CH627454A5 - Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts - Google Patents
Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts Download PDFInfo
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- CH627454A5 CH627454A5 CH506580A CH506580A CH627454A5 CH 627454 A5 CH627454 A5 CH 627454A5 CH 506580 A CH506580 A CH 506580A CH 506580 A CH506580 A CH 506580A CH 627454 A5 CH627454 A5 CH 627454A5
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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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- C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
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Abstract
Description
627454 627454
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PATENTANSPRUCH Verfahren zur Herstellung neuer disubstituierter 2-Phe-nylimino-imidazolidine der Formel I PATENT CLAIM Process for the preparation of new disubstituted 2-phenylimino-imidazolidines of the formula I.
H H
H H
in der Z einen Rest aus der Gruppe 2-Äthyl-6-methylphenyl, 2,6-Difluorphenyl, 2-Chlor-6-fluorphenyl, 2,6-Dimethoxy-phenyl, 2,6-Dihydroxyphenyl, 2,6-Ditrifluormethylphenyl, 2-Brom-6-methylphenyI, 2-Brom-6-chlorphenyl, 2-Chlor-6--trifluor-methylphenyl oder 2-Fluor-6-trifluormethylphenyl bedeutet, sowie deren Säureadditionssalzen, dadurch gekennzeichnet, dass man ein Carbodiimid der Formel II Z is a radical from the group 2-ethyl-6-methylphenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-chlorophenyl, 2-chloro-6-trifluoromethylphenyl or 2-fluoro-6-trifluoromethylphenyl, and their acid addition salts, characterized in that a carbodiimide of the formula II
Z-N=C=N-Z (II). Z-N = C = N-Z (II).
in der Z wie oben angegeben definiert ist, mit Äthylendiamin bzw. dessen Salzen umsetzt und gegebenenfalls die so erhaltene Verbindung in ein physiologisch unbedenkliches Säureadditionssalz überführt. in which Z is as defined above, is reacted with ethylenediamine or its salts and, if appropriate, the compound thus obtained is converted into a physiologically acceptable acid addition salt.
2-Phenylimino-imidazolidine beanspruchen wegen ihrer hervorragenden pharmakologischen und therapeutischen Eigenschaften seit langem ein starkes Interesse. Verbindungen dieses Typs sind daher in der Literatur vielfach beschrieben worden und z.B. in den BE-PSen 623 305, 653 933, 687 656, 687 657 und 705 944 offenbart. In diesen Schrifttumstellen sind auch die wesentlichen Verfahren zur Herstellung von 2-PhenyIimino-imidazolidinen angegeben. 2-Phenylimino-imidazolidines have long been of great interest because of their excellent pharmacological and therapeutic properties. Compounds of this type have therefore been widely described in the literature and e.g. in BE-PS 623 305, 653 933, 687 656, 687 657 and 705 944. These documents also describe the essential processes for the preparation of 2-phenylimino-imidazolidines.
Aufgrund neuerer Untersuchungen wurde festgestellt, dass unter den für eine zentrale, a-adrenerge Stimulierung erforderlichen Strukturmerkmalen bei 2-PhenyIimino-imidazolidi-nen der Konformation eine entscheidende Bedeutung zukommt. Aufgrund von Struktur-Wirkungs-Betrachtungen wurde gefunden, dass nur solche Derivate eine gute blutdrucksenkende Wirkung zeigen, deren Phenyl- und Imidazolidin-ring eine aplanare Konformation zueinander einnehmen. Based on recent investigations, it was found that the structural features of 2-phenylimino-imidazolidines are of crucial importance among the structural features required for central a-adrenergic stimulation. Based on structure-effect considerations, it was found that only those derivatives that have a good hypotensive effect, the phenyl and imidazolidine ring adopt an aplanar conformation to each other.
In diesem Falle ist die freie Drehbarkeit des Phenylringes um die C-N-Einfachbindung gehindert und die beiden Ringe stehen senkrecht bzw. annähernd senkrecht zueinander. In this case, the free rotation of the phenyl ring around the C-N single bond is prevented and the two rings are perpendicular or approximately perpendicular to one another.
Aplanarität lässt sich bei 2-Phenyliminoimidazolidinen dadurch erreichen, dass man die ortho-Positionen des aromatischen Molekülteiles substituiert: Aplanarity can be achieved with 2-phenyliminoimidazolidines by substituting the ortho positions of the aromatic part of the molecule:
Sperrige Atome bzw. Atomgruppen in diesen Stellungen hindern die freie Drehbarkeit des Phenylringes um die C-N-Einfachbindung und damit die Möglichkeit einer koplanaren Einstellung der beiden Ringe zueinander. Bulky atoms or groups of atoms in these positions prevent the free rotation of the phenyl ring around the C-N single bond and thus the possibility of a co-planar adjustment of the two rings to each other.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung neuer in ortho- und ortho'-Stellung disubstituierter 2-Phenylimino-imidazolidine der Formel I The invention relates to a process for the preparation of new 2-phenylimino-imidazolidines of the formula I which are disubstituted in the ortho and ortho 'position
H H
H H
sowie deren physiologisch verträglichen Säureadditionssaizen mit wertvollen therapeutischen, insbesondere antihypertensiven, Eigenschaften. In der Formel I bedeutet Z einen Rest aus der Gruppe 2-Äthyl-6-methylphenyl, 2,6-Difluorphenyl, 2-Chlor-6-fluorphenyl, 2,6-Dimethoxyphenyl, 2,6-Dihydroxy-phenyl, 2,6-Ditrifluormethylphenyl, 2-Brom-6-methylphenyl, 2-Brom-6-chlorphenyl oder 2-Chlor-6-trifluormethylphenyl, 2-Fluor-6-trifluormethylphenyl. as well as their physiologically compatible acid addition seeds with valuable therapeutic, especially antihypertensive, properties. In formula I, Z represents a radical from the group 2-ethyl-6-methylphenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6 -Ditrifluoromethylphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-chlorophenyl or 2-chloro-6-trifluoromethylphenyl, 2-fluoro-6-trifluoromethylphenyl.
Die Herstellung der neuen Verbindungen der Formel I erfolgt durch: The new compounds of the formula I are prepared by:
Umsetzung eines Carbodiimids der Formel II Implementation of a carbodiimide of formula II
Z-N=C=N-Z (H), Z-N = C = N-Z (H),
in der Z die oben genannte Bedeutung besitzt, mit Äthylendiamin bzw. dessen Salzen. in which Z has the meaning given above, with ethylenediamine or its salts.
Beim Carbodiimid-Verfahren erweist es sich als am zweckmässigsten, wenn in inerten Lösungsmitteln, wie z.B. Benzol, bei Raumtemperatur und nach Abdestillieren des Lösungsmittels bei erhöhter Temperatur von etwa 100 bis 220°C gearbeitet wird. In the carbodiimide process, it proves most convenient if in inert solvents such as e.g. Benzene, at room temperature and after distilling off the solvent at an elevated temperature of about 100 to 220 ° C.
Als Ausgangsprodukte für die Verbindungen der Formel II werden die neuen 2,6-disubstituierten Aniline der Formel III The starting materials for the compounds of the formula II are the new 2,6-disubstituted anilines of the formula III
Z-NH2 (III) Z-NH2 (III)
verwendet, deren Herstellung in der Regel nach einem der beiden nachstehend schematisch aufgeführten Reaktionswege erfolgt: used, the production of which is generally carried out according to one of the two reaction routes shown schematically below:
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Reaktionsweg 1: Reaction path 1:
.R .R
Butyl-Lithi Butyl lithi
R* R *
R, R' i Br R, R 'i Br
,R , R
q~ q ~
R' R '
+ CO, + CO,
-60 bis -70°C -60 to -70 ° C
oder or
,R , R
0 0
/7>< / 7> <
R' R '
= Z-NH2 III = Z-NH2 III
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Reaktionsweg 2: Pathway 2:
Z-NH2 III Z-NH2 III
Beim Syntheseweg nach 1. fallen ausser den Benzoesäuren gewöhnlich auch deren Isomere an, die am besten säulen-chromatographisch abgetrennt werden (Kieselgel). In the synthetic route according to 1, apart from the benzoic acids, their isomers are usually also obtained, which are best separated off by column chromatography (silica gel).
Die Synthese von 2,6-Ditrifluormethylphenyl-Lithium, einer Zwischenstufe für die Herstellung von 2,6-Ditrifluor-methylanilin ist z.B. von G. Hailas et al. in J. Soc. Dyers and Colourists 1970, 86, 200 beschrieben. The synthesis of 2,6-ditrifluoromethylphenyl-lithium, an intermediate for the production of 2,6-ditrifluoromethylaniline, is e.g. by G. Hailas et al. in J. Soc. Dyers and Colorists 1970, 86, 200.
Die Verbindungen der Formel II leiten sich von den so hergestellten Anilinen der Struktur der Formel III ab und sind nach bekannten Literaturmethoden zugänglich. Beispielsweise lassen sich die Carbodiimide der Formel II aus den Anilinen der Formel III wie folgt darstellen: The compounds of the formula II are derived from the anilines of the structure of the formula III thus prepared and can be obtained by known literature methods. For example, the carbodiimides of the formula II can be prepared from the anilines of the formula III as follows:
1. + HCOOH Cl Z-NH2 > Z-N=CC 1. + HCOOH Cl Z-NH2> Z-N = CC
2. + S02C12/S0C12 Cl 2. + S02C12 / S0C12 Cl
III III
+ Z-NH2.HC1 + Z-NH2.HC1
> Z-N=C=N-Z > Z-N = C = N-Z
(II). (II).
Die erfindungsgemäss herstellbaren 2-Phenyl-iminoimid-azolidine der Formel I können auf übliche Weise in ihre physiologisch verträglichen Säureadditionssalze überführt werden. Zur Salzbildung geeignete Säuren sind beispielsweise Salzsäure, Bromwasserstoffsäure, Jodwasserstoffsäure, Fluorwasserstoffsäure, Schwefelsäure, Phosphorsäure, Salpetersäure, Essigsäure, Propionsäure, Buttersäure, Capronsäure, Valeriansäure, Oxalsäure, Malonsäure, Bernsteinsäure, Maleinsäure, Fumarsäure, Milchsäure, Weinsäure, Zitronensäure, Äpfelsäure, Benzoesäure, p-Hydroxybenzoesäure, p-Amino-benzoesäure, Phthalsäure, Zimtsäure, Salicylsäure, Ascorbin-säure, Methansulfonsäure, Äthanphosphorsäure, 8-Chlor-theophyllin und dergleichen. The 2-phenyliminoimide azolidines of the formula I which can be prepared according to the invention can be converted into their physiologically tolerated acid addition salts in a customary manner. Acids suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, malic acid p-hydroxybenzoic acid, p-amino-benzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, ethane phosphoric acid, 8-chloro-theophylline and the like.
Die neuen Verbindungen sowie deren Säureadditionssalze haben wertvolle therapeutische und insbesondere blutdrucksenkende Eigenschaften und können daher bei der Behandlung der verschiedenen Erscheinungsformen der Hypertonie Anwendung finden. Verbindungen der Formel I können enterai oder auch parenteral angewandt werden. Die Dosierung liegt bei 0,1 bis 80 mg, vorzugsweise 0,5 bis 30 mg. The new compounds and their acid addition salts have valuable therapeutic and in particular hypotensive properties and can therefore be used in the treatment of the various manifestations of hypertension. Compounds of the formula I can be used enterally or parenterally. The dosage is 0.1 to 80 mg, preferably 0.5 to 30 mg.
Die Verbindungen der Formel I bzw. ihre Säureadditionssalze können auch mit andersartigen Wirkstoffen zum Einsatz gelangen. Geeignete galenische Darreichungsformen sind beispielsweise Tabletten, Kapseln, Zäpfchen, Lösungen oder Pulver; hierbei können zu deren Herstellung die üblicherweise verwendeten galenischen Hilfs-, Träger-, Spreng- oder Schmiermittel oder Substanzen zur Erzielung einer Depotwirkung Anwendung finden. The compounds of the formula I or their acid addition salts can also be used with other active substances. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories, solutions or powders; the galenical auxiliaries, carriers, disintegrants or lubricants or substances commonly used to achieve a depot effect can be used to produce them.
Das folgende Beispiel erläutert die Erfindung, ohne sie zu beschränken. The following example illustrates the invention without restricting it.
Beispiel example
2-(2-Äthyl-6-methylphenylimino)-imidazolidin 2- (2-ethyl-6-methylphenylimino) imidazolidine
Zu der Mischung aus 1,3 g (0,022 Mol) Äthylendiamin in 30 ccm absolutem Benzol werden bei 20 bis 25°C 6 g (0,022 To the mixture of 1.3 g (0.022 mol) of ethylenediamine in 30 cc of absolute benzene are added 6 g (0.022
627454 627454
Mol) N,N'-Di-(2-äthyl-6-methylphenyl)-carbodiimid, gelöst in 10 ccm absolutem Benzol, langsam unter Rührung zugegeben (Eiskühlung!). Hierauf lässt man bei Raumtemperatur 2 Stunden lang nachreagieren und engt die Reaktionsmischung im Vakuum ein. Man erhält 7 g (entsprechend 99,0% der Theorie) des Zwischenproduktes der Formel Mol) N, N'-di- (2-ethyl-6-methylphenyl) carbodiimide, dissolved in 10 cc of absolute benzene, slowly added with stirring (ice cooling!). The mixture is then left to react at room temperature for 2 hours and the reaction mixture is concentrated in vacuo. 7 g (corresponding to 99.0% of theory) of the intermediate of the formula are obtained
N H N H
'N-CH_-CH„-NH 'N-CH_-CH "-NH
CH CH
in Form eines viskosen, gelblich-gefärbten Öls, 3 g des viskosen Öls werden 1 Stunde lang im Wasserstrahlvakuum auf 220°C erhitzt. Hierbei tritt Cyclisierung zu 2-(2-Äthyl-6-me-thylphenylimino)-imidazolidin ein. Zur Aufarbeitung des Reaktionsproduktes wird mit Methanol versetzt und vom Unlöslichen (ca. 0,7 g) abfiltriert. Die methanolische Lösung wird im Vakuum eingeengt und der Rückstand in verdünnter Salzsäure gelöst. Bei aufsteigenden pH-Werten (Alkalisieren mit 2n NaOH!) wird fraktioniert mit Äther ausgeschüttelt. Die dünnschichtchromatographisch-einheitlichen Ätherextrakte werden vereinigt, über wasserfreiem Magnesiumsulfat getrocknet und vom Lösungsmittel im Vakuum befreit. in the form of a viscous, yellowish-colored oil, 3 g of the viscous oil are heated to 220 ° C. in a water jet vacuum for 1 hour. Here cyclization to 2- (2-ethyl-6-methylphenylimino) imidazolidine occurs. To work up the reaction product, methanol is added and the insolubles (about 0.7 g) are filtered off. The methanolic solution is concentrated in vacuo and the residue is dissolved in dilute hydrochloric acid. When the pH values rise (alkalize with 2N NaOH!), The mixture is shaken out with ether. The ethereal extracts, which are uniform in thin-layer chromatography, are combined, dried over anhydrous magnesium sulfate and freed from the solvent in vacuo.
Ausbeute: 0,45 g entsprechend 25,0% der Theorie. Yield: 0.45 g corresponding to 25.0% of theory.
Fp.: 132 bis 134°C. Mp .: 132 to 134 ° C.
Die Substanz ist identisch mit auf andere Weise hergestelltem 2-(2-Äthyl-6-methylphenylimino)-imidazolidin. The substance is identical to 2- (2-ethyl-6-methylphenylimino) imidazolidine produced in another way.
Analog können die folgenden Verbindungen hergestellt werden: The following connections can be made analogously:
Verbindung der Formel I Z = Compound of the formula I Z =
Fp., °C Mp, ° C
2,6-Difluorphenyl 2,6-difluorophenyl
170 170
248 bis 250 (Hydrochlorid) 248 to 250 (hydrochloride)
2-Chlor-6-fluorphenyl 2-chloro-6-fluorophenyl
140 bis 142 140 to 142
260 bis 262 (Hydrochlorid) 260 to 262 (hydrochloride)
2,6-Dimethoxyphenyl 2,6-dimethoxyphenyl
155 bis 157 155 to 157
207 bis 208 (Hydrojodid) 207 to 208 (hydroiodide)
2,6-Dihydroxyphenyl 2,6-dihydroxyphenyl
208 (Hydrobromid) 208 (hydrobromide)
2,6-Di-(trifluormethyl)-phenyl 2,6-di (trifluoromethyl) phenyl
177 bis 178 177 to 178
2-Brom-6-methylphenyl 2-bromo-6-methylphenyl
142 bis 144 142 to 144
2-Brom-6-chlorphenyl 2-bromo-6-chlorophenyl
297 bis 300 (Hydrochlorid) 297 to 300 (hydrochloride)
2-Chlor-6-trifluormethylphenyl 2-chloro-6-trifluoromethylphenyl
277 bis 279 (Hydrochlorid) 277 to 279 (hydrochloride)
2-Fluor-6-trifluormethylphenyl 2-fluoro-6-trifluoromethylphenyl
262 bis 264 (Hydrochlorid) 262 to 264 (hydrochloride)
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2446758A DE2446758C3 (en) | 1974-10-01 | 1974-10-01 | 2- (2-Fluoro-6-trifluoromethylphenylimino) -imidazolidine, its acid addition salts, processes for the preparation of these compounds and their use in combating hypertension |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH627454A5 true CH627454A5 (en) | 1982-01-15 |
Family
ID=5927202
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1267875A CH620682A5 (en) | 1974-10-01 | 1975-09-30 | Process for the preparation of novel 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506280A CH627452A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506480A CH626352A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506380A CH627453A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506580A CH627454A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
Family Applications Before (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1267875A CH620682A5 (en) | 1974-10-01 | 1975-09-30 | Process for the preparation of novel 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506280A CH627452A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506480A CH626352A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
| CH506380A CH627453A5 (en) | 1974-10-01 | 1980-07-01 | Process for the preparation of 2,6-disubstituted 2-phenyliminoimidazolidines and their acid addition salts |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS6018653B2 (en) |
| AT (1) | AT344159B (en) |
| BE (1) | BE834051A (en) |
| BG (2) | BG25220A3 (en) |
| CA (1) | CA1056836A (en) |
| CH (5) | CH620682A5 (en) |
| CS (1) | CS193524B2 (en) |
| DD (1) | DD123602A5 (en) |
| DE (1) | DE2446758C3 (en) |
| DK (1) | DK441875A (en) |
| ES (4) | ES441385A1 (en) |
| FI (1) | FI61883C (en) |
| FR (1) | FR2286649A1 (en) |
| GB (1) | GB1515019A (en) |
| HU (1) | HU178469B (en) |
| IE (1) | IE42130B1 (en) |
| IL (1) | IL48214A (en) |
| LU (1) | LU73472A1 (en) |
| NL (1) | NL7511490A (en) |
| NO (1) | NO143459C (en) |
| NZ (1) | NZ178810A (en) |
| PH (1) | PH13653A (en) |
| PL (2) | PL98984B1 (en) |
| SE (1) | SE418497B (en) |
| SU (1) | SU575026A3 (en) |
| YU (1) | YU230281A (en) |
| ZA (1) | ZA756185B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2630060C2 (en) * | 1976-07-03 | 1984-04-19 | C.H. Boehringer Sohn, 6507 Ingelheim | 2- (2-Bromo-6-fluoro-phenylimino) -imidazolidine, its acid addition salts, medicaments containing them and processes for their preparation |
| DE2806811A1 (en) * | 1978-02-17 | 1979-08-23 | Boehringer Sohn Ingelheim | NEW SUBSTITUTED 2-PHENYLIMINO-IMIDAZOLIDINE, THEIR ACID-ADDITIONAL SALTS, THESE MEDICINAL PRODUCTS AND METHOD FOR MANUFACTURING THE SAME |
| DE2806775A1 (en) * | 1978-02-17 | 1979-08-30 | Boehringer Sohn Ingelheim | NEW SUBSTITUTED 2-PHENYLIMINO IMIDAZOLIDINE THEIR ACID ADDITION SALTS, MEDICINAL PRODUCTS CONTAINING THEM AND METHOD FOR THE PRODUCTION THEREOF |
| ZA801680B (en) * | 1979-04-03 | 1981-03-25 | Fujisawa Pharmaceutical Co | 2-imidazoline derivatives,process for the preparation thereof and the pharmaceutical composition of the same |
| HU192986B (en) | 1984-05-23 | 1987-08-28 | Egyt Gyogyszervegyeszeti Gyar | Process for production of imidasodiline derivatives |
| JP2009524619A (en) * | 2006-01-27 | 2009-07-02 | エフ．ホフマン−ラ ロシュ アーゲー | Use of 2-imidazole for the treatment of CNS disorders |
| KR101174191B1 (en) | 2007-02-02 | 2012-08-14 | 에프. 호프만-라 로슈 아게 | Novel 2-aminooxazolines as taar1 ligands for cns disorders |
| WO2008098857A1 (en) | 2007-02-15 | 2008-08-21 | F. Hoffmann-La Roche Ag | 2-aminooxazolines as taar1 ligands |
| US8242153B2 (en) | 2008-07-24 | 2012-08-14 | Hoffmann-La Roche Inc. | 4,5-dihydro-oxazol-2YL derivatives |
| US8354441B2 (en) | 2009-11-11 | 2013-01-15 | Hoffmann-La Roche Inc. | Oxazoline derivatives |
| US9452980B2 (en) | 2009-12-22 | 2016-09-27 | Hoffmann-La Roche Inc. | Substituted benzamides |
| WO2017157873A1 (en) | 2016-03-17 | 2017-09-21 | F. Hoffmann-La Roche Ag | 5-ethyl-4-methyl-pyrazole-3-carboxamide derivative having activity as agonist of taar |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3236857A (en) * | 1961-10-09 | 1966-02-22 | Boehringer Sohn Ingelheim | 2-(phenyl-amino)-1, 3-diazacyclopentene-(2) substitution products |
| DE1670807A1 (en) * | 1967-02-17 | 1971-03-11 | Bayer Ag | Process for the preparation of cyclic guanidines |
| DE1670918A1 (en) * | 1967-09-07 | 1971-04-08 | Bayer Ag | Process for the preparation of 2-aryl-amino-substituted nitrogen-containing heterocycles |
| BE787683A (en) * | 1971-08-20 | 1973-02-19 | Boehringer Sohn Ingelheim | 2-PHENYLIMINO-IMIDAZOLIDINES, THEIR ADDITIONAL SALTS WITH ACIDS AND METHODS FOR MAKING THEM |
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1974
- 1974-10-01 DE DE2446758A patent/DE2446758C3/en not_active Expired
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1975
- 1975-09-22 AT AT722875A patent/AT344159B/en not_active IP Right Cessation
- 1975-09-23 SU SU7502174605A patent/SU575026A3/en active
- 1975-09-26 PH PH17613A patent/PH13653A/en unknown
- 1975-09-29 BG BG7500031110A patent/BG25220A3/en unknown
- 1975-09-29 DD DD188613A patent/DD123602A5/xx unknown
- 1975-09-29 BG BG7500032014A patent/BG25221A3/en unknown
- 1975-09-29 LU LU73472A patent/LU73472A1/xx unknown
- 1975-09-29 CS CS756573A patent/CS193524B2/en unknown
- 1975-09-30 NZ NZ178810A patent/NZ178810A/en unknown
- 1975-09-30 DK DK441875A patent/DK441875A/en not_active Application Discontinuation
- 1975-09-30 IL IL48214A patent/IL48214A/en unknown
- 1975-09-30 PL PL1975197816A patent/PL98984B1/en unknown
- 1975-09-30 CH CH1267875A patent/CH620682A5/en not_active IP Right Cessation
- 1975-09-30 BE BE160578A patent/BE834051A/en not_active IP Right Cessation
- 1975-09-30 FI FI752728A patent/FI61883C/en not_active IP Right Cessation
- 1975-09-30 ES ES441385A patent/ES441385A1/en not_active Expired
- 1975-09-30 CA CA236,670A patent/CA1056836A/en not_active Expired
- 1975-09-30 GB GB40012/75A patent/GB1515019A/en not_active Expired
- 1975-09-30 NL NL7511490A patent/NL7511490A/en not_active Application Discontinuation
- 1975-09-30 ZA ZA756185A patent/ZA756185B/en unknown
- 1975-09-30 JP JP50118196A patent/JPS6018653B2/en not_active Expired
- 1975-09-30 NO NO753314A patent/NO143459C/en unknown
- 1975-09-30 HU HU75BO1573A patent/HU178469B/en unknown
- 1975-09-30 PL PL1975183670A patent/PL97003B1/en unknown
- 1975-10-01 SE SE7511028A patent/SE418497B/en not_active IP Right Cessation
- 1975-10-01 FR FR7530117A patent/FR2286649A1/en active Granted
- 1975-10-01 IE IE2150/75A patent/IE42130B1/en unknown
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1976
- 1976-02-04 ES ES444900A patent/ES444900A1/en not_active Expired
- 1976-02-04 ES ES444898A patent/ES444898A1/en not_active Expired
- 1976-02-04 ES ES444901A patent/ES444901A1/en not_active Expired
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1980
- 1980-07-01 CH CH506280A patent/CH627452A5/en not_active IP Right Cessation
- 1980-07-01 CH CH506480A patent/CH626352A5/en not_active IP Right Cessation
- 1980-07-01 CH CH506380A patent/CH627453A5/en not_active IP Right Cessation
- 1980-07-01 CH CH506580A patent/CH627454A5/en not_active IP Right Cessation
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1981
- 1981-09-24 YU YU02302/81A patent/YU230281A/en unknown
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| Date | Code | Title | Description |
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| PL | Patent ceased |