Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/30—Oxygen or sulfur atoms
  • C07D233/32—One oxygen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/30—Oxygen or sulfur atoms
  • C07D233/32—One oxygen atom
  • C07D233/34—Ethylene-urea
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
  • C07D337/02—Seven-membered rings
  • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
  • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
  • C07D337/14—[b,f]-condensed

Definitions

• This invention relates to imidazolidinone derivatives, processes for their production, pharmaceutical compositions containing these compounds and the use thereof.
• the invention relates to compounds of the formula wherein X is hydrogen, chloro, methyl, trifluoromethyl, methoxy or methylthio;
• R is lower alkyl of at most 4 carbon atoms
• n 2 or 3; and to pharmaceutically acceptable acid addition salts thereof.
• R can be, as lower alkyl group, e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl group.
• the compounds of this invention have a strong general depressant effect on oral, rectal or parenteral administration, e.g. they reduce motility, potentiate the action of anesthetics and exhibit a positive effect in the test de la traction. Furthermore, they have a pronounced sympathicolytic and antiemetic action and antagonise the action of serotonin. These properties, in combination with a favorable low toxicity, render the compounds of the invention suitable for the treatment of conditions of tension and agitation.
• a preferred subclass are compounds of Formula I, wherein X is chloro, methoxy or methylthio;
• R is methyl, and n is 2 or 3, and the pharmaceutically acceptable acid addition salts thereof.
• mice administered in amounts of about 0.34 mg./kg. subcutaneously to mice, prevents about 50% of the animals, hanging on to a wire with their front paws, from pulling up and gripping'the wire with their hind paws (test de la traction).
• the toxicity of the compounds of the invention as demonstrated in mice on intravenous administration is of favorable low order.
• a compound of the general Formula I is produced according to the invention by reacting a compound of the general Formula II CHI-CH2 X I, and, optionally, converting the reaction product with an inorganic or organic acid into an addition salt.
• Suitable reactive esters of compounds of the general Formula III are, for example, halides, such as chlorides or bromides, also sulphonic acid esters, e.g. the methane sulphonic acid ester or the or p-toluene sulphonic acid ester.
• 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 or toluene, halogen hydrocarbons, such as chloroform, etheral liquids such as ether and dioxane as well as lower alkanones, such as acetone, methyl-ethyl lretone or diethyl ketone.
• a molecular equivalent of an acid is split off.
• This acid can be bound to the excess base of the general Formula II, or to the dibasic reaction product.
• an acid binding agent is added to the reaction mixture.
• Suitable acid binding agents are, e.g. alkali metal carbonates, such as sodium and potassium carbonate, also tertiary organic bases, such as pyridine, triethylamine or especially N,N-diisopropylethylamine. Excess tertiary bases can also be used as solvents.
• an alkali metal derivative of a suchlike base be used for the reactionaccording to the invention, e.g. a sodium, potassium or lithium derivative, then it is advantageous to perform the reaction in a hydrocarbon, e.g. in benzene or toluene.
• Initial compounds are 1-0-chloro-10,11-dihydro-dibenzo[b,f]thiepins, which are substituted in the 8-position by the radical X.--
• Such compounds are reactive esters of hydroxy compounds of the general Formula IV of the second processv (as defined below). They are condensed with the l-piperazine carboxylic acid ethyl ester in benzene to give the corresponding 4-(10,1l-dihydrodibenzo[b,f]thiepin-l0-yl)-l-piperazine carboxylic acid ethyl esters, which are hydrolyzed with potassium hydroxide in ethanol and simultaneously decarboxylated.
• the 1-piperazinyl)-10,1 1-dihydro-dibenzo[b,f] thiepin is described in the literature.
• the second reaction component of the process according to the invention are the reactive esters of compounds of the general Formula III.
• the 1- (2-chloro-ethyl)-and 1-(3-chloro-propyl) 3-methyl-2- imidazolidinone and as well as the 1-(2-chloro-ethyl)- 3-butyl-2-imidazolidinone are for example known. Further compounds of this type can be obtained analogously.
• Suitable reactive esters of compounds of the general Formula IV are, e.g. halides such as chlorides or bro-. mides, also sulphonic acid esters, such as the methane sulphonic acid ester or the 0- or p-toluene sulphonic acid ester.
• Suitable as alkali metal derivatives of compounds of the general Formula V are, e.g. sodium, potassium or lithium derivatives.
• the reaction, according to the invention, of the free bases or of their alkali metal derivatives with the re active esters, can be performed in the same solvents as in the case of the first process. If the free bases are used for the reaction, then the same acid binding agents can also be used.
• reactive esters of compounds of the general Formula IV e.g. the 10-chloro-10,1l-dihydrodibenzo[b,f]thiepin, the 8-chloro-, 8-methyl-, S-methylthioor the 8-methoxy-10-chloro-10,1l-dihydro-dibenzo [b,f]thiepin, are described in US. Pat. No. 3,351,599.
• the 1-[2-(l-piperazinyl)-ethyl]-3-rnethyl- 2-imidazolidinone, the 1- [3- l-piperazinyl -propyl] -3- methyLZ-imidazolidinone, as Well as the corresponding 3-ethyl compounds, are for example known as examples of compounds of the general Formula V. Further compounds of this type can be obtained analogously.
• the compounds of the general Formula I obtained using the process according to the invention are then optionally converted in the usual manner into their addition salts with inorganic and organic acids.
• a solution of a compound of the general Formula I in an organic solvent is mixed with the acid desired as the salt component, or with a solution thereof.
• organic solvents, in which the formed salt has low solubility are chosen for the reaction, so that the salt can be separated by filtration.
• solvents are, e.g. methanol, acetone, methyl-ethyl ketone, acetone/ ethanol, methanol/ether or ethanol/ether.
• salts with acids for use as medicaments, pharmaceutically acceptable acid addition salts can be used in place of free bases, i.e. salts with acids, the anions of which are not toxic in the case of the dosages in question. It is moreover of advantage if the salts to be used as medicaments crystallise well and are not, or only slightly, hygroscopic.
• salt formation with compounds of the general Formula I it is possible to use, e.g.
• hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, ,B-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, furnaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic acid, mandelic acid and embonic acid.
• the new active substances are administered orally, rectally or parenterally.
• the dosage depends on the manner of administration, on the age of the individuum and on the particular condition to 'be treated.
• 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, or of a pharmaceutically acceptable salt thereof.
• Dosage units for oral administration preferably contain as active substance between l% of a compound of the general Formula I or of a pharmaceutically acceptable salt thereof. They are produced by combining the active substance with, e.g. 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 latter are coated, e.g. with concentrated sugar solutions,
• Dyestuffs can be added to these coatings, eg. to distinguish between varying dosages of active substance.
• suitable dosage units for oral administration are hard capsules made of gelatine as well as soft, closed capsules made of gelatine and a softener such as glycerin.
• the hard capsules preferably contain the active substance as a granulate, eg in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilisers, such as sodium metabisulphite (Na S O or ascorbic acid.
• the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, to which stabilisers can also be added.
• dosage units for rectal administration are suppositories which consist of a combination of an active substance or a suitable salt thereof with a fatt foundation, or also gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with polyethylene glycol.
• Ampoules for parenteral, particularly intramuscular, administration preferably contain a water soluble salt of an active substance in a concentration of, preferably, 0.55%, in aqueous solution, optionally together with suitable stabilising agents and butter substances.
• EXAMPLE 1 (a) 8.5 g. of 8-chloro-10-( 1-piperazinyl)-10,1l-dihydrodibenzo[b,f]thiepin are dissolved in 100 ml. of anhydrous acetone. 7.0 g. of potassium carbonate are added to this solution, the mixture heated to boiling and within one hour a solution of 5.0 g. of 1-(2-chloro-ethyl)-3- methyl-2-imidazolidinone in 50 ml. of anhydrous acetone is added dropwise. The reaction mixture is refluxed, while stirring, for 12 hours, then cooled and filtered. The precipitate is washed with acetone and the combined acetone solutions are completely concentrated by evaporation.
• the dihydrochloride is produced by dissolving 9.1 g. (0.02 mol) of the obtained base in a mixture of 10 ml. of benzene and 100 ml. of acetone and mixing the solution with ethereal hydrochloric acid until an acid reaction is obtained on congo paper. Following the addition of 100 ml. of ether, the precipitated dihydrochloride is filtered off, washed with acetone and ether and dried in vacuo.
• EXAMPLE 2 I (a) 4.5 g. of 1-[2-(l-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone in 50 ml. of anhydrous acetone are added dropwise, while stirring, to a solution of 5.8 g. of 8,10- dichloro-10,l1-dihydrodibenzo[b,f]thiepin and 2.3 g. of N,N-diisopropyl-ethyl-amine in 50 ml. of absolute benzene at 10-15. The reaction mixture is refluxed, while further stirring, for 12 hours, then cooled to room temperature and mixed with water.
• the benzene solution is separated, thoroughly washed with water and is extracted four times with 2 N phosphoric acid solution.
• the clear, acid extract is made alkaline with concentrated ammonia, whereby the free base precipitates. It is separated and crystallised from benzene ether.
• the obtained l-[2-[4-(8-chloro-10,1l-dihydro dibenzo[b,f]thiepin 10 yl) 1 piperaziny1]- ethyl1-3-methyl-2-imidazolidinone melts at l24-l26.
• the organic layer is separated, washed with water and shaken out with 50 ml. of l-molar aqueous methane sulphonic acid solution.
• the acid aqueous extract is then made alkaline with 10 ml. of concentrated sodium hydroxide solution and shaken out with ether/methylene chloride (2: 1).
• the organic extracts are then washed with water, dried over magnesium sulphate and the solvent removed under vacuum.
• the obtained crude base is taken up in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid. After filtration, the dihydrochloride is washed with acetone/ether and dried in vacuo.
• EXAMPLE 3 17.1 g. (0.062 mol) of 8-methoxy-lO-chloro-l0,11-dihydrodibenzo[b,f]thiepin are dissolved in ml. of methyl-ethyl ketone and 1.0 g. of pulverised potassium iodide, 5.0 g. (0.03 mol) of potassium carbonate, 14.4 g. (0.068 mol) of 1-[2-(l-piperazinyl)-ethyl]-3-methyl-2- imidazolidinone are added. The mixture is refluxed for 24 hours.
• the acid aqueous solution is subsequently cooled to 20. It is made alkaline with concentrated ammonia and the free, precipitated base extracted with acetic acid ethyl ester. The organic extract is dried over calcium chloride and is concentrated by evaporation in vacuo, whereby a light-orange resin is obtained, which crystallises.
• the crude product is recrystallised from acetonitrile, whereupon the 1-[2-[4-(8-methoxy-10,11-dihydro-dibenzo[b,f] thiepin 10 yl) 1 piperazinyl] ethyl] 3 methyl 2- imidazolidinone is obtained, which melts at 125.5127.5.
• the obtained base is dissolved in methyl-ethyl ketone and ethanolic hydrochloric acid is added until an acid reaction is shown on congo paper, whereupon the dihydrochloride precipitates.
• EXAMPLE 4 10.0 g. (0.034 mol) of 8-methylthio-10-chloro-l0,11- dihydro-dibenzo[b,f] thiepin are dissolved in 75 ml. of absolute benzene and 14.4 g. (0.068 mol) of 1-[2-(1- piperazinyl)-ethyl]-3-methyl-2-imidazolidinone are added dropwise at to this solution. The reaction mixture is refluxed for 16 hours and washed with a mixture of 5 ml. of 2 N sodium hydroxide solution and 100 ml. of water. The organic phase is then extracted with 100 ml. of molar citric acid.
• the crude free base is precipitated with sodium hydroxide solution from the acid extract and is extracted with ether/methylene chloride (2:1).
• the ether/ methylene chloride solution is dried over magnesium sulphate and concentrated by evaporation.
• the residue is dissolved in 50 ml. of acetone, the solution diluted with 350 ml. of ether and mixed with ethereal hydrochloric acid until an acid reaction is obtained on congo paper.
• the precipitated dihydrochloride is washed with ether and dried in vacuo.
• EXAMPLE 5 14.0 g. (0.05 mol) of 8,l0-dichloro-10,ll-dihydro-dibenzo[b,f]thiepin and 22.6 g. (0.1 mol) of 1-[3-(1-piperazinyl)-propyl]-3-methyl-Z-imidazolidinone are dissolved in 100 ml. of absolute toluene and the mixture is refluxed for hours. The reaction mixture is then mixed with 100 ml. of water and 10 ml. of 2 N sodium hydroxide solution, well shaken and the organic phase is separated. The organic phase is washed five times with 200 ml.
• EXAMPLE 6 16.5 g. (0.05 mol) of 8-chloro-10-(l-piperazinyD-IO, 11-dihydro-dibenzo[b,f]thiepin, 10.6 g. (0.0 6 mol) of 1- (3-chloropropyl)-3-methyI-Z-imidazolidinone and 13.8 g. of potassium carbonate in 1 00 ml. of diethyl ketone are refluxed for 36 hours. The reaction mixture is poured on to 300 ml. of ice water and mixed with 50 ml. of 2 N sodium hydroxide solution.
• the organic layer is separated and the aqueous phase extracted with ether/ methylene chloride (2: 1).
• the combined organic extracts are washed with water and then extracted with a l-molar solution of methane sulphonic acid.
• the acid aqueous extracts are then made alkaline with concentrated sodium hydroxide solution and extracted with ether/ methylene chloride (2:1). After washing with water, the organic extracts are dried over magnesium sulphate and the solvents removed under vacuum.
• the free base may be converted in acetone by means of ethereal hydrochloric acid into the dihydrochloride, which melts at l79181 after recrystallising from ethanol/ethyl acetate.
• EXAMPLE 9 Analogously to Example 6, from 17.1 g. (0.05 mol) of S-rnethylthio l l-piperazinyl)-l0,1l-dihydro-dibenzo- [b,f]thiepin and 9.75 g. (0.06 mol) of 1-(2-chloro-ethyl)- 3-methyl-2-imidazolidinone is obtained the 1-[2-[4-(8- methylthio 10,11 dihydro-dibenzo[b,f]thiepin-l-O yl)-1- piperazinyl] ethyl]-3-methyl-2-imidazolidinone dihydrochloride, M.P. 212-214 (from 90% ethanol/ether).
• EXAMPLE l2 Analogously to Example 6, from 10.0 g. (0.03 mol) of 8-chloro-l0-(l-piperazinyl) 10,11 dihydro-dibenzo[b ,f] thiepin and 6.9 g. (0.036 mol) of 1-(3-chloro-propyD-3- ethyI-Z-imidazolidinone is obtained the 1-[3-[4-(8-chloro- 10,11 dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]- propyl]-3-ethyl-2-imidazolidinone-dihydrochloride, M.P. 183-186 (from ethanol/ether).
• EXAMPLE 13 Analogously to Example 6, from 12.1 g. (0.037 mol) of 8-methoxy-10-(l-piperazinyl) 10,11-dihydro-dibenzo [b,f]thiepin and 8.5 g. (0.048 mol) of 1-(3-chloro-propyl)-3-methyl-2-imidazolidinone is obtained the 1-[3-[4- (S-methoxy 10,11 dihydro-dibenzo[b,f]thiepin-10-yl)- 1 piperazinyH-propyl]-3-methyl-2-imidazolidinone-dihydrochloride, M.P. 195-l97 (from ethanol/ether).
• EXAMPLE 14 Analogously to Example 6, from 12.1 g. (0.037 mol) of 8-methoxy-10-(l-piperazinyl) 10,11 dihydrodibenzo [b,f]thiepin and 9.15 g. (0.048 mol) of 1-(3-chloro-propyl)-3-ethyl-2-imidazolidinone is obtained the 1-[3-[4-(8- methoxy 10,11 dihydro-dibenzo[b,f]thiepin-10-yl)-1- piperazinyl]-propyl] 3 ethyl-2-imidazolidinone-dihydrochloride, M.P. 190-192 (from ethanol/ether).
• EXAMPLE 15 Analogously to Example 6, from the 8-trifiuoromethyl- 10-( l-piperazinyl)-10,1 1-dihydro-dibenzo[b,f]thiepin and the 1-(2-chloro-ethyl)-3-methyl-2-imidazolidinone is obtained the 1-[2-[4-(8-trifluoromethyl-10,1l-dihydro-dibenzo[b,f]thiepin-10-yl) 1 piperazinyl]-ethyl]-3-methyl-2- imidazolidinone.
• EXAMPLE 16 250 g. of 1-[2-[4-(8-chloro-10,l1-di:hydro-dibenzoi[b ,f] thiepin-IO-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 moistened with an alcoholic solution of 10 g. of stearic acid and granulated through a sieve. After drying, g. of potato starch, 200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets, each weighing 100 mg. and each containing 25 mg. of active substance. Optionally, the tablets can be provided with grooves for more accurate adjustment of the dosage amount.
• a granulate is produced from 250 g. of 1-[3-[4-(8- chloro 10,1l-dihydro-dibenzo[b,f]thiepin-10-y1)-1-piperazinyl] propyl] -3-methyl-Z-imidazolidinone-dihydrochloride, 175.90 g. of lactose and the alcoholic solution of 10 got stearic acid. After drying, the granulate 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 and the mixture is pressed into 10,000 drage cores.
• EXAMPLE 18 To produce 1000 capsules each containing 25 mg. of active substance, 25 g. of 1-[2-[4-(8-methoxy-l0,11- dihydro-benzo[b,f] thiepin l yl)-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 is granulated through a suitable sieve (e.g. Sieve No. 111, Ph. Helv. V). The granulate is mixed with 10.0 g. of dried maize starch and 15.0 g. of talcum. The mixture is uniformly filled into 1000 hard gelatine capsules, size 1.
• a suitable sieve e.g. Sieve No. 111, Ph. Helv. V
• a suppository foundation is prepared from 2.5 g. of 1 [2 [4 (8 methylthio 10,11 dihydro-dibenzo [b,f] thiepin yl) 1 piperazinyl]-ethyl]-3-methyl-2-imidazolidinone and 167.5 g. of adeps solidus. From the mixture, 100 suppositories are filled, each containing 25 mg. of active substance.
• EXAMPLE 20 A solution of g. of-1-[2- [4-(8-chloro-10,1l-dihydrodibenzo [b,f]thiepin 10 yl) 1 piperazinyl] ethyl]-3- methyl-Z-imidazolidinone-dihydrochloride in one litre of water is filled into 1000 ampoules and sterilised. An ampoule contains a 2.5% solution of 25 mg. of active substance.
• R is lower alkyl of at most 4 carbon atoms
• n 2 or 3;

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• 1968
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• 1969
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