EP0719139A1 - Use of centrally active alphaagonists for inhibing postraumatic metabolic stress - Google Patents
Use of centrally active alphaagonists for inhibing postraumatic metabolic stressInfo
- Publication number
- EP0719139A1 EP0719139A1 EP94925399A EP94925399A EP0719139A1 EP 0719139 A1 EP0719139 A1 EP 0719139A1 EP 94925399 A EP94925399 A EP 94925399A EP 94925399 A EP94925399 A EP 94925399A EP 0719139 A1 EP0719139 A1 EP 0719139A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- imidazoline
- amino
- tetrahydro
- manufacture
- radical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Definitions
- the present invention relates to the use of ⁇ -2 agonists for
- the hormonal changes serve to restore circulation and organ perfusion.
- the metabolism rate is reduced.
- the catabolic flow phase is characterized by an increased metabolism rate and negative nitrogen balances.
- the hormonal changes result in a large number of metabolic changes in the intermediate metabolism.
- Antiinsulinary factors primarily catecholamines, glucagon and cortisol - lead to an increase in hepatic gluconeogenesis with simultaneous inhibition of insulin secretion. Lactate, glycerin, alanine and glutamine are used as substrates.
- the increased supply of glucose is metabolized well by the brain, erythocytes and the wound areas, while the glucose sterilization in the remaining tissues is largely disturbed. Lipolysis and fat oxidation are increased. Fat serves as a source of energy for most organs in the stress metabolism, this applies in particular to the liver, muscles and myocardium.
- the protein breakdown is increased.
- the increasingly mobilized amino acids serve to build up acute phase proteins, intestinal proteins (intestinal mucosa) and various immune factors, as well as a substrate for increased gluconeogenesis.
- Alanine and glutamine play a key role here. These changes normalize as the patient enters the anabolic flow phase. Glucose sterilization increases and fat oxidation decreases, nitrogen balances become positive.
- the postaggressive metabolism is characterized by a characteristic hormonal constellation, the result of which is an increase in the resting energy requirement and an increased nitrogen excretion (protein breakdown rate exceeds the protein synthesis rate). Since there are no protein deposits that can be broken down without loss of function, the immune system and wound healing can be significantly impaired in the postoperative phase. For this reason, an adequate supply of energy substrates and an adequate supply of amino acids to improve the nitrogen balance perioperatively is of the utmost importance.
- the centrally active ⁇ -2 receptor agonist clonidine appears to be suitable for the treatment of the post-aggression syndrome, in particular for the inhibition of the post-aggression metabolism.
- imidazolines of the general formula are of interest
- X, Y, Z may be the same or different, a hydrogen or halogen atom, e.g. F, Cl, Br, an alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitrile, hydroxyl, alkylthio or halothio group, a cyclopropyl radical, Rl a hydrogen atom, an alkyl or tetrahydropyran radical, and the like Acid addition salts.
- halogen atom e.g. F, Cl, Br
- Rl a hydrogen atom, an alkyl or tetrahydropyran radical, and the like Acid addition salts.
- alkyl in the sense of the present definition, branched or unbranched alkyl groups with 1 to 4 are also - insofar as they are part of other radicals Understand carbon atoms, for example the following are mentioned: methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl, sec-butyl and tert-buty.
- Azepines and tetrazines of the general formulas below likewise have a centrally active ⁇ -2-receptor active component and are claimed for the use according to the invention.
- R ⁇ is a hydrogen atom, a straight-chain or branched alkyl radical which may be substituted by a hydroxyl group and has 1-4 carbon atoms, an allyl, cycloalkyl, hexahydrobenzyl, phenyl, phenylethyl or benzyl radical, where the benzyl radical in the nucleus can be substituted by one or two halogen atoms, by one to three methoxy groups, by a trifluoromethyl or alkyl group having 1-3 carbon atoms and if X represents a sulfur atom,
- R represents a hydrogen atom, a straight-chain or branched alkyl radical having 1-5 carbon atoms, an allyl, cycloalkyl, phenyl, benzyl or phenylethyl radical or, if X represents an oxygen atom, a hydrogen atom.
- Preferred compounds are 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4-d] azepine (BHT 933) and 6-allyl-2-amino-4,5,7 , 8-tetrahydro-6H-thiazolo [5,4-d] aze ⁇ in (BHT 920) and, if appropriate, their acid addition salts.
- R 1 is an unsubstituted or halogen atom, preferably fluorine, chlorine or bromine atom, methyl, methoxy or trifluoromethyl group, the same or different mono- to trisubstituted phenyl radical and R2 is a hydrogen atom or an unsubstituted or one to more than one halogen atom, preferably chlorine atom , substituted phenyl radical;
- 6-Quinoxalinamine 5-bromo-N- (4,5-dihydro-lH-imidazol-2-yl) - (brimonidine tartrate), (5-bromo-N- (4,5-dmydro-lH-imidazol-2 -yl) -6-quinoxalinamine); 2H- [l] benzopyrano [3,4] pyridin-7-ol, 1,3,4, 4a, 5, 10b-hexahydro-4-propyl hydrochloride (CGS 15873), (1,3,4, 4a, 5, 10b-hexahydro-4-propyl-2H- [1] benzopyrano [3,4] pyridin-7-ol); lH-imidazole, 4- [l- (2,3-dimethylphenyl) ethyl] -, (4- [l- (2,3-dimethylphenyl) ethyl] - lH-imidazole), (dexmedeto
- Guanidines (4,7-dichloro-l, 3-dihydro-2H-isoindol-2-yl) -; ((4,7-dichloro-l, 3-dihydro-2H-isoindol-2-yl) guanidine), (Aganodine); lH-Imidazole-2-carboxylic acid, l - [[8.beta.) - 6-methylergolin-8-yl] methyl] -, ethyl ester; (l-
- Benzenemethanol 4-hydroxy-.alpha .- [[[3- (2-methoxyphenyl) -l, l-dimethylpropyl] amino] methyl], (4-hydroxy-.alpha .- [[[3- (2-methoxyphenyl ) -l, l-dimethylpropy ⁇ amino] methyl] -benzenemethanol),
- R C] tCH 3 - (4-t-butyl-2,6-dimethyl-3-hydroxy-benzyl) -2-imidazoline. - (4-t-Butyl-2,6-dimethyl-benzyl) -2-imidazoline.
- a dose in the order of 2-5 ⁇ / kg / h can be given continuously intravenously, the hemodynamic behavior of the patient being important for controlling the dose in individual cases.
- the therapy should be terminated gradually (e.g. reduction of the dose by 50% every 12 hours), but at the earliest after 4-5 days.
- the compounds mentioned according to the invention can be used in conventional pharmaceutical preparations. Injection solutions are preferred according to the invention.
- the dosage is of course dependent on the potency of the ⁇ -2 receptor agonist.
- clonidine for example, in an i.V.
- a dosage of 1 - 10 ⁇ g / kg / h can be used.
Abstract
The present invention pertains to the use of alpha -2 receptor agonists in treating postaggression syndrome.
Description
Verwendung von zentral wirksamen α-2-Agonisten zur Hemmung des Postaggressionsstoffwechsels Use of centrally acting α-2 agonists to inhibit the postaggressive metabolism
Die vorliegende Erfindung betrifft die Verwendung von α-2-Agonisten zurThe present invention relates to the use of α-2 agonists for
Behandlung des Postaggressionssyndroms, insbesondere zur Hemmung desTreatment of post-aggression syndrome, especially to inhibit the
Postaggressionsstoffwechsel.Post-aggression metabolism.
Nach einem operativen Eingriff, nach Trauma oder Verbrennungen kommt es zu akuten Veränderungen im Intermediärstoffwechsel, die unter dem BegriffAfter an operation, after trauma or burns, there are acute changes in the intermediate metabolism, which are under the term
Postagressionssyndrom zusammengefaßt werden.Postagression syndrome can be summarized.
Humorale Faktoren spielen hierbei eine entscheidende Rolle bei der Aufrechterhaltung der Homöostase und der Stressadaptation. Sie rufen generelle hämodynamische, metabolische uiϊd immunologische Veränderungen hervor, die der Schwere des Traumas entsprechen.Humoral factors play a crucial role in maintaining homeostasis and stress adaptation. They cause general hemodynamic, metabolic and immunological changes that correspond to the severity of the trauma.
In der Schockphase dienen die hormonellen Veränderungen der Wiederherstellung des Kreislaufs und der Organperfusion. Die Metabolierate ist erniedrigt.In the shock phase, the hormonal changes serve to restore circulation and organ perfusion. The metabolism rate is reduced.
Die katabole Flowphase ist charakterisiert durch eine erhöhte Metabolierate und negative Stickstoffbilanzen. Die hormonellen Veränderungen ziehen eine Vielzahl von metabolischen Veränderungen im Intermediärstoffwechsel nach sich. Antiinsulinäre Faktoren - in erster Linie Katecholamine, Glukagon und Cortisol - fuhren zu einer Steigerung der hepatischen Glukoneogenese bei gleichzeitiger Hemmung der Insulinsekretion. Als Substrate dienen Laktat, Glycerin, Alanin und Glutamin. Die vermehrt bereitgestellte Glukose wird vom Hirn, Erythocyten und den Wundgebieten gut verstoffwechselt, während die Glukoseutilisation in den restlichen Geweben weitestgehend gestört ist. Die Lipolyse und Fettoxidation ist gesteigert. Im Stressstoffwechsel dient Fett den meisten Organen als Energielieferant, dies gilt insbesondere für die Leber, Muskulatur und das Myocard. Der Proteinabbau ist gesteigert. Die vermehrt mobilisierten Aminosäuren dienen dem Aufbau von Akutphaseproteinen, intestinalen Proteinen (Darmmukosa) und verschiedenen Immunfaktoren, sowie als Substrat für die vermehrte Glukoneogenese. Hierbei nehmen Alanin und Glutamin eine Schlüsselstellung ein.
Diese Veränderungen normalisieren sich in dem Maße wie der Patient in die anabole Flowphase kommt. Die Glukoseutilisation steigt und die Fettoxidation sinkt, die Stickstoffbilanzen werden positiv.The catabolic flow phase is characterized by an increased metabolism rate and negative nitrogen balances. The hormonal changes result in a large number of metabolic changes in the intermediate metabolism. Antiinsulinary factors - primarily catecholamines, glucagon and cortisol - lead to an increase in hepatic gluconeogenesis with simultaneous inhibition of insulin secretion. Lactate, glycerin, alanine and glutamine are used as substrates. The increased supply of glucose is metabolized well by the brain, erythocytes and the wound areas, while the glucose sterilization in the remaining tissues is largely disturbed. Lipolysis and fat oxidation are increased. Fat serves as a source of energy for most organs in the stress metabolism, this applies in particular to the liver, muscles and myocardium. The protein breakdown is increased. The increasingly mobilized amino acids serve to build up acute phase proteins, intestinal proteins (intestinal mucosa) and various immune factors, as well as a substrate for increased gluconeogenesis. Alanine and glutamine play a key role here. These changes normalize as the patient enters the anabolic flow phase. Glucose sterilization increases and fat oxidation decreases, nitrogen balances become positive.
Die Veränderungen des Intermediärstoffwechsels nach einem "Trauma" sind für die "Heilung" nur bedingt von großer Bedeutung: wenn bei guter präoperativer Konstellation und Konstitution ein geringes oder mittleres operatives Trauma ohne postoperative Komplikationen vorliegt. In einem solchen Falle werden zwar alle oben beschriebenen Phasen des Postaggressionsstoffwechsels durchlaufen, es kommt aber in der Regel schnell wieder zur anabolen Flowphase.The changes in the intermediate metabolism after a "trauma" are of limited importance for the "healing": if, with a good preoperative constellation and constitution, there is a slight or moderate operative trauma without postoperative complications. In such a case, all phases of the post-aggression metabolism described above are run through, but the anabolic flow phase usually comes back quickly.
Zunehmend größere operative Eingriffe bei immer älteren und kränkeren Patienten stellen den Intensivmediziner jedoch vor Probleme, da vor allem die katabole Flowphase bei vielen Patienten durch immer neue "Agressionen" (z. B. Reoperationen, Sepsis usw.) unterhalten wird und durch Substratzufuhr nicht zu beeinflussen ist.Increasingly larger surgical interventions in increasingly older and sickly patients present problems for the intensive care physician, since the catabolic flow phase in particular is maintained in many patients by ever new "aggressions" (e.g. reoperations, sepsis, etc.) and not by substrate supply is influencing.
Bei diesen Patienten besteht oft über längere Zeit ein "Autokanibalismus" d.h. über einen endogenen Abbau von Muskel- und Funktionsproteinen versucht der Körper genügend Eiweißbausteine (Aminosäuren) für die zur Heilung wichtigen Prozesse bereitzustellen. Dies führt bei kritisch kranken Patienten zu einem Funktionsverlust unterschiedlichster Muskelgruppen (Extremitäten, Atemhilfsmuskulatur incl. Zwerchfell und auch Myocard) mit der Konsequenz einer erschwerten Entwöhnung vom Beatmimgsgerät, von kardiovaskulären Problemen (Herzinsuffizienz) usw.. Neben dem Muskeleiweiß sind auch Funktionsproteine in immunkompetenten Zellen, Darmmukosa u.a. bei Schwerkranken zunehmend beeinträchtigt, so daß die Abwehrlage dieser Patienten extrem geschwächt ist.These patients often have "auto-cannibalism" over a long period of time, i.e. By endogenously breaking down muscle and functional proteins, the body tries to provide enough protein components (amino acids) for the processes that are important for healing. In critically ill patients, this leads to a loss of function in a wide variety of muscle groups (extremities, respiratory muscles including the diaphragm and also myocardium) with the consequence of difficult weaning from the respirator, cardiovascular problems (heart failure) etc. In addition to muscle protein, functional proteins in immune-competent cells are also Intestinal mucosa etc. increasingly seriously impaired in seriously ill patients, so that the immune system of these patients is extremely weakened.
Trauma und operativer Streß führen zu umfangreichen metabolischen Veränderungen. Der Postaggressionsstoffwechsel ist gekennzeichnet durch eine charakteristische hormonelle Konstellation, deren Folge eine Erhöhung des Ruheenergiebedarfs und und eine vermehrte Stickstoffausscheidung (Proteinabbaurate übersteigt die Proteinsyntheserate) ist. Da es keine Proteindepots gibt, die ohne Funktionsverlust abgebaut erden können, kann in der postoperativen Phase die Immunabwehrlage und die Wundheilung erheblich beeinträchtigt werden. Aus diesem Grunde ist eine ausreichende Zufuhr von Energiesubstraten und eine adäquate Aminosäurenbereitstellung zur Verbesserung der Stickstoffbilanz perioperativ von größter Bedeutung.Trauma and surgical stress lead to extensive metabolic changes. The postaggressive metabolism is characterized by a characteristic hormonal constellation, the result of which is an increase in the resting energy requirement and an increased nitrogen excretion (protein breakdown rate exceeds the protein synthesis rate). Since there are no protein deposits that can be broken down without loss of function, the immune system and wound healing can be significantly impaired in the postoperative phase. For this reason, an adequate supply of energy substrates and an adequate supply of amino acids to improve the nitrogen balance perioperatively is of the utmost importance.
Die optimale Zufuhr von Substraten alleine genügt bei großen operativen Traumen jedoch nicht, eine positive Stickstoffbilanz zu erzielen. Eine Reihe von
Wissenschaftlern haben daher versucht, über eine direkte Beeinflussung des postoperativen hormonellen Milieus mit Wachstumshormon, IGF-1 o.a. anabolen Ansätzen einen Protein sparenden Effekt zu erzielen und das Gleichgewicht Eiweißabbau und Eiweißsynthese zu gunsten der letzteren zu beeinflussen.However, the optimal supply of substrates alone is not enough to achieve a positive nitrogen balance for large surgical trauma. A row of Scientists have therefore tried to achieve a protein-saving effect by directly influencing the postoperative hormonal environment with growth hormone, IGF-1 or anabolic approaches and to influence the balance of protein breakdown and protein synthesis in favor of the latter.
Überraschenderweise hat sich gezeigt, daß der zentral wirksame α-2-Rezeptor Agonist Clonidin zur Behandlung des Postaggressionssyndroms, insbesondere zur Hemmung des Postaggressionsstoffwechsels geeignet erscheint.Surprisingly, it has been shown that the centrally active α-2 receptor agonist clonidine appears to be suitable for the treatment of the post-aggression syndrome, in particular for the inhibition of the post-aggression metabolism.
Ausgehend von der These, daß eine zentrale α-2-Stimulation zu einer Minderung der Proteinabbaurate bzw. gleichzeitig zu einer Steigerung der Proteinsyntheserate führt, dürfte der Einfluß von α-2-Agonisten auf den Proteinstoffwechsel und dadurch auf Wundheilung, Immunkompetenz und Infektionsrate, Darmmukosabarriere und damit verbundene Organkomplikationen (Translokation von Keimen) in der postoperativen Phase für viele Patienten von direktem klinischen Nutzen sein.Based on the thesis that central α-2 stimulation leads to a reduction in the rate of protein breakdown or at the same time to an increase in the rate of protein synthesis, the influence of α-2 agonists on protein metabolism and thus on wound healing, immune competence and infection rate, and intestinal mucosal barrier and associated organ complications (translocation of germs) in the postoperative phase can be of direct clinical benefit to many patients.
Zentralwirksamg α-2-Agonisten sind in zahlreichen Strukturvarianten aus dem Stand der Technik bekannt, wobei deren blutdrucksenkende und analgetische Wirkung im Vordergrund stand. So beschreibt beispielsweise die deutsche Patentschrift DE 13 03 149 die Synthese wie auch pharmakologische Eigenschaften von Clonidin und anderen Phenylaminoimidazolinen.Zentraleffktivg α-2 agonists are known in numerous structural variants from the prior art, with their hypotensive and analgesic effect in the foreground. For example, the German patent DE 13 03 149 describes the synthesis as well as the pharmacological properties of clonidine and other phenylaminoimidazolines.
Von Interesse sind demgemäß Imidazoline der allgemeinen FormelAccordingly, imidazolines of the general formula are of interest
XX
in der X, Y, Z gleich oder verschieden sein können, ein Wasserstoff- oder Halogenatom, wie z.B. F, Cl, Br, eine Alkyl-, Halogenalkyl-, Alkoxy-, Halogenalkoxy- , Amino-, Nitr-, Hydroxy-, Alkylthio- oder Halogenthiogruppe, einen Cyclopropylrest, Rl ein Wasserstoffatom, einen Alkyl- oder Tetrahydropyranrest, bedeuten können sowie deren Säureadditionssalze.in which X, Y, Z may be the same or different, a hydrogen or halogen atom, e.g. F, Cl, Br, an alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitrile, hydroxyl, alkylthio or halothio group, a cyclopropyl radical, Rl a hydrogen atom, an alkyl or tetrahydropyran radical, and the like Acid addition salts.
Als Alkyl im Sinne der vorliegenden Definition werden - auch soweit sie Bestandteil anderer Reste sind - werden verzweigte oder unverzweigte Alkylgruppen mit 1 bis 4
Kohlenstoffatomen verstanden, beispielsweise werden genannt: Methyl, Ethyl, n-Propyl-, iso-Butyl, n-Butyl, iso-Butyl, sec.-Butyl und tert.-Buty.As alkyl in the sense of the present definition, branched or unbranched alkyl groups with 1 to 4 are also - insofar as they are part of other radicals Understand carbon atoms, for example the following are mentioned: methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl, sec-butyl and tert-buty.
Azepine und Tetrazine der nachstehenden allgemeinen Formeln weisen ebenfalls eine zentralwirksame α-2-Rezeptor Wirkungskomponente auf und werden für die erfindungsgemäße Verwendung beansprucht.Azepines and tetrazines of the general formulas below likewise have a centrally active α-2-receptor active component and are claimed for the use according to the invention.
ITIT
deren Säureadditionssalze mit physiologisch verträglichen anorganischen oder organischen Säuren, worin R\ ein Wasserstoffatom, einen gegebenenfalls durch eine Hydroxylgruppe substituierten geradkettigen oder verzweigten Alkylrest mit 1 - 4 Kohlenstoffatpmen, einen Allyl-, Cycloalkyl-, Hexahydrobenzyl-, Phenyl-, Phenylethyl- oder Benzylrest, wobei der Benzylrest im Kern durch ein oder zwei Halogenatome, durch ein bis drei Methoxygruppen, durch eine Trifluormethyl- oder Alkylgruppe mit 1 - 3 Kohlenstoffatomen substituiert sein kann und falls X ein Schwefelatom darstellt,their acid addition salts with physiologically compatible inorganic or organic acids, in which R \ is a hydrogen atom, a straight-chain or branched alkyl radical which may be substituted by a hydroxyl group and has 1-4 carbon atoms, an allyl, cycloalkyl, hexahydrobenzyl, phenyl, phenylethyl or benzyl radical, where the benzyl radical in the nucleus can be substituted by one or two halogen atoms, by one to three methoxy groups, by a trifluoromethyl or alkyl group having 1-3 carbon atoms and if X represents a sulfur atom,
R2ein Wasserstoffatom, einen geradkettigen oder verzweigten Alkylrest mit 1 - 5 Kohlenstoffatomen, einen Allyl-, Cycloalkyl-, Phenyl-, Benzyl- oder Phenylethylrest oder falls X ein Sauerstoffatom darstellt, ein Wasserstoffatom bedeutet. Bevorzugte Verbindungen sind 2-Amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4- d]azepin (BHT 933) und 6-Allyl-2-amino-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azeρin (BHT 920) sowie gegebenenfalls deren Säureadditionssalze.R represents a hydrogen atom, a straight-chain or branched alkyl radical having 1-5 carbon atoms, an allyl, cycloalkyl, phenyl, benzyl or phenylethyl radical or, if X represents an oxygen atom, a hydrogen atom. Preferred compounds are 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4-d] azepine (BHT 933) and 6-allyl-2-amino-4,5,7 , 8-tetrahydro-6H-thiazolo [5,4-d] azeρin (BHT 920) and, if appropriate, their acid addition salts.
00
m m
in der Rj einen unsubstituierten oder durch Halogenatome, vorzugsweise Fluor-, Chlor-, oder Bromatom, Methyl-, Methoxy-, Trifluormethylgruppen gleich oder verschieden ein bis dreifach substituierten Phenylrest und R2 ein Wasserstoffatom oder einen unsubstituierten oder ein bis mehrfach durch Halogenatome, vorzugsweise Chloratome, substituierten Phenylrest bedeuten;
Aus der Gruppe der allgemeinen Formeln I, Hund III sind folgende Verbindungen bevorzugt:in which R 1 is an unsubstituted or halogen atom, preferably fluorine, chlorine or bromine atom, methyl, methoxy or trifluoromethyl group, the same or different mono- to trisubstituted phenyl radical and R2 is a hydrogen atom or an unsubstituted or one to more than one halogen atom, preferably chlorine atom , substituted phenyl radical; The following compounds from the group of general formulas I, dog III are preferred:
2-(2,6-Dichloranilino)-2-imidazolin. 2(4-Antino-2,6-dicUoranidino)-2-imidazolin.2- (2,6-dichloroanilino) -2-imidazoline. 2 (4-Antino-2,6-dicUoranidino) -2-imidazoline.
8-(2,6-DicUo henyl)-7-(4-cUorphenyl)-5-oxo-2,3-düιydro__midazol[l,2-a]s-triazin. l-Acetonyl-2-(2,6-dicWorphenylaιnino)-2-imidazolin.8- (2,6-DicUo henyl) -7- (4-cUorphenyl) -5-oxo-2,3-düιydro__midazol [1,2-a] s-triazine. l-Acetonyl-2- (2,6-dicWorphenylaιnino) -2-imidazoline.
2-(2-Brom-6-fluoranilino)-2-imidazolin.2- (2-bromo-6-fluoroanilino) -2-imidazoline.
2-(2-Fluor-6-trifluoιmemylphenylamino)-2-imidazolin.2- (2-fluoro-6-trifluoιmemylphenylamino) -2-imidazoline.
2-(2-CUor-5-trifluomιethylphenylamino)-2-imidazolin.2- (2-Cuor-5-trifluomomethylphenylamino) -2-imidazoline.
2-(2-CWor-4-cyclopropylphenylamino)-2-imidazolin.2- (2-CWor-4-cyclopropylphenylamino) -2-imidazoline.
2-(3-Fluor-4-methylphenylam__no)-2-imidazolin.2- (3-fluoro-4-methylphenylam__no) -2-imidazoline.
2-(6-Chlor-4-memoxy-2-methyl-pyri_nήdm-5-ylammo)-2-ünidazolin. l-Benzoyl-2-(2,6-dichloranilino)-2-imidazolin.2- (6-chloro-4-memoxy-2-methyl-pyri_n ή dm-5-ylammo) -2-unidazoline. l-benzoyl-2- (2,6-dichloroanilino) -2-imidazoline.
2-| -)2,6-DicUorphenyl)-N-tetrahydropyτan-2-yl)-amino]-2-imidazolin.2- | -) 2,6-DicUorphenyl) -N-tetrahydropyτan-2-yl) -amino] -2-imidazoline.
2-(4-Ammo-2,6-dicUorphenylammo)-2-imidazolin.2- (4-Ammo-2,6-dicUorphenylammo) -2-imidazoline.
2-(3,4-Dihydroxy-phenylamino)-2-imidazolin.2- (3,4-dihydroxyphenylamino) -2-imidazoline.
2-Amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]-azepin.2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4-d] azepine.
2-Aιnino-6-(p-chlorbenzyl)-4,5,7,8-tetrahydro-6H-thiazolo-[5,4-d]azepin.2-amino-6- (p-chlorobenzyl) -4,5,7,8-tetrahydro-6H-thiazolo- [5,4-d] azepine.
Besonders bevorzugt ist neben dem 2-(2,6-Dichloramilino)-2-imidazolin (Clonidin) das 2-[(2-brom-6-fluo_ henyl)-m ino]imidazolidin (STH 2130) das beispielsweise in der DE-OS 26 30 060 (Beispiel) beschrieben ist.In addition to the 2- (2,6-dichloramilino) -2-imidazoline (clonidine), the 2 - [(2-bromo-6-fluo_henyl) -m ino] imidazolidine (STH 2130) which is described, for example, in DE OS 26 30 060 (example) is described.
Von Interesse sind ebenfalls l-(6-Methyl-8-beta-ergolinylmethyl)-l,2,4-triazol (Fumarat) (BAM 1110),Also of interest are 1- (6-methyl-8-beta-ergolinylmethyl) -1, 2,4-triazole (fumarate) (BAM 1110),
6-Quinoxalinamin, 5-bromo-N-(4,5-dihydro-lH-imidazol-2-yl)- (Brimonidine tartrate), (5-Bromo-N-(4,5-dmydro-lH-imidazol-2-yl)-6-quinoxalinamin); 2H-[l]Benzopyrano[3,4]pyridin-7-ol, 1,3,4, 4a, 5, 10b-hexahydro-4-propyl- hydrochlorid (CGS 15873), (1,3,4, 4a, 5, 10b-Hexahydro-4-propyl-2H- [ 1 ]benzopyrano[3,4]pyridin-7-ol); lH-Imidazole, 4-[l-(2,3-dimethylphenyl)ethyl]- ,(4-[l-(2,3-Dimethylphenyl)ethyl]- lH-imidazole), (Dexmedetomidine); Gluanabenz acetate; lH-Indol-1-amine, N-propyl-N-4-pyridinyl-, monohydrochloride, (N-Propyl-N-4- pyridinyl-lH-indol-1-amine-monohydrochloride), (HP-749); 2,4-dihydro[l,2,4]triazolo[3,4-c]benzothiazin-l-one, (IDPH-791);
Benzenemethanol, 2-hydroxy-3-(lH-imidazol-4-ylmethyl), (2-Hydroxy-3-(lH- imidazol-4-ylmethyl)-benzenemethanol), (Ledazerol);6-Quinoxalinamine, 5-bromo-N- (4,5-dihydro-lH-imidazol-2-yl) - (brimonidine tartrate), (5-bromo-N- (4,5-dmydro-lH-imidazol-2 -yl) -6-quinoxalinamine); 2H- [l] benzopyrano [3,4] pyridin-7-ol, 1,3,4, 4a, 5, 10b-hexahydro-4-propyl hydrochloride (CGS 15873), (1,3,4, 4a, 5, 10b-hexahydro-4-propyl-2H- [1] benzopyrano [3,4] pyridin-7-ol); lH-imidazole, 4- [l- (2,3-dimethylphenyl) ethyl] -, (4- [l- (2,3-dimethylphenyl) ethyl] - lH-imidazole), (dexmedetomidine); Gluanabenz acetate; 1H-indole-1-amine, N-propyl-N-4-pyridinyl, monohydrochloride, (N-propyl-N-4-pyridinyl-1H-indole-1-amine monohydrochloride), (HP-749); 2,4-dihydro [1,2,4] triazolo [3,4-c] benzothiazin-l-one, (IDPH-791); Benzenemethanol, 2-hydroxy-3- (1H-imidazol-4-ylmethyl), (2-hydroxy-3- (1H-imidazol-4-ylmethyl) -benzenemethanol), (ledazerol);
L-Tyrosine, 3-hydroxy-, alpha.-methyl-, (3-Hydroxy-, alpha.-methyl-L-tyrosine),L-tyrosine, 3-hydroxy-, alpha.-methyl-, (3-hydroxy-, alpha.-methyl-L-tyrosine),
(Methyldopa);(Methyldopa);
Benzamide, 2-hydroxy-3-( 1 H-imidazol-4-ylmethyl)-,(2-Hydroxy-3-( 1 H-imidazol-4- ylmethyl)-benzamide), (Mivazerol);Benzamides, 2-hydroxy-3- (1 H-imidazol-4-ylmethyl) -, (2-hydroxy-3- (1 H-imidazol-4-ylmethyl) benzamides), (mivazerol);
2-Oxazolamine, N-(dicyclopropylmethyl)-,(N-(Dicyclopropylmethyl)-2-oxazolamine),2-oxazolamine, N- (dicyclopropylmethyl) -, (N- (dicyclopropylmethyl) -2-oxazolamine),
(Rilmenidine);(Rilmenidine);
(+)-2-(4,5-dihydro-lH-imidazol-2-yl)-l,2,4,5-tetrahydro-2-propylpyrrolo[3,2, l-h, i] indole HC1,(+) - 2- (4,5-dihydro-lH-imidazol-2-yl) -l, 2,4,5-tetrahydro-2-propylpyrrolo [3,2, l-h, i] indole HC1,
(Deriglidole);(Deriglidole);
Tinabinol;Tinabinol;
Tizanidine;Tizanidine;
2-Oxazolamine, N-(l-cyclohexyl-2,2,2-trifluoroethyl)-4,5-dihydro-, (N-(l-2-oxazolamine, N- (l-cyclohexyl-2,2,2-trifluoroethyl) -4,5-dihydro-, (N- (l-
Cyclohexyl-2,2,2-trifluoroethyl)-4,5-di_hydro-2-oxazolamine),Cyclohexyl-2,2,2-trifluoroethyl) -4,5-di_hydro-2-oxazolamine),
(S-8350);(S-8350);
AGN-191103; *AGN-191103; *
Benzenemethanol, 2-hydroxy-3 -( 1 H-imidazol-4-ylmethyl)-, (2-Hydroxy-3 -( 1 H- imidazol-4-ylmethyl)-benzenemethanol),Benzenemethanol, 2-hydroxy-3 - (1 H-imidazol-4-ylmethyl) -, (2-hydroxy-3 - (1 H-imidazol-4-ylmethyl) -benzenemethanol),
(Ledazerol);(Ledazerol);
Benzamide, 2-hydroxy-3-(lH-imidazol-4-ylmethyl)-, (2-Hydroxy-3-(lH-imidazol-4- ylmethyl)-benzamide),Benzamides, 2-hydroxy-3- (1H-imidazol-4-ylmethyl) -, (2-hydroxy-3- (1H-imidazol-4-ylmethyl) benzamides),
(Mivazerol);(Mivazerol);
U-47,476 A;U-47.476 A;
Apraclonidin;Apraclonidine;
FLA-136;FLA-136;
Piclonidine; (2[2,6-Dichlor-N-(tetrahydro-2H-pyran-2-yl)anilino]-2-imidazolin;Piclonidines; (2 [2,6-dichloro-N- (tetrahydro-2H-pyran-2-yl) anilino] -2-imidazoline;
LR-004;LR-004;
Detomidine; (4(5)-2,3-Dimethylbenzyl)imidazol);Detomidine; (4 (5) -2,3-dimethylbenzyl) imidazole);
MPV-709; 2-[2-2,6-Dimethylphenyl)ethyl]-imidazol;MPV-709; 2- [2-2,6-dimethylphenyl) ethyl] imidazole;
MPV-207;MPV-207;
MPV-295;MPV-295;
MPV-304;MPV-304;
MPV-390;MPV-390;
2H-[l]Benzopyrano[3,4-b]pyridin-7-ol, l,3,4,4a,5, 10b-hexahydro-4-propyl-, hydrochloride, trans-;( trans-l,3,4,4a,5,10b-Hexahydro-4-propyl-2H-[l]benzopyrano[3,4-b]pyridin-7-ol),2H- [l] benzopyrano [3,4-b] pyridin-7-ol, l, 3,4,4a, 5, 10b-hexahydro-4-propyl-, hydrochloride, trans -; (trans-l, 3, 4,4a, 5,10b-hexahydro-4-propyl-2H- [l] benzopyrano [3,4-b] pyridin-7-ol),
(CGS-15873)(CGS-15873)
Guanidine, (4,7-dichloro-l,3-dihydro-2H-isoindol-2-yl)-; ((4,7-Dichloro-l,3-dihydro-2H- isoindol-2-yl)-guanidine), (Aganodine);
lH-Imidazole-2-carboxylic acid, l-[[8.beta.)-6-methylergolin-8-yl]methyl]-, ethyl ester;(l-Guanidines, (4,7-dichloro-l, 3-dihydro-2H-isoindol-2-yl) -; ((4,7-dichloro-l, 3-dihydro-2H-isoindol-2-yl) guanidine), (Aganodine); lH-Imidazole-2-carboxylic acid, l - [[8.beta.) - 6-methylergolin-8-yl] methyl] -, ethyl ester; (l-
[[8.beta.)-6-Methylergolin-8-yl]methyl]-lH-imidazole-2-carboxylic acid-lH-Imidazole-2- carboxylic acid-ethyl ester),[[8.beta.) - 6-methylergolin-8-yl] methyl] -lH-imidazole-2-carboxylic acid-lH-imidazole-2-carboxylic acid-ethyl ester),
(B AM- 1125);(B AM-1125);
BDF-6665; lH-Imidazol-2-amine, l-benzoyl-N-(2,6-dichlorophenyl)-4,5-dihydro- , (l-Benzoyl-N-(2,6- dichlorophenyl)-4,5-dihydro-lH-imidazol-2-amine),BDF-6665; lH-imidazol-2-amine, l-benzoyl-N- (2,6-dichlorophenyl) -4,5-dihydro-, (l-benzoyl-N- (2,6-dichlorophenyl) -4,5-dihydro- 1H-imidazole-2-amines),
(Benchlonidine);(Benchlonidins);
Dibenz[cd,f]indole-9,10-diol, 5-ethyl-4,5,5a,6-tetrahydro-4-propyl-, hydrochloride, (4S-trans)-Dibenz [cd, f] indole-9,10-diol, 5-ethyl-4,5,5a, 6-tetrahydro-4-propyl-, hydrochloride, (4S-trans) -
(CI-201-678); lH-Imidazole, 2-[(2-cyclopropylphenoxy)methyl]-4,5-dihydro-, (2-[(2-(CI-201-678); lH-imidazoles, 2 - [(2-cyclopropylphenoxy) methyl] -4,5-dihydro-, (2 - [(2-
Cyclopropylphenoxy)methyl]-4,5-dihydro-lH-imidazole),Cyclopropylphenoxy) methyl] -4,5-dihydro-1H-imidazole),
(Cirazoline);(Cirazoline);
Benzenemethanol, 4-hydroxy-.alpha.-[[[3-(2-methoxyphenyl)-l,l- dimethylpropyl]amino]methyl] ,(4-Hydroxy-.alpha.-[[[3-(2-methoxyphenyl)-l,l- dimethylpropy^amino]methyl]-benzenemethanol),Benzenemethanol, 4-hydroxy-.alpha .- [[[3- (2-methoxyphenyl) -l, l-dimethylpropyl] amino] methyl], (4-hydroxy-.alpha .- [[[3- (2-methoxyphenyl ) -l, l-dimethylpropy ^ amino] methyl] -benzenemethanol),
(D-2343); lH-Imidazo[l,2-a]imidazole, 2-(2-chloro-6-fluorophenyl)-2,3,5,6-tetrahydro-, monohydrochloride , (2-(2-Chloro-6-fluoropheny(l)-2,3,5,6-tetrahydro- lH-imidazo-(D-2343); lH-imidazo [l, 2-a] imidazole, 2- (2-chloro-6-fluorophenyl) -2,3,5,6-tetrahydro-, monohydrochloride, (2- (2-chloro-6-fluoropheny ( l ) -2,3,5,6-tetrahydro-lH-imidazo-
[ 1 ,2-a]imidazole-monohydrochlorid),[1, 2-a] imidazole monohydrochloride),
(DJ-7141);(DJ-7141);
Buteranol;Bututeranol;
Benzaldehyde, 4-hydroxy-2-methyl-, (4,5-dihydro-lH-imidazol-2-yl)hydrazone;Benzaldehydes, 4-hydroxy-2-methyl-, (4,5-dihydro-lH-imidazol-2-yl) hydrazone;
(Idralfidine);(Idralfidine);
Lidamidine;Lidamidines;
Lofexidine; l-methyl-2-amino-N-2-pyrrolidinylidene-benzeneamine;Lofexidine; l-methyl-2-amino-N-2-pyrrolidinylidenes-benzeneamines;
(SC-39207);(SC-39207);
2-(4-amino-3,5-dichlorobenzyl)imidazoline HCl;2- (4-amino-3,5-dichlorobenzyl) imidazoline HCl;
(Sch-40054); lH-Imidazol-2-amine, N-(2-chloro-4-methyl-3-thienyl)-4,5-dihydro- , (N-(2-Chloro-4-methyl-(Sch-40054); 1H-imidazole-2-amine, N- (2-chloro-4-methyl-3-thienyl) -4,5-dihydro-, (N- (2-chloro-4-methyl-
3 -thienyl)-4, 5 -dihydro- 1 H-imidazol-2-amine),3-thienyl) -4, 5 -dihydro- 1 H -imidazol-2-amine),
(Tiamenidine);(Tiamenidines);
1 H-Imidazol-2-amine, N-(2-chloro-4-methylphenyl)-4, 5 -dihydro-, (N-(2-Chloro-4- methylphenyl)-4,5-dihydro-lH-imidazol-2-amine),1 H-Imidazol-2-amine, N- (2-chloro-4-methylphenyl) -4,5-dihydro-, (N- (2-Chloro-4-methylphenyl) -4,5-dihydro-1H-imidazole -2-amines),
(Tolonidine);(Tolonidine);
2-[2-(2,6-dichloro-phenylamino)-2-imidazoline- 1 -yl]-2-(2-thienyl) acetic acid; lH-Imidazole, 2-(2,3-dihydro-2-methoxy-l,4-benzodioxin-2-yl)-4,5-dihydro-, (R)-;2- [2- (2,6-dichloro-phenylamino) -2-imidazoline-1-yl] -2- (2-thienyl) acetic acid; 1H-imidazoles, 2- (2,3-dihydro-2-methoxy-l, 4-benzodioxin-2-yl) -4,5-dihydro-, (R) -;
((R)-2-(2,3-Dihydro-2-methoxy-l,4-benzodioxin-2-yl)-4,5-dihydro-lH-imidazole),
2-[ 1 -(2,6-Dichlorphenoxy)ethyl-]-2-imidazolin.((R) -2- (2,3-dihydro-2-methoxy-l, 4-benzodioxin-2-yl) -4,5-dihydro-lH-imidazole), 2- [1 - (2,6-dichlorophenoxy) ethyl -] - 2-imidazoline.
2-[(2-Chlor-4-methyl-3-thienyl)amino]-2-imidazolin. 2 - [(2-chloro-4-methyl-3-thienyl) amino] -2-imidazoline.
, 6-Dichlorphenylacetylguanidin. , 6-dichlorophenylacetylguanidine.
l-(2,6-Dichlorbenzylidenamino)guanidin. 1- (2,6-dichlorobenzylideneamino) guanidine.
-(2,6-Dimethylbenzylamino)-4,5-dihydro-6H-l,3-thiazin. - (2,6-Dimethylbenzylamino) -4,5-dihydro-6H-l, 3-thiazine.
,6-Dichlorbenzaldehyd-(4-amino-4H- 1 ,2,4-triazol-3-yl)-hydrazon. , 6-dichlorobenzaldehyde- (4-amino-4H-1, 2,4-triazol-3-yl) hydrazone.
Cl
2-(2,6-Dichlorphenyl)-5,6-dihydroimidazo-[2, 1 ]thiazol.Cl 2- (2,6-dichlorophenyl) -5,6-dihydroimidazo- [2, 1] thiazole.
-(2, 6-Dimethylbenzyl)imidazol . l-(Imidazol-4-yl)-2-(2,6-dimethylphenyl)-ethan. l-(Imidazol-4-yl)-3-(2,6-dimethylphenyl)-propan. - (2, 6-Dimethylbenzyl) imidazole. 1- (imidazol-4-yl) -2- (2,6-dimethylphenyl) ethane. 1- (imidazol-4-yl) -3- (2,6-dimethylphenyl) propane.
1 -(Imidazol-4-yl)-4-(2, 6-dimethylphenyl)-butan.1 - (Imidazol-4-yl) -4- (2,6-dimethylphenyl) butane.
-(2,6-Dichlorphenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[2, l-b]imidazol. -(2-Chlor-6-ήüörρhenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[2,l-b]imidazol. -(2,6-Dichlor-3-methylphenyl)-2,3,6,7-tetrahydro-5H-pyrrolo[2,l-b]imidazol. - (2,6-dichlorophenyl) -2,3,6,7-tetrahydro-5H-pyrrolo- [2, lb] imidazole. - (2-Chloro-6-örüörρhenyl) -2,3,6,7-tetrahydro-5H-pyrrolo- [2, lb] imidazole. - (2,6-dichloro-3-methylphenyl) -2,3,6,7-tetrahydro-5H-pyrrolo [2, lb] imidazole.
ClCl
R=C1R m R=F R t«R = C1R m R = F R t «
R=C] tCH3 -(4-t-Butyl-2,6-dimethyl-3-hydroxy-benzyl)-2-imidazolin. -(4-t-Butyl-2,6-dimethyl-benzyl)-2-imidazolin.R = C] tCH 3 - (4-t-butyl-2,6-dimethyl-3-hydroxy-benzyl) -2-imidazoline. - (4-t-Butyl-2,6-dimethyl-benzyl) -2-imidazoline.
-( 1 ,2,3 ,4-Tetrahydro- 1 -naphthyl)-2-imidazolin - (1, 2,3, 4-tetrahydro-1-naphthyl) -2-imidazoline
-( 1 '-Naphthylmethyl)-2-imidazolin. - (1 '-Naphthylmethyl) -2-imidazoline.
-(2-Methoxy-5-chlorphenyl)azoimidazol. - (2-methoxy-5-chlorophenyl) azoimidazole.
-[N-(4-Hydroxy-2-methylbenzyliden)hydrazino]-2-imidazolin. - [N- (4-Hydroxy-2-methylbenzylidene) hydrazino] -2-imidazoline.
-Dimethylamino-5,6-dihydroxy-l,2,3,4-tetrahydronaphthalin. -Dimethylamino-5,6-dihydroxy-l, 2,3,4-tetrahydronaphthalene.
-Chlor-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazol. -Chlor-4- (2-imidazolin-2-ylamino) -2, 1, 3-benzothiadiazole.
-(2-Imidazolin-2-ylamino)-2-methyl-benzopyrazol. - (2-Imidazolin-2-ylamino) -2-methyl-benzopyrazole.
Amino-l-(2,5-dimethoxyphenyl)-propanol. Amino-l- (2,5-dimethoxyphenyl) propanol.
l-(3-Hydroxyphenyl)-2-methylamino-ethanol. 1- (3-Hydroxyphenyl) -2-methylaminoethanol.
2-[(O-Cyclopropylphenoxy)methyl]-2-imidazolin. 2 - [(O-Cyclopropylphenoxy) methyl] -2-imidazoline.
//
HH
3 '-( 1 -Hydroxy-2-methylaminoethyl)methansulfonanilid.3 '- (1-Hydroxy-2-methylaminoethyl) methanesulfonanilide.
CH , CH,
2-Amino-5-methylthio-8-methoxy-l,2,3,4-tetrahydronaphthalin.2-amino-5-methylthio-8-methoxy-l, 2,3,4-tetrahydronaphthalene.
H H
CH 3 CH 3
Am Beispiel des zentral wirksamen α-2-Rezeptor-Agonisten Clonidin wird die erfindungsgemäße Verwendung erläutert. In einer prospektiv randomisierten Untersuchung zur Effektivität zweier Kohlehydratregime (Vergleich Glukose (n=12) und Glukose/Xylit-Gemisch 1 : 1 (n=12) bei Patienten mit ausgedehnten abdominothorakalen Eingriffen (Ösophaguskardiaresektion mit Gastroösophagonstomie wegen Ösophaguskarzinom) konnten überraschenderweise in einer wegen akuter Alkoholanamnese mit dem zentralen α-2-Agonisten
Clonidin intravenös behandelten Gruppe eine postoperativ signifikant verbesserte kumulative Stickstoffbilanz gefunden werden. Über 6 Tage konnte bei den mit Clonidin behandelten Patienten fast 500 g an Muskelmasse eingespart werden. Die Patienten der Clonidingruppe (7 mit Glukose und 6 mit Glukose-Xylit ernährt) erhielten im Mittel zwischen 1,27 + 0,47 und 1,69 ± 1,60 mg Clonidin pro Tag.The use according to the invention is explained using the example of the centrally active α-2 receptor agonist clonidine. In a prospectively randomized study of the effectiveness of two carbohydrate regimens (comparison glucose (n = 12) and glucose / xylitol mixture 1: 1 (n = 12) in patients with extensive abdominothoracic interventions (esophageal cardiac resection with gastroesophagon stomy due to esophageal carcinoma) surprisingly resulted in one due to acute Alcohol history with the central α-2 agonist Clonidine intravenously treated group found a significantly improved cumulative nitrogen balance postoperatively. Over 6 days, almost 500 g of muscle mass could be saved in the patients treated with clonidine. The patients in the clonidine group (7 glucose-fed and 6 glucose-xylitol-fed) received on average between 1.27 + 0.47 and 1.69 ± 1.60 mg clonidine per day.
Es kann davon ausgegangen werden, daß alle zentral wirkenden α-2-Agonisten einen vergleichbaren Einfluß auf den Postagressionsstoffwechsel haben.It can be assumed that all centrally acting α-2 agonists have a comparable influence on the postagression metabolism.
Als Dosierungsempfehlung am Beispiel des Clonidin kann eine Dosis in der Größerordnung 2- 5 μ/kg/h kontinuierlich intravenös gegeben werden, wobei zur Steuerung der Dosis im Individualfall das hämodynamische Verhalten des Patienten von Bedeutung ist. Die Beendigung der Therapie sollte zur Prophylaxe eines Reboundphenomens schrittweise (z.B. Reduktion der Dosis um 50 % alle 12h) erfolgen, frühestens jedoch nach 4-5 Tagen.As a dosage recommendation using the example of clonidine, a dose in the order of 2-5 μ / kg / h can be given continuously intravenously, the hemodynamic behavior of the patient being important for controlling the dose in individual cases. In order to prevent a rebound phenomenon, the therapy should be terminated gradually (e.g. reduction of the dose by 50% every 12 hours), but at the earliest after 4-5 days.
Die erfindungsgemäß genannten Verbindungen können in üblichen galenischen Zubereitungen angewendet werden. Erfindungsgemäß bevorzugt sind Iηjektionslösungen.The compounds mentioned according to the invention can be used in conventional pharmaceutical preparations. Injection solutions are preferred according to the invention.
Die Dosierung ist Selbstverständlich abhängig von der Wirkungsstärke des α-2-Rezeptor- Agonisten. Für Clonidin kann beispielsweise bei einer i.V. Anwendung eine Dosierung von 1 - 10 μg/kg/h angewendet werden.
The dosage is of course dependent on the potency of the α-2 receptor agonist. For clonidine, for example, in an i.V. A dosage of 1 - 10 μg / kg / h can be used.
Claims
PatentansprücheClaims
1) Verwendung von zentral wirksamen α-2-Rezeptor-Agonisten zur Herstellung eines Arzneimttels zur Behandlung des Postaggressionssyndroms.1) Use of centrally acting α-2 receptor agonists for the manufacture of a medicament for the treatment of post-aggression syndrome.
2) Verwendung von Verbindungen der allgemeinen Formeln2) Use of compounds of the general formulas
in der X; Y, Z gleich oder verschieden sein können, ein Wasserstoff- oder Halogenatom, wie z.B. F, Cl, Br, eine Alkyl-, Halogenalkyl-, Alkoxy-, Halogenalkoxy-, Amino-, Nitr-, Hydroxy-, Alkylthio- oder Halogenthiogruppe, einen Cyclopropylrest, Rl ein Wasserstoffatom, einen Alkyl- oder Tetrahydropyranrest, bedeuten können sowie deren Säureadditionssalze.in the X; Y, Z may be the same or different, a hydrogen or halogen atom, e.g. F, Cl, Br, an alkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitrile, hydroxyl, alkylthio or halothio group, a cyclopropyl radical, Rl a hydrogen atom, an alkyl or tetrahydropyran radical, and the like Acid addition salts.
deren Säureadditionssalze mit physiologisch verträglichen anorganischen oder organischen Säuren, worin Rj ein Wasserstoffatom, einen gegebenenfalls durch eine Hydroxylgruppe substituierten geradkettigen oder verzweigten Alkylrest mit 1 - 4 Kohlenstoffatomen, einen Allyl-, Cycloalkyl-, Hexahydrobenzyl-, Phenyl-, Phenylethyl- oder Benzylrest, wobei der Benzylrest im Kern durch ein oder zwei Halogenatome, durch ein bis drei Methoxygruppen, durch eine Trifluormethyl- oder Alkylgruppe mit 1 - 3 Kohlenstoffatomen substituiert sein kann und falls X ein Schwefelatom darstellt,whose acid addition salts with physiologically compatible inorganic or organic acids, in which Rj is a hydrogen atom, a straight-chain or branched alkyl radical with 1-4 carbon atoms optionally substituted by a hydroxyl group, an allyl, cycloalkyl, hexahydrobenzyl, phenyl, phenylethyl or benzyl radical, where the benzyl radical in the nucleus can be substituted by one or two halogen atoms, by one to three methoxy groups, by a trifluoromethyl or alkyl group having 1 to 3 carbon atoms and if X represents a sulfur atom,
R2 ein Wasserstoffatom, einen geradkettigen oder verzweigten Alkylrest mit 1 - 5 Kohlenstoffatomen, einen Allyl-, Cycloalkyl-, Phenyl-, Benzyl- oder Phenylethylrest oder falls X ein Sauerstoffatom darstellt, ein Wasserstoffatom bedeutet,
0R2 represents a hydrogen atom, a straight-chain or branched alkyl radical having 1-5 carbon atoms, an allyl, cycloalkyl, phenyl, benzyl or phenylethyl radical or if X represents an oxygen atom, a hydrogen atom, 0
M *ιM * ι
in der R\ einen unsubstituierten oder durch Halogenatome, vorzugsweise Fluor-, Chlor-, oder Bromatom, Methyl-, Methoxy-, Trifluormethylgruppen gleich oder verschieden ein bis dreifach substituierten Phenylrest und R2 ein Wasserstoffatom oder einen unsubstituierten oder ein bis mehrfach durch Halogenatome, vorzugsweise Chloratome, substituierten Phenylrest bedeuten; oder deren Säureadditionssalze zur Herstellung eines Arzneimittels zur Behandlung des Postaggressionssyndroms.in which R \ is an unsubstituted or halogen atom, preferably fluorine, chlorine or bromine atom, methyl, methoxy or trifluoromethyl groups, the same or different mono- to trisubstituted phenyl radical, and R2 is a hydrogen atom or an unsubstituted or one to more than one halogen atom, preferably Chlorine atoms, substituted phenyl radical; or their acid addition salts for the manufacture of a medicament for the treatment of post-aggression syndrome.
3) Verwendung von Verbindungen nach Anspruch 1 ausgewählt aus der Gruppe 2-[ 1 -(2,6-Dichloφhenoxy)ethyl-]-2-imidazolin, 2-[(2-Chlor-4-methyl-3-thienyl)amino]-2-imidazolin, 2, 6-Dichloφhenylacetylguanidin, 1 -(2, 6-Dichlorbenzylidenamino)guanidin, 2-(2, 6-Dimethylbenzylamino)-4, 5-dihydro-6H- 1 , 3 -thiazin, 2,6-Dichlorbenzaldehyd-(4-amino-4H-l,2,4-triazol-3-yl)-hydrazon, 2-(2,6-Dichloφhenyl)-5,6-dihydroimidazo-[2, 1 ]thiazol, 4-(2,6-Dimethylbenzyl)imidazol, 1 -(Imidazol-4-yl)-2-(2, 6-dimethylphenyl)-ethan, 1 -(Imidazol-4-yl)-3 -(2, 6-dimethylphenyl)-propan, l-(Imidazol-4-yl)-4-(2,6-dimethylphenyl)-butan, 6-(2,6-Dichlθφhenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[2, l-b]imidazol, 6-(2-Chlor-6-fluoφhenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[2,l-b]imidazol, 6-(2,6-Dichlor-3-methylphenyl)-2,3,6,7-tetrahydro-5H-pyrrolo[2,l-b]imidazol, 2-(4-t-Butyl-2,6-dimethyl-3-hydroxy-benzyl)-2-imidazolin, 2-(4-t-Butyl-2,6-dimethyl-benzyl)-2-imidazolin, 2-( 1 ,2,3 ,4-Tetrahydro- 1 -naphthyl)-2-imidazolin, 2-( 1 '-Naphthylmethyl)-2-imidazolin, 2-(2-Methoxy-5-chloφhenyl)azoimidazol, 2-[N-(4-Hydroxy-2-methylbenzyliden)hydrazino]-2-imidazolin 2-Dimethylamino-5,6-dihydroxy-l,2,3,4-tetrahydronaphthalin,
5-Chlor-4-(2-imidazolin-2-ylamino)-2, 1 ,3-benzothiadiazol,3) Use of compounds according to claim 1 selected from the group 2- [1 - (2,6-dichloφhenoxy) ethyl -] - 2-imidazoline, 2 - [(2-chloro-4-methyl-3-thienyl) amino] -2-imidazoline, 2, 6-dichlorophenylacetylguanidine, 1 - (2, 6-dichlorobenzylidenamino) guanidine, 2- (2, 6-dimethylbenzylamino) -4, 5-dihydro-6H-1, 3 -thiazine, 2,6- Dichlorobenzaldehyde- (4-amino-4H-l, 2,4-triazol-3-yl) hydrazone, 2- (2,6-dichloφhenyl) -5,6-dihydroimidazo- [2, 1] thiazole, 4- ( 2,6-dimethylbenzyl) imidazole, 1 - (imidazol-4-yl) -2- (2,6-dimethylphenyl) -ethane, 1 - (imidazol-4-yl) -3 - (2,6-dimethylphenyl) - propane, l- (imidazol-4-yl) -4- (2,6-dimethylphenyl) butane, 6- (2,6-dichloro-phenyl) -2,3,6,7-tetrahydro-5H-pyrrolo- [2 , lb] imidazole, 6- (2-chloro-6-fluoφhenyl) -2,3,6,7-tetrahydro-5H-pyrrolo- [2, lb] imidazole, 6- (2,6-dichloro-3-methylphenyl ) -2,3,6,7-tetrahydro-5H-pyrrolo [2, lb] imidazole, 2- (4-t-butyl-2,6-dimethyl-3-hydroxy-benzyl) -2-imidazoline, 2- (4-t-Butyl-2,6-dimethyl-benzyl) -2-imidazoline, 2- (1, 2,3, 4-tetrahydro-1-naphthyl) -2-imidazoline, 2- (1 '-Naphthylmethyl) -2-imidazoline, 2- (2-methoxy-5-chloro-phenyl) azoimidazole, 2- [N- (4-hydroxy-2-methylbenzylidene) hydrazino] -2-imidazoline 2-dimethylamino-5,6- dihydroxy-l, 2,3,4-tetrahydronaphthalene, 5-chloro-4- (2-imidazolin-2-ylamino) -2, 1, 3-benzothiadiazole,
4-(2-Imidazolin-2-ylamino)-2-methyl-benzopyrazol,4- (2-imidazolin-2-ylamino) -2-methyl-benzopyrazole,
2-Amino- 1 -(2, 5-dimethoxyphenyl)-propanol,2-amino-1 - (2,5-dimethoxyphenyl) propanol,
1 -(3 -Hydroxyphenyl)-2-methylamino-ethanol,1 - (3-hydroxyphenyl) -2-methylaminoethanol,
2-[(O-Cyclopropylphenoxy)methyl]-2-imidazolin,2 - [(O-cyclopropylphenoxy) methyl] -2-imidazoline,
3 '-( 1 -Hydroxy-2-methylaminoethyl)methansulfonanilid,3 '- (1-hydroxy-2-methylaminoethyl) methanesulfonanilide,
2-Amino-5-methylthio-8-methoxy-l,2,3,4-tetrahydronaphthalin, zur Herstellung eines Arzneimittels zur Behandlung des2-Amino-5-methylthio-8-methoxy-l, 2,3,4-tetrahydronaphthalene, for the manufacture of a medicament for the treatment of
PostaggressionssyndromsPost-aggression syndrome
4) Verwendung von Verbindungen nach Ansprach 1 ausgewählt aus der Grappe4) Use of compounds according to approach 1 selected from the Grappe
2-(2,6-Dichloranilino)-2-imidazolin,2- (2,6-dichloroanilino) -2-imidazoline,
2(4-Aιn__no-2,6-dichloramdino)-2-imidazolin,2 (4-Aιn__no-2,6-dichloramdino) -2-imidazoline,
8-(2,6-Dichloφhenyl)-7-(4-chloφhenyl)-5-oxo-2,3-dihydroimidazol[l,2-a]s- triazin, l-Acetony1-2-(2,6-dicWoφhenylammo)-2-imidazolin,8- (2,6-dichlorophenyl) -7- (4-chlorophenyl) -5-oxo-2,3-dihydroimidazole [1,2-a] s-triazine, l-acetony1-2- (2,6-dicwophenylammo ) -2-imidazoline,
2-(2-Brom-6-fluoranilino)-2-imidazolin,2- (2-bromo-6-fluoroanilino) -2-imidazoline,
2-(2-Fluor-6-trifluormethylphenylamino)-2-imidazolin,2- (2-fluoro-6-trifluoromethylphenylamino) -2-imidazoline,
2-(2-CUor-5-trifluormethylphenylamino)-2-imidazolin,2- (2-CUor-5-trifluoromethylphenylamino) -2-imidazoline,
2-(2-Chlor-4-cyclopropylphenylam__no)-2-imidazolin,2- (2-chloro-4-cyclopropylphenylam__no) -2-imidazoline,
2-(3-Fluor-4-methylphenylamino)-2-imidazolin,2- (3-fluoro-4-methylphenylamino) -2-imidazoline,
2-(6-CUor-4-methoxy-2-methyl-pyrin_ddiιι-5-ylammo)-2-imidazolin, l-Benzoyl-2-(2,6-dicWoranilino)-2-imidazolin,2- (6-Cuor-4-methoxy-2-methyl-pyrin_ddiιι-5-ylammo) -2-imidazoline, l-benzoyl-2- (2,6-dicWoranilino) -2-imidazoline,
2-[ -)2,6-DicUoφhenyl)-N-tetrahydropyran-2-yl)-ammo]-2-__midazolin,2- [-) 2,6-DicUoφhenyl) -N-tetrahydropyran-2-yl) -ammo] -2 -__ midazoline,
2-(4-Aιr_ino-2,6-dic__üo henylammo)-2-i_midazolin,2- (4-Aιr_ino-2,6-dic__üo henylammo) -2-i_midazoline,
2-(3,4-Düιydroxy-phenylam__no)-2-imidazolin,2- (3,4-dydroxy-phenylam__no) -2-imidazoline,
2-Amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]-azepin,2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4-d] azepine,
2-Amino-6-(p-chlorbenzyl)-4,5,7,8-tetrahydro-6H-thiazolo-[5,4-d]azepin,2-amino-6- (p-chlorobenzyl) -4,5,7,8-tetrahydro-6H-thiazolo- [5,4-d] azepine,
oder deren Säureadditionssalze zur Herstellung eines Arzneimittels zur Behandlung des Postaggressionssyndroms.or their acid addition salts for the manufacture of a medicament for the treatment of post-aggression syndrome.
5) Verwendung von Verbindungen nach Anspruch 1 ausgewählt aus der Grappe5) Use of compounds according to claim 1 selected from the Grappe
BAM 1110, Brimonidine tartrate, CGS 15873, Dexmedetomidine,
Gluanabenz acetate,BAM 1110, brimonidine tartrate, CGS 15873, dexmedetomidine, Gluanabenz acetate,
HP-749HP-749
IDPH-791,IDPH-791,
Ledazerol,Ledazerol,
Methyldopa,Methyl dopa,
Mivazerol,Mivazerol,
Rilmenidine,Rilmenidine,
Deriglidole,Deriglidole,
Tinabinol,Tinabinol,
Tizanidine,Tizanidine,
S-8350S-8350
AGN-191103,AGN-191103,
Ledazerol,Ledazerol,
Mivazerol,Mivazerol,
U-47,476 A,U-47.476 A,
Apraclonidin,Apraclonidine,
FLA-136,FLA-136,
Piclonidine,Piclonidines,
LR-004,LR-004,
Detomidine,Detomidine,
MPV-709,MPV-709,
Aganodine,Aganodine,
BAM-1125,BAM-1125,
BDF-6665,BDF-6665,
Benchlonidine,Benchlonidins,
CI-201-678,CI-201-678,
Cirazoline,Cirazoline,
D-2343,D-2343,
DJ-7141,DJ-7141,
Buteranol,Buteranol,
Idralfidine,Idralfidine,
Lidamidine,Lidamidine,
Lofexidine,Lofexidine,
SC-39207,SC-39207,
Sch-40054,Sch-40054,
Tiamenidine,Tiamenidines,
Tolonidine,Tolonidines,
2-[2-(2,6-dichloro-phenylamino)-2-imidazoline- 1 -yl]-2-(2-thienyl) acetic acid,
lH-Imidazole, 2-(2,3-dihydro-2-methoxy-l,4-benzodioxin-2-yl)-4,5-dihydro-, (R)-,((R)- 2-(2,3-Dihydro-2-methoxy-l,4-benzodioxin-2-yl)-4,5-dihydro-lH-imidazole).2- [2- (2,6-dichlorophenylamino) -2-imidazoline-1-yl] -2- (2-thienyl) acetic acid, lH-imidazoles, 2- (2,3-dihydro-2-methoxy-l, 4-benzodioxin-2-yl) -4,5-dihydro-, (R) -, ((R) - 2- (2, 3-dihydro-2-methoxy-l, 4-benzodioxin-2-yl) -4,5-dihydro-lH-imidazole).
6) Verwendung von 2-Amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]azepin (BHT 933) und 6-Allyl-2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepin (BHT 920) oder deren Säureadditionssalze nach Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung des Postaggressionssyndroms.6) use of 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo [5,4-d] azepine (BHT 933) and 6-allyl-2-amino-4,5, 7,8-tetrahydro-6H-thiazolo [5,4-d] azepine (BHT 920) or their acid addition salts according to claim 1 for the manufacture of a medicament for the treatment of post-aggression syndrome.
7) Verwendung von Clonidin oder dessen Säureadditionssalze zur Herstellung eines Arzneimittels zur Behandlung des Postaggressionssyndroms.7) Use of clonidine or its acid addition salts for the manufacture of a medicament for the treatment of post-aggression syndrome.
8) Verwendung von 2-[(2-Brom-6-fluoφhenyl)-imino]imidazolidin (STH 2130) oder dessen Säureadditionssalzes zur Herstellung eines Arzneimittels zur Behandlung des Postaggressionssyndroms.8) Use of 2 - [(2-bromo-6-fluorophenyl) imino] imidazolidine (STH 2130) or its acid addition salt for the manufacture of a medicament for the treatment of post-aggression syndrome.
9) Verwendung einer Verbindung gemäß einem der vorhergehenden Ansprüche zur Herstellung eines Arzneimiteis zur Hemmung des Postaggressionsstoffwechsels.9) Use of a compound according to any one of the preceding claims for the manufacture of a medicament for the inhibition of postaggressive metabolism.
10) Verwendung einer Verbindung gemäß einem der vorhergehenden Ansprüche zur Herstellung einer Injektionslösung zur Behandlung des Postaggressionssyndroms.10) Use of a compound according to any one of the preceding claims for the manufacture of a solution for injection for the treatment of post-aggression syndrome.
11 ) Verwendung einer Verbindung gemäß einem der vorhergehenden Ansprüche zur Herstellung einer Injektionslösung zur Behandlung zur Hemmung des Postaggressionsstofiwechsels.
11) Use of a compound according to any one of the preceding claims for the preparation of an injection solution for treatment for inhibiting the postaggressive metabolism.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19934325491 DE4325491A1 (en) | 1993-07-29 | 1993-07-29 | Use of centrally acting alpha-2 agonists to inhibit post-aggression metabolism |
| DE4325491 | 1993-07-29 | ||
| PCT/EP1994/002475 WO1995003798A2 (en) | 1993-07-29 | 1994-07-27 | USE OF CENTRALLY EFFECTIVE α-2 AGONISTS FOR INHIBITING POSTAGGRESSION METABOLISM |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0719139A1 true EP0719139A1 (en) | 1996-07-03 |
Family
ID=6494011
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP94925399A Ceased EP0719139A1 (en) | 1993-07-29 | 1994-07-27 | Use of centrally active alphaagonists for inhibing postraumatic metabolic stress |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0719139A1 (en) |
| AU (1) | AU7533194A (en) |
| DE (1) | DE4325491A1 (en) |
| WO (1) | WO1995003798A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2196792A1 (en) | 1994-08-04 | 1996-02-15 | Yoon T. Jeon | Novel benzimidazole derivatives |
| KR19980702511A (en) * | 1995-02-28 | 1998-07-15 | 크라우더 티 알 | Use of Moxonidine to Treat Atherosclerosis |
| EP0914128A1 (en) * | 1996-06-06 | 1999-05-12 | Eli Lilly And Company | Formulation and method for treating congestive heart failure |
| US6495583B1 (en) | 1997-03-25 | 2002-12-17 | Synaptic Pharmaceutical Corporation | Benzimidazole derivatives |
| AUPP020297A0 (en) * | 1997-11-05 | 1997-11-27 | University Of Melbourne, The | A novel receptor, and compounds which bind thereto |
| DE19938825A1 (en) * | 1999-08-19 | 2001-04-26 | Boehringer Ingelheim Pharma | Active ingredient combination with clonidine |
| GB0119435D0 (en) * | 2001-02-15 | 2001-10-03 | Aventis Pharm Prod Inc | Method of treating of demyelinating diseases or conditions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5120713A (en) * | 1990-09-10 | 1992-06-09 | Applied Research Systems Ars Holding N.V. | Treatment of obesity with an alpha-2-adrenergic agonist and a growth hormone releasing peptide |
-
1993
- 1993-07-29 DE DE19934325491 patent/DE4325491A1/en not_active Withdrawn
-
1994
- 1994-07-27 EP EP94925399A patent/EP0719139A1/en not_active Ceased
- 1994-07-27 WO PCT/EP1994/002475 patent/WO1995003798A2/en not_active Application Discontinuation
- 1994-07-27 AU AU75331/94A patent/AU7533194A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9503798A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995003798A2 (en) | 1995-02-09 |
| AU7533194A (en) | 1995-02-28 |
| WO1995003798A3 (en) | 2001-05-03 |
| DE4325491A1 (en) | 1995-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7687080B2 (en) | Treatment of neuropathy | |
| DE69737592T2 (en) | MEDIUM AGAINST JUCKREIZ | |
| MARTIN et al. | Inhibition by apomorphine of prolactin secretion in patients with elevated serum prolactin | |
| US20030114509A1 (en) | Prophylactic or therapeutic drug for renal diseases | |
| DE60211913T2 (en) | ARYL (OR HETEROARYL) AZOLYLCARBYNOL DERIVATIVE FOR THE TREATMENT OF HARNINE CONTINENCE | |
| AU678149B2 (en) | 5-HT2 receptor antagonist compositions useful in treating venous conditions | |
| DE69333362T3 (en) | USE OF ANGIOTENSINE ANTAGONISTS (AT1) TO REDUCE DISEASE AND DEATH RISK TO MYOCARDINE FARCT | |
| EP0719139A1 (en) | Use of centrally active alphaagonists for inhibing postraumatic metabolic stress | |
| US6844361B2 (en) | Pharmaceutical composition comprising a sodium hydrogen exchange inhibitor and an angiotensin converting enzyme inhibitor | |
| EP0951907B1 (en) | Use of moxonidine as a thermogenesis stimulating agent | |
| DE69907387T2 (en) | Use of hydantoin derivatives for the manufacture of a medicament for the treatment of refractory vasculitis. | |
| DE60128472T2 (en) | COMBINED TUMOR THERAPY BASED ON DISTAMYCIN ACRYLOYL DERIVATIVES AND ALKYLATIVES | |
| KR100260479B1 (en) | Antihypertensive combinations | |
| EP0028660A1 (en) | Xanthinoxydase inhibitors and utilization of benzotriazine derivatives | |
| DE10352132A1 (en) | Pharmaceutical composition of a beta-3 adrenoceptor agonist and an alpha agonist | |
| CA1330947C (en) | Treatment of cardiac arrhythmias | |
| US11369601B2 (en) | Prophylactic or therapeutic agent for pulmonary hypertension comprising mebendazole and/or itraconazole or salt thereof | |
| DE2462711C2 (en) | Use of 2,6-cis-diphenylhexamethylcyclotetrasiloxane | |
| EP1474134B1 (en) | Combination preparation of the sodium-hydrogen exchange inhibitor cariporide with ramipril for preventing or blocking heart failure | |
| DE2823268A1 (en) | BLOOD PRESSURE REDUCING AGENT | |
| JP2003146877A (en) | Antileishmanial | |
| DE19810515A1 (en) | Composition containing stimulators of cyclic nucleotide monophosphate | |
| JPH07503968A (en) | Use of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine for the treatment of edema and pain | |
| EP0387762A2 (en) | Medicament with positive inotropic activity, containing a synergistically active mixture consisting of a benzimidazole and a beta-blocker, its preparation and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19960229 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
| RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: DR. KARL THOMAE GMBH |
|
| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: BRECHT, HANS-MICHAEL Inventor name: KUHMANN. MARTIN Inventor name: ZANDER, JOSEPH Inventor name: GOETERS, CHRISTIANE Inventor name: MERTES, NORBERT |
|
| RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BOEHRINGER INGELHEIM PHARMA KG |
|
| 17Q | First examination report despatched |
Effective date: 19990406 |
|
| RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: BOEHRINGER INGELHEIM PHARMA KG |
|
| GRAG | Despatch of communication of intention to grant |
Free format text: ORIGINAL CODE: EPIDOS AGRA |
|
| RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7A 61K 31/41 A, 7A 61K 31/55 B, 7A 61P 3/00 B |
|
| RTI1 | Title (correction) |
Free format text: USE OF CLONIDINE FOR INHIBING POSTRAUMATIC METABOLIC STRESS |
|
| RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7A 61K 31/4168 A, 7A 61P 3/00 B |
|
| RTI1 | Title (correction) |
Free format text: USE OF CLONIDINE FOR INHIBING POSTRAUMATIC METABOLIC STRESS |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
| 18R | Application refused |
Effective date: 20020203 |