DK145696B - METHOD FOR PREPARING 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES - Google Patents
METHOD FOR PREPARING 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES Download PDFInfo
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- DK145696B DK145696B DK254275AA DK254275A DK145696B DK 145696 B DK145696 B DK 145696B DK 254275A A DK254275A A DK 254275AA DK 254275 A DK254275 A DK 254275A DK 145696 B DK145696 B DK 145696B
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- imidazoline
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- 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
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Description
145696 i145696 i
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 2-arylamino-2-imidazolinderivater.The present invention relates to a particular process for the preparation of 2-arylamino-2-imidazoline derivatives.
Fra de østrigske patenter nr. 248 428, nr. 250 344 og nr.From the Austrian patents Nos. 248 428, Nos. 250 344 and Nos.
250 345 er det kendt, at 2-arylamino-2-imidazolinderivater, 5 især forbindelsen 2-(2',é1-dichlorphenylamino)-2-imidazo- lin, har en udpræget hypotensiv virkning tillige med en sedativ virkning.It is known that 2-arylamino-2-imidazoline derivatives, especially the compound 2- (2 ', [1-dichlorophenylamino) -2-imidazoline, have a pronounced hypotensive effect as well as a sedative effect.
Fra belgisk patent nr. 741 947 kendes endvidere N-aroyl-derivater af de nævnte 2-arylamino-2-imidazolinderivater, 10 f.eks. 2-[N-benzoyl-(2',6'-dichlorphenyl)-amino]-2-imida-zolin, som ligeledes har denne hypotensive og samtidig sedative virkning.Belgian Patent No. 741,947 also discloses N-aroyl derivatives of said 2-arylamino-2-imidazoline derivatives, e.g. 2- [N-Benzoyl- (2 ', 6'-dichlorophenyl) amino] -2-imidazoline, which also has this hypotensive and simultaneously sedative effect.
Disse N-aroylderivater opnås ved aroylering af de frie ‘ 2-arylamino-2-imidazoliner med de tilsvarende syrechlori-15 der af aromatiske carboxylsyrer, hvorved syreresten udskiftes med det ved anilinnitrogenet bundne hydrogenatom.These N-aroyl derivatives are obtained by aroylating the free '2-arylamino-2-imidazolines with the corresponding acid chlorides of aromatic carboxylic acids, thereby replacing the acid residue with the hydrogen atom attached to the aniline nitrogen.
Det har nu vist sig, at der ved aroyleringen af de nævnte 2-arylamino-imidazoliner ved hjælp af visse aktive amider af aromatiske carboxylsyrer i særdeles godt udbytte og med 20 fremragende renhed dannes aroylderivater med interessante farmakologiske egenskaber. Disse aroylderivater bærer ikke syreresten ved anilinnitrogenatomet, men ved imidazo-linnitrogenatomet. At disse forbindelser er forskellige fra de i belgisk patent nr. 741 947 beskrevne, kan bevises 25 ved forskellige fysiske undersøgelser, blandt andet ved blandingssmeltepunkt og NMR.It has now been found that by the aroylation of said 2-arylamino-imidazolines by certain active amides of aromatic carboxylic acids in very good yield and with excellent purity aroyl derivatives having interesting pharmacological properties are formed. These aroyl derivatives do not carry the acid residue at the aniline nitrogen atom, but at the imidazolinyl nitrogen atom. The fact that these compounds are different from those described in Belgian Patent No. 741,947 can be proved by various physical studies, including by melting point and NMR.
Opfindelsen angår herefter en fremgangsmåde til fremstilling af 2-arylamino-2-imidazolin-derivater med den almene formel: 145696 2 2 β1 N—(la)The invention then relates to a process for the production of 2-arylamino-2-imidazoline derivatives of the general formula:
COCO
uu
RR
eller R2 ' C, /7 N (lb) R3''-' N-or R2 'C, / 7 N (lb) R3' '-' N-
COCO
»4»4
RR
T ? 3 .T? 3.
hvori R , R og R , som kan være ens eller forskellige, betyder hydrogen, halogen, fortrinsvis chlor eller brom, en alkylgruppe med op..til 4 carbonatomer, en alkoxygruppe-med op til 4 carbonatomer eller en: nitrogruppe, idet miridst , 12 3 5 én af grupperne R , R og R er. forskellig fra hydrogen, 4 og R betyder .en phenylgruppe, som eventuelt er substitueret med en alkylgruppe med 1 eller 2 C-atomer. Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man omsætter en 2-arylamino-2-imidazolinderivat med den almene for-10 mel: R1wherein R, R and R, which may be the same or different, mean hydrogen, halogen, preferably chlorine or bromine, an alkyl group of up to 4 carbon atoms, an alkoxy group of up to 4 carbon atoms, or a: nitro group, 12 3 5 is one of the groups R, R and R. other than hydrogen, 4 and R represent a phenyl group optionally substituted with an alkyl group having 1 or 2 C atoms. The process of the invention is characterized by reacting a 2-arylamino-2-imidazoline derivative with the general formula: R1
HH
med et aktivt amid med den almene formel R4-C-X (III)with an active amide of the general formula R4-C-X (III)
IIII
0 3 145896 hvori X betyder en 5-leddet heterocyclisk ring med 2 eller 3 nitrogenatomer i molekylet, af hvilke nitrogenatomer mindst det ene bærer et hydrqgenatom, hvorhos denne 5-leddede hetero-cycliske ring eventuelt kan være kondenseret med benzen, 5 eller hvori X betyder en gruppe med formlen R1 (IW)0 3 145896 wherein X represents a 5-membered heterocyclic ring having 2 or 3 nitrogen atoms in the molecule, at least one of which carries an hydrogen atom, this 5-membered heterocyclic ring being optionally condensed with benzene, 5 or wherein X means a group of formula R1 (IW)
HH
hvori R^, R^, R^ og R^ er defineret som i formel I, idet omsætningen foregår ved normal eller forhøjet temperatur.wherein R 1, R 2, R 2 and R 2 are defined as in Formula I, the reaction taking place at normal or elevated temperature.
forbindelserne med formlen (la) eller (Ib) er kendt fra dansk patentansøgning nr. 941/75.the compounds of formula (Ia) or (Ib) are known from Danish Patent Application No. 941/75.
10 Som "aktive amider" forstås i første række sådanne forbindelser, som ifølge H.A. Staab og W. Rohr's afhandling "Syn-thesen mit heterocyclischen Amiden", jfr. W. Foerst, Neue-re Methoden der pråparativen organischen Chemie, Bind V, side 53, betegnes som "Azolider". I nærværende beskrivelse Λ 15 forstås herved især azoliderne af syrer med formlen R COOtl, som er analoge med eddikesyreazoliderne i nævnte afhandling i tabel I, side 55. Eksempelvis kan nævnes 1,2,3-triazoli-der, 1,2,4-triazolider såvel som de fra benzotriazol og benzimidazol afledte azolider. Særlig fordelagtig er an- Λ 20 vendeisen af imidazolider af syrerne med formlen R C00H.10 "Active amides" are primarily understood to include such compounds as in H.A. Staab and W. Rohr's thesis "Synthesis with heterocyclic Amiden", cf. W. Foerst, The New Method of Preparative Organic Chemistry, Volume V, page 53, is referred to as "Azolides". In this specification Λ 15 is hereby particularly understood the azolides of acids of the formula R COOtl, which are analogous to the acetic acid azolides in the said thesis in Table I, page 55. For example, 1,2,3-triazolides, 1,2,4- triazolides as well as those of benzotriazole and benzimidazole derived azolides. Particularly advantageous is the application of imidazolides of the acids of formula R C00H.
derudover kan også det aktive amid af forbindelsen med formlen II, som holder syreresten bundet til anilinnitrogenet, anvendes til acylering. At acyleringen ved hjælp af azolider forløber forskelligt fra acyleringen ved hjælp af sy-25 rechlorider er meget overraskende, da ifølge den nævnte afhandling reaktionsevnen hos disse azolider og de ved hjælp af syrehalogenider og -hydrider fremstillede azolider skulle være den samme.in addition, the active amide of the compound of formula II which holds the acid residue bound to the aniline nitrogen can also be used for acylation. That the acylation by azolides proceeds differently from the acylation by acid chlorides is very surprising, since according to the aforementioned thesis the reactivity of these azolides and the azolides prepared by acid halides and hydrides should be the same.
Omsætningen af forbindelserne med formel II med de aktive 145696 4 amider ifølge formel III kan ske ifølge velkendte metoder, fordelagtigt går man sådan frem, at man til en opløsning af det aktive amid med formel III sætter en opløsning af 2-arylamino-2-imidazolinen med formel II, som skal acyle-5 res. Omsætningen kan ske ved henstand i stuetemperatur, men man kan også.varme blandingen, fordelagtigt indtil maksimalt det anvendte opløsningsmiddels kogepunkt. Som opløsningsmidler kan eksempelvis nævnes toluen, benzen, xylen, chloroform, dimethylformamid, dioxan og tetrahy-!0 drofuran. Det aktive amid med formel III anvendes i mindst en ækvimolær mængde beregnet på forbindelsen med formel II. Med fordel anvendes et overskud på 10 - 20?ό. Reaktionstiden vælges alt efter det aktive amids reaktionsevne og reaktionstemperaturen og den udgør som regel flere timer.The reaction of the compounds of formula II with the active amides of formula III can be carried out according to well known methods, advantageously such that a solution of the 2-arylamino-2-imidazoline is added to a solution of the active amide of formula III of formula II which is to be acylated. The reaction can take place at room temperature, but it is also possible to heat the mixture, advantageously up to the boiling point of the solvent used. For example, solvents include toluene, benzene, xylene, chloroform, dimethylformamide, dioxane and tetrahydro-drofuran. The active amide of formula III is used in at least one equimolar amount based on the compound of formula II. Advantageously, an excess of 10 - 20? Ό is used. The reaction time is selected according to the reaction ability and reaction temperature of the active amide and it usually constitutes several hours.
15 Når man som aktivt amid med formlen III anvender det amid, 4 hvori R betyder gruppen med formel IV, og nar i denne gruppe med formel IV og i forbindelse med formlen II substituen-12 3 terne R , R og R er identiske, er det ikke nødvendigt at benytte forbindelsen med formlen II i ækvimolær mængde el-20 ler et kun ringe underskud. I.dette tilfælde vil det være tilstrækkeligt med et væsentligt underskud, fordelagtigt mindre end en halv og helt ned til en tiendedel ækvivalent af det aktive amid med formlen III, idet man i løbet af acyleringen løbende frigør forbindelsen med formel II fra 25 det aktive amid med formlen III. Denne variant af fremgangsmåden ifølge opfindelsen sker eksempelvis ved kogning af udgangsmaterialet i et aprotisk, inert opløsningsmiddel, som f.eks. toluen eller xylen.When one is used as active amide of formula III, the amide 4 wherein R is the group of formula IV and when in this group of formula IV and in connection with formula II the substituents R, R and R are identical are it is not necessary to use the compound of formula II in equimolar amount or only a slight deficit. In this case, a substantial deficit will suffice, advantageously less than one-half and as much as one-tenth equivalent of the active amide of formula III, during the acylation, the compound of formula II is continuously released from the active amide. of formula III. This variant of the process according to the invention occurs, for example, by boiling the starting material in an aprotic, inert solvent, such as e.g. toluene or xylene.
Opløsningsmidlet fjernes efter endt reaktion, hvorpå den 30 tørre remanens kan renses ved omkrystallisering. I nogle tilfælde anbefales det først at behandle den tørre remanens med vand, i givet fald under tilsætning af lidt natrium-carbonat- eller natriumbicarbonatop'løsning. Derpå indtræder der enten krystallisation, eller den vandige fase op-35 tages med et organisk opløsningsmiddel. Inddampningsrema-nensen henholdsvis krystallisatet kan da om nødvendigt igen omkrystalliseres.The solvent is removed after the reaction is completed and the dry residue can be purified by recrystallization. In some cases, it is recommended to first treat the dry residue with water, if necessary, with the addition of a little sodium carbonate or sodium bicarbonate solution. Then either crystallization occurs or the aqueous phase is taken up with an organic solvent. The evaporation residue or crystallisate can then be recrystallized if necessary.
145696 5145696 5
Det er ikke nødvendigt i alle tilfælde at fremstille det aktive amid med formlen III i en særskilt arbejdsgang»It is not necessary in all cases to prepare the active amide of formula III in a separate procedure »
Azolider med formlen III kan også fremstilles in situ fra den tilsvarende azol og et syrechlorid med formlen R^COCl 5 og direkte-videreanvendes. Således er det f.eks. muligt 4 at omsætte syrechlorider med formlen R C0C1 i tetrahydro-furan med imidazol og efter endt reaktion at indføre en opløsning af forbindelsen med formlen II i reaktionsopløsningen. En fremstilling in situ af et imidazolid med form-10 len III kan også ske ved omsætning af syren med formlen R^COOH med NjN’-earbonyldiimidazol.Azolides of formula III can also be prepared in situ from the corresponding azole and an acid chloride of formula R 2 COCl 5 and directly re-used. Thus, e.g. possible 4 to react acid chlorides of formula R COC1 in tetrahydrofuran with imidazole and after completion of the reaction introduce a solution of the compound of formula II into the reaction solution. An in situ preparation of an imidazolid of formula III may also be effected by reacting the acid of formula R 2 COOH with NjN'-earbonyldiimidazole.
Aktive amider, hvori X betyder gruppen med formlen IV, opnås ved hjælp af fremgangsmåden ifølge det belgiske patent nr. 741 947.Active amides wherein X represents the group of formula IV are obtained by the method of Belgian Patent No. 741,947.
15 Forbindelserne med formlen la henholdsvis Ib er ensartede, godt krystalliserende produkter. Strukturen af disse forbindelser kan ikke bestemmes entydigt, da det er et åbent spørgsmål, om dobbeltbindingen er anbragt i imidazolin-ringen (la) eller exocyclisk (Ib). Strukturen har meget in-20 teressante farmaceutiske egenskaber. Særligt må man frem hæve forbindelser med formlen la henholdsvis Ib, hvori phenylringen i 2- og 6-stillingen er substitueret med halogen. De forbindelser, hvori R^CD betyder benzoyl eller m- eller p-toluyl, har ganske vist en ligeså blodtryksæn-25 kende virkning som forbindelserne med formlen II, eksem pelvis 2-(2’,6'-dichlor-phenylamino)-2-imidazolin, men ligesom det gælder for de i belgisk patent nr. 741 947 beskrevne aroylderivater, er den sedative virknihgskompo-nent væsentlig mindre udpræget. Et særlig gunstigt for-30 hold mellem blodtryksænkende virkning og sedativ virkning kan findes hos den forbindelse, hvor R t.0 betyder benzoyl, således at bl.a. den som ubehagelig bivirkning optrædende træthed, som viser sig ved forbindelsens anvendelse som hypotensivt middel, bortfalder. Alle disse forbindelser 145696 6 resorberes udmærket oralt, især forbindelserne, hvor R^CO er benzoyl.The compounds of formula Ia and Ib, respectively, are uniform, well crystallizing products. The structure of these compounds cannot be uniquely determined, as it is an open question whether the double bond is located in the imidazoline ring (1a) or exocyclic (1b). The structure has very interesting pharmaceutical properties. In particular, compounds of formula Ia and Ib, respectively, wherein the phenyl ring at the 2- and 6-positions are substituted with halogen must be raised. Admittedly, the compounds wherein R 1 CD represents benzoyl or m- or p-toluyl have the same blood pressure lowering effect as the compounds of formula II, for example 2- (2 ', 6'-dichlorophenylamino) -2 -imidazoline, but, as is true of the aroyl derivatives disclosed in Belgian Patent No. 741,947, the sedative component of action is substantially less pronounced. A particularly favorable relationship between blood pressure lowering and sedative action can be found in the compound where R t.0 means benzoyl. the fatigue, which arises as unpleasant side effect, which is shown by the use of the compound as a hypotensive agent, lapses. All of these compounds are very well absorbed orally, especially those compounds wherein R 2 CO is benzoyl.
Den samme tendens kan også iagttages ved de andre forbindelser med formlen la henholdsvisIbomend i forskelligt 5 omfang.The same tendency can also be observed for the other compounds of formula Ia and Ibomend, respectively, to varying degrees.
Manglen på den sedative henholdsvis centraldæmpende virkning lader sig let påvise ved bestemmelse af tilstedeværelsen af carotissinusreflekser hos bedøvede kaniner efter indgivelse af de nævnte forbindelser la eller Ib i doser 10 på 100 mikrogram/kg. Denne refleks er næsten helt under trykt ved indgivelsen af den samme dosis l-benzoyl-2-(2',6'-dichlorphenylamino)'-2-imidazolin. Endvidere kan den også iagttages under samme forhold på vågne mus efter indgivelse af 5 eller 10 mg/kg af disse benzoyl- eller p-toluenforbin-15 delser med formlen la henholdsvis Ib.The lack of sedative or central attenuation, respectively, is readily demonstrated by determining the presence of carotissin reflexes in anesthetized rabbits after administration of said compounds Ia or Ib at doses 10 of 100 micrograms / kg. This reflex is almost completely suppressed by the administration of the same dose of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline. Furthermore, it can also be observed under the same conditions on waking mice after administration of 5 or 10 mg / kg of these benzoyl or p-toluene compounds of formula Ia and Ib respectively.
44
De nævnte forbindelser med formlen la eller Ib, hvor R CO har betydningen benzoyl eller m- eller p-toluen, kan benyttes i medicinen som hypotensiva i alle til farmaceutisk brug gængse tilberedelsesformer som tabletter, drageer, 20 kapsler, suppositorier, emulsioner, opløsninger eller in jektionsopløsninger.Said compounds of formula Ia or Ib, wherein R CO is benzoyl or m- or p -toluene, may be used in the medicine as hypotensives in all pharmaceutical forms of conventional use such as tablets, drugs, capsules, suppositories, emulsions, solutions or in injection solutions.
Endvidere kan enten de frie baser eller saltene heraf efter indgivningsformen anvendes. Som salte anvendes f.. eks. salte med uorganiske eller organiske syrer, såsom hy-25 drogenhalogenider, phosphater, oxalater, 8-chlortheophyl- linater eller salte med sure syntetiske harpikser.Furthermore, either the free bases or their salts according to the mode of administration can be used. As salts are used, for example, salts with inorganic or organic acids, such as hydrogen halides, phosphates, oxalates, 8-chloro-theophyllinates or salts with acidic synthetic resins.
Fremgangsmåden ifølge opfindelsen illustreres nærmere ved de følgende eksempler. De i disse eksempler angivne NMR-ab-sorptioner er angivet i S-værdier.The process of the invention is further illustrated by the following examples. The NMR absorptions indicated in these examples are given in S values.
7 145695 EKSEMPEL 1 1,47 g benzoesyre (12 mmol) opløses i 50 ml absolut tetra-hydrofuran og der tilsættes 1,95 g N, !\T-carbonyldiimidazol under omrøring. Blandingen hensættes i 45 minutter ved 5 stuetemperatur. Under omrøring tilsættes en opløsning af 2,30 g 2-(2',6'-dichlorphenylamino)-2-imidazolin i 25 ml absolut tetrahydrofuran, og blandingen henstår derefter i 20 timer ved stuetemperatur. Den overskydende del afdes-tilleres ved normalt tryk, og remanensen blandes med ca.EXAMPLE 1 1.47 g of benzoic acid (12 mmol) is dissolved in 50 ml of absolute tetrahydrofuran and 1.95 g of N, T-carbonyldiimidazole is added with stirring. The mixture is allowed to stand for 45 minutes at 5 room temperature. With stirring, a solution of 2.30 g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline in 25 ml of absolute tetrahydrofuran is added and the mixture is left to stand for 20 hours at room temperature. The excess part is distilled off under normal pressure and the residue is mixed with ca.
10 50 ml 0,5¾ i natriumcarbonatopløsning, hvorefter krystalli sationen indtræder. Der filtreres, og krystallisatet vaskes omhyggeligt med h^O og tørres i vakuum over ^an opnår således 3,31 g rå l-benzoyl-2-(21,61-dichlorphenyl-amino)-2-imidazolin, som omkrystalliseres fra isopropanol.10 mL of 0.5¾ in sodium carbonate solution and crystallization occurs. It is filtered and the crystallize washed thoroughly with h 2 O and dried in vacuo to give 3.31 g of crude 1-benzoyl-2- (21,61-dichlorophenylamino) -2-imidazoline which is recrystallized from isopropanol.
15 Udbyttet af rent produkt er 2,65 g (77,2¾) med et smelte punkt på 160-162 °C.The yield of pure product is 2.65 g (77.2¾) with a melting point of 160-162 ° C.
Analyse: ^26^13^2^3^ beregnet: C 57,19 H 3,98 N 12,55 0 5,23 Cl 21,10 fundet : C 57,4 H 4,1 N 12,4 0 5,2 Cl 20,8 pKa: 4,01 (i 70¾ methylcellosolve ved stuetemperatur) UV: ;v. = 237 nm (sh: i_ - 22 100) i ethanol IR: (KBr) 3310 cm-1, 1686 cm-1, 1612 cm"1, 1579 cm"1 NMR: (100 MHz, CDCl^): 3,42 (2H, tilnærmelsesvis triplet) 4,01 (2H, tilnærmelsesvis triplet), ca. 4,10 (m, bred, NH, udskiftes med D2O) 2-[N-benzoyl-(2',6'-dichlorpheny1)-amino]-2-imidazolin i-følge belgisk patent nr. 741 947 har ligeledes et smeltepunkt på 160-161 °C, de to forbindelser har et blandings-20 smeltepunkt på 134-143 °C.Found: C 57.19 H 3.98 N 12.55 0. 5.23 Cl 21.10 Found: C 57.4 H 4.1 N 12.4 0 5, 2 Cl 20.8 pKa: 4.01 (in 70¾ methylcellosolve at room temperature) UV:; v. = 237 nm (sh: 1 - 22 100) in ethanol IR: (KBr) 3310 cm -1, 1686 cm -1, 1612 cm -1, 1579 cm -1 NMR: (100 MHz, CDCl 3): 3.42 (2H, approximately triplet) 4.01 (2H, approximately triplet), ca. 4.10 (m, wide, NH, replaced by D 2 O) 2- [N-benzoyl- (2 ', 6'-dichlorophenyl) amino] -2-imidazoline according to Belgian Patent No. 741,947 also has a melting point at 160-161 ° C, the two compounds have a melting point of 134-143 ° C.
De øvrige kendetegn af forbindelsen ifølge belgisk patent, pK -værdi = 6,10 (i 70¾ methylcellosolve ved stuetemperatur) 3 145696 8 NMR: (100 MHz, CDC13): 3,66 (s,4H), 6,43 (m, bred, NH, udskiftes med D2O), er altså ligeledes tydelig forskellige.The other characteristics of the compound of Belgian patent, pK value = 6.10 (in 70¾ methylcelllosolve at room temperature) NMR: (100 MHz, CDCl3): 3.66 (s, 4H), 6.43 (m, broad, NH, replaced with D 2 O), are thus also distinctly different.
EKSEMPEL 2 4,60 g 2-(2',6'-dichlorphenylamino)-2-imidazolin (20 mmol) og 4,23 g p-toluylimidazolid (23 mmol) koges under tilbagesvaling i 60 ml absolut toluen i 2,3 timer. Derefter ind-3 damper man, og remanensen behandles med 40 ml isopropanol, filtreres og tørres. Man opnår herved 6,27 g rå 1-p-toluyl 2-(',6'-dichlorphenylamino)-2-imidazolin (90,2¾) med smeltepunkt 156-176 °C, som omkrystalliseres fra isopropanol.EXAMPLE 2 4.60 g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline (20 mmol) and 4.23 g of p-toluylimidazolid (23 mmol) are refluxed in 60 ml of absolute toluene for 2.3 hours . Then, vapor-3 is evaporated and the residue is treated with 40 ml of isopropanol, filtered and dried. There is obtained 6.27 g of crude 1-p-toluyl 2 - (', 6'-dichlorophenylamino) -2-imidazoline (90.2 °), mp 156-176 ° C, which is recrystallized from isopropanol.
Man opnår således 5,74 g rent produkt (82,7¾) med smelte-10 punkt 172-175 °C.There is thus obtained 5.74 g of pure product (82.7 °) with melting point 172-175 ° C.
Analyse: CjyH^C^N^OAnalysis: CjyH ^C CN NO
beregnet: C 58,63 H 4,34 Cl 20,36 N 12,06 0 4,59 fundet : C 58,8 H 4,6 Cl 20,2 N 11,9 0 4,9 pK : 4,18 (i 70¾ methylcellosolve ved stuetemperatur) UV: Λ = 236 nm (sh, Σ. = 20 200) i ethanol IR: (KBr): 3310 cm"1, 1689 cm"1, 1650 cm"1, 1620 cm"1 NMR (100 MHz, CDCl^): 3,48 (2H, tilnærmelsesvis triplet), 4,07 (2H, tilnærmelsesvis triplet)calculated: C 58.63 H 4.34 Cl 20.36 N 12.06 0 4.59 Found: C 58.8 H 4.6 Cl 20.2 N 11.9 0 4.9 hp: 4.18 ( in 70¾ methylcellosolve at room temperature UV: Λ = 236 nm (sh,,. = 20,200) in ethanol IR: (KBr): 3310 cm10 1, 1689 cm "1, 1650 cm" 1, 1620 cm "1 NMR ( 100 MHz, CDCl 3): 3.48 (2H, approximately triplet), 4.07 (2H, approximately triplet)
Ca. 4,20 (m, bred, NH, udskiftes med D^O) EKSEMPEL 3 1,63 g imidazol (24 mmol) opløses i 10 ml absolut tetrahy-drofuran. Til denne opløsning sættes dråbevis en opløsning af 1,85 g p-toluylchlorid (12 mmol) i 10 ml absolut 15 tetrahydrofuran og herefter omrøres blandingen endnu i 2 timer ved stuetemperatur. Det udfældede imidazol-hydro-chlorid frafiltreres, dækkes med 5 ml absolut tetrahydrofuran og afsuges omhyggeligt. Til det opnåede filtrat 9 145896 sættes inden for 5 minutter under omrøring en opløsning af 2,30 g 2-(2',6'-dichlorphenylamino)-2-imidazolin (10 mmol), og blandingen henstår i 20 timer ved stuetemperatur. Man inddamper, og remanensen behandles varmt med 25 ml isopro-5 panol og henstår derefter i 4 timer ved stuetemperatur.Ca. EXAMPLE 3 1.63 g of imidazole (24 mmol) is dissolved in 10 ml of absolute tetrahydrofuran. To this solution is added dropwise a solution of 1.85 g of p-toluyl chloride (12 mmol) in 10 ml of absolute tetrahydrofuran and then the mixture is stirred for another 2 hours at room temperature. The precipitated imidazole hydrochloride is filtered off, covered with 5 ml of absolute tetrahydrofuran and carefully suctioned. To the obtained filtrate 9 145896, a solution of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline (10 mmol) was added within 5 minutes with stirring and the mixture was allowed to stand for 20 hours at room temperature. Evaporate and treat the residue hot with 25 ml of isopropanol and then leave for 4 hours at room temperature.
Der filtreres, vaskes med isopropanol og tørres. Man opnår således 2,99 g ren 1-p-toluyl-2-(2',61-dichlorphenyl-amino)-2-imidazolin svarende til 85,9¾ af det teoretiske med smeltepunkt = 172-175 °C, som er identisk med det i 10 eksempel 2 beskrevne produkt.Filter, wash with isopropanol and dry. There is thus obtained 2.99 g of pure 1-p-toluyl-2- (2 ', 61-dichlorophenylamino) -2-imidazoline corresponding to 85.9¾ of the theoretical with melting point = 172-175 ° C, which is identical with the product described in Example 2.
EKSEMPEL 4 3 g o-toluylsyre (22 mmol) opløses i 70 ml absolut tetrahydrofuran, tilsættes 3,57 g N,N'-carbonyldiimidazol og omrøres 1 time ved stuetemperatur. Derefter tilsættes 15 en opløsning af 4,60 g 2-(2',6'-dichlorphenylamino)-2-imi- dazolin i 30 ml tetrahydrofuran. Blandingen henstår natten over ved stuetemperatur. Derpå inddamper man i vakuum og remanensen vaskes grundigt med 150 ml ^0, filtreres, vaskes med vand og tørres. Man opnår således 6,95 g rå l-o-20 toluyl-2-(2',6'-dichlorphenylamino)-2-imidazolin.EXAMPLE 4 Dissolve 3 g of o-toluyl acid (22 mmol) in 70 ml of absolute tetrahydrofuran, add 3.57 g of N, N'-carbonyldiimidazole and stir for 1 hour at room temperature. Then, a solution of 4.60 g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline in 30 ml of tetrahydrofuran is added. The mixture is left to stand overnight at room temperature. Then it is evaporated in vacuo and the residue is thoroughly washed with 150 ml 2 There is thus obtained 6.95 g of crude 1-o-toluyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline.
Smeltepunkt = 160-175 °C (87,1¾).Melting point = 160-175 ° C (87.1¾).
Der omkrystalliseres fra isopropanol , hvorved man opnår 5,61 g (80,9¾) analyserent produkt, smeltepunkt = 179-180 °C.Recrystallize from isopropanol to give 5.61 g (80.9 °) of assay product, mp = 179-180 ° C.
pKg: 3,85 (70¾ methylcellosolve, stuetemperatur) UV: jV. = 242 nm (sh, 5. = 13 150) i ethanol IR: (KBr) 3355 cm-1, 1706 cm"1, 1643 cm"1 NMR (100 MHz, CDCl^), 3,94 (2H, tilnærmelsesvis triplet), 4,05 og ca. 4,20 (tilsammen 3H, deraf IH udskiftelig med D^O, m ved 4,05, 2H).pKg: 3.85 (70¾ methylcellosolve, room temperature) UV: jV. = 242 nm (sh, 5 = 13,150) in ethanol IR: (KBr) 3355 cm -1, 1706 cm -1, 1643 cm -1 NMR (100 MHz, CDCl3), 3.94 (2H, approximately tripled) ), 4.05 and approx. 4.20 (together 3H, thereof 1H interchangeable with D 2 O, m at 4.05, 2H).
10 145598 EKSEMPEL 5 3 g m-toluylsyre (22 mmol) opløses i-70 ml tetrahy-drofuran, tilsættes 3,37 g N,N'-carbonyldiimidazol og omrøres 1 time ved stuetemperatur. Derefter tilsættes en op-5 løsning af 4,60 g 2-(2',61-dichlorphenylamino)-2-imidazo- lin i 30 ml absolut tetrahydrofuran. Blandingen henstår natten over ved stuetemperatur. Derpå tørres ved inddamp-ning i vakuum, remanensen vaskes grundigt med 150 ml 1^0, filtreres, vaskes med vand og tørres. Man opnår således 10 6,92 g rå 1-m-toluyl-(2’,6'-dichlorphenylamino)-2-imidazo- lin, som .til rensning omkrystalliseres med benzen i cyc-lohexan (1 : 1) og isopropanol, hvorved man opnår 6,21 g analyserent. materiale (89,4¾) .EXAMPLE 5 3 g of m-toluyl acid (22 mmol) is dissolved in 70 ml of tetrahydrofuran, 3.37 g of N, N'-carbonyl diimidazole is added and stirred for 1 hour at room temperature. Then, a solution of 4.60 g of 2- (2 ', 61-dichlorophenylamino) -2-imidazoline in 30 ml of absolute tetrahydrofuran is added. The mixture is left to stand overnight at room temperature. Then, by evaporation in vacuo, the residue is thoroughly washed with 150 ml of 100 ° C, filtered, washed with water and dried. There is thus obtained 6.92 g of crude 1-m-toluyl- (2 ', 6'-dichlorophenylamino) -2-imidazoline, which is recrystallized from benzene in cyclohexane (1: 1) and isopropanol. to obtain 6.21 g of analytical grade. material (89.4¾).
Smeltepunkt = 157-158 °C.Melting point = 157-158 ° C.
pK = 4,02 (70¾ methylcellosolve ved stuetemperatur) 3.pK = 4.02 (70¾ methylcellosolve at room temperature) 3.
UV: Λ = 236 nm (sh, X = 18 7000) i ethanol IR: (KBr) 3430 cm-1, 1680 cm"1, 1654 cm-1 NMR: (100 MHz, CDCl^); 3,48 (2H, tilnærmelsesvis triplet), 4,07 (2H, tilnærmelsesvis triplet), ca. 4,2 (m, bred, N-H, delvis overlappende).UV: Λ = 236 nm (sh, X = 18,7000) in ethanol IR: (KBr) 3430 cm -1, 1680 cm -1, 1654 cm -1 NMR: (100 MHz, CDCl 3); 3.48 (2H , approximately triplet), 4.07 (2H, approximately triplet), approximately 4.2 (m, wide, NH, partially overlapping).
15 EKSEMPEL 6 0,65 g benzoesyre (12 mmol) opløses i 20 ml absolut tetrahydrofuran, og der tilsættes 0,86 g M,N1-carbonyldiimidazol (12 mmol). Man lader blandingen henstå til reaktion i 30 til 40 minutter ved stuetemperatur. Til den klare op-20 løsning sættes en opløsning af 0,93 g 2-(2'-chlor-61- methylphenylamino)-2-imidazolin i 10 ml absolut tetrahydrofuran, og der opvarmes under tilbagesvaling i 3,5 timer.EXAMPLE 6 Dissolve 0.65 g of benzoic acid (12 mmol) in 20 ml of absolute tetrahydrofuran and add 0.86 g of M, N1-carbonyldiimidazole (12 mmol). The mixture is allowed to react for 30 to 40 minutes at room temperature. To the clear solution is added a solution of 0.93 g of 2- (2'-chloro-61-methylphenylamino) -2-imidazoline in 10 ml of absolute tetrahydrofuran and heated under reflux for 3.5 hours.
Derefter inddampes der. Remanensen behandles med 20 ml 0,5¾ natriumbicarbonat-opløsning, filtreres, vaskes med Η£θ og 25 tørres. Man opnår således 1,29 g rå l-benzoyl-2-(2'-chlor- 6'-methylphenylamino)-2.-imidazolin (92,8¾).Then evaporate. The residue is treated with 20 ml of 0.5¾ sodium bicarbonate solution, filtered, washed with Η £ θ and dried. There is thus obtained 1.29 g of crude 1-benzoyl-2- (2'-chloro-6'-methylphenylamino) -2.-imidazoline (92,8¾).
11 145696 UV: > = 234 nm (sh; £. = 16 600) i ethanol IR: (KBr) 3415 cm 1 (skarp) 1673 cm"^, 1643 cm-1 NMR: (100 MHz, CDCl^): 3,37 (2H, tilnærmelsesvis triplet), 3,97 (2H, tilnærmelsesvis triplet), 4,70 (m, bred, N-H, udskiftelig med D2O).UV:> = 234 nm (sh; λ = 16,600) in ethanol IR: (KBr) 3415 cm 1 ((sharp) 1673 cm ",, 1643 cm-1 NMR: (100 MHz, CDCl ^): 3 , 37 (2H, approximately triplet), 3.97 (2H, approximately triplet), 4.70 (m, wide, NH, interchangeable with D 2 O).
EKSEMPEL 7 1,47 g benzoesyre opløses i 50 ml absolut tetrahydrofuran.Example 7 1.47 g of benzoic acid is dissolved in 50 ml of absolute tetrahydrofuran.
Under omrøring tilsættes 1,95 g N,N'-carbonyldiimidazol, blandingen henstår i 40 minutter ved stuetemperatur, der 5 tilsættes en opløsning af 3,19 g 2-(2',6'-dibromphenyl- amino)-2-imidazolin i 50 ml tetrahydrofuran, og blandingen henstår i 42 timer ved stuetemperatur. Derefter frades-tilleres den overskydende del ved normaltryk, og remanensen behandles med 40 ml 1% natriumbicarbonatopløsning, 10 hvorved krystalliseringen indtræder. Krystallisatet fra- suges, vaskes godt med vand og tørres.With stirring, 1.95 g of N, N'-carbonyldiimidazole is added, the mixture is allowed to stand for 40 minutes at room temperature, to which a solution of 3.19 g of 2- (2 ', 6'-dibromophenylamino) -2-imidazoline is added. 50 ml of tetrahydrofuran and the mixture is allowed to stand for 42 hours at room temperature. Then, the excess portion is deprotected under normal pressure and the residue is treated with 40 ml of 1% sodium bicarbonate solution, thereby crystallizing. The crystalline extract is extracted, washed well with water and dried.
Man opnår således 4,02 g rå 1-benzoy1-2-(21,6'-dibromphe-nylamino)-2-imidazolin, som omkrystalliseres fra isopro-panol. Man opnår 3,31 g rent produkt (78,6%). Smeltepunkt 15 = 193-197 °C.There is thus obtained 4.02 g of crude 1-benzoyl-2- (21,6'-dibromophenylamino) -2-imidazoline, which is recrystallized from isopropanol. 3.31 g of pure product (78.6%) is obtained. Melting point 15 = 193-197 ° C.
pK : 3,67 (i 70% methylcellosolve ved stuetemperatur) UV: = 240 nm (sh, i. = 17 400) Jl = 290 nm (sh; = 3660) i ethanol IR: (KBr) 3375 cm-1, 1697 cm"1, 1638 cm'1 NMR: (100 MHz, CDCl^): 3,49 (2H, tilnærmelsesvis triplet), 4,11 (2H, tilnærmelsesvis triplet), ca. 4,05 (m, bred, N-H, delvis skjult).pK: 3.67 (in 70% methyl cellulose at room temperature) UV: = 240 nm (sh, i = 17,400) J1 = 290 nm (sh; = 3660) in ethanol IR: (KBr) 3375 cm -1, 1697 cm -1: 1638 cm -1 NMR: (100 MHz, CDCl3): 3.49 (2H, approximately triplet), 4.11 (2H, approximately triplet), about 4.05 (m, wide, NH, partially hidden).
EKSEMPEL 8 200 mg 2-[N-benzoyl-N-(2',6'-dichlorpheny1)-amino ]-2-imida-zolin koges under tilbagesvaling i 32 timer med 15 mg 2-EXAMPLE 8 200 mg of 2- [N-benzoyl-N- (2 ', 6'-dichlorophenyl) amino] -2-imidazoline is refluxed for 32 hours with 15 mg of 2-
14S69B14S69B
12 (2' ,.6'-dichlorphenylamino)-2-imidazolin i lo ml absolut toluen. Derefter tørres ved inddampning, og remanensen om-krystalliseres fra 8 ml isopropanol. Man opnår således 160 mg ren l-benzoyl-2-(2',6,-dichlorphenylamino)-2-imidazolin 5 med smeltepunkt = 160-162 °C, som er identisk med produk tet ifølge eksempel 1.12 (2 ', .6'-dichlorophenylamino) -2-imidazoline in 100 ml of absolute toluene. Then, by evaporation, the residue is recrystallized from 8 ml of isopropanol. There is thus obtained 160 mg of pure 1-benzoyl-2- (2 ', 6, -dichlorophenylamino) -2-imidazoline 5, m.p. = 160-162 ° C, which is identical to the product of Example 1.
EKSEMPEL 9 500 mg 2-[N-m-toluyl-(2’,6,-dichlorphenyl)-amino]-2-imida-zolin (1,43 mmol) opvarmes i 18 timer under tilbagesvaling 10 med 33 mg 2-(21,6,-dichlorphenylamino)-2-imidazolin (0,143 mmol) i 20 ml absolut xylen. Den overskydende del udtrækkes i vakuum, remanensen opløses varmt i 3,5 ml isopropa-nol, og man lader den langsomt udkrystallisere. Man opnår således 342 mg ren l-m-toluyl-2-(21,6’-dichlorphenylamino)-15 2-imidazolin (68,4?ό). Smeltepunkt = 157-158 °C. Produktet er identisk med det i eksempel 5 beskrevne.EXAMPLE 9 500 mg of 2- [Nm-toluyl- (2 ', 6, -dichlorophenyl) amino] -2-imidazoline (1.43 mmol) is heated at reflux for 10 hours with 33 mg of 2- (21, 6-Dichlorophenylamino) -2-imidazoline (0.143 mmol) in 20 ml of absolute xylene. The excess part is extracted in vacuo, the residue is dissolved hot in 3.5 ml of isopropanol and allowed to slowly crystallize. There is thus obtained 342 mg of pure 1-m-toluyl-2- (21,6'-dichlorophenylamino) -15-2-imidazoline (68.4µ). Melting point = 157-158 ° C. The product is identical to that described in Example 5.
Den som udgangsmateriale tjenende 2-[N-m-toloyl-(2’,6'-di-chlorphenyl)-amino]-2-imidazolin fremstilles ved omsætning af 2-(21,6,-dichlorphenylamino)-2-imidazolin med m-toluylsyre-chlorid. Smeltepunkt = 159-164 °C.The 2- [Nm-tholoyl- (2 ', 6'-dichlorophenyl) amino] -2-imidazoline starting material is prepared by reacting 2- (21,6, -dichlorophenylamino) -2-imidazoline with m- toluic acid chloride. Melting point = 159-164 ° C.
20 pKg = 6,68 (i 70?o methylcellosolve ved stuetemperatur).20 pKg = 6.68 (in 70 o of methyl cellulose at room temperature).
EKSEMPEL 10 1,52 g (22 mmol) 1,2,4-triazol opløses i 50 ml vandfri te-trahydrofuran og dertil dryppes under omrøring en opløsning af 1,54 g (11 mmol) benzoylchlorid i 20 ml vandfri 25 tetrahydrofuran ved stuetemperatur. Efter fuldført til- drypning omrøres yderligere i en time, det krystallinske 1,2,4-triazolhydrochlorid affiltreres, og filtratet, som indeholder 1-benzoyl-l,2,4-triazolid, dryppes til en opløsning af 2,30 g (10 mmol) 2-(2,6-dichlorphenylamino)-30 2-imidazolin i 40 ml vandfri tetrahydrofuran ved stuetem- 13 145696 peratur, hvorefter det hele sættes hen natten over ved stuetemperatur. Tetrahydrofuranen fjernes under vakuum og inddampningsresten omkrystalliseres fra isopropanol, hvorved der opnås 2,10 g 1-benzoy1-2-(2',6'-dichlorphe-3 nylamino)-2-imidazolin i et udbytte på 62,9%. Smelte punkt 160-162 °C.EXAMPLE 10 1.52 g (22 mmol) of 1,2,4-triazole are dissolved in 50 ml of anhydrous tetrahydrofuran and, with stirring, a solution of 1.54 g (11 mmol) of benzoyl chloride in 20 ml of anhydrous tetrahydrofuran is dropped at room temperature. . After completion of the addition, the mixture is further stirred for one hour, the crystalline 1,2,4-triazole hydrochloride is filtered off and the filtrate containing 1-benzoyl-1,2,4-triazolid is dripped to a solution of 2.30 g (10 g). mmol) 2- (2,6-dichlorophenylamino) -30-2-imidazoline in 40 ml of anhydrous tetrahydrofuran at room temperature, after which it is added overnight at room temperature. The tetrahydrofuran is removed in vacuo and the residue is recrystallized from isopropanol to give 2.10 g of 1-benzoyl-2- (2 ', 6'-dichlorophen-3-nylamino) -2-imidazoline in a yield of 62.9%. Melting point 160-162 ° C.
EKSEMPEL 11 2,44 g (11 mmol) 1-benzoylbenzimidazolid og 2,30 g (10 mmol) 2-(2,6-dichlorphenylamino)-2-imidazolin koges under tilba-10 gesvaling i 50 ml vandfri benzen i 6 timer, hvorefter ben- zenen fjernes under vakuum., og den krystallinske rest om-krystalliseres fra isopropanol. Man opnår 2,01 g l-benzoyl_ 2-(2',6'-dichlorphenylamino)-2-imidazolin i et udbytte på 60/0 og med et smeltepunkt på 160-162 °C.EXAMPLE 11 2.44 g (11 mmol) of 1-benzoylbenzimidazolid and 2.30 g (10 mmol) of 2- (2,6-dichlorophenylamino) -2-imidazoline are boiled under reflux in 50 ml of anhydrous benzene for 6 hours. whereupon the benzene is removed under vacuum and the crystalline residue is recrystallized from isopropanol. 2.01 g of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are obtained in a yield of 60/0 and with a melting point of 160-162 ° C.
15 EKSEMPEL 12 2,46 g (11 mmol) 1-benzoylbenztriazolid og 1,84 g (8 mmol) 2-(2,6-dichlorphenylamino)-2-imidazolin omsættes som beskrevet i eksempel 11 og oparbejdes. Man opnår 2,15 g 1-benzoyl-2-(2',61-dichlorphenylamino)-2-imidazolin i et 20 udbytte på 78,1 ?ό og med et smeltepunkt på 160-162 °C.EXAMPLE 12 2.46 g (11 mmol) of 1-benzoylbenzetriazolid and 1.84 g (8 mmol) of 2- (2,6-dichlorophenylamino) -2-imidazoline are reacted as described in Example 11 and worked up. 2.15 g of 1-benzoyl-2- (2 ', 61-dichlorophenylamino) -2-imidazoline are obtained in a yield of 78.1 ° C and with a melting point of 160-162 ° C.
Claims (2)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT547474 | 1974-07-03 | ||
| AT547474A AT333749B (en) | 1974-07-03 | 1974-07-03 | PROCESS FOR THE PREPARATION OF NEW 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES |
| JP60076 | 1976-01-01 | ||
| JP60076A JPS5283661A (en) | 1974-07-03 | 1976-01-01 | Novel 22arylaminoo22 imidazoline derivatives and salts thereof* |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK254275A DK254275A (en) | 1976-01-04 |
| DK145696B true DK145696B (en) | 1983-01-31 |
| DK145696C DK145696C (en) | 1983-07-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK254275A DK145696C (en) | 1974-07-03 | 1975-06-06 | PROCEDURE FOR THE PREPARATION OF 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES |
Country Status (10)
| Country | Link |
|---|---|
| JP (2) | JPS5134156A (en) |
| AT (1) | AT333749B (en) |
| BG (1) | BG26527A3 (en) |
| CH (1) | CH613193A5 (en) |
| CS (1) | CS193517B2 (en) |
| DD (1) | DD118639A1 (en) |
| DE (2) | DE2521709C3 (en) |
| DK (1) | DK145696C (en) |
| FI (1) | FI64145C (en) |
| NL (2) | NL177402C (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5297383A (en) * | 1976-02-13 | 1977-08-16 | Ngk Spark Plug Co | Ceramic honeycomb structures for exhaust gas purification |
| JPS5499090A (en) * | 1978-01-23 | 1979-08-04 | Nissan Motor Co Ltd | Monolithic catalyst structure and production thereof |
| DE2811847A1 (en) * | 1978-03-17 | 1979-09-20 | Lentia Gmbh | NEW ARYLAMINOIMIDAZOLINE DERIVATIVES, THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS |
| DE3200258A1 (en) * | 1982-01-07 | 1983-07-21 | Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München | SUBSTITUTED 1-BENZOYL-2-PHENYLIMINO IMIDAZOLIDINE, THE ACID ADDITION SALTS THEREOF, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THE SAME |
| JPS6091220U (en) * | 1983-11-30 | 1985-06-22 | 株式会社 土屋製作所 | honeycomb filtration element |
| EP1333028A1 (en) * | 2002-01-31 | 2003-08-06 | Boehringer Ingelheim Pharma GmbH & Co.KG | 2'-Halo-3',5'-dialkoxyphen-1'-yl-imino-2-imidazolidine derivatives and the use thereof for the treatment of urinary incontinence |
| US6703409B2 (en) | 2002-01-31 | 2004-03-09 | Boehringer Ingelheim Pharma Gmbh & Co Kg | 2′-Halo-3′,5′-dialkoxyphen-1′-yl-imino-2-imidazolidine and the use thereof as a drug |
| WO2012007426A1 (en) | 2010-07-13 | 2012-01-19 | Basf Se | Azoline substituted isoxazoline benzamide compounds for combating animal pests |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE741947A (en) * | 1969-11-19 | 1970-05-04 | N-acyl-2-arylamino-imidazoline |
-
1974
- 1974-07-03 AT AT547474A patent/AT333749B/en not_active IP Right Cessation
-
1975
- 1975-05-15 DE DE2521709A patent/DE2521709C3/en not_active Expired
- 1975-05-15 DE DE2560104A patent/DE2560104C2/en not_active Expired
- 1975-06-06 DK DK254275A patent/DK145696C/en not_active IP Right Cessation
- 1975-06-09 BG BG7530228A patent/BG26527A3/xx unknown
- 1975-06-10 FI FI751721A patent/FI64145C/en not_active IP Right Cessation
- 1975-06-19 CH CH801875A patent/CH613193A5/en not_active IP Right Cessation
- 1975-06-23 NL NLAANVRAGE7507456,A patent/NL177402C/en not_active IP Right Cessation
- 1975-06-24 JP JP50077063A patent/JPS5134156A/en active Granted
- 1975-07-01 DD DD187007A patent/DD118639A1/xx unknown
- 1975-07-03 CS CS754745A patent/CS193517B2/en unknown
-
1976
- 1976-01-01 JP JP60076A patent/JPS5283661A/en active Pending
-
1985
- 1985-04-15 NL NL8501099A patent/NL8501099A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK145696C (en) | 1983-07-18 |
| DK254275A (en) | 1976-01-04 |
| DD118639A1 (en) | 1976-03-12 |
| ATA547474A (en) | 1976-03-15 |
| DE2521709B2 (en) | 1981-06-19 |
| FI751721A (en) | 1976-01-04 |
| DE2521709A1 (en) | 1976-02-05 |
| NL8501099A (en) | 1985-08-01 |
| JPS5134156A (en) | 1976-03-23 |
| BG26527A3 (en) | 1979-04-12 |
| NL7507456A (en) | 1976-01-06 |
| CH613193A5 (en) | 1979-09-14 |
| CS193517B2 (en) | 1979-10-31 |
| DE2560104B2 (en) | 1981-07-16 |
| FI64145B (en) | 1983-06-30 |
| NL177402C (en) | 1985-09-16 |
| FI64145C (en) | 1983-10-10 |
| JPS5230516B2 (en) | 1977-08-09 |
| DE2560104C2 (en) | 1982-03-25 |
| JPS5283661A (en) | 1977-07-12 |
| AT333749B (en) | 1976-12-10 |
| DE2521709C3 (en) | 1982-04-29 |
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