WO1998002157A1 - Formulations pharmaceutiques pour utilisation topique contenant comme principe actif un derive de carbazolyl-(4)-oxy-propanolamine - Google Patents

Formulations pharmaceutiques pour utilisation topique contenant comme principe actif un derive de carbazolyl-(4)-oxy-propanolamine Download PDF

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Publication number
WO1998002157A1
WO1998002157A1 PCT/EP1997/003602 EP9703602W WO9802157A1 WO 1998002157 A1 WO1998002157 A1 WO 1998002157A1 EP 9703602 W EP9703602 W EP 9703602W WO 9802157 A1 WO9802157 A1 WO 9802157A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbazolyl
hydrogen
treatment
active ingredient
compound
Prior art date
Application number
PCT/EP1997/003602
Other languages
German (de)
English (en)
Inventor
Hans-Georg Opitz
Gisbert Sponer
Heinrich Woog
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
Priority claimed from DE19628335A external-priority patent/DE19628335A1/de
Priority claimed from DE1997124752 external-priority patent/DE19724752A1/de
Application filed by Roche Diagnostics Gmbh filed Critical Roche Diagnostics Gmbh
Priority to AU35426/97A priority Critical patent/AU3542697A/en
Priority to EP97931798A priority patent/EP0910374A1/fr
Publication of WO1998002157A1 publication Critical patent/WO1998002157A1/fr

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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

L'invention concerne des formulations pharmaceutiques pour utilisation topique, contenant, comme principe actif, un dérivé de carbazolyl-(4)-oxy-propanolamine de la formule générale (I), dans laquelle R<1> et R<2> représentent, indépendamment l'un de l'autre, hydrogène ou le groupe hydroxy, ou leurs enantiomères, ou bien leurs sels pharmacologiquement tolérés, par exemple le carvedilol, utilisés pour le traitement de troubles circulatoires périphériques, en particulier des extrémités, ainsi que d'inflammations et de plaies ouvertes.
PCT/EP1997/003602 1996-07-13 1997-07-08 Formulations pharmaceutiques pour utilisation topique contenant comme principe actif un derive de carbazolyl-(4)-oxy-propanolamine WO1998002157A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU35426/97A AU3542697A (en) 1996-07-13 1997-07-08 Pharmaceutical formulations for topical application containing as an active ingredient carbazolyl-(4)-oxy-propanol amine derivate
EP97931798A EP0910374A1 (fr) 1996-07-13 1997-07-08 Formulations pharmaceutiques pour utilisation topique contenant comme principe actif un derive de carbazolyl-(4)-oxy-propanolamine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19628335.3 1996-07-13
DE19628335A DE19628335A1 (de) 1996-07-13 1996-07-13 Verwendung von Carbazolyl-(4)-oxy-propanolamin-Derivaten zur topischen Behandlung von peripheren Durchblutungsstörungen
DE1997124752 DE19724752A1 (de) 1997-04-24 1997-04-24 Verwendung von Carbazolyl-(4)-oxy-propanolamin-Derivaten zur topischen Behandlung von Entzündungen und Wunden der Haut
DE19724752.0 1997-04-24

Publications (1)

Publication Number Publication Date
WO1998002157A1 true WO1998002157A1 (fr) 1998-01-22

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Application Number Title Priority Date Filing Date
PCT/EP1997/003602 WO1998002157A1 (fr) 1996-07-13 1997-07-08 Formulations pharmaceutiques pour utilisation topique contenant comme principe actif un derive de carbazolyl-(4)-oxy-propanolamine

Country Status (3)

Country Link
EP (1) EP0910374A1 (fr)
AU (1) AU3542697A (fr)
WO (1) WO1998002157A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6582909B1 (en) 1998-11-04 2003-06-24 Genset, S.A. APM1 biallelic markers and uses thereof
US7626041B2 (en) 2002-06-27 2009-12-01 Smithkline Beecham (Cork) Ltd Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7649010B2 (en) 2002-06-27 2010-01-19 SmithKline Beechman Cork Limited Carvedilol hydrobromide
US7750036B2 (en) 2003-11-25 2010-07-06 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2337154A1 (de) * 1973-07-18 1975-02-06 Schering Ag Neue carbazolderivate und verfahren zu ihrer herstellung
DE3319027A1 (de) * 1983-05-26 1984-11-29 Boehringer Mannheim Gmbh, 6800 Mannheim Verfahren zur herstellung von optisch aktiven carbazol-derivaten, neue r- und s-carbazol-derivate, sowie arzneimittel, die diese verbindungen enthalten
WO1994012178A1 (fr) * 1992-12-01 1994-06-09 Smithkline Beecham Corporation Utilisation cardiopretectrice antioxydante de composes d'hydroxycarbazole et procede de traitement utilisant ces composes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2337154A1 (de) * 1973-07-18 1975-02-06 Schering Ag Neue carbazolderivate und verfahren zu ihrer herstellung
DE3319027A1 (de) * 1983-05-26 1984-11-29 Boehringer Mannheim Gmbh, 6800 Mannheim Verfahren zur herstellung von optisch aktiven carbazol-derivaten, neue r- und s-carbazol-derivate, sowie arzneimittel, die diese verbindungen enthalten
WO1994012178A1 (fr) * 1992-12-01 1994-06-09 Smithkline Beecham Corporation Utilisation cardiopretectrice antioxydante de composes d'hydroxycarbazole et procede de traitement utilisant ces composes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RUFFOLO ET AL.: "Hemodynamic differences between carvedilol and labetalol in the cutaneous circulation", EUR. J. CLIN. PHARMACOL., vol. 38, no. Supp2, 1990, pages S112 - S114, XP002044359 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6582909B1 (en) 1998-11-04 2003-06-24 Genset, S.A. APM1 biallelic markers and uses thereof
US7626041B2 (en) 2002-06-27 2009-12-01 Smithkline Beecham (Cork) Ltd Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7649010B2 (en) 2002-06-27 2010-01-19 SmithKline Beechman Cork Limited Carvedilol hydrobromide
US7759384B2 (en) 2002-06-27 2010-07-20 Smithkline Beecham (Cork) Limited Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7893100B2 (en) 2002-06-27 2011-02-22 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7902378B2 (en) 2002-06-27 2011-03-08 Smithkline Beecham (Cork) Limited Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7750036B2 (en) 2003-11-25 2010-07-06 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment

Also Published As

Publication number Publication date
EP0910374A1 (fr) 1999-04-28
AU3542697A (en) 1998-02-09

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