EP0000220B1 - Dihydrouraciles, procédé pour leur préparation et médicaments les contenant - Google Patents
Dihydrouraciles, procédé pour leur préparation et médicaments les contenant Download PDFInfo
- Publication number
- EP0000220B1 EP0000220B1 EP78200041A EP78200041A EP0000220B1 EP 0000220 B1 EP0000220 B1 EP 0000220B1 EP 78200041 A EP78200041 A EP 78200041A EP 78200041 A EP78200041 A EP 78200041A EP 0000220 B1 EP0000220 B1 EP 0000220B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- group
- phenyl
- dihydrouracil
- formula
- 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.)
- Expired
Links
- 0 C[C@@]1[C@@](C)[C@@](C*)CC1 Chemical compound C[C@@]1[C@@](C)[C@@](C*)CC1 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N CN1CCNCC1 Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- QBUNVSYIVJQMDN-UHFFFAOYSA-N CC(C(C)NC(N1C)=O)C1(C)O Chemical compound CC(C(C)NC(N1C)=O)C1(C)O QBUNVSYIVJQMDN-UHFFFAOYSA-N 0.000 description 1
- ASKXUTBRVBWPNL-UHFFFAOYSA-N CC1(CC2C=CC=CC2)C=CC=CC1 Chemical compound CC1(CC2C=CC=CC2)C=CC=CC1 ASKXUTBRVBWPNL-UHFFFAOYSA-N 0.000 description 1
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 dihydrouracils including their salts, processes for their preparation and medicaments which contain these compounds as active ingredients.
- Piperazine compounds are already known from German laid-open specification 2,242,382 which, in addition to a trifluoromethylphenyl group, can also carry a dihydrouracil radical. However, nothing is reported about their pharmacological effects.
- the analog succinimide compounds described there only have appetite-inhibiting properties. It was therefore not foreseeable that derivatives of such dihydrouracils which do not carry a trifluoromethyl group on the phenyl ring and which have alkyl substituents on the dihydrouracil ring show completely different pharmacological effects.
- the invention thus relates to compounds of the formula (I), including their addition salts, with physiologically tolerated 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 ' is methyl
- one of the radicals R 2 and R 3 is methyl and the other is hydrogen
- R 6 is hydrogen or fluorine in the 4-position, such as compounds Nos. 8, 10 and 14 to 16 of the Table IV.
- 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 or diphenylmethyl.
- Suitable groupings are, for example, 5,6- or 6,6-dimethyl-dihydrouracil-3-yl; 5,6- or 6,6-dimethyl-2-thio-dihydrouracil-3-yl; 1,6,6-trimethyl-2-thio-dihydrouracil-3-yl; 1,6,6-trimethyl-dihydrouracil-3-yl; 6-methyl-dihydrouracil-3-yl.
- Suitable bridge members Q are, for example, ethylene, propylene, butylene, pentylene, hexylene and 2-hydroxypropylene, it being possible for the radicals with at least 3 C atoms to be branched off, so that at least 2 C atoms are still in the chain.
- the invention also relates to a process for the preparation of dihydrouracils of the formula (1), in which a compound of the formula II in which R 1 to R 6 , A, Q, Z and X have the meanings given above and OR 7 is hydroxyl or an alkoxy group having 1 to 4 carbon atoms, cyclized with elimination of R 7 0H and, if desired, the compounds of the formula I. isolated as such or converted with acids into their physiologically acceptable acid addition salts.
- the cyclization of the compound II can be carried out in various ways by conventional condensation methods, especially in a suitable solvent and / or in the presence of mineral acids and / or by heating the reaction mixture obtained in the synthesis of the 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.
- the cyclization of compounds in which R 7 is alkyl is preferably carried out in a suitable solvent and / or in the presence of mineral acids, for example the abovementioned acids and alcohols.
- mineral acids for example the abovementioned acids and alcohols.
- X sulfur
- cyclization in solvents without the addition of mineral acids is particularly preferred.
- compounds of the formula II in which R 7 is alkyl having 1 to 4 carbon atoms first hydrolyzing with an alkali metal hydroxide to give a compound of the formula II in which R 7 is hydrogen, and then cyclizing it.
- This hydrolysis can advantageously be carried out in aqueous or aqueous-acetone or aqueous-alcoholic medium, the alcohol advantageously having 1 to 3 carbon atoms.
- 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-dimethylphenyl) - and 1- (2.6 -Dimethylphenyl) -4- (3-aminopropyl) piperazine, 1- (1-naphthyl) - and 1- (4-fluorine phenyl) -4- (3-aminopropyl) piperazine, 1-phenyl-4- (2-aminoethyl) piperazine, 1- (2-methoxyphenyl) -4- (2-aminoethyl) piperazine, 1- (4- Methoxyphen
- Suitable 3-isocyanato- or isothiocyanatoalkanecarboxylic acid esters of the formula (IV) are, for example, 3-isocyanato-isovaleric acid methyl ester and ethyl ester, 3-isocyanato-isovaleric acid n-and isopropyl ester, the various 3-isocyanato-isovaleric acid butyl ester, 3-isocyanato-isoisoisalerate ester, and isopropyl ester, the various 3-isothiocyanatoisovalerianklabutylester, 2-methyl-3-isocyanatobutterklad- and 2-methyl-3-isothiocyanatobutterklaklad.
- Suitable 3-aminoalkanecarboxylic acid derivatives of the formula (VII) 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 -Methylaminoisovalerianklaremethylester.
- the reactants such as xylene, toluene, mesitylene, benzene, methylene chloride or chloro
- Process variants b) and c) can generally be carried out at room temperature and expediently as a one-pot process.
- process (b) which proceeds particularly well in tetrahydrofuran, the further reaction and the cyclization described above are advantageously carried out at the boiling point of the reaction mixture after addition of compound VII.
- Compounds of formula II; in which R 7 is hydrogen are preferably - after they are isolated in pure form - cyclized by heating without solvent; and 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 cyclohexylsulfamic acid, are suitable for the preparation of the mono- or bisaddition salts, which is carried out by the generally customary methods.
- the stability of the compounds obtained according to the invention allows the preparation of pharmaceutical preparations for oral, parenteral and rectal administration.
- the preparation of these preparations can be made according to the usual practice by admixing suitable and compatible auxiliaries, such as starch, milk sugar, cellulose derivatives, stearic acid or its salts, solvents, solubilizers, suppository mass, carriers such as chlorides, phosphates and carbonates in the usual way to form powders, tablets, dragees , Capsules, suppositories, solutions, pastes or suspensions. It is also possible to administer the pure substances in the form of microcapsules and also to combine them with other active substances.
- Your dosage in humans is 0.1 to 50 mg, preferably 0.5 to 10 mg, in particular 0.5 to 3 mg per os per day.
- 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 check 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).
- mice and rats in intraperitoneal and intravenous administration via mortality occurring within 7 days as the LD 50 and LD 50 range are given in Table III.
- the compounds obtained according to the invention are largely superior to the comparative preparation Pizotifen-HCl.
- animal experiments have shown further advantages over Pizotifen-HCI in such a way that a) the effect occurs much faster, b) no sedation is caused in the therapeutic dose range and c) no unwanted appetite stimulation is caused.
- a particular application of the compounds of formula (1) and their salts obtained according to the invention 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 estrogens.
- suitable active ingredients such as analgesics, ergotamine preparations, other serotonin antagonists, spasmolytics, vasodilatants, ⁇ -sympatholytics, antemetics, antihistamines, sedatives, tranquillizers , Caffeine, nicotinic acid derivatives, vitamins and estrogens.
- the base is dissolved in acetone and the equimolar amount of 1N 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 - piperazino) - propyl) - ureidoJ - isovaleric acid methyl ester - hydrochloride in pure Takes shape. Yield quantitative; Melting range 168 to 170 ° C; C 20 H 33 CIN 4 0 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. It is evaporated under reduced pressure, the residue is dissolved in water and an excess of aqueous sodium hydroxide solution is added. The precipitated base 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-phenyt-piperazino) propyl) ureido] isovaleric acid methyl ester under a nitrogen atmosphere at 200 ° C. for 1.5 hours heated. The course of the cyclization is followed by thin layer chromatography. After the reaction has ended, 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 1N 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 CIN 4 0 2 ; Molecular weight: 380.92.
- a solution of 21.9 g (0.1 mol) of 1-phenyl-4- (3-aminopropyl) 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.
- 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 1N sodium hydroxide solution, the reaction mixture is stirred for 20 hours at room temperature.
- the intermediate product thus obtained is heated to 180-200 ° C for 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 to 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 evaporating the extractant.
- the compound can then be converted into the salts desired in each case by the customary methods.
- a solution of 25.8 g (0.145 mol) of N, N'-thiocarbonyldi-imidazole in 500 ml of anhydrous tetrahydrofuran is 29.8 g (0.145 mol) of 1-phenyl-4- (2-aminoethyl) piperazine drop in 125 ml of anhydrous tetrahydrofuran within 90 minutes with stirring added wisely.
- the mixture is stirred for 90 minutes and then 24.3 g (0.145) mol) of anhydrous 3-aminoisovaieric acid methyl) ester 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 monohydrochloride.
- the pH of a 0.1% aqueous solution is 4.3. Melting range 239 to 240 ° C; Molecular formula: C 18 H 27 CIN 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 CI 2 N 4 O 2 S; Molecular weight 437.42.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Claims (10)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19772727469 DE2727469A1 (de) | 1977-06-18 | 1977-06-18 | Neue hexahydropyrimidine, verfahren zu ihrer herstellung und arzneimittel, die diese verbindungen enthalten |
DE2727469 | 1977-06-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0000220A1 EP0000220A1 (fr) | 1979-01-10 |
EP0000220B1 true 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) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5753481A (en) * | 1980-09-17 | 1982-03-30 | Yoshitomi Pharmaceut Ind Ltd | 4-hydrouracil-piperidines |
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 |
AR242678A1 (es) * | 1986-03-05 | 1993-04-30 | Gonzalez Jorge Alberto | Mejoras en instrumentos musicales de cuerda de arco. |
ZA871449B (en) * | 1986-03-05 | 1987-08-20 | Merrell Dow Pharmaceutical Inc. | Aromatic omega-alkylimino-tetrahydro-6h-1,3-thiazin-6-one derivatives |
PT93824B (pt) * | 1989-04-22 | 1996-09-30 | Wyeth John & Brother Ltd | Processo para a preparacao de derivados de piperazina |
FR2655988B1 (fr) * | 1989-12-20 | 1994-05-20 | Adir Cie | Nouveaux derives de la napht-1-yl piperazine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
DK148392D0 (da) * | 1992-12-09 | 1992-12-09 | Lundbeck & Co As H | Heterocykliske forbindelser |
DK0748800T3 (da) * | 1995-06-09 | 2001-08-27 | Hoffmann La Roche | Pyrimidindion-, pyrimidintrion- og triazindionderivater som alfa-1-adrenergiske receptorantagonister |
US5859014A (en) * | 1995-06-09 | 1999-01-12 | Syntex (U.S.A.) Inc. | Pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives as α1 -adrenergic receptor antagonists |
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 |
MXPA01000637A (es) * | 1998-07-21 | 2002-04-08 | Ranbaxy Lab Ltd | Derivados de arilpiperazina utiles como bloqueadores uroselectivos de alfa 1-adrenoceptor. |
AU1979799A (en) * | 1998-07-21 | 2000-02-14 | Ranbaxy Laboratories Limited | Arylpiperazine derivatives useful as uro-selective alpha-1-adrenoceptor blockers |
WO2002027407A1 (fr) | 2000-09-27 | 2002-04-04 | Hitachi Chemical Co., Ltd. | Motif de reserve, procede de production et d'utilisation dudit motif |
JP4207044B2 (ja) | 2003-11-19 | 2009-01-14 | 日立化成工業株式会社 | 感光性エレメント、レジストパターンの形成方法及びプリント配線板の製造方法 |
IT1392408B1 (it) | 2008-12-23 | 2012-03-02 | Texnology S R L | Dispositivo di trattamento di un velo di carda |
Family Cites Families (5)
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 |
BE788280A (fr) * | 1971-09-04 | 1973-02-28 | Pfizer | Nouvelles 1-(3-trifluoro-methyl-phenyl)-4-((amido cyclique)- alkyl) piperazines et composition pharmaceutique les contenant |
US4100282A (en) * | 1972-12-23 | 1978-07-11 | Boehringer Ingelheim Gmbh | N-Aryl-N'-(phenyl- or phenoxy-alkyl)-piperazines and salts thereof |
-
1977
- 1977-06-18 DE DE19772727469 patent/DE2727469A1/de not_active Withdrawn
-
1978
- 1978-05-29 IE IE1066/78A patent/IE47103B1/en unknown
- 1978-05-31 CA CA304,474A patent/CA1085396A/fr not_active Expired
- 1978-06-01 AU AU36788/78A patent/AU3678878A/en active Pending
- 1978-06-13 ES ES470727A patent/ES470727A1/es not_active Expired
- 1978-06-14 DE DE7878200041T patent/DE2860637D1/de not_active Expired
- 1978-06-14 EP EP78200041A patent/EP0000220B1/fr not_active Expired
- 1978-06-15 US US05/915,899 patent/US4216216A/en not_active Expired - Lifetime
- 1978-06-15 IL IL7854916A patent/IL54916A0/xx unknown
- 1978-06-16 NO NO782108A patent/NO782108L/no unknown
- 1978-06-16 DK DK272778A patent/DK272778A/da not_active Application Discontinuation
- 1978-06-16 IT IT24660/78A patent/IT1099556B/it active
- 1978-06-16 ZA ZA00783465A patent/ZA783465B/xx unknown
- 1978-06-16 AT AT441278A patent/AT358597B/de not_active IP Right Cessation
- 1978-06-17 JP JP7274378A patent/JPS549287A/ja active Granted
Also Published As
Publication number | Publication date |
---|---|
IL54916A0 (en) | 1978-08-31 |
ATA441278A (de) | 1980-02-15 |
AT358597B (de) | 1980-09-25 |
JPS549287A (en) | 1979-01-24 |
AU3678878A (en) | 1979-12-06 |
JPS566420B2 (fr) | 1981-02-10 |
ES470727A1 (es) | 1979-01-16 |
ZA783465B (en) | 1979-07-25 |
IE781066L (en) | 1978-12-18 |
CA1085396A (fr) | 1980-09-09 |
NO782108L (no) | 1978-12-19 |
IE47103B1 (en) | 1983-12-28 |
US4216216A (en) | 1980-08-05 |
DE2727469A1 (de) | 1978-12-21 |
DK272778A (da) | 1978-12-19 |
IT1099556B (it) | 1985-09-18 |
DE2860637D1 (en) | 1981-08-06 |
IT7824660A0 (it) | 1978-06-16 |
EP0000220A1 (fr) | 1979-01-10 |
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