NO144069B - DIFLUORBUTYROPHENON DERIVATIVES USED FOR THE PREPARATION OF THERAPEUTIC ACTIVE BUTYROPHENON DERIVATIVES - Google Patents

Description

The present invention relates to new difluorobutyrophenone derivatives which are usable as starting materials in the production of therapeutically active butyrophenone derivatives.

The new difluorobutyrophenone derivatives are compounds with the general formula:

where Z is a secondary amino group of the formula: 1 2 3 where R is hydrogen or hydroxyl, and R and R are each hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl, or of the formula:

13 14

where R and R are hydrogen, C-^-C^ alkyl, C1~C4 alkoxy or trifluoromethyl, with the proviso that when one of

Il 14

the substituents R and R are hydrogen, the other is hydrogen, C1-C4 alkyl or C1-C4 alkoxy, or of the formula

a 5 6 where R is hydrogen or C1~C4 alkyl, R and R are each hydrogen, halogen or C^-C^ alkyl, and the dotted line is a possible bond between the carbon atoms in the 3- and 4-position of the piperidine ring, or with the formula 7 8 where R is hydrogen or C^-C^ alkyl, and R is hydrogen, halogen, C^-C^ alkyl or C 1~C 4 alkoxy, or with the formula where R 9 is hydrogen, halogen, C^-C ^ alkyl, C^ C^ alkoxy or trifluoromethyl, and m is 0, 1 or 2, or of the formula

where R<10> is hydrogen, halogen, hydroxy, C1-C4 alkyl or C1-C4 alkoxy,

or they are acid addition salts of the compounds of formula (IIA).

In the meanings defined above, alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl and sec-butyl, while C1-C4 alkoxy includes methoxy, ethoxy, n-propoxy, isopropoxy and t-butoxy; C 1 -C 4 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; hydroxy-substituted C 1 -C 8 alkyl includes 2-hydroxyethyl, 3-hydroxy-n-propyl, 2-hydroxy-n-propyl, 2-hydroxy-1-methylethyl-1-hydroxymethyl-n-propyl, 2-hydroxy-1 ,1-dimethylethyl and 5-hydroxy-n-pentyl; C 1 -C 4 alkoxy-substituted C 1 -C 8 alkyl includes 2-methoxyethyl, 2-ethoxyethyl, 2-methoxy-1-methylethyl and 3-methoxy-n-propyl; dialkylamino-substituted C 1 -C 8 alkyl includes 2-methylaminoethyl, 3-dimethylamino-n-propyl, 2-diethylaminoethyl and 4-diethylamino-o-methyl-n-butyl; halogen includes fluorine, chlorine, bromine and iodine; and aralkyl includes optionally substituted benzyl, phenethyl, benzhydryl and naphthylmethyl (e.g. benzyl, p-methoxybenzyl, p-methylbenzyl, o,p-dimethylbenzyl, p-fluorobenzyl, p-chlorobenzyl, ct-ethylbenzyl, phenethyl, 3,4- dihydroxyphenethyl, benzhydryl, 1-naphthalenemethyl.

The new difluorobutyrophenone compounds (IIA) are useful as starting materials in the preparation of therapeutically active butyrophenone compounds of the formula:

in which Z is as above and W is a secondary amino group such as Z or morpholino, pyrrolidino, piperidino or a group of

the formula:

11 12

where R and R are each hydrogen, C₁-C₆ alkyl, hydroxy-substituted C₁-C₆ alkyl, C₁-C₆ alkoxy-substituted C₁-C₆ alkyl, di-(C₁-C₄ alkyl)-amino-substituted C₆- Cg alkyl, C3~C7 cycloalkyl or optionally substituted benzyl.

The butyrophenone compounds of formula (I) have a wide spectrum of pharmacological activity and are useful as psychotropic, sedative, analgesic, antispasmodic, autonomotropic, anti-inflammatory and/or antifungal agents.

The therapeutically active butyrophenone derivatives with the formula (I) can be prepared by a difluorobutyrophenone compound according to the invention, with the formula:

where Z is as above, or an acid addition salt of this compound, is reacted with an amine of the formula H-W, where W is as above, in the presence of a slightly polar solvent,

and, when W is a group of the formula:

11 12

where R and R are as stated above, but at least one of them is an optionally substituted benzyl group, the compound obtained is optionally hydrogenated in a known manner to obtain the corresponding compound where the optionally substituted benzyl group has been eliminated.

When the difluorobutyrophenone compound (IIA) or an acid addition salt thereof is reacted with the amine H-W as indicated above, one should, on the basis of what is previously known from e.g. P. Tarrant: "Fluorine Chemistry Review", Vol. 7, Marcel Dekker, Inc., New York, 1974, pages 1 - 114, expected that the reaction with the amine H-W would be as likely to occur at the fluorine atom in the para-position of the phenyl nucleus as at the fluorine atom in the ortho position. However, it has been shown that when the reaction is carried out in the presence of a slightly polar solvent, such as benzene, toluene, xylene, n-hexane, dioxane or carbon tetrachloride, the reaction takes place selectively at the fluorine atom in the ortho position of the phenyl nucleus.

For a more detailed description of the preparation of the therapeutically active butyrophenone derivatives of formula (I), reference is made to patent application no. 1072/73.

The new 2,4-difluorobutyrophenone compounds (IIA) according to the invention are prepared from compounds with the formula: where X is halogen and R is oxygen, ethylenedioxy or ethylenedithio, by reaction with a secondary amine of the formula: where Z is as stated above. When R is ethylenedioxy or ethylenedithio, the compound obtained is hydrolysed.

The y-Halogen-butyrophenone compound (III), which is used as starting material in the preparation of the new difluorobutyrophenone derivatives, can be conveniently prepared by a Friedel-Crafts reaction between m-difluorobenzene and a y-halo-butyryl halide with

the formula:

where X<1> is halogen, and X is as stated above, with subsequent ketalization of the compound formed (HIA) if the ketal compound (UIB) is desired.

The production of the new difluorobutyrophenone derivatives according to the invention is illustrated by the following reaction core:

In the reaction scheme, Z, R, X and X<1> are as indicated above. Y is ethylenedioxy or ethylenedithio.

The difluorobutyrophenone compound (IIA) can be prepared by reacting the compound (HIA) with the secondary amine of the formula H-Z, where Z is as indicated above, in an inert solvent.

The reaction is preferably carried out in the presence of an acid binding agent such as an inorganic base (eg potassium carbonate, sodium carbonate, sodium bicarbonate) or a tertiary amine (eg pyridine, triethylamine, dimethylaniline). Examples of inert solvents are amides such as dimethylformamide, dimethylacetamide and formamide, aromatic hydrocarbons such as benzene, toluene and xylene, alkanols such as ethanol, propanol and butanol, and alkanones such as acetone, 2-butanone and 4-methyl-2-pentanone. The reaction is usually accelerated by increasing the temperature. A small amount of a catalytic substance such as potassium iodide is also useful to speed up the reaction. The reaction is usually complete within 1-48 hours, and a preferred reaction time is 5-20 hours.

The difluorobutyrophenone compound (IIA) can also be prepared by ketalizing the compound (HIA), reacting the resulting ketal compound (UIB) with the secondary amine as above, and then hydrolyzing the resulting alkylated compound (IIB).

Although the reaction between the ketal compound (UIB) and the secondary amine can be carried out under the same conditions as the reaction between the compound (HIA) and the secondary amine, the former can usually be carried out under milder conditions than the latter. For example, the reaction can be carried out at a temperature from 25 to 100°C within 3 hours. By the aforementioned method, the ketal compounds (IIB) are easily prepared.

The ketalization and the subsequent hydrolysis can be carried out according to conventional methods known per se. For example, the ketalization is carried out by treating the compound (HIA) with a ketalizing agent such as ethylene glycol or ethylenedithioglycol. in the presence of a dehydrating catalyst such as p-toluenesulfonic acid or concentrated sulfuric acid, usually in an inert solvent (eg, benzene, toluene, xylene) at elevated temperature. Further

can e.g. the hydrolysis is carried out by treating the alkylated compound (IIB) with an acidic compound such as a mineral acid (e.g. hydrochloric acid, sulfuric acid, phosphoric acid), an organic acid (e.g. oxalic acid, tartaric acid) or an acidic ion exchange resin in water or a alkanol (e.g. methanol, ethanol, propanol), usually below

mild conditions, e.g. at room temperature.

The 2,4-difluorobutyrophenone compound (IIA) thus produced can be easily transferred to its organic or inorganic acid addition salts in a manner known per se.

The following examples illustrate the preparation of the new difluorobutyrophenone compounds.

Production of starting materials

(A) To a mixture of 340 g of aluminum chloride and 1 liter of carbon disulfide, 114 g of m-difluorobenzene was added while cooling.

A solution of 14 2.5 g of Y-chlorobutyryl chloride in 200 ml of carbon disulfide was then added dropwise to the reaction mixture at a temperature below 15°C. The resulting mixture was gradually heated under continuous reflux for 2 hours. After cooling, the reaction mixture was poured into 3 liters of water and extracted with dichloromethane. The extract was washed with water, a dilute aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, in this order, and then dried over anhydrous sodium sulfate and evaporated to give an oil residue. Vacuum distillation of the oil gave pure Y-chloro-2,4-difluorobutyrophenone. Boiling point 97 - 111°C (1.0 - 1.5 mmHg). n^<6>= 1.507.

(B) While a mixture of 102.3 g of Y~chloro-2,4-difluorobutyro-phenone, 58.1 g of ethylene glycol, 3.2 g of p-toluenesulfonic acid hydrate and

500 g of benzene was heated under reflux for 30 hours, the water formed was removed as an azeotropic mixture. After cooling, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. The benzene layer was evaporated, whereby an oil residue was obtained. Vacuum distillation of the oil gave pure 4-chloro-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane. Boiling point 109 - 120°C

(1.3 - 1.5 mmHg). n^<7->1,495.

Example 1

A mixture of 14.2 g of γ-chloro-2,4-difluorobutyrophenone, 13.8 g of 4-(4-chlorophenyl)-4-hydroxypiperidine, 9.0 g of anhydrous potassium carbonate, 0.5 g of potassium iodide and 170 ml of dimethylformamide was heated for 20 hours at 90 - 110°C. After cooling, the reaction mixture was diluted with water and extracted with ether. The ether extract was washed sufficiently with water, dried over anhydrous sodium sulfate, treated with hydrogen chloride and then evaporated. Trituration and recrystallization of the residue from methanol gave γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride. Melting point 245°C (splitting).

Example 2

A mixture of 5.3 g of 4-chloro-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane, 4.6 g of 4-oxo-1-phenyl-1,3,8-triazaspiro-[ 4,5]-decane,

0.1 g of anhydrous potassium carbonate and 58 ml of dimethylformamide were heated under reflux for 2.5 hours. After cooling, the reaction mixture was poured into 400 ml of cold water with vigorous stirring, and the precipitate was collected and washed with water, whereby 4-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5] -decan-8-yl)-1-(2,4-difluorophenyl)-1,1-ethylenedioxybutane. Melting point 58 - 62°C.

Example 3

A mixture of 2.0 g of 4-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]-decan-8-yl)-1-(2,4-difluorophenyl)-1 ,1-ethylenedioxybutane, 29 ml of methanol, 4.7 ml of 35% hydrochloric acid and 10 ml of water were heated under reflux for 30 minutes. After cooling, the reaction mixture was diluted with water, made alkaline with a saturated aqueous solution of sodium carbonate and extracted with chloroform.

The extract was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol, whereby γ-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]-decan-8-yl)-2,4-difluorobutyrophenone was obtained. Melting point 190 - 204°C.

Example 4

In the same way as in examples 1-3, the following compounds were obtained: Y-[4-(2-oxo-1-benzimidazolinyl)-piperidin-1-yl]-2,4-difluoro-butyrophone hydrochloride, m.p. 160-165°C;

γ-(4-phenylpiperazin-1-yl)-2,4-difluorobutyrophenone hydrochloride, m.p. 219-225°C (dec.);

Y-[4-(2-methoxyphenyl)-piperazin-1-yl]-2,4-difluorobutyrophenone dihydrochloride, m.p. 206-208°C.

Y-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,4-difluorobutyriphenone hydrochloride, m.p. 205-208°C.

Y-[4-(4-chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride, m.p. 226°C (dec.);

Y-[4-(4-chlorobenzyl)-4-hydroxypiperidin-1-yl]-2,4-difluoro-butyrophone hydrochloride, m.p. 183-184°C;

Y-(4-benzyl-4-hydroxypiperidin-1-yl)-2,4-difluorobutyro-phenone hydrochloride, m.p. 164.5-166.5°C.

Claims (2)

1. Difluorobutyrophenone derivatives which are usable as starting materials in the preparation of therapeutically active butyrophenone derivatives with the formula: in which Z is a secondary amino group of the formula: where R<1> is hydrogen or hydroxyl, R 2 and R 3 are each hydrogen, halogen, C^-C^ alkyl, C^-C^ alkoxy or trifluoromethyl, or with the formula: 13 14 where R and R are hydrogen, C^-C^ alkyl, C^-C^ alkoxy or trifluoromethyl, with the proviso that when one of the substituents R 13 and R 14 is hydrogen, the other is hydrogen, C1~C4 alk^ 1 or C1-C4 alkoxy, or with the formula where R4 is hydrogen or C^-C^ alkyl, R5 and R6 are each hydrogen, halogen or C1~C4 alkyl, and the dotted line is a possible bond between the carbon atoms in the 3- and 4-position of the piperidine ring, or with the formula where R 7 is hydrogen or C 1 -C 4 alkyl, and R 8 is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, or with the formula where R 9 is hydrogen, halogen, C - C 1 alkyl, C 1 -C 4 alkoxy or trifluoromethyl, and m is 0.1 or 2, or with the formula where R is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl or C₁ -C₁ alkoxy, and in which W is a secondary amino group such as Z or morpholino, pyrrolidino^ piperidino or a group of the formula: 11 12 where R and R are each hydrogen, C1-C6 alkyl, hydroxy-substituted C^^-C8 alkyl, C1~ C4 alkoxy-substituted C^-Cg alkyl, di-(C1~C4 alkylj-amino-substituted c-^~Cg alkyl, C3~C7 cycloalkyl or optionally substituted aralkyl, and their acid addition salts, characterized in that they have the general formula: where Z is as indicated above, or are acid addition salts of these compounds of formula (IIA). 2. Difluorobutyrophenone derivatives according to claim 1, characterized in that Z is one of the groups: where R1, R2, R3, R13 and R14 are as indicated above, or