FI69068B - FREQUENCY REFRIGERATION OF BRAKING CARDS SUBSTITUTES 2-PHENYLAMINO-IMIDAZOLINER - Google Patents
FREQUENCY REFRIGERATION OF BRAKING CARDS SUBSTITUTES 2-PHENYLAMINO-IMIDAZOLINER Download PDFInfo
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- FI69068B FI69068B FI803799A FI803799A FI69068B FI 69068 B FI69068 B FI 69068B FI 803799 A FI803799 A FI 803799A FI 803799 A FI803799 A FI 803799A FI 69068 B FI69068 B FI 69068B
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- 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
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Abstract
Description
1 690681 69068
Menetelmä valmistaa bradykardisesti vaikuttavia substituoituja 2-fenyyliamino-imidatsoliineja - Förfarande för framställning av bradykardiskt verkande substituerade 2-fenylamino-imidazo-1 inerProcess for the preparation of bradycardically active substituted 2-phenylaminoimidazolines - Preparation of bradycardically active bradycardic network with 2-phenylaminoimidazo-1 iner
Keksinnön kohteena on menetelmä valmistaa bradykardisesti vaikuttavia substituoituja 2-fenyyliamino-imidatsoliineja, joiden kaava I on _^ BrThe present invention relates to a process for the preparation of bradycardically active substituted 2-phenylaminoimidazolines of the formula I
v-O- f-( Jv-O- f- (J
^ Br R H^ Br R H
jossa R on n-propyyli-, syklopropyylimetyyli-, syklopentyyli-metyyli-, allyyli- tai metallyyliryhmä, ja niiden happoaddi-tiosuoloja.wherein R is an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and acid addition salts thereof.
Kaavan I mukaisten yhdisteiden valmistus tapahtuu keksinnön mukaan seuraavasti:The compounds of the formula I are prepared according to the invention as follows:
Kaavan II mukainen 2-(2,6-dibromi-4-metyylifenyyli-imino)-imidätsolidiini «3c-^-n=(J (ii>2- (2,6-Dibromo-4-methylphenylimino) imidazolidine of formula II «3c - ^ - n = (J (ii>
^ Br H^ Br H
saatetaan reagoimaan yleiskaavan III mukaisen halogenidin kanssais reacted with a halide of general formula III
Hal-R (III) 2 69068 jossa Hal on kloori-, bromi- tai jodiatomi ja R tarkoittaa samaa kuin edellä.Hal-R (III) 269068 wherein Hal is a chlorine, bromine or iodine atom and R is as defined above.
Menetelmän reaktio tapahtuu kuumentamalla reaktiokomponentteja lämpötiloissa 40 - 150°C, parhaiten kun mukana on polaarista tai polaaritonta liuotinta.The reaction of the process takes place by heating the reaction components at temperatures of 40 to 150 ° C, preferably in the presence of a polar or non-polar solvent.
Tarkemmat reaktio-olosuhteet riippuvat suuresti reaktiokompo-nenttien reaktiivisuudesta. Alkyloinnissa on suositeltavaa käyttää ylimäärää yleiskaavan III mukaista halogenidia ja suorittaa reaktio happoa sitovan aineen läsnäollessa.The exact reaction conditions depend greatly on the reactivity of the reaction components. In the alkylation, it is preferable to use an excess of the halide of the general formula III and to carry out the reaction in the presence of an acid-binding agent.
Kaavan II mukaiset lähtöyhdisteet tunnetaan kirjallisuudesta (vrt. esimerkiksi belgialainen patentti 623 305 tai Chem. Ber. 107, 2644 (1974 ) tai Liebigs Ann. Chem. 751, 159 (1971)). Kaavan III mukaiset yhdisteet voidaan valmistaa halogenoimalla perustana oleva alkoholi.The starting compounds of the formula II are known from the literature (cf., for example, Belgian patent 623 305 or Chem. Ber. 107, 2644 (1974) or Liebigs Ann. Chem. 751, 159 (1971)). Compounds of formula III may be prepared by halogenation of the base alcohol.
Yleiskaavan I mukaiset 2-fenyyliamino-imidatsoliinit-(2) voidaan tavalliseen tapaan muuntaa fysiologisesti sopiviksi happoadditiosuoloikseen. Suolanmuodostukseen sopivia happoja ovat esimerkiksi suolahappo, bromivetyhappo, jodivetyhappo, fluorivetyhappo, rikkihappo, fosforihappo, typpihappo, etikka-happo, propionihappo, voihappo, kapronihappo, valeriaana-happo, oksaalihapo, malonihappo, meripihkahappo, maleiini-happo, fumaarihappo, maitohappo, viinihappo, sitruunahappo, omenahappo, bentsoehappo, p-hydroksibentsoehappo, p-amino-bentsoehapo, ftaalihappo, kanelihappo, salisyylihappo, askorbiinihappo, metaanisulfonihappo, 8-klooriteofylliini ja vastaavat.The 2-phenylaminoimidazolines (2) of the general formula I can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, lactic acid, valeric acid, oxalic acid, malonic acid, malonic acid, malonic acid, , malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chloroheophylline and the like.
Uudet yleiskaavan I mukaiset yhdisteet ja niiden happoaddi-tiosuolat vaikuttavat erittäin bradykardisesti ja sopivat siten koronaarisairauksien hoitoon. Vaikutus sydämen lyönti- n 3 69068 taajuuteen tutkittiin kaniineilla ja spinaalirotilla sekä intakteilla, narkotisoiduilla rotilla.The new compounds of the general formula I and their acid addition salts have a very bradycardic effect and are therefore suitable for the treatment of coronary heart disease. The effect on the heart rate of 3,69068 was studied in rabbits and spinal rats as well as in intact, anesthetized rats.
Annostus on 0,1 - 80 mg, parhaiten 1-30 mg.The dosage is 0.1 to 80 mg, preferably 1 to 30 mg.
On tunnettua, että 2-[N-allyy1i-N-(2,6-dikloorifenyyli)-amino]-imidatsoliini (St 567) metabolisoituu ainakin osittain 2-(2,6-dikloorifenyyliamino)-imidatsoliiniksi (St 155; klonidiini) seuraavasti: Φ-VoIt is known that 2- [N-allyl-N- (2,6-dichlorophenyl) amino] imidazoline (St 567) is at least partially metabolized to 2- (2,6-dichlorophenylamino) imidazoline (St 155; clonidine) as follows: : Φ-Vo
Cl CH H ^ci HCl CH H ^ ci H
NOF
ch2 st 567 st 155ch2 st 567 st 155
Oletetaan, että muutkin siltatyppiatomissa substituoidut fenyyliamino-imidatsoliinit vastaavalla tavalla metabolisoi-tuvat: tfrO -<^"äIt is assumed that other phenylaminoimidazolines substituted on the bridge nitrogen atom are similarly metabolized: tfrO - <^ "ä
Br H Br HBr H Br H
R: syklopropyylimetyyli (STH 2148) St 464 R: syklopentyylimetyyli (STH 2187) >' i-Q ' =(._R: cyclopropylmethyl (STH 2148) St 464 R: cyclopentylmethyl (STH 2187)> 'i-Q' = (._
^Br H Br H^ Br H Br H
R: syklopropyylimetyyli (STH 2437) St 895 R: syklopentyylimetyyli (STH 2453) R: allyyli (STH 2434) 4 69068R: cyclopropylmethyl (STH 2437) St 895 R: cyclopentylmethyl (STH 2453) R: allyl (STH 2434) 4 69068
Yhdiste St 155 ja yhdiste St 464 ovat molemmat voimakkaasti verenpainetta alentavia ja osoittavat lisäksi klonidiinin tapaista vaikutusta. Kun keskushermosto on eristetty (spinaa-lirotilla) aikaansaa St 155 perifeeristen reseptoreiden stimuloinnin kautta verenpainetta nostavan vaikutuksen. Tämän lisäksi yhdisteellä St 155 on refleksibradykardinen vaikutus.Compound St 155 and Compound St 464 are both potent antihypertensive and further exhibit a clonidine-like effect. When the central nervous system is isolated (in spinal larvae), St 155 produces a hypertensive effect through stimulation of peripheral receptors. In addition, St 155 has a reflex bradycardic effect.
Kiertäjähermon katkaisun jälkeen (frekvenssirotilla) jää sydämen lyöntitaajuutta alentava vaikutus klonidiinin tapaisilla aineilla, kuten yhdisteellä St 155 ja St 464, pysyväksi.After rupture of the circulatory nerve (in a frequency rat), the heart rate-lowering effect with clonidine-like agents such as St 155 and St 464 remains permanent.
Metaboliitti St 895 vaikuttaa kuitenkin tässä suhteessa erilailla. Erona yhdisteelle St 464 on mainitulla metabolii-tilla klonidiinin tapainen sivuvaikutus voimakkaasti heikentynyt, kuten seuraavassa taulukossa esitetyistä arvoista ilmenee. Taulukossa on esitetty koetulokset yhdisteiden klonidiinin tapaisesta vaikutuksesta. Kokeissa on koe-eläiminä käytetty spinaalirottia ja frekvenssirottia jolloinHowever, the metabolite St 895 acts differently in this respect. In contrast to St 464, the clonidine-like side effect of said metabolite is severely reduced, as shown by the values shown in the following table. The table shows the experimental results for the clonidine-like effect of the compounds. In the experiments, spinal rats and frequency rats have been used as experimental animals
Taulukko ITable I
Spinaalirotta: D30 = Annos (pg/kg), joka aikaansaa 30 mm Hg verenpaineen alennuksen (n = 18)Spinal rat: D30 = Dose (pg / kg) that produces a 30 mm Hg reduction in blood pressure (n = 18)
Frekvenssirotta: D50 = Annos (pg/kg), joka aikaansaa sydänfrek- venssin alennuksen, joka on 50 lyöntiä/min.Frequency rat: D50 = Dose (pg / kg) that causes a reduction in heart rate of 50 beats / min.
(n = 18).(n = 18).
Spinaalirotta Frekvenssirotta -----^30 Pg/kg_____D5n pg/kg_Spinal rat Frequency rat ----- ^ 30 Pg / kg _____ D5n pg / kg_
St 895 600 300St 895 600 300
St 464 21 65St 464 21 65
Klonidiini 9,1 1) 7^3 2) 1) n = 126 2) n = 144 5 69068 n tarkoittaa tarkastettujen koe-eläinten lukumäärää.Clonidine 9.1 1) 7 ^ 3 2) 1) n = 126 2) n = 144 5 69068 n means the number of experimental animals tested.
Kaavan I mukaisia yhdisteitä on tämän lisäksi kokeiltu kaneihin niiden sydämen lyöntitaajuntta alentavien vaikutusten selvittämiseksi, jolloin kokeissa on saatu seuraavat tulokset:In addition, the compounds of the formula I have been tested on rabbits for their effects on lowering the heart rate, with the following results:
Taulukko IITable II
Lyöntitaajuuden (lyönti/min) muutos 16 min. koeyhdisteen _R__Esim. (i.v., 1 mg/kg) antamisen jälkeen -CH2-^ 1 - 52 ^CH3 -CHo-C 2 - 27 ^ CH2 n-C3H7 3 - 62 -CH2-CH=CH2 5 - 55Change in heart rate (beats / min) 16 min. test compound _R__Esim. (i.v., 1 mg / kg) after administration of -CH 2 - ^ 1 - 52 ^ CH 3 -CH 0 -C 2 - 27 ^ CH 2 n -C 3 H 7 3 - 62 -CH 2 -CH = CH 2
Keksinnön tarkoituksena oli löytää valmistusmenetelmä sellaiselle yhdisteelle, jolla on yleinen klonidiinirakenne, joka alentaa sydämen lyöntitaajuutta, mutta jolla on vähän tai ei lainkaan vaikutusta verenpaineeseen. Klonidiinilla on erittäin voimakas vaikutus sekä lyöntitaajuuteen että verenpaineeseen.The object of the invention was to find a process for the preparation of a compound having a general clonidine structure which lowers the heart rate but has little or no effect on blood pressure. Clonidine has a very strong effect on both heart rate and blood pressure.
Yhdisteet St 567, STH 2148, 2187, 2437, 2453 ja 2434 ovat esimerkkejä yhdisteistä, jotka täyttävät edellisen vaatimuksen. Perustavaa laatua oleva ero näiden yhdisteiden ja klonidiinin välillä on ryhmä, joka on sitoutunut siltana olevaan typpi-atorni in.The compounds St 567, STH 2148, 2187, 2437, 2453 and 2434 are examples of compounds which satisfy the preceding requirement. The fundamental difference between these compounds and clonidine is the group attached to the bridged nitrogen tower.
6906869068
Keksinnön mukaisella menetelmällä valmistetut yhdisteet, joissa siltana oleva typpiatomi on substituoitu, alentavat sydänfrekvenssiä, kuten taulukossa II on esitetty. Mahdollinen haittapuoli on, että tällaiset yhdisteet metabolisoituvat (vain vähäisessä määrin) klonidiini-tyyppisiksi metabolii-teiksi (St 155, 464, 895), joissa siltana oleva N-atomi on substituoimaton, ja tällaisilla metaboliiteilla voi olla vaikutus verenpaineeseen samoin kuin sydänfrekvenssiin.The compounds prepared by the process of the invention in which the bridge nitrogen atom is substituted lower the heart rate, as shown in Table II. A potential disadvantage is that such compounds are metabolized (only to a limited extent) to clonidine-type metabolites (St 155, 464, 895) in which the bridged N atom is unsubstituted, and such metabolites can have an effect on blood pressure as well as heart rate.
Taulukosta I voi nähdä, otsikon "spinaalirotta" alapuolella, että metaboliitti St 895:n vaikutus verenpaineeseen, mitattuna spinaalirotilla, on 60 kertaa pienempi kuin klonidiinin vaikutus ja 30 kertaa pienempi kuin rakenteellisesti lähellä olevan St 464:n vaikutus.It can be seen from Table I, under the heading "spinal rat", that the effect of the metabolite St 895 on blood pressure, measured in the spinal rat, is 60 times smaller than that of clonidine and 30 times smaller than that of structurally close St 464.
Koska muuttuminen metaboliitiksi tapahtuu vain suhteellisen vähäisessä määrin, on suhteella D30/D50 pieni merkitys, mutta siinä tapauksessa, että metaboliittien sydämenirekvenssiä alentava vaikutus on tuntuva, voidaan jälleen todeta, että St 895 on paljon suotuisampi yhdiste kuin St 464.Because conversion to the metabolite occurs only to a relatively small extent, the D30 / D50 ratio is of little importance, but in the case where the heart rate-lowering effect of the metabolites is appreciable, it can again be stated that St 895 is a much more favorable compound than St 464.
Kaavan I mukaista yhdistettä tai sen happoadditiosuolaa voidaan käyttää myös muunlaisten tehoaineiden kanssa. Sopivia galeeni-sia antomuotoja ovat esimerkiksi tabletit, kapselit, puikot, liuokset tai jauheet; tällöin voidaan niiden valmistukseen käyttää näiden antomuotojen valmistuksessa tavallisesti käytettyjä galeenisia apu-, kanto-, tehostus- tai voiteluaineita tai aineita, joilla saadaan aikaan kestovaikutus.The compound of the formula I or its acid addition salt can also be used with other active ingredients. Suitable galenical administration forms are, for example, tablets, capsules, sticks, solutions or powders; in which case they may be prepared using galenical auxiliaries, carriers, enhancers or lubricants commonly used in the preparation of these dosage forms, or substances which produce a lasting effect.
Seuraavat esimerkit selventävät keksintöä.The following examples illustrate the invention.
IIII
77
Esimerkki 1 69068 2-[N-(syklopropyy1imetyyli)-N-(2,6-dibromi-4-metyy1i-fenyy1i)-amino]-2-imidätsoiiini-hydrokloridi _^Br N_ ch3 —(Cy— «—^ x HC1Example 1 69068 2- [N- (Cyclopropylmethyl) -N- (2,6-dibromo-4-methyl-phenyl) -amino] -2-imidazoline hydrochloride -N-Br3- (Cy- «- ^ x HCl)
Br CH2 hBr CH2 h
AA
4,2 g (0,013 moolia) 2-f(2,6-dibromi-4-metyyli-fenyyli)-imino]-imidatsolidiinia ja 1,7 g (150 S) kloorimetyylisyklopropaania kuumennetaan 42 tuntia refluksoiden ja samalla sekoittaen 25 mlrssa asetonitriiliä. Reaktioseos haihdutetaan tämän jälkeen tyhjiössä kuiviin ja jäännös liuotetaan noin 1 N suolahappoon. Suolahappoliuos uutetaan kaksi kertaa eetterillä (eetteriuutteet heitetään pois) ja sen jälkeen fraktiouutetaan eetterillä nousevissa pH-arvoissa (alkalisointi 2 N natrium-hydroksidilla). Saaduista 12 eetterijakeesta yhdistetään yhtenäiset jakeet (kontrolli ohutlevykromatogrammilla), kuivataan magnesiumsulfaatilla ja lisätään eetteripitoista suolahappoa, kunnes saadaan kongohapan reaktio. Tällöin uusi imidatsoliini-hydrokloridi saostuu. Se erotetaan suodattamalla, pestään eetterillä ja kuivataan.4.2 g (0.013 mol) of 2 - [(2,6-dibromo-4-methyl-phenyl) -imino] -imidazolidine and 1.7 g (150S) of chloromethylcyclopropane are heated at reflux for 42 hours with stirring in 25 ml of acetonitrile. The reaction mixture is then evaporated to dryness in vacuo and the residue is dissolved in about 1N hydrochloric acid. The hydrochloric acid solution is extracted twice with ether (the ether extracts are discarded) and then the fraction is extracted with ether at increasing pH (alkalization with 2N sodium hydroxide). From the 12 ether fractions obtained, the homogeneous fractions are combined (control by thin-layer chromatogram), dried over magnesium sulfate and ethereal hydrochloric acid is added until a Congo acid reaction is obtained. This precipitates new imidazoline hydrochloride. It is filtered off, washed with ether and dried.
Saanto: 1,9 g (vastaa 36,5 % teoreettisesta).Yield: 1.9 g (corresponding to 36.5% of theory).
Sp.: 140°C.M.p .: 140 ° C.
6906869068
Edellisen esimerkin kanssa analogisesti valmistettiin seuraavat kaavan I mukaiset yhdisteet:In analogy to the previous example, the following compounds of formula I were prepared:
Esim. Saanto Sp.Eg Saanto Sp.
n:o___R_( % teor. )_( °C)_ CH3 / 2 -CHo-C 57,7 152-153 % CH2 (emäs) 3 -C3H7n 77,5 280 (hydrobromidi) 4 -CH2-J 9,3 92-93 (emäs) 5 -CH2~CH=CH2 80,7 272-274 (hydrobromidi)n: ___ R_ (% of theory) _ (° C) _ CH3 / 2 -CHo-C 57.7 152-153% CH2 (base) 3 -C3H7n 77.5 280 (hydrobromide) 4 -CH2-J 9.3 92-93 (base) δ -CH 2 ~ CH = CH 2 80.7 272-274 (hydrobromide)
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19792949287 DE2949287A1 (en) | 1979-12-07 | 1979-12-07 | NEW SUBSTITUTED 2-PHENYLAMINO-IMIDAZOLINE (2), THE ACID ADDITION SALTS THEREOF, THE MEDICINAL PRODUCTS CONTAINING THE SAME AND METHOD FOR THE PRODUCTION THEREOF |
DE2949287 | 1979-12-07 |
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FI803799L FI803799L (en) | 1981-06-08 |
FI69068B true FI69068B (en) | 1985-08-30 |
FI69068C FI69068C (en) | 1985-12-10 |
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Application Number | Title | Priority Date | Filing Date |
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FI803799A FI69068C (en) | 1979-12-07 | 1980-12-05 | FREQUENCY REFRIGERATION OF BRAKING CARDS SUBSTITUTES 2-PHENYLAMINO-IMIDAZOLINER |
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EP (1) | EP0030616B1 (en) |
JP (1) | JPS5692274A (en) |
AT (1) | ATE5818T1 (en) |
AU (1) | AU533756B2 (en) |
DE (2) | DE2949287A1 (en) |
DK (1) | DK521680A (en) |
ES (1) | ES497480A0 (en) |
FI (1) | FI69068C (en) |
IE (1) | IE50485B1 (en) |
IL (1) | IL61637A (en) |
NO (1) | NO151412C (en) |
ZA (1) | ZA807611B (en) |
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US4644007A (en) * | 1981-11-20 | 1987-02-17 | Alcon Laboratories, Inc. | 3-chloro-4-(4,5-dihydro-1H-imidazo-2-yl)-amino-5-alkylbenzoic acids, esters, salts, compositions and methods |
US4515800A (en) * | 1981-11-20 | 1985-05-07 | Icilio Cavero | Method of lowering intraocular pressure using phenylimino-imidazoles |
US4517199A (en) * | 1981-11-20 | 1985-05-14 | Alcon Laboratories, Inc. | Method for lowering intraocular pressure using phenylimino-imidazoles |
US4461904A (en) * | 1981-11-20 | 1984-07-24 | Alcon Laboratories, Inc. | 2-(Trisubstituted phenylimino)-imidazolines |
HU192986B (en) * | 1984-05-23 | 1987-08-28 | Egyt Gyogyszervegyeszeti Gyar | Process for production of imidasodiline derivatives |
DE19514579A1 (en) | 1995-04-20 | 1996-10-24 | Boehringer Ingelheim Kg | Use of alpha-1-olone agonists for the treatment of urinary incontinence |
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AT285599B (en) * | 1968-06-21 | 1970-11-10 | Boehringer Sohn Ingelheim | Process for the preparation of new trisubstituted 2-arylaminoimidazolines and their salts |
BE759048A (en) * | 1969-11-17 | 1971-05-17 | Boehringer Sohn Ingelheim | NEW N-AMINOALCOYL-ARYLAMINO-IMIDAZOLINES- (2) SUBSTITUTES AND METHODS FOR MAKING THEM |
DE2259160A1 (en) * | 1972-12-02 | 1974-06-06 | Boehringer Sohn Ingelheim | NEW SUBSTITUTED 2-PHENYLAMINOIMIDAZOLINE, THEIR ACID-ADDITIONAL SALTS AND METHOD FOR MANUFACTURING THE SAME AND THEIR USE AS A MEDICINAL PRODUCT |
DE2523103C3 (en) * | 1975-05-24 | 1979-11-29 | C.H. Boehringer Sohn, 6507 Ingelheim | Substituted 2- [N-Progargyl-N- (2-chlorophenyl) amino] -imidazoline- ^), their acid addition salts, processes for their preparation and their use |
DE2636732A1 (en) * | 1976-08-14 | 1978-02-16 | Boehringer Sohn Ingelheim | NEW SUBSTITUTED 2-PHENYLAMINO IMIDAZOLINE (2), THE ACID ADDITION SALTS THEREOF, THE MEDICINAL PRODUCTS CONTAINING THE SAME AND METHOD FOR THE PRODUCTION THEREOF |
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1979
- 1979-12-07 DE DE19792949287 patent/DE2949287A1/en not_active Withdrawn
-
1980
- 1980-11-03 DE DE8080106725T patent/DE3066104D1/en not_active Expired
- 1980-11-03 AT AT80106725T patent/ATE5818T1/en not_active IP Right Cessation
- 1980-11-03 EP EP80106725A patent/EP0030616B1/en not_active Expired
- 1980-12-05 IL IL61637A patent/IL61637A/en unknown
- 1980-12-05 IE IE2555/80A patent/IE50485B1/en unknown
- 1980-12-05 ES ES497480A patent/ES497480A0/en active Granted
- 1980-12-05 AU AU65136/80A patent/AU533756B2/en not_active Ceased
- 1980-12-05 ZA ZA00807611A patent/ZA807611B/en unknown
- 1980-12-05 JP JP17196380A patent/JPS5692274A/en active Pending
- 1980-12-05 DK DK521680A patent/DK521680A/en not_active Application Discontinuation
- 1980-12-05 FI FI803799A patent/FI69068C/en not_active IP Right Cessation
- 1980-12-05 NO NO803682A patent/NO151412C/en unknown
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Publication number | Publication date |
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FI803799L (en) | 1981-06-08 |
DE2949287A1 (en) | 1981-06-11 |
DK521680A (en) | 1981-06-08 |
ES8201978A1 (en) | 1982-01-01 |
NO151412B (en) | 1984-12-27 |
NO803682L (en) | 1981-06-09 |
ES497480A0 (en) | 1982-01-01 |
ZA807611B (en) | 1982-08-25 |
IL61637A (en) | 1984-11-30 |
IE50485B1 (en) | 1986-04-30 |
IL61637A0 (en) | 1981-01-30 |
NO151412C (en) | 1985-04-10 |
EP0030616B1 (en) | 1984-01-11 |
DE3066104D1 (en) | 1984-02-16 |
AU6513680A (en) | 1981-06-18 |
FI69068C (en) | 1985-12-10 |
IE802555L (en) | 1981-06-07 |
JPS5692274A (en) | 1981-07-25 |
ATE5818T1 (en) | 1984-01-15 |
EP0030616A1 (en) | 1981-06-24 |
AU533756B2 (en) | 1983-12-08 |
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