Background of the Invention

Drugs in use today for the treatment of mental disorders most often are associated with serious side effects. Anti psychotic drugs

5 commonly cause disturbing extrapyram dal symptoms , and long term treat¬ ment may result in tardive dyskinesia. Antidepressants often exhibit cardiotoxicity, and anxiolytic drugs have addicting properties . As a result of these drawbacks efforts are being made to find new pharma¬ cological ly active drugs which have fewer side effects.

1 _Q The present invention relates to novel piperazine- and homopiperazine- carboxa ides bearing a phenoxyalkyl or thiophenoxyalkyl side chain , which exhibit valuable pharmacological properties, and which have a low tendency to cause side effects.

Pharmacologically valuable piperazine-carboxamides are previously

, _Ï‚ known from British patent appl ication No. 2,037,745. However , the compounds according to the British application differ from the compounds according to the present invention in being substituted in the 4-position wi th a very l ipophi lic 4, 4-di phenyl butyl group. Furthermore, these previous compounds are very active in pharmacological models which may indicate potentation of noradrenal ine and serotonine (e.g. inhibition of muricide behaviour) ,

20 which in turn may cause unwanted side effects , e.g. aneroxigenic. The compounds of the present invention are considerably less active in these pharmacological models indicating that fewer side effects are to be expected when compounds according to the present invention are used .

Piperazinecarboxamides substituted in the 4-posi tion with a butyro-

²⁵ phenone side chain are known from Collect. Czech. Chem.Commun 1975, 40(4) , 1218-30. The butyrophenone side chain is chemically distinctly different from a phenoxyalkyl or thiophenoxyalkyl group. Besides , the authors state that their compounds display CNS-activity only at high doses .

The French patent appl ication 2367067 and the Swedish patent appl ica-

30 tion 8100852-6 describe piperazine derivatives having a phenoxyal kyl side chain but in neither case are the compounds piperazinecarboxamides . The compounds according to the French patent application are characteri zed by an analgesic effect that is not accompanied by any secondary effects (cf. the French application page 1 , lines 20-24) .

35

Description of the invention

According to the invention there are provided novel compounds having the general formula:

X- •((CCHH _o - (I)

_.

wherein R-. is selected from hydrogen, halogen or trifluoromethyl; X is oxygen or sulfur;

R ₂ and R ₃ are the same or different and selected from hydrogen or lower alkyl; m is 2 or 3;

Y is oxygen or sulfur; Z is selected from: -NR^Rg or

0

wherein R ₄ and R ₅ are the same or different and selected from hydrogen, alkyl , cycloal kyl , cycloal kyl -al kyl , hydroxy-al kyl , alkoxyalkyl , alkanoyloxyal kyl : phenyl or phenyl-al kyl , wherein the phenyl groups may

be unsubstituted or monosubstituted with halogen or CF ₃ ; n is 0, 1 , 2 or 3;

Rg and R ₇ are the same or different and selected from hydrogen, lower aÏŠkyl, hydroxy, lower alkoxy or lower alkanoyloxy; p is 2 or 3;

Ro and R _g are the same or different and selected from hydrogen or lower alkyl;

R, _Q is hydrogen, lower alkyl or lower alkanoyl, and the pharmaceutically active salts thereof, and when used in the foregoing definitions the term alkyl is meant to include straight and branched, saturated and unsaturated hydrocarbon groups having from 1 to 10 carbon atoms; the term cycloalkyl is meant to include cyclic, saturated and unsaturated hydrocarbon groups having from 3 to 8 carbon atoms; the term alkoxy is meant to include straight and branched, saturated or unsaturated alkoxy groups having from 1 to 10 carbon atoms; the term alkanoyloxy is meant to include straight and branched, saturated and unsaturated alkanoyloxy groups having from 1 to 10 carbon atoms; the term lower is used when the groups mentioned above contain from 1 to

4 carbon atoms and the term halogen is meant to include fluoro, chloro and bromo.

The compounds of formula (I) have basic properties and consequently they may be converted to their therapeutically active acid addition salts by treatment with appropriate acids; e.g. inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, oxalic, succinic, fumaric, tartaric, citric and pamoic acid.

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

In the compounds of the general formula (I) it is preferred that R, is halogen or CF ₃ and that R^ is situated in the m- or p-position.

If selected from halogen it is preferred that R-, is F or Cl , especial¬ ly F.

When R.J is CF ₃ it is preferably situated in the m-position.

It is preferred that X is oxygen, and that R- and R ₃ are hydrogen.

When R ₂ and R ₃ are lower alkyl, methyl and ethyl are preferred, especially methyl.

It is preferred that m=2.

It is preferred that Y is oxygen.

When Z is NR,Rg those compounds are preferred wherein R^ and Rg together contain less than ten carbon atoms. Also, as regards the substituents R ₄ and Rg those compounds are preferred wherein R„ and Rg are selected from hydrogen, alkyl, cyclo¬ alkyl, cycloalkyl-alkyl and hydroxyalkyl, especially alkyl and cyclo¬ alkyl.

As regards the substituents R _β and R^ it is preferred that one of them is hydrogen and the other hydrogen or lower alkyl.

As regards the substituents Rg and R _g those compounds are preferred wherein both of them are hydrogen.

When Z is a heterocyclic ring containing two heteroatoms, it is preferred that one of the heteroatoms is oxygen.

Also as regards Z it is preferred that Z does not contain any asymmetri carbon atoms.

The following compounds are preferred: 4-/3-(p-fluorophenoxy)propyl/-N-methyl-l-piperazinecarboxami de 4-/3-(p-fluorophenoxy)propyl/-N-ethyl-l-piperazinecarboxamid e 4-/3-(p-fluorophenoxy)propyl/-N-cyclopropyl-l-piperazinecarb oxamide 4-/3-(m-trif1uoromethy1-phenoxy)propy1/-N-ethy1-1-piperazine carboxamide 4-/3-(p-fluorophenoxy)propyl/-N-methyl-l-piperazinethiocarbo xamide 4-/3-(p-fluorothiophenoxy)propyl/-N-methyl-l-piperazinecarbo xamide 4-/3-(p-fluorothiophenoxy)propyl/-N-ethyl-l-piperazinecarbox amide 4-/3-(p-fluorothiophenoxy)propyl/-N-cyclopropyl-l-piperazine carboxamide 4-/3-(p-fluorothiophenoxy)propyl/-N-methyl-l-piperazinethioc arboxamide 4-/3-(p-fluorophenoxy)propyl/-N,N-dimethyl-piperazinecarboxa mide 1-morpholinocarbonyl-4-/3-(p-f1uorophenoxy)propy1/-piperazin e

Compounds wherein one or both of R ₂ and R ₃ are alkyl are racemic mixtures, and these may consequently be resolved into enantiomers. The compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties making them useful for treatment of mental disorders such as psychoses, depression and anxiety. For example they may be useful for the prophylaxis and/or treatment of schizophrenia, mania or senile, involutional or organic psychoses as well as depressive psychoses, depression and anxiety.

Psychosomatic disorders caused by anxiety and stress should be alleviated by compounds of formula (I).

The new compounds may also be used in the prophylaxis and treat¬ ment of aggressive behaviour, which may be associated with mentally re¬ tarded and/or behaviourally disturbed patients and other form of aggression of either known or unknown etiology. The new compounds may be useful in the treatment of aggressive be¬ haviour in animals, especially in pigs, and also in promoting the de¬ velopment of a natural hierarchy in groups of animals without bursts of aggression and in calming of anxious and stressed animals.

The compounds of formula (I) have a clear li bic profile of action and are thus not likely to cause extrapyramidal side effects. This is evidenced by their ability to inhibit amphetamine induced locomotion in mice, whereas they do not block amphetamine induced stereotypies. Their ability to inhibit isolation induced aggression in male mice is also the result of activity in limbic brain areas. Extrapyramidale side effects are highly undesirable and are commonly seen with antipsychotics in clinical use today.

Effective quantities of any of the foregoing pharmacologically active compounds of formula (I) may be administered to a human being or an animal for therapeutic purposes according to usual routes of administra¬ tion 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 the parenteral ad¬ ministration of the active substance the carrier of excipient may be a sterile, parenterally acceptable liquid, e.g. water, or a parenterally acceptable oil, e.g. arachidic oil.

The compounds of formula (I) may if desired be administered in various slow release formulations.

Although ver small quantities of the active materials of the present invention are effective when minor therapy is involved or in the cases of administration to subjects having a relatively low body weight, unit dosages are usually from 2 milligrams upwards, preferably 25, 50 or 100 milligrams or even higher depending on the condition to be treated and the age and weight of the patients as well as the response to the medication.

The unit dose may be from 0.1 to 200 milligrams, preferably from 10 to 50 milligrams. Daily dosages should preferably range from 10 milli¬ grams to 400 milligrams. The exact individual dosages as well as daily dosages will, of course, be determined according to standard medical principles under the direction of a physician or veterinarian.

Methods of preparation

The compounds having the general formula (I) may be prepared by conventional methods. Method 1

10 A compound of formula II, wherein R, and X are as defined above, and wherein M is a suitable leaving group such as halogen and alkyl- or arylsulfonate is reacted with a compound of formula (III) wherein R ₂ , R ₃ , Y, Z and m are as defined previously. The reactions may be carried out using standard N-alkylating procedures. 15 Method 2

A compound of formula (IV), wherein R-,, X, R ₂ , R ₃ and m are as defined above, is reacted with an isocyanate of formula (V) or an iso- thiocyanate of formula (VI) or a carba oyl derivative of formula (VII), 25 where.in.R , .Y and Z are as previously defined, and wherein L is a suit¬ able leaving group such as halogen, phenoxy and substituted phenoxy (e.g. p-nitrophenoxy). The reactions may be carried out using standard procedures. The addition of an appropriate base may in some instances facilitate the reaction, and may if acid is formed during the reaction

30 serve to neutralize this. Method 3

A compound of formula (VIII) wherein R ₁ and X are as previously de¬ fined is reacted with a compound of formula (IX) wherein M, R ₂ , R ₃ , m, Y and Z are as defined previously. The reaction is carried out using standard phenolate or thiophenolate alkylating conditions. Method 4

A compound of formula (X) wherein R,, X, R ₂ , R ₃ , , Y and L are as defined above is reacted with a compound of formula Z-H wherein Z is as previously defined. The reaction is carried out using standard procedures,

When L is a poor leaving group and/or when Z-H is a poor nucleophile it may be advantageous to use a large excess of Z-H and/or to heat the reaction mixture for a longer period of time.

The intermediate X may be prepared by standard procedures according to:

Method 5

Y II

IV + L-C-L' > X

XI A compound of formula IV is reacted with a compound of formula XI wherein L and Y are as previously defined, and L' is a suitable leaving group such as halogen, phenoxy and substituted phenoxy (e.g. p-nitro- phenoxy). Most commonly at least one of L and L' is halogen. The reaction is preferably performed in an inert solvent, and an appropriate base may be added to take care of the acid formed during the reaction.

The intermediate IV may be prepared by conventional methods accord¬ ing to:

Method 6

R ₂

I I

A compound of formula II is reacted with an excess of a ine, where¬ in R ₂ and R ₃ are as defined above, using standard N-alkylating condi¬ tions. Examples

The following examples are intended to illustrate but not to limit the scope of the invention, although the compounds named are of particular interest for our intended purposes. These compounds have been designated by a number code, a:b, where "a" means the number of the example wherein the preparation of the compound in question is described, and "b" refers to the order of the compounds prepared according to that example. Thus, compound 1:2 means the second compound prepared according to Example 1.

The structures of the compounds are confirmed by NMR, mass spectra and elementary analysis. When melting points are given, these are un¬ con ⁿ ected. Example 1

3.6 g (0.015 mole) of l-/3-(p-fluorophenoxy)propyl/-piperazine was dissolved in 20 ml of toluen and cooled in an ice bath. 0.9 g (0.015 mole) of methylisocyanate dissolved in 35 ml of toluene was added dropwise during 15 minutes. The reaction mixture was allowed to reach room temperature and the solvent was subsequently removed by evaporation. The residue was recrystallized from toluene/ligroin to yield 4.2 g of 4- /3-(p-fluorophenoxy)propyl/-N-methyl-l piperazinecarboxamide (1:1), M.p. 122-23°C.

The corresponding hydrochloride (1:2) was prepared by dissolving 4.0 g of the base in ether/abs.ethanol and adding and excess of HC1 in ethanol. The hydrochloride which ^~ precipitated was _^ recrystallized from abs.ethanol. Yield 3.6 g, m.p. 222-24°C. _

Using essentially the same procedure the following compounds are prepared (isolated as the free bases or as the corresponding salts) from the corresponding starting materials. 1 :3 4-/3-(p-fluorophenoxy)propyl/-N-ethyl-l-piperazinecarboxamid e hydrochloride, m.p. 211-12°C 1 :4 4-/3-(p-fluorophenoxy)propyl/-N-cyclopropyl-l-piperazinecarb ox- amide hydrochloride, m.p. 217-18°C 1 :5 4-/3-(p-fluorophenoxy)propy1/-N-(1-methylethyl)-!-piperazine - carboxamide

1 :6 4-/3-(p-fluorophenoxy)propyl/-N-hexyl-l-piperazinecarboxamid e 1:7 4-/3-(p-fluorophenoxy)propyl/-N-cyclohexyl-l-piperazinecarbo x¬ amide

1 :8 4-/3-(p-fluorophenoxy)propyl/-N-(2-propenyl)-l-piperazinecar box-

amide

1 :9 4-/3-(p-chlorophenoxy)propyl/-N-ethyl-l-piperazinecarboxamid e

1:10 4-/3-(m-trifluoro ethyl-phenoxy)propyl/-N-ethy1-1-piperazine- carboxamide hydrochloride, m.p. 196-98°C 1:11 4-(3-phenoxypropyl)-N-ethyl-l-piperazinecarboxamide

1:12 4-/3-(p-fluorophenox )propyl/-N-methyl-l-piperazinethiocarbox¬ amide hydrochloride, m.p. 182-83°C

1:13 4-/3-(p-fluorothiophenoxy)propyl/-N-ethyl-l-piperazinecarbox - amide hydrochloride, m.p. 195-7°C 1:14 4-/3-(p-fluorothiophenoxy)propyl/-N-cyclopropyl-l-piperazine - carboxamide

1:15 4-/3-(p-f1uorothiophenoxy)propyl/-N-methy1-1-piperazinethio- carboxamide

1:16 4-/3-(p-fluorophenoxy)propyl/-2,5-trans-dimethyl-N-ethy1-1- piperazinecarboxamide

1:17 4-/3-(p-fluorophenoxy)propyl/-2,5-trans-dimethyl-N-cyclo- propy1-1-piperazinecarboxamide

1:18 4-(3-phenoxypropyl)-2,5-trans-dimethyl-N-(1-methylethyl)-1- piperazinecarboxamide hydrochloride, m.p. 185-6 C

1:19 4-/3-(p-fluorophenoxy)propyl/-N-ethyl-l-(l,4-diazacyclohepta ne- carboxamide)

1 :20 4-/3-(p-fluorophenoxy)propyl/-N-cyclohexyl-l-(l ,4-diazacyclo- heptanecarboxamide) hydrochloride, m.p. 221-4°C (dec.)

1 :21 4-/3-(p-fluorothiophenoxy)propyl/-N-ethyl-l-(l ,4-diazacyclo- heptanecarboxamide)

1 :22 4-/3-(p-fluorophenoxy)propyl/-N-phenyl-l-piperazinecarboxami de, hydrochloride, m.p. 202-3°C

1 :23 4-/3-(p-fluorophenoxy)propyl/-N-p-chlorophenyl-l-piperazine ¬ carboxamide

1 :24 4-/3-(p-fluorophenoxy)propyl/-N-phenylmethy1-1-piperazinecar box¬ amide

Example 2

7.0 g (0.03 ol ) of l-/3-(p-fluorophenoxy)propyl/-piperazine was dissolved in 45 ml of cone, acetic acid. 3.2 g (0.04 mol ) K0CN was dissolved in 20 ml of H D and added to the reaction mixture which sub- sequently was stirred (for) 20 h. at RT. After cooli ng to 0°C the reaction mixture was made basic by addi tion of 5N NaOH. The product separated slowly by crystal l ization and was fil tered off. It was dis¬ sol ved in CH ₂ C1 ₂ and the solution was washed wi th H ₂ 0 , dried wi th Na ₂ S0 ₄ ,

and the solvents evaporated. The residual oi l crystal li zed and was recrystal lized from toluene/1 igroin to yiel d 5.9 g of 4-/3-(p-f!uoro- phenoxy)propyl/-l-piperazine carboxamide (2: 1 ) , m.p . 98-100 C.

The corresponding hydrochloride was prepared by dissolvi ng 5.5 g of 5 the base in 50 ml of a mixture of abs. ethanol /ether. Addition of an excess of HC1 in ethanol and additional ether precipi tated the hydro¬ chloride. After recrystal l ization from isopropanol 4.7 g of the hydro¬ chloride (2:2) was obtained, m.p. 209-10°C.

Using essential ly the same procedure (heating of the reaction 10 mixture is required) the following compound is prepared from the corresponding starting materials:

2:3 4-/3- (p-fluorophenoxy)propyl/-l-piperazi nethiocarboxamide

Example 3

12.5 g (0.031 mol ) of p-ni trophenyl-4-/3-(p-fluorophenoxy)propyl/- _{l Ï‚} 1 -piperazine carboxylate was stirred in a mixture of 20 ml of dimethyl- ami ne and 20 ml of THF at 0°C for 3 days. The reaction mixture was partitioned between ether and H ₂ 0. The ether phase was washed twice with a Na-,C0 ₃ solution and twice wi th a NaCl-solution. The mixture was dried with Na ₂ S0 ₄ . After fi l tration excess of HC1 i n ethanol was added to precipitate the hydrochloride. After filtration and recrystal li za¬

20 tion from ethyl acetate/ ethanol was obtained 5.5 g of 4-/3-(p-fl uoro¬ phenoxy )propyl/-N,N-dimethyl-!-pi perazi necarboxami de, hydrochlori de (3: 1 ) , m.p. 185-7°C .

Using essential ly the same procedure (sometimes omi tti ng the co- solvent THF and heating in the case of more unreactive amines) the ⁵ fol lowing compounds were prepared ( isolated as the free bases or as the corresponding salts) from the corresponding starting materials . 3:2 1 -morphol i nocarbony 1 -4-/3- ( p-f 1 uorophenoxy) propy 1 /-pi perazi ne , hydrochloride, m.p. 192-3°C 3:3 1 -pyrrol idinocarbonyl -4-/3- (p-fluorophenoxy) propy 1 /-piperazine 0 3:4 l-piperidinocarbonyl-4-/3-(p-fl uorophenoxy ) propy! /-piperazine

3:5 1 - ( 4-methyl pi peri di nocarbony! ) -4-/3- ( p-f 1 uorophenox ) propy 1 /- piperazine, hydrochloride, m.p. 216-17°C 3:6 l -(4-hydroxy-piperidinocarbonyl )-4-/3 (p-fluorophenoxy )propyl /- piperazine 5 3:7 1 - (4-methyl -pi perazi nocarbony! )-4-/3- (p-f 1 uorophenoxy ) propy 1 / - piperazine 3 :8 ! -(4-acetyl -pi perazi nocarbony! ) -4-/3- (p-fluorophenoxy )propyl /- piperazine

3:9 4-/3-(p-fluorophenoxy)propy!/-N-(2-hydroxyethyl)-l-piperazin e¬ carboxamide, hydrochloride, m.p. 186-7°C Example 4

25 g (0.105 mol) of l-/3-(p-fluorophenoxy)propyl/-piperazine was dissolved in 300 ml of toluene, 20 ml of triethylamine was added and the mixture was cooled to 0°C. 21.2 g (0.105 mol) of p-nitrophenyl-chloro- formate in 300 ml of toluene was added dropwise. The reaction mixture was stirred at RT for 3 h. The triethylamine hydrochloride was filtered off and the solvents were evaporated. The residue was dissolved in methanol and the product was allowed to crystallize overnight. The product was filtered off to yield 25 g of p-nitrophen 1-4-/3-(p-fluoro- phenoxy)propyl/-l-piperazine-carboxylate (4:1), m.p. 101-02°C. Example 5

82 g (0.43 mol) of l-chloro-3-(p-fluorophenoxy)-propane and 262 g of piperazine were dissolved in 700 ml of isopropanol and refluxed for 16 h. The reaction mixture was allowed to reach RT and piperazine which had precipitated was filtered off. The solvents were evaporated and the residue was dissolved in CH Cl^- After washing with sat. NaCl-solution and drying with a ₂ S0 ₄ the CH,,C1 ₂ was evaporated and the residue destin¬ ed to yield 75 g of l-/3-(p-fluorophenoxy)propy!/-piperazine (5:1), b.p.

104-6°C (0.05 mm Hg). Example 6

This example illustrates the potency of compounds of formula (I) and their pharmaceutically active acid addition salt for treatment of mental disorders. Test: Isolation induced aggressive behaviour test

Male mice subjected to prolonged isolation develop aggressive be¬ haviour against each other when paired (Yen, C.Y. et al., Arch.Int.Pharma- codyn. 123, 179, (1959): Valzelli, L., Adv.Pharmacol. 5, 79 (1967). All clinically used neuroleptics and antidepressants studied in this test inhibit this aggressive behaviour although their activity may differ. Also anxiolytic drugs, e.g. diazepa , are active on this kind of aggressive behaviour. The clinical correlation of this test indicates tranquillizing and anxiolytic activities as well as antiagggressive 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 kind of emotional behaviour might be located in limbic structures

in the brain (MacLean, P.D., Psychoso .Med. 11, 338 (1949)).

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

5 To test aggressiveness the mice were paired in a neutral area, a beaker (14 cm high and diameter 14 cm). A pair is considered aggressive if both the animals show clear signs of fighting _. within 5 minutes. This fighting is characterized by biting and vocalization. As soon as fight¬ ing is seen, the mice are separated and brought to their home cage

10 (every second mouse is marked). If only one of two mice exhibit aggressive behaviour the aggressive one is paired with another to make a well matched, aggressive pair. Animals showing no aggression are discarded.

The frequency of paired mice exhibiting fighting varies from 50-100 per cent depending on the time of the year. The test substance is

â–  _j g administered s.c. (0.2-0.4 ml/20 g). The mice are paired 0.5 hour after the injection for trials of 5 minutes' duration.

The EDgo-value (mg/kg) reported is the dose inhibiting aggressive behaviour among 50 per cent of the pairs 0.5 hour after drug administra¬ tion.

Table

20

Isolation i nduced aggressive behaviour test

Compound EDg _Q mg/kg s .c.

1 :3 5

Thioridazi ne ' 5 5

Diazepam ' 6.7 a) Merck Index, 10th Ed., 9202 b) ^' ' 2967

Example 7 0 The following formulations are representative for all of the phar¬ macologically active compounds of this invention. Example of a suitable capsule formulation:

Per capsule, mg

Active ingredient, as salt 10 5 Lactose 250

Starch 120

Magnesium stearate 5

Total 385

In case of higher amounts of active ingredient, the amount of lactose used may be reduced.

Example of a suitable tablet formulation:

Per tablet, mg

Active ingredient, as salt 10

Potato starch 90

Colloidal silica 10

Talc 20

Magnesium s tea rate 2

5% aqueous solution of gelatin 25

Total 157

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to about 5% by weight. These solutions may also contain stabiliz¬ ing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.

The pharmaceutical preparations may also contain therapeutically useful substances other than the pharmacologically active compounds of formula (I).