EP0910374A1 - Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate - Google Patents
Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivateInfo
- Publication number
- EP0910374A1 EP0910374A1 EP97931798A EP97931798A EP0910374A1 EP 0910374 A1 EP0910374 A1 EP 0910374A1 EP 97931798 A EP97931798 A EP 97931798A EP 97931798 A EP97931798 A EP 97931798A EP 0910374 A1 EP0910374 A1 EP 0910374A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbazolyl
- hydrogen
- treatment
- active ingredient
- compound
- 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.)
- Withdrawn
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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
Definitions
- the present invention relates to pharmaceutical formulations which can be used topically and which have a carbazolyl- (4) -oxypropanolamine derivative of the general formula I as active ingredient
- R 1 and R 2 independently of one another denote hydrogen or the hydroxyl group, or contain their enantiomers or their pharmacologically acceptable salts.
- the invention also relates to new uses of these formulations for the topical treatment of peripheral circulatory disorders, in particular of the extremities, and of inflammation and skin wounds.
- Carbazolyl- (4) -oxypropanolamm derivatives are known to be therapeutically active compounds.
- EP 0 004 920 describes, in addition to other derivatives, the racemic compound of the general formula I with R and R " as hydrogen (Carvedilol *) as a medicament with vasodilating and ⁇ -receptor-blocking action, which are suitable for the treatment and prophylaxis of Cardiovascular and cardiac diseases such as hypertension and angina pectoris are suitable, enteral, parenteral and oral dosage forms are proposed.
- Raceric compounds of the formula I are also described by Yue et al. in "The Journal of Pharmacology and Experimental Therapeutics” 236 (1), pages 92-98 (1992). The authors report that Carvedilol * and, in particular in the carbazole structure or in the phenoxy compound, hydroxylated carvedilol derivatives have an antioxidative effect show and inhibit lipid peroxidation.
- the compounds of the general formula I, their pharmacologically acceptable salts, their enantiomers or their pharmacologically acceptable salts can be used for the topical treatment of locally peripheral blood circulation disorders, in particular of the extremities.
- Peripheral circulatory disorders in the extremities are often accompanied by numbness in the extremities, severely restricted mobility and swelling.
- the severity of circulatory disorders is very different and can have different causes.
- Frequent vasospastic attacks are treated with calcium antagonists or nitro compounds, which can lead to improved blood circulation due to their vasodilatory effects.
- prostaglandm E becomes intravenous administered or the flow conditions of the blood improved by controlled lowering of the fibrinogen, for example by subcutaneous snake venom application or hamodilution treatment.
- Particularly preferred are those hydroxylated carbazole derivatives whose hydroxyl groups are located in positions 1, 3, 6 or 8 of the carbazole chain.
- the compounds having a hydroxyl group in 1- or 3-position of the carbazole are very particularly suitable.
- Inflammation of the skin accounts for well over 50 ° 0 of all skin diseases. Their typical symptoms are reddening of the skin, blistering or excessive cornification, loss of elasticity of the skin, tearing of the skin, open bloody wounds, inflammation.
- hydrocortisone-containing ointments mainly hydrocortisone-containing ointments, light radiation and preparations from coal tar are used.
- anti-metabolites such as methotrexate or immunosuppressants such as Cyclosporm A or FK506 are used.
- These therapeutic agents are only partially effective, often they have no influence on the course of the disease.
- Particularly preferred are those hydroxylated carbazole derivatives whose hydroxyl group is located in positions 1, 3, 6 or 8 of the carbazole group.
- the compounds with hydroxyl group are particularly suitable in 1- or 3-position of the carbazole.
- EP 0 004 920 describes the preparation of the racemic compounds of the formula I with R and R as hydrogen, the separation of which into the optically active forms can be carried out by methods known per se.
- EP 0 127 099 describes the asymmetric synthesis of R- and S-carbazole derivatives of the general formula I with the radicals R 1 and R 2 as hydrogen, the enantiomers having a high optical purity being obtained.
- optically active phases are, for example, optically active polyacrylamides or Polymethacryia ide, e.g. T. also on silica gel (e.g.
- the carbazole derivatives of the general formula I obtained can be converted into pharmacologically acceptable salts by - preferably in an organic solvent - with the equivalent amount of an inorganic or organic acid, e.g. Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
- an inorganic or organic acid e.g. Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
- the carbazole derivatives of the formula I, their enantiomers or pharmacologically tolerable salts are formulated in a manner known per se using suitable pharmaceutical auxiliaries as a cream, ointment, gel, lotion, solution or spray.
- suitable pharmaceutical auxiliaries as a cream, ointment, gel, lotion, solution or spray.
- the medicaments contain one or more compounds of the general formula I in a total amount of 0.5-2% by weight. %.
- Suitable bases for ointments, creams or gels are, for example, petroleum jelly, paraffins, such as hard paraffin, or viscous paraffin, medium-chain triglycerides, natural waxes, wool wax, isopropyl myristate, highly disperse silicon dioxide, bentonite, starch, alginates, cellulose and cellulose ethers, sodium carboxymymethyl cellulose, poly lenglycols and others.
- Suitable solvents for lotions and solutions are water or water-alcohol mixtures.
- the agents according to the invention are applied to the skin.
- the amount of drug applied is generally about 0.01-10 mg / cm 2 skin.
- the compounds and pharmaceutical formulations according to the invention are used in particular for the treatment of Raynaud's disease, collagenosis (systemic lupus erythematosus, chronic polyarthritis, progressive systemic sclerosis), Sjorgen syndrome, thrombangitis obliterans and diabetic polyneuropathy.
- the compounds of the formula I and the formulations according to the invention are used for the treatment of dermatitis and eczema, in particular psoriasis and neurodermatitis.
- Example 1 Ointment with the following composition:
- Carvedilol is micronized using a jet mill or other device.
- the grinding obtained should contain 90% particles of the size 1-10 ⁇ .
- 100 g of the micronized active ingredient are mixed with 300 g of ointment base, e.g. B. ground with lanolin, placed on a roller mill and in this way a rub is produced.
- ointment base e.g. B. ground with lanolin
- the trituration thus obtained is made up to 10 kg with lanolin or another ointment base, stirred vigorously and passed over the roller mill for homogenization.
- This homogeneous mass is filled in m tubes. The tubes are folded and closed with a special machine.
- a patient with diagnosed secondary Raynaud's disease i.e. with severe circulatory disorders of the fingers, was treated with a formulation according to Example 1 for 4 weeks.
- the ointment was applied to the skin and was able to act for about 9 hours during the night. After a few days, the hands were functioning normally, i.e. the numbness of the fingers, their severely restricted mobility and the swelling had disappeared.
- the ointment was applied to the hand regularly throughout the day. After three weeks the wounds were closed, the fingers were painless and the hand was functional.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention concerns pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate of the general formula (I), in which R?1 and R2¿ stand for, independently of one another, hydrogen or the hydroxy group, or their enantiomers, or their pharmacologically tolerated salts, such as carvedilol, for the treatment of peripheral circulatory disturbances, especially of the extremities, as well as of inflammations and open wounds.
Description
Topisch einsetzbare pharmazeutische Formulierungen enthaltend als Wirkstoff ein Topical pharmaceutical formulations containing as an active ingredient
Carbazolyl- (4) -oxy-propanolamin-DerivatCarbazolyl (4) oxypropanolamine derivative
Beschreibungdescription
Die vorliegende Erfindung betrifft topisch einsetzbare pharmazeutische Formulierungen, die als Wirkstoff ein Carbazolyl- (4) -oxy-propanolamin-Derivat der allgemeinen Formel IThe present invention relates to pharmaceutical formulations which can be used topically and which have a carbazolyl- (4) -oxypropanolamine derivative of the general formula I as active ingredient
in der R1 und R2 unabhängig voneinander Wasserstoff oder die Hydroxygruppe bedeuten, oder deren Enantiomere oder deren pharmakologisch verträgliche Salze enthalten.in which R 1 and R 2 independently of one another denote hydrogen or the hydroxyl group, or contain their enantiomers or their pharmacologically acceptable salts.
Gegenstand der Erfindung sind auch neue Verwendungen dieser Formulierungen zur topischen Behandlung peripherer Durchblutungsstörungen, insbesondere der Extremitäten, sowie von Entzündungen und Wunden der Haut.
Es ist bekannt, daß Carbazolyl- (4) -oxy-propanolamm- Derivate therapeutisch wirksame Verbindungen sind. So beschreibt EP 0 004 920 neben anderen Derivaten die racemi- sche Verbindung der allgemeinen Formel I mit R und R" als Wasserstoff (Carvedilol*) als Arzneimittel mit vasodilatie- render und ß-rezeptoren-blockierender Wirkung, die sich zur Behandlung und Prophylaxe von Kreislauf- und Herzerkrankungen, wie zum Beispiel Hypertension und Angina pectoris, eignet. Es werden enterale, parenterale und orale Darrei- chungsformen vorgeschlagen.The invention also relates to new uses of these formulations for the topical treatment of peripheral circulatory disorders, in particular of the extremities, and of inflammation and skin wounds. Carbazolyl- (4) -oxypropanolamm derivatives are known to be therapeutically active compounds. For example, EP 0 004 920 describes, in addition to other derivatives, the racemic compound of the general formula I with R and R " as hydrogen (Carvedilol *) as a medicament with vasodilating and β-receptor-blocking action, which are suitable for the treatment and prophylaxis of Cardiovascular and cardiac diseases such as hypertension and angina pectoris are suitable, enteral, parenteral and oral dosage forms are proposed.
Raceraische Verbindungen der Formel I werden auch von Yue et al. in „The Journal of Pharmacology and Experimental Thera- peutics" 236 (1), Seiten 92-98 (1992) beschrieben. Die Autoren berichten, daß Carvedilol* und insbesondere in der Carbazolstruktur oder im Phenoxynng hydroxylierte Carvedi- lol-Abkommlinge eine antioxidative Wirkung zeigen und die Lipidperoxidation hemmen.Raceric compounds of the formula I are also described by Yue et al. in "The Journal of Pharmacology and Experimental Therapeutics" 236 (1), pages 92-98 (1992). The authors report that Carvedilol * and, in particular in the carbazole structure or in the phenoxy compound, hydroxylated carvedilol derivatives have an antioxidative effect show and inhibit lipid peroxidation.
Es wurde nun überraschenderweise festgestellt, daß die Verbindungen der allgemeinen Formel I, ihre pharmakologisch vertraglichen Salze, ihre Enantiomeren oder deren pharmakologisch vertragliche Salze zur topischen Behandlung lokal peπpherer Durchblutungsstörungen, insbesondere der Extre- mitaten, eingesetzt werden können.It has now surprisingly been found that the compounds of the general formula I, their pharmacologically acceptable salts, their enantiomers or their pharmacologically acceptable salts can be used for the topical treatment of locally peripheral blood circulation disorders, in particular of the extremities.
Periphere Durchblutungsstörungen der Extremitäten, insbesondere der Finger und Zehen, gehen oftmals mit Gefühllosigkeit der Extremitäten, stark eingeschränkter Beweg- lichkeit und Schwellungen einher. Der Schweregrad der Durchblutungsstörungen ist sehr unterschiedlich und kann verschiedene Ursachen haben. Gehäuft auftretende vaso- spastische Attacken werden mit Kalziumantagonisten bzw. Nitroverbmdungen behandelt, die durch ihre gefaßrelaxie- rende Wirkung zu einer verbesserten Durchblutung fuhren können. Sind Ruheschmerzen oder akrale Nekrosen für den Patienten symptomatisch, wird Prostaglandm E intravenös
verabreicht oder die Fließbedingungen des Blutes durch kontrollierte Absenkung des Fibrinogens, etwa durch subkutane Schlangengiftapplikation oder Hamodilutionsbehandlung, verbessert. Diese Methoden sind nur bedingt wirksam (z.B. Toleranzentwicklung gegenüber Nitropraparaten) bzw. sehr aufwendig oder mit Nebenwirkungen versehen.Peripheral circulatory disorders in the extremities, especially the fingers and toes, are often accompanied by numbness in the extremities, severely restricted mobility and swelling. The severity of circulatory disorders is very different and can have different causes. Frequent vasospastic attacks are treated with calcium antagonists or nitro compounds, which can lead to improved blood circulation due to their vasodilatory effects. If rest pain or acral necrosis are symptomatic of the patient, prostaglandm E becomes intravenous administered or the flow conditions of the blood improved by controlled lowering of the fibrinogen, for example by subcutaneous snake venom application or hamodilution treatment. These methods are only partially effective (e.g. development of tolerance to nitropraparates) or are very complex or have side effects.
Es zeigte sich, daß die erfindungsgemäße, einfach durchzuführende topische Anwendung der Verbindungen der allgemei- nen Formel I sowohl zu einer generellen Durchblutung als auch zu einer Abschwellung der betroffenen Extremitäten fuhrt. Erfmdungsgemaß bevorzugt wird Carvedilol11 (1- [Carbazolyl- (4 ) -oxy-] -3- [2- (2-methoxyphenoxy) ethylammo] - propanol- (2) ) oder die im Carbazol-Rest durch eine Hydroxy- gruppe substituierten Verbindungen (R oder R** = OH) einge¬ setzt. Besonderes bevorzugt sind solche hydroxylierten Carbazol-Derivate, deren Hydroxygrupppe in den Positionen 1, 3, 6 oder 8 des Carbazolnnges sitzt. Ganz besonders geeignet sind die Verbindungen mit Hydroxygruppe in 1- oder 3-Posιtιon des Carbazolnnges.It was found that the topical application of the compounds of the general formula I, which is easy to carry out according to the invention, leads to a general circulation as well as to a swelling of the affected extremities. According to the invention, Carvedilol 11 (1- [carbazolyl- (4) -oxy-] -3- [2- (2-methoxyphenoxy) ethylammo] propanol- (2)) or those substituted in the carbazole radical by a hydroxyl group is preferred Connections (R or R ** = OH) used ¬ . Particularly preferred are those hydroxylated carbazole derivatives whose hydroxyl groups are located in positions 1, 3, 6 or 8 of the carbazole chain. The compounds having a hydroxyl group in 1- or 3-position of the carbazole are very particularly suitable.
Ferner wurde gefunden, daß die Verbindungen der allgemeinen Formel I auch zur Behandlung von Entzündungen und offenen Wunden der Haut eingesetzt werden können.It has also been found that the compounds of the general formula I can also be used to treat inflammation and open skin wounds.
Entzündungen der Haut machen weit über 50 °0 aller Hauterkrankungen aus. Ihre typischen Symptome sind Rötung der Haut, Bildung von Bläschen bzw. übermäßige Verhornung, Elastizitatsverlust der Haut, Aufreißen der Haut, offene blutige Wunden, Entzündungen.Inflammation of the skin accounts for well over 50 ° 0 of all skin diseases. Their typical symptoms are reddening of the skin, blistering or excessive cornification, loss of elasticity of the skin, tearing of the skin, open bloody wounds, inflammation.
Therapeutisch werden vorwiegend hydrocortisonhaltige Salben, Lichtbestrahlung und Präparate aus Kohlenteer verwendet. In besonders schweren Fallen werden anti-Metabo- liten wie Methotrexat bzw. Immunsuppressiva wie Cyclosporm A bzw. FK506 eingesetzt. Diese Therapeutika sind nur
bedingt wirksam, nicht selten haben sie keinen Einfluß aui den Krankheitsverlauf.Therapeutically, mainly hydrocortisone-containing ointments, light radiation and preparations from coal tar are used. In particularly severe cases, anti-metabolites such as methotrexate or immunosuppressants such as Cyclosporm A or FK506 are used. These therapeutic agents are only partially effective, often they have no influence on the course of the disease.
Es zeigte sich, daß die erfmdungsgemaße, einfach durchzu- fuhrende topische Anwendung der Verbindungen der allgemeinen Formel I zu einer Entzundunshemmung und Wundheilung der Haut fuhrt. Erfmdungsgemaß bevorzugt eingesetzt werden ebenfalls Carvedilol'"' ( 1- [Carbazolyl- (4 ) -oxy-] -3- [2- (2- methoxyphenoxy) ethylammo] -propanol- (2 ) ) oder die im Carba- zol-Rest durch eine Hydroxygruppe substituierten Verbindungen (R1 oder R2 = OH) . Besonderes bevorzugt sind solche hydroxylierten Carbazol-Derivate, deren Hydroxygrupppe in den Positionen 1, 3, 6 oder 8 des Carbazolnnges sitzt. Ganz besonders geeignet sind die Verbindungen mit Hydroxy- gruppe in 1- oder 3-Posιtιon des Carbazolnnges.It was shown that the inventive topical application of the compounds of the general formula I, which is easy to carry out, leads to an anti-inflammation and wound healing of the skin. According to the invention, Carvedilol '"' (1- [carbazolyl- (4) -oxy-] -3- [2- (2-methoxyphenoxy) ethylammo] -propanol- (2)) or those in the carbazole radical are also preferably used compounds substituted by a hydroxyl group (R 1 or R 2 = OH). Particularly preferred are those hydroxylated carbazole derivatives whose hydroxyl group is located in positions 1, 3, 6 or 8 of the carbazole group. The compounds with hydroxyl group are particularly suitable in 1- or 3-position of the carbazole.
Die Herstellung der m der Erfindung verwendeten Verbindungen der allgemeinen Formel I ist an sich bekannt. So wird in EP 0 004 920 die Herstellung der racemischen Verbindun- gen der Formel I mit R und R als Wasserstoff beschrieben, deren Auftrennung in die optisch aktiven Formen nach an sich bekannten Methoden durchgeführt werden kann. EP 0 127 099 beschreibt die asymmetrische Synthese von R- und S- Carbazolderivaten der allgemeinen Formel I mit den Resten R1 und R2 als Wasserstoff, wobei die Enantiomeren m hoher optischer Reinheit erhalten werden.The preparation of the compounds of general formula I used in the invention is known per se. For example, EP 0 004 920 describes the preparation of the racemic compounds of the formula I with R and R as hydrogen, the separation of which into the optically active forms can be carried out by methods known per se. EP 0 127 099 describes the asymmetric synthesis of R- and S-carbazole derivatives of the general formula I with the radicals R 1 and R 2 as hydrogen, the enantiomers having a high optical purity being obtained.
Auch die Herstellung der erfmdungsgemaß verwendeten, im Carbazolrest hydroxylierten Verbindungen der Formel I ist an sich bekannt und WO-A-94/12178 beschrieben. Die Auftrennung der Racemate in die optisch aktiven Formen wird nach üblichen Methoden (Salzbildung mit optisch aktiven Sauren) durchgeführt. Die Trennung der Racemate in die Enantiomeren kann auch analytisch, semipraparativ und praparativ chromatographisch auf geeigneten optisch aktiven Phasen mit gangigen Elutionsmitteln durcngefuhrt werden.
Als optisch aktive Phasen eignen sich beispielsweise optisch aktive Polyacrylamide oder Polymethacryia ide, z. T. auch an Kieselgel (z. B. ChiraSpher'*' von Merck, Chiral- pak"" OT/OP von Baker), Celluloseester/-carbamate (z.B ChiraceT" OB/OY von Baker/Daicel) , Phasen auf Cyclodextrin- oder Kronenetherbasis (z.B. Crownpak1*' von Daicel) oder mikrokristallines Cellulosetriacetat (Merck) .The preparation of the compounds of the formula I which are hydroxylated in the carbazole radical and used according to the invention is also known per se and is described in WO-A-94/12178. The racemates are separated into the optically active forms by customary methods (salt formation with optically active acids). The separation of the racemates into the enantiomers can also be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases with common eluents. Optically active phases are, for example, optically active polyacrylamides or Polymethacryia ide, e.g. T. also on silica gel (e.g. ChiraSpher '*' from Merck, Chiralpak "" OT / OP from Baker), cellulose esters / carbamates (e.g. ChiraceT "OB / OY from Baker / Daicel), phases on cyclodextrin or crown ether base (for example Crownpak 1 * 'from Daicel) or microcrystalline cellulose triacetate (Merck).
Gewünschtenfalls können die erhaltenen Carbazol-Derivate der allgemeinen Formel I in pharmakologisch verträgliche Salze überführt werden, indem man sie - vorzugsweise in einem organischen Lösungsmittel - mit der äquivalenten Menge einer anorganischen oder organischen Säure, z.B. Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Schwefel- säure, Essigsäure, Citronensäure, Maleinsäure oder Benzoe- säure umsetzt .If desired, the carbazole derivatives of the general formula I obtained can be converted into pharmacologically acceptable salts by - preferably in an organic solvent - with the equivalent amount of an inorganic or organic acid, e.g. Hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
Zur Herstellung von Arzneimitteln zur topischen Anwendung werden die Carbazol-Derivate der Formel I, ihre Enantiome- ren oder pharmakologisch verträglichen Salze in an sich bekannter Weise mit geeigneten pharmazeutischen Hilfs- stoffen als Creme, Salbe, Gel, Lotion, Lösung oder Spray formuliert . Die Arzneimittel enthalten eine oder mehrere Verbindungen der allgemeinen Formel I in einer Gesamtmenge von 0,5-2 Gew . % .For the preparation of pharmaceuticals for topical use, the carbazole derivatives of the formula I, their enantiomers or pharmacologically tolerable salts are formulated in a manner known per se using suitable pharmaceutical auxiliaries as a cream, ointment, gel, lotion, solution or spray. The medicaments contain one or more compounds of the general formula I in a total amount of 0.5-2% by weight. %.
Geeignete Grundlagen für Salben, Cremes oder Gele sind beispielsweise Vaseline, Paraffine, wie Hartparaffin, oder dickflüssiges Paraffin, mittelkettige Triglyceride, natür- liehe Wachse, Wollwachs, Isopropylmyristat, hochdisperses Siliciumdioxid, Bentonit, Stärke, Alginate, Cellulose und Celluloseether, Natriumcarboxymethylcellulose, Polyethy- lenglykole und andere.Suitable bases for ointments, creams or gels are, for example, petroleum jelly, paraffins, such as hard paraffin, or viscous paraffin, medium-chain triglycerides, natural waxes, wool wax, isopropyl myristate, highly disperse silicon dioxide, bentonite, starch, alginates, cellulose and cellulose ethers, sodium carboxymymethyl cellulose, poly lenglycols and others.
Geeignete Lösungsmittel für Lotionen und Lösungen sind Wasser oder Wasser-Alkohol-Mischungen.
Die Anwendung der erfindungsgemäßen Mittel erfolgt durch Auftragen auf die Haut. Die aufgetragene Menge an Arzneimittel beträgt im allgemeinen etwa 0,01-10 mg/cm2 Haut.Suitable solvents for lotions and solutions are water or water-alcohol mixtures. The agents according to the invention are applied to the skin. The amount of drug applied is generally about 0.01-10 mg / cm 2 skin.
Die erfindungsgemäßen Verbindungen und pharmazeutischen Formulierungen werden insbesondere zur Behandlung der Raynaud' sehen Krankheit, von Kollagenosen (systemischer Lupus erythematodes, chronische Polyarthritis, progressiver systemischer Sklerose) , dem Sjorgen-Syndrom, der Thromban- gitis obliterans sowie der diabetischen Polyneuropathie eingesetzt .The compounds and pharmaceutical formulations according to the invention are used in particular for the treatment of Raynaud's disease, collagenosis (systemic lupus erythematosus, chronic polyarthritis, progressive systemic sclerosis), Sjorgen syndrome, thrombangitis obliterans and diabetic polyneuropathy.
Ferner werden die Verbindungen der Formel I und die erfindungsgemäßen Formulierungen zur Behandlung von Dermatitiden und Ekzemen, insbesondere der Schuppenflechte und Neuroder- mitis eingesetzt.Furthermore, the compounds of the formula I and the formulations according to the invention are used for the treatment of dermatitis and eczema, in particular psoriasis and neurodermatitis.
Die nachfolgenden Beispiele sollen die Erfindung erläutern, ohne sie darauf einzuschränken.The following examples are intended to illustrate the invention without restricting it.
Ausführungsbeispiele;Working examples;
Beispiel 1: Salbe mit folgender Zusammensetzung:Example 1: Ointment with the following composition:
Carvedilol wird mit einer Strahlenmühle oder mittels einer anderen Vorrichtung mikronisiert . Die erhaltene Mahlung soll zu 90 % Partikel der Größe 1 - 10 μ enthalten.Carvedilol is micronized using a jet mill or other device. The grinding obtained should contain 90% particles of the size 1-10 μ.
100 g des mikronisierten Wirkstoffes werden mit 300 g Salbengrundlage, z. B. mit Lanolin zerrieben, über einen Walzenstuhl gegeben und auf diese Weise wird eine Verrei- bung hergestellt.
Die so erhaltene Verreibung wird auf 10 kg mit Lanolin oder einer anderen Salbengrundlage aufgefüllt, kraftig durchgerührt und über den Walzenstuhl zur Homogenisierung gegeben. Diese homogene Masse wird m Tuben abgefüllt. Die Tuben werden gefalzt und mit einer Spezialmaschme verschlossen.100 g of the micronized active ingredient are mixed with 300 g of ointment base, e.g. B. ground with lanolin, placed on a roller mill and in this way a rub is produced. The trituration thus obtained is made up to 10 kg with lanolin or another ointment base, stirred vigorously and passed over the roller mill for homogenization. This homogeneous mass is filled in m tubes. The tubes are folded and closed with a special machine.
Beispiel 2 :Example 2:
Eine Patientin mit diagnostizierter sekundärer Raynaud' scher Krankheit, d.h. mit schweren Durchblutungsstörungen der Finger, wurde über 4 Wochen mit einer Formulierung gemäß Beispiel 1 behandelt. Die Salbe wurde auf die Haut aufgetragen und konnte wahrend der Nacht ca. 9 Stunden einwirken. Nach wenigen Tagen waren die Hände normal funktionsfähig, d.h., die gehäuft auftretende Gefuhlslosigkeit der Finger, ihre stark eingeschränkte Beweglichkeit und die Schwellungen waren verschwunden.A patient with diagnosed secondary Raynaud's disease, i.e. with severe circulatory disorders of the fingers, was treated with a formulation according to Example 1 for 4 weeks. The ointment was applied to the skin and was able to act for about 9 hours during the night. After a few days, the hands were functioning normally, i.e. the numbness of the fingers, their severely restricted mobility and the swelling had disappeared.
Beispiel 3 :Example 3:
Ein Patient mit diagnostizierter Psoriasis, dessen Handfla¬ chen stark verhornt waren und tiefe blutige Einrisse bzw. Wunden aufwiesen, wurde über vier Wochen mit einer Formulierung gemäß Bespiel 1 behandelt.One patient was diagnosed with psoriasis, whose Handfla ¬ chen heavily callused and had deep bloody lacerations or wounds, was treated for four weeks with a formulation of recordable first
Die Salbe wurde wahrend des Tages regelmäßig auf die Hand aufgetragen. Nach drei Wochen waren die Wunden der Hand geschlossen. Das Erscheinungsbild der Haut war weitgehend normal, und die Hand war normal funktionsfähig.
Beispiel 4 :The ointment was applied to the hand regularly throughout the day. After three weeks the hand wounds were closed. The appearance of the skin was largely normal and the hand was functioning normally. Example 4:
Ein Patient mit diagnostiziertem Lupus erythrematodes, Dessen Fingerkuppen tiefe, offene Risse aufwiesen, wurde über drei Wochen mit einer Formulierung gemäß Beispiel 1 behandelt.A patient with diagnosed lupus erythrematodes, whose fingertips had deep, open cracks, was treated with a formulation according to Example 1 for three weeks.
Die Salbe wurde wahrend des Tages regelmäßig auf die Hand aufgetragen. Nach drei Wochen waren die Wunden geschlossen, die Finger schmerzfrei und die Hand funktionsfähig.
The ointment was applied to the hand regularly throughout the day. After three weeks the wounds were closed, the fingers were painless and the hand was functional.
Claims
Topisch einsetzbare pharmazeutische Formulierung, enthaltend als Wirkstoff ein Carbazolyl- (4 ) -oxy- propanolamin-Derivat der allgemeinen Formel ITopical pharmaceutical formulation containing as active ingredient a carbazolyl- (4) -oxypropanolamine derivative of the general formula I.
m der R1 und R unabhängig voneinander Wasserstoff oder die Hydroxygruppe bedeuten,m R 1 and R independently of one another denote hydrogen or the hydroxyl group,
oder deren Enantiomere oder deren pharmakologisch vertragliche Salzeor their enantiomers or their pharmacologically acceptable salts
zur Herstellung von Arzneimitteln,for the production of pharmaceuticals,
Pharmazeutische Formulierung zur topischen Behandlung gemäß Anspruch 1, enthaltend 0,5 - 5 Gew.0 des Wirkstoffes.A pharmaceutical formulation for topical treatment according to claim 1, containing from 0.5 to 5 weight 0 of the active ingredient..
Formulierung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Verbindung, in der R1 und R** Wasserstoff sind, eingesetzt wird. 1 0Formulation according to Claim 1 or 2, characterized in that the compound in which R 1 and R ** are hydrogen is used. 1 0
Formulierung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß eine Verbindung, in der R die Hydroxygruppe ist und R** Wassers off bedeutet, eingesetzt wird.Formulation according to Claim 1 or 2, characterized in that a compound in which R is the hydroxyl group and R ** is water off is used.
5. Verwendung von Carbazolyl- (4 ) -oxy-propanolamin- Derivaten der allgemeinen Formel I5. Use of carbazolyl- (4) -oxypropanolamine derivatives of the general formula I
in der R1 und R2 unabhängig voneinander Wasserstoff oder die Hydroxygruppe bedeuten,in which R 1 and R 2 independently of one another denote hydrogen or the hydroxyl group,
oder deren Enantiomere oder deren pharmakologisch verträgliche Salzeor their enantiomers or their pharmacologically acceptable salts
zur Herstellung von Arzneimitteln zur topischen Behandlung von peripheren Durchblutungsstörungen, ' insbesondere der Extremitäten.for the manufacture of medicaments for the topical treatment of peripheral circulatory disorders, especially the extremities.
6. Formulierung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Verbindung, in der R* und R2 Wasserstoff sind, eingesetzt wird. Formulierung gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß eine Verbindung, m der R die6. Formulation according to claim 1 or 2, characterized in that the compound in which R * and R 2 are hydrogen is used. Formulation according to claim 1 or 2, characterized in that a compound m the R the
Hydroxygruppe ist und R Wasserstoff bedeutet, eingesetzt wird.Hydroxy group and R is hydrogen is used.
Verwendung gemäß einem der Ansprüche 5 bis 7, dadurch gekennzeichnet, daß die Verbindungen zur Behandlung der Psoriasis und zur Behandlung von Neurodermitis eingesetzt werden.Use according to one of claims 5 to 7, characterized in that the compounds are used for the treatment of psoriasis and for the treatment of neurodermatitis.
9. Verwendung von Carbazolyl- ( 4 ) -oxy-propanolamin- Derivaten der allgemeinen Formel I9. Use of carbazolyl- (4) -oxypropanolamine derivatives of the general formula I
in der R* und R** unabhängig vonemanαer Wasserstoff oder die Hydroxygruppe bedeuten,in which R * and R ** independently of one another denote hydrogen or the hydroxyl group,
oder deren Enantiomere oder deren pharmakologisch vertragliche Salzeor their enantiomers or their pharmacologically acceptable salts
zur Herstellung von Arzneimitteln zur topischen Behandlung von Entzündungen und Wunαen der Haut. for the manufacture of medicaments for the topical treatment of inflammation and skin wounds.
10. Verwendung gemäß Anspruch 1, dadurch gekennzeichnet, daß die Verbindung, m der R* und R** Wasserstoff sind, eingesetzt wird.10. Use according to claim 1, characterized in that the compound, m the R * and R ** are hydrogen, is used.
11. Verwendung gemäß Anspruch 1, dadurch gekennzeichnet, daß eine Verbindung, in der R' die Hydroxygruppe ist und R" Wasserstoff bedeutet, eingesetzt wird.11. Use according to claim 1, characterized in that a compound in which R 'is the hydroxy group and R "is hydrogen is used.
12. Verwendung gemäß einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß die Verbindungen zur Behandlung der Psoriasis und zur Behandlung von Neurodermitis eingesetzt werden. 12. Use according to one of claims 1 to 3, characterized in that the compounds are used for the treatment of psoriasis and for the treatment of neurodermatitis.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19628335A DE19628335A1 (en) | 1996-07-13 | 1996-07-13 | Use of topical (carbazolyl-oxy)-propanolamine derivatives |
DE19628335 | 1996-07-13 | ||
DE1997124752 DE19724752A1 (en) | 1997-04-24 | 1997-04-24 | Use of carbazol-4-yl-oxy-propanol-amine derivative |
DE19724752 | 1997-04-24 | ||
PCT/EP1997/003602 WO1998002157A1 (en) | 1996-07-13 | 1997-07-08 | Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0910374A1 true EP0910374A1 (en) | 1999-04-28 |
Family
ID=26027495
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97931798A Withdrawn EP0910374A1 (en) | 1996-07-13 | 1997-07-08 | Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0910374A1 (en) |
AU (1) | AU3542697A (en) |
WO (1) | WO1998002157A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000026363A1 (en) | 1998-11-04 | 2000-05-11 | Genset | GENOMIC AND COMPLETE cDNA SEQUENCES OF HUMAN ADIPOCYTE-SPECIFIC APM1 AND BIALLELIC MARKERS THEREOF |
JP2005533823A (en) | 2002-06-27 | 2005-11-10 | エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド | Carvedilol phosphate and / or solvates thereof, corresponding compositions and / or methods of treatment |
WO2004002472A1 (en) | 2002-06-27 | 2004-01-08 | Sb Pharmco Puerto Rico Inc. | Carvedilol hydrobromide |
EP1686986A4 (en) | 2003-11-25 | 2009-05-27 | Sb Pharmco Inc | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2337154C2 (en) * | 1973-07-18 | 1986-04-24 | Schering AG, 1000 Berlin und 4709 Bergkamen | New carbazole derivatives |
DE3319027A1 (en) * | 1983-05-26 | 1984-11-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | METHOD FOR PRODUCING OPTICALLY ACTIVE CARBAZOL DERIVATIVES, NEW R- AND S-CARBAZOL DERIVATIVES, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
ZA938897B (en) * | 1992-12-01 | 1994-08-01 | Smithkline Beecham Corp | Antioxidant neuroprotective use of and method of treatment using hydroxycarbazole compounds |
-
1997
- 1997-07-08 AU AU35426/97A patent/AU3542697A/en not_active Abandoned
- 1997-07-08 WO PCT/EP1997/003602 patent/WO1998002157A1/en not_active Application Discontinuation
- 1997-07-08 EP EP97931798A patent/EP0910374A1/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO9802157A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1998002157A1 (en) | 1998-01-22 |
AU3542697A (en) | 1998-02-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE2827018C2 (en) | ||
DE69732049T2 (en) | PHARMACEUTICAL PREPARATIONS, CONTAINING SALTS OF HYALURONIC ACID AND LOCAL ANESTHETICS | |
EP0252286B1 (en) | Pharmaceutical preparations for topical use, process for their manufacture and their use | |
EP0367103B1 (en) | Topical ointment | |
DE4013696A1 (en) | New azelastin salts | |
EP0369263A2 (en) | Preparations for the topical treatment of skin diseases | |
DE3030868C2 (en) | ||
EP0910374A1 (en) | Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate | |
DE4229050A1 (en) | New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agents | |
DE19724752A1 (en) | Use of carbazol-4-yl-oxy-propanol-amine derivative | |
EP1507524B1 (en) | Topical use of diuretics for treating swellings | |
DE2401446A1 (en) | PHARMACEUTICAL PREPARATIONS FOR THE RELIEF OF SKIN PROLIFERATIONAL DISEASES | |
EP0383162A1 (en) | Use of a mixture of active substances in the treatment of rheumatic diseases | |
EP0996438A1 (en) | Use of cis-6-hexadecenoic acid for treating psoriasis, allergies, auto-immune disorders and dry, sensitive skin | |
DE19628335A1 (en) | Use of topical (carbazolyl-oxy)-propanolamine derivatives | |
EP1087768B1 (en) | Use of 1-(aminoalkyl)-3-quinoxaline-2-one derivatives for the preparation of compounds having an antioxidant action | |
DE2411019C2 (en) | Use of 1- (4- (1-pyrrolidinyl) -2-butynyl) -2-pyrrolidinone or 1- (2-oxo-1-pyrrolidine) -4- (1-pyrrolidine) -2-butyne for the treatment of glaucoma | |
EP0207421B1 (en) | Use of a retinoid for the manufacture of an anti-keratinizing medicament | |
DE19736265C2 (en) | Medicines for the treatment of skin diseases | |
DE2713105A1 (en) | DERMATOLOGICAL MEDICINAL PRODUCT | |
CH645269A5 (en) | Medicine for the skin, and process for its production | |
WO1989003215A1 (en) | Use of oxoquinazoline derivatives for the treatment of hyperlipidemia | |
EP1878433A1 (en) | Topical composition comprising magmatites | |
DE2818554A1 (en) | COMPOSITION FOR THE TREATMENT OF SCULPTURES IN HUMANS AND ANIMALS | |
EP1458389A1 (en) | Use of moxaverin for treating erectile dysfunction, forms of dementia or diseases associated to an arteriosclerotic occlusion |
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: 19990212 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB IT LI NL |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20010201 |