WO1998002157A1

WO1998002157A1 - Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate

Info

Publication number: WO1998002157A1
Application number: PCT/EP1997/003602
Authority: WO
Inventors: Hans-Georg Opitz; Gisbert Sponer; Heinrich Woog
Original assignee: Roche Diagnostics Gmbh
Priority date: 1996-07-13
Filing date: 1997-07-08
Publication date: 1998-01-22
Also published as: AU3542697A; EP0910374A1

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

Topical pharmaceutical formulations containing as an active ingredient

Carbazolyl (4) oxypropanolamine derivative

description

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

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.

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.

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.

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.

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.

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.

It has also been found that the compounds of the general formula I can also be used to treat inflammation and open skin wounds.

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.

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.

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.

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.

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).

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.

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. %.

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.

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.

The following examples are intended to illustrate the invention without restricting it.

Working examples;

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 μ.

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.

Example 2:

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.

Example 3:

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

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:

A patient with diagnosed lupus erythrematodes, whose fingertips had deep, open cracks, was treated with a formulation according to Example 1 for three weeks.

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

claims

Topical pharmaceutical formulation containing as active ingredient a carbazolyl- (4) -oxypropanolamine derivative of the general formula I.

m R ¹ and R independently of one another denote hydrogen or the hydroxyl group,

or their enantiomers or their pharmacologically acceptable salts

for the production of pharmaceuticals,

A pharmaceutical formulation for topical treatment according to claim 1, containing from 0.5 to 5 weight ₀ of the active ingredient..

Formulation according to Claim 1 or 2, characterized in that the compound in which R ¹ and R ^{** are} hydrogen is used. 1 0

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. Use of carbazolyl- (4) -oxypropanolamine derivatives of the general formula I

in which R ¹ and R ² independently of one another denote hydrogen or the hydroxyl group,

or their enantiomers or their pharmacologically acceptable salts

for the manufacture of medicaments for the topical treatment of peripheral circulatory disorders, especially the extremities.

6. 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

Hydroxy group and R is hydrogen is used.

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. Use of carbazolyl- (4) -oxypropanolamine derivatives of the general formula I

in which R ^* and R ^** independently of one another denote hydrogen or the hydroxyl group,

or their enantiomers or their pharmacologically acceptable salts

for the manufacture of medicaments for the topical treatment of inflammation and skin wounds.

10. Use according to claim 1, characterized in that the compound, m the R ^* and R ^{** are} hydrogen, is used.

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. 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.