IL34933A - Process for preparing gamma-piperidino butyrophenone derivatives,certain new gamma-piperidino butyrophenones and pharmaceutical compositions containing them - Google Patents

Description

34933/2 Process for preparing ^-p1per1d1no butyrophenone derivatives, certain new V-p1per1d1no butyrophenonesand pharmaceutical compositions containing them mnpn » rom n»a»»iDB ' uig ^iDoeuii xuvexitXUIl Γβ ΧΘΒ XO a Πθνθΐ prOCSSS ΙΌΓ prOOUCing butyrophenone derivatives* More particularly the invention relates to a ^ novel process for producing central nervous system aotive (-piperidihobuty-rophenone derivatives. The invention also pertains to novel central nervous system active^-piperidinobutyrophenone derivatives and pharmaceutical use of the same.

In Israeli Patent No. 26812 and British Patents Nos. 831893 and 89 09 there are broad disclosures of a general class of compounds having the formula 7 2 wherein R is hydrogen and R is hydrogen or halogen, however the ¾-halogen i fluorine-substituted compounds of the present invention are not specifically described in these patents. Furthermore, there is no teaching or suggestion in the above mentioned patents that the specific selected compounds of the present, invention would possess superior anti-psychotropic activity as shown in comparative tests I and II.

The present inventors studied in order to find an advantageous process in which substituted \ -piperidinobutyrophenone derivative having a substituent at the ortho position can be produced. As a result, the present inventors found a novel and advantageous process for producing various substituted ^-piperidinobutyrophenone derivatives including such ortho-substituted compounds. The most important characteristic of the prodess of our finding is residing in the production of o-acylamino-y-piperidino- butyrophenone derivatives by the oxidation of 3-Y-piperidino- propylindole derivatives. The acylamino group of the thus- obtained o-acylamino-7-piperidinobutyrophenone derivatives can be converted to unsubstituted or substituted amino group by an ordinary hydrolysis reaction and further subsequently to hydrogen, halogen or hydroxyl by an ordinary diazotization decomposition. Therefore according to the process of our finding, various γ-piperidinobutyrophenone derivatives can be produced very advantageously.

Accordingly an object of the present invention is to provide a novel and advantageous process for producing γ-piperidinobutyrophenone derivatives.

Another object of the invention is to provide novel central nervous system active γ-piperidinobutyrophenone derivatives.

A. further object of the invention is to provide a pharmaceutical use of such γ-piperidinobutyrophenone derivatives.

Other objects and merits of the invention will be apparent from the following description.

In order to accomplish these objects, the present invention provides a process for producing a γ-piperidino- butyrophenone compounds of the formula, wherein R1 is hydrogen, halogen, hydroxyl, amino, acylamino, alkylamino or N-acylalkyl'amino, each of said alkyl group having up to 4 carbon atoms; R2 is hydrogen or halogen; R3 is hydrogen or unsubstituted or alkyl-, alkoxy-, halogen- or trifluoromethyl- substituted phenyl, each of said alkyl or alkoxy group having up to carbon atoms, and is hydrogen or hydroxyl, and an acid addition salt thereof, which comprises contacting an indole compound of the formula, R5 wherein R5 and R°" each are hydrogen or alkyl having up to 4 carbon atoms respectively, and R2, R3 and are the same as defined above, with an oxidizing agent to yield a compound of the formula, R3 wherein R2, R3, R^, R5 and are the same as defined above, and if necessary, hydrolyzing the resulting compound of the formula (II) to a compound of the formula, R3 h wherein R , R3, R^ and R5 are -the same as defined above, and further diazotizing, if desired, in case R is hydrogen, the resulting compound of the formula (III) and subsequently diazonium group by hydrogen, halogen or hydroxyl group to yield a compound of the formula, wherein X is hydrogen, halogen or hydroxyl; and R , R3 and R are the same as defined above.

Further the present invention provides a novel compound of the formula, wherein R? is halogen, hydroxyl, amino, alkylamino, acylamino or N-acylalkylamino, each of said alkyl group having up to 4 carbon atoms; R2 is hydrogen or halogen; ^ is hydrogen or unsubstituted alkyl-, alkoxy-, halogen- or trifluoromethyl-substituted phenyl, each of said alkyl or alkoxy group having up to carbon atoms; and ^ is hydrogen or hydroxyl; and a pharmaceutically acceptable acid addition salt thereof.

Furthermore the present invention provides a pharmaceutical composition containing novel compound as defined above as active ingredient.

In the present invention, examples of halogen include fluorine, chlorine, bromine or iodine atom.

These compounds of the present invention coming within the formula (I) above, may be prepared by a process shown by the following reaction schema: R5 Hydrolysis Diazotlzation wherein R2, R3, R5, R6 and χ are as identified above.

The 1- [jB- ( 3-indolyl )propionyl]piperidine compounds of the formula (VIII) used as an intermediate in the present invention are prepared by reacting an indolylpropionic acid of the formula (V), or its functionally active derivative such as acid chloride, acid bromide, acid anhydride, mixed acid anhydride, p-nitrophenyl ester and the like, with a piperidine of the formula (VII). The reaction is preferably carried out in the presence of a basic agent or a condensing agent such as pyridine, triethylamine, sodium carbonate, sodium hydroxide, dicyclohexylcarbodiimide and the like in a suitable inert organic solvent such as tetrahydrofuran, ether, dioxane, benzene, toluene, chloroform, dimet ylform-amide and the like.

The mixed acid anhydride mentioned above includes those prepared by treating with ethyl chloroformate, isobutyl chloroformate or the like.

The intermediate compound of the formula (VIII) can also be prepared by heating a phenylhydrazone compound of the formula (VI). The heating is carried out preferably in the presence of an acidic condensing agent such as, for example, hydrogen chloride, sulfuric acid, phosphoric acid, zinc chloride, copper chloride, boron fluoride, polyphosphoric acid and the like in a suitable solvent such as ethanol, isopropanol, tertiary-butanol, acetic acid, benzene, toluene, water and the like.

According to the method mentioned above, the following compounds can be easily obtained. 1- [ β- (2-Methyl-3-indolyl )propionyl ]-4-phenylpiperidine l-[e-(2-Methyl-5-chloro-3-indolyl )propionyl]-4-phenylpiperidine 1- [β- ( 2-Methyl-3-indolyl )propionyl]piperidine 1- [£-(2-Methyl-5-fluoro-3-indolyl )propionyl]piperidine l-[fl-(2-Methyl-6-fluoro-3-indolyl )propionyl]piperidine l-[j3-(l, 2-Dimethyl-5-fluoro-3-indolyl )propionyl ]-piperidine 1- [j3- ( l-Ethyl-2-methyl-5-fluoro-3-indolyl )propionyl ]-piperidine 1- [β- (l-Isopropyl-2-methyl-5-fl oro-3-indolyl )propionyl] piperidine 1_ [β_ (5-Fluor-3-indolyl )propionyl]piperidine 1- [β- ( l- ethyl-5-fluoro-3-indolyl )propionyl ]piperidine l_[£-(2- ethyl-5-fluoro-3-indolyl)propionyl]-4-phenyl-piperidine 1- [fi-(2-Methyl-5-fluoro-3-indolyl )propionyl]-4- ydroxy-4-phenylpiperidine 1- [β- ( 2-Methyl-5-fluoro-3-indolyl )propionyl]-4-p-chlorophenyl-4-hydroxypiperidine 1- [β- (2-Methyl-5-fluoro-3-indolyl )propionyl J-4-hydrox -4-p-tolylpiperidine 1- [β- ( 2-Methyl-5-fluoro-3-indolyl )propionyl]-4-hydroxy-4-m-trifluoromethylphenylpiperidine 1-[β- (2-Methyl-5-fluoro-3-indolyl )propionyl]-4-hydroxy-4-p-methoxyphenylpiperidine 1- [β- ( 2-Methyl-5-fluoro-3-indolyl )propionyl ]-4-hydroxy-4-p-hydroxyphenylpiperidine l-(/3-3-Indolylpropionyl )-4-hydroxy-4-p-tolylpiperidine 1- [β- ( 1, 2-Dimethyl-3-indolyl )propionyl ] -4-hydroxy- - ^ p-chlorophenylpiperidine 1- [β-U, 2-Dimethyl-5-fluoro-3-indolyl)propionyl]- -hydroxy-4-p-chlorophenylpiperidine 1- [0-(2-Methyl-5-chloro-3-indolyl )propionyl]-4-hydroxy- -p-chlorophenylpiperidine l_[£_(2-Methyl- -fluoro-3-indolyl )propionyl]-4-hydroxy- -p-chlorophenylpiperidine 1- [/3-(2-Methyl-6-fluoro-3-indolyl )propionyl]-4-hydroxy-4-p-chlorophenylpiperidine 1- [β-(1, 2-Dimethyl-5-fluoro-3-indolyl)propionyl]- -hydroxy-4-m-trifluoromethylphenylpiperidine The compounds of the formula (VIII) thus obtained are converted to corresponding 3- (γ-piperidinopropyl )indole compounds of the formula (IX) by reacting the former with a reducing agent. A reducing agent such as alkali metal in alcholic solvent, hydrogen in the presence of a catalyst, metal hydride and the like can be preferably employed. An electrolytic reduction can also be used for the purpose.

It is especially preferable to use metal hydride such as lithium aluminium hydride, diisobutyl aluminium hydride, triisopropyl aluminium hydride, boron hydride or the like, in an inert organic solvent such as, for example, ether tetrahydrofuran, dioxane, N-ethylmorphorine and the like.

According to the method mentioned above, following compounds can be obtained. 2-Methyl-3-(7-piperidinopropyl )-indole 2-Methyl-3- (γ-piperidinopropyl )-5-chloroindole 2-Methyl-3- (γ-piperidinopropyl )-5-fluoroindole 2-Methyl-3- (γ-piperidinopropyl )-4-fluoroindole 2-Methyl-3-( -piperidinopropyl )-6-fluoroindole 1, 2-Dimethyl-3- (γ-piperidinopropyl )-5-fluoroindole l-Ethyl-2-methyl-3- (γ-piperidinopropyl )-5-fluoroindole l-Propyl-2-methyl-3- (γ-piperidinopropyl )-5-fluoroindole 3- (γ-Piperidinopropyl )-5-fluoroindole 1-Methyl-3- (γ-piperidinopropyl )-5-fluoroindole 2- ethyl-3- [y- (4-phenylpiperidino )propyl]-5-fluoroindole 2-Methyl-3- [γ-(4-phenylpiperidino )propyl] indole 2-Methyl-3- [γ-( 4-phenylpiperidino )propyl]-5-chloroindole 2 , 5-Dimethyl-3- [γ- (4-phenylpiperidino )propyl] indole 2-Methyl-3- [γ- ( 4-phenyl-4-hydroxypiperidino )propyl ] -5-fluoroindole 2-Methyl-3- [γ- (4-p-chlorophenyl-4-hydroxypiperidlno)-propyl -5-fluoroindole 2-Methyl-3- [γ- (4-p-fluorophenyl-4-hydroxypiperidino )-propyl ]-5-i"luoroindole 3_ [γ- (4-p-Tolyl-4-hydroxypiperidino )propyl]- indole 1, 2-Dimethyl-3- [ y- (4-phenyl-4-hydroxypiperidino )propyl]-indole 3- [γ- ( 4-p-Chlorophenyl-4-hydroxypiperidino )propyl ] -5-chloroindole 3_ [γ» ( -p-Fluorophenyl-4-hydroxypiperidino )propyl ]-5-fluoroindole 3_ [γ_ ( -m-Trifluoromethylphenyl-4-hydroxypiperidino )-propyl ] -5-fluoroindole l-Methyl-3- _7-(4-m-trifluoromethylphenyl-4-hydroxy-piperidino )propyl ] -5-fluoroindole 3- [γ_ ( 4-p-Chlorophenyl-4-hydroxypiperidino )propyl ]-4-fluoroindole 3- [γ- ( 4-p-Chlorophenyl-½-hydroxypiperidino )propyl ]-5-fluoroindole The acid addition salts of the 3- (γ-piperidino-propyl )indole derivatives are prepared by treating the free base with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, benzoic acid, sulfamic acid, mandelic acid and the like. γ-Piperidinobutyrophenones of the formula (II) can be prepared by contacting the above-obtained 3-Y-piperidino-propyl indoles of the formula (IX) with an oxidizing agent. In the oxidative cleavage reaction it is preferred to use an oxidizing agent such as ozone, hydrogen peroxide, per-formic acid, peracetic acid, perbenzoic acid, chromic acid or potassium permanganate, although the oxidizing agent of the present invention is not limited to the exemplified ones and others may be used.

Generally, the reaction progresses readily at room temperature, but the temperature may be higher or lower as necessary to effect the desired control of the reaction.

The oxidizing agent is preferably chromic acid or ozone.

The reaction is preferably effected in the presence of a solvent. The choice of solvent depends on the oxidizing agent employed, and is selected from the group consisting of water, acetone, carbon tetrachloride, acetic acid, sulfuric acid and the like. The oxidizing agent is used in the stoichiometric amount or more. The reaction temperature varies depending on the oxidizing agent employed.

Where the oxidation is carried out by use of chromic the chromic acid may be used in 2-3 times the equimolar amount and that the reaction may be carried out at room temperature. A 3-7-piperidinopropylindole derivative is dissolved or suspended in the solvent and the oxidizing agent is added to the solution or suspension with stirring.

Generally, the reaction terminates within about 24 hours.

Where the oxidation is carried out by use of ozone, the reaction is preferably carried out at room temperature. A 3-7-piperidinopropylindole derivative is dissolved or suspended in the solvent such as formic acid, acetic acid, carbontetrachloride or the like and ozonized oxygen is bubbled into the solution or suspension with stirring.

The desired γ-piperidinobutyrophenone derivative can be separated from the reaction mixture in a crude form by extraction, with or without prior neutralization, and by evaporation to dryness. The product is further purified, if desired, by recrystallization from a suitable solvent such as ethanol, isopropanol or the like in a standard manner.

The resulting compound of the formula (II) can be hydrolyzed to give a corresponding deacylated compound of the formula (III). The hydrolysis is accomplished under an acidic or alkaline condition according to an ordinary hydrolysis procedure. γ-Piperidinobutyrophenones of the formula (IV) are prepared by diazotization of the above-obtained o-amino-compound of the formula (III) wherein R5 is hydrogen, and subsequent treatment of the resulting diazonium salt with a suitable agent to replace the diazonium group by hydrogen, halogen or hydroxyl group.

The diazotization is performed by a conventional method and the replacement reaction is conducted as follows.

By the treating the diazonium salt with copper powder, fluoroboric acid or a metal salt such as cuprous chloride, cuprous bromide, potassium iodide, mercuric halide pi-BfirJ^ino^ and the like, there can be obtained γ-fbutyrophenones of the formula (IV) wherein X is halogen.

By treating the diazonium salt with a reducing agent such as ethanol, hypophosphorous acid, alkaline formaldehyde, sodium stannite and the like, there can be obtained piperidino^ γ-rou yropnenones of the formula (IV) wherein X is hydrogen.

Further by treating the diazonium salt with water, aqueous sulfuric acid, copper sulfate, sodium sulfate and the •piperidinoj like under heating there can be obtained γ-foutyrophenones of the formula (IV) wherein X is hydroxyl.

The foregoing is a general description, and in order to explain the diazotization and the replacement reaction more clearly, a few reaction schemes will be shown as follows: R- H O 0 wherein R2, R and R^" are the same as described above.

According to the present invention, following piperidinobutyrophenone derivatives are prepared easily. y-Piperidino-2-chlorobutyrophenone γ-Piperidino-2-bromobut rophenone Ωw Y-Piperidino-2-acetamido-butyrophenone γ-Piperidino-2-amino-but rophenone 7-Piperidino-2-chloro-4-fluorobutyrophenone Y-Piperidino-2-bromo-4-fluorobutyrophenone γ-Piperidino-2-chloro-5-fluorobutyrophenone γ-Piperidino-2-acetamido-4-fluorobutyrophenone γ-Plperidino- -amino- -fluorobutyrophenone 7-Piperidlno-2-bromo-5-fl orobutyrophenone Y-Piperidino-2, 4-dichlorobutyrophenone y-Piperidino-2, -dibromobutyrophenone ° - - - - γ- ( 4-Methylpiperidino )-2-bromobutyrophenone γ-( -Methylpiperidino )-2-acetamidobutyrophenone γ- ( -Methylpiperidino )-2-aminobutyrophenone γ- (4-Methylpiperidino )-2-chloro-4-fluorobutyrophenone γ-( -Methylpiperidino )-2-chloro-5-fl orobutyrophenone γ- (4-Ethylpiperidino )-2-chloro-5-fluorobutyrophenone γ-( 4-Ethylpiperidino)-2-chloro-4-fluorobutyrophenone γ- (4-Methylpiperidino )-2-acetarnido-4-fluorobutyrophenone γ- ( 4-Methylpiperidino )-2-acetamido-4-fluorobutyrophenone γ- (4-Methylpiperidino )-2-amino-4-fluorobutyrophenone γ. (4-Methylpiperidino )-2-amino-4-fluorobutyrophenone γ- (4-Phenylpiperidino )-2-chloro-4-fluorobutyrophenone γ- ( 4-Phenylpiperidino )-2-amino-4-fluorobutyrophenone y- ( 4-Phenylpiperidino )r-2-acetamido-4-fluorobutyrophenone γ- (4-Hydroxy-4-phenylpiperidino)-2-acet.amido-4-fluorobutyrophenone γ_ (4-Hydroxy-4-phenylpiperidino )-2-amino-4-fluorobutyrophenone Y_(4_Hydroxy-4-phenylpiperidino )-2-chloro-4-fluorobutyrophenone Y-(4_Hydroxy-4-phenylpiperidino )-2-bromo-4-fluorobutyrophenone γ_ (4-Hydroxy-4-p-chlorophenylpiperidino )-4-fluorobutyrophenone γ_ (4-Hydroxy-4-p-chlorophenylpiperidino )-2-chloro-4-fluorobutyrophenone γ_ (4-Hydroxy-4-p-chlorophenylpiperidino )-2-hydroxy-4-fluorobutyrophenone γ- (4-Hydroxy-4-p-chlorophenylpiperidino )-3- luorobutyrophenone γ_ (4-Hydroxy-4-p-chlorophenylpiperidino )-2-acetamido-5 fluorobutyrophenone Y_(4-Hydroxy- -p-chlorophenylpiperidino )-2-met ylamino 5-fluorobutyrophenone γ_ (4-Hydroxy-4-p-chlorophenylpiperidino )-2-ethylamino-5-fluorobutyrophenone Y-(4-Hydroxy-4-p-chlorophenylpiperidino )-2-chloro-5-fluorobutyrophenone γ» (4-Hydroxy- -p-chlorophenylpiperidino )-2-bromo-5-fluorobutyrophenone Y_(4-Hydroxy-4-p-chlorophenylpiperidino )-2-hydroxy-5-fluorobutyrophenone _(4_Hydroxy-4-p-chlorophenylpiperidino )-2, 5-difluorobutyrophenone 7-(4-Hydroxy- -p-chlorophenylpiperidino )-2,5-dichlorobutyrophenone Y_(4-Hydroxy-4-p-tolylpiperidino )-2-chloro-5-fluorobutyrophenone Y-(4-Hydroxy- -p-methoxyphenylpiperidino)-2-chloro-5-fluorobutyrophenone y-(4-Hydroxy-4-p-hydroxyphenylpiperidino )-2-chloro-5-fluorobutyrophenone 7-(4-Hydroxy- -m-hydroxyphenylpiperidino)-2-chloro-5-fluorobutyrophenone Y_(4_Hydroxy- -rri-chlorophenylpiperidino)-2-chloro-5-fluorobutyrophenone γ- ( -Hydroxy-4-p-chlorophenylpiperidi.no )-2-amino-butyrophenone Y-.(4_Hydroxy- -p-chlorophenylpiperidino )-2-amino-4-fluorobutyrophenone γ_ ( 4-Hydroxy-4-p-tolylpiperidino )-2-amino-5-fluoro y-(4-Hydroxy- -p-tolylpiperidino)-2-hydroxy-5-fluoro-butyrophenone γ_( J|—Hydroxy- -p-tolylpiperidino ) - -fluorobutyrophenone y_(i).-Hydroxy- -p-tolylpiperidino)-2-methylamino-5-flu-orobutyrophenone γ.( -Hydroxy-4-m-trifluoromethylphenylplperidino) -2-amino-5-fluorobutyrophenone 7-( -Hydroxy-4-m-trifluoromethylphenylplperidino )-2-chloro-5-fluorobutyrophenone γ_( 4-Hydroxy- -m-trifluoromethylphenylplperidino ) -2-hydroxy-5-fluorobutyrophenone 7-( -Hydroxy- -m-trifluoromethylphenylplperidino ) -3-fluorobutyrophenone . γ-( ^-Hydroxy- -m-trifluoromethylphenylplperidino ) -4-fluorobutyrophenone These compounds can be formed the corresponding acid-addition salts by a procedure known to the art, for example, by dissolving the free base in an aqueous solution containing an appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base with acid in an organic solvent.

These salts include pharmaceutically acceptable acid addition salts, e.g. hydrochloride, fumarate, formate, acetate, lactate citrate, sulfonate, maleinate, tartrate, methane sulfonate, salicylate and hydrosulfate.

These γ-piperidinobutyrophenone derivatives of the formula (I) and their pharmaceutically acceptable acid addition salts have central nervous system activity and are useful as anti-anxiety, anti-psychotonic, anti-emotional, an i-convulsive or anti-psychosis drug. this invention may be, tration, in tablet as tablet is constituted by from 1 to 2 percent binder, e.g. tragacanth; from 3 to 10 percent lubricant, e.g. talcum; from 0.25 - 1.0 percent lubricant, e.g. magnesium stearate; an average dose of active ingredient j and q. s. 100 percent of filler, e.g. lactose. The usual oral dosage is 1 - 100 mg per os daily.

The following examples are intended to illustrate the present invention, but not to limit its scope.

Example 1 Stage 1 A stirred mixture of 14. g of phenylhydrazine hydrochloride, 19.2 g of l-(7-acetylbutyryl)piperidine and 100 ml of acetic acid was. heated at 75° - 80°C for 4 hours. After cooling, the reaction mixture was poured into 70oml of cold water. The solid material which was separated was filtered, washed with water and recrystallized from ethanol to give l-[]3-(2-methyl-3-indolyl)propionyl]piperidine having a melting point of l4l° - l43°C.

Stage 2 To a stirred mixture of 2.0 g of lithium aluminium hydride and 50 ml of ether was added dropwise a solution of 4.9 g of l-[£-(2-methyl-3-indolyl)propionyl]piperidine in 130 ml of tetrahydrofuran over a period of 30 minutes under gentle refluxing. Stirring and refluxing were continued for additional 3 hours and the reaction mixture was added drop-wise with a mixture of 10 ml of water and 40 ml of tetrahydrofuran under cooling with ice. The resulting precipi-tate was filtered off and the filtrate was evaporated to dr R r ti n f the r due fr m enze gave 2-methyl-3-(7-piperidinopropyl)indole having a melting^ point of 140.5° - l4l°C. ^~ method similar to that of the above procedure, following compounds were obtained. 2-Methyl-3-[ γ-( 4-phenylpiperidino )propyl ] indole, melting point 119.5° - 121.0°C 2-Methyl-3-[ y-( 4-phenylpiperidino)propyl] -5- luoro-indole, melting point 153° - 154°C 2-Methyl-3-[y-( -hydrox -phenylpiperidino )propyl] -5-fluoroindole, melting point l6l° - l62°C Stage 3 L While oxygen containing 3 - 4$ ozone was introduced into a solution of 2.0 g of 2-methyl-3-(¾'.-piperidinopropyl ) -indole in 40 ml of acetic acid solution became pale yellow (in fact, about 35 minutes were required), the temperature was maintained at 16° - 20°C.

After the reaction mixture was made alkaline by addition of 10$ aqueous solution of sodium hydroxide, it was extracted with ethyl acetate. The extract was washed with water and evaporated residue. The residue was crystallized from ether-petroleum ether to give γ-piperidino-2-acetaminobutyrophenone having a melting point of 5° - 48°C.

According to a method similar to that mentioned above, following ' compounds were obtained. y-( 4-Phenylpiperidino) -2-acetaminobutyrophenone hydrochloride, melting point 240°C (decomposition) y-(4-Phenylpiperidino) -2-acetamino-5-fluorobutyro-phenone, melting point 130.0° - 131.0°C, and its hydrochloride, melting point 248°C (decomposition) γ-( 4-Hydroxy-4-phenylpiperidino) -2-acetamino-5-flu-orobutyrophenone, melting point 120.0° - 121.0°C A solution of 3 - 5 g of y- ( 4-piperidino) -2-acet-aminobutyrophenone hydrochloride and 6 ml of concentrated hydrochloric acid in 70 ml of ethanol was heated under re-flux for 3 hours. After cooling the reaction mixture was diluted with 100 ml of water, and made alkaline with 0$ aqueous sodium hydroxide. The resulting oily substance was extracted with ethyl acetate. The extract was washed with water and evaporated to a residue, which was recrystallized from aqueous ethanol to give 7-( -piperidino) -o-aminobutyro-phenone, melting at 92 ° - 93°C.

Stage 5 To a cooled solution of 3.6 g of y-piperidino-2-aminobutyrophenone in 35 ml of 2N hydrochloric acid was added dropwise a solution of 1. 1 g of sodium nitrite in 5 ml of water under stirring below 0°C. The resulting diazonium salt solution was added to a cold suspension of 1. 5 g of cuprous chloride in 5 ml of concentrated hydrochloric acid under vigorous stirring. The mixture was stirred for 30 min-utes under ice-cooling, and an additional stirring was continued for 2 hours at room temperature and then for 1 hour at 55° - 60°C. After cooling, the reaction mixture was made alkaline with ammonium hydroxide and was extracted with ether. The ethereal extract was washed with an aqueous solu- o tion saturated with sodium chloride, dried over anhydrous sodium sulfate and evaporated to give an oily residue. The residual oil was treated with anhydrous hydrogen chloride in ether to give crystals of 7-piperidino-2-chlorobutyro-phenone hydrochloride, which were recrystallized from ethanol. Melting point 166 ° - 167°C.

By a method similar to that of the above procedure, γ-( 4-Phenylpiperidino) -2-chlorobutyrophenone hydrochloride, melting point 182° - l84°C Example 2 Stage 1 To a stirred solution of 15-0 g of /3-(2-methyl-3-indolyl)propionic acid and 7.5 g of triethylamine in 100 ml of tetrahydrofuran was added dropwise 8.0 g of ethyl chlo-roformate at a temperature below -5°C. The stirring was continued for additional 15 minutes at -5°C and thereto was added dropwise a solution of 6.3 g of piperidine in 10 ml of tetrahydrofuran. After addition was completed, the reaction mixture was stirred for 4 hours at a room temperature and then filtered. The filtrate was evaporated under reduced pressure to a residue, which was crystallized by treatment with ether and recrystallized from ethanol to give 1-/3-(2-methyl-3-indolyl)propionyl piperidine, melting at 142° - 142. °C.

Stage 2 According to a procedure similar to that of the stage 2 of the Example 1, 2-methyl-3-(7-piperidino-propyl )indole was obtained, melting point 140.5° - l4l°C. Stage 3 To a stirred solution of 1.1 g of 2 -methyl-3-(γ-piperidinopropyl) indole in 10 ml of acetic acid was added a solution of 1.0 g of chromic anhydride in 1 ml of water below 16°C. After stirring overnight at a room temperature, the reaction mixture was poured into 80 ml of water, made alkaline with 10$ aqueous solution of sodium hydroxide thereto was added 0 ml of chloroform and filtered. The fil-trate was extracted with chloroform and the extract was washed with an aqueous solution saturated with sodium chloride, dried over anhydrous sodium sulfate and evaporated to give crystals of 7-piperidino-2-acetaminobutyrophenone, identical with that obtained by above Example 1' in infrared spectrum. This crystals were treated with hydrogen chloride in ether to give the hydrochloride melting at 1 7° - 148°C. Example 3 Stage 1 To a solution of 10.8 g of phenylhydrazine in 100 ml of 3 % aqueous acetic acid was added 27-3 g of 1- (7-acetylbutyryl)- -phenylpiperidine and the resulting mixture was stirred for 30 minutes at room temperature. The precipitate was filtered, and washed with water. The precipitate was added to l8o ml of 5 ethanolic hydrogen chlo-ride, and mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure to the residue, to which was added 100 ml of water. The resulting solidal substance was recrystallized from ethanol to give l-[ A-(2-methyl-3-indolyl )propionyl ) -4-phenylpiperidine , melting at 121° - 122°C.

By a method similar to that of above example, following compounds were obtained. 1-[ β-( 2-Methyl- -fluoro-3-indolyl) propionyl ] -4-phenylpiperidine, melting point 156.5° - 157.0°C l-[^-(2-Methyl-5-fluoro-3-indolyl)propionyl]-4-hy-droxy-4-phenylpiperidine, melting point 157° - 158°C l-[ -(2-Methyl-5-fluoro-3-indolyl)propionyl] -4-hy-droxy-4-p-chlorophenylpiperidine l-[£-(2-Methyl-5-fluoro-3-indolyl)propionyl]-4-hy droxy-4-p-tolylpiperidine, melting point 177° - 178°C l-[ £-( 2-Methyl-5-fluoro-3~indolyl)propionyl] -4-hy-droxy- ~m-trifluoromethylphenylpiperidine Stage 2 These compounds obtained in the Stage 1 were converted to the following compounds respectively by the method mentioned in the Stage 2 of the Example 1. 2-Methyl -3-[ y-( 4-phenylpiperidino )propyl] indole, melting point 119. 5° - 121. 0°C 2-Methyl-3-[ 7-( -phenylpiperidino )propyl] -5- luoro-indole, melting point 153° - 15 °C 2-Methyl-3-[ γ-( -hydroxy- -phenylpiperidino )propyl] -5-fluoroindole, melting point l6l° - l62°C 2-Methyl-3-[ γ-( ^-hydroxy-^-p-chlorophenylpiperidino)-propyl] -5-fluoroindole 2-Methyl-3-[Y-(^-hydroxy- -p-rtolylpiperidino)propyl] -5-fluoroindole, melting point 183 ° - l84°C 2-Methyl -3 -[ y-( 4-hydroxy-4-m-trifluoromethylphenyl-piperidino)propyl] -5- luoroindole Stage 3 To a solution of 7.6 g of 2-methyl-3-[y-( 4-phenylpiperidino)propyl] indole in 100 ml of acetic acid was introduced 3% ozone oxygen gas for about 2 hours at 15° -20°C. At this time the solution was changed in color gradually from yellow to red and finally to yellow. The result-ing yellow solution was made alkaline with 50$ aqueous sodium hydroxide and was extracted with chloroform. The extract was washed with water, dried over potassium carbonate and evaporated to give oily γ-( 4-phenylpiperidino) -2-acetamino-butyrophenone, which was treated with hydrogen chloride in alcohol to give the hydrochloride, melting at 237° - 239°C.

By a method mentioned above following compounds were obtained.

Y-( -Phenylpiperidino) -2-acetamino-5-fluorobutyrophenone, melting point 130° - 131°C, and its hydrochloride, melting point 248°C (decomposition) γ-( -Hydroxy-4-phenylpiperidino) -2~acetamino-5-fluorobutyrophenone, melting point 120° - 121°C γ-( 4-p-Chlorophenyl-4-hydroxypiperidino )-2-acetamino-5-fluorobutyrophenone 7-( -Hydroxy-4-p-tolylpiperidino)-2-acetamino-5- luorobutyrophenone γ-( 4-Hydroxy- -m-trifluoromethylphenylpiperidino)-2-acetamino-5-fluorobutyrophenone Stage A solution of 3.5 g of 7-(4-phenylpiperidino)- 2-acetaminobutyrophenone hydrochloride and 6 ml of concentrated hydrochloric acid in 70 ml of ethanol was heated under reflux for 3 hours. After cooling, the reaction mixture was diluted with 100 ml of water, and made alkaline with 0$ aqueous sodium hydroxide. The resulting oily substance was extracted with ethyl acetate. The extract was washed with water and evaporated to a residue, which was recrystallized from aqueous ethanol to give ,y-( -phenyl-piperidino)-o-aminobutyrophenone melting at 61° - 6l.5°C.

By a method mentioned above, following compounds were obtained. γ-( 4-Phenylpiperidino) -2-amino-5- luorobutyrophenone, melting point 89.0 - 90.0°C γ-( 4-Hydroxy-4-phenylpiperidino) -2-amino-5-fluoro-butyrophenone, melting point 102.0° - 103.0°C, and its dihydrochloride, melting point l 2.0°C (decomposition) γ-( -Hydroxy-4-p-chlorophenylpiperidino)-2-amino-5-fluorobutyrophenone 7-(4-Hydroxy-4-p-tolylpiperidino)-2-amino-5-fluoro-butyrophenone γ~( -Hydroxy-4-m-trifluoromethylphenylpiperidino) -2-amino~5-fluorobutyrophenone Stage 5 To a cooled solution of 7.13 g of 7-(4-hydroxy- -phenylpiperidino) -2-amino-5- luorobutyrophenone in 200 ml of 5% hydrochloric acid was added portionwise 1.52 g of sodium nitrite under stirring at a temperature from -5°C to 0°C. The resulting diazonium salt solution was added to a cooled solution of 90 ml of 50% aqueous solution of phos-phinic acid with vigorous stirring. After stirring for 2 hours under cooling, the mixture was kept in a. refrigerator overnight. The reaction mixture was alkalized by addition of 10% aqueous sodium hydroxide and extracted with ether. The ethereal extract was washed with water, dried over anhy-drous sodium sulfate and evaporated to dryness. The residual crystalline solid was recrystallized from dlisopropylether to give 7-(4-hydroxy-4-phenylpiperidino)-3-fluorobutyrophenone, melting at 119° - 120.5°C.

By a method mentioned above, following compounds were obtained. 7-(4-Hydroxy-4-phenylpiperidino) -butyrophenone, melting poing 128.5° - 129. °C γ-( 4-Hydroxy-4-phenylpiperidino ) -butyrophenone hydrochloride, melting point l8l.5° - l83.5°C (decomposition) By a method similar to that mentioned above, following compounds were obtained. y-( 4-Phenylpiperidino ) -2-chloro - -fluorobutyrophenone γ-( 4-Hydroxy-4-p-chlorophenylpiperidino) -2-chloro-5-fluorobutyrophenone γ-( 4-Hydroxy-4-p-chlorophenylpiperidino) -2-bromo-5-fluorobutyrophenone γ-( 4-Hydroxy-4-p-tolylpiperidino) -2-chloro-5-fluorobutyrophenone γ-( 4-Hydroxy-4-m-trifluoromethylphenylpiperidino) -2-chloro-5- luorobutyrophenone γ-( 4-Hydroxy-4-p-methoxyphenylpiperidino) -2-chloro-5-fluorobutyrophenone Example 5 To a cooled solution of 1. 5 S of 7-( 4-phenyl-piperidino) -o-aminobutyrophenone in ml of 10$ hydrochloric acid was added 0. 35 g of sodium nitrite in portions under stirring at a temperature from -5°C to 0°C. The resulting diazonium salt solution was added to a cooled solution of 20 ml of 50$ phosphonic acid with vigorous stirring. The stirring was continued for 1. 5 hours. After the reaction mixture was stored in a refrigerator overnight, mixture was made alkaline with 10% aqueous sodium hydroxide. The oil separated was extracted with ether. The ethereal extract was washed with aqueous solution saturated with sodium chloride, dried over anhydrous sodium sulfate and evaporated to a residue. The solidal residue was recrystallized from ethanol to give γ-( -phenylpiperidino)butyrophenone melting at 59° - 60°C.

By a method mentioned above, following compounds were prepared. γ-Piperidinobutyrophenone hydrochloride, melting point 210° - 211°C y-( 4-Hydroxy-4-p-chlorophenylpiperidino) -4-fluoro-butyrophenone, melting point 149° - 150°C f γ_( 4-Hydroxy-4-p-tolylpiperidino) -4-fluorobutyrophenone, melting point 119° - 120°C 7-(4-Hydroxy-4-m-trifluoromethylphenylpiperidino)-4-fluorobutyrophenone hydrochloride, melting point 206° - 207°C 7-[4-Hydroxy-4-(m, p-dichlorophenyl ) -piperidino] -4-fluorobutyrophenone, melting point 135° - 137°C Y-4-Hydroxy-4-( m-methyl-p-chlorophenyl)piperidino-4-fluorobutyrophenone, melting point 123° - 124°C Example 6 To a cooled solution of 7. 13 g of y-(4-hydroxy- 4-phenylpiperidino) -2-amino-5-fluorobutyrophenone in 100 ml of 4N-sulfuric acid was added dropwise a solution of 1 - 5 g of sodium nitrite in 10 ml of water under stirring at a tem-perature from ~5°C to 0°C. The resulting diazonium salt solution was added dropwise to a boiled mixture of 3 ml of concentrated sulfuric acid and 30 ml of water, and the mixture was heated for several minutes under stirring. Thereafter the reaction mixture was allowed to cool.

The cooled reaction mixture was made alkaline with aqueous sodium hydroxide and was extracted with ethyl acetate. The extract was washed with water, evaporated to dryness and the residual product was crystallized by treating with ethanol to give 7-(4-hydroxy-4-phenylpiperidino)-2-hydroxy-5- luorobutyrophenone, whose infrared spectrum showed v nujol max = 1,660 (cm-1).

Treatment with methanolic hydrogen chloride and recrystallization from isopropanol-diisopropylether gave white crystals of the hydrochloride.

Aqoordanqe with the method mentioned above, following compounds w re obtained.

Stage 2 To a stirred mlxtupe of 6.6 g of lithium aluminum hydride and 50 ml. of ether was added dropwlee a solution of 26.9 g of crude 1 —[β-( 6— fluopp-2-aethyl-3-ind01yl)proplonyl]«i÷^P*chlopophenyl- -hydroxyplperldine, which was obtained in Stage 1» In 250 ml. of tetrahydrofuran under gentle refluxing.

Stirring and refluxing were continued for additional 3*5 hours and the reaction mixture was added dropwise to a mixture of water and tetrahydrofuran under cooling with ice. The resulting precipitate was filtered off and the filtrate was evaporated to dryness. The residue was crystallized from toluene to give 2rnethyl-3÷ £ YKi+^^ lCTopheni^--yd oxypiperidin ' Oxygen containing 3- of ozone was introduced into a solution of 1J+.9 g of 2-methyl-3» C * -P*chlorophenyl«^-hydroxy~piperidino)propylJ-6-iluoroindole in 150 ml. of acetic acid at a temperature of Ι5α-2000· While oxygen containing ozone was "butfbled fo one hour, the.reaction mixture "became dark red and then gradually discolored. The reaction mixture obtained was diluted with water, made alkaline with a 20 aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed wit water, dried oyer anhydrous potassium carbonate and evaporated to dryness. The residual. oil was crystallized from aqueous ethanol to giveY-i -p-ohlorophenyl^Hhydroxy^ fluorohutyrophenone havin a melting point of 119.50,-ti21 .p¾.

A solution of 7.3 g Of )(^Ι^^&ονο&&τφ1· * hydroxypiperidino)^ and 8 ml. of concentrated hydrochloric:ao d. in 80 ml.

After ethanol was evaporated to dryness, the residual solid was recryetallised from methanol to giveX-(U^^Morophe l^-hydrox piperidino)- 2-amlno-J+"-fluorohu1¾n?ophenone monohydroehlorids having a melting point of 236°C (decomposition). e: a ove-olDtained hydrochloride was treated with an aqueous potassium carbonate solution to give the free base, whic was reorystalllsed from aqueous ethanol to yield ^ -p-chlorophenyl-^.-hydroxypiperidino)-2«-amino-l+- luorohutyrophenone ha ing a melting point of ΐΙι ·5βΗ4β·5°δ· Stage 5 hydrochloric aoid was added portionwise 0.7 g of sodium nitrite under stirring at a temperature below 5 · Afte the resulting mixture was stirring for additional 30 minutes, the mixture was added to a cooled suspension of .5 of cuprous chloride in 15 ml. of concentrated hydrochloric acid with vigorous stirring. The stirring was continued for additiona 30 minutes at room temperature, and. then 2 hours at 5Q0-70°0. After cooling, the reaction mixture was made alkaline with conoentrated ammonium hydroxide and extracted with chloroform. The extract was washed with water, dried over anhydrous potassium carbonate and evaporated. The residual oil was treated with hydrogen chloride in ether to give -(4-p-chlorophenyl-4-hydroxypiperid±iio)-2-chloro-4-fluorobutyrophenone hydrochloride, which was recrystallized from isopropyl alcohol. Melting point» 185.5°-188.0°C (decom¬ position).

COMPARATIVE TEST I Pharmacological Data tested: ί - (4-Hydro3-y-4-p-chlorophenylpiperidino )-2-acetamido-4- fluorobutyrophenone lf-(4-Hydroxy-4-p-chlorophenylpiperidino )-2-amino-4-fluoro- butyrophenone monohydrochloride Y - (4-Hydroxy-4-¾n-trifluorometh lphenylpiperidino) -2-acetamidO' 4-fluorobutyrophenone 1^-(4-H dro-^-4-m-t ifl^ fluorobutyrophenone Anti-apomorphlne test (rats) Suppression of conditioned avoidance response (rats) Compound ED_ mg/kg (s.c.) (A) 0.046 (B) 0.054 (C ) 0.030 (D) 0.020 Haloperidol 0.105 Acute Toxicity (mice) Compound LD_n mg/kg (s.c.) (A) 1000 (B) , 600 (C) >1200 (D) 600 The testing method for anti-apomorphine test and the test for suppression of conditioned avoidance response, can be found in. "Arzneimittel-Forsohung", Vol. 15, No. 2* pages 104-117 (1965).

COMPARATIVE TEST II The following comparative experimental data shows the superiority of .O-halogen substituted compounds.

Compounds tested) (E) f-(4-Hydroxy-r-p-chlorophenylpiperidino )-2-chloro-4-fluoro- butyrophenone Results: (a) Anti-apomorphine test (rats) Compound (E) 0.40 Suppression of conditioned avoidance response (rats) Compound (Ej 0.080

Claims (9)

What we claim is:

1. A process for producing a γ-piperidinobutyrophenone compound of the formula, wherein R is hydrogen, halogen, hydroxyl, amino, acylamino, alkylamino or N-acylalkylamino, each of said alkyl group having up to 4 carbon atoms; R2 is hydrogen or halogen; R3 is hydrogen or unsubstituted or alkyl-, alkoxy-, halogen- or trifluoromethyl- substituted phenyl, each of said alkyl or alkoxy group having up to 4 carbon atoms; and R^ is hydrogen or hydroxyl, and an acid addition salt thereof, which comprises contacting an indole compound of the formula, wherein R5 and R^ are hydrogen or alkyl having up to 4 carbon atoms respectively, and R2, R3 and R2*" are the . same as identified above, with an oxidizing agent to yield a compound of thg, formula, wherein R2, R3, are the same as defined above, and if necessary, hydrolyzing the resulting compound to a compound of the formula, wherein R2, R3, and R5 are the same as defined above, and further diazotizing, if desired, in the case where R5 is hydrogen, the resulting compound and subsequently decomposing the resulting diazonium compound to replace the diazonium group by hydrogen, halogen or hydroxyl group to yield a compound of the formula, R3 wherein X is hydrogen, halogen or hydroxylj and R , and R^ are the same as identified above.

2. A process according to Claim 1, wherein the said oxidizing agent is ozone, hydrogen peroxide, performic acid, peracetic acid, perbenzoic acid, chromic acid or potassium permanganate.

3. A process according to Claim 1, wherein the said replacement reaction is carried out by treating the diazonium compound with cuprous halide, mercuric halide, potassium halide, copper powder or fluoroboric acid to yield the compound of the formula, wherein R2, R and R^ are the same as defined in Claim 1 and Rl is a halogen atom.

4. A process according to Claim 1, wherein the said compound with ethanol, hypophosphorous acid, alkaline formaldehyde or sodium stannite to yield the objective compound of the formula, 2 ·5 h. wherein R , RJ and . are the same as defined in Claim 1 and R is a hydrogen atom.

5. A process according to Claim 1, wherein the said replacement reaction is carried out by heating the diazonium compound with water in the presence or absence of sulfuric acid, copper sulfate or sodium sulfate to yield the anbje tiive compound of the formula, R3 wherein R R3 and R^ are the same as defined in Claim 1 and R is a hydroxyl group.

6. A compound of the formula, wherein R2 is hydrogen or halogen; R3 is hydrogen or unsub-stituted or alkyl-, alkoxy-, halogen- or trifluoromethyl-substituted phenyl, each of said alkyl or alkoxy group having up to carbon atoms; and R^ is hydrogen or hydroxyl, R7 is halogen ■faji&r-oeen-, hydroxyl, amino, alkylamino, acylamino or N-acyl-alkylamino, each of said alkyl group having up to k carbon atoms, and a pharmaceutically acceptable acid addition salt 34933/2 thereof.

7. A compound according to claim 6, wherein the halogen of 2 R is fluorine. 3

8. 6· A compound according to claim 6, wherein R is phenyl substituted by halogen, alky , alkoxy or trifluoromethyl, and R is hydroxy. ·

9. A pharmaceutical composition consisting of a pharmaceutically effective amount of a compound as claimed in any of Claims 6-8 and a pharmaceutically acceptable diluent or carrier. Attorney for Applicants.