a mechanical stirrer, condenser phlegmy, steam bath, covered with a Teflon thermocouple and inlet for nitrogen, was heated until the beginning of reflux distilled (internal temperature 84-85oC). After 40 minutes were formed g is de reflux distilled was 84-85oC. the reaction course was monitored by analysis using HPLC: 25 cm column DuPont C8-BC, is the ratio of acetonitrile/10 mm (KH2PO4/K2HPO460:40, 1.0 ml/min detection = 220 nm, preparation of sample: 2 μl, the reaction mixture was diluted to a volume of 1 ml with acetonitrile. The approximate retention times:

Retention time (min) - Assignment

4,8 - piperazine 4

8,9 - epoxide 3

15,2 - product of the combination of 5

After 28 hours remaining epoxide 3 and the product of the combination of 5 (according to HPLC data) amounted to 1.5% of the area and 91-93% of the area respectively. The mixture was cooled to 0-5oC and added to 20.9 l 6 NHCl, maintaining the temperature below 15oC. After complete addition, the mixture was heated to 22oC. At this point was observed gas (isobutylene). The mixture was allowed to age at 20-22oC for 6 hours.

Over the course of the reaction was monitored by HPLC method: using the same conditions that were described above. The approximate retention times were as follows:

Retention time (min) - Assignment

7,0 - CIS-aminoindane

11,9 - penultimate 6

15,1 - product of the combination of 5

The mixture was cooled to 0 C and slowly added 7.5 l of 50% NaOH solution to establish a pH of the mixture at pH 11.6, support (3 years). The mixture was stirred and the layers were separated. The organic phase (60 l) was concentrated under reduced pressure (29" Hg; 73,7 mm RT.CT.) and the solvent was replaced with DMF and the resulting mixture was concentrated to a final volume of 10.5 l (KF = 1.8 mg/ml). According to HPLC analysis, the output connection 6 in ethyl acetate was 86,5%. Connection 6 in DMF directly used in the next stage without additional purification. For the selected connection 6:

13C NMR (75,4 MHz, CDCl3) : 175.2, 170.5, 140.8, 140.5, 139.9, 129.1, 128.5, 127.9, 126.8, 126.5, 125.2, 124.2, 73.0, 66.0, 64.8, 62.2, 57.5, 49.5, 47.9, 46.4, 45.3, 39.6, 39.3, 38.2, 28.9

Example 7. Pyrazin-2-tert.-BUTYLCARBAMATE 9

< / BR>
2-Pyrazinecarboxamide acid (8) - 3.35 kg (27 mmol)

Chloride, oxalyl - 3.46 kg (27,2 mol)

Tert.-butylamine (KF = 460 µg/ml) - 9,36 l (89 moles)

EtOAc (KF = 56 ág/ml) - 27 l

DMF - 120 ml

1-Propanol - 30 l

Carboxylic acid, 8 suspended in 27 l of EtOAc and 120 ml of DMF in a 72-liter three-neck flask, equipped with a mechanical stirrer, in an atmosphere of N2and the suspension was cooled to 2oC. Chloride, oxalyl was introduced into the system, maintaining the temperature in the range of 5-8oC.

The addition was completed within 5 hours. In the course of an exothermic adding stood out CO and CO2. Was obrazovni HCl-salt of the acid chloride pyrazinoic acid. Analysis on the formation of carboxylic acids was performed by quenching the anhydrous sample of the reaction mixture of tert.-- butylamine. After completion of the reaction was less than 0.7% of the acid 8.

Analysis on the completeness of the formation of the carboxylic acid is important because incomplete reaction leads to the formation of impurities bis-tert.-butylacetamide.

Over the course of the reaction can be monitored by HPLC method: column DuPont ZORBAX RXC8 dimensions 25 cm, flow rate 1 ml/min and detection at 250 nm; linear gradient from 98% a 0.1% aqueous solution of H3PO4and 2% CH3CN to 5% aqueous solution of H3PO4and 50% of CH3CN for 30 minutes. The retention times: acid 8 = 10,7 min, amide 9 = 28,1 minutes

The reaction mixture was allowed to age for 1 hour in 5oC. the resulting suspension was cooled to 0oC, was added tert.-butylamine with such a rate as to maintain the temperature within the reactor below the 20oC.

Add requires 6 hours if the reaction was strongly exothermic. A small portion of the formed hydrochloride tert.- butylamine taken out from the reaction system in the form of a fluffy white solid.

The mixture gave a stare is mawali 12 l of EtOAc. The combined organic phases were washed with 6 l of 3% NaHCO3and HL saturated aqueous NaCl. The organic phase was treated with 200 g of carbon Darko 60 G and filtered through Solka the Flock and the filter cake was washed with 4 l of EtOAc.

Processing carbon effectively removes the purple color of the product.

A solution of compound (9) in EtOAc was concentrated at a pressure of 10 mbar to 25% of the original volume. Added 30 l of 1-propanol and the distillation continued to a final volume of 20 L.

At this point, the amount of EtOAc was, a value below the limit of detection method1H-NMR (< 1%). The internal temperature of this solvent exchange was the value of < 30oC. Solution of 1-propanol/EtOAc compound 3 was stable until the beginning of reflux distilled at atmospheric pressure for several days.

Evaporation of an aliquot gave a yellowish-brown solid, so pl. 87-88oC.

13C NMR (75 MHz, CDCl3, h/million): 161.8, 146.8, 154.0, 143.8, 142.1, 51.0, 28.5

Example 8. rat-2-tert.-BUTYLCARBAMATE piperazine 10.

< / BR>
Materials:

Pyrazin-2-tert. BUTYLCARBAMATE 9 2.4 kg (23,4 mol) in a solution of 1-propanol 12 l 20% Pd(OH)2/C 16 wt%, water 144,

The solution pyrazin-2-tert.-was butylcatechol at 65oC and a pressure of H240 lb/in2(3 ATM).

After 24 hours the reaction mixture was absorbed theoretical amount of hydrogen and method GC showed the presence of < 1% of compound (9). The mixture was cooled, purged with N2and the catalyst was removed by filtration through Solka Flock. The catalyst was washed with 2 liters of hot 1-propanol.

It was found that the use of warm 1-propanol in the course of washing the precipitate on the filter improves filtration and reduces the loss of product from the precipitate on the filter.

Over the course of the reaction was monitored by GC method: column Megabar length of 30 m, the programming temperature in the range of 100-160oC at a rate of 10oC/min, excerpt 5 minutes, then temperature rise to 250oC at a rate of 10oC/min, retention time: compound 9 = 7.0 minutes, the connection 10 = 9.4 minutes. Over the course of the reaction can also be monitored by TLC using EtOAc/MeOH (50:50) as solvent and ninhydrin as a showing agent.

Evaporation of an aliquot showed that the yield during the amidation and the hydrogenation was 88% and the concentration of compound 10 was 133 g/l

In the evaporation of an aliquot received compound 10 as a white solid, with face to face.-BUTYLCARBAMATE bis(S)camphorsulfonate 11.

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Materials:

rat-2-tert. -BUTYLCARBAMATE-piperazine 10 in a solution of 1-propanol - 4,10 kg (22,12 mole) of 25.5 kg of solvent

(S)-(+)-10-camphorsulfonate - 10,0 kg (43,2 mol)

1-propanol - 12 l

Acetonitrile - 39 l

Water - 2,4 l

A solution of amine 10 in 1-propanol were loaded into a 100 l flask fitted with a centrifuge (concentrator) periodic action. The solution was concentrated under a pressure of 10 mbar and at a temperature < 25oC to a volume of about 12 liters

At this point, the product was precipitated from solution, but came back into solution by heating the mixture to 50oC.

Analysis of homogeneous aliquot showed that the concentration of compound 10 was 341 g/l Concentration was determined by HPLC method: column DuPont ZORBAX PXC8 length 25 cm, feed rate 1.5 ml/min, detection at a wavelength of 210 nm, isocratic (98/2) CH3CN/0.1% aqueous solution of H3PO4. The retention time of compound (10: 2.5 minutes.

Added acetonitrile (39 l) and water (2.4 l) the formation of clear, slightly brownish solution.

Determination of water content (KF) titration and the ratio of CH3CN/1-propanol integrating data1H-NMR showed that the ratio of CH3CN /1-proph were loaded for 30 minutes 4 servings at 20oC. Before adding CSA temperature was increased to 40oC. After a few minutes had formed a viscous white precipitate. The white suspension was heated to 76oC to dissolve all solids, then slightly brownish solution for 8 hours, cooled to 21oC.

The product was precipitated with 62oC. the Product was filtered without aging at the 21oC and the filter cake washed with 5 l of a solvent mixture of CH3CN /1-propanol/H2O in the ratio 26/8/1,6. The obtained solid substance was dried at 35oC in a vacuum furnace with a supply of N2with the formation of 5.6 kg (39%) of compound 11 as a white crystalline solid, so pl. 288-290oC (decomposition).

[]2D5= 18,9o(c = 0.37, H2O).

13C NMR (75 MHz, D2O, h/million): 222.0, 164.0, 59.3, 54.9, 53.3, 49.0, 48.1, 43.6, 43.5, 43.1, 40.6, 40.4, 28.5, 27.2, 25.4, 19.9, 19.8

Value "ee" material was 95% according to the following chiral HPLC analysis: an aliquot of compound (11) (33 mg) suspended in 4 ml of EtOH and 1 ml Et3N. was Added Boc2About (11 mg) and the reaction mixture was allowed to age for 1 hour. The solvent was completely removed in vacuo and the residue was dissolved, about 1 ml of EtOAc, and filtered through a Pasteur pipette through the x in the amount of 1 mg/ml The enantiomers were separated on a column of Diesel Chiracel AS using the solvent system hexane/IPA (97: 3) at a flow rate of 1 ml/min, while detection at 228 nm. The retention times: S the antipode = 7.4 minutes, R = 9.7 minutes.

Example 10. (S)-2-tert.-Butylcarbamoyl-4-tert.- butoxycarbonyl-piperazine 4 of salt 11.

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Materials;

(S)-2-tert. -BUTYLCARBAMATE-pieperazinove Bis(S)- (+)-CSA salt 11, 95% of it is 5.54 kg (8,53 mol)

Di-tert.-BUTYLCARBAMATE - 1.86 kg (8,53 mol)

Et3N - 5,95 l (42,6 mol)

EtOH, fortress 200 - 55 l

EtOAc - 2 l

To (S)-CSA salt 11 in a three-neck flask with a capacity of 110 liters, equipped with a dropping funnel, in an atmosphere of N2added EtOH, then at 25oC was added triethylamine. The solid is easily dissolved by adding Et3N. Boc2O was dissolved in EtOAc and loaded into the addition funnel. A solution of Boc2O in EtOAc was added in such a rate as to maintain the temperature below 25oC. the Addition was continued for 3 hours. The reaction mixture was allowed to age for 1 hour after complete addition, a solution of Boc2O.

Over the course of the reaction can be monitored by the method HPL: column DuPont ZORBAX RHS at a feed rate of 1 ml/min, detection at. 228 nm, isok the unity 4 = 7.2 minutes. Chiral analysis was performed using the same system as on the previous stage. Over the course of the reaction can also be monitored using TLC method, using as a solvent a 100% EtOAc (Rf= 0,7).

Then the solution was concentrated to a volume of approximately 10 liters when the internal temperature < 20oC in a centrifuge (concentrator) periodic actions in vacuum with a pressure of 10 mbar. Replacement of the solvent was completed by adding 20 l of EtOAc and reconcentrating to volume of 10 L. the Reaction mixture was washed in the extractor with 60 l of EtOAc. The organic phase is washed with 16 l of 5% aqueous solution of Na2CO3, 2 x 10 l of deionized water and 2 x 6 l of a saturated aqueous solution of sodium chloride. The combined aqueous leaching liquid was subjected to back extraction with 20 l of EtOAc and the organic phase was washed 2 x 3 l of water and 2 x 4 l of saturated aqueous solution of sodium chloride. The combined EtOAc extracts were concentrated in vacuum at a pressure of 10 mbar, at a temperature within the reaction vessel > 20oC in the centrifuge periodic operation with a capacity of 100 liters, up to a capacity of about 8 liters of Replacement solvent to cyclohexane was carried out by slow addition of about 20 l of cyclohexane and re-conc is, the hen all content passed into the solution. The solution was cooled and added 58oC seed (10 g). The suspension was cooled to 22oC for 4 hours and the product was isolated by filtration after 1 h of aging at the 22oC. the filter cake was washed with 1.8 l of cyclohexane and dried in a vacuum oven at 35oC with the supply of N2, resulting in the received 1.87 kg (77%, > 99.9% of the square, according to HPLC of R-isomer was present in quantities below the level of detection) of compound 4 in the form of slightly yellowish-brown powder.

[]2D5=22,0 (C = 0.20, MeOH), so pl. 107oC;

13C NMR (75 MHz, CDCl3h/million): 170.1, 154,5, 79.8, 58.7, 50.6; 46.6, 43.6, 43.4, 28.6, 38.3.

Although in the present description sets forth the principles of the present invention, and examples are presented for purposes of illustration, it should be borne in mind that the practical implementation of the invention encompasses all of the usual changes, adaptations or modifications within the scope of the following claims and equivalents of the claims.

Appendix 1. Getting connection p. 13 (revised formula p. 7) (hereinafter referred to as compound 13).

The first stage is Getting benzofuran-2-carbinol

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2-Itfinal (500 mg,butylamine (450 μl, 4.5 mmol) and CuI (8.6 mg, 0.045 mmol) are combined into a 4.5 ml TTF and the mixture is heated at 40oC in an atmosphere of N2within 36 hours the Mixture is cooled to room temperature and the solvents removed in vacuo and the residue purified SiO2column chromatography on 100 g of silica gel, elwira 20% ethyl acetate in hexano. 2-(Hydroxymethyl) benzofuran obtained by concentration of the fractions containing the product. [Kudu, N. G.; Pal, M.; Nahanty, J. S.; Dasgupta, F. K.; JCS Chem. Com. 1992, 41].

The second stage is Getting benzofuran-2-chlormethyl

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Benzofuran-2-carbinol (10,38 g and 68.4 mmol) dissolved in methylene chloride (100 ml) and cooled to 5oC. After 5 minutes upload thionyl chloride (5,49 ml, 75.2 mmol) and the reaction mixture was kept at 5oC for 30 minutes and heated to 22oC. the Reaction mixture was incubated at 22oC for 4 hours. Methylenchloride download washed with DI water (4 x 60 ml) and filtered through silica gel. The solution was concentrated in vacuo to obtain a solid when cooled. The crude solid is dissolved in hexano(120 ml) and treated with Darco G-60 (1.0 g). The suspension is filtered and the solution concentrated in vacuo to obtain compound benzofuran-2-chloromethyl in the form of a solid substance.

Tre is,1 g, 25 mmol) are combined with IPAc (60 ml), water (20 ml), KHCO3(4,25 g, 42,5 mmol), sodium iodide (1.88 g, 12.5 mmol) and tetrabutylammonium bromide (600 mg, of 1.86 mmol) and the mixture is heated to 45oC under nitrogen atmosphere. Add 2- (chloromethyl)benzofuran (4.6 g, 27.5 mmol) and the resulting mixture heated to 59-61oC for 5 h Mixture was allowed to cool to room temperature and diluted with IPAc (100 ml) and the aqueous layer was separated. The organic layer was washed with 3 x 50 ml water, then 50 ml brine and dried (MgSO4) and the filtrate was concentrated in vacuo and washed with 100 ml of IPAc and concentrate in ambient conditions up to 80 ml, cooled to 25oC, enter the seed and incubated with stirring for 2 hours the Solid is filtered off and washed with cold IPAc (2 × 15 ml) to obtain Compound 13 (melting point = 152-153,5oC).

Annex 2. Biological data for compounds 13.

Analysis of inhibition expressed by microorganisms HIV protease

Studies of inhibition of the reaction of the protease expressed in Eschericia coli, with a peptide structure [Val-Ser-Gln-Asn-(beta - naphthyl)Ala-Pro-Ile-Val, 0.5 mg/ml, during initiation, the reaction is carried out in 50 mm Na acetate, pH 5.5, 30oC for 1 hour. Various CNAM 15 μl of 0.33 nm protease (0.11 ng) in a solution of 0.133 M Na acetate pH 5.5 and 0.1% bovine serum albumin. The reaction is quenched with 160 µl of 5% phosphoric acid. The reaction products separated by HPLC (VYDAC wide time 5 cm C-18 reverse phase, gradient acetonitrile, with 0.1% phosphoric acid). The degree of inhibition of the reaction is determined by the peak heights of the products. HPLC products, independently synthesized, confirms compliance with the quality standards of analysis and confirms the composition of the product. Connection 13 shows the value of the IC50approximately 0.17 nm.

Analysis of distribution in the cells.

Inhibition of HIV in cell cultures was measured according to Nunberg et al. , J. Virol. , 65, 4887 (1991). In this analysis, T-lymphoid cells MT-4 infect HIV-1 (wild type, except otherwise indicated) using a pre-defined inoculum, and the culture incubated for 24 hours. At this time reveal a 1% positive cells by indirect immunofluorescence assay. The cells are then extensively washed and distributed in 96-well plates to kultivirovanija. Serially twofold diluted inhibitor added to the wells and the cultivation continued for 3 additional days. 4 days after infection 100% of the cells in the control cultures infected. The accumulation of HIV-1 P24 directly crazyy inhibitor in nanomole/liter, which reduces the spread of infection by at least 95% or CIC95. CIC95to Connect 13 - 25 nm.

Annex 3. Pharmaceutical compositions containing the compound 13.

The first stage is the Formation of salt

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The free base of Compound 13 (25 g, to 38.3 mmol) dissolved in absolute ethanol (150 ml) at 22oC. the batch was filtered through a 5 μm filter and the filter is washed with absolute alcohol (50 ml). A solution of sulfuric acid/ethanol to prepare at < 5oC through the introduction of concentrated sulfuric acid (3,91 g, to 38.3 mmol) to a cooled solution < 5oC) absolute ethanol (50 ml) at such a rate that the temperature remained < 5oC. Part acid solution (10 ml, 20 vol.%) download in the solution portion of the Connection 13 at 22oC. At this point in the Connection portion 13 may not necessarily be made of the seed. Connection 13*sulfate*ethanolate (500 mg), 22oC. it is Ideal to make a seed crystal in the Connection portion 13, when the seed helps saturation during crystallization. The suspension is incubated at 20-25oC for 30 minutes. The rest of the acid solution is loaded into a portion of the cannula over 60 minutes. During the addition the temperature of the portion that remains is incubated at 20-25oC for 60 minutes and filtered. The filter cake was washed with absolute ethanol (2 × 25 ml) and dried in vacuum (635 mm Hg, 20oC) for 18 hours in a stream of nitrogen, to obtain monoethanol sulfate Connection 13. Monoethanol sulfate is characterized by the curve of differential scanning calorimetry (DSC) at a heating rate of 10oC/min in an open vessel under a current of nitrogen, detecting the endotherm with an extrapolated initial temperature of about 190oC, peak temperature of about 193oC and an associated heat of about 120 j/g based On the results of TG and TG-FTIR of the endotherm is due to the combination of loss of ethanol and melting with decomposition. Powder characterized by x-ray d-spacing 11,72, 5,56, 5,20, 5,00, 4,60, 4,50, 4,40, 4,26, 4,17, 4,08, 3,90, 3,81, 3,69, 3,24 and 3.33 angstroms.

The second stage is a Drug AND

100 mg sulfate salt of Compound 13 with the First stage is mixed with sufficient finely powdered lactose to obtain the total number 580-590 mg for filling capsules of solid gel On the form.

The third stage is the Preparation Century

Oral suspension is prepared by suspension 400 mg sulfate salt of Compound 13 in 20 ml of water.

Appendix 4. Characteristics of the group of formula I

-

or pharmaceutically acceptable salt of such a compound,

where is a steady 8-10-membered ring of the bicyclic heterocycle, each of the rings which may be saturated or nanosystem and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from the group consisting of N, S or O, and the heterocycle may be unsubstituted or substituted with halogen or lower C1-4by alkyl;

assuming that is not a group;

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< / BR>
or

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2. Connection on p. 1, which represents a steady 8-10-membered ring of the bicyclic heterocycle, any ring of which may be saturated or unsaturated and said heterocycle consists of carbon atoms and 2 heteroatoms selected from the group consisting of N or O, whereby the heteroatoms are present in different rings, or a pharmaceutically acceptable salt of such compounds.

3. Connection on p. 1, which is:

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X represents O or S,

or pharmaceutically acceptable salt of such compounds.

4. Connection on p. 1, which is limited by the fragment

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or pharmaceutically acceptable salt of such compounds.

5. hydroxy-5-(1-(4-(3-furo[2,3-b] pyridylmethyl)-2(S)-N'-(tert-BUTYLCARBAMATE)piperazinil))pentanone, or pharmaceutically acceptable salt of such compounds.

6. Connection on p. 1 formula

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or its pharmaceutically acceptable salt.

7. Connection on p. 6 represented by the formula

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or its pharmaceutically acceptable salt.

8. Pharmaceutical composition, characterized in that as the active component includes an effective amount of a compound according to any one of paragraphs.1-7 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to p. 8, inhibiting HIV protease.

10. Method of inhibiting IV protease, wherein appoint a mammal in need of such treatment, an effective amount of a compound according to any one of paragraphs.1-7.

11. The method according to p. 10, characterized in that prescribe the effective amount of the compounds under item 7.

12. The pharmaceutical composition according to p. 8, characterized in that as the active ingredient contains a connection on p. 7.

13. The pharmaceutical composition according to p. 12, characterized in that it further comprises a non-nucleoside IV reverse transcriptase inhibitor selected from the compounds In connection With and nevirapine where the connection is a 6-chloro-4(S)-till-1,2-dihydro-4(H)-3,1-benzoxazin-2-it.

14. The composition according to p. 13, characterized in that, in addition, contains a nucleoside analog IV reverse transcriptase inhibitor selected from Z, ddi and ddC, where Z represents AZT (Zidovudine), ddi is dideoxyinosine and ddC is dideoxycytidine.

 

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