CS252849B2 - Method of 4-amino-2-phenylquinolines production - Google Patents

Description

The present invention relates to a process for the preparation of the novel 4-amino-2-phenylquinolines of the formula I

in which 1 2

R and R are each hydrogen or alkyl having 1 to 8 carbon atoms, _Y and R are each hydrogen, halogen or alkyl having 1-8 carbon atoms with the proviso that R ^J, and R ⁴ are not both hydrogen, which have valuable pharmacological properties.

As used herein, the term "C 1 -C 8 alkyl" refers to both straight and branched chains of C 1 to C 8, preferably C 1 to C 4, such as methyl, ethyl group, propyl group, isopropyl group, tert-butyl group and the like.

The term alkoxy having 1 to denotes alkyl ether groups, in carbon atoms, as used herein, wherein the alkyl group is an alkyl group as defined above. The term halogen as used herein refers to fluorine, chlorine, bromine and iodine halogen atoms.

In the context of the present invention, a particularly preferred alkyl group is a methyl group and an ethyl group.

R is preferably chlorine, bromine, methyl or ethyl.

Particularly preferred compounds of formula I are the following:

1- [2- (4-chlorophenyl) -4-quinolinyl] -N-ethyl-4-piperidinecarboxamide, 1- [2- (4-chlorophenyl) -6-fluoro-4-quinolinyl] -4-piperidinecarboxamide, 1- [2- (4-chlorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide and 1- [2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxamide.

According to the invention, the 4-amino-2-phenylquinolines of formula I can be prepared by reacting the 4-halo-2-phenylquinoline of formula III

where 3 4

R and R are as defined above and

X is a halogen atom, with an isonipecotamide of formula III

CONR ¹ R ² (III) where 1 2

R and R are as defined above.

The reaction of 4-halo-2-phenylquinoline of formula II with an isonipecotamide of formula III, which is either a known compound or can be directly prepared using known procedures in accordance with the process of the invention, can be carried out in known manner, either in the presence or absence. solvents. When working in the presence of a solvent, a suitable solvent may be lower alkanols, phenols, or other solvents known for use in nucleophilic exchange reactions such as dimethylformamide, dimethylsulfoxide and hexamethylltriamide phosphoric acid. The reaction may be carried out at a temperature between about 70 and 200 ° C, preferably at replicates of about 150 ° C.

Particularly preferred solvents for this reaction are phenol and ethanol. When the reaction is carried out in the absence of a solvent, the quinoline of formula II is reacted with an optional excess of isonipecotamide. about 100 and 180 ° C.

This reaction favors

The 4-halo-2-phenylquinolines of formula II, many of which can be prepared by a variety of methods.

For example, a compound of formula (II) wherein X can be prepared as shown in the reaction scheme below have the meanings given above and Et is ethyl:

at the temperature between the new compounds is chlorine, _{vvv 344}

1, with R and R

->

(VI)

(II)

Condensation of a substituted aniline of formula IV, which is either a known compound or can be readily prepared by known methods, with ethylethoxymethylene malonate is carried out in a known manner by heating a mixture of both components, either in the presence or absence of a solvent such as diphenyl ether or toluene at about 120 ° C . The resulting compound of formula (VII) is then cyclized in a conventional manner, for example by heating to about 200-250 ° C, in the presence of an inert organic solvent such as diphenyl ether.

The resulting quinoline of formula VIII is then decarboxylated in a conventional manner, first by hydrolyzing the ester with a base such as aqueous sodium hydroxide at a temperature of, for example, 100 ° C and sweating by heating the resulting acid to about 250 ° C. or without solvent.

The 4-hydroxyquinoline IX obtained is then treated in a known manner with a chlorinating agent, such as phosphorus oxychloride, to give the 4-chloroquinoline of the formula

X.

Finally, the 4-chloroquinoline of formula X is reacted in a known manner with a phenylllithium derivative of formula XI to give the desired 4-chloro-2-phenylquinoline of formula II. This reaction can be carried out, for example, in an inert solvent such as diethyl ether or tetrahydrofuran at a temperature in the range of about -80 to 20 ° C and under an inert gas atmosphere.

A further process for the preparation of the desired compounds of formula (II) used as starting materials is illustrated in Reaction Scheme 2 below. The symbols Et, ^RJ and R used in the above scheme have the meanings given above:

Reaction Scheme 2

Both the benzoylacetic acid ethyl ester of the formula XII and the substituted aniline of the formula XIII are known compounds or can be readily prepared using known methods.

The reaction of compounds of formula XII with compounds of formula XIII is carried out in a known manner by first condensing both compounds in the presence of an inert organic solvent such as toluene and a mild acid such as p-toluenesulfonic acid with heating to reflux. The condensation product is concentrated in vacuo and then cyclized by heating to a temperature of between about 200 and 260 ° C in an inert organic solvent such as diphenyl ether to give the 4-hydroxy-2-phenyquinoline of formula XIV.

Reaction of a quinoline of formula XIV with a halogenating agent such as phosphorus oxychloride or phosphorus tribromide at reflux, preferably in an inert and organic solvent such as diphenyl ether, provides the desired starting compound of formula II.

As another method for the preparation of the starting compounds of formula (II), it is shown in Reaction Scheme 3 below. The R and R symbols shown in the scheme are as defined above and R is a lower alkyl group.

Reaction Scheme 3

(II)

Both the anthranilic acid ester of formula XV and the substituted acetophenone of formula XIV are known compounds or can be readily prepared using known methods.

This synthetic process requires first condensation of compounds of formulas XV and XVI in the presence of a Lewis acid such as aluminum chloride in a high boiling solvent such as diphenyl ether at reflux to give a compound of formula XIV. The further reaction to obtain the desired compound of formula (II) by treating the compound of formula (XIV) is carried out in the manner already described in connection with Scheme 2.

The last method for the preparation of compounds of formula II is illustrated in Reaction Scheme 4 below, wherein R R, R ^ and X are as defined above:

Reaction Scheme 4

O

(xvii!

COOH I and X, (XX) cox

II (II)

Both the substituted isatin of formula (XVII) and the substituted acetophenone of formula (XIX) are either known compounds or can be readily prepared using known procedures.

The conversion of the isatin of formula XVII to the compound of formula XVIII is carried out in a conventional manner and requires the treatment of a substituted isatin with a base such as sodium hydroxide in ethanol.

Condensation of a compound of formula (XVIII) with an acetophenone of formula (XIX) is also a conventional reaction which can be carried out by refluxing both reagents in a solvent such as ethanol in the presence of a base such as sodium hydroxide.

Conversion of the acid of formula XX to the acid halide of formula XXI is accomplished in a conventional manner by reacting the acid with a halogenating agent, such as thionyl chloride or phosphorus tribromide, while heating to reflux in an inert organic solvent such as toluene.

Finally, the acid halide of formula XXI is converted to the desired 4-halo-2-phenylquinoline of formula II by decarbonylation using a standard reagent such as a rhodium catalyst at elevated temperature.

The compounds of formula (I) have been found to have an anxiolytic action and can therefore be used as medicaments accordingly. Using the procedures described below, the compounds of formula (I) were tested for their antipentetrazole activity and ³ H-diazepam binding activity. The acute toxicity after 24 hours (LD ₅₀ expressed in mg / kg) for each of these compounds was also determined in a standard manner. The results of these tests are summarized in Table 1 below.

Antipentetrazole test (after intravenous administration of pentetrazole)

Male 45-54 days old CF-1 mice housed in the same object for 1 week and not fasted for 24 hours were used for this assay. The test compound dispersed in 5% gum arabic was administered orally at the start of the experiment to three mice at a dose representing 1/10 of the lethal dose (LDj-θ) as determined by the previous experiment. One hour later, pentetrazole (70 mg / kg; the dose necessary to induce convulsions is 100 mg / kg) is intravenously administered and the animals are observed for 30 seconds for a seizure protective effect. If the compound is active when administered orally, 8 animals are used per dose. The dose (in mg / kg) at which 50% of the animals are protected against convulsions is expressed as the ^ED50 dose.

Values and 95% confidence limits are calculated using a computer according to a program based on the method described by D. J. Finney (Probit Analysis, Cambridge University Press, Cambridge, UK, 1971).

Using this method, the efficacy of standard drugs is as follows;

Drug ^ED 50 (95% confidence limit) mg / kg Chlordiazepoxid 3.9 (2.3 - 5.9) Diazepam 1.0 (0.69 - 1.6) Natriumfenobarbital 19 (9.7 - 29)

³ H-Diazepam Binding Assay □

Rat cortex fragments were prepared and used to determine H-diazepam binding as described by Mohler and Okada (Life Sciences, 20, 2101, 1977) except that

That tris-buffer was used instead of Krebs buffer. Test compounds are tested in triplicate. Radioactivity is measured by liquid scintillation counting. The results are expressed as ICj-θ, which is the concentration of compound (in nanomol / liter) required to inhibit the binding of ³ H-diazepam to 50%.

Using this method, the efficacy of standard drugs is as follows:

Drug ^IC 50 Diazepam Flunitrazepam Flurazepam 5.0 1,8 15.6 nm / liter nm / liter nm / liter Tabulkal Compound of Formula I Antipentetrazole test ^ED 50 (mg / kg) @ 1 H-diazepam _IC5Q Binding Assay (nm / L) Acute toxicity ^LD 50 (mg / kg) 1- [2- (4-chlorophenyl) -4-quinolinyl] -N-ethyl-4-piperidinecarboxamia 26 9.0 > 1 000 1- [2- (4-chlorophenyl) -4-quinolinyl] -N, N-diethyl-4-piperidinecarboxamide 500 1- (2- (4-chlorophenyl) -6-fluoro-4-quinolinyl) -4-piperidinecarboxamide 15 Dec 36.0 > 1 000 1- [2- (4-Chlorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide 9 19.5 > 1 000 Ι-Γ 2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxamide 24 29.0 > 1 000 1- (2- (4-Fluorophenyl) -4-quinolinyl) -4-piperidinecarboxamide > 100 1.1 > 1 000 Ι-β-Fluoro-2-phenyl-4-quinolinyl-4-piperidinecarboxamide 120 3.6 > 1 000 N-ethyl-1- (6-fluoro-2-phenyl-4-quinolinyl) -4-piperidinecarboxamide 58 2.8 > 1 000 1-Te-fluoro-2-phenyl-4-quinolinyl-N-propyl-4-piperidinecarboxamide 100 ALIGN! 13.0 > 1 000 1- [6-fluoro-2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide 5 1.0 > 1 000 1- [6-fluoro-2- (4-fluorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide 13 1,8 > 1 000 N-ethyl-1- [β-fluoro-2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide 22nd 3.0 > 1 000 1- [2- (4-Methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide 37 1.7 > 1 000 1- [4- (4-Bromophenyl) -4-quinolinyl] -4-piperidinecarboxamide 41 35.0 > 1 000 1- (6-fluoro-2- (4-methylphenyl) -4-quinolinyl) -4-piperidinecarboxamide 88 5.4 > 1 000 1- [t-Chloro-2- (4-methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide > 100 60.0 > 1 000

Compound of Formula I Antipentetrazole test ^ED 50 (mg / kg) 3 H-Diazepam IC ₅₀ Binding Assay (nm / L) Acute toxicity ^LD 50 (mg / kg) 1- [2- (4-chlorophenyl) -6-fluoro-4-quinolinyl] -N-methyl-4-piperidinecarboxamide > 300 70.0 > 1,000 1- [j) chloro-2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide 29 28.0 > 1,000 1- [6-chloro-2- (4-fluorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide 37 10.5 > 1,000 1- [6-chloro-2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxamide 205.0 1- [6-chloro-2-phenyl-5-quinolinyl] -4-piperidinecarboxamide 50 96.0 > 1,000 1- (6-ethyl) -2-phenyl-4-quinolinyl-4-piperidinecarboxamide 90 28.0 > 1,000 1- [2- (4-fluorophenyl) -6-methyl- -4-quinolinyl] -4-piperidinecar- boxamid > 100 34.0 > 1,000 1- (6-Methyl-2- (4-methylphenyl) -4-quinolinyl) -4-piperidinecarboxamide 290.0 1- [2- (4-chlorophenyl) -6-methyl-4-quinolinyl] -4-piperidinecarboxamide 460.0 1- p- (4-chlorophenyl) -4-quinolinyl] -N, N-dimethyl-4-piperidinecarboxamide 24 80.0 > 1,000

Legend:

indicates that the compound has not been tested for the indicated value

For conversion to a suitable dosage form, the compounds of Formula I are useful for the treatment of seizure attacks or anxiety and fear states.

A suitable dose for the compounds of formula I is in the range of about 10 to 500 mg / d, preferably in the range of about 25 to 200 mg per day, either as a single dose or in divided doses. Obviously, the dose administered to different patients may vary and the dose for each individual patient will depend on clinical judgment, with weight and condition of the patients as well as patient response to the drug being administered as criteria for determining the correct dose.

The compounds of formula I may be administered as medicaments in the form of pharmaceutical compositions comprising a compound of formula I together with a suitable pharmaceutically acceptable carrier. Such a carrier material may be an inert organic or inorganic carrier material suitable for parenteral or enteral administration, for example oral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petrolatum, and the like. The pharmaceutical compositions may be prepared in conventional manner and the final dosage form may be a solid dosage form such as for example tablets, dragees, suppositories, capsules and the like, liquid dosage forms such as solutions, suspensions, emulsions and the like.

The pharmaceutical preparations can then be subjected to conventional pharmaceutical operations, such as sterilization. In addition, the pharmaceutical preparations may contain adjuvants such as preservatives, stabilizers, emulsifiers, aromatic flavors, wetting agents, buffers, salts for varying the osmotic pressure and the like.

The following examples serve to illustrate the present invention in more detail. All temperatures are in degrees Celsius.

Example 1

Preparation of starting material, ie 4- (N-ethylcarbamoyl) piperidine (a) Methylisonicotinate

A suspension of 100 g (0.812 mol) of isonicotinic acid in 250 ml of methanol is stirred while cooling to 10 ° C. 125 ml of sulfuric acid are then added dropwise over 15 minutes while the temperature is kept below 20 ° C. The reaction mixture was then allowed to warm to room temperature spontaneously and then heated to reflux for 4.5 hours.

The reaction mixture is left to stand overnight, poured onto 1 kg of ice and then made alkaline by adding 235 g of sodium carbonate. The solid was filtered, washed with water and ether and set aside. The filtrate is extracted three times with 300 ml of ether each time. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. 80 g (65% of theory) of the crude product are obtained in the form of a light oil.

(b) N-ethylisonicotinamide

A mixture of 200 ml of ethanol and 20 ml of water is cooled in an ice bath and then saturated with ethylamine for 0.5 hours. 80 g of crude methyl isonicotinate are then added to the mixture while cooling. Ethylamine was introduced into the reaction mixture for 10 minutes and then allowed to stand overnight at room temperature. Concentration of the reaction mixture in vacuo afforded 82.82 g of a light oil which was cooled to a semi-solid product by cooling.

(c) 4- (N-ethylcarbamoyl) piperidine

A solution of 82.8 g (0.551 mol) of N-ethylisonicotinamide in 600 ml of ethanol is hydrogenated for 5 hours in the presence of 5.0 g of platinum oxide at 60 ° C and at a pressure of 1.425 MPa. The reaction mixture was then cooled overnight and the catalyst was filtered off. The filtrate was concentrated in vacuo. The residue was crystallized from ether to give 62.09 g of crude product.

Example 2

The following starting materials were prepared in an analogous manner to that described in Example 1:

a) 4- (N-methylcarbamoyl) piperidine

b) 4- (N-propylcarbamoyl) piperidine.

Example 3

Synthesis of 1- (2- (4-chlorophenyl) -6-fluoro-4-quinolinyl) -4-piperidinecarboxamide (a) 2- (4-chlorophenyl) -6-fluoro-4-hydroxyquinoline

A mixture of 140 g (0.617 mol) of ethyl 4-chlorobenzyl acetate, 500 ml of toluene, 59 ml (0.621 mol)

4-fluoroaniline and 3 g of p-toluenesulfonic acid are stirred and refluxed for 4 hours. The reaction mixture was then concentrated in vacuo to give 187 g of a residue. This residue was dissolved in 75 mL of diphenyl ether and added in one portion to 500 mL of diphenyl ether, which was stirred and heated to 245 ° C. The reaction mixture was then cooled to 40 ° C and diluted with hexane. The solid was collected and washed with methylene chloride. 56 g of crude product are obtained. Melting point: > 350 ° C.

(b) 4-chloro-2- (4-chlorophenyl) -6-fluoroquinoline

A mixture of 25 g (91 mol) of 2- (4-chlorophenyl) -6-fluoro-4-hydroxyquinoline and 50 ml of phosphorus oxychloride is stirred and refluxed for 2 hours. The reaction mixture was then cooled, poured onto ice and diluted with 500 ml of methylene chloride. This mixture was then basified with 3N sodium hydroxide solution. The organic phase was separated, and the aqueous phase was extracted with 2 x 200 mL of methylene chloride. The organic extracts were combined, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was collected and washed with hexane. 22.2 g of product are obtained in the form of a brownish solid.

Melting point: 169-172 ° C.

(c) 1- [2- (4-chlorophenyl) -6-fluoro-4-quinolinyl] -4-piperidinecarboxamide

A mixture of 4.4 g (15 mol) of 4-chloro-2- (4-chlorophenyl) -6-fluoroquinoline, 3.9 g (30 mmol) of isonipecotamide and 6 g of phenol is stirred and heated in an oil bath for 2 hours. 165-180 ° C. The reaction mixture was then cooled and diluted with 100 ml of water. Crystallization is induced by scratching with a stick. The solid was collected and washed with ether. 5.2 g of crude product are obtained. Mp 258-260 ° C (dec.). Recrystallization from pyridine / water gave off-white needles, mp 259-261 ° C.

Example 4

Synthesis of 1- [2- (4-chlorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide (a) N-methylisonipecotamide

A mixture of 20 g (0.147 mol) of N-methylisonicotinamide, 100 ml of ethanol and 1.2 g of platinum oxide is hydrogenated in a shaker at 60 DEG C. and a pressure of 0.425 MPa for 8 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from ether. 20.5 g of crude product having a melting point of 115 DEG-121 DEG C. are obtained.

(b) 4-chloro-2- (4-chlorophenyl) quinoline

To a solution of 15.3 g (80 mol) of 4-bromochlorobenzene in 100 mL of ether cooled to -25 ° C was added in three portions a total of 60 mL of a 1.6 M solution of butyllithium in hexane while keeping the temperature below -20 ° C. . The mixture was then allowed to warm to -5 ° C over 15 minutes.

The reaction mixture was then recooled to -20 ° C and a solution of 11.45 g (70 mol) of 4-chloroquinoline in 40 ml of ether was added at -20 ° C. A yellow suspension is formed. The suspension was allowed to warm to 0 ° C over 15 minutes and further stirred at 0-10 ° C for 20 minutes. 20 ml of water and 20 g of iodine are then added to the reaction mixture. After stirring for 20 minutes, 40 ml of 3N sodium hydroxide solution is added and stirring is continued for a further 15 minutes. The reaction mixture was then cooled to 10 ° C and 17.65 g of solid product precipitated, m.p. 119-122 ° C.

(c) 1- [2- (4-chlorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide

A mixture of 5.1 g (21 mmol) of 4-chloro-2- (4-chlorophenyl) quinoline, 6.2 g (42 mmol) of N-methylisonipecot amide and 10 g of phenol is stirred and heated in an oil bath at 160 ° C. for 3.5 hours. The mixture was cooled and diluted with 100 ml of water. Crystallization is induced by scratching the bar on the vessel wall, heating and adding a small amount of ethanol. The solid was collected and washed with ether. 7.0 g of crude product are obtained. Recrystallization from butanol (150 ml) yielded 4.6 g of product, m.p. 251-255 ° C (dec.).

Example 5

Synthesis of 1- (2- (4-chlorophenyl) -4-quinolinyl) -4-piperidinecarboxamide

In an analogous manner to that described in Example 4, 4-chloro-2- (4-chlorophenyl) quinoline was reacted with isonipecotamide in phenol at 170 ° C. The title compound is obtained. 245 DEG-247 DEG C. (decomposition) from ethanol.

Example 6

Synthesis of 1- [2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 2- (4-fluorophenyl- (4-quinolinecarboxylic acid)

To a suspension of 36.78 g (0.25 mol) of isatin in 500 ml of ethanol is added 75 ml of 10N sodium hydroxide solution. After stirring for 5 minutes, a solid precipitated. To this mixture was added 35 ml (0.286 mol) of p-fluoroacetophenone, and the mixture was stirred and refluxed for 1.5 hours. The reaction mixture was allowed to cool slowly and then acidified with 250 mL of 3N hydrochloric acid. The precipitated solid was collected, washed with water and ether and dried. 50.6 g of crude product are obtained. Melting point 205-215 ° C. Recrystallization from ethanol gave the title acid (38.8). Melting point 210 DEG-213 DEG C. (decomposition).

(b) 2- (4-fluorophenyl) -4-quinolinecarbonyl chloride

A mixture of 16.5 g of 2- (4-fluorophenyl) -4-quinolinecarboxylic acid, 100 ml of thionyl chloride and 50 ml of toluene is stirred and refluxed for 4 hours. The reaction mixture is then concentrated in vacuo, more toluene is added to the residue and the mixture is then concentrated in vacuo. The residue was washed with ether. 16 g of the title compound are obtained as a yellow solid.

(c) 4-chloro-2- (4-fluorophenyl) quinoline

A mixture of 3 g of 2- (4-fluorophenyl) -4-quinoline-carbonyl chloride and 0.1 g of tris (triphenylphosphine) rhodium (I) chloride is heated in an oil bath at 220-235 ° C for 40 minutes. The reaction mixture was cooled and extracted with methylene chloride. The extracts are filtered through 100 ml of silica gel and more methylene chloride is used to wash the silica gel. The filtrates were combined and concentrated in vacuo. 0.9 g of crude product is obtained, m.p. 90-93 ° C. Recrystallization from methanol gave an analytical sample, mp 91-93 ° C.

(d) 1- [2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide

A mixture of 1.44 g of 4-chloro-2- (4-fluorophenyl) quinoline, 1.3 g (10 mmol) of isonipecotamide and 3 g of phenol is stirred and heated in an oil bath at 165-170 ° C for 4.5 hours. . The reaction mixture was then cooled and diluted with water. The mixture was then basified with 3N sodium hydroxide solution and crystallization was induced by addition of ether and scratching with a stick on the vessel wall.

The solid was collected and washed with ether.

1.6 g of crude product are obtained. Recrystallization from ethanol-water gave white needles (0.42 g). Mp 218-220 ° C (dec.).

Example 7

Synthesis of 1- [6-fluoro-2-phenyl-4-quinolinyl] -4-piperidinecarboxamide (a) 6-fluoro-2-phenyl-4-quinolinol

A mixture of 100 g of p-fluoroaniline, 160 ml of ethylbenzoylacetate, 200 ml of toluene and 4 g of p-toluenesulfonic acid is stirred and heated to boiling below. reflux condenser with a Dean-Stark water trap to collect 15 ml of water. The reaction mixture was then concentrated in vacuo to give 275 g of a dark oil. This oil was poured into 500 mL of diphenyl ether heated to 240 ° C. After 40 minutes, the heat source was removed and the reaction mixture was allowed to cool to room temperature. The reaction mixture was then diluted with hexane and the solid collected. This solid was washed with hexane and methylene chloride. 104.3 g of 4-fluoro-2-phenyl-4-quinolinol, m.p. 298 DEG-302 DEG C., are obtained.

(b) 4-chloro-6-fluoro-1-phenylquinoline

A mixture of 6-fluoro-2-phenyl-4-quinolinol (30.4 g, 0.127 mol) and phosphorus oxychloride (65 ml) was stirred and refluxed for 2 hours. The reaction mixture was concentrated in vacuo, diluted with methylene chloride and then poured onto ice. The aqueous phase was neutralized with 3N sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. 34.8 g of residue are obtained. This was dissolved in methylene chloride and the methylene chloride solution was filtered through a layer of alumina. Concentration of the filtrate gave 23.7 g of 4-chloro-6-fluoro-2-phenylquinoline, m.p. 96-99 ° C.

(c) 1- (2-phenyl-6-fluoro-4-quinolinyl) -4-piperidinecarboxamide

Reaction of 4-chloro-6-fluoro-2-phenylquinoline and isonipecotamide in a similar manner to Example 3 (c) affords the title compound as prismatic crystals of off-white color. Mp 230-233 ° C (after recrystallization from ethanol).

Example 8

Synthesis of 1- [6-fluoro-2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 6-fluoro-4-hydroxyquinoline

A mixture of 216 ml of diethylethoxymethylene malonate, 95 ml of 4-fluoroaniline and 800 ml of diphenyl ether is stirred and slowly heated to 185 ° C while distilling off the ethanol formed. The reaction mixture was then heated at 145 ° C for 1.5 hours. The total amount of ethanol collected was 105 ml. The reaction mixture was then allowed to cool to 60 ° C, at which point 250 mL of hexane was added. The reaction mixture is left overnight, the product is separated, washed with hexane and dried. 223 g of solid are obtained, m.p. 305 DEG -309 DEG.

A mixture of the solid obtained above, 600 ml of 3N sodium hydroxide solution and 250 ml of water is stirred and refluxed for 2 hours. To the hot brown cloudy mixture was slowly added 600 mL of 3N hydrochloric acid solution to precipitate the product, i.e. 6-fluoro-4-hydroxyquinoline-3-carboxylic acid. The product is filtered from the cooled reaction mixture.

The wet solid and 600 mL of diphenyl ether were slowly heated to 250 ° C while water was allowed to distill off. The reaction mixture is maintained at this temperature for 20 minutes and then allowed to cool to 100 ° C. 500 ml of hexane are added and the mixture is stirred for 1 hour. The product, i.e. 6-fluoro-4-hydroxyquinoline, is collected and washed with hexane. 144 g of product are obtained, m.p. 209-212 ° C.

(b) 4-chloro-8-fluoroquinoline

A mixture of 6-fluoro-4-hydroxyquinoline (52 g, 0.319 mol) and phosphorous oxychloride (100 ml) was stirred and refluxed for 3 hours. The reaction mixture was then concentrated in vacuo. The residue in methylene chloride was poured onto ice-water and the mixture was neutralized with 3N sodium hydroxide solution. The organic phase is separated and the aqueous phase is extracted twice with 250 ml of methylene chloride. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from hexane. 27.95 g of product are obtained, m.p. 71-74 ° C.

(c) 4-chloro-6-fluoro-2- (4-fluorophenyl) quinoline

To a solution of 4.37 g (25 mol) of 1-bromo-4-fluorobenzene in 35 mL of ether cooled to -10 ° C was added portionwise 15 mL of a 1.6 M solution of butyllithium in hexane while maintaining the temperature below 0 ° C . The reaction mixture was stirred at a temperature below 0 ° C for 15 minutes. A solution of 3.63 g (20 mmol) of 4-chloro-6-fluoroquinoline in 20 mL of tetrahydrofuran was then added to the reaction mixture while maintaining the temperature below 0 ° C. The dark solution was stirred at room temperature for 20 minutes. 5 ml of water, 5 g of iodine and 10 ml of 3N sodium hydroxide solution are then added to the reaction mixture.

After stirring for 10 minutes, the solid separated. 2.8 g of product are obtained, m.p. 130-133 ° C.

(d) 1- [6-fluoro-2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide

The title compound was prepared in an analogous manner to that described in Example 3 (c) using 4-chloro-6-fluoro-2- (4-fluorophenyl) quinoline and isonipecotamide as starting materials. 244 DEG-246 DEG C. (decomposition) after recrystallization from ethanol.

Example 9

Synthesis of 1- [6-fluoro-2- (4-fluorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide

The title compound was prepared in an analogous manner to that described in Example 3 (c) using 4-chloro-6-fluoro-2- (4-fluorophenyl) quinoline prepared as described in Example 8 (c) and N-methylisonipecotamide as starting materials. The product is obtained as white prismatic crystals of m.p. 256 DEG-259 DEG C. after recrystallization from acetonitrile.

Example 10

Synthesis of 1- [2- (4-methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 4-chloro-2- (4-methylphenyl) quinoline

To a solution of 4.3 g (25 mmol) of p-bromotoluene in 75 mL of ether cooled to 5 ° C was added dropwise 15 mL of a 1.6 M solution of butyllithium in hexane, maintaining the temperature below 5 ° C. The mixture was stirred at 5 ° C for 10 minutes and at 30 ° C for 10 minutes, and then cooled to -20 ° C. A solution of 3.4 g (20 mmol) of 4-chloroquinoline in 15 mL of ether was then added while maintaining the temperature below -20 ° C. The reaction mixture is then allowed to rise to room temperature over 15 minutes. 10 ml of water, 5 g of iodine and 60 ml of 3N sodium hydroxide solution are then added to the reaction mixture.

After stirring for 20 minutes, the organic layer was separated. The aqueous phase is extracted with an equal volume of ether in three portions. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated in vacuo to give an oil. This oil was dissolved in methylene chloride and filtered through alumina. The filtrate was concentrated in vacuo to give 2.6 g of product, m.p. 75-77 ° C as off-white needles.

(b) 1- [2- (4-methylphenyl) -4-quinolinyl-4-piperidinecarboxamide

In analogy to Example 24, but starting from 4-chloro-2- (4-methylphenyl) quinoline and isonipecotamide, the title compound was prepared.

Mp 230-232 ° C, after recrystallization of acetonitrile.

Example 11

Synthesis of 1- [2- (4-bromophenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 2- (4-bromophenyl) -4-quinolinecarboxylic acid

Reaction of 29.4 g of isatin, 47.8 g of p-bromoacetophenone and 60 ml of 10N sodium hydroxide solution in 400 ml of ethanol according to the procedure of Example 6 (a) without recrystallization afforded 62.5 g of 2- (4-bromophenyl) -4- 238 DEG-240 DEG C. (decomposition) in the form of off-white prismatic crystals.

(b) 2- (4-bromophenyl) -4-quinolinecarbonyl chloride

Starting from 20 g of 2- (4-bromophenyl) -4-quinolinecarboxylic acid, 16 g of 2- (4-bromophenyl) -4-quinolinecarbonyl chloride, melting at 139-142 ° C (decomposition), was reacted with thionyl chloride according to Example 6 (b). ) in the form of yellow prismatic crystals.

(c) 2- (4-bromophenyl) -4-chloroquinoline

Reaction of 3 g of 2- (4-bromophenyl) -4-quinolinecarbonyl chloride with tris (triphenylphosphine) rhodium (I) chloride according to the procedure of Example 6 (c) affords 2.2 g of 2- (4-bromophenyl) -4-chloroquinoline. 115 DEG-117 DEG C. (decomposition) after filtration of the methylene chloride solution through an alumina filter.

(d) 1- [2- (4-bromophenyl) -4-quinolinyl] -4-piperidinecarboxamide

The above compound was prepared in an analogous manner to Example 6 (d) using 2- (4-bromophenyl) -4-chloroquinoline and isonipecotamide as starting materials. The product is obtained in the form of white needle crystals, m.p. 247 DEG-249 DEG C. (decomposition) after recrystallization from ethanol.

Example 12

Synthesis of 1- {6-fluoro-2- (4-methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 4-chloro-6-fluoro-2- (4-methylphenyl) quinoline

To a solution of 4.3 g (25 mmol) of p-bromotoluene in 75 mL of ether cooled to 5 ° C was added dropwise 10 mL of a 1.6 M solution of butyllithium in hexane, maintaining the temperature below 5 ° C. The reaction mixture was stirred at 5 ° C for 10 minutes and then at 39 ° C for 10 minutes, then cooled to -20 ° C. A solution of 3.63 g (20 mmol) of 4-chloro-6-fluoroquinoline prepared as described in Example 8 (b) in 20 ml of ether was then added to the reaction mixture while maintaining the temperature of the reaction mixture at -20 ° C. Deň: 32 ° C.

The temperature of the reaction mixture was allowed to rise to room temperature over 15 minutes. 10 ml of water, 5 g of iodine and 60 ml of 3N sodium hydroxide solution are then added to the reaction mixture. After stirring for 20 minutes, the organic layer was separated. The aqueous phase is extracted with an equal volume of ether. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated in vacuo. 5.8 g of crude product are obtained in the form of a pale orange oil.

(b) 1- [6-fluoro-2- (4-methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide

The title compound was prepared in an analogous manner to that described in Example 3 (c) using 4-chloro-6-fluoro-2- (4-methylphenyl) quinoline and isonipecotamide as starting materials. The product is obtained as white needle crystals, m.p. 246 DEG-249 DEG C. (decomposition) after recrystallization from pyridine.

Example 13

Synthesis of 1- [6-chloro-2- (4-methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 6-chloro-2- (4-methylphenyl) -4-quinolinecarboxylic acid

To a suspension of 18.15 g of 5-chloroisatin in 200 ml of ethanol is added 30 ml of 10N sodium hydroxide solution. To this mixture was added 16 ml (0.12 mol) of p-methylacetophenone, and then the mixture was stirred and heated to reflux for 3.2 hours. The mixture was then concentrated in vacuo and the residue diluted with 250 mL of water. The title acid is precipitated by the addition of acetic acid as a brown solid. Recrystallization from acetonitrile gave 31.6 g of the title acid as a brown solid.

(b) 6-chloro-2- (4-methylphenyl) -4-quinolinecarbonyl chloride

A mixture of 28.4 g of 6-chloro-2- (4-methylphenyl) -4-quinolinecarboxylic acid, 100 ml of thionyl chloride and 200 ml of toluene is stirred and refluxed for 1.5 hours. The reaction mixture is then concentrated in vacuo, more toluene is added to the residue and the mixture is concentrated again in vacuo. The residue was recrystallized from 300 mL of heptane to give 17.7 g of the title compound as a yellow solid.

(c) 4,6-dichloro-2- (4-methylphenyl) quinoline

A mixture of 3 g of 6-chloro-2- (4-methylphenyl) -4-quinolinecarbonyl chloride and 0.2 g of tris (triphenylphosphine), rhodium (I) chloride is heated in an oil bath at 180-200 ° C for 40 minutes. minutes. The reaction mixture was cooled and extracted with methylene chloride. The extracts are filtered through 75 ml of alumina and more methylene chloride is used to wash the alumina. The filtrates were combined and concentrated in vacuo. 0.8 g of crude product is obtained, m.p. 123-125 ° C.

(d) 1- [6-chloro-2- (4-methylphenyl) -4-quinolinyl] -4-piperidinecarboxamide

A mixture of 2.02 g (7 mmol) of 4,6-dichloro-2- (4-methylphenyl) quinoline, 1.6 g (12 mmol) of isonipecotamide, 5 g of phenol and a small amount of sodium iodide and copper powder is stirred and heated. at 160 ° C for 4 hours. The reaction mixture was then diluted with 50 mL of water and basified by the addition of concentrated ammonium hydroxide solution. Addition of ethyl acetate and ether gave 2.7 g of a wet crude product, crystalline, m.p. 260 DEG-265 DEG. Recrystallization from ethanol gave the title compound as white needles, mp 265-267 ° C (dec.).

Example 14

Synthesis of 1- [2- (4-chlorophenyl) -6-fluoro-4-quinolinyl] -N-methyl-4-piperidinecarboxamide

The title compound was prepared in an analogous manner to that described in Example 3 (c) using 4-chloro-2- (4-chlorophenyl) -6-fluoroquinoline prepared as described in Example 3 (d) and N- methylisonipecotamide as starting materials. 279 DEG-282 DEG C. (decomposition) is obtained after recrystallization from pyridine.

Example 15

Synthesis of 1- (6-chloro-2- (4-fluorophenyl) -4-quinolinyl) -4-piperidinecarboxamide (a) 6-Chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester

From a mixture of 216 g of diethylethoxymethylene malonate, 127.6 g of p-chloroaniline and 800 ml of diphenyl ether heated first at 150 to 160 ° C for 15 minutes and then at 245 ° C for 20 minutes, after cooling, it is obtained in the form of a precipitate. said compound. The precipitate was collected and washed with water and hexane. 245 g of wet raw material are obtained, which is used directly for the hydrolase described below.

(b) 6-chloro-4-hydroxyquinoline

The title compound was prepared in a manner analogous to Example 8 from 6-chloro-4-hydroxyquinoline-3-carboxylic acid ethyl ester. Melting point 265-268 ° C after recrystallization from ethanol.

(c) 4,6-dichloroquinoline

The title compound was prepared in a manner analogous to Example 25 (b) from 93.6 g of 6-chloro-4-hydroxyquinoline and 200 ml of phosphorus oxychloride. 63.6 g of the title compound are obtained in the form of white acicular crystals, m.p. 101-104 ° C.

(d) 4,6-Dichloc-2- (4-fluorophenyl) -ftinoline

To a solution of 5.5 ml (50 mmol) of 1-bromo-4-fluorobenzene in 70 ml of ether cooled to a temperature was added 21 ml of a 2.4 M solution of butyllithium in hexane while keeping the temperature below

This mixture was stirred at -15 ° C for 15 minutes. A solution of 7.42 g (40 mmol) of 4,6-dichloroquinoline in 40 mL of tetrahydrofuran was added to the reaction mixture while maintaining the temperature below -20 ° C. The reaction mixture was then allowed to warm to 0 ° C over 15 minutes and then 10 mL of water, 10.16 g (40 mmol) was added. iodine and 15 ml of 3N sodium hydroxide solution. After stirring for 10 minutes, the mixture was cooled to 5 ° C and then the solid was collected. This solid was added in methylene chloride and the methylene chloride solution was filtered through an alumina pad. The filtrate was concentrated in vacuo and the residue crystallized from ethyl acetate to give 5.7 g of crude product, m.p. 150-156 ° C.

(e) 1- [6-chloro-2- (4-fluorophenyl) -4-quinolinyl] -4-piperidinecarboxamide

The title compound was prepared in an analogous manner to that described in Example 3 (c) using 4,6-dichlorophenyl) quinoline and isonipecotamide as starting materials. Recrystallization from ethanol gave the product as white needle crystals, m.p. 250 DEG-252 DEG C. (decomposition).

Example 16 '

Synthesis of 1- [6-chloro-2- (4-fluorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide

The title compound was prepared in an analogous manner to that described in Example 3 (c) using 4,6-dichloro-2- (4-fluorophenyl) quinoline prepared as described in Example 15 and N-methylisonipecotamide as starting materials. After recrystallization from a mixture of pyridine and water, the product is obtained in the form of off-white acicular crystals, m.p. 260 DEG-265 DEG C. (decomp.).

Example 17

Synthesis of 1- [6-chloro-2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxamide (a) 4,6-dichloro-2- (4-chlorophenyl) quinoline

To a solution of 4.78 g (25 mmol) of 1-bromo-4-chlorobenzene in 40 mL of ether cooled to -10 ° C was added 15 mL of a 2.4 M solution of butyllithium in hexane while maintaining the temperature below 0 ° C. . The reaction mixture was stirred at 0 ° C for 15 minutes. Then, a solution of 3.96 g (20 mmol) of 4,6-dichloroquinoline prepared as described in Example 15 (c) in 20 ml of tetrahydrofuran was added at 0 ° C. Stirring was continued at 0 ° C for 25 minutes. 10 ml of water, 5 g of iodine and 50 ml of 3N sodium hydroxide solution are then added to the reaction mixture. After stirring for 10 minutes, the mixture was cooled to 5 ° C and the solid collected. This solid was washed with ether and dried. 6.23 g of the title compound of melting point 204 DEG-208 DEG C. is obtained.

Ťb | 1- [t-Chloro-2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxamide

A mixture of 3.1 g of 4,6-dichloro-2- (4-chlorophenyl) quinoline, 2.56 g (20 mmol) of isonipecotairide and 10 g of phenol is stirred and heated in an oil bath at 160-170 ° C for 40 minutes. hours. The reaction mixture was then cooled and diluted with water. The mixture was then basified with 3N sodium hydroxide solution and crystallization was added by addition of ether and scratching. The solid product was collected and washed with ether. 2.45 g of crude product are obtained. Recrystallization from ethanol gives the title compound as off-white prismatic crystals. Melting point 272-275 ° C.

Ex.18

Synthesis of 1- [6-chloro-2-phenyl-4-quinolinyl] -4-piperidinecarboxamide (a) 6-chloro-2-phenyl-4-quinolinol

From 100 g of p-chloroaniline and 138.5 ml of ethylbenzoylacetate, 115.6 g of 6-chloro-2-phenyl-4-quinolinol of melting point > 350 DEG C. is obtained by reaction according to Example 3 (a).

(b) 4,6-dichloro-2-phenylquinoline

From 25.5 g of 6-chloro-2-phenyl-4-quinolinol and 50 ml of phosphorus oxychloride, 24.86 g of 4,6-dichloro-2-phenylquinoline, m.p. Mp 116 ° C.

(c) 1- [6-chloro-2-phenyl-4-quinolinyl] -4-piperidinecarboxamide

The above compound was prepared in an analogous manner to that described in Example 3 (c) using 4,6-dichloro-2-phenylquinoline and isonipecotamide as starting materials.

The product is obtained in the form of white needle crystals, m.p. 253 DEG-255 DEG C. (decomposition) after recrystallization from ethanol.

Example 19

Synthesis of 1- [6-methyl-2-phenyl-4-quinolinyl] -4-piperidinecarboxamide (a) 4-chloro-6-methyl-2-phenylquinoline

This compound was prepared. in an analogous manner to that described in Example 3 using p-toluidine and ethylbenzoylacetate as starting materials. 90 DEG-93 DEG C. The product is obtained in the form of a slightly colored solid.

(b) 1- [6-methyl-2-phenyl-4-quinolinyl] -4-piperidinecarboxamide

The title compound was prepared in an analogous manner to Example 3 (c) using 4-chloro-6-methyl-2-phenylquinoline and isonipecotamide as starting materials. Recrystallization from pyridine gave the product as a white solid, m.p. 245-247 ° C. (decomposition).

Example 20

Synthesis of 1- [2- (4-fluorophenyl) -6-methyl-4-quinolinyl] -4-piperidinecarboxamide (a) -4-chloro-6-methylquinoline

This compound was prepared in an analogous manner to 4-chloro-6-fluoroquinoline as described in Example 8. The starting materials used were p-toluidine and diethylethoxymethylene malonate. The product is obtained as a solid, m.p. 47-51 ° C.

(b) 4-chloro-2- (4-fluorophenyl) -6-methylquinoline

This compound was prepared in an analogous manner to 4,6-dichloro-2- (4-fluorophenyl) quinoline as described in Example 15. From 3.5 mL of 1-bromo-4-fluorobenzene and 4.3-g of 4-chloro -6-methylquinoline gave 2 g of the title compound as a white solid, m.p. 93 DEG-95 DEG C., after filtration of the product in methylene chloride through silica gel. 1- (2- (4-fluorophenyl) -6). -methyl-4-quinolinyl-4-piperidinecarboxamide

A mixture of 4-chloro-2- (4-fluorophenyl) -6-methylquinoline (2.0g), isonipecotamide (1.88g, 10mmol) and phenol (4g) was stirred and heated in an oil bath at 165-170 ° C for 2 hours. The reaction mixture was then cooled and diluted with water. Crystallization occurs by adding ethanol and scratching the bar on the container wall. The solids were collected and washed with ether. This gave 1.9 g of crude product having a melting point of 264 DEG-271 DEG C. (decomposition). Recrystallization from pyridine 'will yield ·? /. ' The title is in the form of off-white prismatic crystals. Melting point 275 DEG-277 DEG C. (decomposition).

Example 21

Synthesis of 1- (6-methyl-2- (4-methylphenyl) -4-quinolinyl) -4-piperidinecarboxamide (a) 4 ' -chloro-6-methyl-2- (4-methylphenyl) quinoline

To a solution of 4.3 g (25 mmol) of p-bromotoluene in 50 mL of ether cooled to 5 ° C was added dropwise 15 mL of a 1.6 M solution of butyllithium in hexane, maintaining the temperature below 5 ° C. The reaction mixture was stirred at 5 ° C for 10 minutes and then at 30 ° C for 10 minutes, then cooled to -20 ° C. A solution of 4.0 g (22 mmol) of 4-chloro-6-methylquinoline, prepared as described in Example 20, in 20 mL of ether was added to the mixture while maintaining the temperature at -20 ° C during the addition. The reaction mixture was then stirred at room temperature for 15 minutes. 10 ml of water, 5 g of iodine and 60 ml of 3N sodium hydroxide solution are then added to the reaction mixture.

After stirring for 20 minutes, the organic phase was separated. The aqueous phase was extracted with an equal volume of ether. The organic phases were combined, washed with water, dried over sodium sulfate and concentrated in vacuo to give the title 4-chloroquinoline as a yellow oil. A solution of this oil in methylene chloride was filtered through a pad of alumina. The filtrate was concentrated in vacuo to give 3.22 g of the title compound. Melting point 40-50 ° C.

(b) 1- (6-Methyl-2- (4-methylphenyl) -4-quinolinyl) -4-piperidinecarboxamide

A mixture of 3.2 g of 4-chloro-6-methyl-2- (4-methylphenyl) quinoline, 3.06 g (24 mmol) of isonipecotamide and 6 g of phenol is stirred and heated in an oil bath at 160 ° C for 4 hours. . The reaction mixture was then cooled and diluted with water. Addition of ethanol and scratching the stick on the wall of the vessel will cause crystallization. The solid was collected and washed with ether. 3.18 g of crude product is obtained. Recrystallization from n-butanol gave prismat crystals of off-white color. Mp 242-244 ° C (dec.).

Example 22

Synthesis of 1- [2- (4-chlorophenyl) -6-methyl-4-quinolinyl] -4-piperidinecarboxamide (a) 4-chloro-2- (4-chlorophenyl) -6-methylquinoline

The title compound was prepared according to the procedure for EXAMPLE 7 using p-toluidine and ethyl p-chlorobenzoylacetate as the title compound. training substances. M.p. 136-138 ° C.

(b) 1- [2- (4-chlorophenyl) -6-methyl-4-quinolinyl] -4-piperidinecarboxamide

A mixture of 10 g (35 mmol) of 4-chloro-2- (4-chlorophenyl) -6-methylquinoline, g (70 mmol) of isonipecot amide and 20 g of phenol is stirred and heated in an oil bath at 165-170 ° C for 3.5 hours. The reaction mixture was then cooled and diluted with water. Adding stanol and scraping to crystallize. The solid was collected and washed with ether. 11.9 g of crude product are obtained. Recrystallization from pyridine gave the title compound as prismatic crystals of off-white color. Mp 261-265 ° C (dec.).

Example 23

By using the compounds of formula I prepared according to the present invention, the following different types of preparations can be prepared. The compounds of formula I are selected from the group of the following compounds:

1- [2- (4-chlorophenyl) -4-quinolinyl] -N-ethyl-4-piperidinecarboxamide, 1- [2- (4-chlorophenyl) -6-fluoro-4-quinolinyl] -4-piperidinecarboxamide, 1 -4- 2- (4-chlorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide and 1- [2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecaroxamide.

(a) Examples of direct compression tablets:

mg / tablet

1) the compound of formula I 1.0 5.0 10.0 50.0 2) lactose 127.0 142.5 182.0 206.0 3) microcrystalline cellulose 40.0 50.0 60.0 80.0 4) modified starch 10.0 12.5 15.0 20.0 5) cornstarch 20.0 25.0 30.0 40.0 6) magnesium salt stearic acids 2,0 2.5 3.0 4.0 total 200 mg 50 mg 300 mg 40 mg Procedure p First the components 1 to 10 are mixed 5 in suitable mixers during 1 to 15 minutes. Then

component 6 was added to the obtained mixture and stirring was continued for a further 5 minutes. The mixture thus obtained is compressed into tablets in a suitable press.

(b) Examples of mg / capsule capsules

1) Compound of Formula I 1.0 5.0 10.0 50.0 2) lactose 149.0 182.5 215.0 250.0 3) cornstarch 40.0 50.0 60.0 80.0 4) magnesium salt stearic acid 2,0 2.5 3.0 4.0 5) talc 8.0 10.0 12.0 16.0 total 200 mg 250 mg 3 0 0 mg 40 mg

Method:

First, components 1 to 3 are mixed in a suitable mixer. The mixture is ground in a suitable mill. Components 4 and 5 are then admixed and the resulting mixture is filled into capsules by a machine.

(c) Examples of tablets made by wet granulation mg / tablet

1) a compound of formula I

2) lactose

3) pregelatinized starch

4) corn starch

5) modified starch

6) magnesium stearate salt

1,0 5,0

195.0 230.0

12.5 15.0 25.0 30.0 12.5 15.0 4.0 5.0 200 mg 300 mg

10.0 5 0,0 264.0 263.0 17.5 20.0 35.0 40.0 17.5 2 0,0 6.0 7.0 3 5 0 mg 40 0 mg

total

Method:

In a suitable mixer, components _1c to 5 are first mixed and then wetted with water and granulated. The granulate is then dried in an oven overnight. The dry granulate is ground in a suitable mill. Component 6 is then admixed to the obtained mixture and tablets are compressed from the resulting mixture on a suitable press.

The following examples do not directly illustrate the present invention, but serve to illustrate the related issues.

Example 24

Synthesis of 1- [2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxylic acid ethyl ester

A mixture of 10 g (36.4 mmol) of 4-chloro-2- (4-chlorophenyl) quinoline and 20 ml of ethylisonipecotate is stirred under heating at 160-170 ° C for 2 hours. The reaction mixture is then cooled and diluted with 200 ml of water and 5 ml of ethanol. The resulting solid was isolated and recrystallized from ethanol. 5.5 g of the ester, mp 124-126 C. ^U

Example 25

Synthesis of 4-chloro-2- (4-chlorophenyl) quinoline (a) 2- (4-chlorophenyl) -4-quinolinol

To a stirred mixture of ethyl o-aminobenzoate (16.52 g, 0.1 mol), p-chloroacetophenone (15.46 g, 0.1 mol) and diphenyl ether (250 ml) was carefully added aluminum chloride (18.67 g). The reaction mixture was heated to reflux for 2 hours and then cooled to 60 ° C. The solid product is isolated and washed twice with 100 ml of toluene each time. The solid product is titrated twice with a mixture of 500 ml of 6N hydrochloric acid and 50 ml of acetone. In each case, the solid product is isolated, washed with 100 ml of 6N hydrochloric acid solution, 3 x 100 ml of water and 2 x 50 ml of acetone. 22.34 g of the title compound are obtained. Melting point 327-330 ° C.

(b) 4-chloro-2- (4-chlorophenyl) ehinoline

A mixture of 21.6 g of 2- (4-chlorophenyl) -4-quinolinol and 46 ml of phosphorus oxychloride was heated to reflux for 45 minutes, then the reaction mixture was cooled to room temperature and carefully poured onto 750 ml of ice water. . The resulting mixture was neutralized by the addition of 146 ml of 50% sodium hydroxide solution and extracted with 600 ml of methylene chloride divided into three portions. The extracts were combined, filtered through 15 g of filtering agent (Florisil) and concentrated in vacuo. 19.35 g of the title compound are obtained.

Claims (7)

A process for the preparation of 4-amino-2-phenylquinolines of the general formula I CONR ¹ R ² (i) N \ in which 1 2 R and R are each hydrogen or alkyl of 1 to 8 carbon atoms and 34; R @ 1 and R @ 2 are hydrogen, halogen or C1 -C8 alkyl, R @ 2 and R @ 2 are not both hydrogen atoms, characterized in that the 4-halo-2-phenylquinoline of the formula In which: R 1 and R 2 are as defined above and X is a halogen atom, is treated with an isonipecotamide of formula III CONR ¹ R ² (III) where 1 2 R and R are as defined above. 2. A process according to claim 1, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form compounds of formula (I) wherein R < ¹ & gt ^; And R < 3 > are hydrogen, methyl or ethyl, and R and R are as defined in 1. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas II and III are used as starting materials to produce the compounds of the formula 12 3 Wherein R and R are as defined in 1 or 2, R is chlorine, bromine, methyl or ethyl and R 1 is as defined in 1. 4. A process according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to give 1- [2- (4-chlorophenyl) -4-quinolinyl] -N-ethyl- 4-pipe ridinecarboxamide. 5. A process according to claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to give 1- [2- (4-chlorophenyl) -6-fluoro-4-quinolinyl] -4-piperidinecarboxamide. 6. A process according to claim 1, wherein the corresponding compounds of formulas II and III are used as starting materials to give 1- [2- (4-chlorophenyl) -4-quinolinyl] -N-methyl-4-piperidinecarboxamide . 7. A process according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to give 1- [2- (4-chlorophenyl) -4-quinolinyl] -4-piperidinecarboxamide.