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

(1-(4-(3-(p-fluorobenzoyl)-propyl)-1-piperazinyl)-alkyl)-3-alkyl-2-imidazolidinones Download PDF

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US3812126A
US3812126A US00203870A US20387071A US3812126A US 3812126 A US3812126 A US 3812126A US 00203870 A US00203870 A US 00203870A US 20387071 A US20387071 A US 20387071A US 3812126 A US3812126 A US 3812126A
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imidazolidinone
ethyl
acid
piperazinyl
propyl
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L Gysin
A Zuest
W Schindler
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • 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
  • R represents hydrogen, or an alkyl group having 1 to 4 carbon atoms
  • alkylene radicals having 2 to 3 carbon atoms in the compounds of formula I 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • alkali metal amides are used sodium and lithium amide
  • alkali metal hydrides is used sodium hydride
  • 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.
  • 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:
  • Suitable reactive esters of the compounds of the formula IV are, e.g. halides such as chlorides or bromides,
  • sulphonic acid esters e.g. the methanesulphonic acid ester or the 0- or p-toluene-sulphonic acid ester.
  • 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.
  • one molecular equivalent of free base 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
  • alkali metal 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.
  • the second reaction component of the process according to the invention is the reactive esters of compounds of the formula IV.
  • 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.
  • R represents an alkyl group having 1 to 4 carbon atoms
  • R represents hydrogen or an alkyl group having 1 to 4 carbon atoms
  • Y represents halogen
  • 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.
  • 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.
  • alkali metal derivatives can be obtained analogously to the alkali metal derivatives of the first 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.
  • 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.
  • MgHal magnesium halide radical
  • ZnHal zinc halide radical
  • metal-organic cadmium radical metal-organic cadmium radical
  • the halides used in the process are preferably chlorides, bromides or iodides.
  • X is e.g. the group VIII:
  • 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.
  • 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.
  • 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.
  • 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.
  • organic solvents in which the formed salt is difficultly soluble, so that it can be separated by filtration.
  • solvents are, e.g. methanol, acetone, methyl ethyl ketone, acetone/ether, acetone/ethanol, methanol/ether or ethanol ether.
  • salts 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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;
  • EXAMPLE 3 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.
  • 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:
  • 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.
  • 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 s
  • 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:
  • 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.
  • 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'mobenzene is 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.
  • 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 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.
  • I EXAM LE (a Anamount' of 175 (0.1 mole) feri e ql d em 2: 9 ,a abe la a thereof.
  • a compound of the formula I R is an alkyl group having l'to "4 carbon atoms,
  • 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:
  • Ai' is an alkylene group having 2,to 4 carln'm atoms
  • Ri'ishydro gen' or an a ky group having 1 .4 9

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US00203870A 1970-12-07 1971-12-01 (1-(4-(3-(p-fluorobenzoyl)-propyl)-1-piperazinyl)-alkyl)-3-alkyl-2-imidazolidinones Expired - Lifetime US3812126A (en)

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US406041A US3890439A (en) 1970-12-07 1973-10-12 Imidazolidinone derivatives in the treatment of emesis and psychosomatic disturbances

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CH1813370 1970-12-07
CH1058173A CH542864A (de) 1970-12-07 1970-12-07 Verfahren zur Herstellung von neuen Imidazolidinonderivaten

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AT (3) AT309416B (enrdf_load_stackoverflow)
AU (1) AU3650971A (enrdf_load_stackoverflow)
BE (1) BE776277A (enrdf_load_stackoverflow)
CA (1) CA970374A (enrdf_load_stackoverflow)
CH (1) CH541568A (enrdf_load_stackoverflow)
DE (1) DE2158959A1 (enrdf_load_stackoverflow)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3903088A (en) * 1973-03-28 1975-09-02 Soc D Etudes Prod Chimique 4-{8 N-(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)-piperazino{9 -p-fluoro-butyrophenone
US3920636A (en) * 1972-10-30 1975-11-18 Eisai Co Ltd Quinazoline compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE789830A (fr) * 1971-10-09 1973-02-01 Asta Werke Ag Chem Fab Procede de preparation de nouveaux derives cycliques d'uree et de leurssels avec des acides pharmacologiquement acceptables

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920636A (en) * 1972-10-30 1975-11-18 Eisai Co Ltd Quinazoline compounds
US3903088A (en) * 1973-03-28 1975-09-02 Soc D Etudes Prod Chimique 4-{8 N-(2-methyl-3-hydroxy-4-hydroxymethyl-5-pyridylmethyl)-piperazino{9 -p-fluoro-butyrophenone

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FR2116561A1 (enrdf_load_stackoverflow) 1972-07-13
AT314532B (de) 1974-04-10
NL7116454A (enrdf_load_stackoverflow) 1972-06-09
GB1372558A (en) 1974-10-30
BE776277A (fr) 1972-06-06
CH541568A (de) 1973-10-31
FR2116561B1 (enrdf_load_stackoverflow) 1974-11-15
DE2158959A1 (de) 1972-06-15
AU3650971A (en) 1973-06-14
AT309416B (de) 1973-08-27
CA970374A (en) 1975-07-01
AT315165B (de) 1974-05-10

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