US3812126A - (1-(4-(3-(p-fluorobenzoyl)-propyl)-1-piperazinyl)-alkyl)-3-alkyl-2-imidazolidinones - Google Patents

Abstract

COMPOUNDS OF THE CLASS OF 1-(2-(4-(3-(P-FLUOROBENZOYL)-ALKYL) - 1 - PIPERAZINYL)-ETHYL) - 3 - ALKYL-2-IMIDAZOLIDINONE WHICH MAY BE SUBSTITUTED IN THE 4-POSITION OF THE IMIDAZOLIDINONE RING BY AN ALKYL GROUP HAVING 1 TO 4 CARBON ATOMS AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE AN ANTI-EMETIC ACTION AND ALSO A MODERATE CENTRAL DEPRESSANT ACTION, E.G. THEY INHIBIT MOTILITY. THEY MOREOVER EXHIBIT NO CATALEPTIC INHERENT ACTION. SUCH COMPOUNDS CAN BE PREPARED FOR INSTANCE BY REACTION OF 1(2-(1-PIPERAZINYL)-ETHYL)-3-METHYL - 2 - IMIDAZOLIDINONE WITH 4 - CHLORO-4''-FLUOROBUTYROPENONE. THE COMPOUNDS ARE ACTIVE OF INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS.

Description

"United States Patent Office 3,812,126 Patented May 21, 1974 3,812,126 [1-[4-[3-(p-FLUOROBENZOYL)-PROPYL] 1 PIPER- AZINYL1-ALKYL] 3 ALKYL 2 IMIDAZO- LIDINONES Armin Ziist, Birsfeldeu, Basel-Land, and Walter Schindler,

deceased, by Leonhard Gysin, executor, Riehen, Switzerland, assignors to Ciba-Geigy Corporation, Ardsley, N Y

No Drawing. Filed Dec. 1, 1971, Ser. No. 203,870 Claims priority, application Switzerland, Dec. 7, 1970, 18,133/70 Int. Cl.,C07d 51/70 US. Cl. 260-268 H 13 Claims ABSTRACT OF THE DISCLOSURE DETAILED DESCRIPTION The present invention relates to new imidazolidinone derivatives, to processes for their production, to pharmaceutical compositions containing the new compounds, and to the use thereof.

More particularly, the present invention relates to imidazolidinone derivatives of formula I wherein A represents an alkylene group having 2 to 3 carbonatoms, A represents an alkylene group having 2 to 4 carbon atoms,

R represents an alkyl group having 1 to 4 carbon atoms,-

and R represents hydrogen, or an alkyl group having 1 to 4 carbon atoms,

and the pharmaceutically acceptable acid addition salts thereof.

As alkylene radicals having 2 to 3 carbon atoms in the compounds of formula I, A and A are: the ethylene, trimethylene or propylene group; and as an alkylene radical having 4 carbon atoms, A is the tetramethylene, the ethyl ethylene, or a methyltrimethylene group. Furthermore, both R and R as an alkyl group are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or the sec.butyl group- Preferred members of this class are:

(1) 1-[2- [4- [3-(p-fluorobenzoyl)-propyl]-1-piperazinyl] -ethyl] -3 -methyl-2 imidazolidinone.

(2) 1- [2- [4- [3- (p-fiuorobenzoyl -propyl] -1-piperazinyl]-ethyl] -3 -ethyl-2-imidazolidinone.

(3) 1-[2- [4- [3- (p-lfluorobenzoyD-propyl] -1-piperazinyl] -ethyl] -3 -n-butyl-2-imidazolidinone.

(4) 1- [3- [4-[3-(p-fiuorobenzoyD-propyl] -1-piperazinyl] -propyl] -3-rnethyI-Z-imidazolidinone.

(5) 1- [2- [4- [3- (p-fiuorobenzoyl) -propyl]-1-piperazinyl] -ethyl]-3-isopropyl-2-imidazolidinone.

(6) 1- [3- [4- [3 (p-fluorobenzoyl) -propyl]-1-piperazinyl] -propyl] -3-ethyl-2-imidazolidinone.

and the pharmaceutically acceptable acid addition salts thereof.

Compounds of the formula I and the pharmaceutically acceptable acid addition salts thereof have valuable pharmacological properties and a high therapeutic index.

In the case of oral, rectal or parenteral administration, they have an anti-emetic action, as was determined in the apomorphine-vomiting test in the case of the dog and the golden hamster; the said compounds also have a moderate central depressant action, e.g. they inhibit motility. They moreover exhibit no cataleptic inherent effect. These properties, which can be shown by selected standard tests [cp. W. Theobald et al., Arzneimittelforsch, 17, 561 (1967)], characterize the said compounds as being suitable for the treatment of emesis of varying origin, and of psychosomatic disturbances.

The test results indicated in the following table are illustrative, and illustrative only, of the pharmaceutical activity of the subject compounds. The compounds 1 to 6 in the table are the compounds 1 to 6 listed above, compounds 1 to 3, 5 and 6 being for the purposes of testing in the form of their dihydrochloride salt and compound 4 in the form of its bis-maleate salt.

TABLE Antagonistic activity in the apomorphine- 50% Adrenolytic vomiting test a desrease of activity on orientation isolated Golden Compound No. motility l organs 1 hamster Dog l After i.p. administration on mice; dose in mg./kg. 5 In comparison with RE GITIN=1. l Caused by s.c. application, dose ED 50 in mg.,lkg., 30 minutes before 5.0. application of 0.1 mg./kg. of apomorphiue-hydroehloride. Compounds of the formula I are produced in the caseof the first process according to the invention by the reaction of compounds of formula II:

wherein A A R and R have the meanings given under.

formula I, or of the alkali metal derivative of such a compound, with a reactive ester of 3-(p-fluorobenzoyl)-propanol. The product may, optionally, be converted with an inorganic or organic acid into an addition salt.

Suitable reactive esters of 1-(p-fiuorobenzoy1)-propanol are, for example, halides such as the chloride orbromide, also sulphonic acid esters, e.g. the methanesulphonic acid ester, or the oor p-toluene-sulphonic acid ester. These esters are reacted with the free bases of the formula II preferably in the presence of a solvent. Suitable solvents are those which are inert under the reaction conditions, e.g. hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as chloroform, ethereal liquids such as ether or dioxane, as well as lower alkanones, particularly diethyl ketone.

In the reaction according to the invention of one molecular equivalent of reactive ester with one molecular .3 equivalent of free base, one molecular equivalent of acid is split off. This acid can be bound to excess base of the formula II, or to the dibasic reaction product. Preferably, however, an acid-binding agent is added to the reaction mixture. Suitable acid-binding agents are, e.g. alkali metal carbonates such as sodium or potassium carbonate, also tertitry organic bases such as, e.g. pyridine, triethylamine or diisopropylethylamine. Excess tertiary bases may also be used as solvent.

Optionally, the reaction can be accelerated by an alkali iodide, especially potassium iodide. The reaction is performed at ca. 50 to 150 0., preferably at the boiling point of the solvent.

If for the reaction according to the invention is used, instead of the free base of the formula II, an alkali metal derivative thereof, e.g. a sodium, potassium or lithium derivative, then it is advantageous for the reaction to be performed in a hydrocarbon e.g. in benzene or toluene.

The formation of the alkali metal derivatives of the first reaction component is effected preferably in situ, e.g. by the addition of at least one molecular equivalent of alkali metal hydride, alkali metal amide or of an alkali metal organic compound, when starting with one molecular equivalent of a free base. For example, as alkali metal amides are used sodium and lithium amide, as alkali metal hydrides is used sodium hydride, and as alkali metal organic compound phenyllithium or butyllithium.

Examples of compounds of the formula II which are known are, e.g. 1-[2-(1-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone, 1 [3-(l-piperazinyl)-propyl]-3-methyl- 2-imidazolidinone, as well as the corresponding 3-ethyl compounds; they can be produced by various processes. Further compounds of this type can be obtained analogously.

Of the reactive esters suitable as the second reaction component, 4-chloro-4'-fluorobutyrophenone [cp. C. van de Westeringh et al., Ind. chim. belge, 25, 1073 (1960)], for example, is described in the literature.

In a second process according to the invention compounds of the general formula I are produced by reacting a compound of the formula III:

wherein A has the meaning stated under formula I, or an alkali metal derivative thereof with a reactive ester of a compound of the formula IV:

I'M CHz-CH HO-Ar-N N-R II (IV) wherein A R and R have the meaning given under formula I, followed by optional conversion of the obtained product with an inorganic or organic acid into an addition salt.

Suitable reactive esters of the compounds of the formula IV are, e.g. halides such as chlorides or bromides,

also sulphonic acid esters, e.g. the methanesulphonic acid ester or the 0- or p-toluene-sulphonic acid ester.

The reaction according to the invention of the free bases, or of their alkali metal derivatives can be performed in the same solvents or diluents, and at the same reaction temperatures, as in the first process. With the condensation of one molecular equivalent of free base with one molecular equivalent of reactive ester, one molecular equivalent of free acid is split off, which can be bound to the same acid-binding agents as in the case of the first process.

The alkali metal derivatives of the first reaction component, e.g. sodium, potassium or lithium derivatives,

are preferably used in situ in the process according to the invention. These alkali metal derivatives can be obtained in a manner analogous to that for the alkali metal derivatives of the first process.

Of the bases embraced by the formula III, 4'-fluoro- 4-(l-piperazinyl)-butyrophenone is known. Further compounds of this type can be produced analogously.

The second reaction component of the process according to the invention is the reactive esters of compounds of the formula IV. Of these compounds, 1-(2-chloroethyland l-(3 chloropropyl)-3-methyl-2-imidazolidinone, as well as 1-(2-chloroethyl)-3-butyl-2-imidazolidinone, are, for example, known, and can be produced by various processes. Further compounds of this type can be produced analogously.

Compounds of the formula I of which the radical A is an ethylene group can be produced by a third process according to the invention by the reaction of a compound of the previously given formula III, wherein A represents an alkylene group having 2 to 3 carbon atoms, or an alkali metal derivative thereof, with a compound of the general formula V:

wherein R represents an alkyl group having 1 to 4 carbon atoms,

R represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and

Y represents halogen,

or with an alkali metal derivative of such a compound; and, followed by optional conversion of an obtained product with an inorganic or organic acid into an addi tion salt.

The radical Y of the general formula V is a halogen, preferably chlorine or bromine.

The reaction according to the invention of the free bases of the formula III, or of their alkali metal derivatives, with the urea derivatives or their alkali metal derivatives can be performed in the same solvents or diluents, and at the same reactiontemperatures, as in the case of the first process. With the reaction of one molecular equivalent of free base with one molecular equivalent of the free urea derivatvie, two molecular equivalents of hydrogen halide are split off, which can also be bound to the same acid-binding agents. Both reaction components are used as alkali metal derivatives, e.g. sodium, potassium or lithium derivatives, preferably in situ, in the process according to the invention. These alkali metal derivatives can be obtained analogously to the alkali metal derivatives of the first process.

The preparation of the starting materials of the formula III is described following the second process. A starting material embraced by the general formula V is 1-methyl-3,3-bis-(2-chloroethyl)-urea, which can be obtained starting with diethanolamine. Diethanolamine yields, with l-methylisocyanate: l-methyl-3,3-bis-(2-hydroxyethyD-urea, which reacts with thionyl chloride with elimination of sulphur dioxide and hydrogen chloride. Further starting materials of the formula V can be produced analogously.

According to a fourth process, compounds of the formula I are produced by the reaction, according to Grignard, of a compound of the general formula VI:

with a compound of the formula VII:

(VII) wherein A A R and R have the meaning given under under formula I, and one of the two groups X or Z represents a nitrile or carbonylhalide group, and the other a magnesium halide radical (MgHal), zinc halide radical (ZnHal), or a metal-organic cadmium radical; with optional conversion of the obtained product with an inorganic or organic acid into an addition salt.

The halides used in the process are preferably chlorides, bromides or iodides.

As metal-organic cadmium radical, X is e.g. the group VIII:

/CHz-CH; CHI-C H Cd(CH2) a-N N-Ar-N N-R (5 (VIII) wherein A A R and R have the meaning given under formula I, and Z the group IX:

The zinc halide compounds and the cadmium organic compounds are preferably reacted with carbonyl halides, and the magnesium halide compounds preferably with nitriles.

The process according to the invention is carried out under the usual conditions of the Grignard reaction at ca. 0 to 140 C. The usual ethereal solvents suitable for the preparation of the magnesium-organic compounds, such as ether, dibutyl ether or tetrahydrofuran, can be used as reaction media. Optionally, hydrocarbons, such as benzene or toluene, can be added to these solvents, and the reaction temperature raised, towards the end of the reaction, by the distilling off of the ether. The decomposition of the direct reaction products is effected in the usual manner, e.g. with the aid of water and dilute hydrochloric acid.

Of the starting materials embraced by the general formula VI, it is possible to produce, for example, compounds of which the symbols X and A represent MgCl and CH CH respectively, as follows: Starting with l-piperazinepropanol [cp. S. M. McElvain and L. W. Bannister, J. Am. Chem. Soc., 76, 1126 (1954)], this is condensed, in the presence of potassium carbonate, with a chloride of a compound of the formula IV. The condensation product is a compound embraced by the formula VI of which the symbols X and A are -OH and CH CH resp. The obtained compound is converted into the dihydrochloride and transformed with thionyl chloride into the corresponding compound of which the radical X is chlorine. The chloride is subsequently reacted with magnesium according to Grignard. Further compounds of this type can be produced analogously.

Also embraced by the formula VI are compounds of which the symbols X and A are CN and CH CH respectively. Such compounds can be produced, e.g. from the corresponding chlorides, the preparation of which has already been described, by means of calcium cyanide.

The starting compounds embraced by the formula VII of which compounds the symbol Z is CN or MgBr are described in the literature. The starting material embraced by the general formula VII and of which the symbol Z is the group IX can be produced as follows: Starting with p-fluorophenylmagnesium bromide, this is reacted in an ethereal solution with cadmium chloride.

The compounds of the formula I obtained by the processes according to the invention are, optionally, subsequently converted in the usual manner into their addition salts with inorganic and organic acids. For example, to a solution of a compound of the formula I in an organic solvent is added the acid desired as salt component, or a solution of the acid. Preferably chosen for the reaction are organic solvents, in which the formed salt is difficultly soluble, so that it can be separated by filtration. Such solvents are, e.g. methanol, acetone, methyl ethyl ketone, acetone/ether, acetone/ethanol, methanol/ether or ethanol ether.

For use as pharmaceutical compositions, it is possible to use, instead of free bases, pharmaceutically acceptable acid addition salts, i.e. salts with such acids of which the anions are not toxic in the case of the dosage amounts in question. It is moreover of advantage if the salts to be used as pharmaceutical compositions, crystallize well and are not, or only slightly, hygroscopic. For salt formation with compounds of the formula I, it is possible to use, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, Z-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

As previously mentioned, the new active substances are administered orally, rectally or parenterally. The dosage depends on the manner of administration, on the species, on the age, and on the individual condition. The daily dosages of the free bases, or of pharmaceutically acceptable salts thereof, vary between 0.15 mg./kg. and 10.5 mg./ kg. for warm-blooded animals. Suitable dosage units such as drages, tablets, suppositories or ampoules, preferably contain 5-200 mg. of an active substance according to the invention.

I Dosage units for oral administration contain as active substance preferably between 10-90% of a compound of the formula I, or of a pharmaceutically acceptable salt thereof. They are produced by combining the active substance, e.g. with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate, or polyethylene glycols, to form tablets or drage cores. The drage cores are coated, eg with concentrated sugar solutions which may also contain, e.g. gum arabic, talcum and/or titanium dioxide; or with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

Further dosage units suitable for oral administration are hard gelatine capsules, as Well as soft closed capsules made from gelatine and a softener, such as glycerin. The hard capsules preferably contain the active substance as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate, and optionally stabilizers such as sodium metabisulphite (N21 S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as polyethylene glycols, whereby stabilizers may also be added.

Suitable dosage units for rectal administration are, e.g.

suppositories consisting of a combination of an active substance with a suppository base material. Suitable suppository base materials are, e.g. natural or synthetic triglycerides, parafiin hydrocarbons, polyethylene glycols, or higher alkanols. Also suitable are gelatine rectal capsules consisting of a combination of the active substance with a base material. Suitable as a base material are, e.g. liquid triglycerides, polyethylene glycols, or parafiin hydrocarbons.

Ampoules for parenteral administration, especially intramuscular administration, preferably contain a watersoluble salt of an active substance in a concentration of preferably 0.5-5%, optionally together with suitable stabilizers and buffer substances, in aqueous solution.

The following prescriptions further illustrate the production of tablets, drages, capsules, suppositories and ampoules:

(a) 250 g. of 1-[2-[4-[3-(p-fluorobenzoyl)-propyl]1- piperazinyl]-ethyl]-3-methyl-2-imidazolidinone are mixed with 175.8 g. of lactose and 169.70 g. of potato starch; the mixture is then moistened with an alcoholic solution of g. of stearic acid, and granulated through a sieve. After drying of the granulate, 160 g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in; the mixture is subsequently pressed into 10,000 tablets each weighing 100 mg. and each containing 25 mg. of active substance. The tablets can, if required, be provided with grooves for a more precise adjustment of the dosage amount.

(b) A granulate is produced from 250 g. of 1-[2-[4-[3- (p-fluorobenzoyl)-propyl] 1 piperazinylJ-ethyl] 3- methyl-2-imidazolidinone-dihydrochloride, 175.90 g. of lactose, and the alcoholic solution of 10 g. of stearic acid. After drying of the granulate, it is mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum, g. of potato starch and 2.50 g. of magnesium stearate; the mixture is then pressed into 10,000 drage cores. These are subsequently coated with a concentrated syrup made from 502.28 g. of crystallized saccharose, 6 g. of shellac, 10 g. of gum arabic, 0.22 g. of dyestufl and 1.5 g. of titanium dioxide; they are then dried. The obtained drages each weigh 120 mg. and each contain mg. of active substance.

(c) To produce 1000 capsules each containing 25 mg. of active substance, 25 g. of 1-[2- [4-[3-(p-fiuorobenzoyl)- propyl]-1-piperazinyl]-ethyl]-3-methyl 2 imidazolidinone are mixed with 248.0 g. of lactose; the mixture is evenly moistened with an aqueous solution of 2.0 g. of gelatine, and then granulated through a suitable sieve (e.g. sieve III, Ph. Helv. V). The granulate is mixed with 10.0 g. of dried maize starch and 15.0 g. of talcum; the mixture is then evenly filled into 1000 hard gelatine capsules, size 1.

(d) A suppository base mixture is prepared from 2.5 g. of 1-[2-[4-[3-(p-fiuorobenzoyl) propyl]-l-piperazinynethyl]-3-methyl-2-imidazolidinone and 167.5 g. of adeps solidus; the mixture is then filled into 100 suppositories each containing 25 mg. of active substance.

(e) A solution of 25 g. of 1-[2-[4-[3-(p-fluorobenzoyl)- propyl]-l-piperazinyl]-ethyl]-3-methyl 2 imidazolidinone-dihydrochloride in one litre of water is filled into 1000 ampoules, and then sterilized. An ampoule contains a 2.5% solution of 25 mg. of active substance.

Tablets, drages, capsules, suppositories and ampoules can be produced according to the same directions if, instead of 1- [2- [4- 3-(p-fiuorobenzoyl) -propyl]-1-piperazinyl]-ethyl]-3-methyl 2 imidazolidinone, the identical amounts are used of 1- [2-[4-[3- (p-fluorobenzoyl)propyl]- l-piperazinyl]-ethyl]-3-butyl 2 imidazolidinone or of its dihydrochloride.

The following examples further illustrate the production of the new compounds of the formula I and of intermediates not hitherto described; the said examples do not, however, in any way restrict the scope of the invention. The temperatures are given in degrees centigrade; and silica gel, Merck, particle size 0.05-0.2 mm., is employed for the elution chromatography.

EXAMPLE 1 21.2 g. (0.1 mole) of 1-[2-(l-piperazinyl)-ethyl]-3- inethyl-2-imidazolidinone, 24.0 g. (0.12 mole) of 4-chloro-4'-fluorobutyrophenone [cp. C. van de Westeringh et a1., Ind. chim. belge, 25, 1073 (1960) 27.6 g. (0.2 moles) of finely powdered potassium carbonate and 16.6 g. (0.1 mole) of powdered potassium iodide are introduced into 200 ml. of diethyl ketone. The obtained mixture is refiuxed for hours, and then filtered through Celit No. 545 (trade name of Johns Manville International Corp., New York). The filter residue is afterwards washed with acetone, and the filtrate concentrated in vacuo. The residue is taken up in benzene, the benzene solution washed with water, and extracted with 2 N hydrochloric acid. The pH-value of the aqueous extract is adjusted to 13 with concentrated sodium hydroxide solution, and the precipitated free base is taken up in benzene. The benzene solution is washed with water, dried over magnesium sulphate, and concentrated in vacuo. The residue is recrystallized from benzene/petroleum ether. The obtained pure 1-[2-[4-[3-(p-fiuorobenzoyl)-propyl] 1 piperazinyl]-ethyl]-3-methyl-2-imidazolidinone melts at 92-93".

An amount of 3.7 g. (0.01 mole) of the obtained free base is dissolved in 5 ml. of acetone; to the solution is then added ethereal hydrochloric acid until an acid reaction is obtained on a Congo red indicator. The precipitated dihydrochloride hemihydrate melts at 226-230".

EXAMPLE 2 The following final products are obtained, analogously to Example 1, starting with 15.0 g. (0.075 moles) of 4- chloro- 4-fluorobutyrophenone:

(a) With 11.3 g. (0.05 moles) of 1-[2-(1-piperazinyl)- ethyl]-3-ethyl-2-imidazolidinone is obtained: 1-[2-[4-[3- (p-fluorobenzoyl)-propyl]-l piperazinyl]-ethyl]-3-ethyl- 2-imidazolidinone, M.P. -67"; M.P. of the dihydrochloride-hemihydrate: 23 6-23 8 (b) With 12.7 g. (0.05 moles) of 1-[2-(1-piperazinyl)- ethyl]-3-butyl 2 imidazolidinone is obtained: crude 1- [2-[4-[3-(0 fluorobenzoyD-propyl] l piper-azinyl]- ethyl]-3-butyl- 2 imidazolidinone, which is purified by means of elution chromatography. A column of 200 g. of basic silica gel is employed which has previously been impregnated with 0.5 N aqueous sodium hydroxide and again dried. Benzene/methanol (100:1) is used as the elution agent. The eluate is concentrated in vacuo, the residue dissolved in acetone, and to the solution then added ethereal hydrochloric acid until an acid reaction is indicated on a Congo red indicator. The precipitated dihydrochloride is recrystallized from ethanol/ethyl acetate; it melts at 235-237;

(0) With 12.0 g. (0.05 moles) of 1-[2-(1-piperazinyl)- ethyl]-3-isopropyl 2 imidazolidinone is obtained: 1-[2- [4- [3- (p-fluorobenzoyl) -propyl] l-piperazinyl] -ethyl] -3- isopropyl-2-imidazolidinone, M.P. 61-64"; M.P. of the dihydrochloride: 247-250 (d) With 11.3 g. (0.05 mole) of 1-[3-(l-piperazinyl)- propyl]-3-methyl-2-imidazolidinone is obtained: crude 1- [3-[4-[3-(p-fluorobenzoyl)-propyl] 1 piperazinyH-propyl]-3-methyl-2-imidazolidinone; the crude base is dissolved in 50 ml. of acetone, and to the solution is then added a solution of maleic acid in acetone until an acid reaction is obtained, whereupon ether is added. The precipitated 1-[3-[4-[3-(p-fluorobenzoyl) propyl]-1-piperazinyl]-propyl1-3-methyl 2 imidazolidinone-dimaleate is recrystallized from ethanol/ethyl acetate; it melts at 164-166;

(e) With 12.0 g. (0.05 moles) of 1-[3-(1-piperazinyl)- propyl] -3-ethyl-2-imidazolidinone is obtained: crude 1-[3- [4-[3-(p-fluorobenzoyl)-propyl] 1 piperazinyl]-propyl]-3-ethyl-Z-imidazolidinone; M.P. of the dihydrochloride=244-246 and (f) With 13.40 g. (0.05 moles) of 1-[3-(1-piperazinyl)- propyl]-3-butyl-2-imidazolidinone is obtained: crude 1-[3- I [4-[3-(p-fluorobenzoyl)-propyl] 1 piperazinylJ-propyl]-3-butyl-2-imidazolidinone; M.P. of the dihydrochloride=236-240.

EXAMPLE 3 (a) From 11.3 g. (0.05 moles) of 1-[2-(hexahydrolH-1,4-diazepin-1-y1)-ethyl] -3 -methyl-2-imidazolidinone and 15 .0 g. (0.075 moles) of 4-chloro-4'-fluorobutyrophenone is obtained, analogously to Example 1(a), crude 1- [2- [4-[3-(p-fluorobenzoyl) -propyl]-hexahydro-1H-1,4- diazepin-1-yl]-ethyl]-3methyl-2-imidazolidinone, which is purified on a column of 200 g. of basic silica gel (impregnated with sodium hydroxide) by elution chromatography.

9 The elution agent used is benzene/methanol (100:2). The eluate is concentrated in vacuo, the residue (8.0 g.) dissolved in acetone, and the dimaleate precipitated with 4.63 g. (0.04 moles) of maleic acid. The dimaleate is recrystallized from methanol/ ethyl acetate, whereupon it melts at 104-106.

The starting product is produced as follows:

(b) 17.2 g. (0.1 mole) of hexahydro-1H-l,4-diazepinel-carboxylic acid ethyl ester [cp. R. B. Angier et al., J. Med. Chem. 11, 720 (1968), 19.4 g. (0.12 moles) of 1-(2- chloroethyl)-3-methyl-2-imidazolidinone and 27.6 g. of potassium carbonate are refluxed in 50 ml. of diethyl ketone for 24 hours. The hot reaction mixture is then filtered through purified diatomaceous earth, the filter residue extracted three times with benzene, and the combined filtrates concentrated in vacuo. The oily residue is distilled in high vacuum. The obtained 4-[2-(2-oxo-3-methyl-1- imidazolidinyl)-ethyl]-hexahydro-lH-l,4-diazepine-l-carboxylic acid ethyl ester boils at 170-180/0.01 torr; n

An amount of 25.0 g. (0.084 moles) of the compound obtained according to (b) is refluxed with 200 ml. of abs. ethanolic potassium hydroxide solution (20 g. of potassium hydroxide to 100 ml. of solution) for 20 hours. The reaction mixture is then cooled and concentrated in vacuo. The residue is taken up in benzene and water, and the organic phase separated; the aqueous phase is saturated with potassium carbonate and extracted with benzene. The benzene extract is dried over potassium carbonate, the solvent evaporated oil in vacuo, and the oily residue distilled in high vacuum. The pure 1-[2-(hexahydro 1H-l,4-diazepin-l-yl)-ethy1]-3-methyl-2-imidazolidinone boils at 125128/0.01 torr; n 1.5163.

EXAMPLE 4 From 11.3 g. (0.05 moles) of 1-[2-(3-methyl-1-piperazinyl)-ethyl]-3-methyl-2-imidazolidinone and 15 g. (0.075 moles) of 4 chloro-4'-fluorobutyrophenone is obtained, analogously to Example 3(a), 1-[2- [4-[3-(p'fluorobenzoyl) propyl] 3-methyl-1-piperazinyl]-ethyl]-3-methy1-2- imidazolidinone-dimaleate. The starting material, 1-[2-(3- methyll-piperazinyl) -ethyl] -3-methyl-2-imidazolidinone, B.P. 142/ 0.01 torr, n 1.5115, is produced analogously to Example 3. (b-c). Starting with 3-methyl-1-piperazinecarboxylic acid ethyl ester [cp. J. C. Dulf and D. K. Jung, Can. Pharm. 1., 95, 256 (1962)], the intermediate 4-[2- (2 oxo 3-methyl-1-imidazolidinyl)-ethyl]-3-methyl-1- piperazine-carboxylic acid ethyl ester is obtaied, B.P. 170 180/0.01 torr; n 1.4996.

EXAMPLE 5 An amount of 25.0 g. (0.1 mole) of 4-fluoro-4-( 1- .piperazinyl)-butyrophenone is refluxed with 19.4 g. (0.12 moles) of 1 (2-chloroethyl)-3-methyl-2-imidazolidinone and 27.6 g. (0.2 moles) of potassium carbonate in 200 ml. of diethyl ketone for 24 hours. The hot reaction mixture is filtered through purified diatomaceous earth, the residue washed three times with hot benzene, and the combined filtrates concentrated in vacuo. The oily residue is taken up in benzene, the benzene solution washed with water, and extracted with 2 N hydrochloric acid. The .acid aqueous extract is then rendered alkaline with concentrated sodium hydroxide solution, and the precipitated free base extracted with benzene. The benzene solution is washed with water, dried over magnesium sulphate,

vandconcentrated in vacuo. The obtained residue is re- EXAMPLE 6 v The following final product is obtained analogously to Example 5:

.. From 25.0 g. 0.1 mole) of 4'-fluoro-4-(l-piperazinyl)- 'butyropheno'ne and 25.7 g. (0.12 moles) of "1-(2-chloroethyl-3-butyl-2-imidazolidinone is obtained: crude 1-[2- 10 [4 [3-(p-fluorobenzoyl)-propyl]-1-piperazinyl]-ethyl]-3- butyl-Z-imidazolidinone, which is purified through a column of 400 g. of basic silica gel by means of elution chromatography. The eluant used is benzene/methanol (:1). The purified base is converted, analogously to Example 2(b), into its dihydrochloride which, after recrystallization from ethanol/ethyl acetate, melts at 235- 237.

EXAMPLE 7 (a) An amount of 12.5 g. (0.05 moles) of 4'-fluoro-4- (l-piperazinyl)-butyrophenone is refluxed with 11.9 g. (0.06 moles) of l-methyl-3,3 bis-(2-chloroethyl)-urea and 27.6 g. (0.2 moles) of potassium carbonate in 200 ml. of diethyl carbonate for 16 hours. The hot reaction mixture is then filtered through purified diatomaceous earth, the filler residue washed with hot benzene, and the combined filtrates are concentrated in vacuo. The residue is dissolved in benzene, the benzene solution extracted with 2 N hydrochloric acid, the acid aqueous extract made alkaline with concentrated sodium hydroxide solution, and the precipitated free base extracted by being shaken with benzene. The benzene extract is washed with water, dried over magnesium sulphate, and the benzene evaporated oil under vacuum. The residue is chromatographed on a column of 200 g. of basic silica gel, benzene/methanol (100:2) being used as eluant. The fractions containing the crude product are concentrated by evaporation, and the residue is recrystallized from benzene/petroleum ether. The obtained pure 1-[2-[4-[3-(pfluorobenzoyl) propyl]-1-piperazinyl]-ethyl]-3-methyl- Z-imidazolidinone melts at 92-93.

The 1-methyl-3,3-bis-(2-chloroethyl)-urea required as starting material is produced as follows:

(b) An amount of 105.1 g. (1.0 mole) of freshly distilled diethanolamine is dissolved in 1000 ml. of absolute methylene chloride. To this solution are added dropwise at 10, in the course of one hour, 59.0 g. (1.03 moles) of methylisocyanate dissolved in 2.00 ml. of absolute methylene chloride. The reaction mixture is refluxed for minutes and then cooled to 0; to the obtained solution' of 1-methyl-3,3-'bis-(2-hydroxyethyl)-urea is then added dropwise, in the course of one hour, a solution of 250 g. (2.1 moles) of thionyl chloride in 250 ml. of absolute methylene chloride. The reaction mixture is afterwards refluxed for 4 hours, concentrated in vacuo,

'and the residue, crude 1-methyl-3,3-bis-(2-chloroethyl)- urea, dried for 8 hours at 70-'80 under high vacuum.

EXAMPLE 8 (a) Th'e'following final product is produced analogously to Example 7: 7 From 12.5 g. (0.05 moles) of 4'-fluoro-4-(1-piperaziny1)-butyrophenone and 14.5 g. (0.06 moles) of 1- -butyl-3,3-bis-(2-chloroethyl) urea is obtained: 1-[2-[4- tilled diethanolamine is dissolved in 1000 ml. of absolute methylene chloride. To this solution are added dropwise at 10, in the course of one hour, 101.9 g. (1.03 moles) of butylisocyanate dissolved in 200 ml. of absolute methylene chloride. The reaction mixture is refluxed for "150 minutes and'then cooled to 0; to the obtained solution of 1-butyl-3,3-bis-(2-hydroxyethyl)-urea is then added dropwise during 1 hour, a solution of 250 g. (2.1 moles) of thionyl chloride in 250- ml. of absolute methylene chloride. The reaction mixture is then refluxed for 4 hours; it is afterwards concentrated in vacuo, and the residue, crude 1-butyl-3,3-bis-(2-chloroethyl)-urea, dried for 8 hours" at 70-80" under high vacuum.

bro'mobenzeneis slowly added dropwise, atire terriperature, to 2.5 g. (0. 1051noles) of activatedimagnfu'rn chipsjin 100 ml. of absolute ethe The reactio mixture isboiled until practically all the magnesium is consumed; the mixture is then cooled to and a solution 19' 4 g. (0.1 mole) of ,l-[

. EXAMPLE-9, (a) 22.6 g. (0.1 mole) of 1-[2-(1-piperazinyl) ethyl[- 3,4-dimethyl-2-imidazolidinone, 30.0 g. (0.15 moles) of 4-chloro-4'-fiuorobutyrophenone,27.6 g. (0.20rnoles) of potassium carbonate and 16.6 g. (0.1 mole) of potassium iodide are introduced'into' 200 ml. of diethyl ketone-and, with good stirring, refluxed for 24 hours. The lio't -r'eaction mixture is filtered through Celit the residue boiled out twice with acetone, and filtered. The combined filtrates are concentratedin vacuo, and the oily residue is dissolvedin 200 ml. of benzene. After the addition of -10 ml. of 2 N sodium hydroxide solution, the benzene .solution is extracted three times with 100; ml.. of water veachtime. The organic phase is subsequently extracted with 200 ml. of 2 N- hydrochloric acid; the. aqueous acid extractiare rendered strongly alkaline (pH 13) withconcentrated sodium hydroxidesolution, and again extracted with benzene. The organic solutions are washed with water, dried over magnesium sulphate and concentrated in vacuo to dryness. Theobtained crystalline residue is recrystallized from ether/pentane, whereupon the .obtained pure 1-[2-[4-[3-(p-fluorobenzoyl)-propyl].-1-piperazinyl]-ethyl]-3,4-dimethyl-Z-imidazolidinone melts at 73-74".

The dihydrochloride is obtained analogously to,Ex- F ample 1, MP. 228235. I t

The l- 2- (piperazinyl -ethyl] -3,4-dimethyl-2-imidazolidinone required as starting material is produced as follows: 1 (b) Anamount of 17.8 g. (0.2 moles) of rac. 2-methylamino-l-propanol is dissolved in 30 ml. of.:methy-l ene chloride; to this solution is then added dropvvise at 0 a solution of 23.2 g. (0.22 moles) of 2-chloroethylisocyan- .ate in 50 ml. of methylene chloride. The reaction mixture is stirred for 2 hours at room temperature, concentrated in vacuo to dryness, andthe crystallized residue recrystallized from ether. The obtained 1-, (,2-hydroxy-lmethyl ethyl)-1-methyl-3-(2-chloroethyl)-urea melts 'at 76-78.

(0) An amount of 33.4 g. (0.172 moi sj mefia- .tained urea is dissolved in 80 ml. of chloroform; ,to the .The obtained roily residue is distilledrin a watenjet vacuum to obtain 1-(2-chloroethyl)-3,4 dimethy112- imidazolidinone,rB.P.' 151-153"; n =1.4s1, 1. ,1. =1 (d),from 18.8 g..(0.107 mo1es)'0f 1-(2,-.Ghlor ethyl)- 3 ,4vdimethyl-2-imidazolidinone an d18.5.g.v (0.117 moles) of lepiperazinecarboxylie acid ethyl. ester. are obtaiued analogously to Example 3(b), 26.7. g..of 1 -.[2-;(2 oxo- 3,4-dimethyl-1 r imidazolidinyl) .-..ethyl]spiperazinecarboxylic acid ethyl ester; ..B.P. l70..18Q/ 0,0ltorr; n=1.4968. From this are obtained, analogously. to Example 3(c), 18.2 ,g. or 1-[2- 1- i erazin 1 ems/1173;441-

methyl. z. iimidazolidinone; YB.P. 1301344091493;

I EXAM LE (a Anamount' of 175 (0.1 mole) feri e ql d em 2: 9 ,a abe la a thereof.

.- idinone dihydrochloride dihydrate melts L A compound of the formula I R is an alkyl group having l'to "4 carbon atoms,

[3 '(p'-fluo"r obenzoyl)-propyl]'1-piperazinyl] 3 methyl 2-imidazolidinone' or a "ceptable acid addition salt, thereof. '""iSJ'The'dihydrochloride salt of the" 6f 1 [4 f "[3 (p' fluorobenzoyD-propyl] -lpiperazinyl]' -etl;1 yl]- "3-ethyl 2 imidazlidinone'or a pharmaceutically acceptable Q 7 lams-s.

'12 tetrahydrofuran, is added dropwise within 30 minutes. The obtained reaction mixture is refluxed for1 2'hour's, and "afterwards pouredon to a mixture of 200ml of ice water and ml. of 2 N hydrochloric acid. Theobtained acid mixture is allowed tostand fornonlenhou'r at room temperature, and subsequently carefully concentrated at-40 in vacuo to a volume of 200 The obtained solution is diluted with water, and" extracted with ether. The aqueous phase is separated, renderedalkaline with concentrated ammonia, and extracted three by being shaken with benzene. The benzene extracts are washed with water, dried over magnesium sulphatd fiud concentrated in yacuo to dryness.;-'I:he. obtainedfcrystalline residueis dissolved .in beuzene, and the. solo on filtered through magnesium silicate WOeImPIITheeIIiate isconcentrated by evaporation, and the residue recrystallliz edfro'rri ethyl acetate/petroleum ether, The obtained .azinyl]-etliyl] 3-methyl-2-imidazolidinone at methyl-Z-imidazolidinone required as starting niaterial is wpr oduced as follows:

'(b) Anamount of 21.2 g. 0.l,mole) of 1 [2 (1- piperazinyD-ethyl]-3 methyl-2-imidazolidinorie is'fre- -fluxed with 12.6 g. (0.13 moles of. 4-chlorobu'tyronitrile land 27.6 g. (0.21 moles) of. potassium carbonate in 250 ml. of diethyl ketone for 24 hours. Thef obtained mixture is filtered through Celit, and thefilter residue wllashe d put with acetone; the combined filtrates are dried ,Imagnesium sulphate, and subsequently concentrated in vacuo to dryness. The obtained oily residue is dissolved in ethyl acetate, and the hydrochloride precipitated with ethanolic hydrochloric acid. After recrystallization from ethanol/ethyl acetate, the obtained pure 1-[2-[4-(3-cyanopropyl) -1,piperazinyl]-ethyl]-3-methyl Z-imidazol- .What is claimed is: v V

'GHr-CHs wherein A is an alkylene group having2..carbon atoms,

, Ai'is an alkylene group having 2,to 4 carln'm atoms,

Ri'ishydro gen', or an a ky group having 1 .4 9

he pliarmac'eutically acceptable" acid addition salts The compound according-to claim I which is" v 1 aeaw iaa yacompound according to claim 1) whiclriis 1"-[ acid addition salt thereof.

5. The ":dihyd rochloride" salt of the claim4. Y

6. The compound .accordingtovclaim 1 which is 1-[2- '3-n butyl 2-imidazolidinone or a pharmaceuticall acceptableacidaddition salt thereof. I I The"IdihydrochlOIidQT$2 0f 8. The Compound according to claim 1 which is l-[3- [4 [3 (p fluorobenzoyl) propyl]-1-piperazinyl]- propyl] 3 methyl 2 imidazolidinone or a pharmaceutically acceptable acid addition salt thereof.

9. The bis-maleate salt of the compound of claim 8.

10. The compound according to claim 1 which is 1-[2- [4 [3 (p-fluorobenzoyl)-propyl]-1-piperazinyl]-ethyl]- 3-isopropyl-Z-imidazolidinone or a pharmaceutically acceptable acid addition salt thereof.

11. The dihydrochloride salt of the compound of claim 10.

12. The compound of claim 1 which is 1-[3-[4-[3-(pfluorobenzoyl) propyl] l-piperazinyl]-propyl]-3-ethyl- 2-imidazolidinone or a pharmaceutically acceptable acid addition salt thereof.

13. The dihydrochloride salt of the compound of claim 12.

14 References Cited UNITED STATES PATENTS 2,985,657 5/1961 Janssen 260-268 H 3,000,892 9/1961 Janssen 260-268 R 3,320,247 5/1967 Arnold 260-268 H 3,637,704 1/ 1972 Umeomoto 260-268 R 3,646,037 2/1972 Schindler et a1. 260-268 H 3,658,821 4/1972 Fauran et al. 260-268 R 3,699,107 10/ 1972 Schindler et a1. 260-268 H DONALD G. DAUS, Primary Examiner US. Cl. X.R.