NO166410B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 1-PIPERAZINE CARBOXAMIDE DERIVATIVES. - Google Patents

Description

The present invention relates to an analogous method for the production of the 1-piperazine carboxamide type with the general formula I as defined in claim 1's preamble.

A number of pharmacologically active J-pL-perazine carboxamides are previously known which are substituted in the 4-position with an unsubstituted or substituted arylalkyl side chain or a functional derivative thereof. Such connections can be found in the following references:

Japan Kokai 76 08, 283

British Patent No. 2,037,745.

It is also previously known that a number of butyrophenones derive!: from 1-acylpiperazine. They are indicated to show a central inhibitory activity.

US patent 3,000,892 describes as a compound with central nervous system-depressant and hypnotic activity compounds with the formula where Ar is a group from the class of phenyl, methoxyphenyl, halophenyl, dimethoxyphenyl and trimethoxyphenyl and where Z is hydrogen, methoxy or halogen. 1 the article "1-/3-(4-fluorobenzoyl) propyl_7-4-acylpipera-7. i nes and some related compounds" by M. Rajsner et al. in Collect. Czech. Chem. Commun. 1975, 40(4), 1218-30 occurs among the described compounds such as those with the general formula

where R is OEt, Et, NH^ and N(CH 3 ) 2 - The compounds are indicated to show only a weak inhibitory activity which is only evident at high doses.

RI ant- the compounds described in Swedish patent no. 350,497 or compounds under the general formula (B) where R is OR', where R' means an alkyl group with from 1 to 4 carbon atoms, a cyclic hydrocarbon residue, e.g. cyclohexyl or an arylalkyl group, e.g. benzyl. The compounds have f;, e.g. neuroleptic properties.

The compounds in the present invention differ from those above mainly in that they are 1-piperazine carboxamides, where special substituents are in the 4-position, or have a special combination of substituents in the 4 -position of the nitrogen in the amide function.

The pharmacological properties that clearly distinguish the compounds of the present invention from what is previously known are described under the heading "Pharmacological equations."

This invention thus relates to an analogous method for the production of new l-piperazine carboxamide derivatives having the structural formula (I)

and the pharmaceutically acceptable acid addition salts thereof;

in which

R± is selected from hydrogen, halogen or trifluoromethyl,

X is selected from

R2 and R3 are the same or different and selected from hydrogen or lower alkyl of 1-4 carbon atoms,

2 is either oxygen or sulfur,

Y is -NR4R5 in which R4 and R5 are the same or different and selected from hydrogen, alkyl with 1-4 carbon atoms, cycloalkyl, phenyl, where the phenyl group can optionally be substituted with 1-3 substituents which can independently be halogen, methyl, methoxy , trifluoromethyl, where halogen is fluorine, chlorine or bromine, or R4 and R5 together with the nitrogen atom are pyrrolidino or morpholino,

R6 and R7 are the same or different and are selected from hydrogen or alkyl of 1-4 carbon atoms,

with the proviso that when X is /CO, R 4 is hydrogen and R 5 is different from hydrogen,

and in the preceding definitions "lower alkyl" means straight and branched chain hydrocarbon residues of 1 to 4 carbon atoms; the term "lower alkenyl" means straight chain and branched alkenyl radicals having from 2 to 4 carbon atoms; the term "alkyl" means straight and branched chain hydrocarbon radicals having from 1 to 10 carbon atoms; the term "alkenyl" means straight or branched chain alkyl radicals having from 2 to 10 carbon atoms; the term "cycloalkyl" means cyclic hydrocarbon radicals having from 3 to 8 carbon atoms; the term "aryl" means phenyl and substituted phenyl, wherein the substituted phenyl has from 1 to 3 substituents each independently selected from the group of halogen, methyl, methoxy, trifluoromethyl and NR 2 R 2 ; and the term "halogen"

is generic for fluorine, chlorine and bromine;

with the proviso that when X is CO, is hydrogen and R^ is different from hydrogen.

Among: the compounds covered by the general formula (I), it is preferred that R is halogen or CF₂ and that this substituent is in the m- or p-position.

livi.s it is selected from among halogen atoms, it is preferred that R^ is F or Cl, especially F.

When R.j is CF^, it preferably sits in an m-style-1 i n q .

It is preferred that R 1 and R 2 are hydrogen.

When R 2 and R 1 are lower alkyl groups, methyl is preferred

and ethyl, especially methyl.

A group of preferred compounds are those where X is CH_, C=CRCR-, or CHCHR, R -,.

2 6 7 6 7

When X is selected from the groups CHOH, CHORg and CHOCORfi, compounds in which X is CHORR or CH0C0Ro, especially CH0Ro, are preferred. OE OE

Preferred compounds are also those in which X is CO.

For compounds where the group X has polar properties (such as when X is CO or CHOH), higher water solubility is expected.

Compounds where the substituent X has nonpolar properties (such as when X is CH_, C = CR,R.,, CHCH R ,R,, 2 6 7 6 7 CH0Ro or CH0C0Ro) will show a greater tendency to participate in hydrophobic mutual influences. The non-polar properties increase with increasing chain length of the substituents R^, R7 and Rg.

Compounds in which Z is S are markedly more nonpolar than those in which Z is 0. Thus, compounds of the general formula (I) in which Z is S are of particular interest when other groups or substituents are of a polar nature, such as when X is CO or CHOH.

With regard to substituents R 1 and R 2 , such compounds are preferred where one of the substituents is hydrogen or methyl.

With regard to the substituents R 1 and R 1 , such compounds are preferred where R 1 is hydrogen and R 1 is alkyl. or alkenyl or and RR together with the N atom is pyrrolidino or morpholino.

Compounds of formula (I) have basic properties, and consequently they can be converted into their therapeutically active non-toxic acid addition salts by treatment with corresponding acids; e.g. inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as acetic acid, propanoic acid, glycolic acid, lactic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid and pamonic acid.

Conversely, the salt form can be transferred into the free base by treatment with alkali.

Fr ems ti11 in ngsmåts

Compounds of formula (.Ia„ b-, b' , b" , c, d, e) can be prepared according to methods 1 and 2.

Compounds with formula (Ia„ c, d, e) can be prepared according to method 3.

Compounds of formula (Ia, b, b', b", c, d, e) where R^ and R^, both are hydrogen, can be prepared according to the above 4.

Compounds of formula Cia) can be prepared according to the above method 5 .

Compounds of formula (Ib) can be prepared according to the procedure described in step 6.

Compounds of formula (Ic, e) can be prepared according to i" r emq ang sm å t e ') .

Compounds of formula dc, d, e) can be prepared according to method 10.

Methods 11, 12, 13, 14, 15 and 16 describe methods for the production of intermediate products.

Procedure 1

Compounds of formula (Ia, b, c, d, e) can

produced by reacting compounds of formula (II)

(R^, X, R^, R^ are as indicated above) with an isocyanate of formula (III), or an isothiocyanate of formula (IV), or a carbamoyl chloride of formula (V) or a compound of formula (VI ).

R^ and R,- are as indicated above.

R means a phenyl group or when none of the substituents on the N atom is hydrogen, preferably a substituted phenyl group (preferably electronegative substituents, especially p-nitro).

The reactions can be carried out using standard methods and are thus preferably carried out in organic solvents such as diethyl ether, chloroform, toluene etc. The mixtures are reacted over a wide temperature range from approx. 0°C to approx. 110°C (although it is possible to use temperatures above and below this range. The reactions can be carried out in the presence of a base, e.g. triethylamine or potassium carbo-

Procedure 2

Compounds of formula (Ia, b, c, d, e) can be prepared by reacting the corresponding compounds of formula (VII) (R^, X, R^, R^ and Rft are as indicated above) with the corresponding amine (R^ and R^ are as indicated above).

The reaction is carried out using a large excess of amine as solvent, or a smaller excess is combined with a suitable carbonizing agent, such as; lower alkanols (eg methanol, ethanol, propanol, butanol) or an aromatic hydrocarbon (eg benzene, toluene, xylene). You can heat to facilitate the reaction, which may be necessary when less reactive amines are used.

Procedure 3

Compounds of formula (Ia, c, d, e) can be prepared by reacting a corresponding compound (VIII) (R and X are as previously indicated and W is a suitable leaving group such as halogen or alkyl or aryl sulphonate) with a compound of formula (IX) (R2, Rg, Z and Y are as indicated above).

The reaction can be carried out using standard N-alkylation methods. It is thus preferably carried out in an internal solvent such as a lower alkanol (eg methanol, ethanol, propanol, butanol) or an aromatic hydrocarbon (eg benzene, toluene, xylene). The addition of a suitable base such as an amine (eg triethylamine) or an alkali or alkaline earth metal carbonate or hydrogen carbonate may be appropriate to neutralize the acid released during the reaction. A small amount of a metal iodide (eg sodium or potassium iodide) can be added as a reaction ion promoter. Somewhat higher temperatures may be necessary to increase the reaction rate, and in several cases the reaction is preferably carried out at the reflux temperature of the reaction mixture.

Procedure 4

Compounds of formula (Ia, b, c, d, e) can R,

and Rg are both hydrogen, can be prepared by reacting compounds of formula (II) with a corresponding cyanate or thiocyanate (e.g. an alkali metal cyanate or alkali metal thiocyanate) in an acidic medium (e.g. acetic acid or a mixture of acetic acid and water). Heating may be required.

Procedure 5

Compounds of formula (Ib) can be prepared by reduction of a compound of formula (Ia) with a suitable reducing agent, e.g. sodium borohydride and the like The reduction is carried out according to standard methods. A compound of formula (Ia) is thus stirred in a suitable solvent (e.g. ethanol and the like) in the presence of the reducing agent (e.g. lithium borohydride and the like). External cooling may be required.

Procedure 6

Compounds of formula (Ib') (where neither R^ nor R^ is hydrogen) can be prepared by reacting a corresponding compound with formula (Ib) with a compound of Formula F-4-W (Rj| and W are as indicated above) under strongly basic conditions. Thus, the reaction is carried out in an inert apolar solvent such as ether, tetrahydrofuran, toluene or the like, or in an inert polar solvent such as DMF, DMSO etc., using a strong base such as sodium or potassium hydride as a base. The reaction can be carried out within a wide temperature range and less reactive compounds with formula Ro0-W may require refluxing of the reaction mixture.

F r ernqangsm to fe 7

Compounds of formula (Ib") can be prepared by reacting a corresponding compound of formula (Ib) with the rich acylating agent such as an acid halide or acid hydride. The reaction is preferably carried out in the presence of a base ( e.g. pyridine, triethylamine) in an inert solvent (e.g. ether, toluene), or the base can be used as a solvent (e.g. pyridine).

Procedure 8

Compounds of formula (Ie) can be prepared via hydrogenation of compounds of formula (Id) using standard hydrogenation methods, the reaction can thus be carried out in a suitable solvent such as lower alkanols (e.g. methanol, ethanol, propanol, butanol), ethyl acetate, tetrahydrofuran or dioxane, in the presence of hydrogen or a suitable noble metal catalyst. The use of acidic reaction media, such as acetic acid, can increase the reaction rate.

Compounds of formula (Ic) can be prepared from compounds of formula (Ia, b, b', b", f) using similar hydrogenation methods.

Procedure 9

Compounds of formula (Ib<1>, c, d, e, f) where both R and R, - are different from hydrogen and where Z is 0, can be prepared from compounds of formula (lb<1>, c, d, e, f) where one of R^ and R,- is hydrogen and Z is 0 by alkylation using an alkylating agent Rg~w (defined above) and using similar alkylation conditions as described in method 7.

Procedure 10

Compounds of formula (Ila, c, d, e, f) can be prepared by reacting the corresponding compound of formula (VIII) (R^, X and W are as above) with a large excess of a piperazine (R^ and R^ is as stated above).

The reaction is carried out using standard N-alkylation methods as described in procedure 3.

Procedure 11

Compounds with formula (Ila, e, d, e) can be prepared by the following reaction sequence:

<R>l, X, W, R^ and <R>g are as indicated above. RB is lower alkyl (eg methyl, ethyl, isobutyl).

The N-alkylation of (VIII) to form (XI) is carried out according to standard methods described in method 3.

The hydrolysis of (XI) to form (IT) is carried out according to standard methods. Thus, it can be easily carried out by pipe inq and heating, preferably under reflux, of compounds of formula (XI) and an alkali hydroxide (e.g. potassium hydroxide and the like) in a suitable solvent such as a lower alkanol (e.g. methanol, ethanol, propanol , butanol). Alternatively, the hydrolysis can be carried out using acidic conditions such as HBr in acetic acid.

Procedure 12

Compounds of formula (IIb') can be prepared by reacting a compound of formula (IIb) with a corresponding alkylating agent R^-W (R^ and W are as indicated above) using similar reaction conditions as described under method 7.

Procedure 13

Compounds of formula (Ild) can be prepared from compounds of formula (Ila) by a Wittig reaction using the corresponding Wittig reagent (XII) (Rg and R_ are as indicated above) and using standard methods. The reaction is carried out in an inert solvent such as tetrahydrofuran or ether, preferably tetrahydrofuran. Heating speeds up the reaction, and refluxing the reaction mixture may in some cases be necessary.

Procedure I 4

Compounds of formula (Ile) can be prepared by hydrogenating compounds of formula (Ild) using standard methods as described in method 9.

F r omg an<g>srnå te 1 5

Compounds of formula (VII) can be prepared by reacting compounds of formula (II) with the corresponding chlorine carbarnate CICO^R^ (Rft is as indicated above). The reaction can be carried out under standard alkylation conditions. Thus, the reaction is carried out in an inert solvent such as ether, chloroform or toluene. The reaction mixture is generally cooled, and a base, e.g. triethylamine is added to trap the acid formed during the reaction.

The reaction can alternatively be carried out by using a two-phase system containing the above-mentioned organic solvent and an aqueous phase containing a suitable base,

e.g. magnesium oxide.

The following examples are intended to illustrate, although the named conditions are of particular interest for the present purpose. These compounds are indicated with a numerical code, a:b, where a means the example in which the preparation of the compound is described, and b means the order in which the compounds are prepared according to this example. Thus compound 1:2 means the second compound prepared according to example 1.

The structure of the compounds has been confirmed by NMR, mass spectra and elemental analysis. When melting points are given, these are uncorrected.

Example 1

4-/ 4- ( p- f 1 rf enyl ) butylJ7- N- methyl- l- piperazinecarboxamide hydrochloride

To a stirred solution of 0.97 g (0.017 mol) methyl isocyanate in 35 ml toluene was added dropwise over a period of 20 minutes at 5°C 4.0 g (0.017 mol) of 1-/4-(p-fluorophenyl) butyl_7piperazine in 20 ml of toluene. The mixture was then stirred at 30-40°C for 2 hours and evaporated to give the free base of the title compound. This was dissolved in ethanol-ether and acidified with ethanolic HCl. The solid which precipitated was isolated by filtration and recrystallized from 2-propanol to give 4.0 g of 4-(p-fluorophenyl)butyl-7-N-methyl-1-piperazinecarboxamide hydrochloride (1:1); m.p. 195-97°C.

By essentially using the same procedure, the following compounds are prepared (isolated as free bases or as the corresponding salts) from the corresponding starting materials: 1:2 4-(p-fluorophenyl)'-4-oxobutyl_7 -N-methyl-1-piper azine carboxamide hydrochloride. m.p. 185-6°C

1 : 4-/"4-(p-fluorophenyl),-4~oxobutyl/-N-ethyl-1-piperazinecarboxamide hydrochloride m.p. 190-1°C

1:4 4-/"4-(p-fluorophenyl)-4-oxobutylJr-N-(1-methylethyl)-1-piperazinecarboxamide hydrochloride m.p. 217-18°C

I :5 4-(p-fluorophenyl)-4-oxobutyl-N-propyl-1-piperazinecarboxane.dihydrochloride id m.p. 207-9°C

1:6 4-[4-(p-fluorophenyl)-4-oxobutyl]-N-cyclohexyl-1-piperazinecarboxamide hydrochloride, m.p. 230°C (decomposition)

1:7 4-/4 - ( p -fluoro enyl) - 4-oxobutyl lj - 2 , 5- tr ans-dime Lyl-N-e tyl-l-piperazinecarboxamidoxaJ a i: m.p. 160°C

1: S 4-/4- ( p-fluorophenyl)-4-oxobutyl/-3 , 5- ( cis-d.i methyl-N-ethyl-1-piperazinecarboxamide hydrochloride m.p. 146-8°c 1 : 9 4-/" 4 - (p-fluorophenyl 1) buty 1_7 - N-ety 1 -1 - pi pe r a z x n k a r box amide hydrochloride m.p. 193-5°C 1 :10 4-/4- ( p-fluorophenyl) buty 17- N- ( 1-methyl ty 1.) - l-p i. per a-zinc carboxamide hydrochloride m.p. 208-9°C

1:11 4-/"4-(p-fluorophenyl)butyl7-N-cyclohexyl-1-piperazin.n-carboxamide hydrochloride m.p. 252-4

1:12 4-/4-/p-fluoro phenyl)buty lj -N-phen y1-i-pipe r azin ka r bok s-amide hydrochloride m.p. 245-7°C

1:13 4-/"4-(p-fluorophenyl)butyl7-N-benzy 1-1-piperazi ncarboxamide hydrochloride m.p. 189-90°c

1:14 4-(p-fluorophenyl)butyl7-N-(m-trifluoromethylphenyl)-1-piperazinecarboxamide hydrochloride m.p. 19G-1°C

1:15 4-/4- (p-fluorophenyl)butyl 1.7-N- (p-methoxyphenyl)-l-p in per-azinecarboxamide hydrochloride m.p. 235°C (split.)

1:16 4-[4-(p-Fluorophenyl)butyl-2,5-trans-dimethyl-N-methyl-1-piperazinecarboxamidoxalate m.p. 186-7° (split.)

1:17 4-/4-(p-fluorophenyl)butyl/-2,5-trans-dimethyl-N-ethyl-1-piperazinecarboxamide 1 1/2 fumarate m.p. 99-102°C

1:18 4-(p-fluorophenyl)butyl7-3,5-cis-dimethyl-N-ethyl-L-piperazinecarboxamide hydrochloride m.p. 200-1°C

1:19 4-/"4-(p-Fluorophenyl)-4-<p>entenyl_7-N-ethyl-1-piperazinecarboxamide hydrochloride m.p. 195-6°C

1:20 4- [ 4 -(p-Fluorophenyl)-4-octenyl/-N-ethyl-1-piperazine-carboxamidoxalate m.p. 174°C

1:21 4-(p-Fluorophenyl)penty17-N-ethyl-1-piperazinecarboxamide hydrochloride m.p. 190-1°C

1:22 4-(p-Fluorophenyl)-5-methylhexyl7-N-ethyl-1-piperazinecarboxamide hydrochloride m.p. 176-7°C

1:23 4-/4-(p-fluorophenyl)octyl/-N-ethyl-1-piperazinecarboxamidoxate m.p. 150°C

Example 2

4- £4 - i p- fluoro phenyl) buty17- N- methyl- piperazinethiocarbox- a m i d h y d r o c 1 o r i d

5.0 g (0.02 mol) of 1-( p -fluorophenyl)butyl-7-piperazine was evaporated. in 50 ml of ether. 1.55 g (0.02 mol) of methyl isothiocyanate in 10 ml of ether was added dropwise at room temperature. The mixture was stirred for 3 hours at room temperature, whereby the first base of the title compound crystallized. It became

filtered off, dissolved in ethanol, and HCl in ethanol was added to form the hydrochloride. Ether was added to precipitate the hydrochloride and it was filtered off. Recrystallization from 2-propanol gave 4.5 g of the title compound, (2:1) m.p. 15.1 -2 °C.

By essentially using the same procedure, identical compounds (isolated as free bases or as corresponding salts) are then prepared from the corresponding starting materials.

2:2 4-/4 - ( p -fluorophenyl)-4-oxobutyl_/-N-methyl-l~piperazine-thiocarboxamide hydrochloride m.p. 176-7°C

Example 3

4-(4-phenylbutyl)-N-ethyl-1-piperazinecarboxamide hydrochloride

A mixture of 4.4 g (0.02 mol) 1-phenylbutyl-piperazine, 3.3 g (0.02 mol) phenyl-N-ethyl-carbamate, and 4.0 g K2CO3

in 60 ml of toluene was refluxed for 1 hour. After cooling and filtering, the solvents were evaporated. The residue was dissolved in ether and HCl in EtOH was added. The hydrochloride thus formed was filtered off and then dissolved in water. After an extraction with ether, the aqueous solution was made alkaline with NaOH, and the oil that formed was extracted into ether. The ether phase was washed with saturated NaCl solution, dried over Na2SO4 and evaporated to give the free base of the title compound. This was dissolved in ether and HCl in EtOH was added to precipitate the hydrochloride, and this was filtered off. Recrystallization from EtOH/EtOAc gave 3.5 g of the title compound; (3:1) m.p. 201-3°C (3:1 is the same as 1:23).

Using substantially the same procedure, the following compounds (isolated as free bases or as corresponding salts) are prepared from the corresponding starting materials.

3:2 4-(p-Fluorophenyl)-4-oxobutyl7-N-cyclopropyl-1-piperazinecarboxamide hydrochloride m.p. 211-12°C

3:3 4-/4-(p-Fluorophenyl)butyl/-N-cyclopropyl-1-piperazinecarboxamide hydrochloride m.p. 214-16°C

3:4 4-(p-Fluorophenyl)butylJ-N-pentyl-1-piperazinecarboxamide hydrochloride m.p. 202-4°C.

3:5 4-(p-Fluorophenyl)butylJ-N-octyl-1-piperazinecarboxamide hydrochloride m.p. 215-16°C

3:6 4-(p-Fluorophenyl)butylJ-N-(2-phenylethyl)-1-piperazinecarboxamide hydrochloride m.p. 193-4°C

3: 7 4-[4-(p-fluorophenyl)butyl]-N-(p-chlorophenyl)-1-piperazinecarboxamide hydrochloride m.p. 229-30°C

Example 4

1- pyrrolidinocarbonyl- 4-/ 4-( p- fluorophenyl) butyl/ piperazine hydrochloride

3.5 g (8.7 mmol) of 4-L 4-(p-fluorophenyl)butyl_7-l-/carbo-(p-nitrophenoxy)/piperazine was dissolved in 20 ml of pyrrolidine and allowed to stand at room temperature for 1 hour. The reaction mixture was partitioned between 100 ml of t₂O and 100 ml of ether containing some naphtha. The organic phase was separated and washed 3 times with saturated NaCl solution. Drying and evaporation of the solvents gave the free base of the title compound. This was dissolved in EtOAc and the hydrochloride precipitated with HCl in EtOH. Recrystallization from EtOAc/EtOH gave 2.3 g of the title compound; (4:1) m.p. 213-15°C.

Using essentially the same procedure, the following compounds (isolated as free bases or as corresponding salts) are prepared from the corresponding starting materials.

4:2 4- 14-(p-fluorophenyl)butyl7-N,N-dimethyl-1-piperazinecarboxamide hydrochloride m.p. 165°C

4:3 4-/4-(p-Fluorophenyl)butyl/-N,N-diethyl-1-piperazinecarboxamide hydrochloride m.p. 200-2°C

4 : 4 1-Mor f olinocarbonyl-4-/4 - (p-fluoro phenyl) butyl_7piperazine hydrochloride m.p. 186-7°C

Example 5

4 - 1 4-(p-Fluorophenyl)butyl7-1-piperazinecarboxamide 3.5 g (0.015 mol) of 1-(p-fluorophenyl)buty±7piperazine was dissolved in 25 ml of acetic acid containing 10% water. 1.6 g of potassium cyanate in 10 ml of water was added at room temperature over 15 minutes. The mixture was stirred for 15 hours. 50 ml of water was added, the mixture cooled to 0°C and 80 ml of 5N NaOH slowly added. After stirring for 4 hours, the crystalline product was filtered off and washed with water. The solid was dissolved in CH 2 Cl 2 , and the organic phase was washed with water. After drying with Na 2 SO 4 , the solvents were evaporated. The residue was recrystallized from toluene/naphtha to give 3.3 g of the title compound (5:1); m.p. 82-84°C.

The corresponding hydrochloride has m.p. 220-1°C (5:2)

Using essentially the same procedures, the following compound (isolated as free base) is prepared from the corresponding starting materials.

Example 6

4-/ 4-( p- fluorophenyl)- 4- oxobutyl7- N- ethyl- 1- piperazinecarboxamide hydrochloride

To a solution of 14.7 g of crude 4-(p-fluorophenyl)-4,4-ethylenedioxy-butyl 7-N-ethyl-1-piperazinecarboxamide in 25 ml of ethanol was added 25 ml of 5N ethanolic HCl. The mixture was refluxed for 15 hours. After cooling, 250 ml of ether was added. The solid that precipitated was recrystallized from ethanol to give 7.0 g of 4-(p-fluorophenyl)-4-oxobutyl 7-N-ethyl-1-piperazinecarboxamide hydrochloride; (6:1) m.p. 190-191°C. (6:1 is the same as 1:3).

Example 7

4- Z. 4- (p- fluorophenyl)-4- hydroxybutyl/- N- ethyl 1- 1- piperazine-carboxamide hydrochloride

To a stirred slurry of 0.9 g of sodium borohydride in 30 ml of ethanol, 3.9 g (0.012 mol) of 4-(p-fluorophenyl)-4-oxobutyl/-N-ethyl-1-piperazinecarboxamide was added dropwise in 30 ml of ethanol. The reaction mixture was stirred at room temperature for 4 hours. Dilute HCl was then slowly added, and when hydrogen was no longer evolved, the mixture was concentrated. The oily residue was dissolved in H 2 O and extracted with ether (which was discarded). The aqueous phase was made basic with NaOH solution and extracted with Ch2C2.

The organic phase was dried and evaporated to give the free base of the title compound. This was dissolved in ethanol and acidified with ethanolic HCl. Ether was added. The solid which precipitated was isolated by filtration and recrystallized from 2-propanol, yielding 3.1 g of 4-/"4-(p-fluorophenyl)-4-hydroxybutyl-N-ethyl-1-pyr perazinecarboxamide hydrochloride ( 7:1); mp 167-68°C.

Example 8 (Intermediate product)

4-/4-(p-fluorophenyl)butylpiperazine

A solution of 18.7 g (0.1 mol) of 1-chloro-4-(p-fluoro-phenylbutane) and 60.3 g (0.7 mol) of piperazine in 250 ml iso-propanol was refluxed for 24 hours. The solvent was evaporated. Water was added to the residue and this was extracted several times with ether. The combined ether extracts were washed with saturated NaCl solution and dried over anhydrous K 2 CO 3 . The ether was evaporated and the residue distilled to give 18, 9 g of the title compound, bp 96-100°C (0.02 mm Hg).

Example 9 (Intermediate)

1- carboethoxy- 4-/ 4-( p- fluorophenyl) butyl_ 7pi per azine hydrochloride

To a solution of 20.2 g (0.11 mol) of 1-chloro-4-(p-fluoro-phenylbutane) in 110 ml of n-butanol was added 18.0 g (0.11 mol) of 1-carboethoxypiperazine, 17, 2 g of sodium carbonate and 0.1 g of potassium iodide. The mixture was stirred and heated at reflux for 24 hours. The reaction mixture was filtered and the solvent was removed. The residue was dissolved in ether, washed with NaCl solution, dried over Na 2 SO 4 and distilled , which gave 29.7 g of 1-carboethoxy-4-(p-fluorophenyl)-butyl-?piperazine, mp 137-42°C (0.05 mm). The hydrochloride had mp 154-5°C.

Example 10 (Intermediate product)

1- £A - ( p- fluorophenyl) buty 1J piperazine

To a solution of 19.8 g of potassium hydroxide in 200 ml of 2-propanol was added 30.8 g (0.10 mol) of 1-carboethoxy-4-(4-(p-fluorophenyl)butyl/piperazine). The mixture was stirred and refluxed for 26 hours. The reaction mixture was cooled, filtered and concentrated. The oily residue was treated with ether. The mixture was filtered and distilled to give 17.2 g of 1-(4-(p-fluorophenyl)butyl-7-piperazine; kp. 112-17°C (0.1 mm).

Example 11 (Intermediate product)

4-/ 4- ( p- fluorophenyl) buty 17- 1- / carbo- ( p- n i tr of enoxy )_ 7- piperazine

18.0 g (0.076 mol) of 1-(p-fluorophenyl)butyl/piperazine was dissolved in 200 mL of ether + 50 mL of EtOAc. 150 ml of tt^O + 18 g of MgO were added and the mixture stirred vigorously at 0°C. 16.0

g (0.08 mol) of p-nitrophenyl chloroformate in 100 ml of ether was added over 0.5 h. The reaction product crystallized in the mixture, and to dissolve it EtOAc and some EtOH were added. The organic layer was separated and washed with 1N NaOH and 3 times with saturated NaCl solution. After drying and evaporation of the solvents, the residue was taken up in EtOAc/naphtha, and a total of 19.2 g of the title compound crystallized: m.p. 85-8°C. The hydrochloride had m.p. 207-8°C.

Example 12 (Intermediate product)

1-/" 4-(p-fluorophenyl)-4-pentenyl_7piperazine

20.0 g of "instant ylide" (a 1:1 mixture of methyl-tri-phenylphosphonium bromide and sodium amide) was dissolved in 100 ml of tetrahydrofuran and stirred for 10 minutes at room temperature.

10.5 g (0.042 g) of 1-(p-fluorophenyl)-4-oxobutyl/piperazine dissolved in 20 ml of tetrahydrofuran was added over 10 min. The reaction mixture was stirred overnight at room temperature. 100 ml of ether was added and then also naphtha to precipitate the triphenylphosphine formed during

the reaction. The solid material was filtered off and the solvents evaporated under vacuum. The residue was evaporated to give 5.5 g of the title compound, b.p. 103-6°C

(0.08 mm Hg).

Example 13

4- Z" 4 - ( p- fluorophenyl) pent y 17- N- e tyl- 1 - piper azincarboxamide hydrochloride

4.6 g (13 mmol) of 4-[4-(p-fluorophenyl)-4-pentyl]-N-ethyl-1-piperazinecarboxamide hydrochloride was dissolved in 125 ml of abs. ethanol and 0.5 g of 5% palladium on carbon were added. The mixture was hydrogenated at 2.7 atm. at room temperature. The catalyst was removed by filtration and the solvent evaporated. The residue was recrystallized from 2-propanol/ether to give 2.2 g of the title compound; m.p. 190-91°C.

Pharmacological properties

Compounds of formula (I) and their pharmaceutically active acid addition salts have useful pharmacological properties. They are applicable in the treatment of mental disorders and/or aggression in humans and also in the treatment of aggression in animals such as pigs, horses and cattle. They can also alleviate pain and are thus suitable as analgesics. They have no or very few autonomic side effects and a very low degree of cardiac toxicity. They also have a very low general toxicity.

The compounds of formula (I) have a therapeutic activity in the central nervous system with a pharmacological mode of action that is different from clinically used neuroleptic, anti-depressant and anxiolytic agents.

The adverse effects, especially irreversible tardive dyskinesia induced by (long-term) neuroleptic treatment are a serious disadvantage of antipsychotic pharmacotherapy. Alternatives to drugs that are often used in psychiatric medicine have therefore been strongly sought after. There is also a need for better antidepressants with fewer and less serious side effects, especially the cardiotoxic ones. The therapeutic efficacy of known antidepressants is still far from ideal, which means that in most cases electroconvulsive treatment is more effective than any antidepressant medication currently in use.

In contrast to the previously known compounds of formula (A) and (B), which reduce d-amphetamine-induced stereotypy by approx. at the same dosage level at which they produce other neuropharmacological effects, the compounds of the present invention have quite unexpectedly been found not to reduce d-amphetamine-induced stereotypy. The ability to reduce d-amphetamine-induced stereotypy is a characteristic effect of almost all drugs that block central dopamine receptors and has been commonly used as an index of potential antipsychotic activity in humans. However, a disruption of striatal dopamine function is thought to underlie this behavioral change. The extrapyramidal side effects of neuroleptics have been shown to be related to disturbed dopamine neurotransmission in the striatum. Consequently, this would suggest that this behavioral model would rather induce potential side effects rather than antipsychotic effects of a novel compound. In this respect, although they enjoy considerable success in the treatment of schizophrenia, neuroleptics have gained notoriety for the crippling motor side effects that can accompany their use.

The compounds of formula (I) in contrast to known neuroleptics do not inhibit d-amphetamine-induced stereotypies or cause motor consequences such as catalepsy. On the other hand, they antagonize d-amphetamine induced locomotor hyperactivity. They reduce exploratory behavior and can also have an effect on the conditioned avoidance reaction (CAR), one of the most frequently used tests in the development of antipsychotic drugs, qualitatively closely related to what is reported for classic neuroleptic drugs.

The compounds of formula (I) are strong antiaggressive agents. Like clinically used neuroleptics, antidepressants and anxiolytics inhibit aggressive behavior in male mice made aggressive by isolation. The compounds resemble antidepressant drugs in common therapeutic use that have been shown to be potent also by antagonizing the muricidal behavior of rats, an experimental model that is well established in investigations of clinically effective antidepressants.

The compounds of formula (I) are active in the torsion test. The torsion test is a classic pain test where the antinociceptive effects of many classic analgesics have been demonstrated. When activity is observed in this trial during investigation of new compounds, they are clearly believed to be worthy of further attention as potential analgesics. In the twisting test, the compounds of the present invention, like morphine, the drug most commonly used for analgesic purposes, show a very marked antinociceptive effect. It is important that the compounds in the present invention, in contrast to morphine, have been shown not to create physical dependence.

The potency of the compounds of formula (I) and their pharmaceutically active acid addition salts as agents for the treatment of mental disorders and pain is clearly demonstrated by the results obtained in the following experiments.

Experiment 1: Isolation-induced increase in aggressive behavior

Male mice isolated for a long time developed aggressive behavior towards each other when housed in pairs (Yen, C.Y. et al., Arch. Int. Pharmacodyn. 123, 179, (1959): Valzel-li, L., Adv. Pharmacol. 5, 79 (1967)). All clinically used neuroleptics and antidepressants investigated in this trial inhibit this aggressive behavior, although their activity may be different. Also anti-anxiety drugs, e.g. diazepam,' are active on this type of aggressive behavior. The clinical correlation of this trial shows sedative and anxiolytic activities as well as anti-aggressive properties as such (Duncan, R.L. et al., J. Med. Chem. 13, 1 (1970)).

This type of aggression is interesting because it is known that this type of emotional behavior can be located in the brain's limbic structure (MacLean, P.D., Psychosom. Med. 11, 338 (1949)).

Every week, NMRI male mice weighing 20-22 g were isolated in Mak-rolon cages for three weeks with diet and water ad libitum. A piece of cardboard was placed between the cages to prevent visual contact.

To test aggression, the mice were placed in pairs in a neutral area, a beaker (14 cm high and 14 cm diameter). A pair is considered aggressive if both animals show clear signs of fighting within 5 minutes. This fight is characterized by biting and sound. As soon as a fight is seen, the mice are separated and returned to their home cages (every other mouse is marked.). If only one of two mice shows aggressive behavior, the aggressive one is placed with another to form a well-assembled, aggressive pair. Animals that do not show aggression are removed. The frequency of mated mice showing fighting spirit varies from 50-100% depending on the season. The test substance is given subcutaneously (0.2-0.4 ml per 20 g). The mice are mated 0.5 hours after injection for experiments lasting 5 minutes.

The EDj-Q value (mg/kg) found is the dose that inhibits aggressive behavior among 50 percent of the pairs 0.5 hours after drug administration.

Experiment 2: Conditioned Avoidance Response (CAR)

The effect of the test compounds on CAR is measured in a shaking box manufactured by Ugo Basile, Italy. Female rats weighing 150 g were trained to avoid an electric shock (unconditioned stimulus - US) by escaping from one room to another when light from a 15W lamp is switched on (conditioned stimulus - CS). When they responded to the CS, a conditioned response (CR) was considered to have taken place. Rats showing a stable CR of more than 80% after a three-week training program were used in the experiments. Groups of six rats were given subcutaneously different doses of the test compounds. 1 1/2 hours after administration, each rat was placed in an experimental box and the effect on CR was measured. ED^Q values refer to the dose that inhibits CR in 50% of the animals. The mechanisms that regulate conditioned reactions are very complex. Both catecholaminergic and hormonal factors are important.

Experiment 3: Torsion test

The twist test is often used to test for analgesic properties (Witkin, L.B. et al., J. Pharmacol. Exp. Ther. 133, 400 (1961)). If acetic acid (0.5%, 15 ml/kg) is injected intraperitoneally into mice (NMRI), they will without exception develop a writhing behavior characterized by stretching their hind legs. The drugs to be investigated were given subcutaneously to 6 female mice for each dose 20 minutes before the injection of the acetic acid. After 10 minutes, the mouse's behavior was studied for 5 minutes. The ED,-n value is the dose that blocks the writhing behavior in 50% of the animals during the study period of 5 minutes.

The compounds listed in Tables 1, 2 and 3 are not indicated to limit the invention to them, but only to exemplify the applicable pharmacological properties of the compounds within the scope of formula (I).

The compounds of formula (I) and their pharmaceutically active acid addition salts can be used to control mental disorders in humans. E.g. they may be applicable for the prophylaxis and/or treatment of schizophrenia, mania or senile, involutional or organic psychoses as well as depressive psychoses.

The new compounds can also be used in the prophylaxis and treatment of aggressive behaviour, which may be related to mentally retarded and/or behaviorally disturbed patients and other forms of aggression of either known or unknown etiology.

The new compounds are very useful in the treatment of aggressive behavior in animals, especially pigs, and also by inducing the development of natural hierarchy in animal groups without outbreaks of aggression and by calming anxious and stressed animals.

Effective amounts of all the preceding pharmacologically active compounds of formula (I) can be administered to humans or animals for therapeutic purposes according to usual routes of administration and in usual forms, such as orally in solutions, emulsions, suspensions, pills, tablets, and capsules, in pharmaceutically acceptable carriers and parenterally in the form of sterile solutions. For parenteral administration of the active substance, the carrier of excipient may be a sterile, parenterally acceptable liquid. e.g. water, or a parenterally acceptable oil, eg arachis oil.

Although very small amounts of the active materials in the present invention are effective when weak therapy is relevant or in cases of administration to beings with a relatively low body weight, the unit dosages are normally from 2 mg and upwards, preferably 25, 50 or 100 mg or even higher depending on the condition to be treated and the patient's age and weight as well as the reaction to the medication.

The unit dose may be from 0.1 to 200 milligrams, preferably from 10 to 50 mg. Daily doses should preferably range from 10 milligrams to 400 milligrams. The exact individual doses as well as daily doses will of course be determined according to standard medical principles under the guidance of a doctor or veterinarian.

Claims (2)

1. Analogous method for the preparation of therapeutically active 1-piperazine-carboxamide derivatives of the general formula (I) and the pharmaceutically acceptable acid addition salts thereof; in which R± is selected from hydrogen, halogen or trifluoromethyl, X is selected from R2 and R3 are the same or different and selected from hydrogen or lower alkyl of 1-4 carbon atoms, Z is either oxygen or sulfur, Y is -NR4R5 in which R4 and R5 are the same or different and selected from hydrogen, alkyl with 1-4 carbon atoms, cycloalkyl, phenyl, where the phenyl group can optionally be substituted with 1-3 substituents which can independently be halogen, methyl, methoxy , trifluoromethyl, where halogen is fluorine, chlorine or bromine, or R4 and R5 together with the nitrogen atom are pyrrolidino or morpholino, R6 and R7 are the same or different and are selected from hydrogen or alkyl of 1-4 carbon atoms, with the proviso that when X is ) C 0 , R 4 is hydrogen and R 5 is different from hydrogen, characterized by reacting a compound with the formula (II) wherein X, R1-R3 are as defined above with an isocyanate of formula (III) or (2) reacts a compound of formula (II) with an isothiocyanate of formula (IV) or (3) reacts a compound of formula (II) with a carbamoyl chloride of formula (V) or (4) reacts a compound of formula (II) with a compound of formula (VI) where R4 and R5 are as defined above and R^ means a phenyl group, or when none of the substituents on the N atom is hydrogen, preferably a substituted phenyl group, or (5) one reacts a compound of formula (VII) in which X, R^ ^-R 8 and R A are as defined above, with an amine HNR 4 R 5 wherein R 4 and R 5 are as defined above; or one reacts (6) a compound of formula (VIII) in which R 2 and X are as indicated above and W is a suitable leaving group such as halogen or alkyl or aryl sulfonate, with a compound of formula (IX) in which Z, Y, R2 and R3 are as defined above, or a compound of formula (II) is reacted with a cyanate salt or thiocyanate salt in an acidic medium, during which the compounds of formula (I), in which R4 and R5 are hydrogen, are formed, or one reduces a compound of formula (I) in which X is ^CO with a reducing agent, giving compounds of formula (I) wherein X is ^CHOH, or one hydrogenates a compound of formula (I) in which X is /CO=CR6R7 using a standard hydrogenation method whereby a compound of formula (I) in which X is /CH-CHR6R7, or alternatively hydrogenates a compound of formula (I) in which X is ^CO or >CHOH, whereby a compound of formula (I) in which X is )CH2 is obtained, or one alkylates a compound of formula (I) in which X is ^CH2, > C=CR6R7 or >CH-CHR6R7, Z is 0 and wherein R4 is hydrogen using an alkylating agent R|-W, where R| means alkyl with 1-4 carbon atoms and W is defined as above, whereby a compound of formula (I) is obtained in which R4 is lower alkyl with 1-4 carbon atoms. 2. Method according to claim 1 in the preparation of 4-[4-(p-fluorophenyl)-4-oxobutyl]-N-cyclohexyl-1-piperazine-carboxamide hydrochloride.