US3720676A - [4-(10,11-DIHYDRO-5H-DIBENZO[a,d]CYCLOHEPTEN-10-yL-1-PIPERAZINYL]-ALKYL]-3-ALKYL-2-IMIDAZOLIDINONES AS CNS DEPRESSANTS - Google Patents

Abstract

Compounds of the class of 1-(2- and 3-(4-(10,11-dihydro-5Hdibenzo(a,d)cyclohepten-10-yl)-1-piperazinyl)-alkyl)-3-alkyl-2imidazolidinone which can be substituted in 8-position by chloro, methyl or methoxy, and the pharmaceutically acceptable acid addition salts thereof, have a depressant effect on the central nervous system; pharmaceutical compositions comprising these compounds and a method of producing a depressant effect on the central nervous system of warm-blooded animals, are provided; an illustrative embodiment is 1-(2-( 4-(8-methyl-10,11-dihydro-5Hdibenzo(a,d)cyclohepten-10-yl)-1-piperazinyl) -ethyl)-3-methyl-2imidazolidinone-bis-maleate.

Description

United States Patent 1 1 Schindler et al.

1 1March 13, 1973 [4-( l 0,1 l-Dll'lYDRO-SH-DIBENZO A,D

]CYCLOHEPTEN-l0-YL-l- PIPERAZINYL]-ALKYL]-3-ALKYL-2- IMIDAZOLIDINONES AS CNS DEPRESSANTS [75] Inventors: Walter Schindler, Riehen/Baseland; Armin Zuest, Birsfelden/Baseland,

both of Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

221 Filed: Aug. 5, 1970 21 Appl. 110.; 61,435

-[30] I Foreign Application Priority Data Aug. 11, 1969 Switzerland ..l2l20/69 [56] References Cited UNITED STATES PATENTS 3,320,247 5/1967 Arnold et al ..260/268 C 3,496,182 2/l970 Fouche ..260/268 TR 3,646,037 2/1972 Schindler et al ..260/268 TR 3,646,039 2/l972 Schindler et al ..260/268 TR Primary Examiner-Donald G. Daus Att0rneyl(arl F. Jorda and Bruce M. Collins [57] ABSTRACT Compounds of the class of l-[2- and 3-[4-(l0,l1- dihydro-SH-dibenzo[a,d]cyclohepten-l0-yl)-lpiperazinyll-alkyl1-3-alkyl-2 imidazolidinone which can be substituted in 8-position by chloro, methyl or methoxy, and the pharmaceutically acceptable acid addition salts thereof, have a depressant effect on the central nervous system; pharmaceutical compositions comprising these compounds and a method of producing a depressant effect on the central nervous system of warm-blooded animals, are provided; an illustrative embodiment is l-[2-[4-(8-methyl-l0,ll-dihydro-Sl-ldibenzo[a,d]cyclohepten-l0-yl)-1-piperazinyl]-ethyl]- 3-methyl-2-imidazolidinone-bis-maleate.

3 Claims, No Drawings [4-( l0,l l-DIHYDRO-SH-DIBENZO[A,D lCYCLOI-IEPTEN-l O-YL- l -PIPERAZINYL]- ALKYL1-3-ALKYL-2-IMIDAZOLIDINONES AS CNS DEPRESSANTS DETAILED DESCRIPTION The present invention relates to new imidazolidinone derivatives, to processes for their production, to pharmaceutical compositions comprising the new compounds, and to the use thereof.

More particularly, the invention relates to compounds of formula I,

wherein X is hydrogen, chloro, methyl or methoxy;

R is alkyl having one to four carbon atoms;

R is hydrogen or methyl; and

n is theinteger 2 or 3; and the pharmaceutically acceptable acid addition salts thereof.

It has now been found that such compounds, especially l-[2-[4-(8-methyl-l0,ll-dihydro-5H-dibenzo[ a,d]cyclohepten-l-yl)-l-piperazinyl]-ethyl]-3- methyl-2-imidazolidinone, and l-[2 -[4-(8-chloro- 10,1 l-dihydro-5l-l-dibenzo[a,dlcycloheptenl 0-yl)-lpiperazinyl]-ethyl]-3-methyI-Z-imidazolidinone, as well as their pharmaceutically acceptable acid addition salts, possess valuable pharmacological properties, and a high therapeutic index. In the case of oral, rectal or parenteral administration, they have a central depressant action, e.g. they reduce motility, potentiate the effect of anaesthetics, have an anti-emetic action, and have an inhibiting action in the test de la traction." Furthermore, they have a sympathicolytic and serotonin-antagonistic action. These properties, which are determined by means of selected standard tests [cp. R. Domenjoz and W. Theobald, Arch.lnt.Pharmacodyn. I20, 450 (1959) and W. Theobald et al., Arzneimittelforsch. 17,561 (1967)], characterize the compounds as being suitable for the treatment of states of tension and agitation of different genesis.

In the compounds of formula I, as alkyl group having one to four carbon atoms, R can be the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl or the tert.butyl group.

A compound of formula I is produced according to the invention by reacting a compound of formula II,

- orb-CH2 N--H CHz-CHz wherein X and R, have the meaning given under Formula l, or an alkali metal derivative of such a compound, with a reactive ester of a compound of formula III,'

(III) wherein R and n have the meaning given under formula 1; and, optionally, converting the reaction product with an inorganic or organic acid into an addition salt.

Suitable reactive esters of compounds of formula III are, e.g., halides, such as chlorides or bromides, also sulphonic acid esters, e.g., the methanesulphonic acid ester, or the 0- or p-toluenesulphonic acid ester.

These esters are reacted with the free bases 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, toluene or xylene; halogenated hydrocarbons such as chloroform; ethereal liquids such as ether or dioxane; as well as lower alkanones such as acetone, methyl ethyl ketone or diethyl ketone. The reaction temperatures are between ca. 50 and preferably at the boiling point of the applied solvent.

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

If in the reaction according to the invention is used, instead of the free base of 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 reactant is preferably performed 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 initially one molecular equivalent of free base is used. For example, sodium amide and lithium amide are used as alkali metal amides; sodium hydride as alkali metal hydrides; and phenyl lithium or butyl lithium as alkali metal organic compound.

Of the starting materials of formula II, e.g. 8-chlorol0-[ l-piperazinyl)-l0,l l-dihydro-SH-dibenzo [a,d]cycloheptene is described in the literature. 8- Methyl- 1 0-( l-piperazinyl)-l0,l l-dihydro-Sl-l-dibenzo [a,d]cycloheptene can be obtained by another process, e.g., as follows: Starting with 8-methyl-l0-chloro-l0,l l -dihydro-5H-dibenzo[a,d]cycloheptene, this is condensed in benzene with l-piperazinecarboxylic acid ethyl ester to 4-(8-methyI-l0,1l-dihydro-Sl-I-dibenzo [a,d]cyclohepten-l0-yl)-piperazine-l-carboxylic acid ethyl ester; the condensation product is subsequently hydrolyzed and decarboxylated by heating with potassium hydroxide in ethanol. Further starting materials of formula II can be produced analogously.

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

Using a second process according to the invention, compounds of formula I, of which the symbol n denotes 2, are obtained by reacting a compound of formula [1, wherein X and R have the meaning given under formula l, or an alkali metal derivative of such a compound, with a compound of formula IV,

R H (IV) wherein Y represents halogen,

and R has the meaning given under formula I, or with an alkali metal derivative of such a compound; and, optionally, converting the reaction product with an inorganic or organic acid into an addition salt.

As halogen, the radical Y of formula IV is preferably chlorine or bromine.

The reaction according to the invention of the free bases of formula ll, or of their alkali metal derivatives, with the urea derivatives, or their alkali metal derivatives, may be performed in the same solvents or diluents, and at the same reaction temperatures, as in the first process. in the reaction of one molecular equivalent of free base with one molecular equivalent of free urea derivative, two molecular equivalents of hydrogen halide are split off, which can also be bound to the same acid-binding agents. Both reactants are used as alkali metal derivatives, e.g., as 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 production of the starting materials of formula ll is described following the first process. A starting material which is embraced by formula IV is l-methyl- 3,3-bis-(2-chloroethyl)-urea which can be obtained, e.g., starting with diethanolamine. With l-methylisocyanate, the diethanolamine yields l-methyl-3,3-bis-(2 -hydroxyethyl)-urea, which reacts with thionyl chloride, whereby sulphur dioxide and hydrogen chloride are split off. Further starting materials of formula lV can be produced analogously.

Using a third process according to the invention, a reactive ester of a compougdiof formula V,

(EH-CH2 X (11H R2 (V) wherein X and R, have the meaning given under formula l, is reacted with a compound of formula VI,

' CH14-CH2 wherein R and n have the meaning given under formula 1, or with an alkali metal derivative of such a compound; and, optionally, the obtained reaction product is converted with an inorganic or organic acid into an addition salt.

Suitable reactive esters of compounds of formula V are, e.g. halides, such as chlorides or bromides, also sulphonic acid esters such as methane-sulphonic acid ester, 0- or p-toluenesulphonic acid ester, or o-chloroor p-chlorobenzenesulphonic acid ester.

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

Instead of the free bases, it is also possible to use their alkali metal derivatives, eg 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 deriva-' tives in the first process.

Starting materials: reactive esters of compounds of formula V, e.g. lt),l l-dihydrwSH-tllbenzo [a,d]cycloheptene, B-methylor 8-methoxy-l0-chloro- 10,1 l-dihydro-5H-dibenzo[a,d]cycloheptene, are described in the literature. Further starting materials of this type can be produced analogously.

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

The compounds of formula I obtained using a process 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 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 difficulty soluble, so that it can be separated by filtration. Such solvents are, e.g. methanol, acetone, methyl ethyl ketone, acetone/ethanol, methanol/ether or ethanol/ether.

it is possible to use as medicaments, 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 medicaments crystallize well and are not, or only slightly, hygroscopic. For salt formation with compounds of formula I it is possible to use, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethane-sulphonic acid, 2- hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicyclic 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 dragees, tablets, suppositories or ampoules, preferably contain 5-200 mg of an active substance according to the invention.

Dosage units for oral administration contain as active substance preferably between and 90 percent of a compound of 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 dragee cores. The dragee cores are coated, e.g., with concentrated sugar solutions which can 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 (Na,S,O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid 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, paraffin 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 paraffin hydrocarbons.

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

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

a. 250 g of l-[2-[4-(8-methyl-10,1l-dihydro-Sl-ldibenzo[a,d]cyclohepten-l 0-yl)-1-piperazinyl]-ethyl]- 3-methyl-2-imidazolidinone are mixed with 175.80 g of lactose and 169.70 g of potato starch; the mixture is then moistened with an alcoholic solution of 10 g of stearic acid, and granulated through a sieve. After the granulate has dried, 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 then pressed into 10,000 tablets each weighing mg and each containing 25 mg of active substance. These 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-(8- chloro-l0,11-dihydro-5H-dibenzo[a,d]cycloheptenl 0-yl)-1-piperazinyl]-ethyl]-3-methyl-2- imidazolidinone, 17590 g of lactose and the alcoholic solution of 10 g of stearic acid. After the granulate has been dried, it is mixed with 56.60 g of colloidal silicon dioxide, 165 g of talcum, 20 g of potato starch and 2.50 g of magnesium stearate; the mixture is then pressed into 10,000 dragee 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 dyestuff, and 1.5 g of titanium dioxide; and dried. The obtained dragees each weigh mg and each contain 25 mg of active substance.

0. To produce 1000 capsules each containing 25 mg of active substance, 25 g of 1-[2-[4-(8-chloro-l0,11- dihydro-SH-dibenzo[a,d]cyclohepten-10-yl)1- piperazinyH-ethyl]-3-methyl-2-imidazolidinone are mixed with 248 g of lactose; the mixture is then evenly moistened with an aqueous solution of 2.0 g of gelatine, and granulated through a suitable sieve (e.g. sieve III, Ph.l-lelv. V). The granulate is mixed with 10.0 g of dried maize starch and 15.0 g of talcum; it is then evenly filled into 1000 hard gelatine capsules, size 1.

d. A suppository foundation mixture is prepared from 2.5 g of l-[2-[4-(8-methyl-l0,l 1-dihydro-5H- dibenzo[a,d]cyclohepten-10-yl)-l-piperazinyl]-ethyl- ]-3-methyl-2-imidazolidinone and 167.5 g of adeps solidus; from this mixture are poured 100 suppositories each containing 25 mg of active substance.

e. A solution of 25 g of 1-[2-[4-(8-methyl-l0,11-

dihydro-5H-dibenzo[a,d]cyclohepten-10-y1)-1- piperazinyl]-ethyl]-3-methyl-2-imidazolidirionedihydrochloride in one liter of water is filled into 1000 ampoules, and sterilized. An ampoule contains a 2.5 percent solution of 25 mg of active substance.

The following examples further illustrate the production of the new compounds of formula l, and of intermediate products not described hitherto; but these examples in no way limit the scope of the invention. The temperatures are given in degrees Centigrade.

EXAMPLE 1 a. A suspension of 1 1.7 g (0.040 moles) of 8-methyl- 10-( l-piperazinyl)-l0,l l-dihydro-Sl-l-dibenzo [a,d]cycloheptene, 8.46 g (0.044 moles) of 1-(2- chloro-ethyl)-3-methyl-2-imidazolidinone and l 1.0 g (0.08 moles) of potassium carbonate in 80 ml of diethyl ketone is refluxed for 24 hours. The reaction mixture is cooled and filtered off under suction; the precipitate is then washed with acetone, and the filtrate concentrated in vacuo. The residue is taken up in benzene and water, the aqueous phase separated, and the organic phase extracted with l-n methanesulphonic acid. The

free base is precipitated with concentrated ammonia from the acid extract, and the crude base taken up in benzene. The benzene solution is washed with water, dried over magnesium sulphate, and concentrated by evaporation. The crystalline residue is recrystallized from a little ethyl acetate/petroleum ether, whereupon the pure l-[2-[4-(8-methyl-10,l l-dihydro-SH- dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]- 3-methyl-2-imidazolidinone has a M.P. of 116117; yield 11.7 g, 70 percent of the theoretical value.

4,2 g (0.01 mole) of the obtained free base are dissolved in 20 ml of anhydrous ethyl acetate; to this solution is then added a solution of 2.32 g (0.02 moles) of maleic acid in 10 ml of anhydrous acetone. An amount of 50 ml of abs. ether is added and the precipitated bismaleate filtered off; it is subsequently washed with absolute ether, and dried in vacuo. After recrystallization from a little ethanol/ethyl acetate, the pure 1-[2-[4-(8- methyl-10,11-dihydro-5H-dibenzo[a,d] cycloheptenl0-yl)-lpiperazinyl]-ethyl]-3-methyl-2- imidazolidinone-bis-maleate melts at 138-l 40.

8-Methyl-10-(l-piperazinyl)-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene, required as starting material, can be produced as follows:

b. To a solution of 12.1 g (0.05 moles) of 8-methyl- 10-chloro-10,l1-dihydro-5l-l-dibenzo[a,d] cycloheptene in 80 ml of benzene are added 23.7 g (0.15 moles) of l-piperazinecarboxylic acid ethyl ester, the solution is then refluxed for 24 hours. The reaction mixture is poured into 200 ml of ice water; to this are added 25 ml of 2-n sodium hydroxide solution, and the benzene phase is separated. The aqueous phase is shaken out with benzene; the organic phases are washed with water, dried over magnesium sulphate, the solvent is removed in vacuo, and the obtained crude residue further used.

c. An amount of 12.9 g of the crude product obtained according to b) is dissolved in 50 ml of abs. ethanol; to this solution are added 10 g (0.15 moles) of potassium hydroxide, and the mixture is refluxed for 20 hours. The reaction solution is cooled and concentrated in vacuo; water is added to the residue and the base taken up in benzene. The benzene solution is washed with water until neutral, and the acid aqueous phase made alkaline with concentrated sodium hydroxide solution. The free base is extracted with benzene; the benzene solution is washed with water, dried over magnesium sulphate, and dried in vacuo. The crystalline residue is recrystallized from ethyl/acetate/pentane. The pure 8- methyl-10-( l-piperaziny1)-10,1 l-dihydro-5H-dibenzo[ a,d]cycloheptene melts at 95-96; yield 4.4 g, 30 percent of the theoretical value; M.P. of the bis-methane sulphonate l94l96.

EXAMPLE 2 a. Analogously to Example 1 is obtained the following final product: from 11.7 g (0.040 moles) of 8-methyl-l0-(1-piperazinyl)-l0,11dihydro-Sl-l-dibenzo[a,d]cycloheptene and 8.36 g (0.044 moles) of 1-(3-ehloropropyl)-3-ethyl-2- imidazolidinone is obtained: 1-[3-[4-(10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-l0-yl)-1-piperazinyl]- propyl]3-ethyl-2-imidazolidinone; M.P. of the bismaleate, which is produced analogously to Example 1 a), is 113l yield 21.7 g; 80 percent of the theoretical value.

The l-(3-chloropropyl)-3ethyl-2-imidazolidinone, required as starting material, is produced as follows:

b. An amount of 15.6 g (0.175 moles) of 2- ethylaminoethanol is dissolved in 30 ml of abs. methylene chloride. To this solution is added dropwise at 5 to 0, in the course of 45 minutes, a solution of 20.9 g (0.175 moles) of (3-chloropropyl)-isocyanate in 20 ml of abs. methylene chloride. The reaction mixture is stirred for 2 hours at 30, and then cooled to 0. To the cooled solution containing the crude 1-ethyl-1-(2- hydroxyethyl)-3-(3-chloropropyl)-urea is added dropwise, in the course of 30 minutes, a solution of 21.9 g (0.182 moles) of thionyl chloride in 20 ml of abs. methylene chloride. The reaction mixture is afterwards refluxed for 4 hours. and concentrated in vacuo. The obtained residue: crude l-ethyl-l -(2-chloroethyl)-3-(3 -chloropropyl)-urea, is dried under high-vacuum at 80; yield 42.0 g of crude product, which correspond to 39.8 g percent of the theoretical value) of pure compound.

0. With the exclusion of moisture and while thorough stirring is maintained, 42.0 g of the crude urea derivative (obtained according to b)) containing 39.8 g (0.175 moles) of pure compound are heated for 3 hours in a bath at and afterwards for 6 hours in a bath at The obtained crude 1-(3-ch1oropropyl)-3- ethyl-2-imidazolidinone is distilled under high-vacuum; B.P. 101-103/0.01 Torr (n 1.4868), yield 28.1 g, 84.5 percent of the theoretical value.

EXAMPLE 3 a. An amount of 11.9 g (0.049 moles) of 8-methyllO-chl0r0-l0,l l-dihydro-5l-l-dibenzo[a,d]cycloheptene is dissolved in 50 ml of abs. benzene; this solution is then added dropwise at room temperature to a solution of 15.6 g (0.073 moles) of 1-[2-(1-piperazinyl)- ethyl]-3methyl-Z-imidazolidinone in 30 ml of abs. benzene; and the reaction mixture is refluxed for 20 hours. The cooled solution is poured on to 200 ml of ice water; to this are added 20 ml of 2-n sodium hydroxide solution, and the organic phase is separated. The organic phase is washed with water, and extracted with ml of l-n methanesulphonic acid solution. The pH of the aqueous extract is adjusted with concentrated sodium hydroxide solution to 13. The precipitated crude base is extracted with benzene; the benzene solution is washed with water, dried over magnesium sulphate, and concentrated in vacuo. The residue is recrystallized from ethyl acetate/petroleum ether. The obtained pure l-[ 2-[4-(8-methyl-l0,11- dihydro-5l-l-dibenzo[a,d] cyclohepten-10-yl)-1- piperazinyll-ethyl]3-methyl-2-imidazolidinone melts at 116-117.

The 8-methyl-l0-chloro-10,ll-dihydro-SH-dibenzo [a,d]cycloheptene required as starting material is produced as follows:

b. An amount of 11.2 g (0.05 moles) of 8-methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-lO-ole is dissolved in 50 ml of abs. benzene; to the solution are then added 5.14 g (0.065 moles) of pyridine. To this solution is then added dropwise at 5 a solution of 7.14 g (0.06 moles) of thionyl chloride in 25 ml of abs. benzene. The reaction mixture is stirred, while nitrogen is fed in, for 5 hours at 50; it is afterwards poured into 200 ml of ice water. The mixture is extracted with ether/methylene chloride (2:1). The ether/methylene chloride solution is washed with l-n hydrochloric acid,

l-n sodium hydrogen carbonate solution, and water; it is then dried over magnesium sulphate, and concentrated in vacuo. The crystalline residue: 8-methyl-10- chloro-l0,ll-dihydro-SH-dibenzo [a,d]cycloheptene, melts at 6568; yield 11.3 g, 93 percent of the theoretical value.

EXAMPLE 4 An amount of 2.92 g (0.01 mole) of 8-methyl-l0-( lpiperazinyl)-10,l l-dihydro-5H-dibenzo[a,d] cycloheptene is refluxed with 2.80 g (0.014 moles) of crude lmethyl-3,3-bis-(2-chloroethyl)urea and 3.6 g (0.026 moles) of anhydrous potassium carbonate in 36 ml of diethyl ketone for 12 hours. A further 2.4 g (0.018 moles) of potassium carbonate are added after 4 hours reaction time, and the same amount is again added after 8 hours reaction time. The reaction mixture is cooled, diluted with ether, filtered, and the filtrate concentrated in vacuo. The residue (5.22 g) is taken up in ether; the solution is then extracted with l-n hydrochloric acid, the acidified extract washed with ether, and excess sodium carbonate added. The precipitated free base is taken up in ether; the ether solution is then washed with water, dried over sodium sulphate, and concentrated by evaporation. The residue is chromatographed on a column of silica gel (Merck, grain size 0.05 0.2 mm), which has been impregnated with 0.5-n sodium hydroxide solution. Chloroform is used as the eluting agent. The fractions containing the crude product are concentrated by evaporation. The residue is recrystallized from ethyl acetate/petroleum ether, whereupon the pure 1-[2-[4- (8-methyl-10,l1-dihydro-5H-dibenzo[a,d]cyclohepten- 1 -yl)- l -piperazinyl]-ethyl]-3-methyl-2- imidazolidinone melts at 1l6l17; yield 2.72 g, 65 percent of the theoretical value.

EXAMPLE Analogously to Example la) the following end products are obtained:

a. from 31.2 g (0.1 mol) of 8-chloro-l0-(l-piperazinyl)-l0,l1-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g (0.1 1 mol) of l-(2-chloroethyl)-3-methy1-2- imidazolidinone, the l-[2-[4-(8-chloro-l0,1l-dihydro- 5l-l-dibenzo[a,d]-cyclohepten-10-yl)-l-piperazinyl]- ethyl]-3-methyl-2-imidazolidinone, M.P. 134 135; Yield: 33.6 75 percent of the theoretical value.

M.P. of the bis-methanesulphonate, 1" hydrate: 180 181 (from ethanol-diethylether).

b. from 31.2 g (0.1 mol) of 8-chloro-10-(l-piperazinyl)-l 0,1 1-dihydro-5H-dibenzo[a,d]cyc1oheptene and 20.9 g (0.11 mol) of l-(3-chloropropyl)-3-ethyl-2- imidazolidinone, the crude l-[3-[4-(8-chloro-10,l ldihydro-SH-dibenzo[a,d]-cyclohepten-10-yl)1- piperazinyl]-propyl]-3-ethyl-2-imidazolidinone, the bis-maleate of which [prepared according to Example la)] melts at .ll3 1 c. from 31.2 g (0.1 mol) of S-chloro-lO-(l-piperazinyl)-l0,l1-dihydro-5H-dibenzo{a,d]cycloheptene and 24.0 g 0.11 mol) of 1-(3-chloropropyl)-3-butyl-2- imidazolidinone, the crude 1-[3-[4-(8-chloro-10,11- dihydro-5H-dibenzo[a,d] -cyclohepten-10-y1)-1- piperazinyl]-propyl]-3-butyl-2-imidazolidinone. Yield: 35.6 g 73 percent of the theoretical value.

The product is an oily compound, which is dissolved in acetone, to which an ethereal solution of hydrochloric acid is added until congo-acid reaction sets in. A solid precipitates which is filtered by suction and recrystallized from ethanol/ethylacetate containing a small amount of diethylether, whereby the pure 1-[3- [4-(8-chloro-10,l 1-dihydro-5H-dibenzo[a,d]cyclohepten-l0-yl)- l -piperazinyl]-propyl]-3-butyl-2- imidazolidinone-dihydrochloride is obtained as a twothird hydrate. M.P. 195 197.

The 1-(3-chloropropyl)-3-butyl-2-imidazo1idinone required as starting material may be prepared by the following procedure:

d. 19.6 g (0.175 mol) of 2-butylamino-ethanol are dissolved in 30 ml of absolute methylene chloride to which solution are dropped, at a temperature of from 5 to 0, a solution of 20.9 g (0.175 mol) of (3- chloropropyl)-isocyanate in 20 ml of absolute methylene-chloride in the course of 45 minutes. The reaction mixture is stirred at 30 for 2 hours and then cooled to 0. Into the cooled solution containing the crude 1-butyl-l-(2-hydroxy-ethyl)-3(3-chloropropyl)- urea, a mixture of 21.9 g (0.182 mol) of thionylchloride in 20 ml of absolute methylene-chloride is dropped in the course of 30 minutes. The reaction mixture is then refluxed for 4 hours followed by evaporation under a vacuum. The residue which represents the crude l-butyl-l-(2-chloroethyl)-3-(3-chloropropyl)- urea is dried at in a high vacuum, then heated in a bath at for 3 hours, followed by heating in a bath at for 6 hours. The crude product is then distilled in a high vacuum.

8.1. 110 l12/0.05 Torr.

EXAMPLE 6 Analogously to Example 1a) the following final products may be prepared:

a. from 27.8 g (0.1 mol) of 10-(1-piperazinyl)-l0,l ldihydro-5l-l-dibenzo[a,d]cycloheptene and 17.8 g (0.1 1 mol) of 1-(2-chloroethyl)-3-methyl-2- imidazolidinone, the 1-[2-[4-( 10,1 l-dihydro-SH- dibenzo[a,d]cyclohepten-10-y1)-1-piperaziny1]-ethy1]- 3-methyl-2-imidazolidinone. M.P. 117 118; Yield: 34.3 g 85 percent of the theoretical value.

The mono-maleate (from ethanol/diethylether) melts at l72- 173.

b. from 27.8 g (0.1 mol) of 10-( 1-piperazinyl)-10,1 1- dihydro-5H-dibenzo[a,d]cycloheptene and 22.4 g (0.1 1 mol) of 1-(2-chloroethyl)-3-butyl-2- imidazolidinone, the 1-[2[4-(10,l l-dihydro-SH- dibenzo[a,d]cyclohepten-l0-yl)-l-piperazinyl]-ethyl]- 3-butyl-2-imidazolidinone.

M.P. 86 87; Yield: 34.0 g 76 percent of the theoretical value. The mono-tnaleate (from ethanol/diethylether) melts at 133 134.

c. from 27.8 g (0.1 mol) of 10-(1-piperazinyl)-l0,l ldihydro-SH-dibenzo[a,d]cycloheptene and 20.9 'g (0.1 1 mol) of 1-(3-chloropropyl)-3-ethyl-2- imidazolidinone, the crude 1-[3-[4-(10,l l-dihydro- 5H-dibenzo[a,d]cyclohepten-l0-yl)-l-piperazinyl]- propyl]-3-ethyl-2-imidazolidinone. Yield: 33.7 g 78% of the theoretical value.

The bis-maleatelb hydrate prepared analogously to Example 1a) melts at 104 106.

EXAMPLE7 Analogously to Example la), the following end products may be prepared:

a. from 30.8 g (0.1 mol) of crude 8-methoxy-10-(lpiperazinyl)-l0,l l-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g (0.11 mol) of 1-(2-chloro-ethyl)-3- methyl-Z-imidazolidinone, the l-[2-[4-(8-methoxy- 10,1l-dihydro-5ll-dibenzo[a,d]cyclohepten-l0-yl)-lpiperazinyl]-ethyl]-3-methyl-2-imidazolidinone.

M.P. 122 123 (from ethyl acetate/petroleum ether. Yield: 30.4 g 70 percent of the theoretical value.

This bis-maleate (from absolute ethanol/diethylether melts at 144 146.

12. from 0.8 g (0.1 mol) of crude 8-methoxy-l0-(lpiperazinyl)-l 0,1 l-dihydro-5H-dibenzo[a,d]cycloheptene and 19.4 g (0.11 mol) of l-(3-chloropropyl)-3- methyl-2-imidazolidinone, the crude l-[3-[4-(8- methoxy-l0,l l-di-hydro-5H-dibenzo[a,d]cycloheptenl-yl)-l-piperazinyl]-propyl]-3-methyl-2- imidazolidinone.

Yield: 22.8 g 62 percent of the theoretical value. The bis-maleate. 3'4 hydrate (from absolute ethanol) melts at 106 108.

c. The 8-methoxy-l0-(l-piperazinyl)-10,ll-dihydro- H-dibenzo[a,d]cycloheptene required as starting material may be obtained by the following procedure: 48.0 g (0.2 mol) of S-methoxy-lO-hydroxy-SH- dibenzo[a,d]-cycloheptene are dissolved in 200 ml of chloroform, 20.7 g (0.26 mol) of pyridine are added to which solution, in the course of 45 minutes at 0 5, a solution of 28.4 g (0.24 mol) of thionylchloride in 100 ml of benzene are dropped. The reaction mixture is stirred at 45 50 for 2 hours while nitrogen gas is fed in and subsequently poured into V1 liter of ice-water.

After adding an amount of methylenechloride the organic layer is separated and subsequently washed with 200 ml of each l-n. hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and finally with water. The organic layer is separated, dried over magnesium sulphate and evaporated in vacuo, whereby the 8-methoxy-lO-chloro-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene is obtained. MP. 84 86.

d. 25.8 g (0.1 mol) of the compound as prepared under c) are refluxed together with 42.4 g (0.3 mol) of l-piperazine carboxylic acid ethyl ester in 200 ml of benzene for 24 hours. The mixture is then poured into 500 ml of ice-water, 50 ml of 2-n.sodium hydroxide solution are added, and the benzene layer is separated. The aqueous phase is extracted with benzene, the combined benzene phases are washed with water, dried over magnesium sulphate and evaporated in vacuo, whereby an oily residue is obtained. 38.0 g of this crude product are dissolved in 100 ml of absolute ethanol and after adding 20.0 g (0.358 mol) of potassium hydroxide refluxed for hours. The solution is then evaporated in vacuo and to the residue 200 ml of each benzene, and water, are added. The benzene layer is washed with water to neutral and extracted with 200 ml of 2-n. hydrochloric acid, then the acid phase is rendered alkaline by means of concentrated sodium hydroxide solution, whereby a solid precipitates, which is extracted with benzene. The combined benzene extracts are thoroughly washed with water, dried over magnesium sulphate and evaporated in vacuo to dryness.

The residue represents the 8-methoxy-l0-(lpiperazinyl)-l0,l l-dihydro-5H-dibenzo[a,d]cycloheptene and is used in crude state for the subsequent reaction. Yield: 10.8 g 35 percent of the theoretical value.

EXAMPLE 8 a. Analogously to Example la), 30.8 g (0.01 mol) of crude 8-methoxy-l0-( l-piperazinyl)-l0,l l-dihydro- 5H-dibenzo-[a,dlcycloheptene, obtained according to Example 7c) and d) respectively, and 21.0 g (0.11 mol) of l-(2-chloroethyl)-isopropyl-2-imidazolidinone are reacted to produce l-[2-[4-(8-methoxy-10,l l-dihydro- 5l-l-dibenzo[a,d]cyclohepten-l0-yl)-1-piperazinyl]- ethyl]-3-isopropyl-2-imidazolidinone.

Yield: 35.6 g= 77 percent of the theoretical value. M.P. of the bis-maleate. V4 hydrate (from absolute ethanol/diethylether): 125 127.

The l-(2-chloroethy1)-isopropyl-2-imidazolidinone required as starting material may be obtained by the following procedure:

b. 105.1 g (1.0 mol) of freshly distilled diethanolamine are dissolved in 1000 ml of absolute methylenechloride to which solution, in the course of 1 hour, a solution of 89.5 g (1.05 mols) of isopropylisocyanate at a temperature of 0 5 is dropped. The reaction mixture is refluxed for 1 hour while stirring. After cooling to 0, a solution of 250.0 g (2.1 mols) of thionylchloride in 250 ml of absolute methylenechloride is added dropwise at 0 5, in the course of 1 hour. After refluxing for 4 hours the mixture is evaporated in vacuo. The residue which represents the crude l-isopropyl-3,3-bis-(2- chloroethyl)-urea is heated during 3 hours at 120 with exclusion of moisture, followed by heating to 140 for 6 hours.

The product is fractionated in a high vacuum, whereby the pure 1-(2-chloroethyl)-3-isopropyl-2- imidazolidinone distills at 88 90/0.02 Torr; n 1.4855.

EXAMPLE 9 Analogously to Example 1a) the following end products are obtained:

a. from 29.2 g (0.1 mol) of crude S-methyl-lO-(lpiperazinyl)-10,1 1-dihydro-5H-dibenzo[a,d]cycloheptene and 17.8 g (0.11 mol) of l-(2-chloroethyl)-3- methyl-Z-imidazolidinone, the crude l-[2-[4-(5- methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptenl0-yl)-1-piperazinyl]-ethyl]-3-methyl- Zimidazolidinone.

Yield: 32.6 g 78% of the theoretical value.

The di-oxalate. 3t; hydrate melts at (precipitated from acetone/ethylacetate followed by recrystallization from acetone containing a small amount of an ethanol-diethylether mixture.

b. from 29.2 g (0.1 mol) of crude 5-methyl-l0-(lpiperazinyl)-l0,1 l-dihydro-5H-dibenzo[a,d]cycloheptene and 19.4 g (0.11 mol) of l-(3-chloropropyl)-3- methyl-2-imidazolidinone, the crude l-[3-[4-(5- methyl-10,1 l-dihydro-5H-dibenzo[a,d]-cycloheptenl0-yl)-l -piperazinyl]-propyl]-3-methyl-2- imidazolidinone.

Yield: 35.2 g 81.2 percent of the theoretical value.

I diethanol is converted by oxalic acid into the di-oxalate. hydrate. M.P. 120 125 (from ethylacetate/ethanol/diet hylether.

e. from 3.06 g (0.01 mol) of 5,8-dimethyl-10-(1- piperaziny1)-10,1 1 dihydro-5H-dibenzo[a,d]cycloheptene and 2.80 g (0.014 mol) of 1-methyl-3,3-bis-(2- chloro-ethyl)-urea,' the crude l-[2-[4-(5,8-dimethyl- 10,1 1-dihydro-5l-l-dibenzo[a,d]cyclohepten- 1 -y1)-1- piperazinyl]-ethyl]-3-methyl-2-imidazolidinone, the oxalate. hydrate of which melts at 162 168.

EXAMPLE 12' Analogously to Example 4 the following end product is obtained:

a. from 3.08 g (0.01 mol) crude 8-methoxy-l0-(1- piperazinyl)-10,1 l-dihydro-H-dibenzo[a,d]cycloheptene and 3.18 g (0.014 mol) of l-isopropyl-3,3-bis-(2- chloro-ethyl)-urea, the l-[2-[4-(8-methoxy-10,11- dihydro-S l-l-dibenzo[a',d]cyclohepten-10-y1)-1- piperazinyll-ethyl]-3-isopropyl-2-imidazolidinone. Yield 2.92 g.

The bis-maleate. l4 hydrate (precipitated from an acetone/diethylether solution followed by recrystallization from ethanol/diethylether) melts at 125 127.

The 1-isopropyl-3 ,3-bis-( 2-chloro-ethyl)-urea required as starting material is prepared by the following method:

b. To a solution of 10.5 g (0,1 mol) of freshly distilled amine in 100 ml of absolute methylenechloride a solution of 8.95 g (0.105 mol) of isopropylcyanate in ml of absolute methylene chloride is dropped, at a temperature of 0 5 in the course of minutes, followed by stirring each for one hour at ambient temperature and then by refluxing. After cooling to 0, a solution of 25.0 g (0.21 mol) of thionylchloride in absolute methylene-chloride at a temperature of 0 5 is added dropwise and then the mixture is refluxed for 4 hours, evaporated in vacuo to dryness and dried at 40 in a high vacuum.

The 1-isopropyl-3,3-bis-(2-chloroethyl)-urea is ob tained as an oily product.

EXAMPLE 13 Analogously to Example 4 the following end product is obtained:

a. from 2.7 g (0.01 mol) of 10-(1-piperazinyl)-10,1 1- dihydro-5H-dibenzo[a,d]cycloheptene and 3.37 (0.014 mol) of 1-butyl-3,3-bis-(2-chloroethyl)-urea, the 1-[2[4-( 10,1 1-dihydro-5H-dibenzo[a,d]cyclohepten-l 0-yl)-1-piperazinyl]-ethyl]-3-buty1-2- imidazolidinone.

M.P. 86- 87 (from ethylacetate/petroleum ether); Yield: 2.99 g= 62 percent of the theoretical value.

The 1-butyl-3,3-bis-(2-chloroethyl)-urea is prepared analogously to Example 12b):

b. from 10.5 g (0.1 mol) of freshly distilled diethanolamine, 10.4 g (0.105 mol) of butylisocyanate and 25.0 g (0.21 mol) of thionylchloride. The l-butyl- 3,3-bis-(2-chloroethyl)-urea is obtained as an oily product which is used for subsequent reaction.

EXAMPLE 14 Analogously to Example 3a) the following final products are prepared:

a. from 13.2 g (0.05 mol) of 8,10-dichloro-10,1ldihydro-5H-dibenzo[a,d]cycloheptene and 15.9 g (0.075 mol) of 1-[2-(1-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone, the l-[2-[4-(8-chloro-l0,1l-dihydro- 5H-dibenzo[a,d]cyclo-hepten-10-yl)-1-piperazinyl]- ethyl]-3-methyl-2 imidazolidinone.

M.P. 134 Yield: 6.55 g 30 percent of the theoretical value.

The bis-methanesulphonate. 1% hydrate melts at 181 (from ethanol/diethylether).

b. from 11.4 g (0.05 mol) of lO-chloro-l0,11- dihydro-5l-l-dibenzo[a,dlcycloheptene and 15.9 g (0.075 mol) of 1-[2-(1-piperazinyl)'ethyl]-3-methyl-2- imidazolidinone, the 1-[2-[4-( 10,1 1-dihydro-5l-ldibenzo[a,d]cyclohepten-10-yl)-l-piperazinyll-ethyl- 3-methyl-2-imidazolidinone.

M.P. 112 118; Yield: 9.3 g 46 percent of the theoretical value.

The mono-maleate melts at 122 ethanol/diethyl-ether).

c. from 12.9g(0.05 mol) of crude 8-methoxy-10- chlor0-10,1 1-dihydro-5H-dibenzo[a,d]cycloheptene and 15.9 g (0.075 mol) of l-[2-(1-piperaziny1)-ethyl]-3 -methyl-2-imidazo1idinone, the l-[2-[4-(8-methoxy- 10,1 1-dihydro-5H-dibenzo[a,d]cyclohepten10-y1)-1- piperazinyl]-ethy1]-3-methyl-2-imidazolidinone.

M.P. 122 123; Yield: 8.7 g 48 percent of the theoretical value.

The bis-maleate melts at ethanol/diethyl-ether).

d. from 13.2 g (0.05 mol) of 8,l0-dichloro-l0,11- dihydro-5l-l-dibenzo[a,dlcycloheptene and 18.0 g (0.075 mol) 1-[3-(l-piperazinyl)-propyl]-3-ethyl-2- imidazolidinone, the crude 1-[3-[4-(8-chloro-10,lldihydro-5H-dibenzo[a,d]-cyclohepten-10-yl)-lpiperazinyl]propyl]e-3-ethyl-2-imidazolidinone.

Yield: 7.7 g 33 percent of the theoretical value. The bis-maleate melts at 113 115 (from absolute ethanol/diethylether).

e. from 11.4 g (0.05 mol) of 10-chloro-10,11- dihydro-5l-1-dibenzo[a,d]cycloheptene and 18.0 g (0.075 mol) of 1-[3-(1-piperazinyl)-propyl]-3-ethyl-2- imidazolidinone, the crude 1-[3-[4-(l0,11-dihydrodibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]- propyl]-3-ethyl-2-imidazolidinone.

Yield: 10.4 g 48 percent of the theoretical value. The bis-maleate. /z hydrate melts at 104 106 (from acetone and a small amount of ethanol/diethylether).

f. from 12.9 g (0.05 mol) of 8-methoxy-10-chloro- 10,11-dihydro-5l-l-dibenzo[a,d]cycloheptene and 17.0 g (0.075 mol) of 1-[3-(1-piperaziny1)-propy1]-3- methyl-2-imidazolidinone, the crude 1-[3-[4-(8- methoxy-10,1 1-dihydro-5H-dibenzo[a,d l-cyclohepten- 123 (from 144 146 (from The pure oxalate melts at 162 165 (precipitated from acetone/ethylacetate followed by recrystallization from an acetone/ethanol/diethylether mixture.

The 5-methyl-10-(l-piperazinyl)-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene is prepared in the following manner:

0. 44.4 g (0.2 mol) of 5-methyl-l0,ll-dihydro-SH- dibenzo[a,d]cyclohepten-l-one are dissolved in 500 ml of methanol to which solution, during refluxing, a solution of 7.55 g (0.2 mol) of sodium borohydride in 80 ml of water is dropped in the course of 40 minutes. Refluxing is then continued for 2 hours followed by evaporating the solvent in vacuo. The residue is poured into 200 ml of ice-water and this mixture is triturated with a 1-n.sodium-dihydrogenphosphate solution and l-n. hydrochloric acid until pH 7 is reached. The solution obtained is extracted with a diethylether/methylenechloride mixture (2:1 the organic layers washed with water, dried over magnesium sulphate and evaporated in vacuo. The residue thus obtained is recrystallized from benzene/petroleum ether, whereby the pure 5-methyl-l0-hydroxy-10,1 l-dihydrodibenzo-[a,d]cycloheptene is obtained.

M.P. 89 90; Yield: 90 percent of the theoretical value.

d. 40.3 g (0.18 mol) of the compound prepared under c) are dissolved in 200 ml of chloroform, together with 18.9 g (0.234 mol) of pyridine to which solution, at a temperature of 0 5, a solution of 25.6 g (0.216 mol) of thionylchloride in 100 ml of benzene is dropped. The reaction mixture is fed with nitrogen gas whilst stirring at 45 50 for 2 hours, followed by pouring into 500 ml of ice-water. Methylene chloride is added and the organic layer is separated and subsequently washed with 200 ml of each of l-n. hydrochloric acid, water, saturated sodium hydrogencarbonate solution and water until pH 7 is reached. The organic layers are dried over magnesium sulphate and the solvents volatilized in vacuo at 45. The oily residue represents the 5-methyl-10-chloro-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene which is used for the subsequent reaction.

Yield: 43.5 g =quantitative.

e. 43.5 g (0.18 mol) of this crude product and 85.5 g (0.54 mol) of l-piperazine carboxylic acid ethyl ester are dissolved in 400 ml of benzene and refluxed for hours. After cooling, the mixture is poured into 500 ml of ice-water, 100 ml of 2-n.sodium hydroxide solution are added, the benzene layer is separated and the aqueous phase is extracted with benzene. The combined benzene extracts are washed with water, dried over magnesium sulphate and the solvent evaporated in vacuo, yielding an oily residue.

66.0 g of this product are dissolved in 200 ml of absolute ethanol and after adding 40.0 g of potassium hydroxide, the reaction mixture is refluxed for 20 hours, followed by filtration of the warm reaction mixture from precipitated potassium carbonate. The filterresidue is washed with warm ethanol and the combined filtrates are concentrated to syrupy consistence, to which 300 ml of each of benzene and water are added. The benzene layer is separated, washed with water to neutral reaction, followed by extraction with 400 ml of 2-n. hydrochloric acid. The acid solution is rendered alkaline by adding concentrated sodium hydroxide solution, which is then extracted with benzene. The combined benzene layers are washed with water, dried over magnesium sulphate and evaporated in vacuo to dryness.

The residue represents the 5-methyl-10-(1-piperazinyl)-l0,ll-dihydro-5H-dibenzo[a,d]cycloheptene in crude state.

Yield: 52.5 g 40 percent of the theoretical value.

EXAMPLE l0 Analogously to Example 1a) the following end products are obtained:

a. from 30.6 g (0.1 mol) of crude 5,8-dimethyl-l0-(1 -piperazinyl)-l0,l l-dihydro-5H-dibenzo[ a,d]cycloheptene and 17.8 g (0.11 mol) of 1-(2- chloroethyl)-3-methyl-2-imidazolidinone, the crude 1- [2-[4-(5,8-dimethyl-10,1 l-dihydro-5H-dibenzo[ a,d]cyclohepten-l0-yl)-l-piperazinyl1-ethyl1-3- methyl-2-imidazolidinone.

Yield: 30.2 g percent of the theoretical value.

The dioxalate. hydrate (precipitated from acetone/diethylether is recrystallized from ethyl acetate containing a small amount of an ethanol/diethylether mixture) melts at 162 168.

b. from 30.6 g (0.1 mol) of crude 5,8-dimethyl-10-(1 -piperazinyl)-10,1 1-dihydro-5H-dibenzo[ a,d]cycloheptene and 19.4 g (0.11 mol) of l-(3- chloropropyl)-3-methyl-2-imidazolidinone, the crude 1-[3-[4-(5,8-dimethyl-l0,l 1-dihydro-5H-dibenzo[ a,d]cyclohepten-10-y1)-1-piperazinyl1-propyl1-3- methyl-2-imidazolidinone.

Yield: 32.2 g 72 percent of the theoretical value.

The dioxalate. hydrate melts at 198 200.

The crude 5,8-dimethyl-10-(1-piperazinyl)-10,1ldihydro-5l-l-dibenzo[a,dlcycloheptene required as starting material may be prepared analogously to Example 9c) e) from 5,8-dimethyl-10,1l-dihydro-Sl-ldibenzo[a,d]cyclohepten-10-one (M.P. 99 from diethylether) via the following intermediate compounds:

0,. dibenzo-[a,d]cycloheptene; M.P. 87 methyl-cyclohexane/pentane),

c 5,8-dimethyl-10-chloro-10,l l-dihydro-SH- dibenzo-[a,d]cycloheptene as crude product.

5,8-dimethyl-lO-hydroxy-l0,1 l-dihydro-SH- 94 (from EXAMPLE 11 Analogously to Example 4 the following final products are obtained:

a. from 3.1 g (0.01 mol) of 8-chloro-10-( l-piper-aziny1)-10,11-dihydro-51-l-dibenzo[a,d]cycloheptene and 2.80 g (0.014 mol) of l-methyl-3,3-bis-(2- chloroethyl)-urea, the 1-[2-[4-(8-chloro-10,11- dihydro-SH-dibenzo-[a,d]cyclohepten-10-yl)-l piperazinyl]ethyl]3-methyl-2-imidazolidinone.

M.P. 134 Yield: 2.4 g 60 percent of the theoretical value.

b. from 2.7 g (0,01 mol) of 10-( 1-piperazinyl)-10,1 1- dihydro-SH-dibenzo[a,d]cycloheptene and 2.80 g (0.014 mol) of 1-methyl-3,3-bis-(2-chloroethyl)-urea, the 1-[2-[4-(10,l1-dihydro-51-l-dibenzo[a,d]cyclohepten-10-yl)-1-piperazinyl]-ethyl]-3methyl-2- imidazolidinone.

M.P. 117 118; Yield: 2.82 g 70 percent of the theoretical value.

10-yl)-l-piperazinyl]-propyl]-3-methyl-2- imidazolidinone.

Yield: 9.65 g 43 percent of the theoretical value. The bis-maleate. 84 hydrate melts at 106 108 (from ethanol/diethylether).

g. from 11.4 g (0.05 mol) of 10-chloro-10,1ldihydro-l-l-dibenzo[a,dlcycloheptene and 19.0 g (0.075 mol) of 1-[2-(1-piperazinyl)-ethyll-3-butyl-2- imidazolidinone, the 1-[2-[4-(10,1l-dihydro-SH- dibenzo[a,d]cyclohepten--yl)-1-piperazinyl]-ethyl]- 3-butyl-2-imidazo1idinone.

MP. 86 87 (from ethylacetate/petroleum ether). Yield: 8.9 g 40 percent of the theoretical value.

EXAMPLE Analogously to Example 3a) the following end product is obtained:

a. from 13.2 g (0.05 mol) of 8,10-dich1oro-10,11- dihydro-5l-l-dibenzo[a,d]cycloheptene and 20.1 g (0.075 mol) of 1-[3-(1-piperazinyl)-propyl]-3-butyl-2- imidazolidinone, the crude l-[3-[4-(8-chloro-10,11- dihydro-5l-l-dibenzo[a,d]-cyclohepten-l0-yl)-1- piperazinyl]-propyl]-3-butyl-2-imidazolidinone.

Yield: 7.65 g =31 percent of the theoretical value. The dihydrochloride. hydrate melts at 195 197 (from ethanol/ethylacetate/diethylether).

The 1-[3-(1-piperazinyl)-propy1l-3-butyl-2- imidazolidinone requiredv as starting material is prepared by the following procedure:

b. To a solution of 218.0 g (1.0 mol) of 1-(3- chloropropyl)-3-butyl-2-imidazolidinone (prepared according to Example 5d) and 175.0 g (1.1 mols) of 1- piperazine carboxylic acid ethyl ester in 1000 ml of diethylketone are added 304.0 g (2.0 mols) of potassium carbonate and the reaction mixture is refluxed for 24 hours, which mixture is then warm filtered. The residue is boiled two times with 500 ml of chloroform and filtered. The combined filtrates are evaporated in vacuo to dryness and the oily residue is fractioned in a high-vacuum. The pure 1-[3-(4-ethoxycarbonyl-lpiperazinyl)-propyl]-3-butyl-2 imidazolidinone distills at 180 210/0.01 Torr; n,," 1.4946.

Yield: 266.0 g 78 percent of the theoretical value.

c. 340.4 g (1.0 mol) of 1-[3-(4-ethoxycarbonyl)-lpiperazinyl)-propyl]-3-butyl-2-imidazolidinone are added to a solution of 300.0 g of potassium hydroxide in 1500 ml of absolute ethanol and the mixture is refluxed for 16 hours. The precipitate is filtered off and washed with warm ethanol. The combined filtrates are concentrated in vacuo and the residue is triturated with 1000 ml of benzene and 300ml of water. The aqueous phase is separated, saturated with potassium carbonate and extracted four times with benzene.

The combined benzene solutions are dried over potassium carbonate and the solvent volatized in vacuo. The residue is fractionated in a high-vacuum, whereby the pure 1-[3-(1-piperazinyl)-propyl]-3-butyl- 2-imidazolidinone distills at 145- 150/0.01 Torr. n =1.5006;

Yield: 250.0 g =93 percent ofthe theoretical value.

EXAMPLE l6 Analogously to Example 3a) the following end product is obtained:

a. from 12.9 (0.05 mol) crude 8-methoxy-10-chloro- 10,11-dihydro-5l-ldibenzo[a,d]cycloheptene and 18.0 g (0.075 mol) of l-[2-(1-piperazinyl)-ethyl]- 3-isopropyl-2-imidazolidinone, the crude 1-[2-[4- (8-methoxy-10,11-dihydro-5H-dibenzo[a,d]- cyclohepten-l0-yl)-1-piperazinyl]-ethyl]-3- isopropyl-Z-imidazolidinone.

Yield: 10.1 g 44 percent of the theoretical value. The bis-maleate. hydrate melts at 127 (from absolute ethanol/diethylether).

The 1-[2-(1-piperazinyl)-ethyl]-3-isopropy1-2- imidazolidinone is prepared analogously to Example 15b) and c).

b. 190.6 g (1.0 mol) of l-(2-chloroethyl)-3- isopropyl-2-imidazolidinone [prepared according to Example 8b)] are reacted with 175.0 g (1.1 mol) of 1- piperazine carboxylic acid ethyl ester yielding 1-[2-(4- ethoxycarbonyl- 1 -piperazinyl)ethyl]-3-isopropyl-2- imidazolidinone as crude product which is subsequently fractionated in a high vacuum, whereby impurities distill over in the range of from 190/0.01 Torr. The residue is then saponified and gives, finally, the 1-[2-(1-piperazinyl)-ethyl]-3- isopropyl-2-imidazolidinone.

B.P. /0.0l Torr; n 1.5034. Yield: 73 percent of the theoretical value.

EXAMPLE 17 Analogously to Example 3a) the following end products are prepared:

a. from 12.1 g (0,05 mol) of crude 5-methy1-10- chloro-10,1 1-dihydro-5l-l-dibenzo[a,d]cyc1oheptene [prepared according to Example 9d)] and 15.9 g (0,075 mol) of 1-[2-(1-piperazinyl)-ethyl]-3-methy1-2- imidazolidinone, the crude 1-[2-[4-(5-methy1-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-l0-yl)-1- piperazinyl]-ethyl]-3-methyl-2-imidazolidirione.

Yield: 7.2 g 37 percent of the theoretical value.

The dioxalate. as hydrate melts at 120 125 (from ethyl acetate and a small amount of ethanol/diethylether).

b. from 12.1 g (0.05 mol) of crude 5-methy1-10- chloro-l0,1-1-dihydro-5H-dibenzo[a,d]cycloheptene [prepared according to Example 9d)] and 17.0 g (0.075 mol) of 1-[3-(l-piperazinyl)-propyl]-3-methyl- 2-imidazolidinone, the crude 1-[3-[4-(5-methyl-10,1 1- dihydro-5H-dibenzo[a,d]-cyclohepten-10-yl)-1- piperazinyl]-propyl]-3-methyl-2-imidazolidinone. Yield: 7.55 g 35 percent of the theoretical value.

The di-oxalate melts at 162 165 (from absolute ethanol/diethylether).

c. from 12.8 g (0.05 mol) of crude 5,8-dimethyl-10- chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 15.9 g (0.075 mol) of 1-[2-(1-piperazinyl)-ethy1]-3 -methyl-2-imidazolidinone, the crude 1-[2-[4-(5,8- dimethyl-10,1 1-dihydro-5H-dibenzo[a,d]cyclohepten- 10-y1)-1-piperazinyl]-ethyl]-3-methyl-2- imidazolidinone.

Yield: 6.9 g 32 percent of the theoretical value. The dioxalate. A; hydrate melts at 162 168 (from ethanol/ethylacetate/diethylether).

d. from 12.8 g (0.05 mol) of crude 5,8-dimethyl-l0- chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 17.0 g (0.075 mol) of 1-[3-(1-piperazinyl)- propyl]-3-methyl-2-imidazolidinone, the crude 1-[3- [4-(5,8-dimethyl-l0,l l-dihydro-5H-dibenzo( X is hydrogen, chloro, methyl or methoxy; a,d lcyclohepten-lO-yU-l -piperazinyl l-propyl ]-3- R is alkyl having from one to four carbon atoms; methyl-2-imidazolidinone. R is hydrogen or methyl; and Yield: 8.5 g 38 percent of the theoretical value. n is the integer 2 or 3; The di-oxalate. HS hydrate melts at 198 200 (from a 5 and the pharmaceutically acceptable acid addition salts little absolute ethanol/ethylacetate/diethylether). thereof.

What is claimed is: 2. A compound according to claim 1, which is l-[2- 1. A compound of formula I, [4-(8-methyl-l0,l l-dihydro-5H-dibenzo[ "g' c a,d]cyclohepten-lO-yl)-l-piperazinyl]-ethyl]-3- N 1 l methyI-Z-irnidazolidinone, and a pharmaceutically acceptable acid addition salt thereof. Gib-CH H 3. A compound according to claim 1, which is 1-[2- O [4-(8-chloro-l0,l l-dihydro-H-dibenzo[a,dlcyclohepten-.l0-yl)-l-piperazinyl]-ethyl]-3-methyl-2- l5 imidazolidinone, and a pharmaceutically acceptable acid addition salt thereof.

l R: (I) wherein

Claims (2)

1. A compound of formula I,

2. A compound according to claim 1, which is 1-(2-(4-(8-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-10-yl)-1 -piperazinyl)-ethyl)-3-methyl-2-imidazolidinone, and a pharmaceutically acceptable acid addition salt thereof.