EP0000220A1 - Dihydrouraciles, procédé pour leur préparation et médicaments les contenant - Google Patents

Dihydrouraciles, procédé pour leur préparation et médicaments les contenant Download PDF

Info

Publication number
EP0000220A1
EP0000220A1 EP78200041A EP78200041A EP0000220A1 EP 0000220 A1 EP0000220 A1 EP 0000220A1 EP 78200041 A EP78200041 A EP 78200041A EP 78200041 A EP78200041 A EP 78200041A EP 0000220 A1 EP0000220 A1 EP 0000220A1
Authority
EP
European Patent Office
Prior art keywords
formula
hydrogen
compounds
compound
sheet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP78200041A
Other languages
German (de)
English (en)
Other versions
EP0000220B1 (fr
Inventor
Rolf-Ortwin Dr. Weber
Hiristo Anagnostopulos
Ulrich Dr. Gebert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Publication of EP0000220A1 publication Critical patent/EP0000220A1/fr
Application granted granted Critical
Publication of EP0000220B1 publication Critical patent/EP0000220B1/fr
Expired legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to novel hexahydropyrimidines including their salts, processes for their preparation and pharmaceutical t-hold these novel compounds as active ingredients, e n.
  • the invention thus relates to compounds of the formula. (I) including their acid addition salts with suitable inorganic and / or organic acids.
  • the compounds according to the invention exhibit antihistaminic activity, an increase in erythrocyte fluidity, in some cases also psychotropic activity, a weak bradykinin antagonism and hypotensive effects.
  • R 6 represents a 3-position CF 3 group
  • Suitable groupings are, for example, phenyl, 2-, 3- or 4-tolyl, 2,6- or 3,4-dimethylphenyl, 2-, 3- or 4-methoxyphenyl, naphthyl, fluorophenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl or diphenylmethyl.
  • Suitable groupings are, for example, 5,6- or 6,6-dimethyl-5,6-dihydrouracil-3-yl; 5,6- or 6,6-dimethyl-2-thio-5,6-dihydrouracil-3-yl; 1,6,6-trimethyl-2-thio-5,6-dihydrouracil-3-yl; 1,6,6-trimethyl-5,6-dihydrouracil-3-yl; 6-phenyl-5,6-dihydrouracil-3-yl; 6-methyl-5,6-dihydrouracil-3-yl and 5,6-dihydrouracil-3-yl.
  • Suitable bridge members Q are, in addition to a single bond, for example ethylene, propylene, butylene, pentylene, hexylene, 2-hydroxypropylene or butylene, where the radicals can also be branched with at least 3 carbon atoms, so that at least 2 carbon atoms in the Chain stand. Any OH groups should not be geminal to a nitrogen atom.
  • the invention also relates to a process for the preparation of the abovementioned compounds of the formula (I), which is characterized in that a compound of the formula (II) (see formula sheet) in which R 7 is hydrogen or alkyl having 1 to 4 C - Atoms means, with elimination of R 7 OH to the compound I cyclized or a compound of formula (III) (see formula sheet) with.
  • the cyclization can be carried out in various ways by conventional condensation methods. For example, it can be carried out in a suitable solvent and / or in the presence of mineral acids and / or by heating the reaction mixture obtained in the synthesis of compound II or the pure substance (II) isolated therefrom.
  • Compounds in which R 7 represents hydrogen can often be cyclized particularly well with the aid of mineral acids, such as sulfuric acid or hydrohalic acids, preferably hydrochloric acid or hydrobromic acid, in an alcohol such as methanol, ethanol, propanol or isopropanol.
  • the cyclization can, which is preferred, be achieved by heating the pure substances with elimination of water or without addition of solvent and acid by means of suitable dehydrating agents, such as acetyl chloride or acetic anhydride. It is advisable to work at the boiling point of the corresponding solvent or condensing agent.
  • suitable dehydrating agents such as acetyl chloride or acetic anhydride. It is advisable to work at the boiling point of the corresponding solvent or condensing agent.
  • the cyclization of compounds in which R 7 is alkyl is preferably in a suitable solvent and / or in the presence of mineral acids, e.g. B. the above acids and alcohols performed.
  • mineral acids e.g. B. the above acids and alcohols performed.
  • cyclization in solvents without the addition of mineral acids is particularly preferred.
  • This hydrolysis can advantageously be carried out in an aqueous or aqueous-acetone or aqueous-alcoholic medium, the alcohol advantageously having 1 to 3 carbon atoms.
  • the reaction of the halides of the formulas (IV) and (IVa) is advantageously carried out in solvents which are inert to the reaction participants under the reaction conditions, such as methylene chloride, chloroform, toluene or xylene, preferably in the presence of tertiary amines such as triethylamine, tributylamine or pyridine, or even only in the pure tertiary amines or in strongly polar aprotic solvents such as dimethylformamide, the mixture being expediently cooled at the beginning of the reaction and heated to the boil towards the end.
  • solvents which are inert to the reaction participants under the reaction conditions, such as methylene chloride, chloroform, toluene or xylene, preferably in the presence of tertiary amines such as triethylamine, tributylamine or pyridine, or even only in the pure tertiary amines or in strongly polar aprotic solvents such
  • Suitable starting materials of the formula (III) are, for example, 1-phenyl-4- (3-aminopropyl) piperazine, 1- (2-methylphenyl) and 1- (3-methylphenyl) -4- (3-aminopropyl) piperazine, 1- (2-methoxyphenyl) -, 1- (3-methoxyphenyl) - and 1- (4-methoxyphenyl) -4- (3-aminopropyl) piperazine, 1- (3,4-dimethylphenyl) - and 1 - (2,6-dimethylphenyl) -4- (3-aminopropyl) piperazine, 1- (3-trifluoromethylphenyl) -, 1- (1-maphtyl) - and 1- (4-fluorophenyl) -4- (3- aminopropyl) piperazine, 1-phenyl-4- (2-aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2-aminoe
  • Suitable 3-isocyanato- or isothiocyanatoalkane carboxylic acid esters of the formula (V) are, for example, 3-isocyanatoisovaleric acid methyl ester and ethyl ester, 3-isocyanatoisovaleric acid n-and isopropyl ester, the various 3-isocyanatoisovalerianic acid butyl ester, 3-isocyanatooisoisoisyl ester and 3-isothiothio-ethanoate ester - And isopropyl ester, the various 3-isothiocyanatoisovalerianklabutylester, 2-methyl-3-isocyanatobutterkladremethylester, 2-methyl-3-isothiocyanatobutterklad ester, 3-phenyl-3-isocyanatopropionic acid methyl ester and 3-isocyanatopropionic acid methyl
  • Suitable 3-aminoalkanecarboxylic acid derivatives of the formula (VIII) are, for example, those which correspond to the isocyanato compounds mentioned above and which contain an amino group in the 3-position instead of the isocyanato group, such as 3-aminoisovaleric acid methyl ester, 3-amino-2-methylbutyric acid methyl ester and 3 -Aminopropionic acid methyl ester, furthermore 3-methylaminoisovaleric acid methyl ester.
  • Procedure a) is advantageously carried out in solvents which are inert to the reactants, such as xylene, toluene, mesitylene, benzene, methylene chloride or chloroform, preferably at the boiling point of the solvent; however, the reaction can also be carried out at room temperature, the reaction mixture generally warming itself.
  • Process variant b) can in general be carried out particularly well in tetrahydrofuran at room temperature and advantageously as a one-pot process. After addition of compound VIII, the further reaction and cyclization described above is advantageously carried out at the boiling point of the reaction mixture.
  • Compounds of the formula (II) in which R 7 is hydrogen are preferably - after they have been isolated in pure form - cyclized by heating without solvent, advantageously at temperatures above 150 ° C., preferably at about 200 ° C. and under protective gas .
  • Physiologically compatible mineral or sulfonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and cyclohexylsulfarainic acid, are suitable for the preparation of the mono- or bisaddition compounds, which is carried out by the generally customary methods.
  • the stability of the compounds according to the invention allows the preparation of pharmaceutical preparations for oral, parenteral and rectal administration.
  • these preparations can be prepared by admixing suitable and compatible auxiliaries, such as starch, lactose, cellulose derivatives, stearic acid. or their salts, solvents, solubilizers, suppositories, carriers such as chlorides, phosphates and carbonates in the usual way to form powders, tablets, dragees, capsules, suppositories, solutions, pastes or suspensions.
  • suitable and compatible auxiliaries such as starch, lactose, cellulose derivatives, stearic acid. or their salts, solvents, solubilizers, suppositories, carriers such as chlorides, phosphates and carbonates in the usual way to form powders, tablets, dragees, capsules, suppositories, solutions, pastes or suspensions.
  • Administration of the pure substances in the form of microcapsules is also possible, as is
  • Your dosage can be in Henschen z. B. 0.1 to 50 mg, preferably 0.5 to 10 mg, in particular 0.5 to 3 mg per os per day and Hensch.
  • Test a Experimental arrangement according to Konzett and Rössler (Arch. Exp. Path. Pharmak. 195 (1940) 71): Albino guinea pigs from in-house breeding are anesthetized intraperitoneally (ip) with 1.25 g / kg urethane. The bronchial resistance is registered with the chest open via a recording device ("bronchotransducer") from Ugo Basile (Milan); the respiratory rate is kept constant by artificial ventilation with a frequency of 58 strokes / min, the inflation pressure is 9 cm H 2 O-pillar.
  • bronchotransducer Ugo Basile
  • serotonin as serotonin creatinine sulrate
  • KG body weight
  • the test substances are administered in a volume of 1 ml / kg NG either intravenously within 30 s 2 min before the generation of the serotonin spasm or intraduodenally or orally using a pharyngeal tube 15 min before the spasm.
  • the ED 50 corresponds to the dose; by which a serotonin spasm is inhibited by 50% 2 min after iv injection or 15 min after oral or intraduodenal administration of the preparation (see Table I).
  • Test b Serotonin antagonism on the isolated uterus of the rat according to Robert A. Turner: Screening Hethods in Pharmacology, Academic Press 1965 (New York and London): Female Sprague-Dawley rats weighing 180 to 240 g obtained to produce the oestrus 24 Hours before the uterus removal 2 mg / kg oestromon (Merck, Darmstadt) intraperitoneally.
  • the organ bath kept at 22 ° C, contains a Tyrode solution with a specific composition.
  • the preparation is applied to the bath in aqueous solution with a total volume of 0.1 ml.
  • the administered scrotonin concentration is 10 -8 g / ml bath.
  • the EC 50 corresponds to the dose by which a serotonin spasm is inhibited by 50% (see Table 1).
  • Test c 5-hydroxy-L-tryptophan antagonism in the mouse:.
  • a single administration of 5-hydroxy-L-tryptophan causes a strong increase in defecation in mice due to the increased biosynthesis of serotonin from the exogenously supplied amino acid. This defecation effect can be reduced by serotonin antagonists.
  • the test substances are administered orally 45 minutes before the tryptophan is administered.
  • the tryptophan dose is 40 mg / kg i.p ..
  • the assessment is made 1 hour after administration of the preparation by measuring the amount of faeces excreted. A reduction of this amount by ⁇ 25% of the empty control is given depending on the result with 0 or (+), from 25 to 50% with +, from 50 to 75% with ++ and> 75% with +++ (see Table I ):
  • platelet-rich plasma from beagle dogs
  • platelet aggregation is experimentally induced by 5 in vitro administration of adenosine diphosphate (ADP) at a final concentration of 2.5 ⁇ 10 -6 g / ml, which is carried out with the aid of a universal aggregometer from B. Braun / Melsungen is measured.
  • An Ependorf photometer registers the change in the optical density of the plasma.
  • mice and rats in intraperitoneal and intravenous administration via the mortality occurring within 7 days as the LD 50 or ID 50 range is given.
  • the compounds according to the invention are largely superior to the comparative preparation Pizotifen-HCl.
  • animal experiments have shown further advantages over Pizotifen-HCl in such a way that a) the effect occurs much faster, b) no sedation is caused in the therapeutic dose range and c) no undesired appetite stimulation is caused.
  • a particular application of the compounds according to formula (I) according to the invention and their salts is in the combination with other suitable active ingredients, such as analgesics, ergotamine preparations, other serotonin antagonists, spasmolytics, vasodilatants, ⁇ -sympatholytics, antemetics, antihistamines, sedatives, tranquillizers, caffeine , Nicotinic acid derivatives, vitamins and estrogenic.
  • suitable active ingredients such as analgesics, ergotamine preparations, other serotonin antagonists, spasmolytics, vasodilatants, ⁇ -sympatholytics, antemetics, antihistamines, sedatives, tranquillizers, caffeine , Nicotinic acid derivatives, vitamins and estrogenic.
  • the base is dissolved in acetone and the equimolar amount of N hydrochloric acid is added.
  • the solvent is removed under reduced pressure at a maximum of 30 ° C. and the residue is recrystallized from dioxane, whereby the intermediate 3- [3- (3- ⁇ 4-phenyl-1-piperazinyl> -propyl) -ureido] -isovaleric acid methyl ester- receives hydrochloride in pure form. Yield quantitative; Melting range 168 to 170 ° C; C 20 H 33 ClN 4 O 3 ; Molecular weight 412.96.
  • the compound is dissolved in about 10 times the amount of 12% hydrochloric acid and boiled under reflux for two hours, about half of the solvent being distilled off under normal pressure within the last hour. Nan evaporates under reduced pressure, dissolves the residue in water and adds an excess of aqueous sodium hydroxide solution. The precipitated Ease is taken up in methylene chloride, dried over sodium sulfate and, after evaporation, recrystallized from a mixture of methanol and diisopropyl ether. Melting range 135 to 136 ° C.
  • the cyclization can also be carried out by mixing 5.65 g (0.015 mol) of 3 [3- (3- ⁇ 4-phenyl-1-piperazinyl) propyl) -ureido] isovaleric acid methyl ester under a nitrogen atmosphere for about 1.5 hours to 200 ° C heated. The course of the cyclization is monitored by thin-layer chromatography. When the reaction is complete, the solidified melt is rubbed with diisopropyl ether, purified on a chromatography column and recrystallized from methanol-diisopropyl ether. Yield: 2.5 g (48% of theory); Melting range: 134 to 136 ° C.
  • the base is dissolved in methanol and the calculated amount of N hydrochloric acid is added. After evaporation under reduced pressure, the residue is recrystallized from methanol or water. Melting range 236 to 242 ° C; Molecular formula C 19 H 29 ClN 4 O 2 ; Molecular weight: 380.92.
  • a solution of 21.9 g (0.1 mol) of 1-phenyl-4- (3-aninopropyl) piperazine in 100 ml of toluene is, according to procedure a), with stirring, with a mixture of 15.7 g (0.1 mol ) 3-Isocyanatoisovalerianklaremethylester and 100 ml of toluene added.
  • the mixture is briefly heated to boiling, cooled to room temperature, evaporated to dryness and the residue is dissolved in about 1 liter of acetone. After adding 100 ml (0.1 mol) of sodium hydroxide solution, the reaction mixture is stirred for about 20 hours at room temperature.
  • the intermediate product thus obtained is heated to 180-200 ° C. for about 1 hour. After cooling, the solidified base is purified by column chromatography and recrystallized from a mixture of methanol and diisopropyl ether. Melting range: 135 - 136 ° C
  • the cyclization of the open-chain carboxylic acid to the corresponding 5,6-dihydrouracil can be carried out by heating in aqueous-alcoholic hydrochloric acid, acetyl chloride or acetic anhydride for two hours. After removing the corresponding condensing agent (dehydrating agent) under reduced pressure, the residue is dissolved in water and excess potassium hydroxide solution is added. The precipitated base is taken up in methylene chloride, dried over sodium sulfate and, if necessary, purified by column chromatography after evaporation of the extractant.
  • the compound can then be converted into the desired salts in accordance with the usual method a.
  • the evaporation residue is on a silica gel 60 column
  • a solution of 25.8 g (0.145 mol) of N, N'-thiocarbonyl-di-imidazole in 500 ml of anhydrous tetrahydrofuran is, according to process variant b), 29.8 g (0.145 mol) of 1-phenyl-4- (2-aminoethyl) -piperazine in 125 ml of anhydrous tetrahydrofuran added dropwise within 90 minutes with stirring. The mixture is stirred for 90 minutes and then 24.3 g (0.145 mol) of anhydrous methyl 3-aminoisovaleric acid hydrochloride are also added with stirring. The clear solution is refluxed for 120 minutes.
  • the base is dissolved in methylene chloride and an excess of ethanolic hydrochloric acid is added. After adding diethyl ether, a colorless crystalline substance is obtained which is recrystallized twice from ethanol and which is the manohydrochloride.
  • the pH of a 0.1% solution is 4.3. Melting range 239 to 240 ° C; Molecular formula: C 18 H 27 ClN 4 OS; Molecular weight: 382.95.
  • the base is dissolved in a little water-containing methanol and an excess of alcoholic hydrochloric acid is added. After precipitation with diethyl ether, the desired compound is obtained, which is freed from adhering hydrochloric acid under reduced pressure at room temperature and dried over calcium chloride.
  • the pH of a 10% aqueous solution is 1.8. Melting range: 238 to 247 ° C with decomposition; Molecular formula C 18 H 30 Cl 2 N 4 O 2 S; Molecular weight 437.42
  • the base is dissolved in acetone and the equivalent amount of N hydrochloric acid is added. After evaporation under reduced pressure, the crystalline residue from methanol is reprecipitated with diethyl ether. The pH of a 0.1% solution is 3.0.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP78200041A 1977-06-18 1978-06-14 Dihydrouraciles, procédé pour leur préparation et médicaments les contenant Expired EP0000220B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2727469 1977-06-18
DE19772727469 DE2727469A1 (de) 1977-06-18 1977-06-18 Neue hexahydropyrimidine, verfahren zu ihrer herstellung und arzneimittel, die diese verbindungen enthalten

Publications (2)

Publication Number Publication Date
EP0000220A1 true EP0000220A1 (fr) 1979-01-10
EP0000220B1 EP0000220B1 (fr) 1981-04-29

Family

ID=6011783

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78200041A Expired EP0000220B1 (fr) 1977-06-18 1978-06-14 Dihydrouraciles, procédé pour leur préparation et médicaments les contenant

Country Status (14)

Country Link
US (1) US4216216A (fr)
EP (1) EP0000220B1 (fr)
JP (1) JPS549287A (fr)
AT (1) AT358597B (fr)
AU (1) AU3678878A (fr)
CA (1) CA1085396A (fr)
DE (2) DE2727469A1 (fr)
DK (1) DK272778A (fr)
ES (1) ES470727A1 (fr)
IE (1) IE47103B1 (fr)
IL (1) IL54916A0 (fr)
IT (1) IT1099556B (fr)
NO (1) NO782108L (fr)
ZA (1) ZA783465B (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0047990A1 (fr) * 1980-09-17 1982-03-24 Yoshitomi Pharmaceutical Industries, Ltd. Dérivés d'hydrouraciles
EP0236931A2 (fr) * 1986-03-05 1987-09-16 Merrell Dow Pharmaceuticals Inc. Dérivés aromatiques d'oméga-alkylimino-tétrahydro-6H-1,3-thiazin-6-one
EP0238905A2 (fr) * 1986-03-05 1987-09-30 Merrell Dow Pharmaceuticals Inc. Dérivés de carbonyle hétérocycliques substitués par un groupe 4-(2-pyrimidyl)-1-pipérazinyle
GB2230780A (en) * 1989-04-22 1990-10-31 American Home Prod Tertiary alkyl functionalised piperazine derivatives
FR2655988A1 (fr) * 1989-12-20 1991-06-21 Adir Nouveaux derives de la napht-1-yl piperazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
EP0748800A2 (fr) * 1995-06-09 1996-12-18 F. Hoffmann-La Roche Ag Dérivés de pyrimidine dione, pyrimidine trione, triazine dione, tetrahydroquinazoline dione comme antagonistes des récepteurs alpha-1-adrénergiques
US5859014A (en) * 1995-06-09 1999-01-12 Syntex (U.S.A.) Inc. Pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives as α1 -adrenergic receptor antagonists
WO2000005205A1 (fr) * 1998-07-21 2000-02-03 Ranbaxy Laboratories Limited Derives d'arylpiperazine utilises comme agents bloquants les recepteurs alpha1-adrenergiques uroselectifs
WO2000005206A1 (fr) * 1998-07-21 2000-02-03 Ranbaxy Laboratories Limited Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs
US7309559B2 (en) 2000-09-27 2007-12-18 Hitachi Chemical Co., Ltd. Resist pattern, process for producing same, and utilization thereof
US7611818B2 (en) 2003-11-19 2009-11-03 Hitachi Chemical Company, Ltd. Photosensitive resin composition, photosensitive element, resist pattern forming method and process for manufacturing printed circuit board
WO2010073221A2 (fr) 2008-12-23 2010-07-01 Texnology S.R.L. Dispositif de traitement de voile de fibre

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4367335A (en) * 1981-08-03 1983-01-04 Mead Johnson & Company Thiazolidinylalkylene piperazine derivatives
US4579947A (en) * 1983-06-16 1986-04-01 Boehringer Ingelheim Pharmaceuticals, Inc. Substituted phenylalkylpiperazinylpropyl (ureas or thioureas) useful for treatment of immunological, inflammatory and allergic disorder
US4668687A (en) * 1984-07-23 1987-05-26 Bristol-Myers Company Psychogeriatric 1-(2-pyrimidinyl)piperazinyl derivatives of 1-pyrrolidin-2-ones
DK148392D0 (da) * 1992-12-09 1992-12-09 Lundbeck & Co As H Heterocykliske forbindelser
US6083950A (en) * 1997-11-13 2000-07-04 Ranbaxy Laboratories Limited 1-(4-arylpiperazin-1-yl)-ω-[n-(α,ω-dicarboximido)]-alka nes useful as uro-selective α1-adrenoceptor blockers

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2242382A1 (de) * 1971-09-04 1973-03-15 Pfizer Neue piperazinverbindungen

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2672460A (en) * 1952-06-24 1954-03-16 American Cyanamid Co Disubstituted piperazines and methods of preparing the same
US3406023A (en) * 1966-10-31 1968-10-15 Du Pont Herbicidal method
US3726979A (en) * 1971-04-09 1973-04-10 E Hong Method of producing serotonin antagonism
US4100282A (en) * 1972-12-23 1978-07-11 Boehringer Ingelheim Gmbh N-Aryl-N'-(phenyl- or phenoxy-alkyl)-piperazines and salts thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2242382A1 (de) * 1971-09-04 1973-03-15 Pfizer Neue piperazinverbindungen

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0047990A1 (fr) * 1980-09-17 1982-03-24 Yoshitomi Pharmaceutical Industries, Ltd. Dérivés d'hydrouraciles
EP0236931A2 (fr) * 1986-03-05 1987-09-16 Merrell Dow Pharmaceuticals Inc. Dérivés aromatiques d'oméga-alkylimino-tétrahydro-6H-1,3-thiazin-6-one
EP0238905A2 (fr) * 1986-03-05 1987-09-30 Merrell Dow Pharmaceuticals Inc. Dérivés de carbonyle hétérocycliques substitués par un groupe 4-(2-pyrimidyl)-1-pipérazinyle
EP0238905A3 (en) * 1986-03-05 1989-08-09 Merrell Dow Pharmaceuticals Inc. 4-(2-pyrimidinyl)-1-piperazinyl heterocyclic carbonyl derivatives
EP0236931A3 (en) * 1986-03-05 1990-01-17 Merrell Dow Pharmaceuticals Inc. Aromatic omega-alkylimino-tetrahydro-6h-1,3-thiazin-6-one derivatives
GB2230780A (en) * 1989-04-22 1990-10-31 American Home Prod Tertiary alkyl functionalised piperazine derivatives
GB2230780B (en) * 1989-04-22 1992-10-21 American Home Prod Tertiary alkyl functionalized piperazine derivatives
EP0434561A3 (en) * 1989-12-20 1991-09-18 Adir Et Compagnie 1-naphthyl-piperazine derivatives, process for their preparation and pharmaceutical compositions containing them
EP0434561A2 (fr) * 1989-12-20 1991-06-26 Adir Et Compagnie Dérivés de la napht-1-yl pipérazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
FR2655988A1 (fr) * 1989-12-20 1991-06-21 Adir Nouveaux derives de la napht-1-yl piperazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
EP0748800A2 (fr) * 1995-06-09 1996-12-18 F. Hoffmann-La Roche Ag Dérivés de pyrimidine dione, pyrimidine trione, triazine dione, tetrahydroquinazoline dione comme antagonistes des récepteurs alpha-1-adrénergiques
EP0748800A3 (fr) * 1995-06-09 1996-12-27 F. Hoffmann-La Roche Ag Dérivés de pyrimidine dione, pyrimidine trione, triazine dione, tetrahydroquinazoline dione comme antagonistes des récepteurs alpha-1-adrénergiques
US5859014A (en) * 1995-06-09 1999-01-12 Syntex (U.S.A.) Inc. Pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives as α1 -adrenergic receptor antagonists
WO2000005205A1 (fr) * 1998-07-21 2000-02-03 Ranbaxy Laboratories Limited Derives d'arylpiperazine utilises comme agents bloquants les recepteurs alpha1-adrenergiques uroselectifs
WO2000005206A1 (fr) * 1998-07-21 2000-02-03 Ranbaxy Laboratories Limited Derives d'arylpiperazine utiles comme agents bloquants de recepteurs alpha 1-adrenergiques uroselectifs
US7309559B2 (en) 2000-09-27 2007-12-18 Hitachi Chemical Co., Ltd. Resist pattern, process for producing same, and utilization thereof
US7611818B2 (en) 2003-11-19 2009-11-03 Hitachi Chemical Company, Ltd. Photosensitive resin composition, photosensitive element, resist pattern forming method and process for manufacturing printed circuit board
WO2010073221A2 (fr) 2008-12-23 2010-07-01 Texnology S.R.L. Dispositif de traitement de voile de fibre

Also Published As

Publication number Publication date
ES470727A1 (es) 1979-01-16
DE2727469A1 (de) 1978-12-21
AT358597B (de) 1980-09-25
US4216216A (en) 1980-08-05
IE47103B1 (en) 1983-12-28
ZA783465B (en) 1979-07-25
IE781066L (en) 1978-12-18
AU3678878A (en) 1979-12-06
IT1099556B (it) 1985-09-18
DE2860637D1 (en) 1981-08-06
IL54916A0 (en) 1978-08-31
NO782108L (no) 1978-12-19
DK272778A (da) 1978-12-19
JPS566420B2 (fr) 1981-02-10
ATA441278A (de) 1980-02-15
CA1085396A (fr) 1980-09-09
IT7824660A0 (it) 1978-06-16
EP0000220B1 (fr) 1981-04-29
JPS549287A (en) 1979-01-24

Similar Documents

Publication Publication Date Title
DE2614406C2 (fr)
DE1695556C3 (de) 3-Alkyl-1,2,3,4,4a,9-hexahydropyrazino[1,2-f]morphanthridinderivate
EP0000220B1 (fr) Dihydrouraciles, procédé pour leur préparation et médicaments les contenant
CH405314A (de) Verfahren zur Herstellung von Indolylverbindungen
EP0005828B1 (fr) Nouvelles dérivés de la phénylpipérazine substitués, médicaments les contenant et procédés pour leur préparation
EP0047923B1 (fr) Dérivés de l'isoquinoléine, leurs procédés de préparation et compositions pharmaceutiques les contenant
DE2651083C2 (fr)
EP0005232A1 (fr) Isoquinoléines, procédé pour leur préparation et compositions pharmaceutiques les contenant
CH643809A5 (de) Aminoalkohol-derivate.
EP0105210B1 (fr) Dérivés de l'isoquinoléine, leur procédé de préparation compositions pharmaceutiques les contenant et leur utilisation
DD145104B3 (de) Verfahren zur herstellung von polyalkoxyphenylpyrrolidone
EP0018360B1 (fr) N-(5-méthoxybenzofuran-2-ylcarbonyl)-N'-benzylpipérazine et procédé pour sa préparation
EP0064685A1 (fr) Dibenzo(de,g)quinolines, leurs procédés de préparation et les médicaments les contenant
DE3223877C2 (fr)
CH493467A (de) Verfahren zur Herstellung von Dibenzosuberenderivaten
EP0007525A1 (fr) Dérivés de la 2-(4-aminopipéridino)-3.4-dihydroquinoléine, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation
EP0096279A1 (fr) N-(2-méthoxyéthyl)-noroxymorphone, ses sels acides d'addition, des médicaments la contenant et un procédé pour sa préparation
DE2247374A1 (de) Substituierte isochinoline und verfahren zu deren herstellung
EP0029992A1 (fr) Dérivés d'aminopropanol, procédé pour leur préparation et compositions pharmaceutiques contenant ces composés
EP0003298A2 (fr) Dérivés de 4-hydroxy-2-benzimidazoline-thione, leur procédé de préparation et compositions pharmaceutiques les contenant
AT355581B (de) Verfahren zur herstellung neuer pyrido- benzodiazepinone und ihrer salze
DE2508251A1 (de) Neue derivate des indols, verfahren zu deren herstellung sowie diese enthaltende arzneimittel
DE2345422A1 (de) Neue substituierte arylpiperazine, deren saeureadditionssalze, diese enthaltende arzneimittel sowie verfahren zu deren herstellung
DE1962149A1 (de) Organische Verbindungen und Verfahren zu ihrer Herstellung
DE2626677A1 (de) 2-substituierte-9-phenyl-2,3,4,4a, 9,9a-hexahydro-1h-indeno eckige klammer auf 2,1-c eckige klammer zu pyridine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): BE CH DE FR GB LU NL SE

17P Request for examination filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): BE CH DE FR GB LU NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19810630

REF Corresponds to:

Ref document number: 2860637

Country of ref document: DE

Date of ref document: 19810806

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19830525

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19840514

Year of fee payment: 7

Ref country code: CH

Payment date: 19840514

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19840515

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19840630

Year of fee payment: 7

Ref country code: BE

Payment date: 19840630

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19840713

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19850615

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19850630

Ref country code: BE

Effective date: 19850630

BERE Be: lapsed

Owner name: HOECHST A.G.

Effective date: 19850614

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19860101

GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19860228

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19860301

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881117

EUG Se: european patent has lapsed

Ref document number: 78200041.8

Effective date: 19860728

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT