RU1838301C - Method of synthesis of quinoline derivative or its salt - Google Patents

Abstract

Usage: as an inhibitor in relation to acyl-CoA-cholesterol acyl transferase (ACAT). SUMMARY OF THE INVENTION: a product of the general formula I: 6 R5R / 13 ppm II wherein RI is a hydrogen atom or C1-C4 alkyl; R2 is a hydrogen atom, a halogen atom, an alkip, a halogen is C1 C4 alkyl, C1-C4 alkoxy- | a group or a halo - - alkylthio group, a Ci-C4 halogen alkylthio group, a nitro group or a halogen - - and a hydroxy group; Ra is a hydrogen atom, Ci-C4 is alkyl or Ci-Ci is an alkoxy group; RA is a hydrogen atom, Ci-C4 alkyl or Ci-C4 is an alkoxy group; RS is an atom. hydrogen, a halogen atom, Ci-C4 is alkyl, Ci-C4 is a NAKoxy, is alkylthio or hydroxyl; Re represents a hydrogen atom, a halogen atom, a C1-C4 alkoxy group, or Ci-Dj alkyl; Ry is a hydrogen atom, a halogen atom, an alkoxy group or alkyl; Ri3 is a hydrogen atom, Ci-Ce is alkyl or benzyl, which may be substituted with C- | -C4 alkyl and hydroxy; m is 0 or 1; n 0 or 1 and in the case when m 0, then (1) at least one of RS, R6 and R; different from hydrogen or (II) all RS, Re and R are represented by hydrogen atoms and. at least one of Rs, Rg, Rio, Rn and Ri2 is represented by a fluorine atom. Reagent I: product of the general formula; wherein rings A and B are as defined above. I ate with Reagent II: a product of the general formula: {cTHcH7v 2 where ring C has the above values of R13, where 02 is NCO if QI is NH or 02 is NH2, if QI is NCO or Rn, where RIS has NCOX values other than hydrogen , and X - represents a gas atom, and A. B, C. Ria and p have the above meanings and, if necessary, oxidize the resulting compound to the corresponding compound, where m 1. 2 of the table. 00 s 00 s o s

Description

The invention relates to quinoline derivatives having an excellent inhibitory effect on acyl-CoA-cholesterol acyltransferase (ACAT). The compounds of the invention inhibit the absorption of cholesterol in the intestinal tract of a mammal and, in addition, inhibit the accumulation of cholesterol ester on the walls of the vessels, as a result of which they are suitable for use as drugs for the prevention and treatment of IIJC-hypercholesterolemia, atherosclerosis and various diseases caused by them ( for example, coronary heart diseases such as myocardial infarction, cerebrovascular disorders such as cerebral infarction, cerebral apopolexia, etc.).

US Pat. No. 3,862,152 specifically mentions 6-chloro-4-phenyl-3- (3-phenylureido) quinoline (compound A), 6-chloro-3 / 3- (4-chlorophenyl) ureido / -4-phenyl- nolin (compound B) and 3- (3-benzylureido) -b, 7-dimethoxy-4-phenylquinoline. (compound C) with anti-ulcer action.

It is also known that 6-chloro-3-phenyl (or p-chlorophenyl) acetamido-4-phenylquinoline is effective as an anti-trichomonas or anti-ulcer agent (see US Pat. No. 3,798,226).

However, there are no reports or references to the above compounds having pharmacological activity directed against arteriosclerosis, for example, ACAT inhibitory activity and the ability to lower blood cholesterol, and these compounds were not considered from this point of view.

Thus, it was not known that Compounds A, B and C and their analogs are useful as drugs for the treatment of arteriosclerosis.

The physiological activity of the aforementioned compounds A, B, and Ci of their analogues was studied, as a result of which it was found that known compounds, such as compound B, etc., as well as new compounds not specifically described in the above references, are strong with respect to ACAT inhibitory activity and are useful as drugs for the treatment of arteriosclerosis.

The invention relates to an ACAT-inhibiting composition comprising a quinoline derivative of the general formula

NH-iCH2VSP

.0

5

0

5

0

5

0

5

0

5

N

(OV

wherein R represents a hydrogen atom, alkyl or aryl, m and n are 0 or 1, and each of rings A, B and C may have a substituent (s) or a salt thereof.

A new quinoline derivative of formula (1) in which m is 1 or m 0 and ring B has a substituent (s) and ring C is replaced by fluorine atom (s), in other words, at m 1, each of rings A, B and C can have a substituent (s), and at m 0 each of the rings A and C may have substituents) and the ring B has a substituent (s) or. ring C is substituted with fluorine atom (s) if ring B is unsubstituted or their salts.

It is recommended that the alkyl groups under the symbol R in the formula (1) be alkyls of normal or iso-structure with 1-8 carbon atoms, such as: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like.

It is recommended that the aralkyl groups under the symbol R are phenylalkyls having 7-9 carbon atoms such as benzyl, 1-phenylethyl. 2-phenylethyl, 2-phenylpropi, 3-phenylpropyl and the like, in which the benzene ring may be substituted with the same substituents as rings A, B and C, as discussed below. Any other R groups may include heteroalkyl with 5-8 carbon atoms containing a heterocycle, such as a thiophene, furan or pyridine ring instead of the benzene ring of the above phenylalkyl. The recommended value for R is hydrogen.

The values for n may be 0 or 1, but preferably rv 0.

Each of the rings A, B and C may have a substituent (s). Examples of substituents include a halogen atom, possibly a halogenated lower alkyl group, a possibly halogenated lower alkylthio group, a possibly halogenated lower alkoxy group, a nitro group, an optionally esterified carboxyl, hydroxyl, a C1-C4 alcyloxy group (e.g. formyloxy, acetoxy-propionic, , butyloxy group, etc.) and Ci-C3-acyl (e.g. formyl, acetyl, propionyl, etc.). The halogen atom in the above list may be fluorine, chlorine, bromine or iodine.

Perhaps halogenated lower alkyl may be normal or iso-alkyl with 1-6 carbon atoms and such lower alkyl may be substituted with two to five halogen atoms such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2 -bromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trimethylethyl. butyl, 4.4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,6,6-trifluorohexyl or 5-trifluoromethyl pentyl.

The possibly halogenated lower alkoxy group and the possibly halogenated lower alkylthio group may be those formed by a combination of the above alkyls with an oxygen or sulfur atom.

An optionally esterified carboxyl may be a carboxyl esterified with 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

The substituent (s) in rings A, B and C may be in any position of these rings, and such substituents may be the same or different, the number of these substituents may be 1-4. Acceptable substitution positions in the quinoline system are 6- and / or 8 positions for ring A, 2 for ring 2 and 2 and / or 4 positions for ring C. Suitable atom substituents for ring C are atom (s) chlorine or fluorine, and particularly preferably 2,4-difluoro-substituted ring C.

Salts of quinoline derivatives of formula (1) can be salts with organic or inorganic acids, such as: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fumaric acid, maleic acid, citric acid, tartaric acid or salts with alkali metal or alkaline earth metal, such as: sodium, potassium or calcium.

Representative quinoline derivatives of general formula (I) include the following compounds.

(1) Quinoline derivatives of the general formula (la):

R3

NHCNH it Oh

 / Vf

wherein Ra and Pz are the same or different and each represents a halogen atom or Ci-C4 alkyl, or salts thereof.

The halogen atoms under the symbols R2 and Yaz can be chlorine, bromine or iodine atoms. St-C4 - alkyl under the symbols H3 and R / J may be methyl, ethyl, n-propyl, isobutyl, n-butyl, etc. Preferred examples for RI include: chlorine. methyl, ethyl and isopropyl; preferred examples for RS include: chloro and methyl.

(2) Derivatives of quinoline of the general formula s (1 c):.

0

5

where R4 and Rs are the same or different and each is Ci-Gi is alkyl, Ra is as defined above, and their salts.

. C1 to C4 alkyls for R and RS may be the same as above for Ra. Preferably, both R and RS are methyl.

Quinoline derivatives of the general formula

(I) and their salts can be synthesized, for example, by reaction of a compound of the general formula (II a)

or its salt with a compound of the general form 40. ly (Sh.v):

(CH2VR.

or its salt, R

where 02 is the MCO. or CH —MH or RI;

Q2 is NH2 if Qi is -NCO or -NCOX. RI is alkyl or aralkyl; X represents a halogen atom, and other symbols take the above meanings.

Alkyl and aralkyl groups

for an RI symbol may be the same. what

and the above for R. The halogen atom for the symbol X may be a Ci atom

or Br.

The following are more specific methods for the synthesis of compounds of the formula

0).

(Method A)

Wb (CH2) nNCO-- (I)

(til)

(The symbols in the above formulas take the above meanings) 10 (Method B) (if R H)

3DSC) SOON ----- h. OSso%

 A1h ASNDING W

V) ™ N

(Vi)

HEATING

Nco

1gKNL, Ng

)

0) (The symbols in the above formulas take the above meanings) (Method C) (if R H).

sokh, f 1 (vtil tiiMRf m --y, r, coxUi (1) (w

OR СХ3ОСОХ .Д:

(The symbols in the above formulas take the above values) .30 (Method D)

iJ r NH-fCHA- c)

N-II.

Uc °

s8jfYNxc, NH4CH2V

-4ix4 4

N

. (Id)

(The symbols in the formulas take the above meanings).

The above compounds of the formulas (Na), (Ills) and (H) - (VIII) can be used in the form of their salts, as in the above case with the compound of the formula (I).

(Method A).

The compound of formula (1) and its salt can be synthesized by reacting a 3-aminoquinoline derivative of formula (II) or its salt with an isocyanate ester of formula (111),

Typically, the reaction is carried out in an appropriate solvent. Used ras10

fifteen

0

5

0

5

0

5

0

5

the moiety may be any inert solvent, for example, an ether, such as ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran and dioxane; an aromatic hydrocarbon such as benzene, toluene and xylene; an ester such as: methyl acetate and ethyl acetate; a ketone such as acetone and methyl ethyl ketone; pyridine; S, S-dimethylformamyl, etc. The reaction is usually carried out at 0-150 ° C, preferably at 15-120 ° C. The amount of the compound of formula (III) used is usually 1-5 equivalents, preferably 1-3 equivalents with respect to the compound of formula (II). The reaction time is usually 5-70 hours, preferably 10-30 hours, although it may vary depending on the type of starting compounds and solvents used, reaction temperature, etc.

(Method B)

A compound of formula (I) in which R is hydrogen can be synthesized by azidation of a quinoline-3-carboxylic acid of formula (IV) to form a compound of formula (V), heating it to give 3-isocyanatoquinoline of formula (VI), and finally reacting the resulting compound of formula (VI) with an amine of formula (VII).

In the first step of the described process, any known methods for converting a carboxylic acid to an acid azide can be applied. For example, a compound of formula (IV) can be converted to a compound of formula (V) by using diphenyl phosphoryl azide (DFA) as an azidizing agent. Such a reaction is usually carried out in the same inert solvents as indicated for method A. The reaction can be carried out in the presence of a base such as triethylamine, tributylamine or M-methylmorpholine. Typically, the reaction is carried out at 0-50 ° C, preferably at 10-40 ° C. The amount of DFA used is 1-2 equivalents, preferably 1-1.5 equivalents, with respect to the compound of formula (IV). The resulting compound of the formula is usually converted to the isocyanatoquinoline of the formula (VI) by heating without prior isolation, although the compound of the formula (V) can be isolated and purified by conventional methods. Said conversion reaction is carried out by heating at 60-150 ° C, preferably at 80-120 ° C.

The resulting compound of formula (VI) is isolated by known methods or is reacted as a reaction mixture without isolation with the compound

formula (VII) and preparing the target compound of formula (I) in which R represents a hydrogen atom. The reaction with the compound of formula (VII) can be carried out in the same solvent as used in method A. Typically, the reaction is carried out at 20-130 ° C, preferably at 60-120 ° C. The amount used of the compound of formula (VII) is usually 1 to 3 equivalents, preferably 1 to 2 equivalents with respect to the compound of formula (VI). The reaction time is unlimited if the goal of the reaction is achieved.

(Method C)

The target compound of formula (I), in which R is not hydrogen, can also be synthesized by method C.

This method is carried out by the initial reaction. The starting compound of formula (II) in which. R is not hydrogen, with a compound of the formula COX2 or CXxOX (where the symbols are as defined above), e.g. phosgene or trichloromethylchlorocarbonate (phosgene dimer) to form a compound of formula (VIII). The reaction can be carried out in an inert solvent, similar to the solvent used in method A. The reaction can be carried out in the presence of a base such as triethylamine, tributylamine, N-methylmorpholine, pyridine or quinoline, if necessary. Typically, the reaction can be carried out at 0-60 ° C, preferably at 10-40 ° C. When using phosgene, trichloromethylchlorocarbonate, etc. the amounts of these reagents are usually 1-6 equivalents, preferably 2-5 equivalents based on phosgene with respect to the compound of formula (II) in which R is not a hydrogen atom.

. The resulting compound of formula (VIII) is isolated by known methods or used without isolation as a reaction mixture in reaction with a compound of formula (VI) to form a compound of formula (I). And this reaction can be carried out in an inert solvent, similar to the solvent of method A. If necessary, the reaction can be accelerated by the introduction of the base indicated above to obtain the compound of formula (VIII). The reaction temperature is usually 20-150 ° C., Preferably 60-120 ° C. In addition, 4-dimethylsaminopyridine may be added to the reaction mixture to accelerate the reaction.

(Method D).

The target compound of formula (f), where m 1, namely, the compound of formula (Id) can be obtained by oxidation of the target

compounds of formula (I), where m 0, namely, compounds of formula (Ic). The oxidation can be carried out using hydrogen peroxide or an organic acid, such as: formic acid, peracetic acid, trifluoroacetic acid, perbenzoic acid or m-chlorobenbenzoic acid. Although the reaction conditions depend on the nature of the applied

0 oxidizing agent, however, the reaction can be carried out in a solvent, such as formic acid, acetic acid, trifluoroacetic acid and aqueous solutions of these acids, chloroform, dichloromethane and

5 etc., usually at 10-100 ° C, preferably at 20-80 ° C. The amount of oxidizing agent used is usually 1-10 moles, preferably moles per mole, of the compound of formula (Ic).

0 From compounds of formula (I). synthesized by methods AD and having a lower alkoxy group (s) in rings A, B, or C, compounds containing hydroxyl (s) of reaction with

5 with boron tribromide or a similar reagent. The reaction is usually carried out in a solvent (e.g. dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, etc.) at -20-80 ° C, preferably at 0-30 ° C. The amount of boron tribromide used is 1-10 equivalents, preferably 1-5 equivalents per lower alkoxy group.

If the compounds of formula () synthesized by the above-described 5 methods contain an esterified carboxyl or an acyloxy group in any of rings A, B and C., if necessary, these groups can be converted, respectively, into carboxyl

0 or hydroxyl by hydrolysis. Hydrolysis is usually carried out in the presence of an alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or barium hydroxide in a solvent (e.g. alcohol, such as methanol, ethanol, proznol, etc.). The reaction temperature is 0-100 ° C., Preferably 20-80 ° C.

The desired compounds of formula (I) obtained by the above methods can be isolated and purified by known isolation and purification methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

In the preparation of a compound of formula (I) with the basic nitrogen atom (s) in free form and / or, if acid groups such as carboxyl exist in the molecule in free form, salts of these compounds can be prepared by conventional methods. Furthermore, when a compound of formula (I) is prepared as a salt, it can be converted into the free form in the usual manner.

The compounds of formula (I) have an excellent inhibitory effect on acyl-CoA cholesterol acyltransferase (ACAT) and their acute toxicity and repeated toxicity is low.

ACAT is known to be an enzyme associated with esterification of high fatty acids in cholesterol cells and plays an important role in the absorption of cholesterol through the small intestine and the accumulation of cholesterol esters in cells. Correspondingly, ACAT inhibitors can inhibit the absorption of cholesterol absorbed by food through the intestinal tract, limit the level of increase in blood cholesterol, limit the accumulation of cholesterol esters in cells during arteriosclerotic pathological disorders, and can also prevent the development of arteriosclerosis.

The compounds of formula (I) are useful as safe medications for the prevention and treatment of cholesterolemia, atherosclerosis and the diseases they cause (for example, ischemic heart diseases such as myocardial infarction, cerebrovascular disorders such as cerebral

heart attack, cerebral apoplexy, etc.) in mammals (e.g., mice, rats, hamsters, cats, dogs, horses, cattle, sheep, monkeys, humans, etc.).

When using the compounds of formula (I) as drugs for the treatment of the above diseases, they can be administered orally or parenterally in the form of a powder, granules, tablets, capsules, injections, etc., which can be prepared by mixing with an ordinary pharmaceutical acceptable carrier, excipient or thinner. The compound of formula (I) is recommended to be administered orally when used to inhibit cholesterol absorption. The dosage of the compound of formula (I) depends on the type of compound, route of administration, condition and age of the patient, etc. For example, when the compound of formula (I) is orally administered to an adult patient with hypercholesterolemia, 0.005-50 mg, preferably O, OS-10 mg, more preferably 0.2-4 mg of compound per kg of patient weight per day are administered, preferably divided for administration 1 -3 times a day.

The starting compounds for the synthesis of compounds of formula (I) can be prepared by the following methods. (Method E)

N02CH2CH NOH

METASONIC ACID

N02 RECOVERY

NHCOCH,

(xin

where X i is a leaving group and the other symbols are as defined above. (Method F)

ABOUT

BASE

NH-CH CH-N02 W

.... ACETYLING

Nn -------------

N-COCH

HYDROLYSIS

vdsl

NCH7CH (NH

. aV l

(}

where Ra represents lower alkyl and the other (Method G) symbols take the above meanings.

NH-CH C (

(xvin

 81

NH-CH CHCOOR1Q

(xvun

where each of the symbols takes the above meanings.

(Method E).

Methods for the preparation of a 3-aminoquinoline of formula (IP) from 2-aminobenzophenone of formula (IX) as a starting compound through the intermediate formation of compounds of formula (X) and (XI) are described in Journal of Chemical Society, p. 3914 (1953) and published patent Japan No. 6474/1973. The compound of formula (II) can be synthesized by these methods or similar methods.

Acetylation of a compound of formula (IP) may be carried out by the method described in U.S. Patent No. 3,798,226 or Yakugaku Zasshi, T. 93, p. 1263 (1973), or a similar method to obtain a compound of formula (XII).

Then, a compound of formula (XII) is reacted with a compound of formula (XIII) to give a compound of formula (XIV), by hydrolysis of which a compound of formula (II) is obtained.

The reaction of a compound of formula (XII) with a compound of formula (CI) can be carried out in a solvent (e.g. tetrahydrofuran, dimethoxyethane, N.N-dimethylformamide, etc.). The reaction can be accelerated in the presence of a base (e.g. sodium hydride, potassium hydride, sodium methylate, sodium ethylate, sodium amide, potassium t-butoxide, etc.). The reaction temperature is usually -10-120 ° C., Preferably. 0-100 ° C. Departure group X1. halogen (e.g., chlorine, bromine, iodine, etc.), C1 C1-alkanesulfonyloxy group (e.g. methanesulfonyloxy group, ethanesulfonyloxy group, etc.), Ci-4-alkoxy sulfonyloxy group (e.g. meHYDROLYSIS) can serve in this reaction

(Iv)

0

toxisulfonyloxy group, ethoxysulfonyloxy group, etc.), Ce-Cyu arylsulfonyloxy group (e.g., benolsulfonyloxy group, p-toluenesulfonyloxy group, etc.) and the like. The amount of base and compound of formula (XIII) with respect to the compound of formula (XII) is usually 1-3 equivalents. By hydrolysis of the resulting compound of formula (XIV), a compound of formula (II) is obtained. The hydrolysis can be carried out in a solvent (e.g. alcohol, such as methanol, ethanol, propanol,

5 acetic acid, etc.). Typically, the reaction is carried out in the presence of a mineral acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), typically in an amount of 2-20 moles,

0 preferably 3-15 moles per mole of the compound of formula (XIV). The reaction temperature is 60-120 ° C, preferably 70-100 ° C.

 In addition, compounds of formula (II) can be synthesized by reacting a compound of formula (D) with a compound of formula (XIII). This reaction can be carried out in a solvent (e.g., carbon tetrachloride, chloroform, methylene chloride, acetone, tetrahydrofuran, dimethoxyztane, NN-dimethylformamide, etc.) in the presence of a base such as potassium carbonate, sodium carbonate, triethylamine and etc., if necessary. The reaction temperature is usually -20-100 ° C., Preferably 0-60 ° C. The amount of the compound of formula (XIM) used is 1-5 moles, preferably 1-2 moles, per mole of the compound of formula (IP). (Method F).

The method is carried out according to the procedure described in U.S. Patent No. 3,798,226 or z. Yakugaku Zasshi, vol. 93, p. 1263 (1973) or a similar method.

0

5

0

(Way).

The reaction of 2-aminobenzophenone of formula (IX) with an alkoxymethylene malonic acid diester of formula (XVI) can be carried out by the method described in Canadian Journal of Chemistry v. 47, p. 489 (1969), or a similar method. The resulting compound of formula (XVII) is then reacted by heating with sodium chloride or lithium chloride to give a quinoline-3-carboxylic acid ester. The reaction is carried out by heating the reaction mixture at 120-220 ° C, preferably 150-200 ° C.

10

which, as a result of dehydration, cyclizes to the compound of formulas (XIX). The resulting compound of formula (XIX) is hydrolyzed with alkali to the compound of formula (IV). Hydrolysis is usually carried out in a solvent (e.g. methanol, ethanol, propanol, etc.). The reaction can be accelerated in the presence of an alkali metal hydroxide or an alkaline earth metal such as sodium hydroxide, potassium hydroxide or barium hydroxide. The reaction can be carried out at 20-100 ° C, preferably 3t) -90 ° C.

The compounds of formulas (II), (I) and (IV) obtained by the above methods E. Ri

The reaction is recommended to be carried out in a solution of 15 G; they can be used as a heat gun, such as: dimethyl sulfoxy sulfolane, M, M-dimethylformamide, etc. The amount of sodium chloride or lithium chloride used is usually 1-20,

the compounds of the invention after isolation by conventional methods or without isolation as reaction mixtures. In addition, equivalents can be synthesized, preferably 2-10 equivalents of the 3-n-derivative of the formula (XI), valents with respect to the compound of the formula (XVII). It is believed that, as an intermediate in this reaction, a compound of formula (XVIII) is formed.

SNG ° H NVG

substituted by a thio group in ring A or B, for example, according to the following reaction scheme.

(Method H).

CCH 2MCSCr

(

R2Q- X

(Xxiv)

2a

where CH3Cs, HO, (ChbbNCSC. HSf and FT-S means the presence of the substituent CH3CO-, HO-, (CH3) 2MS50-. HS- or R2a-S- in ring A or / and B, respectively, R2a represents a possibly halogenated lower alkyl, X1 is as defined above.

(Method H).

Initially, in the presence of hydrobromic acid, a methyl compound of formula (XX) is demethylated having methoxy group (s) in ring A or / and B,

0

which, as a result of dehydration, cyclizes to the compound of formulas (XIX). The resulting compound of formula (XIX) is hydrolyzed with alkali to the compound of formula (IV). Hydrolysis is usually carried out in a solvent (e.g. methanol, ethanol, propanol, etc.). The reaction can be accelerated in the presence of an alkali metal hydroxide or an alkaline earth metal such as sodium hydroxide, potassium hydroxide or barium hydroxide. The reaction can be carried out at 20-100 ° C, preferably 3t) -90 ° C.

The compounds of formulas (II), (I) and (IV) obtained by the above methods E. Ri

the compounds of the invention after isolation by conventional methods or without isolation as reaction mixtures. In addition, 3-nitro derivatives of formula (XI) substituted with a thio group in ring A or B can be synthesized, for example, according to the following reaction scheme.

(Method H).

CCH 2MCSCr

(Xho

XcH3) 2Ncos

HEATING

HYDROLYSIS

(Hhsh4)

N (

get the compound of the form (XXI). This reaction is usually carried out by heating to boiling using an aqueous solution of hydrobromic acid as a solvent. If necessary

acetic acid may be added to the reaction mixture to dissolve the compound.

The resulting phenolic derivative of formula (XXI) is then reacted with

1M, M-dimethylthiocarbamoyl chloride to give a compound of formula (XXII). This

the reaction is recommended to be carried out in an inert solvent (e.g. diethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, ethyl acetate, N.N-dimethylformamide). The reaction temperature is usually -10-80 ° C, preferably 0-60 ° C. The amount of N.N-dimethylthiocarbomoyl chloride used is usually 1-2 equivalents, preferably 1-1.5 equivalents with respect to the compound of formula (XXI).

The compound of formula (XXII) can be converted into a compound of formula (XXIII) by heating at 150-250 ° C, preferably at 170-230 ° C. The conversion reaction is usually carried out by heating a compound of formula (XXII) above its melting point without the use of solvents.

Hydrolysis of a compound of formula (XXIII) is usually carried out under alkaline conditions. The presence of a solvent (e.g., methanol, ethanol, propanol, 2-methoxyethanol, dioxane, dimethoxyethane, etc.) and the presence of sodium hydroxide, potassium hydroxide, barium hydroxide, etc., contribute to a favorable reaction. The reaction temperature is usually 10-100 ° C., Preferably 20-90 ° C.

Alkylation of a compound of formula (XXfV) is carried out by its reaction with a compound of formula R2a-x in a solvent (e.g. methanol, ethanol, propanol, dimethoxyethane, dioxane, tetrahydrofuran, acetone, NN-dimethylformamide, etc.) in the presence of a base (e.g. potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.). The reaction temperature is usually (-10-100) ° C, preferably 0-80 ° C. The amount of the compound of the formula R2a-X used is 1-2 equivalents, preferably 1-1.5 equivalents with respect to the compound of the formula (XXIV).

If the compound of formula R2a-X is gaseous, the reaction can be carried out by supplying an excess of this compound to the reaction mixture. The resulting compound of formula (XI1) may be isolated by known methods or may be used without isolation as a starting material in the next step.

3-Nitro derivatives of the formula (XI), substituted in the ring A or B with a substituted oxy group, can be synthesized, for example, according to the following reaction scheme,

(Method I)

(Xxi)

1a X1

where R CL- - means the presence of substituent (s) R2a-0- in ring A or / and B, and other symbols are as defined above.

(Method I)

The intermediate compound of formula (XXI) synthesized by method H is reacted with a compound of formula R2a-X to give a compound of formula (XI). The reaction of an intermediate of formula (XXI) with a compound of formula R -X can be carried out analogously to the reaction of a compound of formula (XXIV) with a compound of formula according to the above method H. The resulting compound of formula (XI) can be used as a starting material in the next step without isolation in the form of a reaction mixture, although it can be isolated by known methods.

Compounds of formula (XI) can be synthesized by the direct method described below, in which nitroenamine of formula (XXV) is used instead of the methazonic acid of method E.

(Method J)

Kb

: N-CH CH-N02

(Ix)

(Xxv)

(Xi)

wherein Re and R are the same or different and each represents lower alkyl, phenyl or benzyl, or Re and R together with the nitrogen atom to which they are attached form a ring.

(Method J)

Alkyls for Re and R are those with 1-4 carbon atoms, such as methyl, ethyl. propyl, isopropyl, or butyl. If Re and R together with a nitrogen atom form a cycle, then such a cycle may contain an oxygen atom. For example, such a cycle may be a 5-7 membered ring, such as a pyrrolidine ring, a piperidine ring, a homopiperidine ring or a morpholine ring.

The reaction of a compound of formula (IX) with a compound of formula (XXV) is usually carried out in a solvent in the presence of an acid. Ethyl acetate, acetone, benzene, toluene, etc. can be used as a solvent, and hydrochloric acid, brominated hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. can be used as an acid. Both anhydrous acid and its aqueous solution can be used. The reaction can be carried out in a homogeneous system or in a two-layer solvent system and. water. The amount of the compound of formula (XXV) used is 1-10 moles, preferably 2-6 moles per mole of the compound of formula (IX), and the amount of acid used is 1-20 moles, preferably 2-10 moles of the compound of formula (IX). The reaction temperature is usually 20-100 ° C. preferably 50-80 ° C.

Compounds of formula (XIX) can be synthesized by the following direct method, in which a compound of formula (XXVI) is used instead of the compound of formula (XVI) of method C.

(Method K)

(IX) (Rla) 2CHCH2COORla, (XIX)

where the symbols take the above meanings.

(Method K).

The reaction is usually carried out in a solvent such as benzene, toluene or xylene in the presence of an acid catalyst such as benzenesulfonic acid or p-toluene sulfonic acid. The amount of the compound of formula (XXVI) used is usually 1-5 mol, preferably 1-3 mol per mol of the compound of formula (IX), and the amount of acid used is 0.01-1 mol, preferably 0.05-0.5 mol per mol compounds of formula (IX). The reaction is usually carried out at the boiling point of the solvent, and it is recommended that the water formed during the reaction be removed.

Compounds of formula (XXVIH) can be synthesized using a compound of formula (XXVII) instead of a compound of formula (XXVI) of method K, after which a compound of formula (XXVIII) can be converted to a compound of formula (II) via an intermediate compound of formula (XXIX) (Method L ),

(Method L)

. where the symbols take the above meanings. (Method L)

The reaction of a compound of formula (IX) with a compound of formula (XXVII) can be carried out analogously to the reaction of a compound of formula (IX) with a compound of formula (XXVI) according to method J. Hydrolysis can be carried out in the presence of acid or alkali. Hydrochloric acid, hydrobromic acid, sulfuric acid, etc. are used as the acid, and sodium hydroxide, potassium hydroxide, etc. are used as the alkali. The reaction is carried out in an acceptable solvent (e.g. methanol, ethanol, propanol, dioxane, dimethoxyethane, etc.) or in the absence of a solvent. The reaction temperature is 0-100 ° C., Preferably 20-80 ° C.

Alternatively, the compound of formula (XXVIII) can be converted to the compound of formula (XXIX) by oxidation with hydrogen peroxide in the presence of alkali. This reaction is usually carried out in a solvent similar to the solvent in hydrolysis, and in the presence of

5. alkalis such as sodium hydroxide, potassium hydroxide, etc. Number of used

.-. alkali and hydrogen peroxide is 1-10 moles, preferably 1.5-5 moles per mole of the compound of formula (XXVIII), respectively, the reaction temperature is 10-100 ° C, preferably 20-80 ° C.

The compound of formula (XXIX) is then reacted with bromine or chlorine in the presence of alkali, i.e. under reaction conditions

5 Hoffmann and / get the compound of formula (II). This reaction is carried out by reacting a compound of formula (XXIX) with bromine or chlorine in a solvent and in the presence of alkali. The following can be used as solvents: dioxane, dimethoxyethane, methanol, ethanol, etc., and sodium hydroxide, potassium hydroxide, etc. can be used as alkali. The reaction may be carried out by addition.

5 by adding bromine or chlorine to a mixture of a compound of formula (XXIX) with an alkali or an alkali reaction with bromine or chlorine followed by a reaction of the resulting bromic or perchloric acid, usually at -10-100 ° C;

0 preferably at 0-80 ° C. At a low reaction temperature, an isocyanate derivative of formula (VI) is first formed, by hydrolysis of which a compound of formula (II) is obtained. Accordingly, favorable results are obtained by stepwise carrying out the reaction, namely, at first at 0-20 ° C, followed by a rise in temperature to the desired value. The amount used in the alkali reaction is 2-8 moles, preferably 4-6 moles per mole of the compound of formula (XXIX), and the amount of bromine or chlorine used is 1-3 moles, preferably 1-1.5 mol, per mole of the compound of formula (XXIX) .

Recommended examples of compounds of formula (II) include compounds of formula

PV

where Pz is as defined above, and in ring A there are two substituents selected from the group consisting of: a halogen atom or alkyl with 1-4 carbon atoms, or their salts.

In the definition for Bz and the substituents of ring A, the halogen and alkyl, as well as their position in ring A, may be the same as the 20 indicated in connection with the symbols R2, Pz, R4 and RS of the compounds of formulas (la) and (c).

The intermediate of formula (XXVIII) of method I can be hydrolyzed to the compound of formula (IV) in the following 25 ways:

(Method M)

(XXVIII) hydrolysis (IV)

(Method M) .30 The hydrolysis reaction in this case can be carried out using acid or alkali in a solvent, and it is recommended that it be carried out using alkali. Methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, etc. can be used as a solvent 35, and sodium hydroxide, potassium hydroxide, etc. can be used as an alkali. The amount of alkali used is usually 2-20 moles, 40 preferably 3-10 moles per mole of the compound of formula (XXVIII). The reaction is usually carried out at 60-150 ° C, preferably at 80-130 ° C.

The starting material of formula (IX) above 45 of method E can be obtained by the method described in Journal of Organic Chemistry, vol. 26, p. 4488 (1961), e, vol. 27, p. 3781 (1962), and t .d., or in a similar way. The original compound 50 of formula (XV) of method F can be obtained, for example, by the method described in US patent No. 3798226, Yakugaku Zasshi, t. 3, page 1263 (1973), etc., or a similar method. 55

In addition, the starting compound forums (XXV) of method I can be obtained, for example, by the method described in Synthesis, p. 260 (1982), or a similar manual.

0

5

0

5

0 5 0

5 0 5

Activity

Pharmacological test data showing the excellent applicability of the quinoline derivatives of formula (I) and their salts of the present invention are demonstrated as follows.

1. Inhibitory activity against acyl-CoA-cholesterol acyltraxferase (ACAT).

(Methodology)

The ACAT enzyme was prepared by the Heider method, et al., Described in Journal of LJpId Research, vol. 24, p. 1127 (1982), from the microsomal fraction of the small intestinal mucosa of male Spraque-Dawley rats aged 6 weeks fixed for 20 h

ACAT activity was calculated by Helgerud et al. Described in Journal of Lipid Research, vol. 22, p. 271 (1981), namely by measuring the amount of labeled cholesterol ester formed from (1-14C) -oleoyl-CoA and endogenous cholesterol .

(Results)

In the table. Figure 1 shows the degree of inhibition (%) of the formation of the labeled cholesterol ester with the administration of 10-10 M test compounds, shown as an index of inhibitory activity against ACAT.

From the data table. Figure 1 shows that the quinoline derivatives of formula (I), including Compound B, and their salts exhibit excellent ACAT inhibitory activity.

2. The ability to lower plasma cholesterol in cholesterol-treated rats.

For 7-week-old Spraguc-Dawley rats, male food is fed with 1% cholesterol (containing 0.5% cholic acid and 5% olive oil) for 3 days. Rats were grouped by plasma cholesterol and continued to feed the same food containing 0.0005% of the compound used for 4 days. Blood was collected from rats from 830-10 ° C until noon at the time of eating food and plasma cholesterol levels were determined enzymatically. The amount of rat assayed test compound is calculated based on the rat food eaten.

Results.

As can be seen from the data table. 2, the cholesterol level in rats fed dietary cholesterol was significantly reduced by the test compounds.

From the data table. 1 shows that the quinoline derivatives of formula (I), including compound B, and their salts have excellent inhibitory activity against ACAT.2, The ability to lower plasma cholesterol in rats receiving cholesterol.

7-week old Spraguc-Dawley rats (males) are fed 1% cholesterol (0.5% cholic acid and 5% olive oil) for 3 days. Rats are grouped according to the level of cholesterol in blood plasma and continue to be fed the same food containing 0.0005% of the compound used for 4 days. Blood is taken from rats from 830-10 ° C until noon at the time of eating and the level of content plasma cholesterol is determined enzymatically. The amount of rat assayed test compound is calculated based on the rat food eaten.

Results.

As can be seen from the data table. 2, the cholesterol level in rats fed dietary cholesterol was significantly reduced by the test compounds.

The values reported are mean values ± standard deviations.

p 0.05 (t test against control group).

The data table. 2 prove that the quinoline derivatives of formula (I) and their salts have an excellent ability to lower plasma cholesterol.

In the reference examples and examples, the elution progress in column chromatography is monitored by thin layer chromatography (TLC). TLC was performed using silica gel 60F254 manufactured by Merck Co.nc in the form of TLC plates and using the same solvent as in the elution in column chromatography as a developing solvent, a UV detector was used as a detection device. Silica gel was used for column chromatography gel 60 (70-230 mesh) from Merck Co. Inc.

The abbreviations used in the examples and reference examples have the following meanings: mg - milligram, g - gram, ml - milliliter, mp - melting point.

Further room temperature means 15-25 ° C.

Example 1. To a solution of 3-amino-6-chloro-4-phenylquinoline (509 mg) in anhydrous tetrahydrofuran (8 ml) was added.

2,4-difluorophenyl isocyanate (0.24 ml) and the mixture was allowed to stand at room temperature for 20 hours. Precipitated crystals were separated by filtration, the filtrate was concentrated, and 5 precipitated crystals were separated by filtration. The obtained crystals are combined. And after recrystallization from ethanol, 638 mg (77.8%) of 6-chloro-3- 3- (2,4- - difluorophenyl) ureido} -4-phenyl quinoline is obtained, m.p. 206-207 ° C.

Elemental analysis for C22Hi4CIF2N30. Calculated,%: C 64.48; And 3.44; N, 10.25. Found,%: C 64.23; H 3.55; N, 10.04. The target compounds of the following 15 Examples 2-39 were synthesized by reaction of the corresponding 3-aminoquinoline derivative with an isocyanate according to the procedure of Example 1.

Example 2. 6-Chloro-3- 3- (4-fluorofhe- 20 nyl) ureido-4-phenylquinoline, so pl. 205-207 C (recrystallized from ethanol). Yield 66.5%.

Calculated,%:. C, 67.44; H 3.86; N, 10.72. Elemental analysis for C22HisClFN30. 25 Found,%: C 67.63; H 3.87; N, 10.76. Example 3. 6-Chloro-3- 3- (3-fluoroflu. Nyl) ureido-4-phenylquinoline, so pl. 213- 214 ° C (recrystallized from acetone). Yield 84.1%.

30 Elemental analysis for C22HisC FN30 Calcd.,%: C 67.44; H 3.86; N10.72. Found,%: C 67.51; H 3.86; N, 10.64. PRI me R 4. 6-Chloro-3- 3- (2-fluorophenyl) ureido-4-phenylquinoline, so pl. 197-35 198 ° C (recrystallized from a mixture of acetone with hexane). Yield 77.3%.

Elemental analysis for C22Y1bC1RyZO Calculated,%; C, 67.44; H 3.86; N, 10.72. Found,%: C 67.32; H 3.86; N, 10.70. 40 PRI me R 5. 6-Chloro-3- {3- (3-methylphenyl) ureido-4-phenylquinoline, so pl. 204–206 ° С (recrystallized from a mixture of acetone and ethanol). Yield 78.2%.

Elemental Analysis for C2zH1eC1BiO 45 Calcd. %: C 71.22; H 4.68; N, 10.83 Found,%: C71.16; H 4.67; N, 10.89. Example 6. 6-Chloro-4-phenyl-3- 3- (3-trifluoromethylphenyl) ureido quinoline, so pl. 203-204 ° C (recrystallized from a mixture of 50 acetone with diisopropyl ether). The yield of 80.5%.

Elemental analysis for C2zH1eC1PzMzO Calcd.,%: C 62.52; H 3.42; N, 9.51. Found,%: C, 62.73; H 3.71; N, 9.23. 55 Example. 6-Chloro-3- 3- {2,4-dimethoxy-phenyl) ureido-4-phenylquinoline, mp. 210-211 ° C (recrystallized from a mixture of acetone with ethanol). Yield 41.5%.

Elemental analysis for C24H2oC # Oz Calcd.%: C 66.44; H 4.65; N, 9.68

Found,%: C 66.38; H 4.55; N, 9.63. Example 8. 6-Chloro-3- 3- (3,4-dichlorophenyl) ureido-4-phenylquinoline, mp 226-227 ° C (recrystallized from acetone). Yield 79.3%. Elemental analysis for C22H14C1c # 0 Calcd.,%: C 59.68; H 3.19; N, 9.49. Found,%: C, 59.63; H 3.07; N, 9.55. Example 9. 6-Chloro-3- {3- (2,5-dichlorophenyl) ureido-4-phenylquinoline (solvate with acetone), so pl. 191-192 ° C (recrystallized from a mixture of acetone with diisopropyl ether). The yield of 82.8%.

Elemental analysis for C22Hm3MbO3 SbNbO Calculated,%: C 59.96; H 4.03; N, 8.39 Found. %: C 60.04; H 4.04; N, 8.42. Example 10. 6-Chloro-3- 3- (2,4-dichlorophenyl) ureido-4-phenylquinoline, so pl. 214-215. C (recrystallized from acetone). Yield 74.2%. Elemental analysis for C22HcC1c # 0 Calculated. %: C 59.68; H 3.19; N, 9.49. Found,%: C, 59.53; H 3.10; N9.45 Example 11. 6-Bromo-3- (3- (2,4-difluorophenyl) ureido-4-phenylquinoline, mp 195-197 ° C (recrystallized from smb acetone with diisopropyl ether). 82.1%.

Elemental analysis for C22H i iBrF2N30 Calcd.,%: C 58.17; H 3.11; N, 9.25. Found. %: C 57.96; H 3.06; N, 9.11. Example 12. (2,4-Difluorophenyl) ureido-4-feiylquinoline (solvate with 1/2 ethanol), so pl. 193-195 ° C (recrystallized from ethanol). Yield 74.3%.

Elemental analysis for C22Hi5F2NaO x x1 / 2C2NbO

Calculated,%: C 69.34; H 4.55; N, 10.55 Found,%: C, 69.48; H 4.55; N, 10.57; Example 13, (3,4-Difluorophenyl) ureido-6-methyl-4-phenylquinoline; mp. 189-191 ° C (percrystallized from a mixture of acetone with diisopropyl ether). Yield 72%.

Elemental Analysis for C23Hi F2N30 Calculated. %: C 70.94; H 4.40; N, 10.79 Found,%: C, 70.88; H 4.39; N, 10.80. Example 14. (2.4-Difluorofenil) ureido-6-ethyl-4-phenylquinoline, mp 189-19 ° C (recrystallized from ethanol). The yield of 70.5%.

Elemental analysis for C2 iHigF2N30 Calculated,%: C 71.45; H 4.75; N, 10.42. Found,%: C, 71.28; H 4.78; N, 10.29. Example 15. (2,4-Difluorophenyl) ureido-6-isopropyl-4-phenylquinoline, m.p. 211-212 ° C (recrystallized from ethanol). Yield 74.5%

Elemental analysis for C25H2iF2NsO Calcd.,%: C 71.93; H 5.07; N 10.07

Found,%: C 71.92; H 5.04; N, 9.99 Example 16. 3- {3- (2,4-Difluorophenyl) -ureus} -7-methyl-4-phenylquinoline. so pl. 195 - 197 ° C (recrystallized from acetone). Yield 76.2%.

Elemental analysis for C23Hi7F2NaO Calcd. /%: C 70.94; H 4.40; N, 10.79, Found. %: C 70.99; H 4.38; N, 10.67. Example 17. (2,4-Difluorophenyl) ureido-4-phenyl-6-trifluoromethylquinoline, mp. 203-204 ° C (recrystallized from ethanol). Yield 65.3%.

Elemental analysis for C23Hi4FsN30 Calcd.%: C 62.31; H 3.19; N, 9.48. Found. %: C 62.39; H 3.12; N, 9.52. Example 18. (2.4-Difluorophenyl) ureido-6-methoxy-4-phenylquinoline; mp. 126-130 ° C (recrystallized from a mixture of acetone with diisopropyl ether). Yield 87.7%.

Elemental analysis for C2zH1, P2MzO Calculated,%: C, 68.14; H 4.23; N, 10.37 Found,%: C, 69.20; H 4.18; N, 10.19. Example 19. (2,4-DifluorophenylEureido b-dimethoxy-phenylquinoline, mp 202-203 ° C (recrystallized from methanol). Yield 77.2%.

Elemental Analysis for C24HigF2N3C 3 Calcd. %: C 66.20; H 4.40; N, 9.65. Found,%: C, 65.92; H 4.35; N, 9.49. Example 20. 3- {3- (3,4-Difluorophenyl) ureido-6-nitro-4-phenylquinoline, (solvate with 2/3 of acetone), so pl. 193-194 ° C (recrystallized from acetone). Yield 76.3%.

Elemental analysis for C22Hi qF2N403 x x2 / 3 CzHeO

Calculated,%: C 62.79; H, 3.95; N, 12.20. Found,%: C, 62.84; H 4.05; N, 12.09. Example 21. 4- (2-Chlorophenyl) -3- {3- {2.4-difluorophenyl) ureido quinoline (1/2 solvate with ethanol), so pl. 198-200 ° C (recrystallized from ethanol). The yield of 85.5%.

Elemental analysis for С22НиС Р2МзОх х1 / 2С2Н60

Calculated,%: C 63.82; H 3.96; N, 9.71. Found,%: C, 63.57; H 4.02; N, 9.64. EXAMPLE 22 6-Chloro-3- 3- (2,4-difluorophenyl) ureido-4- (2-fluorophenylquinoline, mp 218-220 ° C. (recrystallized from ethanol). 78.3% yield.

Elemental analysis for C22H- | sC1Pz # 0 Calculated,%: C 61.77; H 3.06; N, 9.82. Found,%: C, 61.51; H 3.03; N, 9.64. Example 23. 6-Chloro-4- (2-chlorophenyl) - (2,4-difluorophenyl) ureido-quinoline. so pl. 210-212 ° C (recrystallized from aqueous acetone). The yield is 86.7%.

Elemental analysis for Cr2H1zC12P2№0 Calcd.,%: C 59.48; H 2.95; N, 9.46

Found,%: C 59.28; H 2.88; N, 9.37. Example 24. 6-Chloro-4- (3-chlorophenyl) - (2.4-difluorophenyl) ureido quinoline, so pl. 207-208 ° C (recrystallized from aqueous acetone). The yield of 68.1%. Elemental analysis for C22Hl3C12P2No Calcd.,%: C 59.48; H 2.95; N, 9.46. Found,%: C, 59.31; H 2.96; N, 9.59. Example 25. b-Chloro-4- (4-chlorophenyl) - (2,4-difluorophenyl) ureido quinoline, so pl. 215-217 ° C (recrystallized from zanol). Yield 74.1%.

Elemental analysis for Ca2Hl3C12P2No Calcd.,%: C 59.48; H-2.95; N, 9.46. Found,%: C, 59.41; H 2.96; N9.59 Example 26. 6-Chloro-3- 3- (2,4-difluorophenyl) ureido | -4- (4-methylphenyl) -quinoline, so pl. 188-189 ° C (recrystallized from ethanol). Yield 79.7%. .

Elemental Analysis for C2zH1bC1P2 # 0 Calculated. %: C 65.18; H 3.80; N, 9.91 Found. %: C 65.19; H 3.78; N, 9.79. Example 27. 6 Chloro-3- 3- (2,4-difluorophenyl) ureido -4- (2-methylphenyl) -quinoline, so pl. 219-220 ° (recrystallized from a mixture of acetone with hexane). The yield of 72.6%.

Elemental analysis for C2zH1bC1P2 # 0 Calculated,%: C 65.18; H 3.80; N, 9.91 Found,%; C 65.34; H 3.79; N 10.04 Example 28. b-Chloro-3- 3- (2,4-difluorophenyl) ureido-4- (4-methoxyphenyl) quinoline, mp. 208-209 ° C (recrystallized from ethanol). The yield of 82.7%.

Elemental analysis for C2zH1bC1P2 # 02 Calculated,%: C 62.81; H 3.67; N, 9.55. Found,%: C, 62.86; H 3.70; N, 9.50 Example 29. 6-Chloro-3- 3- (2,4-difluorophenyl) ureido-4- (2-methoxyphenyl) quinoline, mp. 221-222 ° C (recrystallized from ethanol). The yield of 65.9%. Elemental analysis for C2zH1bC1P2 02 Calcd.,%: C 62.81; H 3.67; N, 9.55 Found,%: C, 62.81; H 3.71; N9.81. Example 30. 4- (2-Chlorophenyl) (2,4-difluorophenyl) ureido-6-methylquinoline, mp. 225-226 ° C (recrystallized from acetone). The yield is 64.7%.

Elemental analysis for C2zH- | bC P2 # 0 Calculated,%: C, 65.18; H 3.80; N9.91 Found,%; C 65.12; H 3.77; N9.87. Example 31. (2,4-Difluorofen nml) ureido-6-methyl-4- (2-methylphenyl) -quinoline. so pl. 218-220 ° C, (recrystallized from acetone with benzene). Yield 65.7%,

Elemental analysis for C24HigF2N30 Calculated,%: C 71.45; H 4.75; N, 10.42. Found,%: C, 71.26; H 4.65; N, 10.30;

PRI me R 32. (4- (2-Chlorophenyl) (2,4-diftarphenyl) ureido-6,8-dimethylquinoline,

so pl. 198-200 ° C (recrystallized from acetone with benzene). The yield of 61.4%.

Elemental analysis for C24H1bC1P2 # 0 Calculated,%: C 65.83; H 4.14; N, 9.60 Found,%:. C 65.67; H 4.13; N, 9.71. Example 33. 4- (2-Chlorophenyl) (2,4-difluorophenyl) ureido-6-ethylquinoline, m.p. 228-229 ° C (recrystallized from acetone). Yield 75.4%.

Elemental analysis for C24HiaCIF2N30 Calcd.%: C 65.83; H 4.14; N, 9.60 Found,%: C, 65.80; H 4.14; N, 9.61. Example 34. 4- (2-Chlorophenyl) (2,4-difluorophenyl) ureido-6-isopropylquinoline, m.p. 232-233 ° C (recrystallized from acetone). Yield 79.3%.

Elemental analysis for C25H2oC P2 # 0 Calculated,%: C 66.45; H 4.46; N, 9.3. Found,%: C, 66.34; H 4.45; N, 9.3. and mer 35, 6-Butyl-4- (2-chlorophenyl) - (2.4-difluorophenyl) ureido-quinoline, so pl. 202-203 ° C (recrystallized from a mixture of acetone with hexane). The yield of 72.7%. Elemental analysis for C26H22CIF2N30 Calcd.,%: C 67.02; H 4.76; N, 9.02. Found,%: C, 66.98; H 4.72; N8.78 Example 36. 4- (2-Chlorophenyl) (2,4-difluorophenyl) ureido-6-fluoroquinoline, m.p. 212-213 ° C (recrystallized from a mixture of acetone with hexane). The yield of 68.3%.

Elemental analysis for C22ЙЙ1зз11РзМзО Calculated,%; C 61.77; H, 3.06; N, 9.82. Found,%: C 61.74; H 3.06; N, 9.68. Example 37, (2,4-Difluorophenyl) ureido-6-methylthio-4-phenylquinoline, m.p. 117-120 ° C (recrystallized from methanol) yield 89.4%.

Elemental analysis for C23Hi F2N30S Calculated,%; C 65.55; H 4.07; N, 9.97. Found,%: C-65.43; H 4.02; N, 9.9T. Example 38. 6-Chloro-4- (2-chlorophenyl) - (2,4-difluorophenyl) ureido-8-methylquinoline, mp. 199-201 ° C (recrystallized from a mixture of acetone with benzene). Yield 67.8%. Elemental analysis for C23Hi5Cl2F2NsO Calcd.%: C 60.28; H 3.3; N, 9.17. Found,%: C, 60.25; H 3.3; N, 9.04. Example 3.9. (2,4-Difluorophenyl) ureido-6,8-dimethyl-4-phenylquinoline (1/2 sulfate with ethanol), so pl. 200-201 ° C (recrystallized from ethanol). Yield 66% .. °

Elemental analysis for C25H21F2N30 xx1 / 2C2H60

Calculated,%: C 70.89; H 5.49; N, 9.54. Found. %: C 70.63; H 5.41; N, 9.46 Example 40. A mixture of 6-chloro-5-methylamino-4-phenylquinoline (0.54 g), 2,4-difluorophenylisocyanate (0.48 ml) and anhydrous luol (10 ml) is boiled t 22 h, after which it is concentrated. The residue was purified by silica gel column chromatography and, after recrystallization from a mixture of ethyl acetate and ethanol, 0.56 g (66%) of 6-chloro-3- 3- (2,4-difluorophenyl) -1-methylureido-4-phenylquinoline was obtained as colorless crystals, mp 200-201 ° C.

Elemental analysis for CasHieCIFaNaO Calcd.%: C, 65.18; H 3.8; N, 9.91. Found,%: C 65.24; H 3.7; N, 9.81. The compounds of the following Examples 41-44 were synthesized in a manner analogous to the method of Example 40.

Example 41. 6-Chloro-3- 3- (2,4-difluorophenyl) -1-ethyl ureido-4-phenyl quinoline, m.p. 141-142 ° C (recrystallized from ethanol). Yield 53.7%.

Elemental analysis for C24H- | 8C1P2 # 0 Calculated,%: C 65.84; H 4.14; N, 9.60. Found,%: C, 65.73; H, 4.22; N 9.68 Example 42. 3- 1-Butyl-3- (2,4-difluorophenyl) in rhea to -6-chloro-4-phenyl quinoline, mp 66-69 pC (recrystallized from ethyl ether C. hexane), Yield 59.5%. Elemental Analysis for CseHaaClFaNsO Calculated. %: C 67.02; H 4.76; N, 9.02. Found. %: C 67.06; H 4.85; N, 8.99. Example 43. 3- 1-Benzyl-3- (2,4-difluorophenyl) ureido-6-chloro-4-phenylquinoline, T; PL. 150-152 ° C (recrystallized from ethanol). Yield 47%.

Elemental analysis for C29H2oC P2 # 0 Calculated,%: C, 69.67; H 5.56; N, 8.40. Found,%: C, 69.66; H, 4.10. N-8.25 Example 44, 6-Chloro-3 3- (2,4-difluorophenyl) -1-heptylurenedino-4-phenyl quinoline, m.p. 109-110 ° C (recrystallized from ethanol). Yield 29.7%.

Elemental analysis for C29H28C1F2N30 Calcd.,%: C 68.57; H 5.56; N, 8.27. Found,%: C, 68.67; H 5.55: N 8.05 Example 45. To a mixture of 353 Mr 6-chloro-3-heptylamino-4-phenylquinoline, 8 mg of activated carbon, 0.14 ml of triethylamine and 6 ml of absolute tetrahydrofuran are added dropwise with stirring 10% solution of trichloromethylchloroformate (1.5 ml) in toluene. After the mixture was stirred for one day at room temperature, nitrogen gas was passed through the mixture to remove excess phosgene. Then, a solution of p-chloroaniline (126 mg) in 6 ml of absolute tetrahydrofuran, 0.28 ml of triethylamine and 24 mg of 4-dimethylaminopyridine was added to the mixture, and the mixture was boiled for 12 hours. The precipitate was filtered off, the filtrate was concentrated, and the residue was recrystallized from ethanol to recrystallize. 207 mg (40.9%) 6-chloro-3- 3- (4-chlorophene and l) -1-heptyl raid o -4-phenyl quinoline, mp 180-182 ° C.

Elemental analysis for C29H29CI2N30

Calculated,%: C 68.77; H 5.77; N, 8.30. Found,%: C 69.00; H 5.80; N 8.01

Example 46. To a mixture of 6-chloro-4-phenyl3-quinolinecarboxylic acid (566 mg), diphenylphosphoryl azide (660 ml) and dioxane

(10 ml) triethylamine (0.34 ml) was added.

0 the mixture is stirred for 15 minutes at room

temperature and then boil t for 20 minutes. After

2,6-difluoroaniline (310 mg) was added to the mixture while cooling, stirred for 15 minutes at

room temperature and then boil t 30

5 minutes. The resulting mixture was diluted with water and

extracted with ethyl acetate. Organic

the layer is washed successively with water, 1

N. hydrochloric acid, water, saturated

aqueous sodium bicarbonate and

0 water. After drying over anhydrous

magnesium sulfate, the solvent is distilled off and

recrystallization of the residue gives 562

mg (68.7%) 6-chloro-2GZ- (2, b-difluorophenyl) ureido-4-phenylquinoline as colorless

5 needles, mp 228-229 ° C ..

Elemental analysis for C22Hi jCIF2N3Q

Calculated,%: C 64.48; H 3.44; N, 10.25

Found. %: C 64.64; H 3.40; N 10.01.

Example 47 (by a method similar to that of Example 46, with a yield of 42.9%, 6-chloro-3- 3- (2,4-dimethylphenyl) ureido-4-phenylquinoline was obtained, mp 230- 231 ° C (recrystallized from acetone).

Elemental analysis for C24H2oC1NO3 5 Calculated,%: C 71.73: H 5.02; N 10.46

Found,%; C 71.75; H4.96; N, 10.46.

Example 48. By a method similar to that of Example 46, 6-chloro-3 3- (2,4-difluorobenzyl) urea- 0 to -4-phenylquinoline was obtained with a yield of 22%, mp. 243-244 ° C (recrystallized from acetone).

Elemental analysis for С2зН1бС1Р2МзО

Calculated,%: C 65.18; H 3.80; N 9.91

Found,%: C 64.91; H 3.72; N9.71 5 PRI me R 49.

(1) 4- (2-Chlorophenyl) -3

- {3- (2,4-difluorophenyl) ureido -6, 8-dimethylquinoline 10 g 0 (2) Lactose 50 t

(3) Corn starch 15 g

(4) Calcium carboxymethyl cellulose 44 g 5 (5) Magnesium stearate 1 g

Total: 120 g (per 1000 tablets)

The entire amount of components (1), (2) and (3) and 30 g of component (4) are mixed with water.

the mixture is dried in vacuo and then granulated. The granular powder is mixed with 14 g of component (4) and 1 g of component (5) and then compressed in a tablet machine into 1000 tablets, each containing 10 mg of component (1).

Compounds of the following Examples 50-55 were synthesized by a method similar to that of Example 1.

Example 50. 6-Chloro-4- (2-chlorophenyl} - (4-chlorophenyl) ureido-quinoline, mp 217-219 ° C (recrystallized from a mixture of acetone and benzene). 56.8% yield.

Elemental analysis for C22H14C s№0; Calculated,%: C 59.68; H 3.19; N, 9.49. Found,%: C, 59.47; H 3.12; N, 9.43. Example 51. 4- (2-Chlorophenyl) (4-chlorophenyl) ureido-6,8-dimethylquinoline, mp. 219-221 ° C (recrystallized from a mixture of acetone with benzene). The yield of 61.3%. Elemental analysis for C24H1eC12MzO Calculated,%: C, 66.06; H 4.39; N9.63 Found,%: C 65.96; H 4.42; N 9.50 PRI me R 52. 6-Chloro-3 3- (2,4-difluorophenyl) ureido-4- (2-methylthiophenyl) -quinoline, so pl. 219-221 ° C (recrystallized from acetone). The yield of 69.1%.

Elemental analysis for C2zH1bC1P2Mz05 Calcd.,%: C 60.59; H 3.54; N, 9.22. Found,%: C, 60.75; H 3.46; N, 9.29. Example 53. 6-Difluoromethylthio-3- 3- (2,4-difluorophenyl) ureido-4-phenylquinoline, so pl. 110-112 ° C (recrystallized from methanol), Yield 20.6%.

Elemental analysis for C23HisF4N30 Calcd.%: C, 60.39. H 3.31; N, 9.19. Found,%: C, 60.44; H 3.28; N, 9.08; Example 54. 6-Difluoromethoxy-3- 3- (2,4-difluorophenyl) ureido-4-phenylquinoline; mp. 102-104 ° C (recrystallized from methanol). Yield 58.5%.

Elemental analysis for C2zH15P4№02 Calcd.,%: C 62.59; H 3.43; N, 9.52. Found,%: C, 62.50; H 3.31; N, 9.44. Example 55. 8-Chloro-4- (2-chlorophenyl} - (2,4-difluorophenyl) ureido 6-methylquinolin, mp 220-222 ° C (recrystallized from a mixture of acetone with benzene), Yield 63 % Elemental analysis for С2зН15С12Р2МзО Calculated,%: C 60.28; H 3.3; N 9.17; Found,%: C 59.98; H 3.2; N 9.13

Example 56. By a method similar to that of Example 40, 3- (1-butyl-3- (2,4-difluorophenyl) ureido-6-chloro-4- (2-chlorophenyl) hmnoline was obtained in 72 yields. pl. 63-66 ° C.

element analysis for C2bH21C12P2 # 0 Calculated,%: C 62.416; H 4.23; N, 8.40. Found,%: C, 62.37; H 4.16; N, 8.33

Example 57. 4- (2-Chlorophenyl), 4-difluorophenyl) ureido-6.8 dimethylquinoline of Example 32 was dissolved by heating to 80 ° C. in a mixture of acetone (10 ml) with 2 N hydrochloric acid (0.5 ml) ), after which the solution is concentrated. The precipitate formed is filtered off and 4- (2-chlorophenyl) (2,4-difluorophenyl) ure-, 8-dimethylquinoline hydrochloride is obtained in the form of pale yellow needles, mp 227-228 ° C. Yield 0.19%. Elemental analysis for C24H1cS1P2M3Ox x HCI

Calculated,%; C 60.77; H 4.04; N, 8.86 Found,%: C, 60.92; H 4.01; N, 8.78. Compounds of the following Examples 58-60 were synthesized by a method similar to that of Example 1.

PRI me R 58. 6-Chloro-3 (4-fluoro-3-nitrophenyl) ureido-4- (2-methylphenyl) quinoline, mp; 229-232 ° C (recrystallized from acetone). Yield 58%.

Elemental analysis for C2zH1bC1P # Oz

Calculated,%: C 61.27; H 3.58; N, 12.43

Found. %: C 60.99; H 3.56; N, 12.34.

Example 59. (2,4-Difluorophenyl) ureido-6-methyl-4- (2-methyl; tyOphenyl) quinoline (solvate with methanol), so pl. 213215 ° C (recrystallized from methanol).

Yield 87%.

Elemental analysis for C24H.19F2N30S x xSW

Calculated,%: C 64.22; H 4.96; N, 8.99.

Found,%: C 64.27; H 4.94; N 9.03.

Example 60. 6-Chloro-3- 3- (2.4-difluorophenyl) ureido -4- (3,4-dimethoxyphenyl) chmnolin, mp 224-136 ° C. 252-254 ° C (recrystallized from acetone). The yield of 85.4%.

Elemental analysis for C24Hi8CIF2Ns03 Calcd.,%: C 61.35; H 3.86; N, 8.94 Found,%: C 61.33; H 3.85; N 8.87 PRI me R 61. According to the method described in example 46, 4- (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarboxylic acid is treated with diphenylphosphoryl azide and then 2,4-difluoroaniline in a yield of 35.9% 4- (2 chlorophenyl) (2,4-difluorophenyl) ureido-6,8-dimethylquinoline is obtained, m.p., 198-200 ° C.

The resulting substance is identical to the compound of example 32.

Example 62. By the method of example 46

4- (2-chlorophenyl) -b, 8-dimethyl-3-quinolinecarboxylic acid is reacted with diphenylphosphoryl azod and then with

2,4,6-trifluoroaniline and in 73% yield

get 4- (2-chlorophenyl) -6,8-dimethyl-3- {3 (2,4,6-trifluorophenyl) -ureido quinoline, so pl.

219-220 ° C (recrystallized from ethanol).

Elemental analysis for С24Н1 С1Рз№0

Calculated,%: C 63.23; H 3.76: N 9.22

Found,%: -C 63.14; H, 3.67: N, 9.08. Example 63. A mixture of 4- (2-chlorophenyl) - (2,4-difluorophenyl) ureido-6,8-dimethylquinoline (1.1 g), m-chloroperbenzoic acid (1.08 g) and dichloromethane (15 ml ) is boiled for 20 hours, then the reaction mixture is washed successively with an aqueous solution of sodium sulfite, an aqueous solution of sodium bicarbonate and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off and recrystallization of the residue from a mixture of chloroform and methanol gave 0.72 g (63.2%) of 4- (2-chlorophenyl) (2,4-difluorophenyl) ure-, 8-dimethylquinolin-1 -oxide in the form of pale yellow prisms, so pl. 230-232 ° C. Elemental analysis for Calculated,%: C 63.51; H 4.00; N, 9.26. Found. %: C 63.89; H 3.91; N, 9.09. Example 64. To a mixture of 3,4,5-trimethoxybenzoic acid (563 mg), diphenylphosphoryl azide (730 mg) and dioxane (10 ml), triethylamine (0.37 ml) was added dropwise with stirring, the mixture was stirred 30 minutes at room temperature and then boiled for 40 minutes to obtain a solution of 3,4,5-trmmethoxyphenyl isocyanate. After cooling, 3-amino-4- (2-chlorophenyl) -6,8-dimethylquinoline (500 mg) was added to the resulting solution, and the reaction mixture was stirred for 24 hours at room temperature. Then the reaction mixture was concentrated, the residue was purified by silica gel column chromatography, and after recrystallization from dichloromethane, 490 mg (56.3%) of 4- (2-chlorophenyl) -6,8-dimeti (3,4.5-trimethoxyphenyl) ureido quinoline as colorless needles, mp 204-206 ° C. Elemental analysis for C27H2bC1NiCSm Calculated. %: C 65.92; H 5.33; N, 8.54. Found,%: C, 65.81; H 5.29; N, 8.47. Compounds of the following Examples 65 and 66 were synthesized in a manner analogous to the method of Example 64.

Example 65. (3.5-Di-tert-butyl-4-hydroxyphenyl) ureido-4- (2-chlorophenyl) -6, 8-dimethylquinoline, m.p. 262-264 ° C (recrystallized from acetone). The yield of 20.6%. Elemental analysis for Cg2HeC Mz02 Calcd.,%: C, 72.50; H 6.84; N, 7.93; Found: C, 72.22; H 6.83: N 7.77. Example 66. (3,5-Di-tert-butyl-4-hydroxyphenyl) ureido-6-chloro-4-phenylquinoline, mp. 277-280 ° C (recrystallized from acetone). Yield 13.2%.

Elemental analysis for C3C03CMCC 2 Calculated. %: C 71.77: H 6.42; N, 8.37 Found,%: C, 71.88; H 6.39; N, 8.36. Example 67. By the procedure of the example similar to that of Example 40, with the yield of 66.2%, (3.5-di-tert-butyl-4-hydroxybenzyl) -3- (2,4-difluorophenyl) urea (2 L orphenyl) -6 was obtained , 8-dimethylquinoline, mp 124-126 ° C (recrystallized from methanol).

Elemental analysis for Cs9H4oC1P2MzOa Calculated,%: C 71.38; H, 6.14; N, 6.4. Found. %: C 71.27; H, 6.43; N, 6.3. Example 68. By a method similar to that of Example 1, with a yield of 94.9%, 6-chloro-3-13- (2.4-difluorophenyl) urea- (2,3,4-trimethoxyphenyl) quinoline was obtained, so pl. 120-122 ° C (recrystallized from methanol).

5 Elemental analysis for C25H2oC P2 No. 04 Calculated,%: C 60.07; H 4.03; N, 8.41 Found,%: C, 59.68; H 4.05; N, 8.30. Example 69. By a method similar to that of Example 1, with a yield of 82% 0, 6-op-3- 3- (2,4-difluorophenyl) ureido} -4 2-hydroxy-3,4-dimethoxyphenyl) quino - lin, mp 218-220 ° C (recrystallization from methanol).

Elemental analysis for С24Н1еС1РМз04 5 Calculated,%: C 59.33; H 3.73; N, 8.65. Found,%: C, 59.53; H 3.67; N 8.50. The compounds of the following Examples 70 and 71 were synthesized in a manner analogous to the method of Example 46.

0 Example 70. 4- (2-Chlorophenyl) -6,8-dimethyl-3- 3- (2,6-dimethylphenyl) ureido quinoline, m.p. 237-238 ° C (recrystallized from ethanol). The yield of 56.5%.

Elemental analysis for C26H24CIN30 5 Calcd.,%: C 72.63; H 5.63; N, 9.77. Found,%: C, 72.85; H 5.64; N, 9.78. Example 71. 4- {2-Chlorophenyl} -3- {3- (2,6-diisopropylphenylureido-6,8-dimethylquinoline, mp 257-258 ° C (recrystallized from ethanol). Yield 63.3%,

Elemental analysis for C3C3N3CM3CO Calcd.%: C, 74.13; H, 6.64; N, 8.65. Found,%: C, 74.32; H, 6.64; N, 8.63. The compounds of the following Examples 5 72-75 were synthesized by a method similar to that of Example 1,

PRI me R 72. 4- (2-Chlorophenyl) -3- {3- {4-nitrophenyl) ureido-6,8-dimethylquinoline, so pl. 228 (decomp.) (Recrystallized from 0 mixture of acetone and hexane). Yield 51.5%. Elemental analysis for Ca HigClN Os Calcd.%: C 64.50; H 4.29; N, 12.54. Found,%: C64.29; H 4.18; N, 12.27. Example 73. 4- (2-Chlorophenyl) (2.4-5 difluorophenyl) ureido-6,7-dimethylquinoline, mp. 220-222 ° C (recrystallized from acetone). Yield 73.8%. . Elemental Analysis for Calculated,%; C 65.83; H 4.14; N, 9.60 Found. %: C 65.65; H 4.08; N, 9.52.

Example 74. 4- (2-Chlorophenyl) (2,4-difluorophenyl) ureidoZ-6,7,8-trimethylquinoline, m.p. 197-199 ° C (recrystallized from a mixture of ethyl ether and hexane). Yield 65.6%.

Elemental analysis for C25H2oC P2 # 0

Calculated,.%: C 66.45; H 4.46; N, 9.30

Found,%: C 66.41; H 4.41; N9.27.

Example 75. To a solution of 6-chloro-3- 3- (2,4-difluorophenyl) ureido -4- (3,4-dimethoxyphenyl quinoline (250 mg) in dichloromethane (20 ml) was added 1 ml of a mixture of boron tribromide and dichloromethane (1: 2 v / v) is added at 0 ° C, after which the mixture is stirred for 30 minutes at 0 ° C, diluted with water and extracted with ethyl acetate.The extract is washed with water and dried over anhydrous sulfate. , the solvent is distilled off and recrystallization of the residue from methanol gives 167 mg (70.8%) of 6-chloro-3- 2- (2,4-difluorophenyl) ureido-4- (3, 4-dihydroxyphenyl) quinoline (1/2 hydrate ), mp 300 ° С.

Elemental analysis for C22H14C1P2NO3 x x 1/2 H20

Calculated,%: C 58.61; And 3.35; N 9.32.

Found,%: C 58.48; H 3.18; N, 9.21.

Example 76. To a mixture of 4-acetoxy-3,5-diisopropylbenzoic acid (238 mg), diphenylphosphoryl azide (300 mg) and benzene (10 ml), triethylamine (0.15 ml) was added dropwise with stirring. after which it is stirred for 30 minutes at room temperature and then boiled for 40 minutes to obtain a solution of 4-acetoxy-3,5-diisopropylphenylisocyanate. After cooling, a solution of 3-amino-4- (2-chlorophenyl} -6,3-dimethylquinoline (255 mg) in benzene (255 mg) and then triethylamine (0.15 ml) were added to the resulting solution. 2 hours at room temperature, then boiled for 3 hours and ethyl acetate was added.The organic layer was separated, washed successively with 2 N hydrochloric acid and water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and after the residue was recrystallized from the mixture 367 mg (74.9%) of (4-acetoxy- (3,5-diisopropylphenyl) -ureido-4- (2-chloro) is obtained from acetone with diisopropyl ether. rphenyl) -6,8-dimethylquinoline in the form of colorless needles, mp 248-249 ° C.

Elemental analysis for Cs2H3C1M3O3 Calcd.% C, 70.64; H, 6.30; N, 7.72. Found,%: C, 70.73; H 6.57; N, 7.48. The compounds of the following Examples 77 and 78 were synthesized in a manner analogous to the method of Example 76.

Example 77. 3- {3- (4-Acetoxy-3,5-dimethyl-phenyl} ureido 4- (2-chlorophenyl) -b, 8-dimethylTILX.INOLIN, mp 179-181 ° C (recrystallized from a mixture of acetone and isopropyl

ether). The yield of 69.9%.

Elemental analysis for C28H2bCM3Oz Calcd.,%: C 68.92; H 5.37; N, 8.61; 5 Found,%: C 68.90; H 5.49; N, 8.48. Example 78. (4-Acetoxy-2,3,5-trimethylphenyl) ureido-4- (2-chlorophenyl) -6,8-dimethylquinoline, mp 222-224 ° C (recrystallized from a mixture of acetone and isopropyl 0 ether). Yield 61.1%.

Elemental analysis for C2eH28C MsO3 Calculated,%: C 69.38; H 5.62; N, 8.37 Found,%: C, 69.24; H 5.62; N, 8.34. PRI me R 79. A mixture of 3- {3- (4-acetoxy-3,5-5-diisopropylphenyl) -ureido-4- (2-chlorophenyl) -6,8-dimethylquinoline (300 mg), methanol (20 ml) and 1N sodium hydroxide (2 ml) were stirred for 1.5 hours at room temperature. After the concentrated mixture was diluted with 0 water, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and after recrystallization of the residue from a mixture of acetone with 5-isopropyl ether, 116 mg (41.9%); 4- (2-chlorophenyl) (4-hydroxy-3, 5-diisopropylphenyl) ureido - 6,8-dimethylquinoline in the form of colorless prisms, so pl. 194-19 ° C.

0 Elemental analysis for C3CH2C Mz02 Calculated,%: C 71.39; H 6.42; N, 8.37 Found,%: C, 71.39; H, 6.22; N, 8.28. By a method similar to that of Example 79, the compounds of the following 5 synthesized examples of 80 and 81 were synthesized.

PRI me R 80. 4- (2-Chlorophenyl) (4-hydroxy-3,5-dimethylphenyl) ureido.-6.8-dimethylquinoline, so pl. 229-231 ° C (recrystallized from a mixture of acetone with isopropyl ether), Yield 54.8%.

Elemental analysis for C26H24CIN302 Calculated,%: C 70.03; H 5.42; N, 9.42. Found,%; C 69.96; H 5.60; N 9.29; Example 81. 4- (2-Chlorophenyl) (4-5 hydroxy-2,3,5-trimethylphenyl) -ureidoZ-6,8-dimethylquinoline; 244-245 ° C (recrystallized from mixtures of acetone and isopropyl ether). Yield 43%.

Elemental analysis for C2 H2bC1Mz02 0 Calculated,%; C 70.50; H 5.70; N, 9.14. Found,%; C, 70.51; H 5.66; N 9.14. Example 82. By the method, similar. the same procedure as in Example 75, with a yield of 83%, 6-chloro-3- 3- (2,5-difluorophenyl) urea-5 (2,3,4-trihydroxyphenyl) quinoline (1/2 hydrate) was obtained; 300 ° C (recrystallized from a mixture of acetone with isopropyl ether).

Elemental analysis for С22Н1-дС Р2№0 1 х х1 / 2 Н2О

Calculated,%: C 56.6; H 3.24; N 9.00

Found,%: C 56.9; H 3.02; N 8.71, Example 83. By a method similar to that of Example 1, 4- (2-chlorophenyl) (2,4-difluorophenyl) ureido-5-methylquinoline was obtained in 64.3% yield; mp. 218-220 ° C (recrystallized from ethanol). Elemental analysis for Cr3H1bC1P2BiO Calcd.,%: C, 65.18; H 3.80; N, 9.91 Found,%: C, 65.39; H 3.72; N, 9.85,. Reference Example 1. (1) 20% hydrochloric acid (40 ml) and methazonic acid (5) were added to a solution of 2-amino-5-trifthomethylbenzophenone (5.3 g) in acetone (100 ml). g, wet).

The mixture was left overnight at room temperature and then diluted with water. Precipitated yellow crystals are filtered off to give 6.4 g (95.2%) of 2- (2-nitro-vinylamino) -5-trifluoromethylbenzophenone. Some crystals were recrystallized from acetone to form yellow needles, mp. 196-198 ° C.

Elemental Analysis for C1bNcRzNO3 Calculated. %: C 57.15; H 3.30; N, 8.33 Found. %: C 57.16; H 3.27; N, 8.21.

(2) To a mixture of 2- (2-nitrovinylamino) -6-trifluoromethylbenzophenone (6 g) and methanol (60 ml), 2N sodium hydroxide solution (9 ml) was added dropwise with stirring, stirred for 30 minutes at room temperature , diluted with water, and 4.88 g (84.5%) of 3-nitro-4-phenyl-6-trifluoro-methylquinquinoline are obtained in the form of crystals, the recrystallization of which from a mixture of chloroform and methanol gives pale yellow needles (4.5 g , 79.2%), mp 192-193 ° C.

Elemental analysis for CieHgF3N202 Calculated,%: C, 60.38; H 2.85; N, 8.80. Found,%: C, 60.16; H 2.82; N, 8.68.

(3) A mixture of 3-nitro-4-phenyl-6-trifluoromethylquinoline (2 g), tin (II) chloride dihydrate (5 g) and conc. hydrochloric acid (20 ml) was stirred for 1 h at 100 ° C. The mixture is neutralized 6 N. sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and by recrystallization of the residue from a mixture of isopropyl ether and hexane, 1.46 g (80%) of 3-amino-4-phenyl-6-trifluoromethylquinoline, t. pl. 107-108 ° C.

Elemental analysis for C- | bNcRz№

Calculated,%; C 66.66; H 3.85; N 9.72

Found. %: C 66.67; H 3.79; N, 9.49.

In a similar manner, the compounds of the following Reference Examples 2-17 were synthesized.

Reference Example 2

(1) 5-Ethyl-2- (2-nitrovinylamino) benzophenone (not isolated),

(2) b-Ethyl-3-nitro-4-phenylquinoline, m.p. 139-140 ° C.

(3) 3-amino-6-etml-4-phenylquinoline. so pl. 206-209 ° C.

Reference PRI me R 3.

(1) 5-Isopropyl-2- (2-nitrovinylamino) benzophenone, m.p. 166-167 ° C

(2) 6-Isopropyl-3-nitro-4-phenylquinoline, m.p. 115-116 ° C.

(3) 3-Amino-b-isopro-4-phenylquinolinol. Mp. 128-129 ° C.

Reference Example 4

(1) 4-Methyl-2- (2-nitrovinylamino) benzophenone. so pl. 163-164 ° C

(2) 7-Methyl-3-nitro-4-phenylquinoline, m.p. 176-177 ° C

(3) 3-amino-7-methyl-4-phenylquinoline, m.p. 167-168 ° C

Reference Example 5

(1) 2-Chloro-2- (2-nitrovinylamino) benzopheno, mp. 140-144 ° C

(2) 4- (2-Chlorophenyl) -3-nitroquinoline, m.p. 124-125 ° C

(3) 3-amino-4- (2-chlorophenyl) quinoline, m.p. 155-156 ° C

Reference Example 6

(1) 5-Chloro-2-fluoro-2- (nitrovinylamino) benzopheno, mp 219-221 ° C

(2) 6-Chloro-4- (2-fluorophenyl) -3-nitroquinoline.pl. 150-151 ° C

(3) 3-amino-6-chloro-4- (2-fluorophenyl) quinoline. Mp. 150-151 ° C

Ref. Example 7

(1) 5,3-Dichloro-2- (nitrovinylamino) benzophenone, m.p. 195-197 ° C

(2) 6-Chloro-4- {3-chlorophenyl) -3-nitroquinoline, m.p. 135-136 ° C

(3) 3-amino-6-chloro-4- (3-chlorophenyl) quinoline, m.p. 154-155 ° C

Reference Example 8

(1) 5,4-Dichloro-2- (2-nitrovinylamino) benzophenone, m.p. 213-220 ° C

(2) 6-Chloro-4-4-chlorophenyl) -3-nitroquinoline. Mp. 148-149 ° C

(3) 3-amino-6-chloro-4- (4-chlorophenyl) quinoline. Mp. 190-191 ° C

Reference Example 9

(1) 5-Chloro-4-methyl-2- (nitrovinylamino) benzophenone, m.p. 227-228 ° C

(2) 6-Chloro-4- (4-methylphenyl} -3-nitroquinoline. Mp 127-128 ° C

(3) 3-amino-6-chloro-4- (4-methylphenyl) quinoline, m.p. 144-145 ° C

Reference Example 10

(1) 5-Chloro-2-methyl-2- (2-nitrovinylamino) benzophenone, m.p. 184-186 ° C

(2) 6-Chloro-4- (2-methylphenyl) -3-nitroquinolin. Mp. 176-177 ° C

(3) 3-amino-6-chloro-4- (2-chlorophenyl) x-NOL.IN, mp. 132-133 ° C

Reference Example 11

(1) 5-Chloro-2-methoxy-2- (2-nitrovinylamino) benzophenone, m.p. 217-218 ° C

(2) 6-Chloro-4- (2-methoxyphenyl) -3-nitroquinone, m.p. 213-214 ° C

(3) 3-amino-6-chloro-4- (2-methoxyphenyl) quinoline, mp 137-138 ° C

Reference Example 12

(1) 2-Chloro-5-methyl-2- (2-nitrovinylamino) benzophenone, m.p. 137-136 ° C

(2) 4- (2-Chlorophenyl) -6-methyl-3-nitroquinoline, m.p. 168-169 ° C

(3) 3-amino-4- (2-chlorophenyl) -6-methylquinoline, m.p. 121-123 ° C

Reference Example 13

(1) 5.2-Dimethyl-2- (2 nitrovinylamino) benzophenone, m.p. 148-149 ° C

(2) b-Methyl-4- (2-methylphenyl) -3-nitroquinoline, m.p. 112-113 ° C

(3) 3-amino-6-methyl-4- (2-methylphenyl) quinoline, oil.

Reference Example 14

(1) 2-Chloro-5-ethyl-2- (2-nitrovinylamino) benzophenone, m.p. 180-181 ° C.

(2) 4- (2-Chlorophenyl) -6-ethyl-6-nitroquinoline, m.p. 151-152 ° C

(3) 3-amino-4- (2-chlorophenyl) -6-ethylquinodyne, m.p. 91-92 ° C

Reference Example 15

(1) 2-Chloro-5-isoprolyl-2- (2-nitro-vinylamino) benzophenone, m.p. 166-167 ° C

(2) 4- (2-Chlorophenyl) -6-isopropyl-3-nitroquinoline, m.p. 166-117 ° C

(3) 3-amino-4- (2-chlorophenyl) -6-isopropylquinoline, mp 101-102 ° C

Reference Example 16

(1) 5-Butyl-2-chloro-2- (2-nitrovinylamino) benzophenone, m.p. 143-144 ° C

(2) 6-Butyl-4- (2-chlorophenyl) -3-nitroquinoline, m.p. 9b-97 ° C

(3) 3-amino-6-butyl-4- (2-chlorophenyl) quinoline, oil.

Reference Example 17

(1) 2-Chloro-5-fluoro-2- (2-nitrovinylamino) benzophenone. so pl. 118-119 ° C

(2) 4- (2-Chlorophenyl) -b-fluoro-3-nitroquinoline, m.p. 195-186 ° C.

(3) 3-amino-4- (2-chlorophenyl) -6-fluoroquinolin. Mp. 131-133 ° C.

Reference Example 18 (1) A mixture of 2-amino-2-chloro-3,5-Dimethyl-benzophenone (1 g), acetone (50 ml), 20% hydrochloric acid (20 ml) and methazone acid. lots (4.5 g wet) were stirred for 2 hours at room temperature and boiled for 4 hours. The mixture was then diluted with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Purification by silica gel column chromatography

get 4- (2-chlorophenyl) -6,8-dimethyl-3-nitroquinoline in the form of crystals, which are recrystallized from a mixture of methanol with chloroform, so pl. 130-131 ° C. Yield 1.95 g (54.2%).

(2) By a methodology similar to that of

Reference Example 1- (3) -4- (2-chlorophenyl) 6, 8-dimethyl-3-nitroquinoline with yield

- 80.1%, reduced to 3-amino-4- (20 chlorophenyl) -6,8-dimethylquinoline, so pl. 152154 ° C.

Reference Example 19. The following compounds were synthesized in a manner analogous to method 5 of Reference Example 18.

(1) 6-Chloro-4- (2-chlorophenyl) -8-methyl-3- nitroquinoline, m.p. 138-139 ° C.

(2) 3-amino-6-chloro-4- (2-chlorophenyl) -8-methylquinoline, mp 138-139 ° C. 0 Reference example 20.

The following compounds were synthesized in a manner analogous to the method of Reference Example 18,

(1) b, 8-Dimethyl-4- (2-methylphenyl) 3-nit-5 roquinolmne, m.p. 10T-102 ° C.

(2) 3-amino-6,8-dimethyl-4- (2-methylphenyl) quinoline, m.p. 204-206 ° C.

Reference Example 21. (1) A mixture of b-methoxy-2-nitro-4-phenyl-0-noline (3.5 g) and 47th hydrobromic acid (50 ml) was boiled for 7 hours. After cooling, the remaining crystals were filtered off and Recrystallization from acetone gives 3.01 g (90.7%) of 6-hydroxy-3-nitro-5 4-phenylquinoline as yellow needles, mp. 282-284 ° C.

Elemental analysis for CcNiuMaOz Calculated,%: C, 67.67; H 3.79; N, 10.52 Found,%: C, 67.68; H 3.79; N, 10.42. 0 (2) To a solution of 6-hydroxy-3-nitro-4-phenylquinoline (2.5 g) in NN-dimethylformamide (30 ml) was added M, M-dimethylthiocarbamoyl chloride (1.28 g) and 1,4-diazobicyclo (2.2.2) octane (1.05 g).

5 The resulting mixture was stirred for a day at room temperature and then transferred to a mixture of water and ice. The precipitate formed is filtered off and, after recrystallization from acetone, 1.7 g of 0- (51.2%) 6- (M, M-dimethylthiocarbamoyloxy) 3-nitro-4-phenylquinoline are obtained in the form of yellow prisms, mp 205-208 ° C.

Elemental analysis for CieHisNsOaS Calcd.%: C 61.18; H 4.28; N, 11.89; 5 Found,%: C, 61.40; H 4.28; N 11.74 (3) 6- (M, M-Dimethylthiocarbamoyloxy) - 3-nitro-4-phenylquinoline (1.5 g) is heated for 3 hours at 215-220 ° C, cooled and 1.3 g are obtained after recrystallization from acetone ( 86.7%) 6- (M, M-dimethylcarbamoylthio) -3 nitro-4-phenylquinoline as yellow needles,

so pl. 171-173 ° C.

Elemental analysis for CieHisNsOa Calcd.%: C 61.18; H 4.28; N, 11.89 Found,%: C, 61.40; H 4.28; N, 11.74.

(4) To a solution of 6 - (, 1H-dimethylcarbamoylthio) -3-nitro-4-phenylquinoline (2.5 g) in dioxane (100 ml) was added 2N. NaOH (50 ml) and methanol (20 ml) and the mixture was stirred for 7 hours at room temperature. After dilution with water, the mixture was acidified with hydrochloric acid, the precipitated crystals were filtered off and, after recrystallization from acetone, 1.86 g (84%) of 6-mercapto-3-nitro-4-phenylquinoline was obtained. so pl. 160-163 ° C.

Elemental analysis for CisHioN202S

Calculated,%: C 63, 82; H 3.57; N, 9.92.

Found,%: C 63.80; H 3.49; N, 9.68.

(5) A solution of potassium carbonate (1.14 g) in water (10 ml) was added to a solution of 6-mercapto-3-nitro-4-phenylquinoline (1.55 g) in dioxane (30 ml) and methyl iodide (1.17 g) and everything was stirred for 2.5 hours at room temperature. After dilution with water, the mixture was acidified with hydrochloric acid, the precipitated crystals were filtered off and, after recrystallization from acetone, 1.39 g (85.3%) of b-methylthio-3-nitr. O-4-phenylquinoline were obtained as yellow needles . so pl. 131-133 ° C.

Elemental analysis for CieHiaNaC S Calculated,%: C 64.85; H 4.08; N, 9.45. Found,%: C, 64.77; H 4.07; N, 9.42

(6) Using a procedure similar to that of Reference Example 1- (3), 6-methylthio-3-nitro-4-phenylquinoline is reduced and 3-amino-6-methylthio-4-phenylquinoline is obtained in the form of colorless rods, -t. pl. 135-137 ° C. Yield 0.77 g (71.3%).

Elemental analysis for CieHi NaS Calculated,%: C, 72.15; H 5.30; N, 10.52. Found. %: C 72.00; H 5.31; N 10.52

Reference Example 22. (1) To a solution of 3-acetamido-6-chloro-4-phenylquinoline (1 g) in NN-dimethylformamide (10 ml) was added 60% sodium hydride in oil (0.15 g) , stirred for 30 minutes at room temperature, methyodide (0.25 ml) was added dropwise with stirring, and stirring was continued for 1 hour at room temperature. After diluting the mixture with water, the precipitated crystals were filtered off and recrystallized from a mixture of methanol with chloroform to obtain 0, 96 g (91.4%) of 6-chloro-3- (M-methylacetamido) 4-phenylquinoline as colorless crystals, mp. 268-270 ° C.

Elemental analysis for Ci8HisCIN20 Calculated,%: C, 69.57; H 4.86; N, 9.01. Found,%: C, 69.52; H 4.85; N 8.89

(2) A mixture of b-chloro-3- (M-methyl-acetamido) -4-phenylquinoline (0.9 g), methanol (5 ml) and conc. hydrochloric acid (5 ml) was boiled for 5 hours, after which it was diluted with water and neutralized with an aqueous solution of sodium hydroxide. The precipitate formed is filtered off and, after recrystallization from methanol, 0.65 g (83.5%) of 6-chloro-3-methylzminino-4-phenylquinoline is obtained in the form of pale yellow crystals, m.p. 139-140 ° C.

Elemental analysis for CieHi3C N2 Calcd.,%: 071.51; H 4.88; N, 10.42. Found,%: C, 71.71; H 4.87; N 10.45 The compounds of the following Reference Examples 23-26 were synthesized in a manner analogous to the method of Reference Example 22.

Reference Example 23

(1) 6-Chloro-3- (M-ethylacetamide) -4-phenylquinoline, m.p. 227-228 ° C.

(2) 6-Chloro-3-ethylamino-4-phenylquinoline.pl. 106-107 ° C

Reference Example 24

(1) 3- (M-Butylacetamido) -6-chloro-4-phenylquinoline, m.p. 108-110 ° C

(2) 3-Butylamino-6-chloro-4-phenylquinolinol. Mp. 71-73 ° C.

Reference Example 25

(1) 6-Chloro-3- (M-heptylacetamido) -4-phenylquinoline, oil.

(2) 6-Chloro-3-heptylamino-4-phenylquinoline, m.p. 62-63 ° C.

Reference Example 26

(1) 3- (M-Benzylacetamido) -6-chloro-4-phenylquinoline, m.p. so pl. 57-61 ° C

. (2) 3-Benzylamino-6-chloro-4-phenylquinoline.pl. 140-141 ° C.

Reference Example 27

The following compounds were synthesized by the method of Reference Example 1.

(1) 5-Chloro-2- (2-nitrovinylamino) -2-methylthiobenzophenone, m.p. 188-190 ° C

(2) 6-Chloro-4- (2-methylthiophenyl) -3-nitroquinoline, m.p. 180-182 ° C

(3) 3-amino-6-chloro-4- (2-methylthiophenyl) quinoline, m.p. 153 155 ° C.

Reference Example 28

(1) In a mixture of 2 N. sodium hydroxide (20 ml) and dioxane (20 ml), 6-mercapto-3-nitro-4-phenylquinoline (1 g) was dissolved and 2 hours were added to the resulting solution at 75-80 ° C. gaseous chlorodifluoromethane. The reaction mixture was then diluted with water and extracted with chloroform. The extract was washed with an aqueous solution of sodium hydroxide and water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and after recrystallization of the residue from isopropyl ether, 948 mg were obtained.

(80.5%) 5-difluoromethylthio-3-nitro-4-phenylquinoline in the form of yellow prisms, so pl. 101-03 ° C.

Elemental analysis for CieHioFaNaOa Calcd.%: C 57.83; H 3.03; N, 8.43 Found,%: C 57.92; H 3.13; N, 8.37 (2) By a method analogous to the method of Reference Example 1- (3), 6-difluoromethylthio-3-, chitro-4-phenylquinoline is reduced to 3-amino-6-difluoromethylthio-4-phenylquinoline (oil), which is used as a starting material without purification.

Reference Example 29

(1) In a mixture of 2 N sodium hydroxide (20 ml) and dioxane (20 ml), 6-hydroxy-3-nitro-4-phenylquinoline (1 g) was dissolved and 3 hours passed at 75-80 ° C gaseous chlorodifluoromethane. Processing by the procedure of Reference Example 28- (1) yields 794 mg (66.8%) of 6-diflumethoxy-3-nito-4-phenylquinoline as pale brown prisms, mp 112-114 ° C.

Elemental analysis for scHoRg oz

Calculated,%: C 60.76; H 3.19; N, 8.86.

Found,%: C 61.04; H 3.24; N, 8.80.

(2) By the procedure of Reference Example 1- (3), the obtained 6-difluoromethoxy-3-nitro-4-phenylquinoline is reduced to

3-amino-6-difluoromethoxy-4-phenylquinoline (oil), which, without purification, is used as the starting material,

Reference Example 30

The following compounds were prepared according to a procedure similar to that of Reference Example 18.

(1) 8-Chloro-4- (2-chlorophenyl) -6-methyl-3- nitroquinoline, m.p. 152-154 ° C.

(2) 3-amino-8-chloro-4- (2-chlorophenyl) -6-methylquinoline, m.p. 148-149 ° C.

Reference Example 31

The following compounds were synthesized by the method described in Reference Example 22.

(1) 3- (L-Butylacetamido) -6-chloro-4- (2-chlorophenyl) quinolmne, m.p. 108-109 ° C.

(2) 3-Butylamino-b-chloro-4- (2-chlorophenyl) quinoline, m.p. 90-91 ° C.

Reference PRI me R 32.

(1) A mixture of (2-benzoyl-4-chlorophenyl) aminomethylene malonic acid diethyl ether (7 g), lithium chloride (3.7 g) and dimethyl sulfoxide is heated for 1.5 hours at 180 ° C. After dilution with water, 6-chloro-4-phenyl-3-quinoline-carboxylic acid ethyl ester is obtained in the form of crystals (3.8 g, 70%), recrystallized from ethanol as needles. so pl. 123-124 ° C.

Elemental analysis for CieHi4CIN02 Calculated,%: C 69.35; H 4.53; N, 4.49.

Found,%: C 69.32; H, 4.48; N, 4.31. (2) A mixture of 6-chloro-4-phenyl-3-quinolinecarboxylic acid ethyl ester (2.5 g). potassium hydroxide (2.24 g) and ethanol (25 ml) 5 are heated for 10 min at 80 ° C. The mixture was then diluted with water, and after acidification with dilute hydrochloric acid, 2.2 g (96.9%) of 6-chloro-4-phenyl-3-quinolinecarboxylic acid were obtained as crystals recrystallized from the mixture methanol with chloroform in the form of yellow prisms, so pl. 269-270 ° C.

Elemental analysis for CieHio N02 Calculated,%: C 67.74; H 3.55; N, 4.94. 5 Found,%: C 67.77; H 3.52; N, 4.94. Reference Example 33

(1) A mixture of 2-amino-2-chloro-3,5-dimethylbenzopheion (2.59 g) of 3.3-dimethoxypropionic acid methyl ester (3.7 g),

0 p-toluenesulfonic acid hydrate (0.19 g) and

benzene (30 ml) is boiled for 16 hours with removal

water in the nozzle Dean-Stark, Solvent

distilled off and purification of the residue column

chromatography. Silica gel is obtained

5 1.9 g (58.5%) of 4- (2-chlorophenyl) -6.8-dimethyl-3-quinolinecarboxylic methyl ester

acids, recrystallized from isopropyl ether as colorless

prisms, so pl. 117-118 ° C.

0 Elemental analysis for CigHi6CIN02

Calculated,%: C 70.50; H 4.95; N, 4.30.

Found,%: C70.14; H 4.97; N, 4.27.

(2) A mixture of 4- (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarboxylic 5 methyl ester (0.98 g), potassium hydroxide (0.5 g) and. 80% ethanol (10 ml) was boiled for 15 minutes. diluted with water and after acidification with dilute hydrochloric acid, 0.9 g (96.8%) of crystalline 4- (2-chlorophenyl) - 0 6.8-dimethyl-3-quinolinecarboxylic acid recrystallized from ethanol b. colorless prisms, mp 234-235 ° C.

Elemental analysis for CisHi4CIN02 Calcd.%: C 69.35; H 4.53; N, 4.49. 5 Found,%: C 69.10; H 4.53; N, 4.41. Reference Example 34. To a mixture of 2-amino-2-chloro-3,5-dimethyl-benzophenone (15.54 g) 6 N hydrochloric acid (60 ml) and ethyl acetate (180 ml) was added 0 1-morpholino- 2-nitroethene (9.48 g) and everything is stirred at 60-70 ° C. After 2 and 4 hours, 1-morpholine-2-nitroethene (9.48 g) was added to the mixture, after which the mixture was stirred for another 4 hours, diluted with water and extracted with ethyl 5 cetate. The extract is sequentially washed. water, sodium bicarbonate solution and water, dried over anhydrous sulfate, the solvent is distilled off and recrystallization from ethanol gives 15.75 g (84.1%) of 4- (2-chlorophenyl) -6,8-dimethyl-3-nitroquinol

ina in the form of yellow crystals, so pl. 132-131 ° C. The resulting substance is identical to the compound of reference example 18- (1). Reference Example 35

(1) By a method similar to that of Reference Example 34, b-chloro-4- (3,4-dimethoxyphenyl) -3-nitroquinoline is obtained, m.p. 188-190 ° C. Yield 83.5%.

(2) By the procedure described in Reference Example 1- (2), by reduction of 6-chloro-4- (3,4-dimethoxyphenyl) -3-nitroquinoline, 3-amino-6-chloro-4 was obtained in 92.9% yield. - (3,4-dimethoxyphenyl) quinoline, m.p. 187-190 ° C.

Compounds of the following Reference Examples 36 and 37 were synthesized in a manner analogous to the method of Reference Example 35.

Reference PRI me R 36.

(1) 4- (2-Chlorophenyl) -6,7-dimethyl-3-nitroquinoline, m.p. 156-158 ° C. Yield 50.9%,

(2) 3-amino-4- (2-chlorophenyl) -6,7-dimethylquinoline, m.p. 194-195 ° C. The yield of 68.9%. Reference Example 37.

(1) 4- (2-Chlorophenyl) -6,7,8-trimethyl-3-nitroquinoline, m.p. 190-191 ° C. Yield 53.3%.

(2) 3-Amino-α-chlorophenyl-E-bL. 3-Trimethylquinoline, m.p. 116-118 ° C. Yield 79.8%.

Reference to Example 38.

A mixture of 2,6-di-tert-butyl-4-methylphenol (2.34 g) N-bromosuccinimide (1.88 g) and carbon tetrachloride (25 ml) is boiled for 2 hours, after which the insoluble matter is filtered to give a solution of 4-bromomethyl-2, b-di-tert-but. and l of phenol. 3-amino-4- (2-chlorophenyl) -6,8-dimethylquinoline (2t) was added to the resulting solution, and the mixture was stirred for 5 hours at room temperature. The mixture was diluted with chloroform, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallized from a mixture of acetone and isopropyl ether to obtain 1.59 g (44.9%) of 4- (2-chlorophenyl) -3- (2,6-di-tert-butyl-4 -hydro-hydroxyphenyl) amino-6,8-dimethylquinoline in the form of colorless prisms, so pl. 183-185 ° C.

Elemental analysis for Sz2vz7s M02

Calculated,%: C 76.7; H 7.44; N, 5.59.

Found,%: C 76.7; H 7.53; N, 5.52.

Reference Example 39

(1) A mixture of 2-amino-2-chloro-3,5-dimethyl-benzophenone (20 g), 2,2-dimethoxypropionitrile (11.5 g), M-toluenesulfonic acid hydrate (1.46 g) and toluene (200 ml) was boiled with 3 hours removal of water into a Dean-Stark nozzle. The mixture was then washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and the solvent was distilled off. The precipitate formed is filtered off and after washing with hexane, 20.7 g (92%) of 4- (2-chlorophenyl} -6.8-dimethyl-3-quinolinecarbonitrile recrystallized from ethanol as pale yellow plates, mp 153-154 °, are obtained. WITH.

Elemental analysis for CiaHi3CIN2

Calculated,%: C 73.85; H 4.48; N, 9.57.

Found,%: C 73.66; H 4.42; N, 9.54.

(2) A mixture of 4- (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarbonitrile (0.5 g), 6 N sodium hydroxide (1.5 ml) and 2-methoxyethanol (3 ml) bales stirring for 8 hours, then diluted with water and acidified with hydrochloric acid. Filtration of the precipitate formed gives 4- (2-chlorophenyl) -6,8-dimethyl-2-quinolinecarboxylic acid (0.46 g of 86.8%), recrystallized from ethanol as colorless prisms, so pl. 234-235 ° C., The resulting compound is identical to the compound of reference freezes 33.

Reference Example 40

(1) A mixture of 4- (2-chlorophenyl) t6,8-dimethyl-3-quinolinecarbonitrile (17.6 g) obtained in Reference Example 39- (1) and 97% sulfuric acid (120 ml) was stirred 24 h at room temperature, after which it was transferred to ice water, made basic with aqueous ammonia and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. By adding methanol to the residue, 18.5 g (90.2%) of 4- {2-chlorophenyl) -6,8-dimethyl-3-chi.olinocarboxamide (solvate with methanol) recrystallized from methanol in the form of colorless prisms so pl. 163-164 ° C.

Elemental analysis for CisHisCI O CH Calcd.%: C, 66.57; H 5.59; N, 8.17 Found,%: C, 66.75; H 5.52; N, 8.19.

(2) To a solution of sodium hydroxide (10.4 g) as (100 ml), bromine (3.2 ml) was added dropwise under stirring and cooling with ice, then solution 4 was added dropwise to the mixture - (2-chlorophenyl) -6,8-dimethyl-3-quinolinecarboxamide as a solvate with methanol (13.5 g) in dioxane (100 ml) and the mixture was stirred for 30 minutes at room temperature and 40 minutes at 90 ° WITH. By adding 6 N hydrochloric acid, the mixture was adjusted to pH 1, stirred for 30 minutes at room temperature and then a small amount of the red precipitate formed was removed by filtration. The filtrate was made basic with a 6N sodium hydroxide solution, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and after recrystallization of the residue from hexane, 3-amino-4- (2-chlorophenyl) -6,8-dimethylquinoline (14 g, 91.7%), t. pl. 151-152 ° C. The resulting product is identical to the compound of reference example 18.

Reference Example 41

(1) A mixture of 5-chloro-2-trzylaminobenzoic acid (14 g), thionyl chloride (30 ml) and M, 1M-dimethylformamide (0.5 ml) is boiled for 40 minutes and concentrated under reduced pressure to dryness. The residue was dissolved in 1,2-dichloroethane (100 ml) and anhydrous aluminum chloride (6.88 g) was added to the resulting solution. After stirring for 10 minutes at room temperature, 1,2,3-trimethoxybenzene (8.67 g) was added to the mixture, and the mixture was stirred for 10 minutes at room temperature and then boiled for 45 minutes; After cooling, 2 N hydrochloric acid was added to the mixture and stirred for 30 minutes at room temperature. Organic; Separated and extracted with dilute sodium hydroxide solution. The alkaline solution was acidified with hydrochloric acid and extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from acetone to give 2-tosylamino-5-chloro-2-hydroxy-3, 41-dimethoxybenzophenone prisms (5.89 g, 29.6%), mp 185-18.7 ° C. Elemental analysis for C22H2oCINp6 Calcd.%: C 57.21; And 4.36; N s; 03 Found,%: C 57.16; H 4.24; N 3.17.

(2) A mixture of 2-tosylamino-5-chloro-2-hydroxy-3, 4-dimethoxybenzophenone (5.89 g) and 70% sulfuric acid (50 ml) is heated for 1 h at 90 ° C, after which diluted with water; l extracted with magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography and, after recrystallization from a mixture of ether and hexane, 3.01 g (76.8%) of 2-amino-5-chloro-2-hookrokey-3, 4-dimethoxybenzophenone b colorless prisms, mp 112 - 115 ° C.

Elemental analysis for Ci5Hi4CIN04 Calcd.%: C 58.55; H 4.59; N, 4.55 Found,%: C58.65; H 4.61; N 4.51

Reference Example 42

The 2-amino-5-chloro-2-hydroxy-3,4-dimethoxybenzophenone of Reference Example 41 was introduced and the reactions were carried out according to the procedure of Reference Example 41 to give the following compounds.

(1) 6-Chloro-4- (2-hydroxy-3,1-dimethoxyphenyl) -3-nitroquinoline, m.p. 15b-158 ° C. Yield 91.8%.

(2) 3-amino-6-chloro-4- (2-hydroxy-3,4-dimethoxyphenyl) quinoline, m.p. 198-201 ° C. Yield 60.5%.

Reference Example 43. (1) A mixture of 6-chloro-4- (2-hydroxy-3,4-dimethoxyphenyl) 3-nitroquinoline (1.2 g) NN-dimethylformamide (20 ml), potassium carbonate powder (0.92 g) and methyl iodide (0.41 ml) were stirred for 10 minutes at 0 ° C for 2 hours at room temperature, then diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Recrystallization of the residue from methanol gave 1.12 g (89.6%) of 6-chloro-4- (2,3,4-trimethoxyphenyl) -3-nitroquinoline as yellow crystals, m.p. 114-116 ° C.

(2) The above 6-chloro-4- (2.3.4-trimethoxyphenyl) -3-nitroquinoline, according to the procedure of Reference Example 1- (2), is reduced to 95.9% in 3-amino-6-chloro-4- (2,3,4-trimethoxyphenyl) quinoline, m.p. 180 - 181 ° C .::. -.- :.

Reference Example 44. Following a procedure analogous to that of Reference Example 35, the following compounds were synthesized.

(1) 4- (2-Chlorophenyl 5-methyl-3-nitroquinoline, mp 147-148 ° C. Yield 69.8%. (2) 3-amino-4- (2.-chlorophenyl) -5-methylquinoline, mp 152-1530 ° C. 97.8% yield. Formula and method. Preparation of a quinoline derivative of the general formula I

R6

, Re R9 n r) r

if

ABOUT

m

where Ri is hydrogen or C1-C4 alkyl;

R2 is hydrogen, halogen, C1-C4-alkyl, halogen-C1-C4-alkyl, C | -C4-alkoxy, C1-C4-alkylthio, halogen-C1-C4-el-0 kilthio, nitro or halogen-Ci- C4 alkoxy;

P3-hydrogen, C1-C4-alkyl or C1-C4-alkoxy;

R4 is hydrogen, C1-C4-alkyl or C1-C4-al-5-hydroxy;

RS is hydrogen, halogen, C1-C4 alkyl, Ci-C4 alkoxy, C1-C4 alkylthio or hydroxy;

Re is hydrogen, halogen, a C1-C4 alkoxy group or hydroxyl;

 hydrogen, halogen, Ci-C3 alkyl, Ci-C4 alkoxy or hydroxyl;

Re is hydrogen, halogen, C1-C4 alkyl;

Rg is hydrogen, halogen, a C1-C4 alkoxy group or C1-C4 alkyl;

Rio is hydrogen, halogen. A C | -C4 acyloxy, C1-C4 alkoxy group, C1-C4 alkyl, hydroxyl or nitro group;

RH is hydrogen, halogen, C1-C4-alkyl, halom-Cg-C3-alkyl, nitro or C1-C4-alkoxy;

Ri2 is hydrogen, halogen C1-C4 alkoxy group or C1-C4 alkyl;

Ri3 is hydrogen, d-St alkyl or aralkyl. which may be substituted with C1-C4 alkyl and hydroxyl;

m is 0 or 1;

n 0 or 1 and in the case when m 0, then (1) at least one of Rs, Re and R is different from hydrogen or (I) all of Rs, Re and R is hydrogen and at least one of R8- R12 is fluorine or its salts, characterized in that. what

a compound of the formula

where have the indicated meanings,

or its salt, with a compound of the general formula

9.8 R1 (TQ- (CH2lh-Q2

11 "12 where Rg-Ri2 have the indicated meanings,

Ria where Q2 is NCO if SI is NH or

R13

Q2 is NH2 if Qi is -NCO or NCOX wherein RIS is other than hydrogen;

X - halogen

n takes the indicated values, or with its salt, and, if necessary, oxidize the resulting compound to the corresponding compound, where m 1.

Priority by signs:

07/12/08 at RI is hydrogen or C1-4 alkyl; R2 is hydrogen, halogen, St-C4-alkyl, halo-C1-C4-alkyl. A C1-C4 alkoxy group, an alkylthio group, a halogen C1-C4 alkylthio group, a nitro group or a halogen C1 C4 alkoxy group; Ra is hydrogen, C1-C4 alkyl or

C1-C4 alkoxy group; R is hydrogen, Ci-C4 alkyl or a C1-C4 alkoxy group; RS is hydrogen, halogen, C1 C4-alkyl, C1-C4-alkoxy group, C1 C4-alkylthio group or hydroxyl; Re-hydrogen, halogen, Ci-C alkoxy or hydroxyl; R is hydrogen, halogen, C1-C4 alkyl. C1 C4 alkoxy group or hydroxyl; Re is hydrogen, halogen, C1-C4-alkyl, Rg-hydrogen, halogen, C1-C4-alkoxy or Ci-Gi-alkyl; Nu-hydrogen, halogen, CiC4 alkoxy group, C1-C4 alkyl, hydroxyl or nitro group, C1-C4 acyloxy; RII is hydrogen, halogen. C1 C4 alkyl, halogen-Cg-C4 alkyl, nitro group or C1-C4 alkoxy group; Ri2 is hydrogen, halogen, a C1-C4 alkoxy group or C1-C4 alkyl; Ria is hydrogen, St-Cb alkyl or benzyl, which may be substituted with C1-C4 alkyl or hydroxyl; m 0, n 0 or 1. 03/27/89

Ri-Ria radicals are as defined above; m 1.

Table 1

Continuation of the table. 1

g Compound B - 6-chloro-3- / 3- {4-chlorophenyl} ureido / -4-phenylquinoline (US Patent No. 3,862,152, obtained according to claim 14).

table 2

The values shown are mean ± standard deviation. p 0.05 (t-test versus control group)

Continuation of the table. 1