Derivatives cycloalkane-pyridine, pharmaceutical composition and the intermediate

 

(57) Abstract:

The invention relates to new derivatives cycloalkane-pyridine of General formula (I), where a is aryl with 6-10 carbon atoms, unsubstituted or monosubstituted with halogen, D-aryl with 6-10 carbon atoms, unsubstituted or substituted by phenyl, nitro, halogen, trifluoromethyl or triptoreline, or a residue of the formula presented in the claims, E-cycloalkyl with 3-8 carbon atoms, a linear or branched alkyl with 1-8 carbon atoms or phenyl, unsubstituted or substituted with halogen or trifluoromethyl, R1and R2together form a linear or branched alkylenes chain with 1-7 carbon atoms, which is substituted by a carbonyl group and/or a residue of the formula shown in the formula of the invention, mixtures of their isomers, or individual isomers, their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl. Also disclosed are intermediate compounds for obtaining the derivatives of cycloalken-pyridine and pharmaceutical composition thereof. The invention can be used in medicine for the treatment and prevention of hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia or arteriosclerosis activity the inhibitory protein transfer of ester cholesterol and stimulating the reverse transport of cholesterol, specifically derivatives cycloalkanones, pharmaceutical compositions on their basis and intermediate compounds.

Known derivatives cycloalkanones and-azaindole with antiatherosclerotic activity (see application DE 4435477, C 07 D 471/04, And 61 To 31/645, publ. 11.04.1996 year).

The objective of the invention is the development of biologically active compounds that may constitute the active ingredient of the pharmaceutical composition having an activity of inhibiting the protein transfer of ester cholesterol and stimulating the reverse transport of cholesterol.

The problem is solved proposed cycloalkanones General formula (I)

< / BR>
where a is aryl with 6-10 carbon atoms, unsubstituted or monosubstituted by halogen;

D - aryl with 6-10 carbon atoms, unsubstituted or substituted by phenyl, nitro, halogen, trifluoromethyl or triptoreline, or a residue of the formula

R3-L-

< / BR>
R7-T-O-X- ,

where R3, R4and R7independently from each other mean cycloalkyl with 3-6 carbon atoms or aryl with 6-10 atoms BR>
R6is hydrogen, halogen, azido, trifluoromethyl, hydroxyl or a residue of formula-NR8R9,

where

R8and R6the same or different and denote hydrogen or alkyl with 1-6 carbon atoms;

or

R5and R6together form a residue of the formula =NR10,

where

R10means hydrogen or a linear or branched alkyl and acyl, each with 1-6 carbon atoms;

L is a linear or branched alkylene and alkenylamine chains, each with 1-8 carbon atoms, unsubstituted or substituted once by hydroxyl;

T and X are identical or different and denote a linear or branched alkylenes chain with 1 to 8 carbon atoms; or

T or X mean link;

E - cycloalkyl with 3-8 carbon atoms, a linear or branched alkyl with 1-8 carbon atoms or phenyl, unsubstituted or substituted with halogen or trifluoromethyl;

R1and R2together form a linear or branched alkylenes chain with 1-7 carbon atoms, which is substituted by a carbonyl group and/or residues of the formula

< / BR>
< / BR>
< / BR>
-OR11or

< / BR>
where a and b are identical or different and denote the number 1, 2 or 3,

R11is hydrogen, linear or razvetvlennoy by hydroxyl, linear or branched alkoxyl with 1-6 carbon atoms or phenyl, unsubstituted or substituted by a residue from the group comprising halogen, nitro, trifluoromethyl, triptoreline or alkyl, unsubstituted or substituted group of the formula-OR12,

where

R12- linear or branched acyl with 1 to 4 carbon atoms or benzyl,

or

R11- linear or branched acyl with 1 to 20 carbon atoms or benzoyl, unsubstituted or substituted with halogen, trifluoromethyl, nitro or triptoreline, or a linear or branched forall with 1-8 carbon atoms and 1-9 fluorine atoms;

thus carbocycle, if necessary also in genialnom position can be substituted by 1 to 6 identical or different residues from the group comprising hydroxyl, cycloalkyl with 3-7 carbon atoms, alkoxyl or alkylthio, each with 1-6 carbon atoms, and linear or branched alkyl with 1-6 carbon atoms, substituted by one or twice by hydroxyl, and/or phenyl which may be substituted with halogen or trifluoromethyl;

and/or carbocycle, also in genialnom position can be momentarily replaced by a residue from the group comprising phenyl, benzoyl and thiophenyl, unsubstituted or substituted Gal who SUB>-NR13R14or =O,

where d is the number 0 or 1,

R13and R14the same or different and mean hydrogen, cycloalkyl with 3-6 carbon atoms, a linear or branched alkyl with 1-6 carbon atoms or phenyl, unsubstituted or once substituted by halogen, trifluoromethyl or nitro-group,

and/or formed carbocycle can be substituted spirostane balance formula

< / BR>
< / BR>
< / BR>
< / BR>
where Y and Y1together form a 2 - to 6-membered linear or branched alkylenes chain;

e - the number 1, 2, 3, 4, 6, or 7;

R16and R16together they form a 3 - to 7-membered heterocycle containing an oxygen atom;

the mixture of their isomers, or individual isomers, their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

Preferred derivatives cycloalkane-pyridine above formula (I),

where a is naphthyl or phenyl, unsubstituted or monosubstituted by fluorine, chlorine, bromine;

D is phenyl, unsubstituted or substituted by nitro, fluorine, chlorine, bromine, phenyl, trifluoromethyl or triptoreline, or a residue of the formula

R3-L-

< / BR>
R7-T-O-X- ,

where R3, R4and R7independently druett formula

< / BR>
< / BR>
where R5is hydrogen, fluorine, chlorine or bromine;

R6is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl or a residue of formula-NR8R9,

where

R8and R9the same or different and denote hydrogen or alkyl with 1-4 carbon atoms;

or

R5and R6together form a residue of the formula =NR10,

where

R10means hydrogen or a linear or branched alkyl and acyl, each with 1-4 carbon atoms;

L is a linear or branched Allenova and Alcanena chains, each with 1-6 carbon atoms, unsubstituted or substituted once by hydroxyl;

T and X are identical or different and denote a linear or branched alkylenes chain with 1-6 carbon atoms;

or

T or X mean link;

E - cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, linear or branched alkyl with 1-6 carbon atoms or phenyl, unsubstituted or substituted by fluorine, chlorine or trifluoromethyl;

R1and R2together form a linear or branched alkylenes chain with 1-6 carbon atoms, which is substituted by a carbonyl group and/or a residue of the formula

< / BR>
< / BR>
< / BR>
-OR11or

< / BR>
the l with 1-7 carbon atoms, linear or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted by hydroxyl, linear or branched alkoxyl with 1-4 carbon atoms or phenyl, unsubstituted or substituted by a residue from the group comprising fluorine, chlorine, bromine, nitro, trifluoromethyl, triptoreline, or alkyl, unsubstituted or substituted group of the formula-OR12,

where

R12- linear or branched acyl with 1 to 3 carbon atoms or benzyl,

or

R11- linear or branched acyl with 1 to 18 carbon atoms or benzoyl, unsubstituted or substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or cryptomaterial, linear or branched forall with 1-6 carbon atoms;

thus carbocycle if necessary also in genialnom position can be substituted by one to five identical or different residues from the group comprising hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkoxy, alkylthio, each with 1-5 carbon atoms, or a linear or branched alkyl with 1-5 with carbon atoms, substituted by one or twice by hydroxyl, and/or phenyl which may be substituted by fluorine, chlorine, bromine or trifluoromethyl;

and/or carbocycle, tagger, unsubstituted or substituted by fluorine, chlorine, bromine or trifluoromethyl, or can be substituted by the residue formula

-SO2-C6H5, -(CO)d-NR13R14or =O.

where d is the number 0 or 1,

R13and R14the same or different and mean hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, linear or branched alkyl with 1-5 carbon atoms or phenyl, unsubstituted or once substituted by fluorine, chlorine, bromine or trifluoromethyl;

and/or formed carbocycle can be substituted spirostane balance formula

< / BR>
< / BR>
< / BR>
where Y and Y1together form a 2 - to 5-membered linear or branched alkylenes chain,

e - the number 1, 2, 3, 4, 5 or 6;

the mixture of isomers, or individual isomers, and their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

Particularly preferred derivatives cycloalkane-pyridine above formula (I),

where a is phenyl, unsubstituted or monosubstituted by fluorine, chlorine, bromine,

D is phenyl, unsubstituted or substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or a residue of the formula

R3-L-

< / BR>
R7-T-O-X- ,

Anil, naphthyl,

R3and/or R4mean residue formula

< / BR>
< / BR>
where R5is hydrogen or fluorine,

R6is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, or a residue of formula-NR8R9,

where

R8and R9the same or different and denote hydrogen or alkyl with 1 to 3 carbon atoms,

or

R5and R6together form a residue of the formula =NR10,

where

R10means hydrogen or a linear or branched alkyl and acyl, each with 1-4 carbon atoms;

L is a linear or branched Allenova and Alcanena chains, each with 1-5 carbon atoms, unsubstituted or substituted once by hydroxyl;

T and X are identical or different and denote a linear or branched alkylenes chain with 1-3 carbon atoms;

or

T or X mean link;

E - cyclopropyl, cyclopentyl, cyclohexyl or phenyl, unsubstituted or substituted by fluorine or trifluoromethyl, or a linear or branched alkyl with 1-4 carbon atoms;

R1and R2together form a linear or branched alkylenes chain with 1-5 carbon atoms, which is substituted by a carbonyl group and/or a residue of the formula

< / BR>
< / BR>
< / BR>
if extensive celelalte with 1-6 carbon atoms, linear or branched alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, linear or branched alkoxyl with 1-3 carbon atoms or phenyl, unsubstituted or substituted by a residue from the group comprising fluorine, chlorine, bromine, nitro, trifluoromethyl, triptoreline, or alkyl, unsubstituted or substituted group of the formula-OR12,

where

R12- linear or branched acyl with 1 to 3 carbon atoms or benzyl,

or

R11- linear or branched acyl with 1 to 15 carbon atoms and benzoyl, unsubstituted or substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or cryptomaterial, or a linear or branched forall with 1-4 carbon atoms,

thus carbocycle, if necessary also in genialnom position can be substituted by one to four identical or different residues from the group comprising hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkoxy or alkylthio, each with 1-5 carbon atoms, and linear or branched alkyl with 1-5 carbon atoms, substituted by one or twice by hydroxyl, and phenyl which may be substituted by fluorine, chlorine, bromine or trifluoromethyl;

and/or carbocycle, tagger,

or can be substituted by the residue formula

-SO2-C6H5, -(CO)d-NR13R14or =O,

where d is the number 0 or 1,

R13and R14the same or different and mean hydrogen, cyclopropyl, cyclopentyl, linear or branched alkyl with 1-4 carbon atoms or phenyl, unsubstituted or once substituted by fluorine, chlorine or bromine;

and/or formed carbocycle can be substituted spirostane balance formula

< / BR>
< / BR>
< / BR>
where Y and Y1together form a 2 - to 6-membered linear or branched alkylenes chain,

e - the number 1, 2, 3, 4, 5 or 6;

the mixture of isomers, or individual isomers, and their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

The proposed compounds of General formula (I) can be obtained due to the fact that

(A) if D is aryl, the compound of General formula (II)

< / BR>
where a, E, R1and R have the above significance,

subjected to interaction with the ORGANOMETALLIC reagent in an inert solvent, aimed at the introduction of the substituent D,

in either case, if D is a residue of formula R7-T-O-X,

(B) a compound of General formula (III)

< / BR>
where Ormula (IV)

R7-T-Z (IV)

where R7and T have the abovementioned meaning, and

Z denotes halogen, preferably chlorine or bromine,

in an inert solvent, optionally in the presence of a base and/or auxiliary substances;

or

(C) a compound of General formula (III) by reacting with a compound of General formula (V)

< / BR>
where R17linear alkyl with 1-4 carbon atoms,

transferred to the compound of General formula (VI)

< / BR>
where a, E, X, R1, R2and R17have the above meaning,

and then subjected to interaction with the compound of General formula (VII)

R7-T-O-H (VII),

where R7and T have the abovementioned meaning,

followed, if necessary, removing the protective group,

or

(G) to obtain compounds of General formula (Ia)

< / BR>
where a and R4have the above meaning,

R18and R16the same or different and mean cycloalkyl with 3-7 carbon atoms, alkoxyl or alkylthio, each with 1-6 carbon atoms, a linear or branched alkyl with 1-6 carbon atoms, or phenyl, benzoyl, thiophenyl, unsubstituted or substituted with halogen or trifluoromethyl,

or

R18and R19oznaczanie value,

the compound of General formula (VIII)

< / BR>
where R4, R18, R19, A and E have the abovementioned meaning,

oxidized to compounds of General formula (IX)

< / BR>
where R4, R18, R19, A and E have the abovementioned meaning,

which by asymmetric recovery turn to compounds of General formula (X)

< / BR>
where R4, R18, R19, A and E have the abovementioned meaning,

which by introducing a protective group for hydroxyl transferred to the compound of General formula (XI)

< / BR>
where R4, R18, R19, A and E have the abovementioned meaning, and

R20- protective group for hydroxyl, preferably a radical of the formula

-SiR21-R22R23,

where

R21, R22and R23the same or different and denote alkyl with 1-4 carbon atoms,

from which by diastereomeric recovery get the connection of General formula (XII),

< / BR>
where R4, R18, R18, R20, A and E have the abovementioned meaning,

which is subjected to interaction with a fluorination agent such as, for example, diethylaminoethyl sulfur and derivatives timetraveled, to obtain the compounds of General formula (XIII)
what are the protective group by conventional methods and, if necessary, the values of the radicals D, E and/or R1and R2change in the framework of the above definition by the usual methods.

The above methods are illustrated by the diagrams (A), (B), (C), (D), using the following abbreviations:

DAST - TRIFLUORIDE diethylaminoethyl

THF - tetrahydrofuran

Me - methyl

tBu is tert.butyl

Meon - methanol

Ms - melesat.

As solvents in the implementation of the above methods is suitable ethers like diethyl ether, dioxane, tetrahydrofuran, glycolytically ether, or hydrocarbons as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons like dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or esters of acetic acid or triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, triamide hexamethylphosphoric acid, acetonitrile, acetone or nitromethane. You can also use mixtures of these solvents. Prefer dichloromethane.

As a basis for the implementation of individual stages suitable standard strong basic compounds. These are preferably organic compounds of lithium, lithium, amide, sodium or potassium amide, or hexamethyldisilane lithium, or hydrides of alkali metals as sodium hydride or potassium hydride. Especially prefer ad-utility, sodium hydride or diisopropylamide lithium.

When carrying out methods [B] and [B], furthermore, suitable standard inorganic bases. Preferred are the alkali metal hydroxide or alkaline-earth metals, such as sodium hydroxide or potassium hydroxide, or barium hydroxide, carbonates of alkali metals, such as sodium carbonate or potassium, or sodium bicarbonate. Particularly preferred sodium hydride or potassium hydroxide.

As ORGANOMETALLIC reagents suitable system, such as, for example, a mixture of magnesium and bromobenzonitrile, and N.-triptoreline.

As a rule, the reaction of recovery occurs preferably with the use of reducing agents which are suitable for recovery of the ketone to hydroxyl compounds. Particularly suitable is the restoration with the use of metal hydrides or complex metal hydrides in inert solvents, optionally in the presence of trialkylborane. Of reduction reaction is carried out Oia, boronat potassium, boronat tin, triacylglyceride-NAT lithium, diisobutylaluminum or alumoweld lithium. In particular, preferred as reducing diisobutylaluminum or sodium borohydride.

Typically, the reducing agent is used in quantities of 1 to 6 mol, preferably 1-4 mol in terms of mol subjected to restore connections.

The reduction occurs, as a rule, at temperatures from -78oC to + 50oC, preferably from -78oWith 0oWhen used as a reductant of diisobutylaluminium, 0oWith up to room temperature when applied as reducing agent sodium borohydride, particularly preferably at -78oWith, depending on the reducing agent and solvent.

Typically, the reduction is carried out at atmospheric pressure, however, it is possible to work at elevated or reduced pressure.

The hydrogenation is carried out according to standard methods using hydrogen in the presence of a catalyst based on noble metals, such as palladium on charcoal, platinum on coal or Raney Nickel, in an environment of one of the foregoing solvents, before the o +100oC, preferably from 0oC to +50oC, at atmospheric or increased pressure.

Preferably used in the process [And] first, the compounds of General formula (II) where carbocycle radicals R1/R2first substituted by a group-OSiR24R25R26where R24, R25and R26the same or different and denote phenyl or linear or branched alkyl with 1-5 carbon atoms, and after removing the protective group is administered according to a standard method above the rest, for example, R11.

Generally, cleavage of protective groups is carried out in one of the above alcohols and tetrahydrofuran, preferably in a mixture of methanol and tetrahydrofuran in the presence of hydrochloric acid at a temperature of from 0oWith up to 50oC, preferably at room temperature and atmospheric pressure. In unusual cases, the cleavage of the protective groups takes place preferably with the use of tetrabutylammonium fluoride in tetrahydrofuran.

In the framework of visheukazannim values protective group for hydroxyl, usually means a protective group from the group of: trimethylsilyl, triisopropylsilyl, tert.-butyl dimethylsilane, benzyl, benzyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzenesulfonyl, tetrahydropyranyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichlorocyanuric, methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-perbenzoic, 4-chlorobenzoyl or 4-methoxybenzoyl. Prefer tetrahydropyranyl, tert. butyldimethylsilyl and triisopropylsilyl. Especially preferred is tert.butyldimethylsilyl.

As solvents in the implementation of individual stages suitable ethers like diethyl ether, dioxane, tetrahydrofuran, glycolytically ether, or hydrocarbons as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons like dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene. You can also use mixtures of these solvents.

As an oxidizing agent to obtain compounds of General formula (IX) is suitable, for example, nitric acid, ammoniumnitrate cerium(IV), 2,3-dichloro-5,6-disinsertion, chlorproma pyridinium, chlorproma pyridinium on basic aluminum oxide, cityregional osmium and manganese dioxide. Preferred manganese dioxide and nitric acid.pochitaetsya dichloromethane and water.

The oxidant used in the amount of 1-10 mol, preferably 2-5 mol per mol of the compounds of General formula (VIII).

The oxidation is usually carried out at a temperature from -50oC to +100oC, preferably from 0oWith up to room temperature.

Typically, the oxidation occurs at atmospheric pressure. It can, however, also be carried out at elevated or reduced pressure.

The reaction of asymmetric recovery to compounds of General formula (X) is usually carried out in one of the abovementioned ethers or toluene, preferably tetrahydrofuran and toluene.

Typically, the reduction is carried out using pure enantiomeric 1R, 2S-aminoindazole and complexes Baranov, such as, for example, NR3x tetrahydrofuran, NR3x sulfoxide and NR3x (C2H5)N6H5. Preferred system diethylaniline of borane/1R,2S-aminoindane.

Typically, the reducing agent is used in quantities of 1 to 6 mol, preferably 1-4 mol in terms of mol subjected to restore connections.

The reduction occurs, as a rule, at temperatures from -78oC to +50

As a rule, the introduction of protective groups for hydroxyl is carried out in one of the above hydrocarbons, dimethylformamide or tetrahydrofuran, preferably in toluene in the presence of lutidine at a temperature of from

-20oC to +50oC, preferably from -5oWith up to room temperature, and at atmospheric pressure.

Reagents for the introduction of a protective group for silila are usually rubs. butyldimethylsilyl or tert. butyldimethylchlorosilane. Prefer tert.butyldimethylchlorosilane.

The reduction to compounds of General formula (XI) occurs in one of the above hydrocarbons, preferably toluene.

Typically, response and recovery to compounds of General formula (XII) using standard reducing agents. Preferred reductants are suitable for recovery of the ketone to hydroxyl compounds. Particularly suitable is the restoration of using metal hydrides or complex metal hydrides in inert solvents, if necessary the integral of metal hydrides, such as, for example, boronat lithium boronat sodium, boronat potassium, boronat tin, dialkylhydroxylamines lithium, diisobutylamine, bis-(2-methoxyethoxy)-dehydroalanine sodium or alumoweld lithium. In particular, preferred as a reducing agent bis-(2-methoxyethoxy)-dehydroalanine sodium.

Typically, the reducing agent is used in quantities of 1 to 6 mol, preferably 1-3 mol, in terms of mol subjected to restore connections.

The reduction occurs, as a rule, at temperatures from -20oC to +110oC, preferably from 0oWith up to room temperature.

Typically, the reduction is carried out at atmospheric pressure, however, it is possible to work at elevated or reduced pressure.

In the implementation of reduction reaction to compounds of General formula (XII) in the mother solution, there are small remnants of unnecessary diastereoisomer. To obtain a protected compound (XI) these balances can be subjected to repeated oxidation using standard oxidizing agents such as, for example, chlorproma pyridinium or activated pyrolusite, in particular, with the use of activated pyrolyze who is Deputy fluorine is carried out in one of the above hydrocarbons or methylene chloride, preferably in toluene in an argon atmosphere.

Among the derivatives of timetraveled normally apply diethylaminocoumarin sulfur or substituted 2,2'-bistrom amines, such as diethyl-1,2,3,3,3-hexadecylamine.

The reaction is carried out usually at a temperature of from -78oWith up to 100oC, preferably from -78oC to room temperature in the case of Diethylenetriamine sulfur, and from room temperature to 80oWith when getting diethyl-1,2,3,3,3-hexadecylamine.

Generally, cleavage of protective groups is carried out in one of the above alcohols and tetrahydrofuran, preferably in a mixture of methanol and tetrahydrofuran in the presence of hydrochloric acid at a temperature of from 0oWith up to 50oC, preferably at room temperature and atmospheric pressure. In unusual cases, the cleavage of the protective groups takes place preferably with the use of tetrabutylammonium fluoride in tetrahydrofuran at room temperature.

As reactions by varying the values radicals include, for example, the following types of reactions:

oxidation, reduction, hydrogenation, halogenoalkane, the Wittig reaction/Grignard is odni standard strong basic compounds. These are preferably organic compounds of lithium, such as, for example, ad-utility, Deut.utility or finality, or amides, such as, for example, diisopropylamide lithium, sodium amide or potassium amide, or hexamethyldisilane lithium, or hydrides of alkali metals as sodium hydride or potassium hydride. Especially prefer ad-utility, sodium hydride or diisopropylamide lithium.

In addition, as a reason suitable the standard inorganic bases. Preferred are the alkali metal hydroxide or alkaline-earth metals, such as sodium hydroxide or potassium hydroxide, or barium hydroxide, carbonates of alkali metals, such as sodium carbonate or potassium, or sodium bicarbonate. Particularly preferred sodium hydroxide or potassium hydroxide.

As solvent for the individual reaction stages is also suitable alcohols as methanol, ethanol, propanol, butanol or tert.butanol. Preferred tert.butanol.

If necessary to carry out the reaction stage in an argon atmosphere.

Halogenoalkane is usually carried out in an environment of one of the above-mentioned chlorinated hydrocarbons. Preferred metal is Flintridge sulfur or sulphonylchloride.

Halogenoalkane usually carried out at a temperature from -78oWith 0oWith depending on the particular halogenation agent and solvent.

As a rule, halogenoalkane occurs at atmospheric pressure. It can, however, also be carried out at elevated or reduced pressure.

Compounds of General formula (II) and (III) are new and can be obtained by reacting compounds of General formula (XIV)

< / BR>
where E has the above value, and

R27-alkoxycarbonyl with 1-4 carbon atoms or aryl (D = aryl) with the aldehyde of General formula (XV)

A-CHO (XV) ,

where a has the above meaning,

and the compound of General formula (XVI)

< / BR>
where R28and R29together with the carbonyl group are specified above for the radicals R1and R2value

and the resulting compound of General formula (XVII)

< / BR>
where A, E, R27, R28and R29have the above meaning,

put the recovery in the manner described above to hydroxymethylene functions (in the case of obtaining compounds of General formula (III)),

and then alkoxycarbonyl group (R27) can be converted to aldehyde groups by redox re is th ether, dioxane, tetrahydrofuran, glycolytically ether, or hydrocarbons as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons like dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl ester of acetic acid or triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, triamide hexamethylphosphoric acid, acetonitrile, acetone or nitromethane. You can also use mixtures of these solvents. Preferred is methylene chloride.

As a suitable oxidant, for example, nitric acid, ammoniumnitrate cerium(IV), 2,3-dichloro-5,6-dicyan-benzoquinone, chlorproma pyridinium, chlorproma pyridinium on basic aluminum oxide, cityregional osmium and manganese dioxide. Prefer complex of sulfur trioxide and pyridine in a mixture of dimethyl sulfoxide and methylene chloride and chlorproma pyridinium on basic aluminum oxide.

The oxidation is carried out in one of the above chlorinated hydrocarbons and water. Preferred dichloromethane and water.

The oxidant used in the amount of 1-10 mol, preferably 2-5 mol per mol of the compounds of General formula (XVII).

Okelani temperature.

Typically, the oxidation occurs at atmospheric pressure. It can, however, also be carried out at elevated or reduced pressure.

Compounds of General formula (VI), (V), (VII), (XIV), (XV) and (XVI) in themselves known, or they can be obtained by standard methods.

Compounds of General formula (VI) and (XV) are partly known and can be obtained by the above methods.

Compounds of General formula (VI) and (XV) are new and can be obtained by the above methods.

Compounds of General formula (VIII) and (XV) are new and can be due to the fact that the compounds of General formula (XVa), (XVIII) and (XIX)

A-CHO (XVa)

< / BR>
and

< / BR>
where a, E, R4, R18R19have the above meaning,

subjected to interaction with acid.

As a solvent to obtain compounds of General formula (VIII) suitable abovementioned ethers or alcohols. Preferred simple diisopropyl ether.

Generally, as the acid to obtain the compounds of General formula (VIII) suitable organic carboxylic acids and inorganic acids such as, for example, oxalic acid, maleic acid, phosphoric acid, fumaric acid and triperoxonane acid. edocfile 1 mol per mol of the compounds of General formula (XIX).

The reaction generally takes place at atmospheric pressure. It can, however, also be carried out at elevated or reduced pressure.

Typically, the reaction is carried out at a temperature of phlegmy used solvent.

Compounds of General formula (XV) and (XIX) by themselves are known or can be obtained by known methods.

Compounds of General formula (XVIII) are new and can be due to the fact that, first, by reacting compounds of General formula (XX)

E-CO2-R30(XX)

where E has the above value, and

R30is alkyl with 1-4 carbon atoms,

with compounds of General formula (XXI)

< / BR>
where R4has the above value,

in the environment of a solvent and in the presence of simple kronologi ether obtain compounds of General formula (XXII)

< / BR>
where R4and E have the abovementioned meaning,

which are then subjected to interaction with ammonium acetate in an inert solvent.

As a solvent for the first stage of the previous method is suitable above-mentioned ethers, and hydrocarbons, and prefer tetrahydrofuran.

As solvent for the implementation wnol. Preferred is ethanol.

Both stage is carried out at present in a given case temperature phlegmy suitable solvent and atmospheric pressure.

Compounds of General formula (XX) and (XXI) are partly new, or they can be obtained by known methods.

Compounds of General formula (XXII) are new and can be obtained by the above methods.

An additional object of the present invention are intermediate compounds selected from the group comprising 3-amino-3-cyclopentyl-1-(4-triptoreline)propane formula

< / BR>
2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-4,6,7,8-tetrahydro-1H-quinoline-5-it formula

< / BR>
2-cyclopentyl-4-(forfinal)-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-7,8-tetrahydro-6N-quinoline-5-it formula

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[2-cyclopentyl-4-(4-forfinal)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanon formula

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[5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanon formula

< / BR>
[5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanon methyl] 7,7-dimethyl-5,6,7,8-tetrahydroquinolin formula

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The proposed compounds of General formula (I) are inhibitors of protein migration of ester cholesterol and stimulate reverse transport of cholesterol. They cause a decrease in level of a complex of cholesterol to low density lipoprotein ("LDL"=low-density lipoprotein) in the blood, while increasing levels of complex cholesterol to high density lipoprotein ("HDL"=high-density lipoprotein). Therefore, they can be used for the treatment and prevention of hypolipoproteinemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia or arteriosclerosis.

Therefore, a further object of the invention is a pharmaceutical composition for activity, inhibiting protein transfer of ester cholesterol and stimulating the reverse transport of cholesterol containing at least one pharmaceutically acceptable inert carrier and at least one derivative of 2-aryl-substituted pyridine of the above General formula (I), a mixture of its isomers, or an individual isomer or its physiologically acceptable salt in an effective amount.

Pharmacological action the proposed substances is illustrated by the following experiments.

the ester cholesterol

Protein transfer of ester cholesterol get in partially purified from human plasma by differential centrifugation and column chromatography. For this purpose, human plasma was adjusted to a density of 1.21 g/ml with the use of sodium bromide and centrifuged at 50000 rpm at 4oC for 18 hours. The fraction taken from the bottom of the column, the higher density of 1.21 g/ml served in the column type SephadexPhenyl-Sepharose 4B company Pharmacia, washed with a buffer with pH 7.4, containing of 0.15 m sodium chloride and 0.001 m Tris/HCl, followed by elution with distilled water. Active against protein transfer of ester cholesterol fractions are collected, deleteroute with 50 mmol of sodium acetate at pH equal to 4.5, and served in a column of type CM-Sepharosecompany Pharmacia. The mixture is then elute using a linear gradient (0-1 m sodium chloride). The collected fractions of protein migration of ester cholesterol deleteroute using buffer 10 mmol Tris/HCl having a pH value equal to 7.4, and then purified by chromatography on a column of Mono Qcompany Pharmacia.

Getting radioactively labeled HDL

50 ml of fresh human plasma environment eti in the centrifuge of The type 65-Rotor at 50000 rpm atoC for 18 hours. The upper phase is used to get cold LDL. The lower phase deleteroute three times using a PDB buffer (10 mmol Tris/HCl, pH value of 7.4, 0.15 mmol of sodium chloride, 1 mmol ethylendiaminetetraacetic acid, 0.02% of sodium azide), taken 4 HP For every 10 ml volume of retentate serves 20 ál3H-cholesterol (product NET-725 firm DuPont; 1 mccoury/µl, in the form of a solution in ethanol) and incubated at 37oC in an atmosphere of nitrogen for 72 hours.

The mixture is then adjusted to a density of 1.21 g/ml with the use of sodium bromide and centrifuged in a centrifuge of The type 65-Rotor at 50000 rpm at 20oC for 18 hours. The upper phase is separated and the lipoprotein fractions purified gradient centrifugation. To do this, the separated labeled fraction lipoprotein adjusted to a density of 1.26 g/ml with the use of sodium bromide. In test tubes for centrifuges of the type SW 40-Rotor for every 4 ml of this solution was poured 4 ml of a solution with a density of 1.21 g/ml and 4.5 ml of solution density 1,063 g/ml, and the solutions consist of PDB buffer and sodium bromide. The mixture is then centrifuged in a centrifuge of the type SW 40-Rotor at 38000 rpm at 20oWith in 24 hours. Intermediate layer, soderjasim-buffer taken in the amount of 100 volumes. Retentate contains radioactively labeled complex air3H-cholesterol HDL, which after adjusting to approximately 5x106reports per minute/ml used in the following experience.

The experiment

To test the activity of the protein migration of ester cholesterol determine the transfer of ester3H-cholesterol (found in human HDL, biotinylated LDL. The reaction is stopped by applying Streptavidin-SPAbeads company Amersham and transferred radioactivity determined directly in a scintillation counter.

At 37oC for 18 hours incubated 10 ál of ester3H-cholesterol in the composition of HDL (~ 50,000 reports per minute) mixed with 10 ál of biotinylated LDL (Biotin-LDL company Amersham) in 50 mmol Hepes buffer (of 0.15 m sodium chloride, 0.1% albumin production of serum and 0.05% sodium azide) with a value of pH of 7.4, in the presence of 10 μl of protein migration of ester cholesterol (1 mg/ml) and 3 μl of a solution of the test substance in 10% dimethyl sulfoxide and 1% bovine serum albumin. Then the mixture was fed 200 μl of solution SPA-Streptavidin-Bead company Amersham (product TRKQ 7005). incubated for one hour with the same is stuudy mixture, containing 10 μl of protein buffer and 10 ál of protein migration of ester cholesterol, inkubiruemykh at 4oWith, as well as a mixture containing 10 μl of protein migration of ester cholesterol, inkubiruemykh at 37oC. Measured in the control mixtures at 37oWith the activity of the protein migration of ester cholesterol take over 100%. The concentration of substance at which the transfer is reduced by half, is a concentration of inhibition (hereinafter CT50).

In the table And the data on CT50(mol/l) for inhibitors of protein migration of ester cholesterol.

Activity ex vivo, we offer connections

Syrian hamsters do not give food for 24 hours and then narcoticyou, and subcutaneously give 0,80 mg/kg atropine, 0,80 mg/kg Ketavetand after 30 minutes vnutribruchinno give 50 mg/kg of Nembutal. Then the jugular vein expose and introduce the cannula. The test substance is dissolved in a suitable solvent, typically in solution gives (placebo), consisting of 60 g of glycerol. 100 ml of water and 1000 ml of PEG with a molecular weight of 400, and give hamsters introduced into the jugular vein of polyethylene catheter. The control animals given the same amount of solvent without test is to perform oral, when this substance was dissolved in dimethyl sulfoxide and suspended in 0.5% of tylose and then give hamsters orally using a stomach probe. The control animals given the same amount of solvent without test substance.

Several times within 24 hours after the issuance of the test substance blood sample (approximately 250 μl) by puncture of retroorbital venous plexus hamsters. Incubation at 4oWith during the night ends coagulation, then the mixture is centrifuged for 10 minutes at 6000 g. The activity of the protein migration of ester cholesterol thus obtained serum was determined in a modified experience, and transfer of ester3H-cholesterol (found in HDL, biotinylated LDL measured in the same manner as in the above experience.

The reaction is stopped by applying Streptavidin-SPAbeads company Amersham and transferred radioactivity determined directly in a liquid scintillation counter.

The experience of the conduct described above in the section "experiment". For testing serum 10 ál of protein migration of ester cholesterol replace 10 µl of the corresponding serum samples. In the quality.

Transferred to the control mixtures using the control serum activity is taken as 100%. The concentration of substance at which the transfer is reduced by half, is a factor ED50(see tab. B).

The activity in vivo of the proposed compounds

In experiments to determine the oral effects on lipoproteins and triglycerides test substance dissolved in dimethyl sulfoxide and suspended in 0.5% of Tolosa, give Syrian hamsters orally using a stomach probe. For determining the activity of protein migration of ester cholesterol blood sample (approximately 250 μl) by retroorbital puncture prior experience. Then the subjects substances give hamsters orally using a stomach probe. The control animals given the same amount of solvent without test substance. Then hamsters deprived of food and several times within 24 hours after the issuance of the test substance take blood by puncture of retroorbital venous plexus hamsters.

Incubation at 4oWith during the night ends coagulation, then the mixture is centrifuged for 10 minutes at 6000 g. Cholesterol and triglycerides in the thus obtained serum od sample 14366 company Merck, triglycerides - using samples 14364 firm Merck). Serum was diluted appropriately physiological common salt solution.

In microtiter plates with 96 cups in 100 ál of diluted serum serves 100 µl of the test substance and the mixture is incubated at room temperature for 10 minutes. Then the optical density is determined at a wavelength of 492 nm using an automatic reader. The concentration of a mixture of triglycerides and cholesterol was determined by simultaneously measuring the reference curve.

The content of HDL was determined after precipitation containing APO In lipoproteins with trading reagent (Sigma 352-4) according to the manufacturer's instructions.

The results of the experiment are summarized in table Century.

Activity in vivo human protein transfer of ester cholesterol in transgenic mice

Transgenic mice, diluted to Dinoco, HART, Gonzales, Pocket, Schmidt, Wireco (BBA (1995), 1295. 301), give the subjects substances along with food. Prior experience retroorbital take blood for determination of serum cholesterol and triglycerides. Serum get described above, in the experiments with hamsters way in which to determine lipoprotein and triglycerides. Modifying the received data converted to percentage change compared with the original data.

The results of the experiment are summarized in table G

New active substances is possible in a known manner to translate into ordinary dosage forms such as, for example, tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. Thus therapeutically effective compound may be present in concentrations from about 0.5 to 90% by weight of the mixture, i.e. in amounts sufficient to achieve the above dosage.

Dosage forms get, for example, by dilution of active principles solvents and/or carriers, optionally using emulsifiers and/or dispersants, and using as diluent water can be applied, if necessary, organic solvents as auxiliary solvents.

Drugs give the usual way of intravenous, oral, parenteral or crazyace, in particular orally.

When injecting the country you can use the solutions of an active nanotribology the cottage is advantageous to use the active ingredient in amounts of from 0.001 to 1 mg/kg, preferably 0.01 to 0.5 mg/kg of body weight, and when giving oral 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

However, if necessary, possible deviations from these quantities, depending on body weight, route of drug administration, the patient's response to medication, dosage forms and the time or period in which injected a drug. So, in some cases, may be sufficient to accept less than the specified minimum amount, while in other cases it is necessary to take more than the specified quantity. In the case of giving large quantities of active principle, it is recommended to divide the dose into several doses and apply them during the day.

The source connection

Example I

Methyl ester of 4-(4-forfinal)-2-isopropyl-5-oxo-1,4,5,6,7,8-hexa-hydrochinon-3-carboxylic acid

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50,14 g (0,404 mol) p.-forventelige, 45,3 g (0,404 mol) of 1,3-cyclohexandione and 57,89 g (0,404 mol) of a compound methyl ester 3-amino-4-methyl-Penta-2-ene acid in 1000 ml of ethanol is heated under reflux for 60 hours. The mixture is cooled to room temperature and concentrated to dryness. The residue is subjected to hot-dissolved in 500 ml of toluene, after which ohlord the move: 100,8 g (72,6% of theory)

Rf= 0,15 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 8:1)

Example II

Methyl ester of 4-(4-forfinal)-2-isopropyl-5-oxo-5,6,7,8-tetrahydroquinolin-3-carboxylic acid

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To a solution of 46,04 g (0,1341 mol) of the compound of example I in 645 g of dichloromethane was added 30,44 ml (0,1341 mol) of 2,3-dichloro-5,6-dicyan-p.-benzoquinone, then stirred at room temperature overnight. Then suck on 500 ml of silica gel 60, optionally washed with 700 ml of dichloromethane, and the combined filtrates concentrated to dryness.

Output: 24.2 g (52,87% of theory)

Rf= 0,54 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 8:2)

Example III

Methyl ester of 4-(4-forfinal)-2-isopropyl-5-hydroxy-5,6,7,8-tetrahydroquinolin-3-carboxylic acid

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70,64 g (0,207 mol) of the compound of example II is dissolved in an argon atmosphere at 706 g of toluene and cooled to -78oWith, then added dropwise 228 ml (0,228 mol; 1.1 EQ. ) diisobutylaluminium from 1.0 molar in toluene) for 20 minutes. After 5 minutes stirring at -78oWith more time added 35 ml of 0.15 EQ.) diisobutylaluminium and stirred for 10 minutes. Then at -78oTo give precapitalist hours of additional stirring the aqueous phase is separated and extracted twice with complex ethyl ester acetic acid, the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on 1000 g of silica gel 60 using as eluent toluene and mixtures of toluene and complex ethyl ester of acetic acid in the ratio 9: 1 and 8: 2. Containing the desired compound fractions are collected and concentrated to 100 ml, then add petroleum diethyl ether. Fallen crystallized sucked off and dried in high vacuum over night.

Output: 1 faction: 61,69 g (86.8% of theory)

Output: the 2nd fraction: 6,34 g (8.9% of theory)

Rf= 0,14 (a mixture of toluene and ethyl ester of acetic acid in the ratio 9:1)

Example IV

Methyl ester 5-(tert.butyldimethylsilyloxy)-4-(4-forfinal)-2-isopropyl-5,6,7,8-tetrahydroquinolin-3-carboxylic acid

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68,0 g (0,198 mol) of the compound of example III are dissolved in 340 g of dimethylformamide, and the resulting solution was sequentially added 59,69 g (0,396 mol, 2 EQ.) tert.butyldimethylsilyloxy, 48,54 g (0,713 mol; 3.6 EQ. ) imidazole and 0,484 g (0,00396 mol; 0.02 EQ.) N-dimethylaminopyridine. The mixture is stirred at room temperature overnight, distributed in 800 ml of ammonium chloride solution and 400 ml of complex ethyl ester acetic acid is the aqueous phase is extracted twice with complex ethyl ester acetic acid, the combined organic phases are dried over sodium sulfate, filtered and concentrated. Dissolved in toluene, the residue applied to 1800 ml of silica gel and elute first with toluene and then with a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1. After thickening, the eluates get a white crystalline product.

Output: 87,5 g (96.7% of theory)

Rf= 0,68 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1)

Example V

5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-hydroxymethyl-2-isopropyl-5,6,7,8-tetrahydroquinolin

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87,4 g (0,191 mol) of the compound of example IV are dissolved in 500 g of toluene and cooled in an argon atmosphere to -78oC. 690 ml (0,690 mol; 3,61 EQ.) diisobutylaluminium from 1.0 molar in toluene) pin for one hour, then stirred for further at -78oC for 90 minutes. To a cooled to -78oC the solution carefully add 30 ml of a solution of tartrate of potassium and sodium and stirred at -78oC for 30 minutes. After this mixture is allowed to warm to room temperature, add 400 ml of a solution of tartrate of potassium and sodium and diluted with complex ethyl ester of acetic acid. Finally, add another 1.2 l solution of potassium tartrate and n the times extracted complex ethyl ester of acetic acid. The combined organic phases are dried over sodium sulfate, filtered and concentrated. Semi-solid residue is dissolved in 400 ml of toluene, applied to 1100 ml of silica gel 60, pre-treated with toluene, and elute first with toluene and then with a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1.

Containing the desired compound fraction is condensed, the resulting oil was added petroleum ether, and falls crystalline product mushy consistency.

Output: 72,52 g (92.0% of theory)

Rf= 0,28 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1)

Example VI

5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-2-isopropyl-5,6,7,8-tetrahydroquinolin-3-carbaldehyde

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To a solution of 67.1 g (0,156 mol) of the compound of example V 671 g of dichloromethane was added 31.8 g (0,312 mol, 2 EQ.) neutral aluminum oxide and 67,3 g (0,312 mol, 2 EQ. ) Harrogate pyridinium and stirred at room temperature for 90 minutes. The reaction solution was applied to the 1100 ml of silica gel 60 (dry) and elute first with toluene, and then a complex mixture of ethyl ester of acetic acid and methanol in the ratio 9:1. Containing the desired compound faction is 100 ml of toluene,

put 250 ml of silica gel 60 and elute first with toluene and then with a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9: 1. Eluate thicken, get the oil vykristallizovyvalas petroleum ether.

Output: 1 faction: 28.8 g (43.1% of theory)

Output: the 2nd fraction: of 10.05 g (15,1% of theory)

Rf= 0,72 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1)

Example VII

5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-[hydroxy-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinoline (a mixture of diastereoisomer a and diastereoisomer B)

< / BR>
341 mg (14,03 mmol; 6 EQ.) magnesium shavings served in 30 ml of tetrahydrofuran in an argon atmosphere heated under reflux, was added dropwise with a syringe 1,052 g (4,676 mmol; 2 EQ.) 4-bromobenzonitrile in pure form. Refluxed for 45 minutes, then the mixture is allowed to cool to room temperature. 1.0 g (2,338 mmol) of the compound of example VI was dissolved in 20 ml of tetrahydrofuran and cooled in an argon atmosphere to approximately -78oWith, then added with stirring a freshly prepared Grignard reagent. The cooling bath removed and the reaction mixture stirred for Caia and 250 ml complex ethyl ester of acetic acid. The organic phase is separated, the aqueous phase is extracted twice with complex ethyl ester acetic acid, the combined organic phases are dried over sodium sulfate, filtered, concentrated and dried in high vacuum over night.

Yield: 1.18 g (97.5% of theory; mixture of diastereomers a and B)

The separation of the two pairs of diastereomers (a and B) is carried out by chromatography on 100 ml of silica gel 60, treated with cyclohexane. Dissolved in 4 ml of cyclohexane mixture of diastereomers elute on a silica gel 60 first with cyclohexane and then with a mixture of cyclohexane and tetrahydrofuran in the ratio of 9:1. After concentration of fractions get both pairs of diastereomers.

The output of diastereoisomer A: 789 mg (65.2% of theory)

Rf= 0,42 (a mixture of cyclohexane and tetrahydrofuran in the ratio 9:1)

The output of diastereoisomer B: 410 mg (33,9% of theory)

Rf= 0,24 (a mixture of cyclohexane and tetrahydrofuran in the ratio 9:1)

Example VIII

5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinoline (a mixture of diastereoisomer a and diastereoisomer B)

< / BR>
To a solution of 876 mg (at 1.521 mmol) of a mixture of diastereoisomers a and B of example VII in 70 ml of dichloromethane using a syringe add planetele stirred for 30 minutes. Then the reaction solution vmeshivat in the solution of complex ethyl ester of acetic acid and ammonium chloride, the organic phase is separated, the aqueous phase is extracted three times difficult ethyl ester acetic acid, and all the organic extract is dried over sodium sulfate, filtered, concentrated and dried in high vacuum.

Yield: 690 mg (78.5% of theory)

Rf= 0,57 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1)

Example IX

5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl]-2-isopropyl-5,6,7,8-tetrahydroquinolin (diastereoisomer A)

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Analogously to example VIII 250 mg (0,436 mmol) of diastereoisomer a of example VII in 10 ml of dichloromethane is subjected to interaction with 0,086 ml (0,654 mmol; 1.5 EQ.) TRIFLUORIDE diethylaminoethyl at -78oC.

Output: 233 mg (92,8% of theory)

Rf= 0,76 (a mixture of cyclohexane and tetrahydrofuran in the ratio 9:1)

Example X

5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-[fluoro-(4-trifluoromethyl-phenyl)-methyl]-2-isopropyl-5,6,7,8-tetrahydroquinolin (diastereoisomer B)

< / BR>
Analogously to example VIII 250 mg (0,436 mmol) of diastereoisomer B of example VII in 10 ml of dichloromethane is subjected to interaction with 0,086 ml (0,054 mmol; 1,5 EC is lorexane and tetrahydrofuran in the ratio 9:1)

Example XI

8-bromo-5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl]-2-isopropyl-5,6,7,8-tetrahydroquinolin

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In a solution of 18.7 g (32.5 mmol) of the compound of example X in 500 ml of carbon tetrachloride are served in an atmosphere of argon 9.3 g (52,5 mmol) N-bromosuccinimide and 500 mg of nitrile asuitable acid. Heated under reflux, and after 10 minutes there is a strong reaction. After two and a half hours, cooled to room temperature, sucked off and thicken. The crude product elute on a silica gel 60 with a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio of 15:1, fractions are concentrated and dried in high vacuum.

Output: 9,9 g (47% of theory)

Rf= 0,58 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 9:1)

Example XII

8-butyl-5-(tert. butyldimethylsilyloxy)-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl]-2-isopropyl-5,6,7,8-tetrahydroquinolin

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179 mg (2 mmol) of copper cyanide (I) is suspended in an argon atmosphere in 3 ml of absolute toluene, which is then distilled off in vacuum. After that, suspended in 2.6 ml of absolute tetrahydrofuran and cooled to -65oC. At this temperature prokopiv omnitele stirred for one hour. To get the pin solution at -65oTo a solution of 654 mg (1 mmol) of the compound of example XI in 2 ml of absolute tetrahydrofuran and stirred for one hour. Processing of the reaction mixture is as follows. Add a mixture of 4.5 ml of a saturated solution of ammonium chloride and 0.5 ml of concentrated ammonia solution, diluted with 30 ml water and three times extracted with diethyl ether, taken in an amount of 15 ml the combined organic phases are dried over sodium sulfate, filtered and concentrated. The crude product on silica gel elute (0,04-0,0063 mm) with a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio of 98:2. Yield: 200 mg (32% of theory)

Rf= 0,33 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 98:2)

Example XIII

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6-dihydroquinoline-5-ol

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To a solution of 1.3 g (2 mmol) of 5-(tert.butyldimethylsilyloxy)-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinoline in 13 ml of tetrahydrofuran was added dropwise at room temperature 10.9 ml 1,1-molar solution of tetrabutylammonium fluoride. After an hour vmeshivat a mixture of 100 ml of water and 50 ml of toluene. The phases are separated, and wooga state, dried over sodium sulfate and concentrated. The crude product on silica gel elute (0,04-0,063) mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 8:2, the fraction is thickened, and the product is crystallized.

Output: 640 mg (70% of theory)

Rf= 0,17 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 8:2)

Example XIV

1-cyclopentyl-3-(4-triptoreline)-propane-1,3-dione

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1.97 kg of tert. the butyl potassium, 2.26 kg complicated methyl ester cyclopentanecarbonyl acid, 1,66 kg p.-triftoratsetofenona and 36 g kronologi ester in 18 l of tetrahydrofuran is refluxed for 4 hours. The reaction is stopped by adding 16 l of 10% hydrochloric acid at room temperature. The aqueous phase is extracted with complex ethyl ester acetic acid, and the combined organic phases are washed with a saturated solution of salt. After removal of the solvent distil in vacuo 1.5 mbar, created by means of the oil pump. Get kzt1.664 kg 1-cyclopentyl-3-(4-triptoreline)-propane-1,3-dione as an oil, which upon standing fully crystallized.

Boiling point: 138-145oWith/1.5 mbar

Example XV

3-amino-3-Cyclops is 0 g of ammonium acetate in 4.9 litres of ethanol is refluxed overnight. The ethanol is distilled off in vacuo, and the residue is served in 4 l of methylene chloride. The solution is washed once with water and twice with saturated sodium bicarbonate solution and dried over sodium sulfate. After distillation of the methylene chloride, the residue is recrystallized from 6 l of hot cyclohexane. After drying receive 1018 g of colorless crystals, the purity of which is to 98.6% according to high performance liquid chromatography.

Melting point: 106oWITH

Thin layer chromatography: Rf= 0,2 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 4:1)

Example XVI

2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-4,6,7,8-tetrahydro-1H-quinoline-5-he

< / BR>
984 g of 3-amino-3-cyclopentyl-1-(4-triptoreline)-propenone, 714 g of 5,5-dimethyl-1,3-cyclohexandione, 647,8 g p.-forventelige and to 139.3 g triperoxonane acid in 15 liters of diisopropyl ether is refluxed for 5 hours. After cooling, the precipitated crystals are sucked off, washed with diisopropyl ether and dried. Receive 1018 g of colorless crystals, the purity of which is to 98.6% according to high performance liquid chromatography.

Melting point: 117oWITH

Tonko is)

Examples of receipt of the proposed compounds

Example 1

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinolin-5-ol (mixture of diastereomers a and B)

< / BR>
To 680 mg (1,177 mmol) of the compound of example VIII, dissolved in 30 ml of methanol and 15 ml of tetrahydrofuran, add 10 ml of 3 molar hydrochloric acid and stirred at room temperature for one hour. The reaction solution vmeshivat in 100 ml of a saturated solution of sodium bicarbonate, which is a layer of 100 ml of complex ethyl ester of acetic acid. The organic phase is separated, the aqueous phase is twice extracted with complex ethyl ester of acetic acid. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is subjected to chromatography on 50 g of silica gel 60 with subsequent alyazia first with toluene and then with a mixture of toluene and complex ethyl ester of acetic acid in the ratio 8:2.

Yield: 240 mg (44.2% of theory)

Rf= 0,19 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 9:1)

Example 2

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinolin-5-ol of rageragerage mixed with 3 ml of 3 molar hydrochloric acid at room temperature over night. Chromatography of the crude product is carried out in 40 ml of silica gel 60 pre-excalibercasino cyclohexane. Alualu spend cyclohexane with the addition of tetrahydrofuran, using a gradient from 10% to 20%.

Yield: 167 mg (93.3% of theory)

Rf= 0,43 (a mixture of cyclohexane and tetrahydrofuran in the ratio 8:2)

Example 3

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinolin-5-ol (diastereoisomer B)

< / BR>
Analogously to example 1 236 mg (0,410 mmol) of the compound of example X in 9 ml of methanol and 9 ml of tetrahydrofuran is stirred with 3 ml of 3 molar hydrochloric acid at room temperature over night. Chromatography of the crude product is carried out in 40 ml of silica gel 60 pre-excalibercasino cyclohexane. Alualu spend cyclohexane with the addition of tetrahydrofuran, using a gradient from 10% to 20%.

Output: 182 mg (98.9 per cent of theory)

Rf= 0,41 (a mixture of cyclohexane and tetrahydrofuran in the ratio 8:1)

Examples 4 and 5

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinolin-5-ol (enantiomer I and II)

< / BR>
82 mg of diastereoisomer B of example 3 dissolved in a mixture of 8 ml of ad-heptane and 2-propanol in the ratio of 9: 1 and the section is elem brand Chiracel OD; 20 μm). As eluent a mixture of ad-heptane and 2-propanol in a ratio of 98:2. At a temperature of 40oWith 30 minutes time movement and the feed rate of 7 ml/min to carry out a total of 20 injections of 0.4 ml (detection at 230 nm). Get 9 fractions, after which the analytical control by high-performance liquid chromatography distinguish, as in the front (enantiomer I; retention time: 6,13 min) and rear (enantiomer II; retention time: 8,10 min) fractions. Rear fraction (retention time: 8,10 min) is subjected to repeated chromatography on a column containing silica gel brand Chiracel OD, using as eluent a mixture of ad-heptane and 2-propanol.

Output enantiomer I: 37 mg (45.1% of theory)

Output enantiomer II: 32 mg (39.6% of theory)

Analytical high performance liquid chromatography:

column: 250 x 4.6 mm (silica gel brand Chiracel OD-H; 5 μm)

feed rate: 1.0 ml/min

eluent: 98% BC-heptane and 2% 2-propanol

temperature: 40oWITH

delivery volume: 10 ál

detection: 220 nm

Example 6

8-butyl-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinolin-5-ol

< / BR>
180 mg (0.28 mmol) of the compound of example XII in solution Azov. Then vmeshivat in 70 ml of saturated sodium bicarbonate solution and diluted with 20 ml of toluene. The organic phase is separated, washed with water, dried over sodium sulfate, filtered and concentrated. The crude product elute on 25 g of silica gel 60 using as eluent a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 9: 1.

Yield: 44 mg (30% of theory)

Rf= 0,20 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 9:1)

Example 7

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-5,6,7,8-tetrahydroquinolin-5-he

< / BR>
Into a solution of 16 g (of 36.4 mmol) of the compound of example 2 in 655 ml dichloromethane with vigorous stirring serves portions 11,16 g (109,2 mmol) of neutral alumina and 23,54 g Harrogate pyridinium. After an hour add 140 g of silica gel 60 and sucked off. The eluate concentrated and dried.

Yield: 10.5 g (70% of theory)

Rf= 0,55 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 9:1)

Example 8

4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -2-isopropyl-6-(4-trifluoromethyl-phenyl)-methyl-5,6,7,8-tetrahydroquinolin-5-he

< / BR>
0,88 ml (1.4 mmol) of a 1.6 molar solution of ad-utility in ad-hexane and 0.2 is his stirred at -50oWith in an hour. To this solution was added dropwise at -50oWith 460 mg (1 mmol) of a solution of the compound of example 7 and stirred for a further hour. Then was added dropwise a solution of 335 mg (1.4 mmol) of triftormetilfosfinov in 1 ml of absolute tetrahydrofuran and after an hour at -50oWith hydrolyzing water. Processing is as follows. Vmeshivat a mixture of 5% aqueous solution of sodium chloride and toluene, the phases are separated, the aqueous phase is additionally extracted and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The crude product elute on 90 g of silica gel 60 with a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 9:1.

Output: 443 mg (72% of theory)

Rf= 0,23 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 9:1)

Example 9

4-(4-forfinal)-3-fluoro-(4-triptoreline)-methyl] -2-isopropyl-6-(4-trifluoromethyl-phenyl)-methyl-5,6,7,8-tetrahydroquinolin-5-ol

< / BR>
To a solution of 100 mg (0.32 mmol) of the compound of example 8 in 1.6 ml of toluene was added dropwise at -70oWith of 0.48 ml of 1-molar solution of diisobutylaluminium in toluene. After 2 hours, add 5 ml of 20% aqueous solution of tartrate of sodium and potassium and stirred at room those who nd elute the product on silica gel 60 with a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio of 85:15.

Yield: 58 mg (59% of theory)

Rf= 0,23 (a mixture of cyclohexane and complex ethyl ester of acetic acid in the ratio 85:15)

As mentioned above receive data shown in table D compounds, which uses the following abbreviations, meaning eluent:

Cyclohex

WM} = cyclohexane

Su

IT = difficult ethyl ester acetic acid

PE = petroleum-diethyl ether

THF = tetrahydrofuran

Tol = toluene

Meon = methanol

tO = ethanol

Si 60 = silicagel 60

Si 100 = silicagel 100

Example 367

2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-7,8-dihydro-6N-quinoline-5-he

< / BR>
843 g 2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-4,6,7,8-tetrahydro-6N-quinoline-5-it in 28 liters of methylene chloride are oxidized to pyridine using 7021,3 g of activated pyrolusite at room temperature for one hour. After separation of pyrolusite and distillation of the methylene chloride is recrystallized from petroleum ether. Receive 618 g of crystals, the purity of which is 99,3% obtained by high-performance liquid chromatography data. From the mother liquor of crystallization by chromatography on si is to 4:1 are further 4.1 g of the target product of the same quality.

Melting point: 186oWITH

Thin layer chromatography: Rf= 0,8 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 4:1)

Example 368

[2-cyclopentyl-4-(4-forfinal)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanon

< / BR>
625,3 g 2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-7,8-dihydro-6N-quinoline-5-it in 6 l of tetrahydrofuran is subjected to recovery with the help of 56.4 g of 1R,2S-aminoindazole and 800 g boundedrangemodel complex at a temperature of from 0 to -5oC. Termination of the reaction carried out in approximately 20 hours by adding 500 ml of 1,2 ethanediol. The tetrahydrofuran is distilled off, the resulting oil is added to the complex ethyl ether, acetic acid, and the organic phase is washed with 2 N. hydrochloric acid and saturated sodium bicarbonate solution, dried and concentrated. The residue is recrystallized from hot cyclohexane. Get the whole 574 g of colorless crystals, the purity of which was 99.4% as obtained by high-performance liquid chromatography data (purity isomer 97,4%).

Melting point: 114oWITH

Thin layer chromatography: Rf= 0,2 (a mixture of petroleum ether and with whom XI)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanon

< / BR>
a) 574 g of [2-cyclopentyl-4-(4-forfinal)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanone and 522 ml of lutidine, dissolved in 5.4 liters of toluene are subjected to interaction with a mixture 593,2 g of tert.butyldimethylchlorosilane and 1 l of toluene for 150 minutes at a temperature of from room temperature up to -5oC. the Reaction is stopped by adding 10% aqueous ammonium chloride solution, the organic phase is washed with 0.1 N. hydrochloric acid and saturated aqueous sodium bicarbonate and dried. After removal of the solvent in vacuo the residue is recrystallized from ethanol. Get the whole 633 g of colorless crystals, the purity of which is to 99.2% as obtained by high-performance liquid chromatography data (purity isomer 98,7%).

Melting point: 108oWITH

Thin layer chromatography: Rf= 0,8 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 9:1)

b) To 50 mg of SYN - and 50 mg of anti-[5-(tert.butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanone dissolved in 2 ml of dichloromethane, add portions 320 mg manganese dioxide (Merck, Zack. 805958, 90 is orestano on the column, containing silica gel. By chromatography using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 15:1 obtain 93 mg of the product.

Thin layer chromatography: Rfor = 0.6 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 9:1)

Example 370

[5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanol

< / BR>
To a solution of 9 g of [5-(tert.butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl] -(4-triptoreline)-methanol in 60 ml of toluene was added dropwise to 16.5 ml of 65% aqueous solution of bis-(2-methoxy-ethoxy)-dehydroalanine sodium in toluene. After 3 and a half hours the reaction is stopped by adding methanol, extracted with complex ethyl ester acetic acid, and the organic phase is successively washed with a solution of tartrate of potassium and sodium and saturated aqueous sodium bicarbonate and dried. After removal of the solvent in vacuo the residue is recrystallized from petroleum ether. Get only 4.8 g of colorless crystals, the purity of which was 99.4% obtained when vysokopreosv which indicate further 1.8 g of the target product of the same quality by chromatography on silica gel using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 9:1.

Melting point: 142oWITH

Thin layer chromatography: Rf= 0,5 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 9:1)

Example 371

5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin

< / BR>
To a solution of 3.8 g of [5-(tert.butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl] -(4-triptoreline)-methanol of 37.8 ml of toluene was added dropwise at -5oTo a solution of 1.46 g of the TRIFLUORIDE diethylaminoethyl in 10 ml of toluene. After 30 minutes the reaction is stopped by adding saturated aqueous sodium bicarbonate solution, the organic phase is again washed with saturated aqueous sodium bicarbonate and dried. After removal of the solvent in vacuo the residue is recrystallized from ethanol. Get all of 3.33 g of colorless crystals, the purity of which was 99.4% as obtained by high-performance liquid chromatography data. From the mother liquor of crystallization get further 0.26 g of the target product of the same quality by chromatography on silica gel using as eluent a mixture of petroleum ether and complex atilo ecografia: Rf= 0,8 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 9:1)

Example 372

5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin

< / BR>
2 g of [5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-triptoreline)-methanol and 2.14 ml of N,N-diethyl-1,1,2,3,3,3-hexadecylamine in 25 ml of toluene is stirred in an argon atmosphere at 60oC for 18 hours. After that, the mixture was poured into saturated sodium bicarbonate solution, the organic phase is separated, again extracted with saturated sodium bicarbonate solution, dried and concentrated in vacuum. The residue is recrystallized from hot ethanol, and after drying obtain 1.3 g of colorless crystals, the purity of which was 99.4% as obtained by high-performance liquid chromatography data. From the mother liquor of crystallization get further 0.3 g of the target product of the same quality by chromatography on silica gel using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 10:1.

Example 373

2-the Cyclops is pet.butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] -7,7-dimethyl-5,6,7,8-tetrahydroquinoline in a mixture 913 ml of 5 N. hydrochloric acid, 1364 ml of methanol and 902 ml tetrahydrofuran stirred at 40oC for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with complex ethyl ester of acetic acid. After repeated washing with saturated aqueous sodium bicarbonate solution the organic phase is dried. After removal of the solvent in vacuo the residue is recrystallized from cyclohexane. After drying in the vacuum that is created when using the oil pump, get only 71.1 g of colorless crystals, the purity of which was 99.4% as obtained by high-performance liquid chromatography data (purity isomer of 99.5%). From the mother liquor of crystallization get further 10.8 g of the target product of the same quality by chromatography on silica gel using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 7:1.

Melting point: 140oWITH

Thin layer chromatography: Rf= 0,2 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 9:1) T

1. Derivatives cycloalkane-pyridine of General formula (I)

< / BR>
where a is aryl with 6-10 carbon atoms, an is m, nitro, halogen, trifluoromethyl or triptoreline, or a residue of the formula

R3-L-

< / BR>
R7-T-O-X-

where R3, R4and R7independently from each other mean cycloalkyl with 3-6 carbon atoms or aryl with 6-10 carbon atoms; R3and/or R4mean residue formula

< / BR>
< / BR>
R5is hydrogen or halogen;

R6is hydrogen, halogen, azido, trifluoromethyl, hydroxyl or a residue of formula-NR8R9where R8and R9the same or different and denote hydrogen or alkyl with 1-6 carbon atoms;

or R5and R6together form a residue of the formula= NR10where R10means hydrogen or a linear or branched alkyl and acyl, each with 1-6 carbon atoms:

L is a linear or branched alkylene and alkenylamine chains, each with 1-8 carbon atoms, unsubstituted or substituted once by hydroxyl;

T and X are identical or different and denote a linear or branched alkylenes chain with 1 to 8 carbon atoms; or T or X mean link;

E - cycloalkyl with 3-8 carbon atoms, a linear or branched alkyl with 1-8 carbon atoms or phenyl, unsubstituted or substituted with halogen or trifluoromethyl;

R1and a carbonyl group and/or residues of the formula

< / BR>
< / BR>
< / BR>
-OR11or

< / BR>
where a and b are identical or different and denote the number 1, 2 or 3;

R11is hydrogen, linear or branched celelalte with 1-8 carbon atoms, a linear or branched alkyl with 1-8 carbon atoms, unsubstituted or substituted by hydroxyl, linear or branched alkoxyl with 1-6 carbon atoms or phenyl, unsubstituted or substituted by a residue from the group comprising halogen, nitro, trifluoromethyl, triptoreline or alkyl, unsubstituted or substituted group of the formula-OR12where R12- linear or branched acyl with 1 to 4 carbon atoms or benzyl; or R11- linear or branched acyl with 1 to 20 carbon atoms or benzoyl, unsubstituted or substituted with halogen, trifluoromethyl, nitro or triptoreline, or a linear or branched forall with 1-8 carbon atoms and 1-9 fluorine atoms,

thus carbocycle, if necessary also in genialnom position can be substituted by 1 to 6 identical or different residues from the group comprising hydroxyl, cycloalkyl with 3-7 carbon atoms, alkoxyl or alkylthio, each with 1-6 carbon atoms, and linear or branched alkyl with 1-6 carbon atoms, substituted single or double is in genialnom position, can be momentarily replaced by a residue from the group comprising phenyl, benzoyl and thiophenyl, unsubstituted or substituted with halogen or trifluoromethyl, or can be substituted by the residue formula

-SO2-C6H5, -(CO)d-NR13R14or = O,

where d = 0 or 1,

R13and R14the same of different and mean hydrogen, cycloalkyl with 3-6 carbon atoms, a linear or branched alkyl with 1-6 carbon atoms or phenyl, unsubstituted or once substituted by halogen, trifluoromethyl or nitro-group,

and/or formed carbocycle can be substituted spirostane balance formula

< / BR>
< / BR>
< / BR>
< / BR>
where Y and Y1together form a 2 - to 6-membered linear or branched alkylenes chain;

e = 1,2,3,4,6, or 7;

R15and R16together they form a 3 - to 7-membered heterocycle containing an oxygen atom,

the mixture of isomers, or individual isomers, and their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

2. Derivatives cycloalkane-pyridine of the formula (I) under item 1, where a is naphthyl or phenyl, unsubstituted or monosubstituted by fluorine, chlorine, bromine; D is phenyl, unsubstituted or substituted by nitro, fluorine, chlorine, br-X-

where R3, R4and R7independently from each other mean cyclopropyl, cyclopentyl or cyclohexyl, phenyl, naphthyl; R3and/or R4mean residue formula

< / BR>
< / BR>
where R5is hydrogen, fluorine, chlorine or bromine;

R6is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl. hydroxyl or a residue of formula - NR8R9where R8and R9the same or different and denote hydrogen or alkyl with 1-4 carbon atoms;

or R5and R6together form a residue of the formula= NR10where R10means hydrogen or a linear or branched alkyl and acyl, each with 1-4 carbon atoms;

L is a linear or branched Allenova and Alcanena chains, each with 1-6 carbon atoms, unsubstituted or substituted once by hydroxyl;

T and X are identical or different and denote a linear or branched alkylenes chain with 1-6 carbon atoms; or T or X mean link;

E - cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, linear or branched alkyl with 1-6 carbon atoms or phenyl, unsubstituted or substituted by fluorine, chlorine or trifluoromethyl; R1and R2together form a linear or branched alkylenes chain with 1-6 is 1or

< / BR>
where a and b are identical or different and denote the number 1, 2 or 3;

R11- linear or branched siliaski with 1-7 carbon atoms, a linear or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted by hydroxyl, linear or branched alkoxyl with 1-4 carbon atoms or phenyl, unsubstituted or substituted by a residue from the group comprising fluorine, chlorine, bromine, nitro, trifluoromethyl, triptoreline, or alkyl, unsubstituted or substituted group of the formula-OR12where R12- linear or branched acyl with 1 to 3 carbon atoms or benzyl, or R11- linear or branched acyl with 1 to 18 carbon atoms or benzoyl, unsubstituted or substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or cryptomaterial, linear or branched forall with 1-6 carbon atoms;

thus carbocycle if necessary also in genialnom position can be substituted by one to five identical or different residues from the group comprising hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkoxy, alkylthio each with 1-5 carbon atoms, or a linear or branched alkyl with 1-5 with carbon atoms, substituted with one or Ducret is CLI in genialnom position, can be momentarily replaced by a residue from the group comprising phenyl, benzoyl and thiophenyl, unsubstituted or substituted by fluorine, chlorine, bromine or trifluoromethyl, or can be substituted by the residue formula

-SO2-C6H5, -(CO)d-NR13R14or = O,

where d = 0 or 1;

R13and R14the same or different and mean hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl linear or branched alkyl with 1-5 carbon atoms or phenyl, unsubstituted or once substituted by fluorine, chlorine, bromine or trifluoromethyl;

and/or formed carbocycle can be substituted spirostane balance formula

< / BR>
< / BR>
< / BR>
where Y and Y1together form a 2 - to 5-membered linear or branched alkylenes chain;

e= 1, 2, 3, 4, 5 or 6;

the mixture of isomers, or individual isomers, and their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

3. Derivatives cycloalkane-pyridine of the formula (I) under item 1, where a is phenyl, unsubstituted or monosubstituted by fluorine, chlorine, bromine,

D is phenyl, unsubstituted or substituted by nitro, trifluoromethyl, phenyl, fluorine, chlorine or bromine, or a residue of the formula

R3-L-

3and/or R4mean residue formula

< / BR>
< / BR>
R5is hydrogen or fluorine;

R6is hydrogen, fluorine, chlorine, bromine, azido, trifluoromethyl, hydroxyl, or a residue of formula - NR8R9where R8and R9the same or different and denote hydrogen or alkyl with 1-3 carbon atoms,

or R5and R6together form a residue of the formula = NR10where R10means hydrogen or a linear or branched alkyl and acyl, each with 1-4 carbon atoms;

L is a linear or branched Allenova and Alcanena chains, each with 1-5 carbon atoms, unsubstituted or substituted once by hydroxyl;

T and X are identical or different and denote a linear or branched alkylenes chain with 1-3 carbon atoms; or T or X mean link;

E - cyclopropyl, cyclopentyl, cyclohexyl or phenyl, unsubstituted or substituted by fluorine or trifluoromethyl, or a linear or branched alkyl with 1-4 carbon atoms; R1and R2together form a linear or branched alkylenes chain with 1-5 carbon atoms, which is substituted by a carbonyl group and/or a residue of the formula

< / BR>
< / BR>
< / BR>
-OR11or

< / BR>
where a and b are the same or once inany or branched alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, linear or branched alkoxyl with 1-3 carbon atoms or phenyl, unsubstituted or substituted by a residue from the group comprising fluorine, chlorine, bromine, nitro, trifluoromethyl, triptoreline, or alkyl, unsubstituted or substituted group of the formula-OR12where R12- linear or branched acyl with 1 to 3 carbon atoms or benzyl; or R11- linear or branched acyl with 1 to 15 carbon atoms and benzoyl, unsubstituted or substituted by fluorine, chlorine, bromine, trifluoromethyl, nitro or cryptomaterial, or a linear or branched forall with 1-4 carbon atoms,

thus carbocycle, if necessary also in genialnom position can be substituted by one to four identical or different residues from the group comprising hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, alkoxy or alkylthio, each with 1-4 carbon atoms, and linear or branched alkyl with 1-4 carbon atoms, substituted by one or twice by hydroxyl, and phenyl which may be substituted by fluorine, chlorine, bromine or trifluoromethyl; and/or carbocycle, also in genialnom position may be substituted once the rest of the group, include the B>d-NR13R14or = O,

where d = 0 or 1,

R13and R14the same or different and mean hydrogen, cyclopropyl, cyclopentyl, linear or branched alkyl with 1-4 carbon atoms or phenyl, unsubstituted or once absorbed fluorine, chlorine or bromine,

and/or carbocycle can be substituted spirostane balance formula

< / BR>
< / BR>
< / BR>
where Y and Y1together form a 2 - to 6-membered linear or branched alkylenes chain;

e= 1, 2, 3, 4, 5 or 6;

the mixture of isomers, or individual isomers, and their salts and N-oxides and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

4. 3-amino-3-cyclopentyl-1-(4-triptoreline)propane formula

< / BR>
representing an intermediate product for producing compounds of formula (I) under item 1.

5. Intermediates for producing compounds of formula (I) under item 1 of the group, including:

a) 2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-4,6,7,8-tetrahydro-1H-quinoline-5-it formula

< / BR>
b) 2-cyclopentyl-4-(forfinal)-4-(4-forfinal)-7,7-dimethyl-3-(4-trifloromethyl)-7,8-tetrahydro-6N-quinoline-5-it formula

< / BR>
C) [2-cyclopentyl-4-(4-forfinal)-5-hydroxy-7,7-dylanology)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl] -(4-triptoreline)-methanon formula

< / BR>
e) [5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl] -(4-triptoreline)-methanon formula

< / BR>
(e) [5-(tert. butyldimethylsilyloxy)-2-cyclopentyl-4-(4-forfinal)-3-[fluoro-(4-triptoreline)-methyl] 7,7-dimethyl-5,6,7,8-tetrahydroquinolin formula

< / BR>
6. Pharmaceutical composition with activity, inhibiting protein transfer of ester cholesterol and stimulating the reverse transport of cholesterol containing at least one active substance and at least one pharmaceutically suitable carrier, characterized in that it as the active agent contains a compound of General formula (I) under item 1, it is a mixture of isomers or a single isomer, N-oxide or its physiologically acceptable salt in an effective amount.

Priority points and features:

08.07.1996 - values of the radicals A, D, E, R1, R2specified in the claims, with the exception of the following values: R1and R2together form a linear or branched alkylenes chain with 1-7 carbon atoms, which is substituted by a residue OR11where R11means a linear or branched forall with 4-8 carbon atoms and 8 or 9 fluorine atoms;16together they form a 3 - to 7-membered heterocycle containing an oxygen atom;

24.02.1997 - values radicals: R1and R2together form a linear or branched alkylenes chain with 1-7 carbon atoms, which is substituted by a residue OR11where R11means a linear or branched forall with 4-8 carbon atoms and 8 or 9 fluorine atoms; the resulting carbocycle can be substituted spirostane balance formula

< / BR>
where R15and R16together they form a 3 - to 7-membered heterocycle containing an oxygen atom in PP. 4-6;

08.07.1997 - values radicals: the resulting carbocycle can be substituted spirostane balance formula



 

Same patents:

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to a new use of derivatives of imidazole, to new derivatives of imidazole, the way they are received, to the new obtained intermediate products and to pharmaceutical compositions based on derivatives of imidazole

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to (S)-(-)-2-trifluoromethyl-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H)-chinolone and its pharmaceutically acceptable salts that can be used to treat urinary incontinence

The invention relates to quinolone and acridinium compounds of the formula I or their pharmaceutically acceptable salts, where R2- H, (C1-C6)alkyl (C1-C4)foralkyl; R3IS H, CN, (C1-C6)alkyl, (C1-C6)foralkyl, ethanol or R2and R3form 1,4-butandiol; R4means a group of formula II; R7- H, R8- H, (C1-C4)alkoxy, NO2CN, (C1-C4)foralkyl, halogen, (C1-C4)alkyl; R9- H, halogen, (C1-C4)alkyl or (C1-C4)foralkyl or R8and R9taken together form a (C1-C3)alkylenedioxy; R10and R11- H, (C1-C4)alkyl

The invention relates to new chemical compounds and applies to new zemedeneh almond acid derivatives, method of production thereof and drugs containing these compounds

The invention relates to medicine, namely, neurology

The invention relates to medicine

The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

f is zero, 1, 2, 3 or 4;

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

The invention relates to orthotamine benzoylpyridine formula (1), where R(1) denotes R(13)-SOmm denotes the number 2; R(13) denotes alkyl, one of the substituents R(2) and R(3) represents hydrogen; and the other CHR(30)R(31), R(30) represents-(CH2)g-(CHOH)h-(CH2)I-(CHOH)k-R(32), R(32) denotes hydrogen or methyl, g, h, I is equal to zero, k is 1, R(2) and R(3) represents-C(OH)R(33)R(34), R(31), R(33) R(34) denote hydrogen or alkyl, R(4) denotes alkyl, alkoxy, F, Cl, Br, I

The invention relates to medicine, in particular to pharmaceutical preparations used in the treatment of hypercholesterolemia (primary, combined with hypertriglyceridemia, atherosclerosis
The invention relates to medicine, particularly cardiology, and can be used to prepare for hyperbaric oxygen therapy patients with coronary heart disease
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