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 derivate

Info

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
Authority
EP
Grant status
Application
Patent type
Prior art keywords
hydrogen
characterized
used
carbazolyl
oxy
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Withdrawn
Application number
EP19970931798
Other languages
German (de)
French (fr)
Inventor
Hans-Georg Opitz
Gisbert Sponer
Heinrich Woog
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/403Heterocyclic 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

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

Topically applicable pharmaceutical formulations containing as active ingredient an

Carbazolyl (4) -oxy-propanolamine derivative

description

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.

Embodiments;

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.

Example 2:

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.

Example 3:

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.

Claims

claims
Topically applicable pharmaceutical formulation comprising as active ingredient a carbazolyl (4) oxy propanolamine derivative of the general formula I
m wherein R 1 and R are independently hydrogen or hydroxy group,
or its enantiomers, or its pharmacologically salts contractual
for the preparation of medicaments
A pharmaceutical formulation for topical treatment according to claim 1, containing 0.5 - 5 percent of the active ingredient 0..
A formulation according to claim 1 or 2, characterized in that the compound in which R 1 and R ** is 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 ** water off means is employed.
5. Use of carbazolyl (4) -oxy-propanolamin- derivatives 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
for the preparation of medicaments for the topical treatment of peripheral circulatory disorders, 'in particular of the extremities.
6. A formulation according to claim 1 or 2, characterized in that the compound in which R * and R 2 are hydrogen, is used. A formulation according to claim 1 or 2, characterized in that a compound m where R has the
is hydroxy and R is hydrogen, is used.
Use according to one of claims 5 to 7, characterized in that the compounds for the treatment of psoriasis and for the treatment of atopic dermatitis can be used.
9. Use of carbazolyl (4) -oxy-propanolamin- derivatives of the general formula I
wherein R * and R ** are, independently vonemanαer hydrogen or hydroxy group,
or its enantiomers, or its pharmacologically salts contractual
for producing drugs for the topical treatment of inflammation and Wunαen the skin.
10. Use according to claim 1, characterized in that the compound m where R * and R ** are hydrogen, is used.
11. Use according to claim 1, characterized in that a compound in which R 'is the hydroxyl group and R "is hydrogen, is used.
12. Use according to any of claims 1 to 3, characterized in that the compounds for the treatment of psoriasis and for the treatment of atopic dermatitis can be used.
EP19970931798 1996-07-13 1997-07-08 Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate Withdrawn EP0910374A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE19628335 1996-07-13
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
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 true EP0910374A1 (en) 1999-04-28

Family

ID=26027495

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)

Country Link
EP (1) EP0910374A1 (en)
WO (1) WO1998002157A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Title
See references of WO9802157A1 *

Also Published As

Publication number Publication date Type
WO1998002157A1 (en) 1998-01-22 application

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