Synthesis of carbamoyl pyridone inhibitors of hiv integrase and intermediate compounds

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining pyridine compounds (AA),(BB) and (CC) of respective formulas:

,

,

.

said compounds possess inhibiting action with respect to HIV-integrase. method consists in carrying out the following stages: P-1) bromination of compound of formula (I-I) with obtaining bromine-compound of formula (II-II)

,

where value R represents -CHO, -CH(OH)2, -CH(OH)(OR4), -CH(OH)-CH2OH or -CH(OR5)(OR6); P1 represents benzyl; P3 represents H or protective group of carboxyl; R4 represents lower alkyl; R5 and R6 independently represent lower alkyl or R5 and R6 can represent alkyl and be connected with formation of 5-, 6- or 7-member ring, P-2) formation of side chain of 2,4-di-fluorophenyl-CH2-NH-C(O)- with application of reagents 2,4-di-fluorophenyl-CH2-NH2 and carbon monoxide, stage of formation of Q ring by means of respective amine, selected from 3-amino-butan-1-ol, 2-amino-propan-1-ol and 2-pyrrolidinyl methylamine, and stage of debenzylation with obtaining compound of formula (AA), (BB) or (CC), where said stage P-2 is carried out after formation of Q ring.

EFFECT: method makes it possible to simplify obtaining target compounds due to carrying out regioselective bromination at the first stage.

6 cl, 3 ex, 7 dwg

 

The scope of the invention

The present invention includes modifications of known methods of synthesis of compounds with inhibitory activity against HIV integrase.

Prior art

In the published international application WO 2006/116764, published November 2, 2006, incorporated by reference in its entirety, describes the various connections and detailed scheme of the synthesis of their receipt. In particular, the sequence of reactions shown on page 79 of the specified application, where 3-benzyloxy-2-methyl-1H-pyridin-4-one of formula 3 bromilow to bromopyridine 4, which is then subjected to interaction with methanol and carbon monoxide to obtain methyl ester nicotinic acid 5, which, after several stages is subjected to interaction with benzylamine with the formation of pyridine with nesoderzhaschii side chain 10. Thus, the amide side chain is in place before the formation of the ring Z1Z2the final product of formula (I) according to the reaction shown on page 80 of compound 16 to compound 17-1.

The second sequence of reactions shown on page 113 in WO 2006/116764 where pyrolidine connection 102 enable condensation to tricyclic compounds 103, which then bromilow obtaining bromine compounds 104, which is then subjected to interaction with what anselmino with the formation of the tricyclic compounds with amide-containing side chain 105. Thus, bromination occurs after the formation of the ring Z1Z2the final product of formula (I).

N-Methoxy-N-methylamide can be obtained by Pd-catalyzed aminocarbonylmethyl the approach formulated above, as described J.R.Martinelli et al in Organic Letters, Vol.8, No.21, pages 4843-4846 (2006). Bromoaniline and bromoanisole converted into esters, as described J.Albaneze-Walker et al in Organic Letters, Vol.6, No.13, pages 2097-2100 (2004).

Summary of the invention

The proposed methods, which used an early stage of the synthesized upon receipt of compounds useful as having inhibitory activity against HIV integrase, as described in WO 2006/116764. Bromination provides a leaving group to join amide side chain to Spiridonova ring.

Detailed description of the invention

The method of synthesis Spiridonovka compounds of the following formula (AA), (BB) or (CC):

incorporating the following stages:

P-1) of the synthesized compounds of the following formula (I-I) obtaining bromine compounds of the following formula (II-II):

where R represents-Cho, -CH(OH)2, -CH(OH)(OR4), -CH(OH)-CH2OH, or-CH(OR5)(OR6);

R1represents H or a protective group of hydroxyl;

R3represents H or a protective group carboxyl;

R4represents lower alkyl;

R5and R6independently represent lower alkyl or R5and R6can represent a lower alkyl and may be connected with the formation of 5-, 6 - or 7-membered ring,

and

R-2) education of the side chain of 2,4-di-forfinal-CH2-NH-C(0)- using reagents 2,4-di-forfinal-CH2-NH2and carbon monoxide.

The term "lower alkyl", alone or in combination with any other term, refers to a saturated aliphatic hydrocarbon radical with a straight or branched chain, containing from 1 to 6 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl, and the like, but are not limited to.

The term "lower cycloalkyl" refers to saturated or partially saturated carbocyclic ring consisting of 3 to 6 carbon atoms in any chemically stable configuration. Examples of suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.

The term "lower alkenyl", alone or in combination with any other term, refers to an alkyl group with straight or branched chain with one who, or two carbon-carbon double bonds. Examples alkenyl radicals include ethynyl, propenyl, Isopropenyl, butenyl, Isobutanol, pentanol, hexanol, hexadienyl and the like, but are not limited to.

The term "lower alkylene" refers to a divalent hydrocarbon radical with a straight or branched chain, preferably having from one to six carbon atoms, unless otherwise stated. Examples of "alkylene"as it is used here, include methylene, ethylene, propylene, butylene, isobutylene and the like, but are not limited to.

The term "lower albaniles" refers to a divalent hydrocarbon radical with a straight or branched chain having one or two carbon-carbon double bonds.

The term "lower alkoxy" refers to Olkiluoto ether radical, where the term "alkyl" is defined above. Examples of suitable alilovic ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, but are not limited to.

The term "halogen" refers to fluorine (F), chlorine (CL), bromine (Br) or iodine (I).

The term "aryl", alone or in combination with any other term, refers to carbocyclic aromatic group (such as phenyl or naphthyl)containing 6 carbon atoms, and more preferably from 6 to 10 carbon atoms. Examples of aryl is of dikalov include phenyl, naphthyl, indenyl, azulene, fluorene, anthracene, phenanthrene, tetrahydronaphthyl, indanyl, phenanthridines and the like, but are not limited to. Unless otherwise noted, the term "aryl" also includes every possible positional isomers of aromatic hydrocarbon radical, such as 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1-phenanthridines, 2-phenanthridines, 3-phenanthridines, 4-phenanthridines, 7-phenanthridines, 8-phenanthridines, 9-phenanthridines and 10-phenanthridines. Examples of aryl radicals include phenyl, naphthyl, indenyl, azulene, fluorene, anthracene, phenanthrene, tetrahydronaphthyl, indanyl, phenanthridines and the like, but are not limited to. The term "aralkyl" refers to an alkyl group substituted by aryl. Examples Uralkalij groups include benzyl and phenethyl, but are not limited to.

The terms "heterocyclic group" and "heterocycle"as used here refer to a 3-7-membered monocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclic ring system any ring of which is saturated, partially saturated or unsaturated and which, when it is monocyclic, may be condensed with a benzene ring. Each heterocycle consists of one or more than one carbon atom and from about the nogo up to four heteroatoms, selected from the group consisting of N, O and S, and where the heteroatoms nitrogen and sulfur can be oxidized, and the nitrogen atom may be possible Quaternary, including any bicyclic group in which any of the above defined heterocyclic rings condensed with the benzene ring. Heterocyclic ring may be attached at any carbon atom or heteroatom, provided that the accession leads to the formation of stable structures. Preferred heterocycles include 5-7-membered monocyclic heterocycles, and 8-10-membered bicyclic heterocycles. When the heterocyclic ring has substituents, it is understood that substituents may be attached to any atom in the ring, whether it is a heteroatom or carbon atom, provided that the result is a stable chemical structure. "Heteroaromatic group" or "heteroaryl" included in heterocycles as defined above, and generally refer to heterocycle, in which the ring system is an aromatic monocyclic or polycyclic ring radical containing from five to twenty carbon atoms, preferably from five to ten carbon atoms, in which one or more than one ring carbon atom, preferably one to four, are each replaced by a heteroatom such as N, O, S and R. P is impactfully heteroaryl groups include 5-6-membered monocyclic heteroaryl and 8-10-membered bicyclic heteroaryl. In addition, the scope of the term "heterocycle", "heterocyclic" or "heterocyclyl included in the group in which the non-aromatic ring containing a heteroatom, condensed with one or more than one aromatic ring, such as in indolinyl, chromanol, phenanthridine or tetrahydroquinoline, where the radical or point of connection is a non-aromatic ring containing a heteroatom. Unless otherwise noted, the term "heterocycle", "heterocyclic" or "heterocyclyl" also includes every possible positional isomer heterocyclic radical, such as 1-indolinyl, 2-indolinyl, 3-indolinyl. Examples of heterocycles include imidazolyl, imidazolines, imidazolidinyl, hinely, ethanolic, indolyl, indazoles, indazolinone, targetability, pyridil, pyridyl, pyrrolyl, pyrrolidyl, pyrrolidinyl, pyrazolyl, pyrazinyl, minoxodil, piperidinyl, pyranyl, pyrazolyl, piperazinil, pyrimidinyl, pyridazinyl, morpholinyl, thiomorpholine, furyl, thienyl, triazolyl, thiazolyl, carbolines, tetrazolyl, diazolidinyl, benzofuranyl, themorphological, oxazolyl, oxadiazolyl, benzoxazolyl, oxopiperidine, oxopyrrolidin, oxazepines, azepine, isoxazolyl, isothiazolin, furutani, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazolyl, dioxole dioxines, oxacillin, benzo is yoxall, ditolyl, thiophenyl, tetrahydrothiophene, sulfolane, dioxane, dioxolane, tetrahydrofurfuryl, tetrahydropyrimidines, dihydropyran, tetrahydrofurfuryl and tetrahydrofurfuryl.

Possible substituents are hydroxy, halogen, amino and lower alkyl.

The protective group can be selected from groups known to specialists in this field of technology, including protective groups disclosed in Greene, Theodora W.; Wuts, Peter G. M.. Protective Groups in Organic Synthesis. 2nd Ed. (1991), 473 pp. or Kocienski, Philip J. Protecting Groups. 3rd Ed. 2005, (2005), 679 pp.

Spiridonova ring depicted in formula (I-I) and (II-II), which is directly attached-PR1turns into the formula AA, BB and CC in the ring, which is shown adjacent the ring Q, namely:

Thus, stage (P-2) may be performed before or after the formation of the ring Q, and such stage of the formation of ring Q described herein and in WO 2006/1116764.

According to the present invention, a method as described above, where the specified stage (P-2) is conducted before the formation of ring Q, and where the specified Spiridonova compound is a compound of formula AA, or formula BB, or formula SS.

According to the present invention, a method as described above, where the specified stage (P-2) is conducted after the formation of the ring Q and where is the th Spiridonova compound is a compound of formula AA, or formula BB, or formula SS.

According to the present invention, a method as described above, where the specified Spiridonova compound is a compound of formula AA.

According to the present invention, a method as described above, where the specified Spiridonova compound is a compound of formula CENTURIES.

According to the present invention, a method as described above, where the specified Spiridonova compound is a compound of formula SS.

In addition, part of the present invention is a new intermediate compounds, such as compounds of the following formula (DD):

where R1is such as described above, in particular benzyl.

Method for obtaining Spiridonovka compounds of the following formula (AA), (BB) or (CC):

incorporating the following stages:

P-1) of the synthesized compounds of the following formula (I-I) obtaining bromine compounds of the following formula (II-II):

where R represents-Cho, -CH(OH)2, -CH(OH)(OR4), -CH(OH)-CH2OH, or-CH(OR5)(OR6);

R1represents H or a protective group of hydroxyl;

R3represents H or protect the tou group carboxyl;

R4represents lower alkyl;

R5and R6independently represent lower alkyl or R5and R6can represent a lower alkyl and may be connected with the formation of 5-, 6 - or 7-membered ring,

and

R-2) education of the side chain of 2,4-di-forfinal-CH2-MN-C(0)- using reagents 2,4-di-forfinal-CH2-ÌÍ2 and carbon monoxide to obtain the compounds of formula Ill-Ill

P-3) condensation and dibenzylamine the compounds of formula III-III of obtaining the compounds of formula AA, BB or CC.

According to the present invention is also methods, as described above, where R1represents benzyl; R3represents methyl and R represents-Cho, -CH(OH)(OR4), -CI(OR5)(OR5), where R4and R5represent lower alkyl.

In addition, there is described a method for obtaining compounds of the following formula (I):

where R represents-Cho, -CH(OH)2or-CH(OH)(OR4);

R1represents H or a protective group of hydroxyl;

R3represents H or a protective group carboxyl;

R3represents H, halogen, hydroxy, possibly substituted lower alkyl, possibly substituted cycloalkyl, possibly substituted lower alkenyl, vozmojnostey lower alkoxy, possibly substituted lower alkenylacyl, possibly substituted aryl, possibly substituted, aryloxy, possibly substituted heterocyclic group, possibly substituted, heterocyclic and possibly substituted amino;

R4represents lower alkyl;

Rxrepresents H, halogen or R2-X-NR1-C(O)-;

R2represents a possibly substituted aryl;

X represents a simple bond, a heteroatomic group selected from O, S, SO, SO2and NH, or lower alkylene, or lower albaniles, each of which can be embedded heteroatom; and

R1represents H or lower alkyl, which includes stages:

1) interaction of the compounds of formula (II):

with an amine of formula (III) or (IV):

where R5and R6independently represent lower alkyl, or R5and R6can represent alkyl and can be connected with the formation of 5-, 6-or 7-membered ring

obtaining the intermediate of formula (V) or (VI), respectively:

and

2) parafunctional the compounds of formula (V) or (VI) to obtain the compounds of formula (I).

Specific compounds used in these methods, VK is ucaut compounds of the following formulas (IIA), (VIa), (VIb) and (Ia)used in the "Examples" section below:

The product (Ia) sequence synthesis can be condensing with an amine, for example of the formula H2NCH2CH2CH2OH, bronirovat, if Rxrepresents H, carbanilate and lidirovat and, finally, to dibenzylamine getting connection WO 2006/116764 denoted by (I-7) on page 240, where (R)mis a 4-F, and Rarepresents N. Alternatively, this compound can be synthesized from compounds of formula (I), where Rxis a para-F-phenyl-CH2-NH-C(O)-, R3represents H, R1represents benzyl (EAP) and R3represents a protective group of carboxyl.

More specifically, stage (1) can be carried out in a proton or an aprotic solvent such as tO, THF (tetrahydrofuran) or DMF (dimethylformamide)at a temperature of about 50 to 150 º C for about 1-10 hours.

More specifically, stage (2) can be conducted for source materials diol type (VI) using an oxidant such as NalO4, RUO Li4or Pb(OAc)4in a solvent such as H2O, MeOH, or CH3SP, at ambient temperature cf the waters within one or more than one hour. The original matter acatalog type, such as (V), the interaction can be carried out in acid, such as Hcl, CF3COOH or SON may when heated.

Stage (2) can also include a change of purpose on the position Rxfor example, Rx=H in Rx=Br possible with the subsequent change of purpose in Rx=R2-X-NR1-C(O)-. Stage (2) may also include the change of purpose R3for example, R3=N in R3=IU.

More specifically, stage (P-1) may be conducted by treatment of compounds of formula I-I source of bromine, including N-bromosuccinimide or bromine, but not limited to, in a solvent such as N,N-dimethylformamide, THF or acetic acid, and the like. This transformation can be carried out, in particular, at temperatures from -10 º C to 50 º C with obtaining the compounds of formula II-II.

More specifically, stage (P-2) may be conducted by treatment of compounds of formula II-II 2,4-differenl-CH2-NH2, carbon monoxide, a suitable base and a source of palladium(0) and possibly the corresponding ligand in an inert solvent, it is possible during heating. Carbon monoxide may be at atmospheric pressure (14.7 psi (101 kPa), or at elevated pressure, in particular in the range up to 60 psi (413,7 kPa), but in some of the cases may require higher pressure. Bases include tertiary amines, such as diisopropylethylamine and triethylamine and the like, but are not limited to. Inorganic bases such as potassium acetate and potassium phosphate, are also important. Suitable sources of Pd(0) include tetrakis(triphenylphosphine)palladium(0), but are not limited to them. In some cases, Pd(II) precursor may be used to generate Pd(0) in situ. Suitable Pd(II) precursors include Pd(OAc)2Pd(OCOCF3)2, but are not limited to, ligands include Xantphos (9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene), diphenylphosphinite (dppf), triphenylphosphine and the like. Solvents include N,N-dimethylformamide, THF, toluene, DMSO (dimethylsulfoxide), and the like. You may use the heated mixture in the range of from ambient temperature to 150 º C.

According to the present invention also suggested that the crystalline forms of the salts of the compounds of formula AA (compound 13, example 1) and its hydrate. According to the present invention proposed:

1) salt or a hydrate salt of the compounds of formula AA:

2) the crystalline form of sodium salt or hydrate sodium

salts of compounds of formula AA:

3) the crystalline form of compound (2)having one or more than one physical property, in the curse of the group, consisting of (1) and (2):

1) having characteristic diffraction peaks at angles 2-theta equal to 6,4º±0,2º; 9,2º±0,2º; 13,8º±0,2º; 19,2º±0,2º and 21,8º±0,2º at the picture of the x-ray diffraction on the powder; and

2) having characteristic infrared absorption spectra at 1641 cm-1±2 cm-1, 1536 cm-1±2 cm-1, 1503 cm-1±2 cm-1and 1424 cm-1±2 cm-1;

4) the crystalline form of compound (2)having characteristic diffraction peaks at angles 2-theta equal to 6,4º±0,2º; 9,2º±0,2º; 13,8º±0,2º; 19,2º±0,2º and 21,8º±0,2º at the picture of the x-ray diffraction on the powder;

5) the crystalline form of compound (2)having characteristic diffraction peaks at angles 2-theta equal to 6,4º±0,2º; 9,2º±0,2º; 13,8º±0,2º; 14,6±0,2º; 15,2º±0,2º; 17,6±0,2º; 19,2º±0,2º; 21,8º±0,2º; 24,1º±0,2º and 28,7th±0,2º, the picture of the x-ray diffraction on the powder;

6) the crystalline form of compound (2)having characteristic infrared absorption spectra at 1641 cm-1±2 cm-1, 1536 cm-1±2 cm-1, 1503 cm-1±2 cm-1and 1424 cm-1±2 cm-1;

7) the crystalline form of compound (2)having characteristic infrared absorption spectra at 1641 cm-1±2 cm-1, 1536 cm-1±2 cm-1, 1503 cm-1±2 cm-1, 1424 cm-1±2 cm-1, 1282 cm-1±2 cm-1, 1258 cm-1±2 cm -1, 1093 cm-1±2 cm-1and 1069 cm-1±2 cm-1;

8) the crystalline form of compound (2)having one or more than one range selected from the group consisting of (a)-(C):

a) picture of the x-ray diffraction on the powder, essentially as shown in figure 1;

b) infrared absorption spectra, essentially as shown in figure 2; and

c)13C-NMR spectra in the solid state, essentially as shown in Figure 3.

9) the crystalline form of compound (2)having one or more than one physical property selected from the group consisting of (3) and (4):

3) having characteristic diffraction peaks at angles 2-theta equal to 8,0º±0,2º; 9,3º±0,2º; 11,3º±0,2º; 16,0º±0,2º and 22,8º±0,2º at the picture of the x-ray diffraction on the powder; and

4) having characteristic infrared absorption spectra at 1637 cm-1±2 cm-1, 1536 cm-1±2 cm-1, 1501 cm-1±2 cm-1and 1422 cm-1±2 cm-1;

10) the crystalline form of compound (2)having characteristic diffraction peaks at angles 2-theta equal to 8,0º±0,2º; 9,3º±0,2º; 11,3º±0,2º; 16,0º±0,2º and 22,8º±0,2º at the picture of the x-ray diffraction on the powder;

11) the crystalline form of compound (2)having characteristic diffraction peaks at angles 2-theta equal to 8,0º±0,2º; 9,3º±0,2º; 11,3º±0,2º; 15,4º±0,2º; 16,0º±0,2º; 18,7th±0,2º; 19,1º±0,2º; 19,8º±0,2º; 2,8º±0,2º and 26,8º±0,2º, the picture of the x-ray diffraction on the powder;

12) the crystalline form of compound (2)having characteristic infrared absorption spectra at 1637 cm-1±2 cm-1, 1536 cm-1±2 cm-1, 1501 cm-1±2 cm-1and 1422 cm-1±2 cm-1;

13) the crystalline form of compound (2)having characteristic infrared absorption spectra at 1637 cm-1±2 cm-1, 1536 cm-1±2 cm-1, 1501 cm-1±2 cm-1, 1422 cm-1±2 cm-1, 1277 cm-1±2 cm-1, 1258 cm-1±2 cm-1, 1093 cm-1±2 cm-1and 1069 cm-1±2 cm-1;

14) the crystalline form of compound (2)having one or more than one range selected from the group consisting of (d) and (e):

d) picture of the x-ray diffraction on the powder, essentially as shown in Figure 4; and

e) infrared absorption spectra, essentially as shown in Figure 5;

15) a pharmaceutical composition comprising a crystalline form as defined in any of(2)-(14);

16) a method of obtaining a crystalline form as defined in any of(2)-(14).

According to the present invention proposed crystalline form of the salt of the compounds of formula AA, in particular the sodium salt.

According to the present invention proposed a crystalline form of a hydrate salt of the compounds of formula AA, in which lastnosti sodium salt.

This invention also includes a crystalline form of the compound of formula AA (compound 12, example 1). The details shown in paragraphs (17) through (22):

17) the crystalline form of the compound of formula AA:

having one or more than one physical property selected from the group consisting of (5) and (b):

5) having characteristic diffraction peaks at angles 2-theta equal to 5,4º±0,2º; 10,7th±0,2º; 12,3º±0,2º; 15,2º±0,2º and 16,4º±0,2º at the picture of the x-ray diffraction on the powder; and

6) has a characteristic infrared absorption spectra at 1658 cm-1±2 cm-1, 1628 cm-1±2 cm-1, 1540 cm-1±2 cm-1and 1498 cm-1±2 cm-1;

18) the crystalline form of the compound of formula AA:

having characteristic diffraction peaks at angles 2-theta equal to 5,4º±0,2º; 10,7th±0,2º; 12,3º±0,2º; 15,2º±0,2º and 16,4º±0,2º at the picture of the x-ray diffraction on the powder;

19) the crystalline form of the compound of formula AA:

having characteristic diffraction peaks at angles 2-theta equal to 5,4º±0,2º; 10,7th±0,2º; 12,3º±0,2º; 14,3º±0,2º; 15,2º±0,2º; 16,4º±0,2º; 21,7th±0,2º; 24,9º±0,2º; 25,4º±0,2º and 27,9º±0,2º at the picture of the x-ray diffraction on the powder;

20) the crystalline form of the compound of formula AA:

with the nature of isticheskie infrared absorption spectra at 1658 cm -1±2 cm-1, 1628 cm-1±2 cm-1, 1540 cm-1±2 cm-1and 1498 cm-1±2 cm-1;

21) the crystalline form of the compound of formula AA:

having characteristic infrared absorption spectra at 1658 cm-1±2 cm-1, 1628 cm-1±2 cm-1, 1540 cm-1±2 cm-1, 1498 cm-1±2 cm-1, 1355 cm-1±2 cm-1, 1264 cm-1±2 cm-1, 1238 cm-1±2 cm-1, 1080 cm-1±2 cm-1and 1056 cm-1±2 cm-1;

22) the crystalline form of the compound of formula AA:

having one or more than one range selected from the group consisting of (O (d):

f) picture of the x-ray diffraction on the powder, essentially as shown in Fig.6; and

g) infrared absorption spectra, essentially as shown in Fig.7.

Crystals of compounds 13 and 13b (monohydrate form compound 13) show a high solubility in water or physiological solution, high bioavailability (DB), high maximum concentration of drug (Cmax), a short time to reach the maximum concentration of drug (TM), a high stability to heat and light, and/or ease of handling. Therefore, the crystals of compounds 13 and 13b are suitable as a pharmaceutical ingredient of the century

In the following examples and in the description can be used the following abbreviations: Me (methyl), Bn (benzyl), aq. (water), Et (ethyl), C (Celsius).

EXAMPLES

In the following examples, which show the reaction of synthesized and amidation of the present invention, the included examples, example 2 and the example of the SS.

The following examples are intended for illustration only and are not intended to limit the scope of the invention.

Examples 1 and 3

The starting material in example 1E and 3E is a compound of formula (At), which is also shown as compound 5 below and the compound #101 on page 113 in WO 2006/116764. The product, shown below as compound 8, is a compound of formula (I). The final product, shown below as compound 13, is a compound of formula (I-7) on page 240 in WO 2006/116764, where (R)m represents a 2,4-di-R, and Rarepresents H, provided, however, that in the position marked R16in the formula (XXVI) on page 65, is alpha-methyl.

Thus, in the above sequence of example 1 compound 5 is identical to the connection 101 on page 113 in WO 2006/116764 and the compound of formula (IIA) of the method according to the present invention;

the above compound 6 is identical to the compound of formula (VIa) of the method according to the present invention;the above connection 7 is identical to the compound of formula (VIb) of the method according to the present invention; and the connection 8 is identical to the compound of formula (1A) of the method according to the present invention. Stage (1) of the method according to the invention includes compounds 5 and 6 above, whereas stage (2) includes compounds with 6 to 8.

Example 1A

To a suspension of 2000 g of compound 1 (1.0 EQ.) in 14,0 l of MeCN was added 2848 g benzylbromide (of 1.05 equiv.) and 2630 g2CO3(1.2 EQ.). The mixture was stirred at 80 ° C for 5 hours and cooled to 13º. The precipitate was filtered and washed 5,0 l MeCN. The filtrate was concentrated and to the residue was added a 3.0 l of THF. This THF solution was concentrated to obtain 3585 g of the crude compound 2 in the form of oil. Compound 2 was used in the next stage without additional purification.

1H-NMR (300 MHz, CDCl3) δ 7.60 (d, J=5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d, J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H).

Example 1b

To 904 g of the crude compound 2 was added 5,88 l of THF and this solution was cooled to-60OC. 5,00 l 1.0 M bis(trimethylsilylmethyl) lithium in THF (1.25 EQ.) was added dropwise within 2 hours to a solution of compound 2 at-60OC. Then was added a solution of 509 g of benzaldehyde (1.2 EQ.) in 800 ml of THF at -60 º C and the reaction mixture was stirred at 60 ° C for 1 hour. The THF solution was poured into a mixture of 1.21 l conc. HCl, 8,14 l of ice water and 4.52 l EUAs at a temperature below 2OC. The organic layer was washed 2,71 l of brine (twice) and the aqueous layer was extracted with 3,98 l tO. About yedinenye organic layers were concentrated. To the mixture was added 1,63 l of toluene and concentrated (twice) with a toluene suspension of compound 3. Filtration, washing of 0.90 l of cold toluene and drying gave 955 g of compound 3 (yield 74% from compound 1) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.62 (d, J=5.7 Hz, 1H), 7.5-7.2 (m, 10H), 6.38 (d, J=5.7 Hz, 1H), 5.16 (d, J=11,4 Hz, 1H), 5.09 (d, J=11,4 Hz, 1H), 4.95 (dd, J=4,8, and 9.0 Hz, 1H), 3.01 (dd, J=9,0, 14.1 Hz, 1H), 2.84 (dd, J=4,8, 14.1 Hz, 1H).

Example 1C

To a solution of 882 g of compound 3 (1.0 EQ.) in 8,82 l THF was added 416 g Et3N (1.5 EQ.) and 408 g of methanesulfonamide (1.3 EQ.) at temperatures below 30ºC. After confirming that the connection 3 fully expended, to this reaction mixture at a temperature below 30 º C were added to 440 ml of NMP and 1167 g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (2.8 equiv.) and the reaction mixture was stirred for 30 minutes. The mixture was neutralized 1,76 l 16% sulfuric acid and the organic layer was washed 1,76 l 2% aq. Na2SO3. After concentrating the organic layer was added to 4.41 l of toluene and the mixture was concentrated (three times). After addition of 4.67 liters of hexane and the mixture was cooled in an ice bath. Filtration, washing 1.77 liters of hexane and drying gave 780 g of compound 4 (yield 94%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.69 (d, J=5.7 Hz, 1H), 7.50-7.25 (m, 10H), 7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H), 6.41 (d, J=5.7 Hz, 1H), 5.27 (s, 2H).

Example 1d

To a mixture of 822 g with the unity 4 (1.0 EQ.) and 11.2 g RuCl 3·nH2O (0.02 EQ.) in 2,47 l N, 2,47 l tO and 2,47 l H2O added 2310 NalO g4(4.0 EQ.) at temperatures below 25ºC. After keeping for 1 hour to the mixture at a temperature below 25 ºC was added 733 g of NaClO2(3.0 EQ.). After standing for 1 hour the precipitate was filtered and washed by 8.22 l tO. To the filtrate was added 1,64 l 50% aq. Na2S2O3, 822 ml H2O and 630 ml conc. HCl. The aqueous layer was extracted 4,11 l tO and the organic layers were combined and concentrated. To the residue was added 4 l of toluene and the mixture was concentrated and cooled in a water bath. Filtration, washing with 1 l of toluene and drying gave 372 g of compound 5 (yield 56%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) 5 7.78 (d, J=5.7 Hz, 1H), 7.54-7.46 (m, 2H), 7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6 (brs, 1H), 5.31 (s, 2H).

Example 1E

The mixture 509 g of compound 5 (1.0 EQ.) and 407 g of 3-amino-propane-1,2-diol (2.5 EQ.) in 1,53 l tO was stirred at 65 º C for 1 hour and at 80 ° C for 6 hours. After addition of 18.8 g of 3-amino-propane-1,2-diol (0.1 EQ.) 200 ml tO the mixture was stirred at 80 ° C for 1 hour. After addition of 18.8 g of 3-amino-propane-1,2-diol (0.1 EQ.) 200 ml tO the mixture was stirred at 80 ° C for 30 minutes. After cooling and adding 509 ml of N2O the mixture was concentrated. To the residue was added 2,54 l H2O and 2.54 l of AcOEt. After separation the aqueous layer was washed 1,02 l tO. In gnome layer was added 2,03 l 12% sulfuric acid at a temperature below 12º with obtaining the crystal of compound 6. Filtration, washing of 1.53 liters of cold H2Oh and drying gave 576 g of compound 6 (yield 83%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 7.67 (d, J=7.5 Hz, 1H), 7.5-7.2 (m, 5H), 6.40 (d, J=7.5 Hz, 1H), 5.07 (s, 2H), 4.2-4.0 (m, 1H), 3.9-3.6 (m, 2H), 3.38 (dd, J=4.2, and the 10.8 Hz, 1H), 3.27 (dd, J=6,0, to 10.8 Hz, 1H).

Example 1f

To a suspension of 576 g of compound 6 (1.0 equiv.; contains a 5.8% N2O) 2.88 l of NMP was added 431 Panso3(3.0 EQ.) and 160 ml under the conditions (1.5 EQ.) and the mixture was stirred at room temperature for 4 hours. After cooling to 5 º C to this mixture at a temperature below 10 º C was added 1,71 l 2 N. HCl, and 1.15 l of 20% aq. NaCl obtaining crystalline compound 7. Filtration, washing 1,73 l H2O and drying gave 507 g of compound 7 (yield 89%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 7.59 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H), 5.12 (d, J=10,8 Hz, 1H), 5.07 (d, J=10,8 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 3.97 (dd, J=2,4, a 14.1 Hz, 1H), 3.79 (s,, 3H), 3.70 (dd, J=9,0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H), 3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H).

Example 1q

To a mixture of 507 g of compound 7 (1.0 EQ.) in 5,07 l MeCN, 5,07 l H2O and 9,13 g Asón (0.1 EQ.) added 390 g NalO4(1.2 equiv.) and the mixture was stirred at room temperature for 2 hours. After addition of 1.52 l of 10% aq. PA2S2O3the mixture was concentrated and cooled to 10ºC. Filtration, washing with N2O and drying gave 386 g of compound 8 (yield 80%) as to istoricheskogo substances.

1H-NMR (300 MHz, DMSO-d6) δ 7.62 (d, J=7.5 Hz, 1H), 7.42-7.30 (m, 5H), 6.33 (d, J=6.0 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H), 5.08 (s, 2H), 4.95-4.85 (m, 1H), 3.80 (s,3H),3.74(d,J=5,1 Hz, 2H).

Example 1h

After dissolution, the mixture of 378 g of compound 8 (1.0 EQ.) 3.78 l Meon while heating this solution was concentrated. To the residue was added 1,51 l of toluene and the mixture was concentrated. To the residue was added 1.89 l of toluene, 378 ml Asón and 137 g (R)-3-amino-butane-1-ol (1.3 EQ.) this mixture was heated to 90ºC, was stirred at 90ºC for 2.5 hours and concentrated. To the residue was added 1.89 l of toluene and the mixture was concentrated. The residue was extracted with 3,78 l and 1.89 l l3and washed 2×1,89 l H2O. the Organic layers were combined and concentrated. To the residue was added 1,89 l tO and the mixture was concentrated. After adding 1,89 l tO, filtration, washing of 1.13 l tO and drying received 335 g of compound 9 (yield 83%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.70-7.58 (m, 2H), 7.40-7.24 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H), 5.35 (d, J=10,2 Hz, 1H), 5.28 (d, J=10,2 Hz, 1H), 5.12 (dd, J=3,9, 6.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.07 (dd, J=3,9, 13,5 Hz, 1H), 4.00-3.86 (m, 3H), 2.23-2.06 (m, 1H), 1.48 (ddd, J=2,4, from 4.5 to 13.8 Hz, 1H), 1.30 (d, J=6.9 Hz, 3H).

Example 1i

To a suspension of 332 g of compound 9 (1.0 EQ.) 1.66 l of NMP was added 191 g of NBS (N-bromosuccinimide) (1.1 EQ.) and the mixture was stirred at room temperature for 2 hours. After addition of 1.26 l H2O the mixture was stirred within 30 minutes. After adding 5,38 l H2O and keeping the mixture at 10 º C for 30 minutes and at 5 º C for 1 hour, filtration, washing of 1.33 liters of cold H2O and drying received 362 g of compound 10 (yield 89%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.69-7.63 (m, 2H), 7.59 (s, 1H), 7.38-7.24 (m, 3H), 5.33 (d, J=10,2 Hz, 1H), 5.25 (d, J=9.9 Hz, 1H), 5.12 (dd, J=3,9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.11 (dd, J=3,9, 13,2 Hz, 1H), 4.02-3.88 (m, 3H), 2.21-2.06 (m, 1H), 1.49 (ddd, J=2,4, 4,5, 14.1 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H).

Example 1j

In an atmosphere of carbon monoxide mixture of 33.5 g of compound 10 (1.0 EQ.), 34.8 ml ISO-RG2Been certified with qi net (2.5 equiv.) of 14.3 ml of 2,4-differentiatin (1.5 EQ.) and to 4.62 g of Pd(PPh3)4(of 0.05 EQ.) in 335 ml of DMSO was stirred at 90ºC for 5.5 hours. After cooling, the precipitate was filtered and washed with 50 ml of 2-propanol. After adding 502 ml of N2O and 670 ml of AcOEt to filtrate the organic layer was washed 335 ml of 0.5 n aq. HCl and 335 ml of N2O and the aqueous layer was extracted with 335 ml of AcOEt. The organic layers were combined and concentrated. To the residue was added 150 ml of 2-propanol and the mixture was concentrated. After adding 150 ml of 2-propanol, concentration, cooling to 20 ° C and filter obtained crude crystalline compound 11. After dissolving the crude crystalline substance in 380 ml of acetone with heating the precipitate was filtered and the filtrate was concentrated. After adding 200 ml tO, it is tsentrirovannaja, add 150 ml tO, concentration, cooling and filtering the obtained crude crystalline compound 11. After dissolution of this crude crystalline substance in 450 ml of acetone with heating, the solution was concentrated. To the residue was added 150 ml of 2-propanol and the mixture was concentrated (twice). After cooling the residue, filtration, washing with 2-propanol and drying received 34.3 g of compound (11) (yield 84%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 10.40 (t, J=6.0 Hz, 1H), 8.35 (s, 1H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J=9.9 Hz, 1H), 5.26 (d, J=10,2 Hz, 1H), 5.15 (dd, J=3,9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.22 (dd, J=3,9, 13,5, 1H), 4.09 (dd, J=6,0, 13,2 Hz, 1H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1H), 1.50 (ddd, J=2,4, 4,5, 14.1 Hz, 1H), 1.33 (d, J=7.2 Hz, 3H).

Example 1k

In an atmosphere of hydrogen the mixture of 28.0 g of compound 11 (1.0 EQ.) and 5.6 g of 10% Pd-C in 252 ml of THF and 28 ml Meon was stirred for 1 hour. After the precipitate (Pd-C) was filtered and washed with 45 ml of THF, was added 5.6 g of 10% Pd-C and the mixture was stirred for 1.5 hours in an atmosphere of hydrogen. After Pd-C was filtered and washed with 150 ml of a mixture of Cl3/Meon (9/1), the filtrate was concentrated. After dissolving the residue 1.38 l tO with the help of heating, the solution was gradually cooled to room temperature. After filtration, the filtrate was concentrated and cooled. Filtration, washing EUN and drying gave of 21.2 g of compound 12 (yield 92%) in the ideal crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.36 (t, J=5.7 Hz, 1 H), 8.50 (s, 1H), 7.39 (td, J=8,7, 6.3 Hz, 1H), 7.24 (add, J=2,6, 9,5, and 10.8 Hz, 1H), 7.12-7.00 (m, 1H), 5.44 (dd, J=3,9, 5.7 Hz, 1H), 4.90-4.70 (m, 1H), 4.65-4.50 (m, 1H), 4.54 (d, J=5,1 Hz, 2H), 4.35 (dd, J=6,0, to 13.8 Hz, 1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48 (m, 1H), 1.33 (d, J=6.9 Hz, 3H).

Example 1l

After dissolving 18.0 g of compound 12 (1.0 EQ.) in 54 ml tO with heating, followed by filtration to this solution at 80 ° C was added a 21.5 ml of 2 n aq. NaOH (1.0 EQ.). The solution was gradually cooled to room temperature. Filtration, washing with 80 ml tO and drying gave 18,8 g of compound 13 (yield 99%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 10.70 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.12 (m, 1H), 4.87-4.74 (m, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.35-4.25 (m, 1H), 4.16 (dd, J=1,8, a 14.1 Hz, 1H), 4.05-3.90 (m, 1H), 3.86-3.74 (m, 1H), 2.00-1.72 (m, 1H), 1.44-1.32 (m, 1H), 1.24 (d, J=6.9 Hz, 3H).

Example 1m

Example 1 illustrates the method of obtaining crystalline compounds 13b, which is monohydrate form of connection 13.

After dissolving 30.0 g of compound 13 (1.0 EQ.) in 600 ml of THF-water (8:2) at 30 º C to this solution was added to 36.0 ml of 2 n aq. NaOH (1.0 EQ.). The mixture was stirred at room temperature for 2 hours. The precipitate was filtered off, washed with 150 ml of THF-water (8:2), 150 ml of THF. Drying at 85 º C and setting the desired humidity gave a 30.4 g of compound 13b (monohydrate form of connection is in 13, yield 93%) as a crystalline substance.

Example 3

Example 3A

To a suspension of 2000 g of compound 1 (1.0 EQ.) in 14,0 l of MeCN was added 2848 g benzylbromide (of 1.05 equiv.) and 2630 g2CO3(1.2 EQ.). The mixture was stirred at 80 ° C for 5 hours and cooled to 13º. The precipitate was filtered and washed 5,0 l MeCN. The filtrate was concentrated and to the residue was added a 3.0 l of THF. This THF solution was concentrated to obtain 3585 g of the crude compound 2 in the form of oil. Compound 2 was used in the next stage without additional purification.

1H-NMR (300 MHz, CDCl3) δ 7.60 (d, J=5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37 (d, J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H).

Example 3b

To 904 g of the crude compound 2 was added 5,88 l of THF and this solution was cooled to-60OC. 5,00 l 1.0 M bis(trimethylsilylmethyl) lithium in THF (1.25 EQ.) was added dropwise within 2 hours to a solution of compound 2 at-60OC. Then was added a solution of 509 g of benzaldehyde (1.2 EQ.) in 800 ml of THF at -60 º C and the reaction mixture was stirred at 60 ° C for 1 hour. This THF solution was poured into a mixture of 1.21 l conc. HCl, 8,14 l of ice water and 4.52 l tO at a temperature below 2OC. The organic layer was washed 2,71 l of brine (twice) and the aqueous layer was extracted with 3,98 l tO. The combined organic layers were concentrated. To the mixture was added 1,63 l of toluene and concentrated (twice) with a toluene suspension of compound 3. Filtrat what I flushing of 0.90 l of cold toluene and drying gave 955 g of compound 3 (yield 74% relative to compound 1) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.62 (d, J=5.7 Hz, 1H), 7.5-7.2 (m, 10H), 6.38 (d, J=5.7 Hz, 1H), 5.16 (d, J=11,4 Hz, 1H), 5.09 (d, J=11,4 Hz, 1H), 4.95 (dd, J=4,8, and 9.0 Hz, 1H), 3.01 (dd, J=9,0, 14.1 Hz, 1H), 2.84 (dd, J=4,8, 14.1 Hz, 1H).

Example 3C

To a solution of 882 g of compound 3 (1.0 EQ.) in 8,82 l THF was added 416 g E t3M (1.5 EQ.) and 408 g of methanesulfonamide (1.3 EQ.) at temperatures below 30ºC. After confirming that the connection 3 fully expended, to this reaction mixture at a temperature below 30 º C were added to 440 ml of NMP and 1167 g of DBU (2.8 equiv.) and the reaction mixture was stirred for 30 minutes. The mixture was neutralized 1,76 l 16% sulfuric acid and the organic layer was washed 1,76 l 2% aq. Na2SO3. After concentrating the organic layer was added to 4.41 l of toluene and the mixture was concentrated (three times). After addition of 4.67 liters of hexane and the mixture was cooled in an ice bath. Filtration, washing 1.77 liters of hexane and drying gave 780 g of compound 4 (yield 94%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.69 (d, J=5.7 Hz, 1H), 7.50-7.25 (m, 10H), 7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H), 6.41 (d, J=5.7 Hz, 1H), 5.27 (s, 2H).

Example 3d

To a mixture of 10.0 g of compound 4 and 13.6 mg RuCl3·nH2O in 95 ml of MeCN and 10 ml of water was added a mixture of 155 ml of water, 7.2 g of hydrosulphuric acid and 15.5 g NalO4for the tion of 2.5 hours at 20ºC. After standing for 1 hour the organic and aqueous layers were separated and the aqueous layer was extracted with 30 ml ethyl acetate. The aqueous layer was extracted again with 30 ml of ethyl acetate and the organic layers were combined. 6 ml of 5% solution NSO3added to the combined organic layer and the layers were separated. The organic layer was brought to pH of 6.0 by adding 4.0 g of 2 M NaOH solution and the aqueous layer was separated. After adding 60 ml of 5% solution Panso3and 257 mg of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) to this reaction mixture at 25 º C for 1 hour was added with 25.9 g of the solution of NaClO and was stirred for 30 minutes, to check that the reaction has ended. After separation of the layers was added to 42.5 ml of 5% solution of Na2SO3and 30 ml of AcOEt and shared. The aqueous layer was extracted with 30 ml of AcOEt and shared. To the reaction mixture at 20 ° C for 1 hour was added 12% H2SO4and the mixture was cooled to 5ºC. After stirring the mixture for 30 minutes, the mixture was filtered, washed twice with 30 ml water and dried to obtain 5.7 g of compound 5 (yield 70%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.78 (d, J=5.7 Hz, 1H), 7.54-7.46 (m, 2H), 7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6 (brs, 1H), 5.31 (s, 2H).

Example 3E

The mixture 509 g of compound 5 (1.0 EQ.) and 407 g of 3-amino-propane-1,2-diol (2.5 EQ.) in 1,53 l tO was stirred at 65 º C for 1 hour and at 80 ° C for 6 hours the century After addition of 18.8 g of 3-amino-propane-1,2-diol (0.1 EQ.) 200 ml tO this mixture was stirred at 80 ° C for 1 hour. After addition of 18.8 g of 3-amino-propane-1,2-diol (0.1 EQ.) 200 ml tO this mixture was stirred at 80 ° C for 30 minutes. After cooling and adding 509 ml of N20 the mixture was concentrated. To the residue was added 2,54 l H2O and 2.54 l of AcOEt. After separation the aqueous layer was washed 1,02 l tO. To the aqueous layer was added 2,03 l 12% sulfuric acid at a temperature below 12º with obtaining the crystal of compound 6. Filtration, washing of 1.53 liters of cold H20 and drying gave 576 g of compound 6 (yield 83%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 7.67 (d, J=7.5 Hz, 1H), 7.5-7.2 (m, 5H), 6.40 (d, J=7.5 Hz, 1H), 5.07 (s, 2H), 4.2-4.0 (m, 1H), 3.9-3.6 (m, 2H), 3.38 (dd, J=4.2, and the 10.8 Hz, 1H), 3.27 (dd, J=6,0, to 10.8 Hz, 1H).

Example 3f

To a suspension of 576 g of compound 6 (1.0 equiv.; contains a 5.8% N2O) 2.88 l of NMP was added 431 Panso3(3.0 EQ.) and 160 ml under the conditions (1.5 equiv.) this mixture was stirred at room temperature for 4 hours. After cooling to 5 º C to this mixture at a temperature below 10 º C was added 1,71 l 2 N. HCl, and 1.15 l of 20% aq. NaCl obtaining crystalline compound 7. Filtration, washing 1,73 l H2O and drying gave 507 g of compound 7 (yield 89%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 7.59 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 5H), 6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H) 5.12 (d, J=the 10.8 Hz, 1H), 5.07 (d, J=10,8 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 3.97 (dd, J=2,4, a 14.1 Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=9,0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H), 3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H).

Example 3g

To a mixture of 15.0 g of compound 7 (1.0 EQ.) in 70.9 g MeCN was added to a mixture of 60 ml of N2Oh, 2.6 g H2SO4and 11.5 g NalO4in the temperature range from 17º to 14º. After stirring the reaction mixture for 1 hour the precipitate was filtered. The filtrate was added to a solution of 11.8 g of sodium salt of ascorbic acid, 64 g of water and 60 mg of H2SO4. After concentrating the mixture, cooling to 5ºC, filtering, rinsing, N2O and drying received by 12.9 g of compound 8 (yield 90%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 7.62 (d, J=7.5 Hz, 1H), 7.42-7.30 (m, 5H), 6.33 (d, J=6.0 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H), 5.08 (s, 2H), 4.95-4.85 (m, 1H), 3.80 (s, 3H), 3.74(d,J=5,1 Hz, 2H).

Example 3h

To a mixture of 10.0 g of compound 8 and 33.3 g of diglyme was added a solution of 3.3 g of (R)-3-amino-butane-1-ol 4.7 g diglyme and 1.0 g of acetic acid at 60°C. After stirring the reaction mixture at 95 º C for 9 hours this reaction mixture was cooled to -5 º C and filtered. Wet crystalline substance was washed and dried with the receipt of 8.3 g of compound 9 (78%).

The data of XRD (x-ray diffraction):

1H-NMR (300 MHz, CDCl3) δ 7.70-7.58 (m, 2H), 7.40-7.24 (m, 3H), 7.14 (d, J=7.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H), 5.35 (d, J=10,2 Hz, 1H), 5.28 (d, J=10,2 Hz, 1H), 5.12 (dd, J=3,9, 6.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.07 (dd, J=3,9, 13,5 the C, 1H), 4.00-3.86 (m, 3H), 2.23-2.06 (m, 1H), 1.48 (ddd, J=2,4, from 4.5 to 13.8 Hz, 1H), 1.30 (d, J=6.9 Hz, 3H).

Example 3i

To a suspension of 5.7 g of NBS 26.5 g of dichloromethane was added 10 g of compound (9) in 92.8 g of dichloromethane at room temperature. After stirring the reaction mixture for 6.5 hours, this reaction mixture was added to a solution of 2.0 g PA2SO3and 40.3 g of water. The organic layer was washed with dilute NaOH solution and with water, the dichloromethane was concentrated and was replaced by methanol. The mixture was cooled to -5 º C and was filtered and the wet crystalline substance was washed and dried to obtain 10.3 g of the compound 10 (84%).

1H-NMR (300 MHz, CDCl3) δ 7.69-7.63 (m, 2H), 7.59 (s, 1H), 7.38-7.24 (m, 3H), 5.33 (d, J=10,2 Hz, 1H), 5.25 (d, J=9.9 Hz, 1H), 5.12 (dd, J=3,9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.11 (dd, J=3,9, 13,2 Hz, 1H), 4.02-3.88 (m, 3H), 2.21-2.06 (m, 1H), 1.49 (ddd, J=2,4, 4,5, 14.1 Hz, 1H), 1.31 (d, J=6.9 Hz, 3H).

Example 3i

In an atmosphere of carbon monoxide mixture of 25.0 g of compound 10, 11.6 g ISO-RG2NEt, 12.8 g of 2,4-differentiatin, 335 mg of Pd(OAc)2and 1.9 g of 1,4-bis(diphenylphosphino)butane in 188 ml of DMA (dimethylacetamide) was stirred at 85 º C for 4 hours. After cooling, the reaction mixture was shared 10/25 mixture used in the next stage. To this reaction mixture at -40 ° C was added 6.6 g AcOEt, and 29.9 g of water and 3 mg of seed crystals. After stirring for 7 minutes was added and 29.9 g of water and cooled to room temperature. Crystalline substance on filytrovali at room temperature and washed to 47.2 g of ethanol to obtain 10.1 g of compound (11) (yield 83%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 10.40 (t, J=6.0 Hz, 1H), 8.35 (s, 1H), 7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J=9.9 Hz, 1H), 5.26 (d, J=10,2 Hz, 1H), 5.15 (dd, J=3,9, 5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.22 (dd, J=3,9, 13,5, 1H), 4.09 (dd, J=6,0, 13,2 Hz, 1H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1H), 1.50 (ddd, J=2,4, 4,5, 14.1 Hz, 1H), 1.33 (d, J=7.2 Hz, 3H).

Example 3k

In an atmosphere of hydrogen a mixture of 4.0 g of compound (11) and 0.8 g of 5% Pd-C with a humidity of 50% 67,6 ml THF and 1.6 ml of H2O was stirred for 1.5 hours at 50'C. Then to this reaction mixture was added a mixture of 80 mg NaHSO3and 2.0 ml of purified water and the reaction mixture was stirred for 1 hour, the precipitate was filtered off, washed with 20 ml THF and the filtrate was concentrated until of $ 11.97, After the addition of 6.7 ml of ethanol and 33.6 ml of purified water for 1 hour, the reaction mixture was cooled to 25 OC. Filtering, washing and 26.9 ml tO and drying gave 2,33 g of compound 12 (yield 82%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.36 (t, J=5.7 Hz, 1H), 8.50 (s, 1H), 7.39 (td, J=8,7, 6.3 Hz, 1H), 7.24 (ddd, J=2,6, 9,5, and 10.8 Hz, 1H), 7.12-7.00 (m, 1H), 5.44 (dd, J=3,9, 5.7 Hz, 1H), 4.90-4.70 (m, 1H), 4.65-4.50 (m, 1H), 4.54 (d, J=5,1 Hz, 2H), 4.35 (dd, J=6,0, to 13.8 Hz, 1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48 (m, 1H), 1.33 (d, J=6.9 Hz, 3H).

Example 3l

After dissolving 18.0 g of compound 12 (1.0 EQ.) in 54 ml tO with heating, followed by filtration to this solution at 80 ° C was added a 21.5 ml of 2 n aq. NaOH (1.0 EQ.). The solution was gradually cooled to room temperature. Phi is Tracy, wash 80 ml tO and drying gave 18,8 g of compound 13 (yield 99%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 10.70 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7,16 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.12 (m, 1H), 4.87-4.74 (m, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.35-4.25 (m, 1H), 4.16 (dd, J=1,8, a 14.1 Hz, 1H), 4.05-3.90 (m, 1H), 3.86-3.74 (m, 1H), 2.00-1.72 (m, 1H), 1.44-1.32 (m, 1H), 1.24 (d, J=6.9 Hz, 3H).

The equipment and conditions used for the preparation of graphic materials (Fig.1-7)are as follows.

Measurement pattern x-ray diffraction on powder

The used measurement conditions were the same as General Metrology measurements on the pattern of x-ray diffraction on the powder described in the Pharmacopoeia of Japan, fifteenth edition".

Instrumentation

Diffractometer RINT TTR III

The method

Mode of data collection was as follows.

Measurement method: method of parallel beam

The anode: si

Radiation: cuα

The current generator: 300 mA

Alternator voltage: 50 kV

The sample was prepared on an aluminum substrate.

The angle of incidence: 4º and 40º

Measurement in the analysis by infrared spectroscopy method

Mode of data collection was as follows.

Instrumentation

Spectrophotometer FT/IR-4200 type A (from JASCO Corporation)

The method

Measurement method: method of NGOs (frustrated total reflection)

Resolution: 4 (cm-1)

Detector: DLATGS

The accumulation of 32 scans

Measurement13C-NMR spectra in the solid state

The spectrum was obtained using the method of cross-polarization and rotation under magic angle (CP/MAS). Mode of data collection was as follows.

Instrumentation

Spectrometer: an NMR system Varian (1H frequency: 599,8 MHz)

The method

Sample: 3.2 mm T3 HX Probe

Width range: 43103,4 Hz

Time studies: 0.04

Delay repeat cycle: 10

Contact time: 3 MS

External standard: adamantane (carbon Metin: 38,52 million-1)

Temperature: 10

Speed MAS: 20 kHz.

Example

The starting material in example a is the connection 8, which is identical to the compound of formula (Ia). Thus, the Example And shows how to obtain the intermediate compounds for the compounds of formula 17 below, which is an isomer of the compound ZZ-2 on page 237 in WO 2006/116764 Brian Johns et al.

Example AA

After dissolution, the mixture of 320 g of compound 8 (1.0 EQ.) in 3,20 l Meon with the help of heating, the solution was concentrated. To the residue was added 1,66 l N, 5,72 ml Asón (0.1 EQ.) and of 82.6 g (5)-2-amino-propane-1-ol (1.1 EQ.) this mixture was heated to 70 º C, stirred at 70 º C for 4 hours and concentrated. To the residue was added 1,67 l of 2-propanol and the mixture was concentrated (twice). After cooling, the residue is shown that the emission, rinse 500 ml of cold 2-propanol and drying received 167 g of compound 14 (yield 52%) as a crystalline substance.

1H-NMR (300 MHz, CDCl3) δ 7.61-7.55 (m, 2H), 7.40-7.20 (m, 4H), 6.53 (d, J=7,2, 1H), 5.46 (d, J=10.5 Hz, 1H), 5,23 (d, J=10,2 Hz, 1H), 5.20 (dd, J=3,9, 9.6 Hz, 1H), 4.46-4.34 (m, 1H), 4.31 (dd, J=6,6, and 8.7 Hz, 1H), 4.14 (dd, J=3,9, 12.3 Hz, 1H), 3.79 (dd, J=9,9, 12.3 Hz, 1H), 3.62 (dd, J=6,9, and 8.7 Hz, 1H), 1.38 (d, J=6.3 Hz, 3H).

Example Ab

To a suspension of 156 g of compound 14 (1.0 equiv.) in 780 ml of NMP was added 93,6 g of NBS (1.1 EQ.) and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was added 3,12 l H2O. Filtering, washing 8,0 l H2O and drying gave 163 g of compound 15 (yield 84%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.55-7.50 (m, 2H), 7.42-7.25 (m, 3H), 5.34 (dd, J=3,6, 9.9 Hz, 1H), 5.18 (d, J=10,8 Hz, 1H), 5.03 (d, J=10.5 Hz, 1H), 4.53 (dd, J=3,6, 12.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.99 (dd, J=9,9, 11.7 Hz, 1H), 3.64 (dd, J=5,7, 8,1 Hz, 1H), 1.27 (d, J=6.3 Hz, 3H).

Example AC

In an atmosphere of carbon monoxide mixture 163 g of compound 15 (1.0 equiv.) 163 ml ISO-RG2Been certified with qi net (2.5 equiv.) 68,4 ml 2,4-differentiatin (1.5 EQ.) and 22.5 g of Pd(PPh3)4(of 0.05 EQ.) in 816 ml of DMSO was stirred at 90ºC for 7 hours. After cooling, removing the precipitate, washing with 50 ml of DMSO and added 11.3 g of Pd(PPh3)4(0,025 EQ.) the reaction mixture is again stirred at 90ºC for 2 hours in an atmosphere of carbon monoxide. After cooling, removal of sediment and add 2.0 l AcOEt 2.0 l H 2O the organic layer was washed with 1.0 l of 1 n aq. HCl and 1.0 l H2On (twice) and the aqueous layer was extracted with 1.0 l of AcOEt. The organic layers were combined and concentrated. Column chromatography of the residue on silica gel gave compound 16 (yield 96%) as a foam.

1H-NMR (300 MHz, CDCl3) δ 10.38 (t, J=6.3 Hz, 1H), 8.39 (s, 1H), 7.75-7.25 (m, 7H), 6.90-6.70 (m, 2H), 5.43 (d, J=10,2 Hz, 1H), 5.24 (d, J=10,2 Hz, 1H), 5.19 (dd, J=3,9, 9.9 Hz, 1H), 4.63 (d, J=6.0 Hz, 2H), 4.50-4.25 (m, 3H), 3.86 (dd, J=9,9, 12.3 Hz, 1H), 3.66 (dd, J=6,9, and 8.4 Hz, 1H), 1.39 (d, J=6.0 Hz, 3H).

Example Ad

In an atmosphere of hydrogen the mixture of 184 g of compound 16 (1.0 equiv.) and 36.8 g of 10% Pd-C in 3,31 l THF and 0.37 l Meon was stirred for 3 hours. After sediment filtration (Pd-C), rinsing with a mixture of THF/Meon (9/1) and add to 36.8 g of 10% Pd-C the mixture was stirred for 20 minutes in a hydrogen atmosphere. After sediment filtration (Pd-C) and washing with a mixture of THF/Meon (9/1), the filtrate was concentrated. After adding to the residue 200 ml of AcOEt filtration gave the crude solid connection 17. Sediments were combined and extracted with 4.0 l of a mixture Cl3/Meon (5/1). After concentration of this solution l3/Meon and adding to the residue 250 ml of AcOEt filtration gave the crude solid connection 17. The crude solids were combined and dissolved in 8.2 liters of a mixture of MeCN/H2O (9/1) by using heat. After filtration, the filtrate was concentrated. To the residue was added 1.5 l tO and the mixture was concentrated three times. After cooling the residue, filtering and drying, got 132 g of compound 17 (yield 88%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 11.47 (brs, 1H), 10.31 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 7.40 (td, J=8,6, 6,9 Hz, 1H), 7.24 (ddd, J=2,6, 9,4, 10,6, 1H), 7.11-7.01 (m, 1H), 5.39 (dd, J=4,1, 10.4 Hz, 1H), 4.89 (dd, J=4.2, and 12.3 Hz, 1H), 4.55 (d, J=of 6.0 Hz, 2H), 4.40 (dd, J=6,8, 8.6 Hz, 1H), 4.36-4.22 (m, 1H), 4.00 (dd, J=10,2, 12.3 Hz, 1H), 3.67 (dd, J=6,7, 8.6 Hz, 1H), 1.34 (d, J=6.3 Hz, 3H).

Example AE

After the dissolution of 16.0 g of compound 17 (1.0 EQ.) at 2.56 l tO and 0.64 l H2About using heating with subsequent filtering to this solution at 75º was added 39 ml of 1 n aq. NaOH (1.0 EQ.). The solution was gradually cooled to room temperature. Filtration, washing with 80 ml tO and drying gave 13.5 g of compound 18 (yield 80%) as a crystalline substance.

1H-NMR (300 MHz, DMSO-d6) δ 10.73 (t, J=6.0 Hz, 1H), 7.89 (s, 1H), 7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.07-6.98 (m, 1H), 5.21 (dd, J=3,8, 10,0 Hz, 1H), 4.58 (dd, J=3,8, 12.1 Hz, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.75 (dd, J=10,0, 12.1 Hz, 1H), 3.65-3.55 (m, 1H), 1.27 (d, J=6,1 Hz, 3H).

The example In

This example uses the method of inclusion ring nitrogen atom instead of an oxygen atom in pernovae ring and education equivalent of aldehyde catalyzed by osmium oxidation of the double bond. Thus, this example is not bromirovanii according to the invention.

Example VA

To bromobenzophenone (238 ml) solution of the is placed And (23,8 g; 110 mmol) was added selenium dioxide (24.4 g; 220 mmol). This reaction mixture was stirred for 13 hours at 140º with removal of water using nozzles Dean-stark. Insoluble particles were removed by filtration after cooling and the solvent evaporated. To the residue was added toluene and precipitation was filtered. After concentration under vacuum, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate). Compound (16.5 g; 65%) was obtained as a yellow oil.

1H-NMR (CDCl3) δ: 5.51 (2H, s), 6.50 (1H, d, J=5.4 Hz), 7.36 (5H, s), 7.75 (1H, d, J=5.4 Hz), 9.88(1H, s).

Example Bb

To a chilled on ice water (465 ml) solution of sodium chlorite (38,4 g, 424 mmol) and sulfamic acid (54,9 g, 566 mmol) was added acetone (465 ml) solution of the compound In (46,5 g, 202 mmol) and the mixture was stirred for 40 minutes at room temperature. After removal of the acetone under vacuum, the precipitation was collected by filtration and washed with cold water. Connection With (42.8 g; 86%) was obtained as a colourless crystalline substance.

1H-NMR (DMSO-d6) δ: 5.12 (2H, s), 6.54 (1H, d, J=5.6 Hz), 7.33-7.46 (5H, m), 8.20(1H, d, J=5.6 Hz).

Example Be

Ethanol (17 ml) solution of allylamine (13,2 g, 231 mmol) was added to ethanol (69 ml) suspension of compound C (17,2 g; 70 mmol), then the mixture was stirred for 4.5 hours at 50 º C and for 3 hours at 75 the S. To the cooled reaction mixture was added 2 N. hydrochloric acid and ice, and precipitation was collected by filtration. Compound D obtained in the form of a colorless crystalline substance.

1H-NMR (CDCl3) δ: 4.37 (2H, brs), 4.95 (2H, s), 5.26-5.39 (2H, m), 5.81-5.94 (1H, m), 6.32 (1H, dd, J=0,8, 7,2 Hz), 7.29-7.37 (3H, m), 7.48-7.51 (2H, m), 7.99 (1H, dd,J=0,8 and 7.6 Hz), 8.11 (1H, brs).

Example Bd

To the combined acetonitrile (146 ml) suspension of compound D (14.6 g; 51 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15.5 g; 102 mmol) and methyliodide (18,2 g, 128 mmol) and the mixture was stirred for 15 hours at room temperature. After evaporation of the solvent the residue was purified by column chromatography on silica gel (chloroform/methanol). Compound E (14.2 g; 93%) was obtained as colorless solid.

1H-NMR (CDCl3) δ: 3.75 (3H, s), 4.40 (2H, d, J=5.7 Hz), 5.16-5.35 (2H, m), 5.29 (2H, s), 5.81-5.94 (1H, m), 6.62 (1H, d, J=7.5 Hz), 7.27-7.42 (6N, m).

Example Be

To diethylamino (390 ml) solution of compound E (13.3 g; 44 mmol) was added dihydrate potassium osmate(VI) (1,62 g; 4.4 mmol) and metaperiodate sodium (28,1 g, 132 mmol). The mixture was stirred for 2.5 hours at room temperature and the precipitates were collected by filtration. The collected solid was dissolved in a mixture of chloroform-methanol and insoluble particles were filtered off. Concentration under vacuum gave the crude product of compound F (14.3 g).

1H-NMR (DMSO-d 6) δ: 3.23 (3H, s), 3.82 (3H, s), 3.87 (2H, t, J=4.4 Hz), 4.62 (1H, dd, J=11,7, 4,8 Hz), 5.11 (2H, s), 6.31 (1H, d, J=7.5 Hz), 6.78 (1H, d, J=6.6 Hz), 7.33-7.40 (5H, m), 7.64 (1H, d, J=7.5 Hz).

Example Bf

To chloroform (108 ml) and methanol (12 ml) solution of compound F (11,7 g, crude product) was added 3-aminopropanol (2,77 g; 36,9 mmol) and acetic acid (1.2 ml) and the mixture was stirred for 90 minutes at 70 º C. After concentration under vacuum, the residue was purified by column chromatography on silica gel (chloroform/methanol). Compound G (8,48 g; 72% over two stages) received in the form of a colorless crystalline substance.

1H-NMR (CDCl3) δ: 1.54-1.64 (1H, m), 1.85-2.01 (1H, m), 3.00 (1H, dt, J=3,6, 12.9 Hz), 3.74 (1H, dt, J=2.7, and 12.3 Hz), 3.93 (1H, dd, J=5,1, and 13.5 Hz), 4.07-4.21 (2H, m), 4.63-4.69 (1H, m), 4.94 (1H, t, J=4,8 Hz), 5.25 (2H, dd, J=10,2, 24.6 Hz), 6.56 (1H, d, J=7.5 Hz), 7.22-7.38 (5H, m), 7.63-7.66 (2H, m).

Example VD

To acetic acid (93 ml) solution of compound G (6,1 g; to 18.7 mmol) was added dropwise acetic acid (31 ml) solution of bromine (1,44 ml; 28,0 mmol) for 15 minutes. The mixture was stirred for 3 hours at room temperature. After addition of 5% aqueous hydrosulfite sodium (8 ml) dropwise over 20 minutes was added 2 n sodium hydroxide (500 ml). Precipitation was collected by filtration and washed with a mixture of dichloromethane and diisopropyl ether. Connection N (6,02 g; 79%) was obtained as a colourless crystalline substance.

1H-NMR (DMSO-d6)δ: 1.55-1.74 (2H, m), 3.12 (1H, dt, J=3,0, 12.3 Hz), 3.84 (1H, dt, J=2.7, and an 11.7 Hz), 4.00-4.05 (1H, m), 4.20-4.26 (1H, m), 4.40-4.46 (2H, m), 5.03 (2H, s), 5.15-5.17 (1H, m), 7.31-7.40 (3H, m), 7.56-7.58 (2H, m), 8.39 (1H, s).

Example Bh

To dimethylsulfoxide (1,42 ml) solution of compound H (71 mg; 0,175 mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.035 mmol) was added 4-forbindelsen (0.06 ml; 0,525 mmol) and Diisopropylamine (0.15 ml; 0,875 mmol), then the mixture was stirred in an atmosphere of carbon monoxide for 5 hours at 80 ° C. After cooling, was added saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The extract was washed with water and dried with anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (ethyl acetate/methanol). Compound I (74,5 mg; 89%) was obtained as a colourless crystalline substance.

1H-NMR (DMSO-d6) δ: 1.58-1.74 (2H, m), 3.10-3.18 (1H, m), 3.80-3.88 (1H, m), 4.02-4.07 (1H, m), 4.43-4.59 (5H, m), 5.05 (2H, s), 5.20 (1H, t, J=3,9 Hz), 7.13-7.19 (2H, m), 7.32-7.40 (5H, m), 7.56-7.59 (2H, m), 8.61 (1H, s).

The example

Synthesis of methyl 5-bromo-1 -[2-hydroxy-2-(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic (in equilibrium with the corresponding aldehyde).

This example demonstrates the change of purpose of compound 6, as shown above in Example 1 (compound of formula (VI)), including bromination position Rx, to obtain the final product is tov 20 and 21 (the compound of formula (I)). Such compounds with Br for Rxcan be subjected to interaction, as in Examples 1 and 2, attach the side chain R2-X-NR1-C(O)-.

Example Sa

Methyl-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic

The reactor was loaded 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridylcarbonyl acid 6 (4,302 kg; 13,47 mol) followed by loading Panso3(1,69 kg; 20,09 mol) and 242 g of deionized water. To this was added 21,4 kg of NMP, and the mixture was stirred and the temperature brought up to 28-35. To this reaction mixture for 1-3 hours was added dropwise via an addition funnel dimethylsulfate (2,34 kg; 18,30 mol), maintaining the temperature at 28-33º. The suspension was stirred at this temperature for 14 hours. When the process is deemed complete, the reaction mixture was cooled to 5ºC or below and the mixture was neutralized to pH 6 by adding HCI (561 ml conc. HCl in 2806 g deionized water). In the reaction vessel was slowly loaded cold 20% brine, consisting of 8,7 kg NaCl, 20 kg of deionized water and 14.8 kg of ice with a maximum temperature of 10ºC. The mixture was stirred at 0-10 º C for 2.5 hours. The suspension was filtered under vacuum and the residue on the filter was washed for 15 kg of deionized water two times. In the most important solid product was dried at 45-55 º C under vacuum until reaching constant weight. The desired product, methyl-1 -(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)-oxy]-1,4-dihydro-2-pyridinecarboxylic 7, received in the form of a light yellow solid (3.77 kg; purity 99,42% by HPLC; 84%).

1H-NMR (300 MHz, DMSO-d6) δ 7.60 (d, J=7.5 Hz, 1H), 7.36 (m, 5 H), 6.28 (d, J=7.5 Hz, 1H), 5.23 (d, J=5.4 Hz, 1H), 5.10 (Abq, J=10,8 Hz, 2H), 4.85 (m, 1H), 3.98 (dd, J=14,3, 2.4 Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=14,3, 9.0 Hz, 1H), 3.58 (m, 1H), 3.23 (m, 1H).

Example Cb

Methyl-5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic

The reactor was loaded methyl-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 7 (3,759 kg; 11,27 mol) and 188 l DMF. To this stirred mixture at 18-20 ° C was added N-bromosuccinimide (2,220 kg; 12,47 mol) over 20 minutes via a bulk hopper. The resulting mixture was stirred at room temperature for 16 hours. At this point it was determined through HPLC presence of less than 1% of the original substance. Half batch of this mixture was treated by cooling to 10 º C and added to a mixture of ice/water (12 kg of ice in 35 kg of deionized water) and the mixture was stirred, then filtered. This procedure was repeated for the second half of the party. The combined precipitate on the filter is washed with 14 l of water and dried in a vacuum oven to obtain 4,033 kg methyl-5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(fenil the Teal)oxy]-1,4-dihydro-2-pyridinecarboxylic 19 (of 91.6%) as a yellowish powder with a purity of 99.2% by HPLC.

1H-NMR (300 MHz, Methanol-d4) δ 8.21 (s, 1H), 7.41-7.33 (m, 5H), 5.16 (s, 2H), 4.17 (dd, J=14,3, 2.4 Hz, 1H), 3.90 (dd, J=14,3, 9.0 Hz, 1H), 3.81 (s, 3H), 3.78 (m,1),3.52(dd,J=11,3,4,8rH, 1H), 3.41 (dd, J=11,3, 6.3 Hz, 1H).

Example SS

Methyl-5-bromo-1-[2-hydroxy-2-(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)-oxy]-1,4-dihydro-2-pyridinecarboxylic (in equilibrium with the corresponding aldehyde)

The reactor was loaded periodate sodium (1,67 kg; 7.8 mol) and 44 liters of deionized water. To this stirred mixture was added to 8.5 kg of ice. It stirred up until all the ice is melted and the temperature of the mixture was 1,4ºC. To this was added methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridine-carboxylate 19 (2,73 kg; 6.62 mol) through a bulk hopper. The mixture was left to warm to room temperature and the suspension was stirred for 16 hours. The sample was controlled by means of1H NMR, and it was shown that starting material had been consumed. This mixture was filtered and the filter cake washed with 20 kg of deionized water. This procedure was repeated until then, until he received a negative result on ikramullah paper (4×20 l leaching). The solids were dried in a vacuum oven at 45-55ºC to obtain methyl 5-bromo-1-(2,2-dihydroxy-ethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 20 (2,176 kg; 88%) as a mixture with appropriate estoya aldehyde form 21. Found that the purity was 99.5% by HPLC.

1H-NMR (300 MHz, acetone-d6) δ 8.12 (s, 1H), 7.49-7.30 (m, 5H), 5.56 (dd, J=6,0, 2.4 Hz, 1H), 5.23 (m, 1H), 5.20 (s, 2H), 3.97 (d, J=5,1 Hz, 2H), 3.87 (s, 3H).

Example 2

Methyl-5-({[(2,4-differenl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic (in equilibrium with the corresponding aldehyde)

This example demonstrates the interaction of compound 5 of formula (II) with one of the compounds of the formula (III) in stage 1 and stage parafunctional (2) compounds of the formula (V) (compounds 22, 23, 24 and 25) to obtain the compounds of formula (I).

Example 2A

1-[2,2-Bis(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-piridinkarbonovaya acid

In a flask (1 l), loaded with 500 ml of anhydrous ethanol was added and 49.2 g (0.2 mol) of 4-oxo-3-[(phenylmethyl)oxy]-4H-Piran-2-carboxylic acid 5.

The suspension was slowly heated to 55~60 º C, then added dimethylacetal 2-amino-acetaldehyde (84,1 g; 0.8 mol). The reaction mixture was brought to 65 º C and was further stirred for 18 hours. The solvent was removed under reduced pressure to obtain 1-[2,2-bis(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridine-carboxylic acid 22 (crude) as a brown oil, which was used directly the next stage.

Example 2b

Methyl-1-[2,2-bis(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic

The crude 1-[2,2-bis(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridylcarbonyl acid 22 obtained as described above was dissolved in DMF (500 ml). To this solution was added Panso3(50.5 g; 0.6 mol). The suspension was intensively stirred with a mechanical stirrer while introduction of CH3I in TWO (tert-butyl methyl ether) (2.0 M; 300 ml) via a dropping funnel within 30 minutes. After the addition the reaction mixture was stirred over night at room temperature. The reaction mixture was then diluted tO (about 1.5 l) and washed with water and brine. The organic layer was dried over anhydrous Na2SO4. Evaporation of the solvent gave methyl-1-[2,2-bis(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 23 in the form of a brown oil which was used directly in the next stage.

Example 2C

Methyl-1-[2,2-bis(metiloksi)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic

In flask 2 l, equipped with a mechanical stirrer, was loaded methyl-1-[2,2-bis(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridine-carboxylate 23, which is obtained above, and 500 ml dichloro the Ana. In this flask portions was added NBS (30 g; to 0.17 mol). The reaction mixture was stirred at room temperature until completion of the interaction (controlled by TLC (thin layer chromatography), approximately 6 hours). This mixture then was diluted with dichloromethane and washed with NaHCO3(ss). The organic phase was dried over Na2SO4then the solvents evaporated. The crude product was purified by column chromatography (silica gel, tO/DHM: 0-40%) to give methyl 1-[2,2-bis(metiloksi)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 24 in the form of a light brown solid (50 g; 60% in three stages).

1H-NMR (400 MHz, chloroform-d) δ million-17.7 (s, 1H), 7.4 (m, 2H), 7.3 (d, J=7.9 Hz, 3H), 5.3 (s, 2H), 4.4 (s, 1H), 3.8 (d, J=4,8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H+): calculated 426 detected 426.

Example 2d

Methyl-1-[2,2-bis(metiloksi)ethyl]-5-({[(2,4-differenl)methyl]amino}-carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic

In the pressure vessel was loaded methyl-1-[2,2-bis(metiloksi)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 24 (6.4 g; 15 mmol), 2,4-differentiatin (3.2 g; to 22.5 mmol), K3RHO4(of 9.45 g; 45 mmol), Pd(OCOCF3)2(398 mg; 1.2 mmol), Xantphos (694 mg; 1.2 mmol) and toluene (200 ml). The mixture was purged WITH (4x), then was heated to 100ºC for cashow in the atmosphere (60 psi (0,41 MPa)). After cooling to room temperature the solids were filtered off through celite and washed tO. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, tO/hexane 0~80%) to give methyl 1-[2,2-bis(metiloksi)ethyl]-5-({[(2,4-differenl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 25 in the form of a light brown oil (4.7 g; 61%).

1H NMR (400 MHz, chloroform-d) δ million-110.4 (m, 1H), 8.4 (s, 1H), 7.4 (m, 6H), 6.8 (d, J=9,3 Hz, 2H), 5.3 (s, 2H), 4.6 (d, J=5.7 Hz, 2H), 4.5 (s, 1H), 4.0 (d, J=4,8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H+): calculated 517 detected 517.

Example 2E

Methyl-5-({[(2,4-differenl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(metiloksi)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic (in equilibrium with the corresponding aldehyde)

Methyl-1 -[2,2-bis(metiloksi)ethyl]-5-({[(2,4-differenl)methyl]amino}-carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic 25 (11.6 g) was treated with 90% formic acid (250 ml) at -40 ° C for about 12 hours (monitored by LC-MS (liquid chromatography-mass spectrometry)). After evaporation of the solvents at <40 º C, the residue was re-dissolved in tO (about 1 l) and the resulting solution was washed Panso3and brine. The organic phase is then dried over Na2SO4After evaporation of the solvents listed in the connection header 26 and 27 received in the form of an equilibrium mixture of about 80/20 (10,57 g).

1H-NMR (400 MHz, DMSO-d6) δ million-110.3 (m, 1H), 9.47 (s, aldehyde-H. ~N), 8.4 (m, 1H), 7.3 (s, 6H), 7.2 (m, 1H), 7.0 (m, 1H), 6.3 (m, 2H), 5.1 (s, 3H), 4.9 (m, 1H), 4.5 (m, 3H), 3.9 (m, 2H), 3.8 (s, 3H). LC-MS for 26 (M+N+): calculated 503, 503; 27 (M+H2O+N+): calculated 489, found 489.

Example SS

(4aS,13R)-N-[(2,4-Differenl)methyl]-10-hydroxy-9,11-dioxo-2,3,4A,5,9,11,13,13A-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-8-carboxamide

Example SAA: (4aS,13R)-8-Bromo-10-[(phenylmethyl)oxy]-2,3,4A,5,13,13A-hexahydro-1 H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-9,11-dione (DD)

The reactor was loaded [(2)-2-pyrrolidinyl]amine (0.75 kg) was added 4,6 l of DMF followed by the addition of 0.45 kg of glacial acetic acid. Then was added acetonitrile (41,4 l) and the mixture was stirred for 15 minutes. To the reaction mixture was added methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridine-carboxylate (2.30 kg). After stirring for 20 minutes at ambient temperature the mixture was heated at 75-to 85 º C until HPLC analysis did not confirm the expenditure bromides educt (approximately 6 hours). Upon completion the mixture was cooled to until delegacia not decreased, then loaded 6.9 l of methanol and the mixture was heated under reflux for about 45 minutes, then ohlord is whether to 15ºC, was filtered and dried to obtain (4S,13R)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4A,5,13,13A-hexahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-9,11-dione (1,93 kg; 78%) as a white solid.

1H-NMR (300 MHz, DMSO-d6) δ million-18.65 (m, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 5.15 (d, 1H), 4.99 (d, 1H), 4.60 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.06-2.84 (m, 3H), 1.92-1.60 (m, 4H).

Example b: (4S,13R)-N-[(2,4-differenl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4A,5,9,11,13,13A-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-8-carboxamide

Into a reaction vessel were loaded (4S,13R)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4A,5,13,13A-hexahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-9,11-dione (1.4 kg), 2,4-differentiatin (705 g), the base Hunya (1.4 l), dppf (60 g) and DMSO (12 l). The mixture was degirolami nitrogen of high purity 4 times. To this mixture was added triptorelin palladium(II) (18 g) in DMSO (2 l). The mixture was again degirolami 3 times with nitrogen of high purity and then blew WITH 3 times and left in an atmosphere of 45 psi (0.31 MPa). This mixture was heated at 80 ° C in an atmosphere of 45 psi (0.31 MPa) WITH up until HPLC analysis is not confirmed that the interaction is complete (24 hours). The mixture was cooled to room temperature and slowly transferred into ice-cold suspension of ammonium chloride. The mixture was filtered and washed with water and isopropanol. The residue was recrystallized from isop OPANAL to obtain (4aS, 13R)-N-[(2,4-differenl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4A,5,9,11,13,13A-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-8-carboxamide (952 g; 56%). Recrystallization mother liquor from isopropanol gave the second portion of the crystals of the desired product in the amount of 327 g (19%).

1H-NMR (300 MHz, DMSO-d6) δ million-110.44 (m, 1H), 8.55 (s, 1H), 7.56-7.07 (m, 8H), 5.18 (d, 1H), 5.03 (d, 1H), 4.62-4.54 (m, 4H), 4.06-3.60 (m, 3H), 3.20-2.80 (m, 3H), 1.93-1.60(m, 4H).

Example CAS: (4aS,13R)-N-[(2,4-differenl)methyl]-10-hydroxy-9,11-dioxo-2,3,4A,5,9,11,13,13A-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-8-carboxamide

In the reaction the pressure vessel was loaded (4aS,13aR)-N-[(2,4-differenl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4A,5,9,11,13,13A-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-8-carboxamide (950 g), 192 g of palladium on coal (moisture content 50%), ethanol (9,5 l) and concentrated ammonium hydroxide (124 ml). The mixture was degirolami with nitrogen 3 times and then placed in an atmosphere of 50 psi (0,345 MPa) of hydrogen as long as the interaction is not ended. The mixture was again degirolami nitrogen and then filtered through celite. The precipitate on the filter was extracted dephlegmation dichloromethane and then filtered. The combined filtrates were concentrated to small volume (4 l)was subjected to azeotropic distillation with ethanol (28,5 l) to a final volume of 9 liters of the Slurry was filtered whom, washed with ethanol and dried to obtain (4aS,13aR)-N-[(2,4-differenl)methyl]-10-hydroxy-9,11-dioxo-2,3,4A,5,9,11,13,13A-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazin-8-carboxamide (616 g; 78,4%) as a white solid.

1H-NMR (300 MHz, DMSO-d) δ million-110.37 (m, 1H), 8.42 (s, 1H), 7.41-7.05 (m, 3H), 4.72-4.53 (m, 4H), 4.05 (m, 1H), 3.86 (m, 1H), 3.70 (m, 1H), 3.16 (m, 1H), 2.88 (m, 2H), 1.92-1.60 (m, 4H).

1. The method of obtaining Spiridonovka the compounds of formula (AA), (BB) or (CC):


,
incorporating the following stages:
- P-1) of the synthesized compounds of the following formula (I-I) obtaining bromine compounds of the following formula (II-II):
,
where R represents-CHO, -CH(OH)2, -CH(OH)(OR4), -CH(OH)-CH2OH, or-CH(OR5)(OR6);
P1represents benzyl;
P3represents H or a protective group carboxyl;
R4represents lower alkyl;
R5and R6independently represent lower alkyl or R5and R6can represent alkyl and be connected with the formation of 5-, 6 - or 7-membered ring,
- P-2) education of the side chain of 2,4-di-forfinal-CH2-NH-C(O)- using reagents 2,4-di-forfinal-CH2-NH2and carbon monoxide,
- the stage of formation of ring Q using the appropriate amine selected from 3-amino-butane-1-ol, 2-amino-propane-1-ol and 2-pyrrolidinedione, and
- stage dibenzylamine with obtaining the compounds of formula (AA), (BB) or (CC),
where specified stage R-2, conducted after the formation of the ring Q.

2. The method according to claim 1, where the specified Spiridonova compound is a compound of formula (AA).

3. The method according to claim 1, where the specified Spiridonova compound is a compound of formula (BB).

4. The method according to claim 1, where the specified Spiridonova compound is a compound of formula (CC).

5. The compound of the following formula (DD):

where P1represents benzyl.

6. The method according to claim 1, where P1represents benzyl; P3represents methyl and R represents-CHO, -CH(OH)(OR4), -SN(OR5)(OR5), where R4and R5represent lower alkyl.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

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10 cl, 45 ex, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel spirocyclic azaindole derivatives of formula I: , where: one of A stands for N, and the other ones stand for CR7-10; W stands for NR4; X stands for O, S; R1 and R2, independently on each other stand for H; C1-5-alkyl each time saturated, branched or unbranched, non-substituted or monosubstituted with -OC1-6alkyl; phenyl, thienyl, morpholinyl, benzothiophenyl or benzodioxilyl, each time non-substituted or monosubstituted with F, C1-6alkyl; or 5-membered heteroaryl, containing three nitrogen atoms as heteroatoms, substituted with C1-3alkyl; bound with C1-3-alkyl group phenyl non-substituted or monosubstituted with F or C1-6alkyl; R4 stands for H; R5 stands for H; R6 stands for H; R7, R8, R9 and R10 stand for H or CP3; in form of siastereomers, mixtures of diastereomers or separate diastereomer; bases and/or salts of physiologically compatible acids. Compounds are suitable for treatment of a number of diseases, for instance, pain, stress, depressions, etc. Described is method of their obtaining.

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11 cl; 1 tbl; 34 ex

FIELD: chemistry.

SUBSTANCE: compounds, which have formula I , in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have values given in description and are inhibitors of receptor tyrosinkinases, useful in treatment of diseases, mediated by class 3 and class 5 receptor tyrosinkinases. It has been also discovered that specific compounds of the claimed invention are Pim-1 inhibitors. Also claimed is method of obtaining formula I compound.

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27 cl, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

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14 cl, 2 tbl, 8 ex

FIELD: medicine; pharmacology.

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14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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23 cl, 1 tbl, 57 ex

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5 cl, 17 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

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7 cl, 1 dwg, 24 ex

FIELD: organic chemistry of heterocyclic compounds, biology, medicine, pharmacy.

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9 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

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22 cl

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16 cl, 98 ex

FIELD: medicine.

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20 cl, 9 dwg, 7 ex

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to new imidazolidine formulas (I) and (II) in which a is a =N-CR=CR-CR=, =CR-N=CR-CR=, =CR-CR=N=CR or = CR-CR= CR-N= ; B represents-NR-C(R)2-C(R)2-C(R)2C(R)2-NR-C(R)2-C(R)2, -C(R)2-C(R)2-NR-C(R)2or C(R)2-C(R)2-C(R)2-NR, where R is hydrogen, R1is hydrogen, unsubstituted or substituted C1-20-alkyl, C1-20-alkylene-NR3-Q-X-R4where Q represents-CO-or-SO2-, X is a simple bond, -O - or-NR3and R4- aryl, heteroaryl, heterocyclyl or1-20-alkyl or C2-20alkenyl
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FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: presented group of inventions refers to medicine. What is presented is a pharmaceutical composition representing a tablet formulation containing ritonavir in a first layer and atazanavir in a second layer, and a polymer. What is presented is a method for preparing the above pharmaceutical composition wherein a hot melt of rinonavir is extruded to prepare an extrudate to be placed into the first tablet layer, and atazanavir - into the second layer; the first and second layers are combined providing a single multilayer tablet. What is presented is a composition prepared by the method described above to be used in treating HIV or AIDS, and a method of treating HIV or AIDS.

EFFECT: presented group of inventions is effective in creating the multilayer tablet providing a good bioavailability for ritonavir, wherein atazanavir is not degraded in preparation.

19 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

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