Derivatives indolizine, the method of production thereof, pharmaceutical composition, method of inhibiting testosterone 5-reductase

 

(57) Abstract:

Derivatives indolizine formula I, where R1- carboxyl, the ester carboxyl; R2is hydrogen, lower alkyl, halogen; R3is aryl or ar(lower)alkyl, (lower) allylcarbamate(lower)alkyl, (lower)alkylaminocarbonyl- (lower)alkyl; R11is hydrogen, lower alkyl; - lower alkylene, possibly substituted by exography, lower Alcanena; Q is carbonyl, lower alkylene; R4, R5is hydrogen, lower alkyl; y is a bond, lower alkylene; z - low alkylene, lower albaniles, R6is hydrogen, lower alkyl, ar(lower) alkyl which may have suitable Deputy; and their pharmacologically acceptable salts. Produced by interaction of the compounds of formulas II and III, where W10acid residue. The compounds I can be used as inhibitors of testosterone-5-reductase for the treatment and prevention mediated testosterone-5-reductase diseases, such as alopecia, acne, prostatism. 4 C. and 9 C.p. f-crystals.

This invention relates to new heterocyclic compounds and their pharmaceutically acceptable salts. More specifically, this invention relates to new heterocyclic compounds and to their farmaci is wearing a testosterone-5-reductase, and similar, to a method for producing these compounds and their salts, containing their pharmaceutical compositions and to the use of these compositions as medicaments.

In accordance with the present invention is the creation of new heterocyclic compounds and their pharmaceutically acceptable salts that can be used as inhibitors of testosterone-5 - reductase.

Another objective of the present invention is to develop a method of obtaining the above heterocyclic compounds and their salts.

The next objective of the present invention to provide pharmaceutical compositions containing as active ingredient specified heterocyclic compounds or their pharmaceutically acceptable salts.

Another objective of the present invention is the use of these heterocyclic compounds or their pharmaceutically acceptable salts as drugs, such as inhibitors of testosterone-5 - reductase inhibitor used to treat or prevent mediated testosterone-5-reductase diseases, such as alopecia, acne, prostatism and detailed, in humans and animals.


< / BR>
where

R1represents carboxyl or protected carboxyl group;

R2represents a hydrogen atom, a lower alkyl group or halogen atom;

R3represents aryl or ar(lower)alkyl group, each of which may contain suitable substituents, [substituted carbarnoyl] (lower)alkyl group or a group of the formula

< / BR>
in which

represents a nitrogen-containing heterocyclic group, and n is 0 or 1;

R11represents a hydrogen atom or a lower alkyl group;

A represents the lower alkylenes group, which may contain as a substituent oxoprop, or lower alkynylamino group;

Q represents carbonyl or lower alkylenes group;

X is a

where

R4represents a hydrogen atom, a lower alkyl group or a group Y-Z - R3and R5represents a hydrogen atom, a lower alkyl group,

Y represents a chemical bond or a lower alkyl group,

Z represents alkylenes group, lower alkenilovyh group, -O - or , where R6represents a hydrogen atom, is the group for amino group.

According to the present invention, the target compound of formula (I) can be obtained by the following methods.

In the diagrams above reactions R1, R2, R3, R4, R5, R11A, Q, X, Y, and Z take on the values specified above;

R1arepresents a protected carboxyl group;

R3ais an ar(lower)alkyl group, which may contain suitable substituents, [substituted carbarnoyl]-(lower)alkyl group or a group of the formula

< / BR>
where

and n take the values defined above;

R6brepresents a protective group for amino group;

R6crepresents a lower alkyl group, ar(lower)-alkyl group, which may contain suitable substituents, or a protective group for amino group;

R7represents an aryl group which may contain suitable substituents;

R8represents a protective group for carboxyl group;

R9represents an amino group which may contain suitable substituents;

W1represents a leaving group;

each of the groups W1aalkylenes group;

Z1represents-O - or where R6arepresents a hydrogen atom, a lower alkyl group or a protective group for amino group and

Z2represents-O - or where R6takes the values defined above.

Suitable salts of the compounds of formula (I) are conventional, well known, non-toxic, pharmaceutically acceptable salts include salts obtained by the interaction with the bottom, and salt, obtained as a result of the merger acids, such as salts with inorganic bases, for example alkali metal salts (for example, salts of sodium, potassium, cesium, and so on), ammonium salts, salts of alkaline earth metals (e.g. calcium salt, magnesium, and so on); salts with organic bases, for example salts of organic amines (for example, salts of triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenziletilendiaminom and so on) and so on; salt accession inorganic acid (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); salt accession of organic carboxylic or sulfonic acids (e.g., formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, p-toluensulfonate, glutaminovoi acid and so on); and salts, similar to the above. Preferred salts are obtained as a result of the merger acid.

As for the salts of compounds (I-a)-(I-k), (II), (III), (IIIa), (IV), (V), (VI), (VII), (VIII), (XII) and (XXI), referred to in ways 1-10, for them examples of preferred salts are similar to those for the target compound (I).

Below is given a detailed explanation of those definitions, which are found above and below in the text of this description.

The term "lower", unless otherwise specified, means from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.

Groups covered by the term "lower alkyl" may include groups of normal or branched chain structure with a number of carbon atoms from 1 to 10, such as methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, tert-bucilina, pentilla, hexeline, heptylene, anjilina, Danilina, decile and similar groups are preferably the number of carbon atoms from 1 to 6, more preferably the number of carbon atoms from 1 to 4.

The term "halogen atom" means fluorine atoms, chlorine, bromine and iodine.

The term "lower Allenova covers the bivalent nissaya, tetramethylaniline, pentamethylene, hexamethylene, propylene and similar groups, which may contain as a substituent oxoprop.

The term "leaving group" includes a hydroxyl group, a reactive group derived from the hydroxyl group, and similar groups.

The term "reactive group derived from the hydroxyl group", covers the remains of acids and similar groups.

The term "acid residues" refers to the atoms of halogen (e.g. fluorine, chlorine, bromine, iodine), alloctype (for example, acetoxy, tosyloxy, mesilate, etc) and similar groups.

The term "lower Alcanena covers alkenylamine group with the number of carbon atoms from 2 to 6, such as venelinova, propylea and similar.

The term "aryl group which may contain suitable substituents" includes groups such as aryl (e.g. phenyl, naftalina and so on), substituted aryl, for example, lower kalkilya (for example, Tomilina, xylella, mesitylene, camelina, isobutylphenyl and so on), halogenoalkane (for example, chloraniline, etc. and similar.

The term "ar(lower)alkyl, y is 1-C10alkyl group, a normal or branched structure, substituted by one or more aryl groups; examples of the ar(lower)alkyl groups, which may contain suitable substituents include groups such as ar(lower)alkyl (e.g., triticina, benzydamine, benzyl, fenetylline, naphthylmethyl, 1-phenylethylene, phenylpropionate, phenylbutyrate, phenylmethylene, phenylhexane, phenylephrine, phenylethylene, finaldestiny, 2,2-dimethyl-1-phenylpropionate and so on), substituted [ar(lower)-alkyl] , for example, ar(lower)alkyl, substituted by one or more substituents, such as the above alkyl groups, the above-mentioned halogen atoms, cyano, carboxyl group, protected carboxyl group, containing the following protective group, the above-mentioned aryl group, which may contain suitable substituents listed below amidarone carboxyl group, lower alkoxygroup (for example, methoxy, ethoxy-, propoxy -, etc.,), hydroxy(lower)alkyl groups (for example, hydroxyisobutyrate group, etc.,), protected hydroxy(lower)alkyl groups such as lower alkanoyloxy(lower)alkyl groups (for example, the PAP, cyclobutylmethyl group and so on), the lower alkeneamine group (for example, vinyl, protanilla, bucinellina and so on) and lower alkyline group (for example, etinilnoy, proponila, Butyrina group and so on). Specific examples of certain so "ar(lower)alkyl groups, which may contain suitable substituents" may serve the following groups: methylaniline, isobutylbenzene, (were)ethyl, (isobutylphenyl)ethyl, (were)through (isobutylphenyl)through (isobutylphenyl)bucilina, (were)pencilina, (isobutylphenyl)pencilina, (isobutylphenyl)exilda, (isobutylphenyl)Reptilia, (isobutylphenyl)anjilina, bis(were)methyl, bis(propylphenyl)methyl, bis(butylphenyl)methyl, (cyano)(isobutylphenyl)methyl, (carboxy)(isobutylphenyl)methyl, (benzyloxycarbonyl)(isobutylphenyl)methyl, (N,N-diethylcarbamoyl)(isobutylphenyl)of methyl (tert-butylcarbamoyl)(isobutylphenyl)methyl, (isobutylparaben)(isobutylphenyl)methyl, (butylcarbamoyl)(isobutylphenyl)methyl, (heptylcarbinol)(isobutylphenyl)methyl, (ethoxy)(isobutylphenyl)ethyl, (isobutylphenyl)triptoreline, (phenyl)(isobutylphenyl)methyl, [(isobutyl)(IU shall etoksietil)phenyl] pencilina, (cyclopropylmethyl)bucinellina, (isobutylphenyl)Butyrina, (isobutylphenyl)bucinellina, (isobutylphenyl)penttila and similar.

"Aminosidine group" can be a well-known protective groups used in organic chemistry, for example, acyl groups such as lower alcoholnye (for example, formyl, acetyl, propylaniline, Butyrina, isobutylene, valerina, isovaleryl, bialoleka, hexanoyl and so on), the lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc. and similar.

"Carboxyamide group" may be an esterified carboxy group.

Examples of the ester residue "esterified carboxyl group" may serve as the lower alkalemia esters (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl methyl ether, pentalogy ester, hexyl ester, 1-cyclopropylethyl ether and so on), which may contain at least one suitable Deputy, for example, lower alkanoyloxy(lower)alkalemia esters (naprimer, pivaloyloxymethyl ether, hexaniacinate ester, 1(or 2)-ecotoxicology ester, 1(or 2 or 3)-acetoxypropionyl ester, 1(or 2 or 3 or 4)-acetoxyvalerenic ester, 1(or 2)-propionylacetate ester, 1(or 2 or 3)-propionoxypiperidine ester, 1(or 2)-butyrylacetate ester, 1(or 2)-isobutyrylacetate ester, 1(or 2)-hexanolactone ether, isobutyrylacetate ether, 2-ethylbutyraldehyde ether, 3,3-dimethylbutylamino ether, 1(or 2)-pentanedinitrile ether, etc.,), the lower alkanesulfonyl(lower)alkalemia esters (for example, 2-mutilative ether, etc.,), mono (or di - or tri-)-halogeno (lower)alkalemia esters (for example, 2-iodoethylene ether, 2,2,2-trichlorethylene ether, etc.,), lower alkoxycarbonyl (lower)alkalemia esters (for example, methoxycarbonylmethyl ether, ethoxycarbonylmethylene ether, 2-methoxycarbonylethyl ether, 1-ethoxycarbonylmethylene ether, 1-isopropoxycarbonyloxymethyl ether, etc.,), thalidomide(lower)alkalemia esters or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)-(lower)alkalemia esters (for example, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3 dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3 dioxol-4-yl) ethyl ester, etc.,) Nissi levy ether, propenyloxy ether and etc.); ar(lower)alkalemia esters, which may contain at least one suitable substituent (for example, benzyl ester, 4-methoxybenzyloxy ether, 4-nitrobenzyloxy ether, finitely ether, trailovic ether, benzhydrylamine ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ether, 4-hydroxy-3,5-di-tert-butylbenzylamine ether, etc.,); arrouye esters, which may contain at least one suitable substituent (for example, phenyl ester, 4-hlorfenilovy ether, trilogy ether, tert-BUTYLPEROXY ether, Kilroy ether, mesityloxy ether, tomilovy ether, etc.,); palidrome esters and similar.

Examples of preferred esterified carboxyl groups mentioned above include lower alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, solutionline, tert-butoxycarbonyl, ventilatsiooniga, tert-ventilatsiooniga, hexyloxymethyl, 1-cyclopropanecarbonyl and so on).

"Protective group for a carboxyl group may be an ester residues defined above "protected carbon the groupings (for example, benzyl, etc., and similar.

"Amino group which may contain suitable substituents", are known amino group used in the pharmaceutical field, and can include amino group, mono - or di(lower)alkylamino (for example, methylamino-, dimethylamino-, ethylamino, diethylamino, butylamino-, tert-butylamino, heptylamine and so on), killingray (for example, phenylaminopropyl, etc.,), (lower)alkylarylsulfonate (for example, isobutyleneisoprene, etc. and similar.

"Nitrogen-containing heterocyclic group" may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom. Particularly preferred heterocyclic groups are 5 - or 6-membered aliphatic heterogenities group (for example, morpholinyl, pyrrolidinyl, imidazolidinyl, piperideine, piperazinilnom and etc.), unsaturated condensed heterocyclic groups, such as dibenzo(6 - or 7-membered unsaturated)heterogenities group (for example, phenoxystyrene, phenothiazinyl, 10,11-dihydro-5H-dibenzazepine, etc) and similar.

Kodama substituents; examples include karbamoilnuyu group, mono - or di(lower) alkylcarboxylic group (for example, methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol, diethylcarbamoyl, butylcarbamoyl, tert-butylcarbamoyl, heptylammonium etc.) (lower)alkylaminocarbonyl group (for example, isobutyleneisoprene, etc) and similar.

The term "[substituted carbarnoyl] (lower)alkyl" encompasses carbarnoyl(lower)alkyl group in which carbamoyl residue contains one or two substituent; examples of suitable substituents include groups such as the aforementioned lower alkyl and aryl containing the above-mentioned suitable substituents. Specific examples defined thus "[substituted carbarnoyl] (lower)alkyl" groups are butylcarbamoyl, 1-(heptylcarbinol)ethyl, isobutyltrimethoxysilane, 1- (isobutylphenyl)-ethyl and the like groups.

Preferred values for R1, R2, R3, R11, A, Q, X, Y, and Z are the following:

for R1: carboxyl group; esterified carboxyl group, such as lower alkoxycarbonyl, more prefer the(lower)alkoxycarbonyl group, more preferably mono-, di - or triphenyl(C1-C4)alkoxycarbonyl (for example, benzyloxycarbonyl and so on);

for R2: a hydrogen atom; a lower alkyl group, more preferably - C1-C4alkyl (e.g. methyl, etc); or a halogen atom (for example, chlorine and so on);

for R3: aryl group which may be substituted by a lower alkyl group, more preferably phenyl group, substituted C1-C4alkyl group (for example, isobutylphenyl and etc.); ar(lower)alkyl group, which may contain one or more substituents selected from the group consisting of lower alkyl groups, halogen atoms, ceanography, carboxy groups, protected carboxy groups, emitirovannykh carboxyl groups, lower alkoxygroup, hydroxy(lower)alkyl group, a protected hydroxy(lower)-alkyl group, cyclo(lower)alkyl groups, lower alkenyl groups and lower etkinlik groups, more preferably mono-, di - or triphenyl(lower)alkyl group which may contain from one to four substituents selected from lower alkyl groups, halogen atom, ceanography, carboxyl group, phenyl(lower)and infininininini groups, lower alkoxygroup, hydroxy(lower)alkyl group, a lower alkanoyloxy(lower)alkyl group, cyclo(lower)alkyl(lower)alkyl groups, lower alkenyl groups and lower etkinlik groups, most preferably mono-, di - or triphenyl(C1-C10)alkyl group, which may contain from one to four substituents selected from (C1-C10))alkyl groups, halogen atoms, ceanography, carboxyl group, phenyl(C1-C4)alkoxycarbonyl groups, mono - or di(C1-C10)-alkylcarboxylic groups, phenylcarbamoyl groups, (C1-C4)-alkylresorcinols groups, (C1-C4)alkoxygroup, hydroxy(C1-C4)alkyl groups, (C1-C4)alkanoyloxy (C1-C4)alkyl group, cyclo(C3-C6)alkyl(C1-C4)alkyl groups, (C2-C4)-alkenyl groups, and (C2-C4)etkinlik groups (e.g. benzyl, isobutylbenzene, (isobutylphenyl)ethyl, (isobutylphenyl)through (isobutylphenyl)bucilina, (isobutylphenyl)pencilina, (isobutylphenyl)exilda, (isobutylphenyl)-heptylene, (isobutylphenyl)anjilina, bis(isobutylphenyl)methyl, bis(chlorophenyl)methyl, (cyano is, (tert-butylcarbamoyl)(isobutylphenyl)methyl, (N,N-diethylcarbamoyl)(isobutylphenyl)-methyl, (phenylcarbamoyl)(isobutylphenyl)methyl, (isobutylparaben)(isobutylphenyl)-methyl, (butylcarbamoyl)(isobutylphenyl)methyl, (heptylcarbinol)(isobutylphenyl)methyl, (ethoxy)(isobutylphenyl)ethyl, (isobutylphenyl)(Cryptor)bucilina, (phenyl)(isobutylphenyl)methyl, [(isobutyl)(methoxy)phenyl] pencilina, [(fluoride)(isobutyl)phenyl] pencilina, [(fluoride)(hydroxyisobutyryl)phenyl] pencilina, [(fluoride)(acetoxyisobutyryl)phenyl] pencilina, (cyclopropylmethyl)bucinellina, (isobutylphenyl)Butyrina, (isobutylphenyl)bucinellina, (isobutylphenyl)penttila group and so forth; carbarnoyl(lower)alkyl group in which carbamoyl residue contains one or two substituent selected from the group consisting of lower alkyl and lower alkylphenyl groups, more preferably - (C1-C10)allylcarbamate(C1-C4)-alkyl group, or (C1-C4)alkylresorcinol (C1-C4)an alkyl group (for example, heptylcyclopentanone, isobutyltrimethoxysilane, isobutyltrimethoxysilane group and so on); 5 - or 6-membered aliphatic, heterophilically the I group (for example, phenoxypyridine, phenothiazinyl, 10, 11-dihydro-5H-dibenzo [b,f]aspenlea group and so on);

for R11: a hydrogen atom; a lower group, more preferably - C1-C4alkyl group (e.g. methyl, etc.,);

for A lower Allenova group which may be substituted by exography, more preferably - C1-C4Allenova group which may be substituted by oxopropoxy (for example, ethylene, trimethylene, extremelyeasy group and so on); or lower alkenylamine group, more preferably a C2-C4alkenylamine group (for example, propylea group and so on);

for a Q: a carbonyl group or a lower Allenova group, more preferably a C1-C4Allenova group (for example, methylene group, and so on);

for X: ,

where

R4represents a hydrogen atom or a lower alkyl group, more preferably a C1-C4alkyl group (e.g. methyl group, etc.,), R5represents a hydrogen atom, a lower alkyl group, more preferably a C1-C4alkyl group (e.g. methyl, etc.,), or ar(lower)alkylamino, which can be substituted one or several whom SUB>1-C4)alkylenediamine - or N-(C1-C4)alkoxycarbonyl-N-(C1-C4) alkylenediamines (for example, isobutylbenzene-, N-tert-butoxycarbonyl-N-isobutylbenzene and so on);

for Y: a chemical bond; or lower Allenova group, more preferably - C1-C4Allenova group (e.g. methylene, etc.,);

for Z: lower Allenova, more preferably C1-C4Allenova (for example, methylene, etc.) group, a lower Alcanena, more preferably C2-C4Alcanena (for example, venelinova etc.) group; -O - or where R6represents a hydrogen atom, a lower alkyl group, preferably - C1-C4alkyl group (e.g. methyl, ethyl, etc.,), the lower alkoxycarbonyl, preferably - C1-C4alkoxycarbonyl group (e.g. tert-butoxycarbonyl and so on), ar(lower)alkyl group which may be substituted by a lower alkyl group, more preferably a mono-, di - or triphenyl(lower)alkyl group which may be substituted by a lower alkyl group, most preferably mono-, di - or triphenyl-(C1-C6) alkyl group, which ="ptx2">

How 1-10 obtain the target compound (I) of the present invention are described in detail below.

Method 1. The target compound (I-a) or its salt can be obtained by reaction of compound (II) or its salt with the compound (III) or its salt.

Typically, this reaction is performed in the environment of a solvent, such as alcohol (e.g. methanol, ethanol, etc.,), dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether, toluene or any other solvent that does not adversely influence the reaction.

If W1in compound (III) represents the balance of acid, the reaction can be carried out in the presence of inorganic or organic bases, such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.,), a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, etc.,), bicarbonate of an alkali metal (e.g. sodium bicarbonate, potassium bicarbonate, etc.,), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.,), three(lower)alkylamine (for example, trimethylamine, triethylamine, diisopropylethylamine and etc.), pyridine or its derivative (e.g. picoline, lutidine, 4-dimethylaminopyridine, etc) and similar. In this case,ASS="ptx2">

If W1in compound (III) is a hydroxyl group, the reaction is usually carried out in the presence of standard condensing agent such as N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinobutyrophenone, N-cyclohexyl-N'-(4-diethylaminoethoxy)carbodiimide, N,N'-diethylcarbamoyl, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N, N'-carbonyl-bis(2-Mei), pentamethylene-N-cyclohexylamine, diphenylethan-N-cyclohexylamine, ethoxyacetylene, 1-alkoxy-1-chlorethylene, trialkylphosphites, etiloleat, isopropylpalmitate, phosphorus oxychloride (phosphorylchloride), trichloride phosphorus, thionyl chloride, oxalicacid, lower alkylhalogenide (for example, ethylchloride, isopropylcarbamate and so on), the combination of triarylphosphine (for example, triphenylphosphine, etc.,) or three(lower)alkylphosphine (for example, triethylphosphine and so on) with di(lower)alkylsalicylate (for example, diethylazodicarboxylate and so on ), salt with 2-ethyl-7-hydroxybenzotriazole, intramolecular salt of 2-ethyl-5-(metasulfite)isoxazole, 1-(parachlorobenzotrifluoride)-6-chloro-1H-benzotriazol, the so-called reagent of Vilsmeier obtained by the reaction of N,N-dimethylformamide with thionyl chloride, is ur reaction is not a significant factor; the reaction can be carried out with cooling, at room temperature or when heated.

Method 2. The target compound (I-b) or its salt can be obtained by reaction of the compound (IV) or its salt with the compound (V) or its salt.

Typically, this reaction is performed in the environment of a solvent, such as alcohol (e.g. methanol, ethanol, etc.,), dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent that does not adversely influence the reaction.

The reaction can be carried out in the presence of inorganic or organic bases, such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.,), a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, etc.,), bicarbonate of an alkali metal (e.g. sodium bicarbonate, potassium bicarbonate, etc.,), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.,), three(lower)alkylamine (for example, trimethylamine, triethylamine, diisopropylethylamine and so on), pyridine or its derivative (e.g. picoline, lutidine, 4-dimethylaminopyridine) and similar. In the case when the base is liquid, it can simultaneously sluice when cooled, at room temperature or when heated.

Method 3. The target compound (I-c) or its salt can be obtained by reaction of the compound (VI) or its salt with the compound (IIIa) or its salt.

This reaction can be performed exactly the same as the reaction of method 2, therefore, the reaction conditions (solvent, temperature, etc) are the same as described above in method 2.

This reaction includes the option that, when R1represents a carboxyl group, it protects or during the reaction, or after it on a separate stage.

Method 4. The target compound (I-e) can be obtained by deprotection carboxyl group in compound (I-d) or its salt.

For this reaction deprotection can be applied to any of the standard methods used to delete a group that protects carboxyl, for example hydrolysis, repairing, removing, using a Lewis acid, etc., When the protective group is an ester group can be removed by hydrolysis or elimination using Lewis acid. Preferably the hydrolysis is carried out in the presence of a base or acid.

Examples of suitable osnovanijah potassium, and so p.), hydroxide of alkaline earth metals (e.g. magnesium hydroxide, calcium hydroxide, etc.,), carbonates of alkali metals (e.g. sodium carbonate, potassium carbonate, etc.,), carbonates of alkaline earth metals (e.g. magnesium carbonate, calcium carbonate, etc.,), bicarbonates of alkali metals (e.g. sodium bicarbonate, potassium bicarbonate, etc.,), the acetates of alkali metals (e.g. sodium acetate, potassium acetate, etc.,), phosphates of alkaline earth metals (e.g. magnesium phosphate, calcium phosphate, etc.,), the hydrogen phosphates of alkali metals (e.g. sodium phosphate, potassium phosphate, etc., and similar, and also organic bases, such as trialkylamine (for example, trimethylamine, triethylamine, etc.,), picoline, N-methylpyrrolidine, N-methylmorpholine, 1.5-diazabicyclo [4.3.0]non-5-he, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[5.4.0]undecen-5 and similar to them. The hydrolysis using a base is usually carried out in water or a hydrophilic organic solvent or a mixture thereof.

Examples of suitable acids include organic acids (e.g. formic acid, acetic acid, propionic acid, etc.,), and inorganic acids (e.g. hydrochloric acid, bromatological, water or mixtures thereof.

The reaction temperature is not a significant factor and can be chosen based on the type of the protective group and the method for its removal.

Removal (elimination) using Lewis acid is preferred, if you want to eliminate substituted or unsubstituted ar(lower)alkyl ester group; this elimination is performed by the reaction of the compound (I) or its salt with a Lewis acid, such as trihalogen boron (for example, trichloride boron, boron TRIFLUORIDE, etc.,), tetravalent titanium (for example, titanium tetrachloride, tetrabromide titanium, etc.,), tetravalent tin (for example, tin tetrachloride, tetrabromide tin, etc.,), aluminum halide (e.g., aluminum chloride, bromide aluminia and so on), trigonostoma acid (e.g., trichloroacetic acid, triperoxonane acid, etc., and similar. This elimination reaction is preferably carried out in the presence of agents capable of trapping cations (e.g. anisole, phenol, etc.,) and is usually carried out in an environment of a solvent, such as nitroalkane (for example, nitromethane, nitroethane, etc.,), alkylthiophene (for example, methylene chloride, ethylene chloride, etc.,), dioxane, dietology teenie reaction. These solvents may be used as mixtures with each other.

Reductive elimination is preferable to use for the removal of such protective groups, as halogeno(lower)-alkyl (e.g., 2-iodoaniline, 2,2,2-trichlorethylene etc.) ester group, ar (lower)alkyl (e.g. benzyl, etc.,) ester group and similar.

Recovery methods applicable for the implementation of the elimination reaction include, for example, recovery using a combination of metal (e.g. zinc, zinc amalgam, etc., or salts of compounds of chromium (e.g., chromium chloride, chromium acetate, etc., and organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.,) and conventional catalytic reduction in the presence of conventional metal catalyst (e.g. palladium on charcoal, Raney Nickel, etc.,).

The reaction temperature is not a significant factor; typically the reaction is carried out under cooling, at room temperature or when heated.

Method 5. The target compound (I-g) or its salt can be obtained by deprotection carboxyl group in compound (I-p) or the AI (for example, acid, base, reducing agents, catalysts, solvents, reaction temperature, etc.,) are the same as described above for method 4.

Method 6. The target compound (I-h) or its salt can be obtained by reaction of the compound (I-g) or its reactive derivative at the carboxy group or its salt with the compound (VII) or its reactive derivative at the amino group or its salt.

Suitable reactive derivatives of the compound (VII) the amino group include imine type Schiff bases or their tautomeric enamines, obtained by reaction of the compound (VII) with a carbonyl compound such as aldehyde, ketone and similar; silyl derivative obtained by the reaction of the compound (VII) with a silyl compound such as bis(trimethylsilyl)ndimethylacetamide, mono(trimethylsilyl)acetamide", she bis(trimethylsilyl)-urea and similar; derivative obtained by the reaction of the compound (IX) with phosphorus trichloride or phosgene, etc.

Suitable reactive derivatives of the compound (I-g) carboxyl group include halides (galodamadruga) acid, acid anhydride, activated amides, activated esters, etc., Examples reaktsionnosposobnykh phosphoric acid (for example, dialkylphosphinate acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, etc.,), dialkylphosphorous acid, sulfurous acid, tisera acid, sulfuric acid, sulfonic acid (e.g., methanesulfonate acid and etc.), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, somalina acid, Pavlova acid, pentane acid, isopentane acid, 2-ethylmalonate acid, trichloroacetic acid, etc. or an aromatic carboxylic acid (e.g. benzoic acid, etc.,); a symmetrical acid anhydride; activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (for example, cinematology ether, methoxymethyl ether, dimethylaminomethylene ether, vinology ether, propargilovyh ether, para-nitrophenyloctyl ether, 2,4-dinitrophenoxy ether, trichloranisole ether, pentachlorphenol ether, methylphenylene ether, phenylazophenyl ester, a phenyl thioether, para-nitrophenyloctyl tiefer, parkreserve tiefer, carboxymethoxy tiefer, paranjoy ether, pyridyloxy ether, piperidinyl EPE-hydroxy-2-(IH)-pyridone, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc. and similar. The choice of the reactive derivative of the above list produced in accordance with what exactly the compound (I-g) intend to use.

Usually the reaction is carried out in a standard solvent such as water, alcohol (e.g. methanol, ethanol, etc.,), acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent that does not adversely influence the reaction. This standard solvent may also be used in a mixture with water.

If in this reaction, the compound (I-g) is used in the form of a free acid or a salt thereof, preferably the reaction is carried out in the presence of standard condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinobutyrophenone; N-cyclohexyl-N'-(4-dimethylaminoethoxy) carbodiimide; N,N'-diethylcarbamoyl; N,N'-diisopropylcarbodiimide; N-ethyl - N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis-(2-Mei); pentamethylene-N-cyclohexylamine; diphenylethan-N-cyclohexylamine; it (phosphorylchloride); trichloride phosphorus; diphenylphosphoryl; thionyl chloride; oxacillin; (lower alkyl)halogenated (for example, ethylchloride, isopropylcarbamate etc.); triphenylphosphine; salt of 2-ethyl-7-hydroxybenzotriazole; intramolecular salt of 2-ethyl-5-(meta-sulfophenyl)isoxazolidinone; 1-(para-chlorobenzene-sulfonyloxy)-6-chloro-1H-benzotriazol; the so-called reagent of Vilsmeier obtained by the reaction of N,N'-dimethylformamide with chloride tiomila, phosgene, trichlorochloroform, phosphorus oxychloride, etc.,; and similar.

The reaction can also be carried out in the presence of inorganic or organic bases such as bicarbonate of an alkali metal, three(lower)alkylamine, pyridine, N-(lower)-alkyl-research, N,N-di(lower)alkylenediamine and similar.

The reaction temperature is not a significant factor; typically the reaction is carried out under cooling or under heating.

Method 7. The target compound (I-j) or its salt can be obtained by deprotection amino group in compound (I-i) or its salt.

This reaction can be performed exactly the same as the reaction of method 4, therefore, the reaction conditions (bases, acids, reducing agents, catalysts, rastvorityelye (I-k) or its salt can be obtained by reaction of the compound (I-j) or its salt with the compound (VIII) or its salt.

This reaction can be performed exactly the same as the reaction of method 2, therefore, the reaction conditions (solvents, reaction temperature, etc.,) are the same as described above for method 2.

In the case when R1represents a carboxyl group, it is possible to protect or during the reaction or on a separate stage at the end of the reaction.

Method 9. The target compound (I-d) or its salt can be obtained by introducing a compound (I-e) or its salt of the protective group for carboxyl group.

This reaction can be performed exactly the same as the reaction of method 2, therefore, the reaction conditions (solvents, reaction temperature, etc. are identical to those described for method 2.

The method 10. The target compound (I) or its salt can be obtained by reaction of the compound (XII) or its salt with the compound (XXI) or its salt.

This reaction can be performed exactly the same as the reaction of method 2, therefore, the reaction conditions (solvents, reaction temperature, etc. are identical to those described for method 2.

In the case when R1represents a protected carboxyl group, it can be depotentiate or during the reaction or on a separate stage after the reaction.

Source soedinenii, or the usual ways,

where

R1R1a, R2, R6d, R11, A, Q, X, Y, Y1, Z1and W2take the values defined above; R6drepresents a lower alkyl group or aminosidine group; R10represents a protected hydroxyl group;

each of the groups W4, W5, W6, W7, W8and W9represents the balance of acid; A1represents the lowest alkylenes group containing oxoprop, and A2represents the lowest alkylenes group.

Methods A - D can be implemented using standard techniques.

The target compound (I) according to the present invention can be isolated and purified by standard methods, for example by extraction, precipitation, fractional crystallization, recrystallization, chromatography, etc.,

Thus obtained target compound (I) can be converted into its salt by the known methods.

The target compound (I) according to the present invention is used as an inhibitor of testosterone-5 - reductase and effectively in the treatment of mediated testosterone--5-reductase diseases, t the measures in women, androgenic alopecia or male pattern hair loss), acne (eg, acne vulgaris, pimples, etc), other types of hyperandrogenism, etc.

To illustrate the effectiveness and usefulness of the target compounds corresponding to General formula (I), the following data pharmacological activity of representative compounds according to the present invention.

1. Test connection:

(I) 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizine-1-yl] oil acid

(2) 4-[1-[4-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizine-3-yl] oil acid

(3) 4-[3-[3-[bis(4-isobutylphenyl)methoxy]benzoyl]indolizine-1-yl]butyric acid

(4) 4-[1-[4-[1-(4-isobutylphenyl)propyloxy]benzoyl] indolizine-3-yl]butyric acid

(5) 4-[1-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl] indolizine-3-yl]butyric acid

2. Activity in the inhibition of testosterone-5-reductase in rats: test

1) Materials

1,2,6,7 -3H-testosterone (85 - 105 CI/mmol):

1,2,6,7 -3H-testosterone (85 - 105 CI/mmol) is a mixture of 1,2,6,7 -3H-testosterone and testosterone, containing 85 - 105 CI 1,2,6,7 -3H-testosterone in millimoles of testosterone; purchased from f):

brand, purchased from businesses in new England nuclear, Boston, Massachusetts, USA.

2) Preparation of prostatic testosterone-5 - reductase.

Adult male rats of Spray-doli (age 7 - 8 weeks) were killed diethyl ether. Ventral prostate were removed from their shells, and their total volume was determined by displacement in a few milliliters of medium A, ice (Wednesday A: of 0.32 M sucrose, 0.1 mm of dithiothreitol and 20 mm sodium phosphate, pH 6.5). Unless otherwise noted, all subsequent operations were performed at 0 - 4oC. Prostate was trenirovki, bashed and homogenized in 3 to 4 volumes (calculated on the amount of tissue) environment using a homogenizer glass trademark "Pyrex". Homogenizate was fractionally using differential zentrifugenbau at 3000 g for 15 minutes. The obtained tablets resuspendable in environment A. Suspension (20 to 30 mg protein/ml) was stored at -80oC.

3) Inhibition of testosterone-5 - reductase.

The reaction solution contains 1 mm dithiothreitol, 40 mm sodium phosphate, pH 6.5, 50 M NADPH, 1,2,6,7 -3H-testosterone/testosterone (2,210-9M) and cooked above suspension (0.8 mg protein) in a total volume of 565 μl. Test the Connection, add 10 ál of 10% ethanol is t add a suspension of the enzyme. After incubation for 30 minutes at 37oC, the reaction mixture was extracted with 1 ml ethyl acetate. 50 μl of the ethyl acetate phase chromatographic on the plates of silicon plastic Kieselgel 60 F254firm Merck, using as mobile phase mixture ethyl acetate: cyclohexane (1:1). Plastic plate is air-dried and cut out from them the areas corresponding to testosterone and 5 - dihydrotestosterone. Radioactivity was measured in 5 ml Aquasol-2 Packages.com scintillation counter (PACKARD TRI - CARB 4530), and calculate the degree of inhibition.

(3) test Results:

Connection - 1C50(M)

(1) - 2,310-9< / BR>
(2) - 4,410-10< / BR>
(3) - 6,710-9< / BR>
(4) - 5,510-10< / BR>
(5) - 1,810-9< / BR>
When introduced into the body for therapeutic or prophylactic purposes, the target compound of formula (I) according to the present invention is used in the standard form of pharmaceutical compositions which contain these compounds as active ingredients in a mixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid fillers, which are suitable for oral or parenteral administration and for outdoor ispolzavolai, or in liquid form such as solution, suspension, syrup, emulsion, lemonade, lotion, etc.

If necessary, the composition of the above compositions can be included AIDS, stabilizers, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, etc.

As for the used doses of the compounds of formula (I), they depend on the age and condition of the patient, type of disease, from what the compound of formula (I) is proposed to use, etc., As a rule, the daily dose, administered to the patient, may be from 0.01 to about 500 mg, and even more. In the treatment of diseases can be used a single dose of the target compounds (I) equal to 0,05, 0,1, 0,25, 0,5, 1, 20, 50, 100 mg.

The following methods and examples are given to illustrate the present invention.

Methodology 1.

To a solution of ethyl-3-chloropropionate (1.65 g) and aluminum chloride (1.78 g) in methylene chloride (20 ml) at room temperature add rastraguru her chloroform. The organic layers are washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate. After evaporation of the solvent the residue chromatographic on silica gel, elwira a mixture hexanitrate (3:2), and obtain the following connections:

Ethyl-4-(3-indolizinyl)-4-oxybutyrate (0.74 g)

NMR (CDCl3, ): of 1.28 (3H, t, J = 7 Hz), and 2.79 (2H, t, J =7 Hz), 3,29 (2H, t, J = 7 Hz), 4,18 (2H, K, J = 7 Hz), 6,51 (1H, d, J = 5 Hz), at 6.84 (1H, dt, J = 1 Hz, 6 Hz), 7,12 (1H, m), 7,52 (1H, m), 7,58 (1H, d, J = 5 Hz), 9,83 (1H, DD, J = 1 Hz, 6 Hz),

Ethyl-4-(1-indolizinyl)-4-oxybutyrate (0.26 g)

NMR (CDCl3, ): of 1.28 (3H, t, J = 7 Hz), 2,78 (2H, t, J = 7 Hz) at 3.25 (2H, t, J = 7 Hz), 4,17 (2H, K, J = 7 Hz), 6,77 (1H, dt, J = 1 Hz, 7 Hz), 7,12 (1H, m), 7,22 (2H, m), 8,03 (1H, dt, J = 7 Hz, 1 Hz), 8,44 (1H, dt, J = 9 Hz, 1 Hz).

Method 2

To a solution of ethyl-4-(3-indolizinyl)-4-oxybutyrate (556 mg) in tetrahydrofuran (5 ml) at 0oC add a solution of borane in tetrahydrofuran (concentration of 1 M, 3.6 ml). After stirring at room temperature for 10 minutes the reaction is quenched at 0oWith the addition of potassium dihydrophosphate, and the resulting mixture extracted with ether. The organic layers are washed with water, aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. After evaporation of the solvent the residue chromatographic/P> NMR (CDCl3, ): of 1.26 (3H, t, J = 7 Hz), of 2.08 (2H, m), 2,43 (2H, t, J = 7 Hz), 2,89 (2H, t, J = 7 Hz), 4,14 (2H, K, J = 7 Hz), 6,3 - 6,7 (4H, m), 7,37 (1H, dt, J = 9 Hz, 1 Hz), 7,78 (1H, dt, J = 6 Hz, 1 Hz).

Method 3

The following compound was obtained in the same way as described in method 2:

Ethyl-4-(1-indolizinyl)butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J= 7 Hz), to 1.98 (2H, m), of 2.34 (2H, t, J = 7 Hz), and 2.79 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 6,37 (1H, dt, J = 1 Hz, 7 Hz), 6,56 (1H, m), 6,62 (IH, d, J = 3 Hz), 7,21 (1H, d, J = 3 Hz), 7,29 (1H, d, J = 9 Hz), to 7.84 (1H, d, J = 7 Hz).

Method 4

To a solution of 3-nitrobenzotrifluoride (314 mg) in methylene chloride (20 ml) at room temperature add aluminum chloride (305 mg). After stirring for 10 minutes, to this mixture is added a solution of ethyl-4-(3-indolizinyl)butyrate (297 mg) in methylene chloride (3 ml). After 1 hour, add ice, and the resulting mixture was extracted with chloroform. The organic layers are washed with water, aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. After evaporation of the solvent the residue chromatographic on silica gel (hexane: ethyl acetate 2: 3), receiving stil-4-[1-(3-nitrobenzoyl)indolizine-3-yl]butyrate (352 mg).

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), of 2.08 (2H, m), 2,46 (2H, t, J = 7 Hz), with 2.93 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), to 6.80 (1H, s), 6,98 (1H, dedica 5

The following compounds were obtained according to the method 4.

(1) Ethyl-4-[1-(4-nitrobenzoyl)indolizine-3-yl]butyrate

NMR (CDCl3, ): a 1.25 (3H, t, J = 7 Hz), 2,04 (2H, m), 2,46 (2H, t, J = 7 Hz), 2,90 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 6,76 (1H, s), of 6.99 (1H, dt, J = 1 Hz, 7 Hz), 7,32 (1H, m), 7,95 (2H, d, J = 9 Hz), 8,10 (1H, d, J = 7 Hz), 8,35 (2H, d, J = 9 Hz), 8,54 (1H, d, J = 8 Hz).

(2) Ethyl-4-[3-(3-nitrobenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), a 2.01 (2H, m), is 2.37 (2H, t, J = 7 Hz), of 2.81 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 7,02 (1H, dt, J = 1 Hz, 7 Hz), 7,11 (1H, s), 7,28 (1H, dt, J = 1 Hz, 8 Hz), a 7.62 (1H, dt, J = 8 Hz, 1 Hz), 7,69 (1H, t, J = 7 Hz), 8,12 (1H, m), scored 8.38 (1H, m), 8,63 (1H, m), 9,98 (1H, d, J = 7 Hz).

(3) Ethyl-4-[3-(4-nitrobenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), from 2.00 (2H, m), a 2.36 (2H, t, J = 7 Hz), and 2.79 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 7,02 (1H, dt, J = 1 Hz, 7 Hz), 7,07 (1H, s), 7,28 (1H, m), to 7.61 (1H, dt, J = 9 Hz, 1 Hz), to 7.93 (2H, d, J = 9 Hz), at 8.36 (2H, d, J = 9 Hz), 9,98 (1H, d, J = 7 Hz).

(4) Ethyl-4-[1-(4-methoxybenzoyl)indolizine-3-yl]butyrate

NMR (CDCl3, ): a 1.25 (3H, t, J = 7 Hz), 1,98-2,17 (2H, m), of 2.45 (2H, t, J = 7 Hz), 2,90 (2H, t, J = 7 Hz), with 3.89 (3H, s), 4,14 (2H, K, J = 7 Hz), 6,84? 7.04 baby mortality (4H, m), 7,12-7,22 (1H, m), 7,80-of 7.90 (2H, m), 8,01 (1H, d, J = 7 Hz), 8,48 (1H, d, J = 9 Hz).

(5) Ethyl-4-[1-(3-methoxybenzoyl)indolizine-3-yl]butyrate

NMR (CDCl3, of 1.26 (3H, t, J = 7 Hz), 1,97-of 2.15 (2H, m) 2,44 (2H, t, J = 7 Hz), 2,89 (2H, t, J = 7 Hz), 3,88 (3H, s), 4,13 ethoxybenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), 1,92 is 2.10 (2H, m) to 2.35 (2H, t, J = 7 Hz), and 2.79 (2H, t, J = 7 Hz), 3,90 (3H, s), of 4.12 (2H, K, J = 7 Hz), 6,85-of 7.23 (5H, m), 7,54 (1H, d, J = 9 Hz), to 7.77-7,88 (2H, m).

(7) Ethyl-4-[3-(3-methoxybenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), 1,90-of 2.08 (2H, m), a 2.36 (2H, t, J = 7 Hz), 2,78 (2H, t, J = 7 Hz), 3,88 (3H, s), of 4.12 (2H, K, J = 7 Hz), 6.87 in-7,07 (3H, m), 7,13-7,40 (5H, m), 7,44 (1H, d, J = 9 Hz).

Methodology 6

To a solution of ethyl-4- [1-(3-nitrobenzoyl)indolizine-3-yl]butyrate (350 mg) in a mixture of dioxane-ethanol (1: 1, 10 ml) is added the catalyst is 10% palladium on coal (210 mg) and hydronaut at a pressure of 4 ATM hydrogen for 4 hours, then filter the mixture through celite. After removal of the solvent receive ethyl-4-[1-(3-aminobenzoyl)indolizine - 3-yl]butyrate (325 mg).

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), was 2.05 (2H, m), 2,43 (2H, t, J = 7 Hz), is 2.88 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 6,90 (1H, m) 6,91 (1H, s), and 7.1 to 7.4 (5H, m), 8,01 (1H, d, J = 7 Hz), 8,48 (1H, dt, J = 8 Hz, 1 Hz).

Methodology 7

The following compounds were obtained according to the method 6.

(1) Ethyl-4-[1-(4-aminobenzoyl)indolizine-3-yl]butyrate

NMR (CDCl3, ): a 1.25 (3H, t, J = 7 Hz), 2,07 (2H, m) 2,44 (2H, t, J = 7 Hz), 2,89 (2H, t, J = 7 Hz), 4,14 (2H, K, J = 7 Hz), 6,78 (2H, d, J = 9 Hz), 6,86 (1H, dt, J = 1 Hz, 7 Hz), 6,92 (1H, s), 7,12 (1H, m), 7,76 (2H, d, J = 9 Hz), to 7.99 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 8 Hz).

(2) e t, J = 7 Hz), 6,8-7,0 (2H, m) 7,1-7,3 (6H, m), 7,54 (1H, dt, J = 8 Hz, 1 Hz), 9,94 (1H, d, J = 7 Hz).

(3) Ethyl-4-[3-(4-aminobenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): 1,24 (3H, so J = 7 Hz), 2,0 (2H, m) to 2.35 (2H, t, J = 7 Hz), 2,80 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), 6.73 x (2H, d, J = 9 Hz), 6.87 in (1H, dt, J = 1 Hz, 7 Hz), 7,02 (1H,m), 7,20 (1H, s), 7,51 (1H, dt, J = 9 Hz, 1 Hz), 7,72 (2H, d, J = 9 Hz), 9,86 (1H, d, J = 7 Hz).

Technique 8

To a mixture of ethyl-4-[1-(4-methoxybenzoyl)indolizine-3-yl]butyrate (640 mg) and ethanthiol (2.5 ml) in dichloromethane (8 ml) at 0oC add aluminum chloride (700 mg). After stirring for 10 minutes the solvent is evaporated, and pour the residue into a mixture of ethyl acetate and ice water. Separate the organic layer, washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated. The remainder chromatographic on a column of silica gel, elwira a mixture of chloroform-ethyl acetate (4:1); get ethyl-4-[1-(hydroxybenzoyl)indolizine-3-yl] butyrate (344 mg) as a yellow solid.

NMR (DMCO-D6, ): to 1.14 (3H, t, J = 7 Hz), 1.85 to 2,03 (2H, m), is 2.41 (2H, t, J = 7 Hz), with 2.93 (2H, t, J = 7 Hz), 4,01 (2H, K, J = 7 Hz), 6,84 - 7,06 (4H, m), 7,19-7,30 (1H, m), to 7.67 (2H, d, J = 8 Hz), 8,25-to 8.40 (2H, m).

Methodology 9

The following compounds were obtained according to the method 8.

(1) Ethyl-4-[1-(3-hydroxine the 3 (2H, K, J = 7 Hz), 6,86-6,97 (2H, m), 6,99-to 7.09 (1H, m), 7,16-7,37 (3H, m), of 7.48 (1H, s), 8,01 (1H, d, J = 7 Hz), and 8.50 (2H, m, J = 9 Hz),

(2) Ethyl-4-[3-(4-hydroxybenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), 1,92 is 2.10 (2H, m), of 2.38 (2H, t, J = 7 Hz), and 2.79 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 6,86-6,98 (3H, m), 7,12-of 7.25 (2H, m), 7,55 (1H, d, J = 9 Hz), to 7.67 for 7.78 (2H, m).

(3) Ethyl-4-[3-(4-hydroxybenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), 1,90-of 2.08 (2H, m), of 2.34 (2H, t, J = 7 Hz), was 2.76 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 6.87 in-7,07 (3H, m), 7,13-7,40 (5H, m), 7,55 (1H, d, J = 9 Hz).

The method 10

To a suspension of aluminum chloride in (6.67 g) in dichloromethane (70 ml) at 0oC add hexanoate (7 ml). After stirring the mixture for 15 minutes at 0oC it adds isobutylbenzene (7.9 ml). This mixture was stirred at 0oC for 30 minutes and poured into ice water. The organic layer is washed with water, aqueous sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate and evaporated, obtaining 4'-isobutylacetophenone (10,52 g) as a colourless oil.

NMR (CDCl3, ): 0,84-and 0.98 (9H, m), 1.30 and USD 1.43 (4H, m), 1.60-to a 2.01 (3H, m), 2,53 (2H, d, J = 8.5 Hz), to 2.94 (2H, t, J = 7 Hz), 7,22 (2H, d, J = 8.5 Hz), 7,88 (2H, d, J = 8,5 Hz).

Technique 11.

To a solution of 4'-isobutylacetophenone (10.5 g) in propanol-2 (elewaut in ice water and acidified with 6 N hydrochloric acid. The aqueous solution is extracted with ethyl acetate, the organic layer washed with water and brine, dried over magnesium sulfate and evaporated, obtaining 1-(4-isobutylphenyl)hexane-1-ol (to 9.32 g) as a colourless oil.

NMR (CDCl3, ): 0,83-to 0.96 (9H, m), 1,16-of 1.40 (6H, m), 1.60-to a 1.96 (3H, m), 2,48 (2H, d, J = 7 Hz), with 4.64 (1H, t, J = 7 Hz), 7,11 (2H, d, J = 8.5 Hz), 7,25 (H, d, J = 8,5 Hz).

Methodology 12

To a solution of 1-(4-isobutylphenyl)hexane-1-ol (9,15 g) and chetyrehpostovye carbon (25,9 g) in tetrahydrofuran (250 ml) is added triphenylphosphine (20.5 g). The resulting mixture was stirred at room temperature for 6 hours. After filtering off the white solid precipitate, the filtrate is evaporated. To the residue is added n-hexane (300 ml), and the precipitation is filtered off. The filtrate is evaporated, and the oily residue is distilled under reduced pressure, obtaining 1-(1-bromohexyl)-4-isobutylbenzene (3,52 g) as a colourless oil.

NMR (CDCl3, ): of 0.82 to 0.97 (9H, m), 1,20-1,60 (8H, m), 1,74-of 1.97 (1H, m), 2.00 in of 2.38 (2H, m), 2,46 (2H, d, J = 7 Hz), 4,96 (1H, t, J = 7.5 Hz), 7,10 (2H, d, J = 8.5 Hz), 7,29 (2H, d, J = 8,5 Hz).

Methodology 13

A suspension of sodium hydride (3.04 from g; 60% in mineral oil) in dimethyl sulfoxide (100 ml) with stirring, heated at 80oC for 40 minutes. Then the solution is cooled. To him dobavlyayut, at room temperature, add 2-pyridinecarboxamide (3,96 g), after which the resulting mixture was stirred for 2 hours. Add water to the mixture and acidifying it to a pH of 5 1 N hydrochloric acid. The mixture is extracted with ethyl acetate, the organic layer washed with water, dried and concentrated. The remainder chromatographic on silica gel (ethyl acetate:methanol = 10:1) to give (4E)-5-(2-pyridyl)-4-pontenova acid (1.6 g).

NMR (CDCl3, ): of 2.5-2.8 (4H, m), 6,6-6,9 (2H, m), 7,19 (1H, m), 7,37 (1H, d, J = 8 Hz), of 7.70 (1H, dt, J = 1 Hz, 8 Hz), 8,59 (1H, d, J 5 Hz).

Technique 14

To a solution of (4E)-5-(2-pedicel)-4-pentenol acid (1.6 g) in ethanol (50 ml) add d-camphor-10-sulfonic acid (2.3 g), and the mixture was refluxed containing molecular sieves 3A. After 2 hours the mixture is evaporated, diluted with saturated aqueous sodium bicarbonate, then extracted with ethyl acetate. The organic layers washed with brine, dried over sodium sulfate and evaporated in vacuum, obtaining ethyl-(4E)-5-(2-pyridyl)-4-pentenoate (1.84 g).

NMR (CDCl3, ): of 1.26 (3H, t, J = 7 Hz), 2,45 is 2.7 (4H, m) to 4.16 (2H, K, J = 6 Hz), 6,53 (1H, d, J = 16 Hz), to 6.75 (1H, dt, J = 16 Hz, 7 Hz), 7,11 (1H, m), 7,25 (1H, d, J = 8 Hz), 7,63 (1H, dt, J = 1 Hz, 8 Hz), 8,55 (1H, d, J = 4 Hz).

Methodology 15

To a solution of ethyl-(4E)-5-(2-pyridyl)'re asked 3 hours in hydrogen atmosphere (4 ATM), and then filtered through a pad of celite. After removal of solvent in vacuo get ethyl-5-(2-pyridyl)pentanoate (1.84 g).

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), 1,6-1,9 (4H, m), of 2.34 (2H, t, J = 7 Hz), 2,82 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 7,05 to 7.2 (2H, m), a 7.62 (1H, dt, J = 1 Hz, 8 Hz), charged 8.52 (1H, d, J = 4 Hz).

Methodology 16

To a solution of ethyl-5-(2-pyridyl)pentanoate (1.07 g) in acetone (5 ml) add bromoacetone (0.51 ml) and the resulting mixture is refluxed for 2 hours. After removal of solvent the residue is dissolved in aqueous sodium bicarbonate solution (1 g of sodium bicarbonate/20 ml water) and 30 minutes and refluxed. The mixture is extracted with ethyl acetate. The combined organic layers washed with brine, dried over sodium sulfate, evaporated in vacuum and chromatographic on silica gel (dichloromethane) to give ethyl-4-(2-methylindolin-1-yl)butyrate (778 mg).

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), at 1.91 (2H, m), of 2.23 (3H, s), 2,32 (2H, t, J = 7 Hz), is 2.74 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), 6,32 (1H, dt, J = 1 Hz, 7 Hz), 6,53 (1H, m), was 7.08 (1H, s), 7,21 (1H, d, J = 9 Hz), 7,76 (1H, dt, J = 7 Hz, 1 Hz).

Methodology 17

The following compound was obtained according to Method 1.

Ethyl-4-(2-methylindolin-3-yl)-4-oxybutyrate

NMR (CDCl3, ): of 1.28 (3H, t, J = 7 Hz), 2,65 (3H, s), 2,P CLASS="ptx2">

Method 18

The following compound was obtained according to method 2.

Ethyl-4-(2-methylindolin-3-yl)butyrate

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), 1,90 (2H, m), of 2.28 (3H, s), 2,35 (2H, d, J = 7 Hz), 2.91 in (2H, d, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), and 6.25 (1H, m), 6,47 (1H, m), 6,60 (1H, m), 7,28 (1H, d, J = 8 Hz), 7,79 (1H, m).

Methodology 19

The following compounds were obtained according to method 4.

(1) Ethyl-4-[2-methyl-3-(4-nitrobenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), to 1.79 (3H, s) to 1.86 (2H, m), of 2.34 (2H, t, J = 7 Hz), of 2.72 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), 6,92 (1H, dt, J = 1 Hz, 7 Hz), 7,24 (1H, m), 7,52 (1H, d, J = 9 Hz), 7,74 (2H, d, J = 9 Hz), a 8.34 (2H, d, J = 9 Hz), 9,87 (1H, d, J = 8 Hz).

(2) Ethyl-4-[2-methyl-3-(3-nitrobenzoyl)indolizine-1-yl]butyrate

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), of 1.84 (3H, s), a 1.88 (2H, m) to 2.35 (2H, t, J = 7 Hz), 2,73 (2H, m, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), make 6.90 (1H, dt, J = 1 Hz, 7 Hz), 7,22 (1H, m), 7,52 (1H, d, J = 9 Hz), to 7.68 (1H, t, J = 8 Hz), to 7.93 (1H, m), of 8.37 (1H, m), 8,46 (1H, m), 9,83 (1H, d, J = 7 Hz).

(3) Ethyl-4-[2-methyl-1-(4-nitrobenzoyl)indolizine-3-yl]butyrate

NMR (CDCl3, ): of 1.27 (3H, d, J = 7 Hz), at 1.91 (2H, m), are 2.19 (3H, s) to 2.41 (2H, d, J = 7 Hz), with 2.93 (2H, d, J = 7 Hz), is 4.15 (2H, K, J = 7 Hz), at 6.84 (1H, dt, J = 1 Hz, 7 Hz), 7,02 (1H, m), 7,51 (1H, dt, J = 9 Hz, 1 Hz), 7,80 (2H, d, J = 8 Hz), of 8.09 (1H, d, J = 7 Hz), 8,32 (2H, d, J = 8 Hz).

(4) Ethyl-4-[2-methyl-1-(3-nitrobenzoyl)indolizine-3-yl]butyrate

NMR (CDC(1H, m), 7,53 (1H, dt, J = 8 Hz, 1 Hz), to 7.68 (1H, t, J = 8 Hz), 8,0-of 8.15 (2H, m), scored 8.38 (1H, m), and 8.50 (1H, m).

The method 20

The following compounds were obtained according to method 6.

(1) Ethyl-4-[3-(4-aminobenzoyl)-2-methylindolin-1-yl]butyrate

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), a 1.88 (2H, m) to 1.99 (3H, s), of 2.34 (2H, t, J = 7 Hz), 2,73 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), 6,64 to 6.75 (1H, m), of 6.68 (2H, d, J = 8 Hz), 7,00 (1H, m), 7,42 (1H, dt, J = 9 Hz, 1 Hz), 7,53 (2H, d, J = 8 Hz), 9,88 (1H, d, J = 7 Hz).

(2) Ethyl-4-[3-(4-aminobenzoyl)-2-methylindolin-1-yl]butyrate

NMR (CDCl3, ): 1,22 (3H, t, J = 7 Hz), 1,75-of 1.95 (2H, m), 1,89 (3H, s), 2,32 (2H, t, J = 7 Hz), of 2.72 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), 6,78 (1H, dt, J = 1 Hz, 7 Hz), 6,85 of 7.3 (5H, m), 7,44 (1H, d, J = 9 Hz), RS 9.69 (1H, d, J = 7 Hz).

(3) Ethyl-4-[1-(4-aminobenzoyl)-2-methylindolin-3-yl]butyrate

NMR (CDCl3, ): a 1.25 (3H, t, J = 7 Hz), at 1.91 (2H, m) to 2.29 (3H, s), 2,39 (2H, t, J = 7 Hz), with 2.93 (2H, t, J = 7 Hz), is 4.15 (2H, K, J = 7 Hz), 6,69 (1H, dt, J = 7 Hz), 6,7 - 6,9 (3H, m), 7,46 (1H, d, J = 9 Hz), to 7.64 (2H, d, J = 8 Hz), of 7.96 (1H, d, J = 7 Hz).

(4) Ethyl-4-[1-(3-aminobenzoyl)-2-methylindolin-3-yl]butyrate

NMR (CDCl3, ): of 1.27 (3H, t, J = 7 Hz), with 1.92 (2H, m), of 2.28 (3H, s), 2,39 (2H, t, J = 7 Hz), with 2.93 (2H, t, J = 7 Hz), 4,14 (2H, K, J = 7 Hz), 6,72 (1H, dt, J = 1 Hz, 7 Hz), 6,8 - 6,95 (2H, m), of 7.0, and 7.1 (2H, m), 7,21 (1H, t, J = 8 Hz), 7,46 (1H, dt, J = 8 Hz, 1 Hz), to 7.99 (1H, d, J = 7 Hz).

Methodology 21

To a solution of 4-acetoxybenzoic acid (50 g) and oxalyl room temperature. Evaporate the solvent and dissolve the residue in n-hexane (200 ml). After filtration the solution is evaporated, receiving 4-acetoxybenzoic in the form of a yellow oil (55,1 g).

NMR (CDCl3, ): 2,35 (3H, s), 7,27 (2H, d, J = 9 Hz), 8,16 (2H, d, J = 9 Hz).

Methodology 22

To a suspension of aluminum chloride (36.5 g) in dichloromethane (500 ml) is added 4-acetoxybenzoic (53,6 g). After stirring the mixture for 20 minutes at room temperature there was added a solution of ethyl-4-(indolin-3-yl)-butyrate (57,8 g) in dichloromethane (50 ml). The mixture is stirred at room temperature for 2 hours and the solvent is evaporated. The residue is dissolved in ethyl acetate (500 ml) and washed with water. To the solution was added N, N-dimethylaminopropylamine (20 ml). The resulting mixture was washed with diluted hydrochloric acid, water, sodium bicarbonate (aqueous solution) and water. The solution is dried over magnesium sulfate, and vacuum to remove the solvent. The residue was washed with diisopropyl ether, receiving ethyl-4-[1-(4-acetoxybenzoic)indolizine-3-yl]-butyrate in the form of a yellow powder (36.5 g).

NMR (CDCl3, ): ): 1,25 (3H, t, J = 7 Hz), of 2.0 - 2.2 (2H, m) to 2.35 (3H, s), 2,43 (2H, t, J = 7 Hz), 2,90 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 6,85 - 7,0 (2H, m), 7,15 - of 7.3 (1H, m), 7,25 (2H, d, J = 8 Hz), 7,88 (2H, d, J = 8 Hz), 8,zoilus)indolizine-3-yl] butyrate (36,1 g) in ethanol (200 ml) and tetrahydrofuran (200 ml) is added sodium hydride (60% dispersion in mineral oil, of 4.38 g). The mixture is stirred for 20 minutes at 0oC and evaporated. The remaining solution was poured into a mixture of dilute hydrochloric acid and ice and extracted with a mixture of chloroform and methanol (10 : 1). The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated. The residue is washed with ethyl acetate and diethyl ether, receiving ethyl-4-[1-(4-hydroxybenzoyl)indolizine-3-yl] butyrate in the form of a yellow powder (29.3 g).

NMR (CDCl3, ): a 1.25 (3H, t, J = 7 Hz), of 2.0 - 2.2 (2H, m), of 2.45 (2H, t, J = 7 Hz), 2,89 (2H, t, J = 7 Hz), is 4.15 (2H, K, J = 7 Hz), 6,8 - 7,0 (4H, m), 7,18 (1H, t, J = 9 Hz), 7,78 (2H, d, J = 8.5 Hz), 8,00 (1H, d, J = 5,5 Hz) and 8.50 (1H, d, J = 9 Hz).

Technique 24

To a solution of (+)-B-chlorodiisopinocampheylborane (2.10 g) in tetrahydrofuran (4 ml) at 25oC add 4'-isobutylacetophenone (1.2 g). After 5 hours, remove the solvent and dissolve the residue in ethyl ether (20 ml). To this mixture add diethanolamin (1,4 ml) and stirred for 2 hours. Solid components are filtered off and washed with ethyl ether. The United filtrates are concentrated, and the residue chromatographic on silica gel (eluent - hexane: methylene chloride 1: 2) to give (R)-1-(4-isobutylphenyl)butane-1-ol (937 mg).

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), to 0.92 (3H, t, 25

The following compound was obtained according to method 24 processing 4'-isobutylacetophenone(-)-B-chlorodiisopinocampheylborane.

(S)-1-(4-isobutylphenyl)butane-1-ol

NMR (CDCl3, ): 0,85 - 1,0 (9H, m), 1,15 - of 1.95 (5H, m), 2,47 (2H, d, J = 7 Hz), of 4.66 (1H, t, J = 7 Hz), 7,12 (2H, d, J = 8 Hz), 7,25 (2H, d, J = 8 Hz).

Technique 26

To a solution of chlorotrimethylsilane (16.3 g) and triethylamine (30,3 g) in N,N-dimethylformamide (50 ml) is added 4'-isobutylacetophenone (22,0 g). Immediately filtered off solid yellow product, and the filtrate is refluxed for 20 hours. The mixture is cooled, diluted with hexane and washed with cold aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and concentrated. The residue is distilled under reduced pressure, obtaining 4-isobutyl- -- trimethylsilylmethyl (9.0 g) in the form of butter.

NMR (CDCl3, of 0.16 (9H, s), 1,65 - of 1.85 (1H, m), 2,35 (2H, d, J = 7 Hz), 4,27 (1H, d, J = 1.5 Hz), was 4.76 (1H, d, J = 1.5 Hz), 6,98 (2H, d, J = 8.5 Hz), 7,38 (2H, d, J = 8,5 Hz).

Methodology 27

Itoilet (2,18 g) dissolved in ethanol (45 ml), and to the resulting solution add apirat boron TRIFLUORIDE (2.55 g). The mixture is stirred at -70oC and add to it 4-isobutyl- --/ trimethylsilylmethyl (2.24 g). This mixture was stirred at which water is added. Neutralize the mixture with an aqueous solution of sodium bicarbonate. Extracted with a mixture of dichloromethane, the organic phase is dried over magnesium sulfate and concentrated. The remainder chromatographic on silica gel, elwira a mixture of hexane-ethyl acetate (94: 6); get 4'-isobutyl-2-ethoxyacetophenone (1.90 g) as oil.

NMR (CDCl3, ): of 0.91 (6H, d, J = 7 Hz), of 1.30 (3H, t, J = 7 Hz), 1,80 - 2,0 (1H, m), 2,53 (2H, d, J = 7 Hz), the 3.65 (2H, K, J = 7 Hz), 4,74 (2H, s), from 7.24 (2H, d, J = 8 Hz), 7,78 (2H, d, J = 8 Hz).

Technique 28

The following compound was obtained according to method 24 processing 4'-isobutyl-2-ethoxyacetophenone (-)-B-chlorodiisopinocampheylborane.

(R)-1-(4-isobutylphenyl)-2-ethoxyethanol

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), 1,75 - of 1.95 (1H, m), 2,47 (2H, d, J = 7 Hz), 3,35 is 3.7 (4H, m), to 4.87 (1H, DD, J = 5.5 Hz, 6.5 Hz), 7,13 (2H, d, J = 8.5 Hz), 7,29 (2H, d, J = 8,5 Hz).

Methodology 29

The following compound was obtained according to method 24 processing 4'-isobutyl-2-ethoxyacetophenone (+)-B-chlorodiisopinocampheylborane.

(S)-1-(4-isobutylphenyl)-2-ethoxyethanol

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), 1,75 - of 1.95 (1H, m), 2,47 (2H, d, J = 7 Hz), and 2.79 (1H, s), 3,35 is 3.7 (4H, m), to 4.87 (1H, DD, J = 5.5 Hz, 6.5 Hz), 7,13 (2H, d, J = 8.5 Hz), 7,29 (2H, d, J = 8,5 Hz).

The method 30

The following compounds were polisin - 3-yl] butyrate

NMR (CDCl3, ): of 1.23 (3H, t, J = 7 Hz), was 2.05 (2H, m), 2,42 (2H, t, J = 7 Hz), of 2.86 (2H, t, J = 7 Hz), 4,07 (2H, s), 4,11 (2H, K, J = 7 Hz), to 5.21 (2H, s), 6,8 - 7,0 (3H, m) and 7.1 to 7.4 (9H, m), 8,01 (1H, d, J = 8 Hz), 8,48 (1H, d, J = 9 Hz).

(2) Ethyl-4-[1-[3-[1-(benzyloxycarbonyl)amino)benzoyl] -indolizine-3-yl]butyrate

NMR (CDCl3, ): 1,24 (3H, t, J = 7 Hz), of 1.52 (3H, d, J = 7 Hz), was 2.05 (2H, m), 2,42 (2H, t, J = 7 Hz), 2,85 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 4,27 (1H,, J = 7 Hz), 5,16 (2H, s), 6,7-7,0 (3H, m), of 7.1 to 7.4 (9H, m), of 8.00 (1H, d, J = 7 Hz), 8,48 (1H, d, J = 9 Hz).

Methodology 31

To a solution of ethyl-4-[1-[3-(1-benzyloxycarbonylamino)amino]benzoyl] indolizine-3-yl] butyrate (0.20 g) in ethanol (10 ml) is added the catalyst is 10% palladium on coal (0.1 g). The resulting mixture is stirred in hydrogen atmosphere at room temperature for 2 hours. After removal of the catalyst and evaporation of the solvent ethyl receive-4-[1-[3-(1-carboxymethylamino)benzoyl] indolizine-3-yl]butyrate (0.15 g) as a yellow powder.

NMR (CDCl3, ): a 1.25 (3H, t, J = 7 Hz), of 1.57 (3H, d, J = 7 Hz), 2,0-2,3 (2H, m) of 2.50 (2H, t, J = 7 Hz), and 2.83 (2H, t, J = 7 Hz), 4,16 (3H, K, J = 7 Hz), 6,8-7,0 (3H, m) and 7.1 to 7.4 (4H, m), of 7.96 (1H, d, J = 7 Hz), 8,55 (1H, d, J = 9 Hz).

Technique 32

The following compound was obtained according to the method 31.

Ethyl-4-[1-(3-carboxymethylaminomethyl)indolizine-3-yl]butyrate

NMR (CDCl3, ): of 1.28 (3H, Is, J = 9 Hz).

Methodology 33

To a mixture of (cyclopropylmethyl)benzene (1,32 g) and dichlorodimethyl ether (1.25 ml) in dichloromethane (20 ml) at 0oC in an atmosphere of nitrogen was added 1.0 M solution of titanium chloride (IV) in dichloromethane (15 ml). The mixture was stirred at 0oC for 10 minutes, then poured into ice water. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (9:1); get 4-(cyclopropylmethyl)benzaldehyde (580 mg) as oil.

NMR (CDCl3, ): 0,5-0,65 (2H, m), 0,9-1,2 (1H, m), 2.63 in (2H, d, J = 7 Hz), the 7.43 (2H, d, J = 8.5 Hz), 7,82 (2H, d, J = 8.5 Hz), 9,99 (1H, s).

Technique 34

To a solution of allylanisole (1.0 M solution in diethyl ether, 3 ml) in diethyl ether (5 ml) dropwise at 0oC add 4-(cyclopropylmethyl)benzaldehyde (240 mg) in diethyl ether (2 ml). After 15 minutes, the reaction mixture is "quenched" by adding an aqueous solution of ammonium chloride and the resulting mixture extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (85:15); paluck), to 2.55 (2H, d, J = 6.5 Hz), 4.72 in (1H, t, J = 6.5 Hz), 5,1-a 5.25 (2H, m), 5,7-5,95 (1H, m), 7,15-to 7.35 (4H, m).

Methodology 35

The following compound was obtained according to the method 34.

1-(4-isobutylphenyl)-3-butene-1-ol

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), of 1.85 (1H, m), 2,47 (2H, d, J = 7 Hz), 2,52 (2H, m), 4.72 in (1H, m), 5,1-a 5.25 (2H, m), of 5.83 (1H, m), 7,13 (2H, d, J = 8 Hz), 7,27 (2H, d, J = 8 Hz).

Methodology 36

To a solution of pyridine (1,98 ml) in dichloromethane (15 ml) under stirring at 0oC add the chromium oxide (VI) (1.23 g). After 30 minutes, add 1-(4-isobutylphenyl)-3-butene-1-ol (525 mg) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was filtered through Florisil and washed with ether. The filtrate was concentrated in vacuo and chromatographic on silica gel (hexane:dichloromethane 1:1); get 1-(4-isobutylphenyl)-3-butene-1-he (424 mg).

NMR (CDCl3, ): to 0.92 (6H, d, J = 7 Hz), 1,90 (1H, m), 2,53 (2H, d, J = 7 Hz), of 3.75 (2H, dt, J = 7,1 Hz), 5,18 (1H, m), 5.25-inch (1H, m), 6,10 (1H, m), 7.23 percent (2H, d, J = 8 Hz), 7,89 (2H, d, J = 8 Hz).

Methodology 37

A mixture of 2-hydroxy-4-methylbenzoic acid (to 7.61 g), iodomethane of 15.6 ml) and potassium carbonate (17.3 g) in N,N-dimethylformamide (100 ml) was stirred at room temperature for 5 hours. The reaction mixture is filtered and pour the filtrate into the mixture etelaat. The remainder chromatographic on silikagelevye column, elwira a mixture of n-hexane and ethyl acetate (4:1); get methyl-2-methoxy-4-methylbenzoate (7,99 g) in the form of butter.

NMR (CDCl3, ): 2,39 (3H, s), 3,88 (3H, s), 3,90 (3H, s), 6.75 in-6,85 (2H, m), 7,73 (1H, d, J = 8,5 Hz).

Methodology 38

The following compound was obtained according to the method 37.

Methyl-3-methoxy-4-methylbenzoate

NMR (CDCl3, ): of 2.27 (3H, s), 3,88 (3H, s), 3,91 (3H, s), 7,18 (1H, d, J = 8 Hz), 7,45 and 7.6 (2H, m).

Methodology 39

A mixture of methyl 2-methoxy-4-methylbenzoate (6,95 g), N-bromosuccinimide (8,24 g) and a catalytic amount of benzoyl peroxide (20 mg) in carbon tetrachloride (100 ml) for 2 hours and refluxed. The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated and the residue chromatographic on silikagelevye column, elwira a mixture of n-hexane and ethylacetate (85:15); get methyl-4-methyl bromide-2-methoxybenzoate (2,92 g) in the form of butter.

NMR (CDCl3, ): the 3.89 (3H, s), 3,93 (3H, s), 4,47 (2H, s), 6,95-7,05 (2H, m), to 7.77 (1H, d, J = 8,5 Hz).

The method 40

The following compound was obtained according to the method 39.

Methyl-4-methyl bromide-3-methoxybenzoate

NMR (CDCl3, ): 3,93 (3H, s), of 3.97 (3H, s), 4,56 (2H, s), 7,40 (1H, d, J = 8 Hz), 7.5 to the 7.65 (2H, m).

the nitrogen at 50oC for 30 minutes. Then the temperature was raised to 200oC for 2 hours. After this bright yellow liquid cooled and chromatographic on silikagelevye column, elwira with ethyl acetate; receive diethyl-(3-methoxy-4-methoxycarbonylbenzyl)-phosphonate (1.28 g) in the form of butter.

NMR (CDCl3, ): 1,2-1,4 (6H, m), 3,18 (2H, d, J = 22 Hz), 3,88 (3H, s) to 3.92 (3H, s), 3.95 to 4.2V (4H, m), 6,85-7,0 (2H, m), to 7.77 (1H, d, J = 8 Hz).

Methodology 42

The following connection get the technique 41.

Diethyl-(2-methoxy-4-methoxycarbonylbenzyl)phosphonate

NMR (CDCl3, ): 1,24 (6H, t, J = 7 Hz), 3,29 (2H, d, J = 22 Hz), with 3.89 (3H, s), 3,91 (3H, s), 3.95 to a 4.1 (4H, m), 7,38 (1H, DD, J = 8 Hz), 7.5 to the 7.65 (2H, m).

Methodology 43

To a mixture of diethyl-(3-methoxy-4-methoxycarbonylbenzyl)phosphonate (1.28 g) and acetone (1.5 ml) in N,N-dimethylformamide (5 ml) is added 60% dispersion of sodium hydride in oil (162 mg). The reaction mixture was stirred at room temperature for 14 hours, then poured into ice 10% citric acid. The resulting mixture is extracted with ether, the organic layer washed with water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira a mixture of n-hexane and ethyl acetate (85:15); methyl get = 1.5 Hz), the 3.89 (3H, s), 3,91 (3H, s), 6,27 (1H, s), 6.8 or 6.9 (2H, m), 7,78 (1H, d, J = 8 Hz).

Technique 44

The following compound was obtained according to the method 43.

Methyl-3-methoxy-4-(2-methyl-1-propenyl)benzoate

NMR (CDCl3, ): to 1.83 (3H, d, J = 1.5 Hz), of 1.97 (3H, d, J = 1.5 Hz), with 3.89 (3H, s) to 3.92 (3H, s), 6,33 (1H, s), 7,25 (1H, d, J = 8 Hz), 7,52 (1H, d, J = 1.5 Hz), a 7.62 (1H, DD, J = 8 Hz, 1.5 Hz).

Methodology 45

To a solution of methyl 2-methoxy-4-(2-methyl-1-propenyl)benzoate (178 mg) in methanol (3 ml) and 1,4-dioxane (3 ml) was added 1 N aqueous solution of sodium hydroxide (2 ml). The mixture is stirred for 3 hours at 50oC, then poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent gives 2-methoxy-4-(2-methyl-1-propenyl)benzoic acid (142 mg) as a solid.

NMR (CDCl3, ): 1,91 (3H, d, J = 1.5 Hz), 1,95 (3H, d, J = 1.5 Hz), 4,08 (3H, s), 6,27 (1H, s), 6.87 in (1H, s), 7,01 (1H, DD, J = 1.5 Hz, 8 Hz), to 8.12 (1H, d, J = 8 Hz).

Technique 46

The following compound was obtained according to method 45.

3-methoxy-4-(2-methyl-1-propenyl)benzoic acid

NMR (CDCl3, ): of 1.85 (3H, s) of 1.97 (3H, s), 3,90 (3H, s), 6,34 (1H, s), 7,28 (1H, d, J = 8 Hz), 7,58 (1H, s), of 7.70 (1H, d, J = 8 Hz).

Methodology 47

A mixture of 1-iodobutane (185 mg) this mixture is added a solution of tetrakis(triphenylphosphine)palladium (31 mg) and 2-methoxy-4-(2-methyl-1-propenyl)of benzoyl chloride (obtained from 138 mg of 2-methoxy-4-(2-methyl-1-propenyl)benzoic acid and 0.07 ml of oxalicacid) in benzene (2 ml) and the resulting reaction mixture was stirred at room temperature for 30 minutes. The mixture is filtered, the filtrate concentrated. The residue is dissolved in ethyl acetate, the organic solution is washed with water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (9:1); get 2'-methoxy-4'-(2-methyl-1-propenyl)valerophenone (91 mg) as oil.

NMR (CDCl3, ): of 0.93 (3H, t, J = 7.5 Hz), 1,25-1,5 (2H, m), 1,55-1,75 (2H, m), 1,90 (3H, d, J = 1.5 Hz), of 1.93 (3H, d, J = 1.5 Hz), of 2.97 (2H, t, J = 7.5 Hz), 3,86 (3H, s), 6,27 (1H, s), is 6.78 (1H, s), 6.87 in (1H, d, J = 8 Hz), 7,66 (1H, d, J = 8 Hz).

Technique 48

The following compound was obtained according to the method 47.

3'-methoxy-4'-(2-methyl-7-propenyl)valerophenone

NMR (CDCl3, ): 0,97 (3H, t, J = 7.5 Hz), the 1.3 to 1.55 (2H, m), 1,6-1,8 (2H, m) of 1.84 (3H, d, J = 1.5 Hz), of 1.97 (3H, d, J = 1.5 Hz), of 2.97 (2H, t, J = 7.5 Hz), 3,90 (3H, s), 6,33 (1H, s), 7,26 (1H, d, J = 8 Hz), 7,45 and 7.6 (2H, m).

Methodology 49

A mixture of 2'-methoxy-4'-(2-methyl-1-propenyl)valerophenone (88 mg) and 10% palladium on coal (30 mg) is stirred in hydrogen atmosphere for 30 minutes. Filtration to remove the catalyst and concentrating the filtrate. The residue is dissolved in methanol (5 ml), and then add sodium borohydride (16 mg). The reaction mixture was stirred at room temperature for 30 minutes. The mixture is then poured into ice and my brine, dried over magnesium sulfate and concentrated, obtaining 1-(4-isobutyl-2-methoxyphenyl)pentanol (88 mg) as oil.

NMR (CDCl3, ): 0,8-0,95 (9H, m), 1,2-1.55V (4H, m) of 1.65 to 2.0 (3H, m), 2,46 (2H, d, J = 7 Hz), of 2.54 (1H, d, J = 6.5 Hz), 3,85 (3H, s), to 4.81 (1H, DD, J = 6 Hz, 13 Hz), of 6.65 (1H, s), of 6.73 (1H, d, J = 8 Hz), 7,17 (1H, d, J = 8 Hz).

The method 50

The following compound was obtained according to method 49.

1-(4-isobutyl-3-methoxyphenyl)pentanol

NMR (CDCl3, ): 0,8-0,95 (9H, m), 1.2 to 1.5 (4H, m) of 1.65 to 2.0 (4H, m), 2,47 (2H, d, J = 7 Hz), 3,82 (3H, s), 4,55-4,7 (1H, m), 6.75 in-6,9 (2H, m),? 7.04 baby mortality (1H, d, J = 7 Hz).

Methodology 51

A mixture of (4-bromo-2-terbisil)triphenylphosphorane (3,82 g) and of potassium tert-butylate (786 mg) was stirred at room temperature for 30 minutes. Then add acetone (1.0 ml) and heated the reaction mixture under reflux for 40 hours. The mixture is filtered, the filtrate concentrated. The residue is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and the solvent is evaporated. The remainder chromatographic on silikagelevye column, elwira hexane; get 1-(4-bromo-2-forfinal)-2-methyl-1-propene (0,70 g) in the form of butter.

NMR (CDCl3, ): or 1.77 (3H, s) of 1.92 (3H, s), 6,12 (1H, s), 7,0 is 7.3 (3H, m).

Methodology 52

A solution of 3-fluoro-4-(2-methyl-1-propenyl)phenyl-1-propene (0,70 g). To a solution of the Grignard reagent is added dropwise a solution of valeric aldehyde (526 mg) in ether (5 ml) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture an aqueous solution of ammonium chloride, the organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (85:15); receive 1-[3-fluoro-4-(2-methyl-1-propenyl)phenyl]pentanol (369 mg) in the form of butter.

NMR (CDCl3, ): to 0.88 (3H, t, J = 6.5 Hz), of 1.15 to 1.5 (4H, m), 1,6-of 1.85 (5H, m), with 1.92 (3H, s).

Methodology 53

A mixture of 1-[3-fluoro-4-(2-methyl-1-propenyl)phenyl]pentanol (300 mg) and 10% palladium on coal (90 mg) in methanol (10 ml) is stirred for 30 minutes at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration and the solvent evaporated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (85:15); get 1-(3-fluoro-4-isobutylphenyl)pentanol (167 mg) as oil.

NMR (CDCl3, ): 0,8-0,95 (9H, m), of 1.15 to 1.5 (4H, m), 1,6-2,0 (4H, m), 2.49 USD (2H, DD, J = 1 Hz, 7.5 Hz), 4,55-4,7 (1H, m), 6,95 to 7.2 (3H, m).

Technique 54

Sodium (317 mg) was dissolved in ethanol (30 ml), then add 2-nitropropane. To this mixture to the indicate at room temperature, after filtered off the insoluble products. The filtrate is concentrate and dissolve the residue in diethyl ether and water. The organic layer was washed with 1 N sodium hydroxide solution and water, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (20:1); get 4-bromo-2-forbindelse (2.28 g) as a solid.

NMR (CDCl3, ): 7,35-of 7.55 (2H, m), 7,7-a 7.85 (1H, m).

Methodology 55

The solution butylacrylamide prepare in the usual way from diethyl ether (5 ml), magnesium (111 mg) and 1-bromobutane (624 mg). To a solution of the Grignard reagent is added dropwise a solution of 4-bromo-2-forventelige (925 mg) in diethyl ether (5 ml). After the addition, the reaction mixture was stirred for 30 minutes at room temperature. The reaction is stopped by the addition of aqueous ammonium chloride solution, separating the organic layer, washed with water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (85: 15); get 1-(4-bromo-2-fluoro-phenyl)pentanol (635 mg) in the form of butter.

NMR (CDCl3, ): of 0.90 (3H, t, J = 7 Hz), 1.2 to 1.5 (4H, m) of 1.65 to 1.9 (3H, m), 4,9-of 5.05 (1H, is RA (196 mg) and triethylamine (246 mg) was stirred at room temperature for 3 hours. The mixture is then poured into ice water and extracted with ethyl acetate. The organic layer was washed with 0.5 N hydrochloric acid, water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (19:1); get 1-(4-bromo-2-forfinal)-1-(methoxyethoxy)pentane (558 mg) in the form of butter.

NMR (CDCl3, ): to 0.89 (3H, t, J = 7 Hz), 1.2 to 1.5 (4H, m), 1,6-1,9 (2H, m) to 3.36 (3H, s), 4,5-4,6 (2H, m), 4,88 (1H, DD, J = 5.5 Hz, 8 Hz), 7,15-to 7.35 (3H, m).

Methodology 57

To a solution of 1-(4-bromo-2-forfinal)-1-(methoxyethoxy)pentane (368 mg) in diethyl ether (5 ml) is added 1.6 M solution of n-utility in hexane (1.4 ml). The reaction mixture is stirred for 1 hour at -60oC, then add to it a solution of isobutyl aldehyde (161 mg) in diethyl ether (1 ml). After 30 minutes, to this mixture an aqueous solution of ammonium chloride. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (4:1); receive 1-[3-fluoro-4-[1-(methoxyethoxy)pentyl]phenyl]-2-methylpropanol (108 mg) as oil.

NMR (CDCl3, ): 0,8-of 1.05 (9H, m), 1,15-of 2.05 (8H, m), 3,37 (3H, s), to 4.38 (1H, d, J = 6.5 Hz), 4,5-4,6 (2H, m) to 4.92 (1H, DD, J =enyl] -2-methylpropanol (104 mg), acetic anhydride (66 mg) and N,N-dimethylaminopyridine (2 mg) 1 hour and stirred at room temperature. The mixture is then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate (85:15); receive 1-[3-Vitor-4-[1-methoxyethoxy)-pentyl] phenyl] -2-methylpropionate (113 mg) as oil.

NMR (CDCl3, ): 0,75-1,0 (9H, m), 1.2 to 1.5 (4H, m), 1,6-1,9 (2H, m), 1,95-2,15 (4H, m) to 3.36 (3H, s), 4,5-4,6 (2H, m), the 4.90 (1H, DD, J = 5.5 Hz, 8 Hz), 5,44 (1H, d, J = 6.5 Hz), to 6.95 (1H, DD, J = 1 Hz), 10.5 Hz), 7,05 (1H, DD, J = 1 Hz, 8 Hz), 7,35 (1H, t, J = 8 Hz).

Methodology 59

A mixture of 1-[3-fluoro-4-[1-methoxyethoxy)pentyl] phenyl]-2-methylpropylamine (110 mg) and 1 N hydrochloric acid (0.3 ml) in acetic acid (3 ml) for 1 hour and stirred at room temperature. The solvent is distilled off under reduced pressure and dissolve the residue in ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The remainder chromatographic on silikagelevye column, elwira with a mixture of hexane and ethyl acetate; receive 1-[3-fluoro-4-(1-hydroxyphenyl)phenyl]-2-methylpropionate (70 mg) in the form of the (1H, d, J = 10.5 Hz), 7,06 (1H, d, J = 8 Hz), 7,41 (1H, t, J = 8 Hz).

The method 60

To a solution of (3-methoxycarbonylbenzyl)triphenylmethylchloride (6.0 g) in tetrahydrofuran (120 ml) add a solution of potassium tert-butylate (2.0 g) in tetrahydrofuran (50 ml) at 0oC. After stirring the mixture for 30 minutes and to it was added 4-isobutylbenzene (2.2 g). The mixture is stirred for 2 hours, poured into ice and diluted hydrochloric acid, extracted the organic layer with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated. The residue is purified column chromatography on silica gel (300 g), elwira a mixture of ethyl acetate and n-hexane (1:50); get methyl-3-TRANS-[2-(4-isobutylphenyl)vinyl]benzoat (of 2.23 g) as a white powder and methyl-3-CIS-[2-(4-isobutylphenyl)vinyl]benzoate (1.25 g) as a colourless oil.

Methyl-2-TRANS-[2-(4-isobutylphenyl)vinyl]benzoat

NMR (CDCl3, ): to 0.92 (6H, d, J = 7 Hz), a 1.88 (1H, m), 2,50 (2H, d, J = 7 Hz), of 3.95 (3H, s), was 7.08 (1H, d, J = 16 Hz), to 7.15 (2H, d, J = 9 Hz), 7,20 (1H, d, J = 16 Hz), the 7.43 (1H, m), 7,45 (2H, d, J = 9 Hz), 7,68 (1H, d, J = 7 Hz), 7,92 (1H, d, J = 8 Hz), to 8.20 (1H, s).

Methyl-3-CIS-[2-(4-isobutylphenyl)vinyl]benzoate

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), of 1.85 (1H, m), 2,43 (2H, d, J = 7 Hz), a 3.87 (3H, s), 6,55 (1H, d, J = 11 Hz), of 6.65 (1H, d, J = 11 Hz), 7,00 (2H, d, J = 8 Hz), 7,12 (2H, d, J = 8 Hz), 7,28 (1H, t, J ENES according to the method 60.

Methyl-4-TRANS-[2-(4-isobutylphenyl)vinyl]benzoate

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), a 1.88 (1H, m), 2,50 (2H, d, J = 7 Hz), 3,93 (3H, s), was 7.08 (1H, d, J = 16 Hz), to 7.15 (2H, d, J = 9 Hz), 7,20 (1H, d, J = 16 Hz), was 7.45 (2H, d, J = 9 Hz), 7,55 (2H, d, J = 9 Hz), 8,03 (2H, d, J = 9 Hz).

Methyl-4-CIS-[2-(4-isobutylphenyl)vinyl]benzoate

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz) and 1.83 (1H, m), 2,43 (2H, d, J = 7 Hz), 3,90 (3H, s), 6,55 (1H, d, J = 11 Hz), of 6.68 (1H, d, J = 11 Hz), 7,00 (2H, d, J = 9 Hz), 7,13 (2H, d, J = 9 Hz), 7,32 (2H, d, J = 9 Hz), 7,89 (2H, d, J = 9 Hz).

Technique 62

To a solution of methyl-3-TRANS-[2-(4-isobutylphenyl)vinyl]benzoate (2,23 g) in dioxane (20 ml) was added 1 N aqueous solution of sodium hydroxide (10 ml). The mixture is stirred for 45 minutes at 100oC and poured into ice and diluted hydrochloric acid. The organic layer is extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated. The residue was washed with n-hexane; get 3-TRANS-[2-(4-isobutylphenyl)vinyl]benzoic acid as a white powder (1,74 g).

NMR (CDCl3+ CD3OD, ): to 0.92 (6H, d, J = 7 Hz), 1,89 (1H, m), 2,50 (2H, d, J = 7 Hz), was 7.08 (1H, d, J = 16 Hz), 7,21 (1H, d, J = 16 Hz), to 7.15 (2H, d, J = 8 Hz), was 7.45 (2H, d, J = 8 Hz), 7,43 (1H, m), of 7.69 (1H, d, J = 8 Hz), 7,95 (1H, d, J = 8 Hz), by 8.22 (1H, s).

Methodology 63

The following compounds were obtained according to the method 62.

(1) 4-TRANS-[2-(4-isobutylphenyl)wines,15 (2H, d, J = 9 Hz), 7,22 (1H, d, J = 16 Hz), was 7.45 (2H, d, J = 9 Hz), 7,56 (2H, d, J = 9 Hz), 8,02 (2H, d, J = 9 Hz).

(2) 3-CIS-[2-(4-Isobutylphenyl)vinyl]benzoic acid

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), of 1.85 (1H, m), of 2.45 (2H, d, J = 7 Hz), to 6.58 (1H, d, J = 12 Hz), 6,70 (1H, d, J = 12 Hz), 7,00 (2H, d, J = 9 Hz), 7,13 (2H, d, J = 9 Hz), 7,31 (1H, t, J = 8 Hz), to 7.50 (1H, d, J = 8 Hz), to 7.93 (1H, d, J = 8 Hz), 8,00 (1H, s).

(3) 4-CIS-[2-(4-Isobutylphenyl)vinyl]benzoic acid

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), to 1.87 (1H, m), of 2.45 (2H, d, J = 7 Hz), 6,55 (1H, d, J = 11 Hz), 6,70 (1H, d, J = 11 Hz), 7,02 (2H, d, J = 9 Hz), 7,14 (2H, d, J = 9 Hz), was 7.36 (2H, d, J = 9 Hz), of 7.97 (2H, d, J = 9 Hz).

Methodology 64

To a suspension of 3-TRANS-[2-(4-isobutylphenyl)vinyl] benzoic acid (0.56 g) in dichloromethane (10 ml) add oxalicacid (0.5 ml) and N,N-dimethylformamide (0.05 ml). The mixture is stirred for 30 minutes at room temperature and evaporated. The residue is dissolved in n-hexane (10 ml) and filtered. The filtrate is evaporated, getting the 3-TRANS-[2-(4 - isobutylphenyl)vinyl] benzoyl chloride (0.54 g) as a white powder.

NMR (CDCl3, ): of 0.93 (6H, d, J = 7 Hz), 1,90 (1H, m), 2,50 (2H, d, J = 7 Hz) was 7.08 (1H, d, J = 16 Hz), 7,18 (2H, d, J = 9 Hz), 7,21 (1H, d, J = 16 Hz), was 7.45 (2H, d, J = 9 Hz), and 7.5 (1H, m), 7,81 (1H, d, J = 7 Hz), of 8.00 (1H, d, J = 9 Hz), by 8.22 (1H, s).

Methodology 65

The following compounds were obtained according to methods analogous to the methods 64.

(1) 4-qi = 11 Hz), 6,77 (1H, d, J = 11 Hz), 7,02 (2H, d, J = 9 Hz), 7,13 (2H, d, J = 9 Hz), 7,38 (2H, d, J = 9 Hz), of 7.97 (2H, d, J = 9 Hz).

(2) 4-TRANS - [2-(4-Isobutylphenyl)vinyl]benzoyl chloride

NMR (CDCl3, ): to 0.92 (6H, d, J = 7 Hz), to 1.38 (1H, m), 2,50 (2H, d, J = 7 Hz), was 7.08 (1H, d, J = 16 Hz), 7,18 (2H, d, J = 9 Hz), 7,30 (1H, d, J = 16 Hz), of 7.48 (2H, d, J = 9 Hz), 7,60 (2H, d, J = 9 Hz), 8,10 (2H, d, J = 9 Hz).

(3) 3-CIS-[2-(4-Isobutylphenyl)vinyl]benzoyl chloride

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), of 1.85 (1H, m), 2,43 (2H, d, J = 7 Hz), 6,55 (1H, d, J = 12 Hz), 6,72 (1H, d, J = 12 Hz), 7,02 (2H, d, J = 9 Hz), 7,12 (2H, d, J = 9 Hz), 7,34 (1H, t, J = 8 Hz), 7,55 (1H, d, J = 8 Hz), 7,92 (1H, d, J = 8 Hz), 8,02 (1H, s).

Technique 66

The following compound was obtained by treating 1-(4-isobutyl - phenyl)-3-butene-1-it (+)-B-chlorodiisopinocampheylborane similar to the method described in method 24.

(R)-1-(4-isobutylphenyl)-3-butene-1-ol

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), to 1.86 (1H, m), 2,46 (2H, d, J = 7 Hz), 2,52 (2H, m), 4,71 (1H, t, J = 7 Hz), 5,12 (1H, m), is 5.18 (1H, m), of 5.83 (1H, m), 7,13 (2H, d, J = 8 Hz), 7,27 (2H, d, J = 7 Hz).

Methodology 67

The following compound was obtained analogously to the method described in method 10.

4-Isobutylbenzene

NMR (CDCl3, ): to 0.94 (6H, d, J = 7 Hz), 1,75 - 2,05 (1H, m), 2.57 m (2H, d, J = 7 Hz), 7,27 (2H, d, J = 9 Hz), 7,35 - a 7.85 (7H, m).

Technique 68

To a solution of 4,4,4-triptoreline acid (4.15 g) in Dehli at room temperature for 1 hour, and the solvent drove away. The residue was dissolved in dichloromethane (100 ml), and then to the solution was added aluminum chloride (3,89 g) at 0oC. Then the mixture was stirred at 0oC for 30 minutes, then added isobutylbenzene (to 3.92 g). The mixture was stirred at 0oC for 1 hour and poured into ice-cold water. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, dried over magnesium sulfate. After evaporation of the solvent was obtained 4'-4,4,4-trifluromethane (6,80 g) in the form of butter.

NMR (CDCl3, ): of 0.91 (6H, d, J = 7 Hz), 1,75-2,05 (1H, m), a 2.45 - 2.7 (4H, m) of 3.25 (2H, t, J = 8 Hz), 7,26 (2H, d, J = 8 Hz), 7,39 (2H, d, J = 8 Hz).

Technique 69

The following compounds were obtained according to the method similar to the method 11.

(1) (4-Isobutylphenyl)benzyl alcohol

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), 1,7 - of 1.95 (1H, m), of 2.45 (2H, d, J = 7 Hz), 2,19 (1H, d, J = 4 Hz), 5,33 (1H, d, J = 4 Hz), 7,11 (2H, d, J = 8 Hz), 7,15 was 7.45 (7H, m).

(2) 4,4,4 - Triflora-1-(4-isobutylphenyl)butanol

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), of 1.75 to 2.4 (6H, m), 2,48 (2H, d, J = 7 Hz), 4.72 in (1H, t, J = 6.5 Hz), to 7.15 (2H, d, J = 8 Hz), 7,25 (2H, d, J = 8 Hz).

The method 70

The following compound was obtained according to the method similar to the method 12.

(4-Isobutylphenyl)benzylbromide

NMR (CDCl32">

To a solution of ethyl-4-[1-(3-aminobenzyl)-indolizine-3-yl]butyrate (320 mg) in methylene chloride (10 ml) under stirring was added diisopropylethylamine (0,22 ml) and bis(4-isobutylphenyl)chloromethane (340 mg) in methylene chloride (5 ml) at room temperature. After stirring for 18 hours the reaction mixture was evaporated and extracted with ether. The organic layer was washed with water and brine and dried over sodium sulfate. After evaporation of the solvent the residue is chromatographically purified on silica gel, elwira a mixture of methylene chloride:ethyl acetate 20 : 1 with the formation of ethyl-4-[1-1[3-[bis(4-isobutylphenyl)-methylamino] benzoyl]indolizine-3-yl]butyrate (279 mg).

NMR (CDCl3, ): to 0.92 (12H, d, J = 7 Hz), of 1.28 (3H, t, J = 7 Hz), to 1.87 (2H, m), of 2.08 (2H, m), 2,4 - by 2.55 (6H, m), is 2.88 (2H, t, J = 7 Hz), 4,25 (2H, K, J = 7 Hz), to 5.56 (1H, s) 6,70 (1H, m) 6,86 (1H, s), make 6.90 (1H, dt, J = 1 Hz), 7,0 - 7,4 (12H, m), 8,02 (1H, d, J = 7 Hz) and 8.50 (1H, d, J = 9 Hz).

Example 2.

The following compounds were obtained analogously to the method described in example 1.

(1) Ethyl-4-[1-[4-[bis(4-isobutylphenyl)methylamino]benzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): to 0.89 (12H, d, J = 7 Hz), 1,24 (3H, t, J = 7 Hz), of 1.85 (2H, m), is 2.05 (2H, m), 2,35 - 2,5 (6H, m), is 2.88 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), to 5.56 (1H, s), 6,59 (2H, d, J = 9 Hz), PC 6.82 (1H, dt, J = 1 Hz, 7 Hz), 6,92 (1H, s), to 7.09 (1H, m), 7,12 (4H, d, J = 8 Htmlpanel)methylamino]benzoyl indolizine-1-yl]butyrate

NMR (CDCl3, ): of 0.87 (12H, d, J = 7 Hz), to 1.22 (3H, t, J = 7 Hz), 1,7-of 2.05 (4H, m), 2,32 (2H, t, J = 7 Hz), 2,43 (4H, d, J = 7 Hz), 2,73 (2H, t, J = 7 Hz), 4,10 (2H, K, J = 7 Hz), 5,52 (1H, s), of 6.68 (1H, m), to 6.88 (1H, dt, J = 1 Hz, 7 Hz), 7,0 is 7.3 (13H, m), 7,52 (1H, dt, J = 8 Hz, 1 Hz), 9,92 (1H, d, J = 7 Hz).

(3) Ethyl-4-[3-[4-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizine-1-yl] butyrate

NMR (CDCl3, ): to 0.89 (12H, d, J = 7 Hz), to 1.22 (3H, t, J = 7 Hz), a 1.7-2.1 (4H, m), 2,32 (2H, t, J = 7 Hz), a 2.45 (4H, d, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), to 5.57 (1H, s), 6,59 (2H, d, J = 9 Hz), 6,83 (1H, dt, J = 1 Hz, 7 Hz), 7,0-to 7.35 (10H, m), 7,49 (1H, d, J = 9 Hz), to 7.68 (2H, d, J = 9 Hz), to 9.93 (1H, d, J = 7 Hz).

Example 3.

A mixture of ethyl-4-[1-(4-hydroxybenzoyl)indolizine-3-yl] butyrate (334 mg), bis(4-isobutylphenyl) chloromethane (559 mg) and potassium carbonate (394 mg) in N, N-dimethylformamide (5 ml) was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue is chromatographically purified on silica gel, using as eluent a mixture of n-hexane and ethyl acetate (3:1) with the formation of 4-[1-[4-[bis(4-isobutylphenyl)-methoxy]benzoyl]indolizine-3-yl]butyrate (95 mg) as oil.

NMR (CDCl3, ):/ to 0.89 (12H, d, J = 7 Hz), of 1.26 (3H, t, J = 7 Hz), 1,74-2,), 8,44 (1H, d, J = 9 Hz).

Example 4.

A mixture of ethyl-4-[1-(4-hydroxybenzoyl)indolizine-3-yl]butyrate (61 mg), 1-bromo-1-(4-isobutylphenyl) propane (53 mg) and potassium carbonate (72 mg) in N, N-dimethylformamide (2 ml) was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue is chromatographically purified on silica gel, using as eluent a mixture of n-hexane and ethyl acetate (2: 1) with the formation of 4-[1-[4-[1-(4-isobutylphenyl)- propyloxy] benzoyl]indolizine-3-yl]butyrate (80 mg) as oil.

TLC Rf: 0,48 (n-hexane-ethyl acetate 2:1).

Example 5.

The following compound was obtained in a manner analogous to the method described in example 3.

Ethyl-4[1-[3-[bis(4-isobutylphenyl)methoxy]benzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), 1,74-2,11 (4H, m), 2,33-2,49 (6H, m), 2,87 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 6,28 (1H, s), 6,76-7,47 (15H, m), 8,02 (1H, d, J = 9 Hz), of 8.47 (1H, d, J = 9 Hz).

Example 6.

The following compound was obtained in a manner analogous to the method described in example 4.

Example 7.

A mixture of ethyl-4-[3-(4-hydroxybenzoyl)indolizine-1-yl] butyrate (400 mg), bis-(4-isobutylphenyl) chloromethane (430 mg) and diisopropylethylamine (736 mg) in dichloromethane (20 ml) was heated for 14 hours and was evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate and evaporated. The residue is chromatographically purified on silica gel, using as eluent a mixture of n-hexane and ethyl acetate (4:1) with the formation of 4-[3-[4-[bis-(4-isobutylphenyl)methoxy]benzoyl]indolizine-1-yl] butyrate (158 mg) as oil.

NMR (CDCl3, ): to 0.89 (12H, d, J = 7 Hz), to 1.22 (3H, t, J = 7 Hz), 1,74-2,07 (4H, m), of 2.33 (2H, t, J = 7 Hz), 2,46 (4H, d, J = 7 Hz), 2,77 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), 6,27 (1H, s), 6,82-7,20 (9H, m), 7,33 (1H, d, J = 9 Hz), 7,52 (1H, d, J = 9 Hz), 7,72 (1H, d, J = 9 Hz).

Example 8.

The following compound was obtained in a manner analogous to the method described in example 7.

Ethyl-4-[3-[3-[bis(4-isobutylphenyl)methoxy] benzoyl] indolizine-1-yl] butyrate

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz), 1,73 e 2.06 (4H, m), of 2.33 (2H, t, J = 7 Hz), a 2.45 (4H, d, J = 7 Hz), was 2.76 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz) the-4-[3-[bis(4-isobutylphenyl)methylamino] benzoyl] indolizine-3-yl] butyrate (279 mg) in ethanol (10) ml was added a 4 N solution of sodium hydroxide (of 0.44 ml). Stirring was continued for 1 hour at a temperature of 40oC. the Reaction mixture was evaporated in vacuum, after which was added an aqueous solution of potassium dihydrophosphate in water and 1 N hydrochloric acid (26 ml) and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. After evaporation of the solvent the residue is chromatographically purified on silica gel, using as eluent ethyl acetate with the formation of 4-[1-[3-[bis-(4-isobutylphenyl)methylamino] benzoyl] indolizine-3-yl] butyl acid (229 g).

NMR (CDCl3, ): of 0.87 (12H, d, J = 7 Hz) and 1.83 (2H, m), 2,22 (2H, m), 2,4-2,5 (6H, m), 2,85 (2H, t, J = 7 Hz), the 5.51 (1H, s), 6,69 (1H, m), PC 6.82 (1H, s), at 6.84 (1H, dt, J = 1 Hz, 7 Hz), 7,0 is 7.3 (12H, m), 7,94 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 9 Hz).

Example 10.

The following compounds were obtained in a manner analogous to the method described in example 9.

(1) 4-[1-[4-[bis(4-isobutylphenyl)methylamino] benzoyl]indolizine-3-yl]butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), of 1.84 (1H, m) to 2.06 (2H, m), 2,4 - by 2.55 (6H, m) is 2.88 (1H, t, J = 7 Hz), to 5.56 (1H, s), to 6.57 (2H, d, J = 9 Hz), to 6.80 (1H, dt, J = 1 Hz), 6,92 (1H, s), was 7.08 (1H, m), 7,11 (4H, d, J = 8 Hz), 7.23 percent (4H, d, J = 8 Hz), 7,72 (2H, d, J = 9 Hz), 7,92 (1H, d, J = 7 Hz), to 8.41 (1H, d, J = 8 Hz).

(2) 4-[3-[3-[bis-(4-isobutylphenyl)methylamino]benzoyl]indolizine-1-yl]butyl acid
<8 (1H, dt, J = 1 Hz, 7 Hz), 7,0 is 7.3 (13H, m), 7,49 (1H, dt, J = 8 Hz), to 9.91 (1H, d, J = 7 Hz).

(3) 4-[3-[4-[bis(4-isobutylphenyl)methylamino] benzoyl]indolizine-1-yl]butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), a 1.7 - 2.1 (4H, m), 2,39 (2H, t, J = 7 Hz), a 2.45 (4H, d, J = 7 Hz), and 2.79 (2H, t, J = 7 Hz), to 5.57 (1H, s), to 6.58 (2H, d, J = 9 Hz), PC 6.82 (1H, dt, J = 1 Hz, 7 Hz), 7,0 is 7.3 (10H, m), 7,49 (1H, d, J = 9 Hz), to 7.68 (2H, d, J = 7 Hz), to 9.93 (1H, d, J = 7 Hz).

Example 11.

To a solution of ethyl-4-[1-[bis(4 - isobutylphenyl)methoxy]benzoyl-indolizine-3-yl] butyrate (90 mg) in ethanol (1 ml) and 1,4-dioxane (1 ml) was added 1 N aqueous sodium hydroxide solution (0.5 ml). The mixture was stirred at room temperature for 2 hours and then poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated with the formation of 4-[1-[4-[bis (4 - isobutylphenyl)methoxy] benzoyl]indolizine-3-yl] butyl acid (79 mg) in powder form.

NMR (CDCl3, ): to 0.89 (12H, d, J = 7 Hz), 1,73 - of 1.97 (2H, m), 2.40 a is 2.55 (6H, m), 2,89 (2H, m), 6,27 (1H, s), 6,79 - of 6.90 (2H, m), 6,98 - to 7.18 (7H, m), 7,28 - 7,38 (4H, m), of 7.75 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

Example 12.

The following compounds were obtained in a manner analogous to the method described in example 11.

(1) 4-[1-[4-[1-(4-isobutylphenyl), 17 (5H, m), 2.40 a is 2.55 (4H, m), is 2.88 (2H, t, J = 7 Hz), to 5.08 (1H, t, J = 7 Hz), 6,79 - 6,98 (4H, m), 7,07 - to 7.32 (2H, d, J = 9 Hz), 7,94 (1H, d, J = 7 Hz), 8,42 (1H, d, J = 9 Hz).

(2) 4-[1-[3-[Bis(4-isobutylphenyl)methoxy] benzoyl]indolizine-3-yl] butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,76 - of 1.92 (2H, m), 1,99 and 2.13 (2H, m), 2.40 a is 2.55 (6H, m), is 2.88 (2H, t, J = 7 Hz), 6,27 (1H, s), 6,76 - 7,46 (15H, m), 7,98 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 9 Hz).

(3) 4-[1-[3-[1-(4-Isobutylphenyl)propyloxy] benzoyl]indolizine-3-yl] butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 0,99 (3H, t, J = 7 Hz), 1.70 to 3,14 (5H, m), 2,37 - of 2.56 (4H, m), is 2.88 (2H, t, J = 7 Hz), to 5.08 (1H, t, J = 7 Hz), 6,76 - 7,38 (11H, m), of 7.97 (1H, d, J = 7 Hz), of 8.47 (1H, d, J = 9 Hz).

(4) 4-[3-[4-[Bis(4-isobutylphenyl)methoxy] benzoyl]indolizine-1-yl] butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,73 - of 2.08 (4H, m), 2,35 - of 2.50 (6H, m), 2,80 (2H, t, J = 7 Hz), 6,27 (1H, s), for 6.81 - 7,22 (9H, m), 7,32 (4H, d, J = 8 Hz), 7,51 (1H, d, J = 9 Hz), 7,71 (2H, d, J = 9 Hz).

(5) 4-[3-[3-[Bis(4-isobutylphenyl)methoxy] benzoyl] indolizine-1-yl]butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,72 - of 2.05 (4H, m), 2,33 - 2,48 (6H, m), 2,78 (2H, t, J = 7 Hz), 6,27 (1H, s), 6,84 - of 6.96 (1H, m),? 7.04 baby mortality - 7,42 (14H, m).

Example 13.

4 N hydrochloric acid in ethyl acetate (0.5 ml) was added to a solution of 4-[1-[3-[bis(4-isobutylphenyl)methylamino] benzoyl]indolizine-3-yl]butyl acid (0,60 g) in ethyl acetate (5 ml). PEFC is-[1-[3-[bis(4 - isobutylphenyl)methylamino]benzoyl]indolizine-3-yl]butyl acid hydrochloride in the form of a yellow powder of 0.62 g

So pl. 136 - 138oC decomp.

NMR (DMCO-d6, ): to 8.40 (1H, d, J = 7 Hz), 8,30 (1H, d, J = 9 Hz), 7,35 (2H, d, J = 9 Hz), 7,10 (2H, d, J = 9 Hz) and 6.9 to 7.4 (6H, m), 6,72 (1H, s), 5,67 (1H, s), is 2.88 (2H, t, J = 7 Hz), 2.40 a (4H, d, J = 7 Hz), of 2.33 (2H, t, J = 7 Hz), 1,7 - 2,0 (4H, m) of 0.82 (12H, d, J = 7 Hz).

Example 14.

To a solution of 4-[1-[3-[bis(4-isobutylphenyl)methylamino] benzoyl-3-yl]butyl acid (244 mg) in ethanol was added 1 N sodium hydroxide solution. After removal of solvent the residue was dissolved in benzene, filtered through cotton and evaporated in vacuum with the formation of 4-[1-[3-[bis(4-isobutylphenyl)methylamino]-benzoyl]indolizine-3-yl] butyrate sodium (240 mg).

NMR (CD3OD, ): to 0.88 (12H, d, J = 7 Hz), equal to 1.82 (2H, m) of 1.97 (2H, m), 2,31 (2H, t, J = 7 Hz), 2,44 (4H, d, J = 7 Hz), is 2.88 (2H, t, J = 7 Hz), to 5.56 (1H, s), 6,74 (1H, s), for 6.81 (1H, m), the 6.9 and 7.3 (5H, m), was 7.08 (4H, d, J = 8 Hz), 7,28 (1H, d, J = 7 Hz), 8,25-8,35 (2H, m).

Example 15.

The following compounds were obtained according to the method similar to that described in example 1.

(1) Ethyl 4-[3-[4-[LMS[4-isobutylphenyl)methylamino]benzoyl]-2-methylindolin-1-yl]butyrate

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz), 1,75-2,0 (4H, m), from 2.00 (3H, s), 2,32 (2H, t, J = 7 Hz), 2,46 (4H, d, J = 7 Hz), of 2.72 (2H, t, J = 7 Hz), 4,11 (2H, K, J = 7 Hz), to 5.57 (1H, s), 6,55 (2H, d, J = 8 Hz), of 6.65 (1H, dt, J = 1 Hz, 7 Hz), 6,98 (1H, m), 7,11 (4H, d, J = 8 Hz), 7,24 (1H, d, J = 8 Hz), 7,38 (1H, d is endolysin]-1-yl butyrate

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz), of 1.76 (3H, s) and 1.83 (2H, m), 2,31 (2H, t, J = 7 Hz), 2,42 (4H, d, J = 7 Hz), 2,68 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), the 5.51 (1H, s), 6,65-to 6.95 (4H, m), was 7.08 (4H, d, J = 8 Hz), 7,0 is 7.3 (2H, m), 7.23 percent (4H, d, J = 8 Hz), 7,42 (1H, d, J = 9 Hz), to 9.66 (1H, d, J = 7 Hz).

(3) Ethyl-4-[1-[4-[bis(4-isobutylphenyl) methylamino]benzoyl]-2-methylindolin-3-yl]butyrate

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), to 1.87 (4H, m), and 2.27 (3H, s), of 2.38 (2H, t, J = 7 Hz), a 2.45 (4H, d, J = 7 Hz), of 2.92 (2H, t, J = 7 Hz), 4,14 (2H, K, J = 7 Hz), to 5.56 (1H, s), of 6.52 (2H, d, J = 9 Hz), 6,66 (1H, dt, J = 1 Hz, 7 Hz), to 6.80 (1H, m), 7,10 (4H, d, J = 8 Hz), 7,22 (4H, d, J = 8 Hz), 7,46 (1H, d, J = 9 Hz), to 7.59 (2H, d, J = 8 Hz), to 7.93 (2H, d, J = 7 Hz).

(4) Ethyl-4-[1-[3-[bis(4-isobutylphenyl)methylamino] benzoyl]-2-methylindolin-3-yl]butyrate

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), of 1.27 (3H, t, J = 7 Hz), 1,7-2,0 (4H, m), of 2.20 (3H, s), of 2.38 (2H, t, J = 7 Hz), 2,43 (4H, d, J = 7 Hz), 2,90 (2H, t, J = 7 Hz), 4,14 (2H, K, J = 7 Hz), the 5.51 (1H, s), 6,63-of 6.78 (2H, m), 6,8-7,0 (2H, m), 7,05 of 7.3 (10H, m), 7,44 (1H, d, J = 8 Hz), of 7.97 (1H, d, J = 7 Hz).

Example 16.

The following compounds were obtained by the method similar to that described in example 4.

(1) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indolizine-3-yl] butyrate

NMR (CDCl3, ): to 0.80-0.95 (9H, m), 1,26-of 1.65 (9H, m), 1.70 to to 2.15 (4H, m), 2,35-of 2.50 (4H, m), 2,87 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 5,15 (1H, DD, J = 2 Hz, 7 Hz), 6,80-6,97 (4H, m), 7,07-7,31 (5H, m), 7,72 (2H, d, J = 9 butyrate

NMR (CDCl3, ): to 0.80-0.95 (9H, m), 1,17-to 1.63 (9H, m), 1,72-2,12 (5H, m), 2,32 (2H, t, J = 7 Hz), 2,46 (2H, d, J = 7 Hz), was 2.76 (2H, t, J = 7 Hz), 4,10 (2H, K, J = 7 Hz), 5,14 (1H, DD, J = 1.5 Hz, 7 Hz), for 6.81-6,98 (3H, m), 7,06-7,19 (4H, m), 7,27 (2H, d, J = 9 Hz), 7,51 (1H, d, J = 9 Hz), to 7.68 (2H, d, J = 9 Hz), 9,87 (1H, d, J = 7 Hz).

(3) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)octyloxy] benzoyl]indolizine-3-yl] butyrate

NMR (CDCl3, ): 0,8-0,95 (9H, m), 1,15-1,65 (13H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), 5,15 (1H, DD, J = 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

(4) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)heptyloxy]benzoyl]indolizine-3-yl] butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,2-1,65 (11H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), 5,15 (1H, DD, J = 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,74 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(5) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl] indolizine-3-yl] butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,2-1,65 (7H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 4,12 (12H, K, J = 7 Hz), 5,15 (1H, DD, J = 2 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,73 (2H, d, J = 9 Hz), to 7.99 (1H, d, J = 7 Hz), 8,44 (2H, d, J = 9 Hz).

(6) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)butylochki]benzoyl] indolizine-3-yl] butyrate

NMR (CDCl3, ): 0,8-of 1.05 (9H, m) of 1.24 (3H, t, J = 7 Hz), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), 2,87 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), 5,17 (12">

A mixture of ethyl-4-[1-(3-aminobenzoyl)indolizine-3-yl]butyrate (175 mg), 1-bromohexyl-4-isobutylbenzene (177 mg) and diisopropylethylamine (194 mg) in dichloromethane (3 ml) was boiled for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over magnesium sulfate and evaporated. The residue is chromatographically purified by silica gel, using as eluent n-hexane and ethyl acetate (3: 1) with the formation of ethyl-4-[1-[3-[1-(4-isobutylphenyl)hexylamino]benzyliden-3-yl]-butyrate (170 mg) as oil.

NMR (CDCl3, ): to 0.80-0.95 (9H, m), 1,27 of 1.50 (9H, m), 1,68-2,12 (5H, m), 2,34-2,48 (4H, m), 2,85 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), 4,33 (1H, t, J = 7 Hz), 6,63 (1H, d, J = 7.5 Hz), 6,80-6,91 (2H, m), 6,94-7,28 (9H, m), 7,98 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 9 Hz).

Example 18.

The following compounds were obtained by the method similar to that described in example 17.

(1) Ethyl-4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl] indolizine-1-yl]butyrate

NMR (CDCl3, ): 0,78-to 0.96 (9H, m), 1,20-1,50 (9H, m), 1,64-2,07 (5H, m), 2,25-2,48 (4H, m) of 2.75 (2H, t, J = 7.5 Hz), 4,11 (2H, K, J = 7 Hz), 4,33 (1H, t, J = 7 Hz), only 6.64 (1H, d, J = 7.5 Hz), 6,83-7,30 (11H, m), 7,52 (1H, d, J = 9 Hz).

(2) Ethyl-4-[1-[3-[1-(4-isobutylphenyl)butylamino]benzoyl] indolizine-3-yl] butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,2-1.55V (5H, the J = 7 Hz), to 8.45 (1H, d, J = 9 Hz).

Example 19.

The following compounds were obtained by the method similar to that described in example 11.

(1) 4-[3-[4-[1-(4-Isobutylphenyl)hexyloxy]benzoyl]indolizine-1-yl]butyl acid

NMR (CDCl3, ): 0,81-to 0.96 (9H, m), 1,20-of 1.62 (6H, m), 1,72-of 2.15 (5H, m), 2,34-2,49 (4H, m), and 2.79 (2H, t, J = 7 Hz), 5,14 (1H, DD, J = 1.5 Hz, 7 Hz), 6,80-6,97 (3H, m), 7,06-to 7.18 (4H, m), 7,26 (2H, d, J = 9 Hz), to 7.50 (1H, d, J = 9 Hz), to 7.68 (2H, d, J = 9 Hz), 9,87 (1H, d, J = 7 Hz).

(2) 4-[1-[4-[1-(4-Isobutylphenyl)exercse]benzoyl]indolizine-3-yl]butyl acid

NMR (CDCl3, ): 0,82-of 0.95 (9H, m), 1,23-of 1.65 (6H, m), 1.70 to to 2.15 (5H, m), 2,38 is 2.55 (4H, m), is 2.88 (2H, t, J = 7 Hz), 5,14 (1H, DD, J = 2 Hz, 7 Hz), 6,78-6,97 (4H, m), 7,05-7,30 (5H, m), 7,72 (2H, d, J = 9 Hz), 7,94 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(3) 4-[1-[4-[1-(4-Isobutylphenyl)octyloxy]benzoyl] indolizine-3-yl]butyl acid

NMR (CDCl3, ): to 0.80-0.95 (9H, m), 1,15-1,65 (10H, m), 1.7 to 2.2 (35H, m), 2,4-by 2.55 (4H, m), 2,89 (2H, t, J = 7.5 Hz), 5,15 (1H, DD, J = 2 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(4) 4-[1-[4-[1-(4-Isobutylphenyl)heptyloxy] benzoyl] indolizine-3-yl]butyl acid

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,2-1,65 (8H, m), 1,7-of 2.15 (5H, m), 2,4-by 2.55 (4H, m), 2,89 (2H, t, J = 7.5 Hz), 5,15 (1H, DD, J = 2 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,73 (2H, d, J = 9 Hz), 7,95 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(5) 4-[1-[4-[1-(4-Isobutylphenyl)Penta is m), is 2.88 (2H, t, J = 7.5 Hz), 5,14 (1H, DD, J = 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,73 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(6) 4-[1-[4-[1-(4-Isobutylphenyl)butoxy]benzoyl]indolizine-3-yl]butyl acid

NMR (CDCl3, ): 0,8-of 1.05 (9H, m), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,4-by 2.55 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 5,16 (1H, DD, J = 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 0.7 Hz), 8,42 (1H, d, J = 0.9 Hz).

Example 20.

To a solution of ethyl 4-[3-[3-[1-(4-isobutylphenyl) hexylamino]benzoyl]indolizine-1-yl]butyrate (117 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml) was added 1 N aqueous sodium hydroxide solution (1 ml). The mixture was stirred at room temperature for 3 hours, then poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to education 4-[3-[3-[1-(4-isobutylphenyl)hexylamino] benzoyl] indolizine-1-yl] butyl acid (98 mg) in powder form.

NMR (CDCl3, ): 0,78-to 0.96 (9H, m), 1,15-of 1.50 (6H, m), 1,68-2,07 (5H, m), 2,32-2,48 (4H, m), 2,77 (2H, t, J = 7.5 Hz), 4,32 (1H, t, J = 7 Hz), only 6.64 (1H, d, J = 7.5 Hz), 6,82-7,28 (11H, m) to 7.50 (1H, d, J = 9 Hz).

Example 21.

The following compounds were obtained in a manner analogous to the method of example 20.

(1) 4-[1-[3-[1-(4-Isobutylphenyl)hexylamino] benzoyl] what,5 Hz), 4,32 (1H, t, J = 7 Hz), 6,62 (1H, d, J = 7.5 Hz), 6,79-of 6.90 (2H, m), 6,94-7,27 (9H, m), 7,95 (2H, d, J = 7 Hz), to 8.45 (1H, d, J = 9 Hz).

(2) 4-[1-[3-[1-(4-Isobutylphenyl)butylamino] benzoyl] indolizine-3-yl]butyl acid

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1.2 to 1.5 (2H, m), 1,65-of 2.15 (5H, m), 2,35-2,5 (4H, m), of 2.86 (2H, t, J = 7.5 Hz), 4,34 (1H, t, J = 7 Hz), only 6.64 (1H, d, J = 8 Hz), 6,8-6,95 (2H, m), 7,0 is 7.3 (9H, m), 7,95 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

Example 22.

The following compounds were obtained in a manner analogous to the method of example 9.

(1) 4-[3-[4-[Bis(4-isobutylphenyl)methylamino]benzoyl]-2-methylindolin-1-yl]butyl acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,7-2,0 (4H, m), a 2.01 (3H, m), 2,39 (2H, t, J = 7 Hz), 2,46 (4H, d, J = 7 Hz), is 2.74 (2H, t, J = 7 Hz), to 5.57 (1H, s), 6,53 (2H, d, J = 8 Hz), only 6.64 (1H, dt, J = 7 Hz), to 6.95 (1H, m), 7,11 (4H, d, J = 8 Hz), 7,22 (4H, d, J = 8 Hz), 7,37 (1H, d, J = 9 Hz), to 7.50 (2H, d, J = 8 Hz), of 9.30 (1H, d, J = 7 Hz).

(2) 4-[3-[3-[Bis(4-isobutylphenyl)methylamino] benzoyl] -2-methylindolin-1-yl] butane acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,74 (3H, s), 1,75-of 1.95 (2H, m), is 2.37 (2H, t, J = 7 Hz), 2,42 (4H, d, J = 7 Hz), 2,69 (2H, t, J = 7 Hz), the 5.51 (1H, s), 6,6-6,8 (3H, m), to 6.88 (1H, d, J = 7 Hz), 7,07 (4H, d, J = 7 Hz), 7,0 is 7.3 (2H, m), 7.23 percent (4H, d, J = 7 Hz), 7,40 (1H, d, J = 8 Hz), 9,67 (1H, d, J = 7 Hz).

(3) 4-[1-[4-[Bis(4-isobutylphenyl)methylamino] benzoyl] -2 - methylindolin-3-yl] butane acid

NMR (CDCl3, ): to 0.88 (12H, t, J = 7 Hz), ,09 (4H, d, J = 8 Hz), 7,25 (4H, d, J = 7 Hz), was 7.45 (1H, d, J = 8 Hz), 7,58 (2H, d, J = 9 Hz), of 7.90 (1H, d, J = 7 Hz).

(4) 4-[1-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl-2 - methylindolin-3-yl] butane acid

NMR (CDCl3, ): to 0.88 (12H, d, J = 7 Hz), 1,7-2,0 (4H, m) to 2.18 (3H, s), 2,42 (4H, d, J = 7 Hz), a 2.45 (2H, t, J = 7 Hz), only 2.91 (2H, t, J = 7 Hz), of 5.50 (1H, s), of 6.6 to 7.3 (6H, m), 7,06 (4H, d, J = 8 Hz), 7,22 (4H, d, J = 8 Hz), was 7.45 (1H, d, J = 8 Hz), 7,92 (1H, d, J = 7 Hz).

Example 23.

To a mixture of ethyl-4-[1-(4-hydroxybenzoyl)indolizine-3-yl] butyrate (392 mg), (R)-1-(4-isobutylphenyl)butane-1-ol (230 mg) and triphenylphosphine (292 mg) in tetrahydrofuran (3 ml) and toluene (15 ml) was added diethylazodicarboxylate (0,178 ml) at -20oC in nitrogen atmosphere. Then the mixture was stirred at -20oC in nitrogen atmosphere for 2.5 hours, then was added acetic acid (0.05 ml) and the mixture was heated to room temperature. The solvent is kept under reduced pressure and the residue was poured into a mixture of ethyl acetate and water. The organic portion was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue is chromatographically purified on a column of silica gel, using as eluent a mixture of n-hexane and ethyl acetate (4:1) with the formation of ethyl-4[1-[4[(S)-1-(4-isobutylphenyl) butoxy]benzoyl]indolizine-3-yl]-butyrate (295 mg) as oil.C), of 4.12 (2H, K, J = 7 Hz), to 5.17 (1H, DD, J = 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

Example 24.

To a solution of ethyl-4-[1-4[(S)-1-(4-isobutylphenyl) butoxy]indolizine-3-yl] butyrate (282 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1 N aqueous sodium hydroxide solution (2 ml). The mixture was stirred at room temperature for 2 hours, then poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to education 4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy] benzoyl] indolizine-3-yl] butane acid (232 mg) in powder form.

NMR (CDCl3, ): 0,8-of 1.05 (9H, m), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,4-by 2.55 (4H, m), is 2.88 (2H, m, J = 7.5 Hz), 5,16 (1H, DD, J = 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 7 Hz), 8,42 (1H, d, J = 9 Hz),2D5= -78,3o(C=0.5, CHCl3).

Example 25.

The following compounds were obtained in a manner analogous to the method described in example 23.

Ethyl-4-[1-[4-[(R)-1-(4-isobutylphenyl)butoxy]benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,8-of 1.05 (9H, m) of 1.24 (3H, t, J = 7 Hz), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), 2,87 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), to 5.17 (1H, DD, J 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 what about the way similar to the method described in example 24.

4-[1-[4-[(R)-1-(4-Isobutylphenyl)butoxy] benzoyl] indolizine-3-yl] butane acid

NMR (CDCl3, ): 0,8-of 1.05 (9H, m), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,4-by 2.55 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 5,16 (1H, DD, J = 7 Hz), 6,8-6,95 (4H, m), 7,05-7,53 (5H, m), 7,72 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 7 Hz), 8,42 (1H, d, J = 9 Hz).

2D5= = +79o(C = 0.5, CHCl3).

Example 27.

To a solution of ethyl-4-[1-[3-[(1-carboxyethyl)amino]benzoyl] indolizine-3-yl] butyrate (60 mg), heptylamine (16 ml) and 1-hydroxybenzotriazole (20 mg) in dichloromethane (3 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (30 mg). The mixture was stirred at room temperature for 3 hours, evaporated and dissolved in ethyl acetate (10 ml). The solution was washed with diluted hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed under reduced pressure with the formation of 4-[1-[3-[[(1-(heptylcarbinol)ethyl]amino]benzoyl] indolizine-3-yl] butyrate (70 ml) as a yellow oil.

NMR (CDCl3, ): 0,84 (3H, m), 1.1 to 1.4 (11H, m) to 1.45 (2H, m), and 1.54 (3H, d, J = 7 Hz), was 2.05 (2H, m), 2,43 (2H, t, J = 7 Hz), is 2.88 (2H, t, J = 7 Hz), 3,23 (2H, K, J = 7 Hz), 3,90 (1H,, J = 7 Hz), 4,12 (1H, K, J = 7 Hz), 6.75 in (1H, m), to 6.88 (1H, s), 6,93 (1H, m), 7,1-7,3 (3H, m), 7,45 (1H, m), 7,7-7,9 (1H, m), 8,03 (1H, d, J = 7 Hz), 8,49 (1H, d, J = 9 Hz).

(1) Ethyl-4-[1-[3-[[(butylcarbamoyl)(4-isobutylphenyl)methyl]amino]benzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,1-1,3 (5H, m), USD 1.43 (2H, m), equal to 1.82 (2H, m), is 2.05 (2H, m), of 2.3 to 2.6 (4H, m), 2,87 (2H, t, J = 7 Hz) at 3.25 (2H, m), 4,11 (2H, K, J = 7 Hz), 4,88 (1H, s), 6,7-7,0 (3H, m), of 7.1 to 7.4 (1H, d, J = 7 Hz), 8,48 (1H, d, J = 9 Hz).

(2) Ethyl-4-[1-[3-[(heptylcarbinol)(4-isobutylphenyl)methyl] aminobenzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,1-1,3 (11H, m) to 1.45 (2H, m), of 1.85 (1H, m), of 2.0-2.2 (2H, m), 2.4 to a 2.6 (4H, m), is 2.88 (2H, t, J = 7 Hz), 3,26 (2H, m), of 4.12 (2H, K, J = 7 Hz), 4,70 (1H, s), 6,6-7,0 (3H, m), 7,1-7,3 (6H, m), 7,35 (2H, d, J = 9 Hz), and 8.0 (1H, d, J = 7 Hz), of 8.47 (1H, d, J = 9 Hz).

(3) Ethyl-4-[1-[3-[[N-(4-isobutylphenyl)carbarnoyl] methylamino] -benzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): of 0.87 (6H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), a 1.7-2.1 (3H, m), 2,3-2,5 (4H, m), 2,82 (2H, t, J = 7 Hz), of 3.95 (2H, s), 4,11 (2H, K, J = 7 Hz), 6,7-7,0 (3H, m), to 7.09 (2H, d, J = 9 Hz), of 7.1 to 7.4 (4H, m), 7,45 (2H, d, J = 9 Hz), 8,02 (1H, d, J = 7 Hz) and 8.50 (1H, s), 8,58 (1H, s).

(4) Ethyl-4-[1-[3-[[1-[N-(4-isobutylphenyl)carbarnoyl] ethylamino] benzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), of 1.23 (3H, d, J = 7 Hz), of 1.62 (3H, d, J = 7 Hz), to 1.70 (1H, m), 1,9-2,1 (2H, m), 2,3-2,5 (4H, m), 2,80 (2H, t, J = 7 Hz), of 3.96 (1H,, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 6,7-7,0 (3H, m), 7,0 is 7.3 (4H, m), between 7.4 to 7.5 (3H, m), 7,76 (1H, m), 8,03 (1H, d, J = 7 Hz) and 8.50 (1H, d, J = 9 Hz), 8,83 (1H, s).

Example 29.

The following connection byliny)methyl]-amino]benzoyl] indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1,25 (3H, d, J = 7 Hz) and 1.83 (1H, m), 1,9-2,1 (2H, m), 2,3-2,5 (4H, m), 2,85 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), 5,14 (2H, s), 5,19 (1H, s), 6,7-7,0 (3H, m), 7,0-of 7.3 (11H, m), 7,38 (2H, d, J = 9 Hz), and 8.0 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 9 Hz).

Example 30.

The following compounds were obtained by the method similar to that described in example 9.

(1) 4-[1-[3-[[Heptylcarbinol)(4-isobutylphenyl)methyl] amino] -benzoyl] indolizine-3-yl]butane acid

NMR (CDCl3, ):/ is 0.8 - 1.0 (9H, m), 1,1 - 1,3 (11H, m) of 1.40 (2H, m), of 1.85 (1H, m), 2,0 - 2,3 (2H, m), 2.4 to a 2.6 (4H, m), 2,95 (2H, t, J = 7 Hz), up 3.22 (2H, m), is 4.93 (1H, c), 6,8 - 7,5 (11H, m), of 7.96 (1H, d, J = 7 Hz), 8,54 (1H, d, J = 9 Hz).

(2) 4-[1-[3-[[1-(Heptylcarbinol)ethyl] amino] benzoyl] indolizine-3 - yl] butane acid

NMR (CDCl3, ): 0,8 - 1,0 (5H, m), 1,1 - 1,5 (6H, m), and 1.56 (3H, d, J = 7 Hz), by 2.0 - 2.4 (4H, m), 2,47 (2H, t, J = 7 Hz), 2,95 (2H, t, J = 7 Hz), 3,17 (2H, m), 3,95 (1H,, J = 7 Hz), 6,8 - 7,1 (3H, m), 7,2 - 7,4 (4H, m), 7,94 (1H, d, J = 7 Hz), 8,55 (1H, d, J = 9 Hz).

(3) 4-[1-[3-[[1-[N-(4-Isobutylphenyl)carbarnoyl] ethyl]amino]benzoyl]indolizine-3-yl]butane acid

NMR (CDCl3, ): 0,86 (6H, d, J = 7 Hz), of 1.62 (3H, d, J = 7 Hz), of 1.78 (1H, m), 1,92 is 2.2 (2H, m), 2,3 - 2,5 (4H, m), and 2.83 (2H, t, J = 7 Hz), of 4.05 (1H, m), 6,83 (1H, s), the 6.9 to 7.0 (2H, m), 7,05 (2H, d, J = 9 Hz), 7,1 - 7,5 (6H, m), 7,95 (1H, d, J = 7 Hz) and 8.50 (1H, d, J = 9 Hz), of 8.95 (1H, c).

(4) 4-[1-[3-[[Butylcarbamoyl)(4-isobutylphenyl)methyl]amino], is), of 2.21 (2H, m), 2.4 to a 2.6 (4H, m), 2,96 (2H, t, J = 7 Hz), 3,24 (2H, m), 4,99 (1H, s), 6,8 - 7,0 (3H, m), 7,0 - 7,4 (8H, m), of 7.96 (1H, d, J = 7 Hz), 8,53 (1H, d, J = 9 Hz).

(5) 4-[1-[3-[[N-(4-Isobutylphenyl)carbamoylmethyl] amino]benzoyl]-indolizine-3-yl] butane acid

R (CDCl3, ): ): 0,88 (6H, d, J = 7 Hz), of 1.80 (1H, m), 2,02 (2H, m), 2,3 - 2,5 (4H, m), 2,84 (2H, t, J = 7 Hz), of 3.94 (2H, s), 6,8 - 7,0 (3H, m), was 7.08 (2H, t, J = 7 Hz), and 7.1 to 7.4 (4H, m), 7,40 (2H, d, J = 9 Hz), to 7.95 (1H, d, J = 7 Hz) and 8.50 (1H, d, J = 9 Hz), to 8.57 (1H, s)

Example 31. The following compounds were obtained in a manner analogous to the method described in example 24.

(1) 4-[1-[4-[(S)-1-(4-Isobutylphenyl)-2-ethoxyethoxy] benzoyl] - indolizine-3-yl] butane acid

R (CDCl3, ): ): 0,88 (6H, d, J = 7 Hz), to 1.22 (3H, t, J = 7 Hz), 1,7 - of 2.15 (3H, m), 2,4 - by 2.55 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 3,5 - of 3.75 (3H, m), 3,8 - of 3.95 (1H, m), 5,41 (1H, DD, J = 4.5 Hz, 6 Hz), 6.8 or 6.9 (2H, m), 6,97 (2H, d, J = 9 Hz), 7,05 to 7.2 (3H, m), 7,25 - to 7.35 (2H, m), 7,72 (2H, d, J = 9 Hz), 7,94 (1H, d, J = 7 Hz), 7,42 (1H, d, J = 9 Hz)

(2) 4-[1-[4-[(R-1-(4-Isobutylphenyl)-2-ethoxyethoxy] benzoyl] -indolizine-3-yl] butane acid

NMR (CDCl3, ): ): 0,88 (6H, d, J = 7 Hz), 1,7 - of 2.15 (3H, m), 2,4 - by 2.55 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 3,5 - of 3.75 (3H, m), 3,8 - of 3.95 (1H, m), 5,41 (1H, DD, J = 4.5 Hz, 5,41 Hz), 6.8 or 6.9 (2H, m), 6,97 (2H, d, J = 9 Hz), 7,05 to 7.2 (3H, m), 7,25 - to 7.35 (2H, m), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz)

Example 32. The following compounds were obtained in a manner analogous to BR>
NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), 1,15 - of 1.13 (6H, m), 1,7 - of 2.15 (3H, m), 2,35 - 2,5 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 3,5 - of 3.75 (3H, m), 3,8 - of 3.95 (1H, m), 4,13 (2H, K, J = 7 Hz), 5,41 (1H, DD, J = 4.5 Hz), 6.8 or 6.9 (2H, m), 6,97 (2H, d, J = 9 Hz), 7,05 to 7.2 (3H, m), 7,25 - to 7.35 (2H, m), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 7,43 (1H, d, J = 9 Hz).

(2) Ethyl-4[1-[4-[(R)-1-(4-isobutylphenyl)-2 - ethoxyethoxy]benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), 1,15 - 1,3 (6H, m), 1,7 - of 2.15 (3H, m), 2,35 - 2,5 (4H, m), is 2.88 (3H, t, J = 7.5 Hz), 3,5 - of 3.75 (3H, m), 3,8 - of 3.95 (1H, m), 4,13 (2H, K, J = 7 Hz), 5,41 (1H, DD, J = 4.5 Hz), 6.8 or 6.9 (2H, m), 6,97 (2H, d, J = 9 Hz), 7,05 to 7.2 (3H, m), 7,25 - to 7.35 (2H,m), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

Example 33.

The following compound was obtained in a manner analogous to those described in method 31.

Ethyl-4-[1-[3[-[[(carboxy)(4 - isobutylphenyl)methyl]amino]benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): to 0.89 (6H, d, J = 7 Hz), of 1.23 (3H, t, J = 7 Hz) and 1.83 (1H, m), 1,9 - 2,2 (2H, m), of 2.3 to 2.6 (4H, m), 2,82 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), to 5.08 (1H, s), 6,7 - 7,0 (3H , m), 7,0 - 7,4 (6H, m), 7,42 (2H, d, J = 9 Hz), of 7.96 (1H, d, J = 7 Hz), charged 8.52 (1H, d, J = 9 Hz).

Example 34.

The following compounds were obtained in a manner analogous to the method described in example 23.

(1) Ethyl-4-[1-[4[1-(4-isobutylphenyl)-2-butenyloxy]benzoyl]-indolizine-3-yl]butyrate

NMR (CDl3, ): to 0.92 (6H, d, J = 7, 7 Hz), 6,93 (1H, s), 7,1 - 7,3 (5H, m), 7,52 (2H, d, J = 9 Hz), the 7.85 (2H, d, J = 10 Hz), 8,01 (1H, d, J = 7 Hz), 8,48 (1H, d, J = 8 Hz).

(2) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)-3-butenyloxy] benzoyl] - indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), of 1.84 (1H, m), 2,03 (2H, m), 2,35 - 2,5 (4H, m), 2,5 - 2,9 (2H, m), 2,87 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), of 5.05 and 5.3 (3H, m), by 5.87 (1H, m), 6,8 - 6,97 (4H, m), 7,12 (2H, d, J = 8 Hz), 7,14 (1H, m), 7,28 (2H, d, J = 8 Hz), 7,74 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 8 Hz), 8,43 (1H, d, J = 10 Hz).

(3) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)-4-pentyloxy] - benzoyl]-indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1,25 ((3H, t, J = 7 Hz), 1,7 - to 2.35 (7H, m), 2,42 (2H, t, J = 7 Hz), 2,46 (2H, d, J = 7 Hz), is 2.88 (2H, m, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 4.95 points - of 5.25 (3H, m), by 5.87 (1H, m), 6,85 (1H, m), 6.87 in (1H, s), 6,93 (2H, d, J = 9 Hz), 7,12 (1H, d, J = 8 Hz),? 7.04 baby mortality (1H, m), 7,28 (2H, d, J = 8 Hz), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 8 Hz), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 8gts), 8,43 (1H, d, J = 9 Hz).

(4) Ethyl-4-[1-[4-[(S)-1-(4-isobutylphenyl)-3-butenyloxy] benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1,25 (3H, d, J = 7 Hz), 1,7-of 2.15 (3H, m), 2,43 (2H, t, J = 7 Hz), 2,46 (2H, d, J = 7 Hz), 2,5-2,9 (3H, m), 2,87 (2H, t, J = 7 Hz), of 4.12 (2H, K, J = 7 Hz), of 5.05-5,3 (3H, m), by 5.87 (1H, m), 6,8-6,97 (4H, m), 7,12 (2H, d, J = 8 Hz), 7,14 (1H, m), 7,28 (2H, d, J = 8 Hz), 7,74 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 8 Hz), 8,43 (1H, d, J = 10 Hz).

(5) Ethyl-4-[1-[4-[4,4,4-triflora-1-(4-isobutylphenyl)butoxy] benzoyl]indolizine-3-yl]butyrate

(6) Ethyl-4-[1-[4-[1-(4-isobutyl-2-methoxyphenyl)pentyloxy]benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,15-1,6 (7H, m), 1.7 to 2.2 (5H, m), 2,35-2,5 (4H, m), 2,87 (2H, t, J = 7.5 Hz), 3,91 (3H, s), of 4.13 (2H, K, J = 7 Hz), ceiling of 5.60 (1H, DD, J = 5 Hz, 8 Hz), 6,6-7,0 (6H, m), 7,05-to 7.35 (2H, m), 7,72 (2H, d, J = 9 Hz), of 7.97 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

Ethyl-4-[1-[4-[1-(4-isobutyl-3-methoxyphenyl)pentyloxy] benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): of 0.8-1.0 (9H, m), 1,2-1,7 (7H, m), 1,75-of 2.15 (5H, m), 2,35-2,5 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), with 3.79 (3H, s), of 4.13 (2H, K, J = 7 Hz), 5,12 (1H, DD, J = 5 Hz, 8 Hz), 6,8-7,2 (8H, m), 7,74 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

(8) Ethyl-3-[1-[4-[1-(3-the fluorescent-4-isobutylphenyl)pentyloxy] benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,85-1,0 (9H, m), of 1.2-1.6 (7H, m), 1,75-of 2.15 (5H, m), 2,35-2,5 (4H, m), is 2.88 (2H, t, J = 7.5 Hz), 4,13 (2H, K, J = 7 Hz), 5,14 (1H, DD, J = 5 Hz, 8 Hz), 6,8-7,2 (8H, m), 7,74 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

(9) Ethyl-4-[1-[4-[1-[4-(1-acetoxy-2-methylpropyl)-2-forefeel] pentyloxy]benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,75-1,0 (9H, m), 1,25 (3H, t, J = 7 Hz), 1.3 to 1.6 (4H, m), 1,75-of 2.15 (8H, m), 2,42 (2H, t, J = 7 Hz), is 2.88 (2H, t, J = 7.5 Hz), of 4.12 (2H, t, J = 7 Hz), 5,44 (1H,, J = 7 Hz), 5,52 (1H, DD, J = 5 Hz, 8 Hz), 6,8-7,2 (7H, m), 7.3 to 7.4 (1H, m), of 7.75 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

3, ): 0,45-0,7 (2H, m), 0,85-1,1 (1H, m), 1,25 (3H, t, J = 7 Hz), 1,95-2,15 (2H, m), 2,35-2,95 (8H, m), of 4.12 (2H, K, J = 7 Hz), of 5.05 and 5.3 (3H, m), of 5.75 to 6.0 (1H, m), 6,8-7,0 (4H, m), 7,05-to 7.35 (5H, m), 7,73 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

Example 35

The following compound was obtained in a manner analogous to the method of example 1.

Ethyl-4-[1-[3-[(4-isobutylphenyl)methylamino] benzoyl] indolizine-3-yl] butyrate

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), a 1.7-2.1 (3H, m), 2,3-2,5 (4H, m), 2,82 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), and 4.40 (1H, Shir. C) of 5.55 (1H, s), 6,6-to 6.95 (3H, m), 7,0 was 7.45 (13H, m), to 7.99 (1H, d, J = Hz), 8,48 (1H, d, J = 9 Hz).

Example 36.

To a solution of ethyl-4-(4-endolysin)butyrate (0.20 g) and 3-TRANS-[2-(4-isobutylphenyl)vinyl] benzoyl chloride (0.40 g) in dichloromethane (6 ml) was added diisopropylethylamine (0,23 g). The mixture was boiled for 8 hours, poured into ice, diluted hydrochloric acid and was extracted with ethyl acetate (30 ml). The organic layer was washed, dried over magnesium sulfate and evaporated. The residue is chromatographically purified on silica gel, elwira n-hexane and ethyl acetate (3: 1) with the formation of 4-[1-[3-TRANS-[2-(4-isobutylphenyl)vinyl]benzoyl]indolizine-3-yl]butyrate (0,29 g) as a yellow oil.

NMR (CDCl3, ): of 0.91 (6H, d, J = 7 Hz), 1,24 (3H, t, J = 7 Hz), a 1.88 (1H, m), is 2.05 (2H, m), of 2.45 (2H, t, J = 7 Hz), 2,50 (2H, d, J=), of 8.04 (1H, d, J = 7 Hz), charged 8.52 (1H, d, J = 9 Hz).

Example 37.

The following compounds were obtained in a manner analogous to the method of example 36.

(1) Ethyl-4-[1-[4-TRANS-[2-(4-isobutylphenyl)vinyl] benzoyl]indolizine-3-yl]butyrate

So pl. 94-95oC.

NMR (CDCl3, ): to 0.92 (6H, d, J = 7 Hz), of 1.36 (3H, t, J = 7 Hz), a 1.88 (1H, m), of 2.0-2.2 (2H, m), 2.4 to a 2.6 (4H, m), 2,90 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 6,8-7,0 (2H, m), 7,1-7,3 (5H, m), 7,47 (2H, d, J = 9 Hz), a 7.62 (2H, d, J = 9 Hz), the 7.85 (2H, d, J = 9 Hz), 8,02 (1H, d, J = 7 Hz), 8,51 (1H, d, J = 9 Hz).

(2) Ethyl-4-[1-[4-CIS-[2-(4-isobutylphenyl)vinyl] benzoyl]indolizine-3-yl] butyrate

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), 1,25 (3H, t, J = 7 Hz), of 1.85 (1H, m), of 2.0-2.2 (2H, m), 2,4-2,5 (4H, m), 2,89 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 6,60 (1H, d, J = 11 Hz), of 6.68 (1H, d, J = 11 Hz), 6,85-7,0 (2H, m), 7,02 (2H, d, J = 9 Hz), 7,15-of 7.3 (3H, m), 7,39 (2H, d, J = 9 Hz), 7,71 (2H, d, J = 9 Hz), 8,02 (1H, d, J = 7 Hz) and 8.50 (1H, d, J = 9 Hz).

(3) Ethyl-4-[1-[3-CIS-[2-(4-isobutylphenyl)vinyl]benzoyl] indolizine-3-yl] butyrate

NMR (CDCl3, ): of 0.85 (6H, d, J = 7 Hz), of 1.28 (3H, t, J = 7 Hz), of 1.80 (1H, m), is 2.05 (2H, m), 2.40 a (2H, d, J = 7 Hz), 2,42 (2H, t, J = 7 Hz), 2,85 (2H, t, J = 7 Hz), 4,13 (2H, K, J = 7 Hz), 6,62 (2H, s), 6,79 (1H, C) 6,89 (1H, t, J = 7 Hz), 7,00 (2H, d, J = 8 Hz), 7,18 (2H, d, J = 8 Hz), 7,1-7,2 (1H, m), 7,3-7,5 (2H, m), the 7.65 (1H, d, J = 8 Hz), 7,71 (1H, s), 8,02 (1H, d, J = 7 Hz), 8,48 (1H, d, J = 9 Hz).

Example 38.

The following compounds were obtained by the method, and Ulanova acid

NMR (DCl3, ): to 0.92 (6H, d, J = 7 Hz), to 1.87 (1H, m), 1,90 (3H, d, J = 3 Hz), of 2.08 (2H, m), 2.49 USD (2H, d, J = 7 Hz), 2,50 (2H, t, J = 7 Hz), only 2.91 (2H, t, J = 7 Hz), by 5.87 (1H, m), 6.87 in (1H, dt, J = 2 Hz, 7 Hz), 6,92 (1H, s), 7,1 - of 7.25 (5H, m), 7,52 (2H, d, J = 9 Hz), to 7.84 (2H, d, J = 10 Hz), of 7.97 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 8 Hz).

(2) 4-[1-[4-[1-(4-Isobutylphenyl)-3-butenyloxy] benzoyl]indolizine-3-yl] butyl acid

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), of 1.84 (1H, m), is 2.05 (2H, m) 2,44 (2H, d, J = 7 Hz), 2,48 (2H, t, J = 7 Hz), 2,5 - 2,9 (2H, m), is 2.88 (2H, t, J = 7 Hz), 5,03 at 5.27 (3H, m), by 5.87 (1H, m), at 6.84 (1H, m), 6,87 (1H, s), 6,92 (2H, d, J = 10 Hz), 7,11 (2H, d, J = 8 Hz), 7,13 (1H, m), 7,27 (2H, d, J = 8 Hz), 7,72 (2H, d, J = 10 Hz), 7,94 (1H, d, J = 7 Hz), 8,42 (1H, d, J = 9 Hz).

(3) 4-[1-[4-[1-(4-Isobutylphenyl)-4-pentyloxy]benzoyl] indolizine-3-yl] butane acid

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1,7 - to 2.35 (7H, m), 2,43 (2H, d, J = 7 Hz), 2.49 USD (2H, t, J = 7 Hz), 2,89 (2H, t, J = 7 Hz), 4.95 points to 5.1 (2H, m), is 5.18 (1H, m), 5,86 (1H, m), at 6.84 (1H, m), to 6.88 (1H, s), 6,92 (2H, d, J = 9 Hz), 7,11 (2H, d, J = 8 Hz), 7,13 (1H, m), 7,27 (2H, d, J = 8 Hz), 7,73 (2H, d, J = 9 Hz), 7,94 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(4) 4-[1-[4-[(S)-1-(4-Isobutylphenyl)-3-butenyloxy] benzoyl] indolizine-3-yl] butane acid

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), of 1.84 (1H, m), is 2.05 (2H, m) 2,44 (2H, d, J = 7 Hz), 2,48 (2H, t, J = 7 Hz), 2,5 - 2,9 (2H, m), is 2.88 (2H, t, J = 7 Hz), 5,03 at 5.27 (3H, m), by 5.87 (1H, m), at 6.84 (1H, m), 6,87 (1H, c), 6,92 (2H, d, J = 10 Hz), 7,11 (2H, d, J = 8 Hz), 7,13 (1H, m), 7,27 (2H, d, J = 8 Hz), 7,27 (2H, d, J = 10 Hz), 7,94 (1H, d, J is a diversified way of example 11

(1) 4-[1-[4-[4,4,4-Triflora-1-(4-isobutylphenyl)butoxy] benzoyl]-indolizine-3-yl]butane acid

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), 1.7 to 2,55 (11H, m), 2,39 (2H, t, J = 7.5 Hz), a 5.25 (1H, t, J = 5.5 Hz), 6,8 - 7,0 (4H, m) and 7.1 to 7.2 (3H, m), 7,27 (2H, d, J = 8 Hz), of 7.75 (2H, d, J = 9 Hz), 8,97 (1H, d, J = 7 Hz), 8,46 (1H, d, J = 9 Hz).

(2) 4-[1-[4-[(4-Isobutylphenyl)(phenyl)methylamino]benzoyl] indolizine-3-yl] butane acid

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz), a 1.7 - 2.1 (3H, m), 2,35 is 2.55 (4H, m), 2,85 (2H, t, J = 7.5 Hz)), of 5.55 (1H, s), 6,6 - 6,9 (3H, m), 6,95 was 7.45 (13H, m), 7,95 (1H, d, J = 7 Hz), of 8.47 (1H, d, J = 9 Hz).

(3) 4-[1-[4-[1-(4-Isobutyl-2-methoxyphenyl)pentyloxy] benzoyl] indolizine-3-yl]butane acid

NMR (CDCl3, ): of 0.8 - 1.0 (9H, m), 1,2 - 1,65 (4H, m), 1.7 to 2.2 (5H, m), 2,4 - by 2.55 (4H, m), 2,89 (2H, m, J = 7.5 Hz), 3,90 (3H, c), 5,59 (1H, DD, J = 5 Hz, 8 Hz), 6,78 (2H, d, J = 7 Hz), 6,8 - 6,95 (4H, m), 7,05 of 7.3 (2H, m), 7,72 (2H, d, J = 9 Hz), 7,94 (1H, d, J = 7 Hz), 8,42 (1H, d, J = 9 Hz).

(4) 4-[1-[4-[1-(4-Isobutyl-3-methoxyphenyl)pentyloxy] benzoyl] -indolizine-3-yl]butyl acid

NMR (CDCl3, ): of 0.8 - 1.0 (9H, m), 1,25 - 1,6 (4H, m), 1,75 - of 2.15 (5H, m), 2,45 is 2.55 (4H, m), 2,89 (2H, t, J = 7.5 Hz), of 3.78 (3H, s), 5,12 (1H, DD, J = 5 Hz, 8 Hz), 6.75 in to 7.2 (8H, m), 7,73 (2H, d, J = 9 Hz), 7,95 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

(5) 4-[1-[4-[1-(4-the Fluorescent-4-isobutylphenyl)pentyloxy] benzoyl]indolizine-3-yl]butyl acid

NMR (CDCl3, ): of 0.8 - 1.0 (9H, m), 1,2 - 1,6 (4H, m), 1,75 - of 2.15 (5H, m)>/P>(6) 4-[1-[4-[1-(4-Cyclopentylmethyl)phenyl]-3 - butenyloxy]indolizine-3-yl] butane acid

NMR (CDCl3, ): 0,45 - 0,6 (2H, m), 0,85 - 1,1 (1H, m), 1,95 - 2,15 (2H, m), 2.4 to a 3.0 (8H, m), 5,0 - 5,3 (3H, m), of 5.75 to 6.0 (1H, m), 6,8 - 7,0 (4H, m), 7,05 to 7.4 (5H, m), 7,72 (2H, d, J = 9 Hz), 1,95 (1H, d, J = 7 Hz), 8,43 (1H, d, J = 9 Hz).

Example 40.

To a solution of ethyl-4-[1-[3-TRANS-[2-(4 - isobutylphenyl)vinyl]benzoyl]indolizine-3-yl] butyrate (0.24 g) in dioxane (5 ml) was added 1 N aqueous sodium hydroxide solution (1 ml). The mixture was stirred for 4 hours at 40oC, poured into ice and diluted hydrochloric acid. The organic layer was extracted with ethyl acetate (15 ml), washed with water, dried over magnesium sulfate and evaporated. The residue is chromatographically purified by silica gel (20 g), elwira with a mixture of chloroform and methanol (50:1) with the formation of 4-[1-[3-TRANS - [2-(4-isobutylphenyl)vinyl] benzoyl] indolizine-3-yl]butane acid (0.20 g) as a yellow powder.

NMR (CDCl3, ): of 0.90 (6H, d, J = 7 Hz), of 1.85 (1H, m), of 2.0 - 2.2 (2H, m), 2.4 to a 2.6 (4H, m), 2,90 (2H, t, J = 7 Hz), 6,8 - 7,0 (2H, m), 7,1 - 7,3 (5H, m), between 7.4 to 7.5 (3H, m), and 7.6 to 7.7 (2H, m), to 7.93 (1H, s), to 7.99 (1H, d, J = 7 Hz), 8,51 (1H, d, J = 9 Hz).

Example 41.

The following compounds were obtained in a manner analogous to the method of example 40.

(1) 4-[1-[4-TRANS-[2-(4-Isobutylphenyl)vinyl] benzoyl]indolinyl), 2,4 - 2,6 (4H, m), 2,90 (2H, t, J = 7 Hz), 6,8 - 7,0 (2H, m), 7,0 - 7,2 (5H, m), 7,47 (3H, d, J = 9 Hz), 7,60 ( 2H, d, J = 9 Hz), 7,82 (2H, d, J = 9 Hz), of 7.97 (1H, d, J = 7 Hz), 8,51 (1H, d, J = 9 Hz).

(2) 4-[1-[4-CIS-[2-(4-Isobutylphenyl)vinyl] benzoyl] indolizine - 3-yl]butane acid

NMR (CDCl3, ): 0,88 (6H, d, J = 7 Hz) and 1.83 (1H, m), of 2.0 - 2.2 (2H, m), 2.4 to a 2.6 (4H, m), of 2.92 (2H, t, J = 7 Hz), to 6.58 (1H, d, J = 11 Hz), of 6.68 (1H, d, J = 11 Hz), 6,85 - to 6.95 (2H, m), 7,0 (2H, d, J = 9 Hz), 7,1 - 7,2 (1H, m), 7,2 (2H, d, J = 9 Hz), 7,38 (2H, d, J = 9 Hz), of 7.70 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,49 (1H, d, J = 9 Hz).

(3) 4-[1-[3-CIS-[2-(4-Isobutylphenyl)vinyl] benzoyl]indolizine-3-yl]butane acid

NMR (CDCl3, ): or 0.83 (6H, d, J = 7 Hz), of 1.80 (1H, m), 1,9 - of 2.15 (2H, m), 2.40 a (2H, d, J = 7 Hz), 2,46 (2H, t, J = 7 Hz), 2,87 (2H, t, J = 7 Hz), 6,62 (2H, s), 6,79 (1H, s), to 6.88 (1H, t, J = Hz), 7,00 (2H, d, J = 9 Hz), 7,1-7,3 (3H, m), 7,3-7,5 (2H, m), the 7.65 (1H, d, J = 7 Hz), of 7.70 (1H, s), of 7.96 (1H, d, J = 7 Hz), 8,48 (1H, d, J = 9 Hz).

Example 42.

To a solution of ethyl-4-[1-[4-[1-[4-(acetoxy-2-methylpropyl)-2-forefeel]pentyloxy] benzoyl] indolizine-3-yl] butyrate (300 mg) in ethanol (3 ml) and 1,4-dioxane (3 ml) was added 1 N aqueous sodium hydroxide solution (1.5 ml). The mixture was stirred at room temperature for 1 hour, then poured into a mixture of ethyl acetate and 0.5 N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated. Estate (25:1) with the formation of 4-[1-[4-[1-[2-the fluorescent-4-(1-hydroxy-2-methylpropyl)-phenyl] pentyloxy] benzoyl] indolizine-3-yl] butane acid (151 mg) in powder form.

NMR (CDCl3, ): 0,75-of 1.05 (9H, m), 1,2-1,65 (4H, m), 1,75-of 2.15 (5H, m), of 2.45 (2H, t, J = 7 Hz), 2,84 (2H, t, J = 7 Hz), 4,35 (1H, d, J = 6.5 Hz), of 5.53 (1H, DD, J = 5 Hz), of 5.53 (1H, DD, J = 5 Hz), 6.75 in to 7.2 (7H, m), 7,25 to 7.4 (1H, m), of 7.70 (2H, d, J = 9 Hz), to $ 7.91 (1H, d, J = 7 Hz), 8,42 (1H, d, J = 9 Hz).

Example 43.

The following compounds were obtained in a manner analogous to the method of example 36.

(1) Ethyl-4-[1-[4-[1-(4-isobutylphenyl)butylochki] benzoyl]indolizine-3-yl] butyrate

NMR (CDCl3, ): 0,8-of 1.05 (9H, m) of 1.24 (3H, t, J = 7 Hz), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), 2,87 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), to 5.17 (1H, DD, J = 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

(2) Ethyl-4-[1-[4-[(S)-1-(4-isobutylphenyl)butoxy]benzoyl]indolizine-3-yl]butyrate

NMR (CDCl3, ): 0,8-of 1.05 (9H, m) of 1.24 (3H, t, J = 7 Hz), 1,3-1,65 (2H, m), 1,7-of 2.15 (5H, m), 2,35-2,5 (4H, m), 2,87 (2H, t, J = 7.5 Hz), of 4.12 (2H, K, J = 7 Hz), to 5.17 (1H, DD, J = 2 Hz, 7 Hz), 6,8-6,95 (4H, m), 7,05 of 7.3 (5H, m), 7,72 (2H, d, J = 9 Hz), 7,98 (1H, d, J = 7 Hz), 8,44 (1H, d, J = 9 Hz).

1. Derivatives indolizine General formula I

< / BR>
where

R1- carboxyl, the ester carboxyl;

R2is hydrogen, lower alkyl, halogen;

R3is aryl or ar(lower)alkyl, each of which may have suitable at least one Deputy or represents (lower) allylcarbamate(lower)alkyl, you replaced exography, lowest Alcanena;

Q - carbonyl, lower alkylene;

< / BR>
R4is hydrogen, lower alkyl;

R5hydrogen, lower alkyl;

The Y - connection, the lower alkylene;

Z - low alkylene, lower albaniles,

R6is hydrogen, lower alkyl, ar(lower)alkyl which may have suitable Deputy,

and their pharmacologically acceptable salts.

2. Derivatives indolizine under item 1, where R3- aryl which may be substituted by lower alkyl, ar(lower)alkyl which may be substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, cyano, carboxy, esterified carboxy, laminirovannogo carboxy, lower alkoxy, hydroxy (lower)alkyl, protected hydroxy(lower)alkyl, cyclo(lower) alkyl(lower)alkyl, lower alkenyl and lower quinil, carbarnoyl(lower)alkyl, in which carbamoyl fragment substituted by one or two substituents, selected from the group consisting of lower alkyl and lower alkylaryl; R6is hydrogen, lower alkyl, ar(lower)alkyl which may be substituted by lower alkyl or acyl.

3. Derivatives indolizine on p. 2, where R1- carboxyl, lower alkoxycarbonyl or mono-, or d the l(lower)alkyl, which may be substituted by one to four substituents selected from the group consisting of lower alkyl, halogen, cyano, carboxy, mono-, or di-, or triphenyl(lower) alkoxycarbonyl, mono - or di(lower) allylcarbamate, phenylcarbamoyl, lower alkylresorcinol, low alkoxygroup, hydroxy (lower)alkyl, lower alkanoyloxy(lower) alkyl, cyclo(lower) alkyl, lower alkanoyloxy(lower) alkyl, cyclo(lower) alkyl(lower) alkyl, lower alkenyl and lower quinil, lowest allylcarbamate(lower) alkyl, lower alkylresorcinol(lower) alkyl; R6is hydrogen, lower alkyl, mono-, di - or triphenyl (lower) alkyl which may be substituted by lower alkyl or lower alkoxycarbonyl.

4. Derivatives indolizine under item 3, which is represented by the formula

< / BR>
where R3is phenyl, substituted lower alkyl, mono - or diphenyl (lower) alkyl which may be substituted by one to four substituents selected from the group consisting of lower alkyl, halogen, cyano, carboxy, phenyl(lower) alkoxycarbonyl, mono - or di(lower) allylcarbamate, phenylcarbamoyl, lower alkylresorcinol, lower alkoxy, hydroxy (lower) alkyl,Nile, lowest allylcarbamate(lower) alkyl, lower alkylresorcinol(lower) alkyl;

R11is hydrogen or lower alkyl;

A - lowest alkylen;

Z - low alkylene, lower albaniles, in which R6is hydrogen, lower alkyl or phenyl(lower)alkyl.

5. Derived indolizine under item 4, where R3- isobutylphenyl, isobutylparaben, isobutylphenyl, isobutylphenyl, isobutylphenyl, isobutylphthalate, isobutyryloxy, bis(isobutylphenyl)methyl, (carboxy)-(isobutylphenyl)methyl, (benzyloxycarbonyl-isobutylphenyl)methyl, (butylcarbamoyl) (isobutylphenyl)methyl, (heptylcarbinol) (isobutylphenyl)methyl, (ethoxy) (isobutylphenyl) ethyl, (isobutylphenyl)(Cryptor)butyl, (phenyl) (isobutylphenyl)methyl, [(isobutyl) (methoxy)phenyl]pentyl, [(fluoride)(isobutyl)phenyl]pentyl, [(fluoride)(hydroxyisobutyryl)phenyl] pentyl, [(fluoride) (acetoxyisobutyryl)phenyl]pentyl, (cyclopropylmethyl)butenyl, (isobutylphenyl)butinyl, (isobutylphenyl)butenyl, (isobutylphenyl)pentenyl, heptylcyclohexyl, isobutyleneisoprene or isobutylbarbituric; R11is hydrogen or methyl; A - trimethylene and Z - vinile, -O - or

6. Derivatives indolizine under item 5, which is selected from the group consisting of: a
4-[1-[4-[1-(4-isobutylphenyl)butylochki] benzoyl]indolizine-3-yl] butane acid and

4-[1-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl]indolizine-3-yl] butane acid.

7. Derivatives indolizine under item 6, in which the R - or S-configuration compound selected from the group consisting of:

4-[1-[4-[1-(4-isobutylphenyl)propyloxy]benzoyl]indolizine-3-yl] butane acid,

4-[1-[4-[1-(4-isobutylphenyl)butylochki] benzoyl]indolizine-3-yl] butane acid and

4-[1-[4-[1-(4-isobutylphenyl)pentyloxy]benzoyl]indolizine-3-yl] butane acid.

8. Derivatives indolizine on p. 3, represented by formula

< / BR>
where R3- mono - or diphenyl(lower) alkyl which may be substituted by one or two substituents selected from lower alkyl, halogen, cyano, carboxyl, phenyl(lower)alkoxycarbonyl, mono - or di (lower) allylcarbamate, phenylcarbamoyl and lower alkylresorcinol;

R11is hydrogen or lower alkyl;

A - lowest alkylen;

Z - low alkylene, -O - or where R6is hydrogen, lower alkyl or phenyl (lower) alkyl.

9. Connection on p. 8, where R3- isobutylphenyl or bis(isobutylphenyl)methyl; R11is hydrogen or methyl; A - trimethylene and Z Is-O - or

-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizine-1-yl] butane acid and

4-[3-[3-[bis(4-isobutylphenyl)methoxy] benzoyl] indolizine-1-yl] butane acid.

11. The method of obtaining the compounds of formula I on p. 1, characterized in that the compound of formula II

< / BR>
where R1, R2, R11and A are defined above,

or its salt is subjected to interaction with the compound of the formula III

W10- Q - X - Y - Z - R3,

where R3, Q, X and Z are defined above;

W10acid residue

or its salt.

12. The pharmaceutical composition inhibiting testosterone 5-reductase, comprising the active principle and a pharmaceutically acceptable excipients, characterized in that the active agent it contains an effective amount of a derivative indolizine formula I

< / BR>
where R1- carboxyl;

R2is hydrogen;

R3the phenyl (lower) alkyl, substituted lower alkyl;

R11is hydrogen;

A - lowest alkylen;

Q is carbonyl;

X - group

< / BR>
where R4is hydrogen;

R5is hydrogen;

The Y - connection;

Z is-O - or ,

R6is lower alkyl or phenyl(lower) alkyl, substituted lower alkyl.

13. A method of inhibiting testosterone 5-reductase, including the impact on her biologicheskogo of indolizine formula I, described in paragraph 12.

Priority points and features:

17.06.91 under item 1, where R1- carboxyl or the ester carboxyl, R2is hydrogen, lower alkyl or halogen, R3is aryl or ar(lower)alkyl, each of which may have suitable substituent (s), R11is hydrogen, A lower alkylene, possibly substituted by oxopropoxy or lower Alcanena, Q is carbonyl or lower alkylene,

< / BR>
in which R4is hydrogen or lower alkyl, R5hydrogen, lower alkyl, Y is a bond or lower alkylene, Z - low alkylene, -O - or , where R6is hydrogen, lower alkyl, ar(lower)alkyl which may have suitable Deputy, and their pharmacologically acceptable salts;

30.09.91 under item 1, where R1- carboxyl or the ester carboxyl, R2is hydrogen, lower alkyl or halogen, R3is aryl or ar(lower)alkyl, each of which may have suitable substituent (s), R11- a lower alkyl, A lower alkylene, possibly substituted by oxopropoxy or lower Alcanena, Q is carbonyl or lower alkylene,

< / BR>
in which

R4is hydrogen or lower alkyl and R5is hydrogen, lower alkyl, Y is a bond or lower alkylene, Z - low alkylene, -O - or where R6is hydrogen, lower and>/BR>21.02.92. under item 1, where R1- carboxyl or the ester carboxyl, R2is hydrogen, lower alkyl or halogen, R3- (lower) allylcarbamate (lower) alkyl, (lower) alkylaminocarbonyl (lower) alkyl, R11is hydrogen or lower alkyl, A lower alkylene, possibly substituted by oxopropoxy or lower Alcanena, Q is carbonyl or lower alkylene,

< / BR>
in which

R4is hydrogen or lower alkyl and R5hydrogen, lower alkyl, Y is a bond or lower alkylene, Z - low alkylene, -O - or where R6is hydrogen, lower alkyl, ar(lower) alkyl which may have suitable Deputy, and their pharmacologically acceptable salts.

 

Same patents:

The invention relates to new derivatives hinolincarbonova acids of the formula I, their pharmaceutically acceptable salts and their hydrates

The invention relates to imidazopyridine, in particular, there are some derivatives of 4-substituted-1-/2-methylimidazo [4,5-C]pyrid-1-yl)-benzene and alkylbenzene

The invention relates to a derivative of thiazolidinedione formula

,

where X is unsubstituted or substituted indayla, indolenine, asiandaily, asiandaily, imidazopyridine or imidazopyridine group; Y is an oxygen atom or a sulfur atom; Z-2,4-dioxothiazolidine-5-ylidenemethyl, 2,4-dioxothiazolidine-5-ylmethylene, 2,4-dioxoimidazolidin-5-ylmethylene, 3,5-dioxoimidazolidin-2-ylmethylene or N-gidroksilaminopurina group; R is a hydrogen atom, an alkyl group, alkoxygroup, halogen atom, hydroxy-group, a nitrogroup, kalkilya group or unsubstituted or substituted amino group; and m is an integer from 1 to 5

The invention relates to substituted the pyrimidines, which can be used for the treatment of hypertension

The invention relates to derivatives of 7-isoindoline and 7-sonderedition, which can be used in medicine, as manifesting a strong antibiotic activity with slight toxicity

The invention relates to new chemical substances possessing valuable properties, in particular derivatives pyridyl General formula (I)

< / BR>
where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to medicine, namely to psychiatry

The invention relates to esters of arylsulfonamides and sultamicillin-2 carboxylic acid, containing their pharmaceutical compositions and method of producing compositions

The invention relates to pharmaceutical technology and relates to a new pharmaceutical composition with analgesic activity

The invention relates to a derivative of asola used as antifungal therapeutic agents and their use

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

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