EP0910374A1 - Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate - Google PatentsPharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate
- Publication number
- EP0910374A1 EP0910374A1 EP19970931798 EP97931798A EP0910374A1 EP 0910374 A1 EP0910374 A1 EP 0910374A1 EP 19970931798 EP19970931798 EP 19970931798 EP 97931798 A EP97931798 A EP 97931798A EP 0910374 A1 EP0910374 A1 EP 0910374A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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, rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, 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, 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
Topically applicable pharmaceutical formulations containing as active ingredient an
Carbazolyl (4) -oxy-propanolamine derivative
The present invention relates to topically applicable pharmaceutical formulations comprising as active ingredient a carbazolyl (4) -oxy-propanolamine derivative of the general formula I
in which R 1 and R 2 are independently hydrogen or hydroxy group, or their enantiomers, or their pharmacologically acceptable salts.
The invention also relates to novel uses of these formulations for topical treatment of peripheral circulatory disorders, particularly of the extremities, and of inflammation and wounds of the skin. It is known that carbazolyl (4) -oxy-propanolamm- derivatives are therapeutically active compounds. Thus, in addition to other derivatives EP 0004920 describes the specific racemic compound of the general formula I where R and R "as a hydrogen (Carvedilol *) as pharmaceutical compositions with vasodilatie- render and ß-adrenergic receptor-blocking activity, useful in the treatment and prophylaxis of circulatory and heart disease, such as hypertension and angina pectoris, is suitable. There are proposed enteral, parenteral and oral forms Pharma- chung.
Raceraische compounds of 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 especially in the Carbazolstruktur or Phenoxynng hydroxylated carvedilol Abkommlinge an antioxidant effect show and inhibit lipid peroxidation.
It has now surprisingly been found that the compounds of general formula I, their pharmacologically acceptable salts, their enantiomers or their pharmacologically contractual salts for the topical treatment locally peπpherer circulatory disorders, particularly mitaten the extremes can be used.
Peripheral circulatory disorders of the extremities, especially the fingers and toes often go with numbness of the extremities, friendliness severe movable and swelling associated. The severity of circulatory disorders varies greatly and can have various causes. Increasing incidence vaso spastic attacks are treated with calcium channel blockers or Nitroverbmdungen that can lead by their gefaßrelaxie--saving effect in improved blood circulation. Are resting pain or necrosis acral for the patient symptomatic Prostaglandm E is administered intravenously or the flow conditions of the blood is improved by controlled lowering of the fibrinogen, such as snake venom by subcutaneous application or Hamodilutionsbehandlung. These methods are only partially effective (for example, development of tolerance to Nitropraparaten) or provided with very complicated or side effects.
It was found that the application of the invention is simple to implement topical of the compounds of general formula I NEN leads both to a general blood circulation as well as to a swelling of the affected limbs. Carvedilol is Erfmdungsgemaß preferably 11 (1- [carbazolyl (4) oxy] -3- [2- (2-methoxyphenoxy) ethylammo] - propanol- (2)) or those substituted in the carbazole moiety by a hydroxy group compounds (R or R ** = OH) ¬ is inserted. Particular preference is given to hydroxylated carbazole derivatives, their Hydroxygrupppe sitting in positions 1, 3, 6 or 8 of the Carbazolnnges are. Very particularly suitable compounds having the hydroxy group in 1- or 3-Posιtιon of Carbazolnnges are.
Further, it was found that the compounds of general formula I can also be used to treat inflammation and open wounds of the skin.
Inflammation of the skin make more than 50 ° 0 of all skin diseases from. Its typical symptoms are reddening of the skin, formation of bubbles or hyperkeratosis, Elastizitatsverlust the skin, tearing the skin, open bloody wounds, inflammation.
Therapeutically predominantly hydrocortisone-containing ointments, light irradiation and preparations from coal tar are used. In particularly severe cases, anti-metabolites such as methotrexate or be liten immunosuppressants such Cyclosporm A and FK506 used. These drugs are only partially effective, often they have no influence aui disease progression.
It was found that the erfmdungsgemaße, easy to be carried Leading topical application of the compounds of general formula I to a Entzundunshemmung and wound healing of the skin leads. Erfmdungsgemaß are preferably used also Carvedilol '' '(1- [carbazolyl (4) oxy] -3- [2- (2-methoxyphenoxy) ethylammo] -propanol- (2)) or in carba zol-Rest by a hydroxy-substituted compounds (R 1 or R 2 = OH). particular preferred are those hydroxylated carbazole derivatives, their Hydroxygrupppe sitting in positions 1, 3, 6 or 8 of the Carbazolnnges. especially suitable are the compounds having hydroxy group are in 1- or 3-Posιtιon of Carbazolnnges.
The preparation of the m of the invention compounds of the general formula I used is known per se. So in EP 0004920 the preparation of the racemic Verbindun- gen of formula I will be described with R and R is hydrogen, their separation can be carried out in the optically active forms according to methods known per se. EP 0127099 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 m high optical purity can be obtained.
The preparation of the compounds of formula I erfmdungsgemaß used, hydroxylated in the carbazole is known per se and WO-A-94/12178 described. The separation of the racemates into the optically active forms is carried out by customary methods (salt formation with optically active acids). The separation of the racemates into the enantiomers can also be analytically semipraparativ and preparatively chromatographed on durcngefuhrt suitable optically active phases with gangigen eluents. As optically active phases, for example, optically active polyacrylamides or Polymethacryia ide are, for. T. also on silica gel (z. B. ChiraSpher '*' of Merck, Chiralpak "" OT / OP of Baker), Celluloseester / carbamates (eg ChiraceT "OB / OY of Baker / Daicel), phases cyclodextrin or crown ether (eg Crownpak 1 * 'from Daicel) or microcrystalline cellulose triacetate (Merck).
If desired, the resultant carbazole derivatives of the general formula I into pharmacologically acceptable salts can be transferred by being - preferably in an organic solvent - acid with an equivalent amount of an inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid , reacting citric acid, maleic acid or benzoic acid.
are the carbazole derivatives of the formula I for the preparation of medicaments for topical application, reindeer their enantiomeric or pharmacologically acceptable salts in a known per se materials with suitable pharmaceutical excipients, as a cream, ointment, gel, lotion, solution or spray formulated. The pharmaceutical compositions containing one or more compounds of general formula I in a total amount of 0.5-2 wt. %.
Suitable bases for ointments, creams or gels are, for example, vaseline, paraffins, such as hard paraffin or liquid paraffin, medium chain triglycerides, natural Liehe waxes, lanolin, isopropyl myristate, fumed silica, bentonite, starch, alginates, cellulose and cellulose ethers, sodium carboxymethylcellulose, polyethylene glycols and others.
Suitable solvents for lotions and solutions are water or water-alcohol mixtures. If the application of the compositions of the invention by application to the skin. The coated amount of the drug is generally about 0.01-10 mg / cm 2 skin.
The inventive compounds and pharmaceutical formulations are especially seen in the treatment of Raynaud 'disease, connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis), the Sjorgen syndrome, the Thromban- GITIS obliterans and of diabetic polyneuropathy used.
Further, the compounds of Formula I and formulations of the invention for the treatment of dermatitis and eczema in particular psoriasis and neurodermatitis are used.
The following examples illustrate the invention without limiting it.
Example 1: Ointment having the following composition:
Carvedilol is micronized with a jet mill or by means of another device. The grinding obtained is said 90% particle size of 1 - 10 μ included.
100 g of the micronized active substance are charged with 300 g ointment base, z. B. triturated with Lanolin, added over a roller mill and in this way a Verrei- bung is prepared. Trituration so obtained is made up to 10 kg with lanolin or other ointment base, vigorously stirred, and passed through the roll mill for homogenization. This homogeneous composition is dispensed m tubes. The tubes are folded and sealed with a Spezialmaschme.
A patient diagnosed with secondary Raynaud's disease, ie with severe circulatory disorders of the finger, was treated for 4 weeks with a formulation according to Example. 1 The ointment was applied to the skin and could affect about 9 hours during the night. After a few days the hands were functioning normally, that is, the increasing incidence Gefuhlslosigkeit the fingers, their very limited mobility and swelling were gone.
A patient diagnosed with psoriasis, whose Handfla ¬ chen were heavily callused and had deep bloody lacerations or wounds, was treated for four weeks with a formulation of recordable first
The ointment was applied during the day regularly on hand. After three weeks, the wounds of the hand were closed. The appearance of the skin was largely normal, and the hand was normal functioning. Example 4:
A patient diagnosed with lupus erythrematosis, having Meanwhile fingertips deep, open cracks, was treated for three weeks with a formulation according to Example. 1
The ointment was applied during the day regularly on hand. After three weeks, the wounds were closed, the finger pain-free and hand functional.
Priority Applications (5)
|Application Number||Priority Date||Filing Date||Title|
|DE1996128335 DE19628335A1 (en)||1996-07-13||1996-07-13||Use of topical (carbazolyl-oxy)-propanolamine derivatives|
|DE1997124752 DE19724752A1 (en)||1997-04-24||1997-04-24||Use of carbazol-4-yl-oxy-propanol-amine derivative|
|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|
|Publication Number||Publication Date|
|EP0910374A1 true true EP0910374A1 (en)||1999-04-28|
Family Applications (1)
|Application Number||Title||Priority Date||Filing Date|
|EP19970931798 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 (2)
|EP (1)||EP0910374A1 (en)|
|WO (1)||WO1998002157A1 (en)|
Families Citing this family (4)
|Publication number||Priority date||Publication date||Assignee||Title|
|EP1127120B1 (en)||1998-11-04||2008-05-28||Serono Genetics Institute S.A.||Genomic and complete cdna sequences of human adipocyte-specific apm1 and biallelic markers thereof|
|US20050261355A1 (en)||2002-06-27||2005-11-24||Sb Pharmco Puerto Rico Inc.,||Carvedilol hydobromide|
|CN103288715A (en)||2002-06-27||2013-09-11||史密斯克莱.比奇曼（科克）有限公司||Carvedilol phosphate salts and/or solvates thereof, correspondinq compositions, and/or methods of treatment|
|WO2005051383A1 (en)||2003-11-25||2005-06-09||Sb Pharmco Puerto Rico 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, De|
|DE3319027A1 (en) *||1983-05-26||1984-11-29||Boehringer Mannheim Gmbh||A process for the preparation of optically active carbazole derivatives, new R- and S-carbazole derivatives, and pharmaceutical compositions containing these compounds|
|CN1042795C (en) *||1992-12-01||1999-04-07||史密丝克莱恩比彻姆公司||Antioxidant neuroprotective use of and method of treatment using hydroxycarbazole compounds|
Non-Patent Citations (1)
|See references of WO9802157A1 *|
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