NO128822B - - Google Patents

Description

Analogy method for the production of

new, therapeutically active acyloxyalkyl heterocyclic compounds.

The present invention relates to an analogue method for the preparation of new, therapeutically active acyloxyalkyl heterocyclic compounds of the general formula (i) in which Z is sulphur, oxygen or lower alkylimino, A is lower alkylene, R^ is hydrogen, halogen or trifluoromethyl, R2 acyl is selected from the group consisting of higher aliphatic acyl, phenyl(lower)alkanoyl and benzoyl, in which the phenyl part may be substituted with up to 3 halogen atoms, lower alkyl groups and/or lower alkoxy groups, or acid addition salts thereof, and the peculiarity of the method according to the invention is that

a) a compound with the general formula

wherein Z and has the above meaning, or its metal salt, is reacted with a carbamoyl compound of the general formula

wherein X is an acid residue and A and R^ have the above meaning, or

b) a compound with the general formula

wherein Z and have the above meaning, or their reactive

derivative is reacted with an amine of the general formula

wherein A and R 2 have the above meaning, or a salt thereof, or

c) a compound with the general formula

wherein Z and has the above meaning, is replaced by a

acyloxyalkyl compound of the general formula

X-A-OR2

wherein X, A and R 2 have the above meaning, or

d) a compound with the general formula

wherein Z, A and R.^ have the above meaning, or a salt thereof, is reacted with an acylating agent of the general formula

wherein it has the above meaning, or its reactive derivative, after which the resulting compound of formula I

if desired is converted to its acid addition salt.

The compounds that can be prepared according to the invention have

in and of themselves anti-inflammatory, antipyretic and analgesic effects, but in addition, <q>g unlike closely related compounds, do not have a bitter taste so that they are suitable for oral administration.

The invention will be easier to understand from the following detailed presentation of preferred embodiments.

The compounds of formula (I) can be prepared from corresponding condensed heterocyclic starting compounds of the general formula (II)

wherein Z and have the above meaning,

respectively from the corresponding carboxylalkyl compound of the general formula (III)

wherein Z and have the previously indicated meaning. respectively from the corresponding heterocyclic compound of the general formula (IV) in which Z and have the previously stated meaning, respectively from the corresponding hydroxyalkylheterocyclic compound of the general formula (V)

in which Z, A and R^ have the meaning given above.

When the starting compound is the compound with (II), this is subjected to an N-substitution. The N-substitution can be carried out by reacting the compound of formula (II) (J. Pharm. Soc. Japan, 77, 349 (1957) ) or its metal salts (e.g. the sodium salts, potassium salts, calcium salts, etc.) with a carbamoyl compound with the general formula (VI) in which X is an acid residue (e.g. chlorine, bromine, iodine, methyl sulfate, ethyl sulfate, benzene sulfonate, toluene sulfonate, methyl carbamate, ethyl carbamate, etc. ) and A and has the above meaning.

The reaction is usually carried out in an inert solvent such as e.g. benzene, toluene, ether, methanol, ethanol, dimethylformamide, etc. Where the compound of formula II is used as such, it is desirable to use a basic condensing agent, e.g. alkali hydroxide such as sodium hydroxide, potassium hydroxide, etc., alkali carbonate such as e.g. sodium carbonate, potassium carbonate, etc., alkali alkoxide such as e.g. sodium methoxide, sodium ethoxide, potassium ethoxide, etc., alkali hydride such as sodium hydride, potassium hydride, etc., alkali amide such as sodium amide, potassium amide, lithium amide, etc, and the like. The reaction temperature depends on the starting compound of formula (II), the reaction component of formula (VI), the basic condensing agent and the solvent used in practice.

When the starting compound is the compound of formula (III), this is subjected to an amidation. The amidation can be carried out by reacting the compound of formula (III) (see British Patent No. 862,226) or its reactive derivative with an amine of the general formula (VII)

in which A and R 2 have the above-mentioned meaning, or a salt thereof such as e.g. the hydrochloride, hydrobromide, sulphate, picrate, tartrate, etc.

Examples of reactive derivatives of the compound with formula (III) are acid halides such as e.g. the acid chloride, the acid bromide, etc., acid anhydrides such as alkyl phosphoric anhydride, aromatic carboxylic acid anhydrides, etc., further acid amides such as the acid amide with imidazole, the acid amide with 4-substituted imidazole, etc., further acid esters such as e.g. methyl ester, ethyl ester, cyanomethyl ester, p-nitrophenyl ester, etc., as well as the acid azide.

When the compound of formula (III) is used as such, it is usually necessary to use a condensing agent. Examples of condensing agents are NjN^-dicyclohexylcarbodiimide, polyphosphoric acid, ethyl polyphosphate, isopropyl polyphosphate, etc.

The reaction is usually carried out in an inert solvent such as e.g. acetone, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, ethylene dichloride, tetrahydrofuran, ethyl acetate, pyridine, etc. If necessary, a basic substance such as e.g. alkali carbonate, alkali hydrogen carbonate, trialkylamine, pyridine, etc. be present during the turnover. The reaction temperature is varied over a wide range, but the reaction is usually carried out during cooling or at room temperature.

When the starting compound is the compound of formula (IV), this is subjected to N-acyloxyalkylation. The N-acyloxyalkylation can be carried out by reacting the compound of formula (IV)

with the acyloxyalkyl compound of the general form. (VIII)

wherein X, A and R 2 have the meaning given above.

The compound with (IV) can be prepared by reacting the corresponding carboxylalkyl compound of formula (III) with piperazine (or diazepine) in the presence of the condensing agent mentioned for the previously mentioned amidation. The reaction can be carried out in an inert solvent such as e.g. methanol, ethanol, ether, benzene, acetone, dimethylformamide, dimethylsulfoxide, etc. and if necessary in the presence of the basic condensing agent mentioned for the previously mentioned N-substitution. The reaction temperature depends on the starting compound of formula (IV), the reaction component of formula (VIII), the basic condensing agent and the solvent used in practice, the reaction temperature being varied from room temperature to around the boiling point of the solvent.

When the starting compound is the compound of formula (V), this is subjected to an acylation. The acylation can be carried out by reacting the compound of formula (V) or a salt thereof such as, e.g. the hydrochloride, the hydrobromide, the sulfate, the acetate, the picrate, the citrate, the tartrate, etc. with an acylating agent of the general formula (IX)

wherein R 2 has the above meaning, or its reactive derivatives. The compound of formula (V) is new and can be prepared by reacting the corresponding condensed heterocyclic compound of formula (II) with a 4-hydroxyalkyl-1-piperazinyl (or diazepinyl)carbonylalkyl compound of the general formula

wherein X and A are as previously defined, in the presence of a basic condensing agent.

Examples of reactive derivatives of the compound of formula (IX) are acid halides, acid anhydrides, acid amides, acid esters and acid azides as specified in more detail under the section on amidation. When the compound of formula (IX) is used as such, it is usually necessary to use a condensing agent which is also discussed under the section on amidation. The reaction is usually carried out in an inert solvent such as e.g. acetone, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, chloroform, ethylene dichloride, tetrahydrofuran, ethyl acetate, pyridine, etc. The reaction temperature can be varied over a wide range and depends on the starting compound of formula (V), the reaction component of formula (IX), the condensing agent and the solvent used in practice.

As previously indicated, the compounds of formula (I) are in and for

useful as anti-inflammatory agents. Some of the test results showing their utility are shown below, but as mentioned, a distinctive and special advantage of the compounds of formula I is that they do not have a bitter taste so that they are suitable for oral administration.

The inhibitory effect on swelling induced by means of albumin or carrageenan is compared on the basis of the comparison compound 3-/4-(2-palmitoyloxyethyl)-1-piperazinyl/carbonyl-methyl-5-chloro-2-benzo-thiazolinone.

Methodology:

Male Wistar rats each weighing 150 to 200 g were divided into two groups. One group (10 rats) orally received 1 cc of a suspension of the test compound in 1% carboxymethyl cellulose solution per 100 g body weight (test group), and the other group (10 rats) received 1 cc of 1% carboxymethyl cellulose solution alone per 100 g body weight in a similar way (control group). 1 h after gavage, egg white albumin (1094, 0.1 ml) or corragenin (1%, 0.1 ml) was administered to the animals in their hind paws to induce swelling. Paw thickness was measured using calipers at various times after injection of the swelling-inducing substance. Swelling percentage and inhibitory percentage of swelling were calculated from the following equations:

T: Paw thickness for supplying the swelling-inducing agent

substance.

t: Paw thickness at different times after the

swelling-inducing substance was added.

C: Swell-^ in the control group.

D: Swell-/? in the sample group.

Several hours after injection of the swelling-inducing substance (3 hours for the albumin injection and h hours for the carrageenin injection), the animals were killed. Both hind paws were cut off and weighed. Swelling-$ and inhibitory % for the swelling were calculated from the following equations:

W: Weight of the paw that was not injected with swelling-inducing substance.

w: Weight of the paw injected with the swelling inducer

substance.

E: Swell-^ for control group.

F: Swelling for treated group.

Results;

The results are shown in the following tables 1 and 2.

The compound of formula (I) produced according to the invention can be converted into an acid addition salt such as, for example the hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, acetate, citrate, tartrate, lactate, etc.

The compound of formula (I) has antipyretic and analgesic properties in addition to anti-inflammatory activity. Among the starting compounds for the preparation of the compound of formula (I), the compound of formula (V) exhibits the same powerful pharmaceutical activity. However, the compound of formula (V) has a bitter taste which is not suitable for pharmaceutical preparations for oral administration such as e.g. powders, granules, pills,

elixir, syrup, emulsions, etc. The bitter taste of the compound of formula (V) could be removed without reducing the pharmaceutical effect by means of the conversion to the compound of formula (I), in which the hydroxy group of the compound of formula (V) is covered by the acyl group.

The compounds of formula (I) are useful for the treatment of fever, pain and inflammatory conditions associated with pain, fever, chills and/or swelling.

The compound of formula (I) can be supplied by usual methods,

with common types of unit dose or with common pharmaceutical carriers to produce anti-inflammatory, antipyretic and analgesic effects in animals and humans. The compounds can thus be used in the form of pharmaceutical preparations, which are mixed with a pharmaceutically acceptable organic or inorganic carrier suitable for enteral, parenteral or local administration. Oral administration using the powder, tablets, capsules or in liquid forms such as e.g. suspensions, solutions or emulsions are particularly advantageous. When the compounds are formed into tablets, the usual binding agents and dissolution promoting agents can be used in the therapeutic unit doses.

Examples of binders include glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate and talc. Cereal starch, keratin, colloidal silicon oxide and potato starch can be mentioned as examples of loosening-promoting agents. When supplied as liquids, ordinary liquid carriers can be used.

The unit dosage for therapeutically effective amounts of the compound of formula (I) for human therapeutic use varies within wide limits so that the upper limit is determined only by the desired effect and economic considerations. Furthermore, of course, the dosage for the therapeutic agent used can vary considerably according to the age of the patient and the degree of desired therapeutic effect. Each unit dose may preferably contain from 5 to 95% of the new therapeutically active compounds, with the remainder then constituting ordinary pharmaceutical carriers. Pharmaceutical carriers do not mean therapeutically effective materials that are usually used in unit doses and these then include fillers, diluents, binders, lubricants, dissolution promoting agents and solvents. It is also, of course, possible to administer the compounds, i.e. the pure ones, without the use of any pharmaceutical carrier.

Practical and preferred embodiments of the method according to the invention are detailed in the following embodiment examples.

Example 1

(1) A solution of 3-[ti-(2-hydroxyethyl)-1-piperazinyl-7-carbonyl-methyl-5-chloro-2-benzothiazolinone (15.0 g) and triethylamine (16.6 g)

in dry chloroform (330 cc) was kept at 20°C and a solution of palmitoyl chloride (3<*>+.7 g) in dry chloroform (60 cc) was added dropwise thereto with stirring over 2 hours. The mixture was further stirred for 3 hours and, after complete reaction, 10% aqueous sodium hydroxide solution • (100 cc) and water (100 cc) were added. The chloroform layer was separated, washed three times with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resulting residue was crystallized from a mixture of benzene and petroleum ether to give 3-[t|~(2-palmitoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone (1<l>+j5 g ) as colorless flakes with melting point 8k to 86°C.

(2) A solution of 3-^+-(2-hydroxypropyl)-1-piperazinyl-carbonylmethyl-5-chloro-2-benzothiazolinone (2.0 g) and triethylamine (1.1 g) in dry chloroform (20 cc ) was kept at 15 to 20°C with stirring. A solution of palmitoyl chloride (5.9 g) in dry chloroform (10 cc) was added dropwise over <*>+0 min. and the mixture was stirred further for Hr hour. After completion of the reaction, water was added to the reaction mixture. The chloroform layer was separated, washed with an aqueous sodium carbonate solution three times and then with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was chromatographed on alumina using ethyl acetate as developer. The resulting effluent was evaporated to give 3-[<*>*-(2-palmitoyloxy-propyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone

(0)9g). This substance was recrystallized from the mixture of petroleum ether and benzene and gave a colorless powder with a melting point of 9h at 95°C.

(3) A solution of 3-[^-(2-hydroxyethyl)-1-pit>erazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone (5.0 g) and anhydrous potassium carbonate (3*89 g) in dry chloroform (100 cc) was kept at

o

20 to 23 C with stirring and a solution of stearoyl chloride (17.1 g) in dry chloroform (20 cc) was added dropwise thereto over 55 min. The mixture was stirred for 7 hours with stirring and after completion of the reaction the chloroform layer was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oil (8.3 g). The benzene solution of the oil was chromatographed on an alumina column to give an oil (5.9 g). The oil thus obtained was crystallized and the crystals recrystallized from petroleum ether four times to give (2-stearoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone as colorless waxy crystals with m.p. 7^ to 76°C.

(<*>f) A solution of 3-ZIi-(2-hydroxyethyl)-1-piperazinyl7-carbonylmethyl-5-chloro-2-benzothiazolinone (20.0 g) and pyridine (8.85 g) in dry chloroform ( 250 cc) was maintained at 15 to 20°C with stirring. A solution of phenylacetyl chloride Q+.7 g) in dry chloroform

(30 cc) was added dropwise over 1 hour and the mixture was stirred for 3.1 hours at room temperature. After completion of the reaction, an aqueous sodium carbonate solution was added to the reaction mixture. The chloroform layer was separated, washed with sodium carbonate and extracted with 10% hydrochloric acid. The hydrochloric acid layer was set aside overnight and precipitated crystals were collected by filtration and then recrystallized from ethanol to give 3-/<1>+-(2-phenyl-acetoxyethyl)-1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone n-hydrochloride as goodbye; flake with m.p. 206 to 207°C.

(5) A mixture of 3-(J+-(2-hydroxypropyl)-1-piperazinyl7-carbonylmethyl-5-chloro-2-benzothiazolinone (2.0 g) and triethylamine (0.55 g) in dry chloroform (20 cc ) was kept at 20 to 25°C with stirring. A solution of phenylacetyl chloride (1.01 g) in dry chloroform (10 cc) was added dropwise thereto and the mixture was stirred for h hours at room temperature. After completion of the reaction, water was added to the reaction mixture. The chloroform layer was separated, washed with dilute sodium hydroxide, water, dilute hydrochloric acid and water in the order indicated and dried over anhydrous

l

magnesium sulfate. The solvent was distilled off and the remaining oil was subjected to chromatography with benzene on it

an alumina column. The effluent was evaporated to an oil (0.0 g) and ethanolic hydrochloric acid was added. Precipitated crystals were isolated by filtration and recrystallized from aqueous ethanol solution to give 2-phenylacetoxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone hydrochloride as a colorless powder m.p. 250°C (decomposition). (6) A mixture of 3-(1-(2-hydroxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone (1.0 g), 3,5-trimethoxy-benzoyl chloride (0.7 g) and anhydrous potassium carbonate (2.0 g) in dimethylformamide (20 cc) was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was dried and the solvent distilled off and the residue chromatographed on alumina using ethyl acetate as developer. The resulting effluent was evaporated and the residue was dissolved in a small amount of dry ethanol and converted to a solid by the addition of an ethereal solution of maleic acid. Crystals separated were recrystallized from dry ethanol to give 3-Z<1>+-(2-(3,<l>f,5-trimethoxybenzoyloxy)-ethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzo-thiazolinone- maleate (0.3 g) with m.p. 123" to 130°C (decomposition). (7) A mixture of 3-/If-(2-hydroxyethyl)-1-piperazinyXfearbonyl-methyl-5-chloro-2-benzocasazolinone (1.0 g) palmitoyl chloride ( 0.89 g), potassium carbonate (0.^-1 g) and dry dimethylformamide (0.5 cc) were stirred for 3 hours. After completion of the reaction, ethyl acetate and water were added to the reaction mixture. The ethyl acetate portion was washed with water and dried over anhydrous magnesium sulfate The solvent was removed by distillation to give 3-(--(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone (1.2 g).

This substance was recrystallized from pertrol ether and gave a colorless powder with m.p. 72 to 7<l>f°C.

(8) To a solution of 3-methyl-6-chloro-1 -/*+-(2-hydroxyethyl)-1-piperazinyl7carbonylmethyl-2-benzimidazolinone (0.35 g) in dimethylacetamide (7 cc) was added potassium carbonate ( 0.3g). A solution of palmitoyl chloride was further added to the mixture

(0.3 g) in dimethylformamide (3 cc). The mixture thus obtained was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was poured onto ice-mixed water and extracted with ethyl acetate several times. The extract was thoroughly washed with water and dried. The solvent was removed by distillation and the residue was recrystallized from a mixture of benzene and a hexane to give 3-methyl-6-chloro-1-Ztt-(2-palmitoyloxyethyl)-1-piperazinyl7-carbonylmethyl-2-benzimidazolinone (0.25 g) with m.p. 97 to 98°C. (9) 3-Zt(—(2-lauroyloxyabyl)-1-piperazinyl7-carbonylmethyl-5-chloro-2-benzothiazolinone (0.5 g) was prepared as an oil in much the same manner as above by reacting -3/ **~(2-Hydroxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothia.zolinone (0.72 g) with lauroyl chloride (0.^ g). This substance was conventionally converted to the maleate in the form of colorless crystals, mp 168 to 171° C. (10) 3-[tt-(2-linoloyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone (0.5 g) was prepared as an oil in much the same manner as above by reacting 3-(If-(2-hydroxy-ethyl)-1-piperazinyl-7-carbpnylmethyl-5-chloro-2-benzothiazolinone (0.7^ g) with linoloyl chloride (0.8 g ). The maleate consisted of colorless crystals with m.p. 150 to 152°C (dec.). (11) 3-(5+-(2-lauroyloxypropyl)-1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone (0.8 g ) was prepared in the form of an oil in much the same manner as above by reacting 2-hydroxy-propyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-b enzothiazolinone (0.9 g) with lauroyl chloride (0<J>.6V g). The maleate had m.p. 162 to 165 °C (12) 3-[th-(2-linoloyloxypropyl)-1-piperazinyi/carbonylmethyl-5-chloro-2-benzothiazolinone was prepared in the form of an oil in much the same manner as above by reacting 3- /^^2-Hydroxypropyl)-1^piperazinyi7-carbonylmethyl-5-chloro-2-benzothiazolinone (0.9 g)

with linoleyl chloride (0.8 g),. The maleate consisted of colorless crystals with m.p. 1^-7 to lk9°C (cleavage).

(13) 3-A-(2-palmitoyloxyethyl)-1-<p>i<p>erazine<y>l7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone (1.3 g) in the form of colorless crystals with m.p. 98 to 99 C after recrystallization 'from petroleum ether was prepared by reacting 3-/'+-(2-hydroxyethyl)-1-piperazinyl7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone

(1.5 g) with palmitoyl chloride (0.71 g).

(1^) 3-(5+-(2-stearoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone (1.5 g) in the form of colorless crystals with m.p. 95 to 96°C recrystallized from ethyl acetate was prepared by reacting 3-(1<-(2-hydroxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone (1.0 g) with stearoyl chloride (0 .78 g).

Example 2

(1) To a solution of 3-O-piperazinylcarbonylmethyl)-5-chloro-2-benzothiazolinone (1.5 g) in dimethylformamide (15 cc) is added a solution of 2-palmitoyloxyethyl bromide (1.8 g) and potassium carbonate (1.5 g) in dimethylformamide (5 cc) and the mixture is stirred for several hours at room temperature. The reaction mixture is poured onto ice-cold water and extracted repeatedly with ethyl acetate. The ethyl acetate layer is washed with water and passed over anhydrous magnesium sulfate. The solvent" is distilled off and the residue is dissolved in ethyl acetate and chromatographed on alumina using ethyl acetate as the developer. The residue thus obtained was evaporated to give 3-(Tf-(2-palmitoyloxyethyl)-1-piperazinyl/carbonylmethyl-5-chloro-2-benzothiazolinone) The substance was recrystallized from a mixture of petroleum ether and benzene and gives colorless flakes with a melting point of 86°C.

In a similar way as above, the following compounds can be prepared: 3-A-(2-lauroyloxyethyl)1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate forms colorless crystals with m.p. 168 - 171°C. 3-[Tt-(2-linoleoxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone as an oil. The maleate forms colorless crystals with m.p. 150 to 152°C (decomposition). 3-A-(2-stearoyloxyethyl)-1-piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone in the form of waxy crystals with m.p. 7<*>+ to 76°C. 3-(2-lauroyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 162 to 165 C. 3-[5-(2-palmitoyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone in the form of a colorless powder with m.p. 9*+ to 95°C. 3-ZI+-(2-linoloyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone in the form of an oil. The maleate forms colorless crystals with m.p. 1^7' to 1^9 C (cleavage). 3-^+-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone. The maleate is a colorless powder with m.p. 72 to 7<l>f°C. 3-methyl-6-chloro-1 -Z1+-(2-palmitoyloxyethyl)-1-piperazinylcarbonyl--methyl-2-benzimidazolinone with m.p. 97 to 98°C. 3- £+~( 2.- f enylacetoxyethyl) -1 -piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms colorless flakes with m.p. 206 to 207°C. 3-A-(2-phenylacetoxypropyl)-1-piperazinyl-3-7carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms a colorless powder with m.p. 250°C (decomposition). 3-Z^-(2-O,k,5,-trimethoxybenzoyloxy)ethyl)-1-piper azinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 123 to 130°C (decomposition). 3-[<*>+-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone. Colorless crystals with m.p. 98 to 99°C.

3-(1-(2-Steayloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone. Colorless crystals of the compound have a melting point of 95 to 96°C.

Example

(1) A solution of palmitoyloxyethylpiperazine (2.0 g) in dimethylformamide (5 cc). The mixture is stirred for 5 hours at room temperature and, after completion of the reaction, the reaction mixture is poured onto ice-mixed water and extracted several times with ethyl acetate. The ethyl acetate layer is washed with water and then dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue thus obtained is taken up in ethyl acetate and chromatographed on aluminum oxide using ethyl acetate to give 3-(2-palmitoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzo-thiazolinone (0.7 g) as colorless crystals with m.p. 8<*>+ to 86°C.

In a similar way, the following compounds can be prepared: 3-Æ-(2-lauroyloxyethyl) 1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate forms colorless crystals with m.p. 168 to 171°C 3-Z?+-(2-Linoloyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone as an oil. The maleate forms colorless crystals with m.p. 150 to 152°C (decomposition). 3-(1*--(2-stearoyloxyethyl)-T-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. Waxy crystals melt at 7k to 76°C. 3-N-(2-lauroyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 162 to 165°C. 3-(2-palmitoyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. Colorless powder with m.p. 9<*>+ to 95°C. 2-linoloyloxypropyl)-1-piperazinyl.7carbonylmethyl-5-chloro-2-benzothiazolinone in form; of an oil. The maleate forms colorless crystals with m.p. 15-7 to 15-9°C (cleavage). 3-A-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone. The maleate forms a colorless powder with m.p. 72 to 7<l>+°C.

3-methyl-6-chloro-1-£+-{2-palmitoyloxyethyl)-1-piperazinyl-7carbonyl-methyl-2-benzimidazolinone with m.p. 97 to 98 C.

3-(5--(2-phenylacetoxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms colorless flakes with m.p.

206 to 207°C

3-(5-(2-phenylacetoxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone). The hydrochloride is a colorless powder with m.p. 250°C (decomposition).

3- /5-(2-Q,5-,5-trimethoxybenzoyloxy)ethyl)-1-piperazinyl/carbonyl-methyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 123 to 130°C (decomposition).

3-(5-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone). Colorless crystals thereof have m.p.

98 to 99°C

3-(5-(2-stearoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone) consists of colorless crystals with m.p.

95 to 96°C

Example h

(1) To a solution of 5-chlorobenzothiazolinone (0.93 g) in dry acetone (20 cc) is added potassium carbonate (0.5 g) and 1-chloroacetyl-5~(2-palmitoyloxyethyl)piperazine (2.1 g) . The mixture is refluxed for 5 hours with stirring and reaction

t

the mixture is filtered and the filtrate is concentrated. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate.

The solvent is distilled off and the resulting residue is chromatographed on alumina using ethyl acetate and gives 3-^-(2-palmitoyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone (0.1 g) as colorless crystals with m.p. 85- to 86°C.

In a similar way, the following compounds can be prepared: 3-Z5-(2-lauroyloxyethyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate forms colorless crystals with m.p. 168 to 171°C. 3-A-(2-Linoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone in the form of an oil. The maleate forms colorless crystals with m.p. 150 to 152°C (decomposition). 3_/<5>~(2-stearo<y>lox<y>et<y>l)-1 -piperazinyl7carbonylmethyl-5-chloro-2-benzothiazolinone in the form of waxy crystals with m.p. 7h to 76°C. 3-Z5-(2-lauroyloxypropyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The maleate has a m.p. 162 to 165°C. 3-Z5-(2-palmitoyloxypropyl)-1-piperazinyl-7carbonylmethyl-5-chloro-2-benzothiazolinone in the form of colorless powder with m.p. 95 to 95°C. 3- /5-(2-linoloyloxypropyl)-1-piperazinyl/carbonylmethyl-5-chloro-2-benzothiazolinone in the form of an oil. The maleate forms colorless crystals with m.p. 1^-7 to 1 5-9 C (cleavage). 3- /5-(2-palmitoyloxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzoxazolinone. The maleate forms a colorless powder with m.p. 72 to 7*f°C.

3-methyl-6-chloro-1-(5-(2-palmitoyloxyethyl)-1-piperazinyl-7-cartonyl-methyl-2-benzimidazolinone with m.p. 97 to 98°C.

3-(5-(2-Phenylacetoxyethyl)-1-piperazinyl-7-carbonylmethyl-5-chloro-2-benzothiazolinone. The hydrochloride forms colorless flakes with m.p. 206 to 207°C.

in

3-(4-(2-phenylacetoxypropyl)-1-piperazinyl/carbonylmethyl-5-chloro-2-benzothiazolinone). The hydrochloride forms a colorless powder with m.p. 250°C (decomposition).

3- /4-(2-(3,4,5-trimethoxy<y>benzo<y>loxy)et<y>l-l-<p>i<p>erazin<y>l/carbonyl-methyl-5- chloro-2-benzothiazolinone The maleate has mp 123 to 130°C (decomposition).

3-(4-(2-palmitoyloxyethyl)-1-piperaziny],7carbonylmethyl-5-trifluoromethyl-2-benzothiazolinone in the form of colorless crystals with m.p. 98 to 99°C.

3-(4-(2-stearoyloxyethyl)-l-piperaziny l/carbonylmethyl-5-trifluoromethyl-2-benzbthiazolinone in the form of colorless crystals with m.p. 95 to 96°C.

Claims (1)

Analogous process for the preparation of new, therapeutically active acyloxyalkyl heterocyclic compounds of the general formula (I) wherein Z is sulfur, oxygen or lower alkylimino, A is lower alkylene, is hydrogen, halogen or trifluoromethyl, R2 is acyl selected from the group consisting of higher aliphatic acyl, phenyl(lower)alkanoyl and benzoyl, wherein the phenyl moiety may be substituted with up to 3 halogen atoms, lower alkyl groups and/or lower alkoxy groups, or acid addition salts thereof, characterized in that a) a compound with the general formula wherein Z and has the above meaning, or its metal salt, is reacted with a carbamoyl compound of the general formula in which X is an acid residue and A and R2 have the above meaning, or b) a compound of the general formula in which Z and R 2 have the above meaning, or its reactive derivative is reacted with an amine of the general formula in which A and R 2 have the above meaning, or a salt thereof, or c) a compound of the general formula in which Z and has the above-mentioned meaning, is reacted with an acyloxyalkyl compound of the general formula in which X, A and R 2 have the above-mentioned meaning, or d) a compound of the general formula in which Z, A and R 2 have the above-mentioned meaning, or a salt thereof, is reacted with an acylating agent of the general formula wherein R 2 has the above meaning, or its reactive derivative, after which the resulting compound of formula I is optionally converted to its acid addition salt.