WO2005046692A1 - Traitement de maladies d'origine genetique par des quinolones ou des naphtyridones - Google Patents

Traitement de maladies d'origine genetique par des quinolones ou des naphtyridones Download PDF

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Publication number
WO2005046692A1
WO2005046692A1 PCT/EP2004/011607 EP2004011607W WO2005046692A1 WO 2005046692 A1 WO2005046692 A1 WO 2005046692A1 EP 2004011607 W EP2004011607 W EP 2004011607W WO 2005046692 A1 WO2005046692 A1 WO 2005046692A1
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WIPO (PCT)
Prior art keywords
diseases
active ingredients
treatment
quinolone
cystic fibrosis
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PCT/EP2004/011607
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German (de)
English (en)
Inventor
Igor Knezevic
Harald Labischinski
Stephan Bartel
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Bayer Healthcare Ag
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Publication of WO2005046692A1 publication Critical patent/WO2005046692A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of quinolone or naphthyridone active ingredients for the manufacture of medicaments, medicaments and dosage forms for the treatment and / or prophylaxis of genetically caused diseases of higher organisms which are based on 5 point mutations and / or comparable defects, such as e.g. Cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchenne's muscular dystrophy, cystinosis and others.
  • Cystic fibrosis cystic fibrosis
  • Hurler's syndrome Duchenne's muscular dystrophy
  • cystinosis and others.
  • the present invention relates to the use of quinolone or naphthyridone active ingredients for the production of medicaments, medicaments and dosage forms for the treatment and / or prophylaxis of infections in the case of underlying genetic diseases of higher organisms which are based on point mutations and / or comparable defects, such as eg Cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchenne's muscular dystrophy, cystinosis and others.
  • Cystic fibrosis cystic fibrosis
  • Hurler's syndrome Duchenne's muscular dystrophy
  • cystinosis and others.
  • Stop codons generated by point mutation5 (“premature stop codons” or nonsense mutations) have been shown to trigger gene defects that cause diseases such as cystic fibrosis (cystic fibrosis), Hurler's syndrome, Carney complex, Duchenne's muscular dystrophy, cystinosis and others.
  • Drug treatment of these diseases has not yet been possible, but aminoglycosides have recently come into focus for a possible therapeutic approach.
  • Aminoglycosides0 are antibiotic substances that are used above all for severe infections, especially nosocomial infections. They are particularly effective against enterobacteria and pseudomonas, but are limited in use due to their pronounced nephro and ot toxicity.
  • Aminoglycosides inhibit bacterial protein biosynthesis by interacting with the 16S rRNA of the 5 30S subunit of the ribosome (Moazed and Noller, 1987). This interaction leads to the stabilization of the "RAM” conformation of the ribosome and thus to a reduction in the reading accuracy when translating the mRNA into the protein sequence, which is also referred to as "miscoding” or misreading (Pape et al., 2000; Carter et al., 2000; Ogle et al. 2001). The reading inaccuracy induced by aminoglycosides can also suppress 0 nonsense mutations (Martin et al., 1989).
  • DMD Duchenne's muscular dystrophy
  • Cystic fibrosis is caused by the loss of the CFTR protein (Scriver et al., 2001). Howard and co-workers were able to show that suppression of the two most common nonsense mutations in the CFTR gene by the aminoglycoside antibiotic G-418 and gentamicin is possible in cell culture (Howard et al., 1996). In addition, this finding was confirmed in cftr " mice and also with topical " administration of gentamicin to the nasal mucosa of patients with cystic fibrosis (Jones et al. 2002; Wilschanski et al., 2003)
  • Quinolone or naphthyridone active ingredients have long been used primarily for the treatment of bacterial infectious diseases caused by various gram-positive and gram-negative bacteria and, due to their detailed structure, have different effects against enzymes from the group of topoisomerases of bacteria or higher Organisms also partially usable activities against diseases caused by other pathogens such as viruses or eukaryotes such as the pathogen of malaria or are being tested in cancer therapy. In addition to the effect on topoisomerases, their ability to bind nucleic acids also plays a role in these applications.
  • Representatives of this structural class which already play an outstanding role in particular in combating bacterial infections, include, for example, ciprofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gemifloxacin, gatifloxacin and others (for an overview of typical representatives of this structural class and their known properties, see, for example, “The Quinolones ", Third Edition, Chapters 1 and 2, page 2-82, Edited by Vincent. T. Andriole, Academic Press, San Diego, ISBN 0-12-059517-6).
  • Ciprofloxacin (I) is an antibacterial agent (EP 49 355 Bl, US 4,670,444) that has been known for about 20 years and can be used extremely successfully both for the prophylaxis and for the treatment of systemic and local bacterial infections, particularly the urinary tract Ciprofloxacin is also effective against anthrax.
  • EP 49 355 B1 mentions tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays as administration forms of ciprofloxacin. It has only recently been found that the control of bacterially caused lung diseases is extremely successful when ciprofloxacin, in the form of its betaine, is applied locally (WO 2004/069253). The drug concentrations in the lungs (and serum) can be kept at a level over a longer period of time, which is desirable from a medical point of view for optimal treatment.
  • the genetic defect is based on the fact that, during the process of translating the genetic DNA, information about the messenger RNA (m-RNA) belonging to a particular gene into the associated protein that is ultimately decisive for the gene function, certain mutations (point mutations, non -Sense mutations, stop mutations: from a codon for an amino acid, the codon for an interruption of protein biosynthesis arises) to an early stop of protein formation and thus to a shortened, not fully or not fully functional protein. It was already known from some substance groups that by using a principle known as "read-through", they can bypass such stop mutations by further reading the genetic information while still vibrating an amino acid instead of interpreting the stop sequence, and thus lead to a correction of the genetic defect (Thompson et al., 2002). Surprisingly, it was found that the action of quinolone or naphthyridone active ingredients makes it possible to construct such gene defects effectively.
  • This effect of the quinolone or naphthyridone active ingredients could be shown in a cell-based assay format, which indicates the suppression of stop codons by a corresponding nonsense mutation in a reporter gene.
  • the described effect of the quinolone or naphthyridone active ingredients can be used as a therapeutic approach for diseases which are based on a genetic defect.
  • the suppression of a nonsense situation by the action of quinolone or naphthyridone active ingredients can be used in patients with diseases such as cystic fibrosis (cystic fibrosis), Hurler's syndrome, Carney complex, Duchenne's muscular dystrophy, cystinosis.
  • the invention therefore relates to the use of quinolone or naphthyridone active ingredients for the production of medicaments for combating diseases which are attributable to genetic defects, such as e.g. Cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchenne's muscular dystrophy and cystinosis, although this list is not exhaustive.
  • Another object of the invention is the use of quinolone or naphthyridone active ingredients for the manufacture of medicaments for combating ear infections in diseases which are attributable to genetic defects, such as e.g.
  • Cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchenne's muscular dystrophy and cystinosis, although this list is not exhaustive, which results in a particularly advantageous combination effect of the antibiotic effects of the drug with the phenotypic correction of the accompanying and / or infection-relevant gene defect .
  • the gene defects underlying cystic fibrosis (cystic fibrosis) regularly lead to severe lung infections with various quinolone-sensitive bacteria such as Pseudomonads (Lyzcak et al. 2002), which are particularly advantageous in combination with a phenotypic correction of the gene defect by quinolones, e.g. Ciprofloxacin betaine can be controlled.
  • Another object of the invention is therefore the use of quinolone or naphthyridone active ingredients for the manufacture of medicaments for the treatment and / or prophylaxis of hip disorders in underlying diseases which are attributable to gene defects, such as e.g. Cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchenne's muscular dystrophy and cystinosis, although this list is not exhaustive, whereby a combination effect of an antibiotic effect with the phenotypic correction of the invigorating and / or underlying gene defect is particularly advantageous.
  • gene defects such as e.g. Cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchenne's muscular dystrophy and cystinosis, although this list is not exhaustive, whereby a combination effect of an antibiotic effect with the phenotypic correction of the invigorating and / or underlying gene defect is particularly advantageous.
  • quinolone active ingredient (s) denotes the class of substances which can be used as anti-infectives and have a quinolone backbone, in particular quinolone carboxylic acids, and their salts, solvates or solvates of the salts.
  • Preferred quinolone agents include ciprofloxacin, olamufloxacin, clinafloxacin, cadrofloxacin, gatifloxacin, rufloxacin, sparfloxacin, levofloxacin, hoxacin, grepafloxacin, moxifloxacin, prulifloxacin, gemufifloxacin, pazufloxin Lomefioxacin and Nitrosoxacin-A.
  • the most preferred quinolone drug is ciprofloxacin and its hydrates.
  • naphthyridone active ingredient denotes the class of substances which can be used as anti-infectives and have a naphthyridone backbone, in particular naphthyridone carboxylic acids, and their salts, solvates or solvates of the salts.
  • a preferred naphthyridone active ingredient is trovafloxacin or alatrofloxacin mesylate.
  • chlorone active ingredient (s) and naphthyridone active ingredient (s) also include quinolone and naphthyridone derivatives which only release the active ingredient in the body (so-called prodrugs), e.g. Ester of a quinolone carboxylic acid or naphthyridone carboxylic acid.
  • two or more quinolone and / or naphthyridone active ingredients can also be used.
  • a combination, preferably a mixture, of two different quinolone derivatives is used according to the invention, for example a mixture of two different quinolone salts.
  • the mixture of a free quinolone or naphthyridone base and its salt is used as active ingredient according to the invention.
  • Mixtures of ciprofloxacin hydrochloride and ciprofloxacin betaine are particularly preferred.
  • Dosage forms include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders, and sprays, which are manufactured using techniques well known in pharmaceutical formulation can.
  • the pharmacologically acceptable auxiliaries include binders (e.g. corn starch, gelatin), stabilizers (e.g. antioxidants such as ascorbic acid), carriers (e.g. microcrystalline cellulose, lactose, sucrose, calcium phosphate, corn starch), lubricants (e.g. talc, stearic acid, magnesium, calcium or zinc stearate), flavorings and / or fragrances.
  • suitable preparations by selecting suitable auxiliaries according to type and amount is not a problem.
  • it has proven to be advantageous to administer amounts of about 1-2000 mg, preferably 20-800 mg, particularly preferably 40-500 mg, in order to achieve effective results.
  • the application can be systemic (eg oral, intravenous, intramuscular, subcutaneous) or local (topical application, inhalation).
  • the invention relates to the use of quinolone active ingredients for the manufacture of medicaments for the treatment and / or prophylaxis of genetically caused diseases of higher organisms, including humans, which are based on point mutations and / or comparable defects.
  • naphthyridone active ingredients for the production of medicaments for the treatment and / or prophylaxis of genetically caused diseases of higher organisms, including humans, which are based on point mutations and / or comparable defects.
  • Part of the invention is the use of quinolone or naphthyridone active ingredients for the manufacture of medicaments for the treatment and / or prophylaxis of genetically caused diseases of higher organisms, including humans, the active ingredients being one or more active ingredients selected from the group from ciprofloxacin HC1, ciprofloxacin betaine, trovafloxacin and moxifloxacin.
  • Also part of the invention is the use of quinolone active ingredients for the manufacture of medicaments for the treatment and / or prophylaxis of infection diseases of higher organisms, including humans, in the case of underlying genetic disorders which are based on punk mutations and / or comparable defects.
  • naphthyridone active ingredients for the production of medicaments for the treatment and / or prophylaxis of infectious diseases of higher organisms, including humans, in the case of underlying genetic diseases, which are based on point mutations and / or comparable defects, is also according to the invention.
  • Part of the invention is the use of quinolone or naphthyridone active ingredients for the manufacture of medicaments for the treatment and / or prophylaxis of infection-related diseases of higher organisms, including humans, in the case of underlying genetic diseases which are based on point mutations and / or comparable defects, whereby the active ingredients are one or more active ingredients selected from the group consisting of ciprofloxacin HC1, ciprofloxacin betaine, trovafloxacin and moxifloxacin.
  • the genetically determined diseases mentioned in the uses according to the invention can be, for example, cystic fibrosis (cystic fibrosis), Hurler's syndrome, Duchemie's muscular dystrophy or cystinosis.
  • the infections to be treated with the medicaments to be obtained via the uses according to the invention can be opportunistic infections.
  • the infections in connection with the invention can be infections triggered by gram-positive or gram-negative pathogens. But it can also be a mixed infection.
  • the infections to be treated with the medicaments to be obtained via the uses according to the invention can be infections triggered by pseudomonas.
  • Fig. 1 Stop codon readthrough inducing effect of ciprofloxacin, ciprofloxacin betaine in comparison to gentamicin.
  • Control unfilled triangles; Ciprofloxacin: filled squares; Ciprofloxacin betaine: open squares; Gentamicin: filled triangles.
  • Fig. 2 Stop codon readthrough inducing effect of trovafloxacin and moxifloxacin compared to gentamicin.
  • Control unfilled squares; Gentamicin: filled squares; Moxifloxacin: filled triangles; Trovafloxacin: unfilled triangles. Examples
  • the assay used here detects the activity of the Firefly luciferase in E. ' coli via the luminescence in the event of suppression of a stop codon introduced in the 5' region of the luc gene.
  • Escherichia coli C600 cells which contain a plasmid with the mutated luc gene, are incubated with the corresponding substance for four hours at 37 ° C. in L-Broth when sowing OD 6u ⁇ 0.2.
  • the luminescence is then measured in an appropriate luminescence detector directly after adding 1 mM luciferin solution.
  • 103 quinolone or naphthyridone drugs with high structural variability were identified, which enable a significant suppression of the nonsense mutation in the luc gene.
  • Keeling KM Brooks DA, Hopwood JJ, Li P, Thompson JN, Bedwell DM; 2001: Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation.

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Abstract

L'invention concerne l'utilisation de principes actifs quinolone ou naphtyridone pour produire des produits pharmaceutiques, des médicaments et des formes galéniques servant au traitement et/ou à la prévention de maladies d'origine génétique d'organismes supérieurs liées à des mutations ponctuelles et/ou à des défauts comparables, comme la fibrose kystique (mucoviscidose), le syndrome de Hurler, la dystrophie musculaire de Duchenne, la cystinose et autres. L'invention concerne également l'utilisation de principes actifs quinolone ou naphtyridone pour produire des produits pharmaceutiques, des médicaments et des formes galéniques servant au traitement et/ou à la prévention d'infections lors de maladies d'origine génétique sous-jacentes liées à des mutations ponctuelles et/ou à des défauts comparables, comme la fibrose kystique (mucoviscidose), le syndrome de Hurler, la dystrophie musculaire de Duchenne, la cystinose et autres.
PCT/EP2004/011607 2003-10-28 2004-10-15 Traitement de maladies d'origine genetique par des quinolones ou des naphtyridones WO2005046692A1 (fr)

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DE10350409.5 2003-10-28
DE10350409A DE10350409A1 (de) 2003-10-28 2003-10-28 Behandlung genetisch bedingter Krankheiten

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015207A2 (fr) * 1998-09-15 2000-03-23 Naeja Pharmaceutical Inc. Therapie combinee pour le traitement des inflammations, utilisant un ou plusieurs inhibiteurs d'elastase et un ou plusieurs agents antibacteriens
US6303572B1 (en) * 1997-06-27 2001-10-16 University Of New England, Of Armidale Control of acidic gut syndrome
US20030044851A1 (en) * 1998-06-16 2003-03-06 Human Genome Sciences, Inc. Secreted protein HCEJQ69
WO2003061767A1 (fr) * 2002-01-25 2003-07-31 Atopic Pty Ltd Techniques et compositions destines au traitement de l'asthme et de troubles associes
WO2004048525A2 (fr) * 2002-11-21 2004-06-10 Genentech, Inc. Therapie de maladies ou troubles benins a l'aide d'anticorps anti-erbb2

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6303572B1 (en) * 1997-06-27 2001-10-16 University Of New England, Of Armidale Control of acidic gut syndrome
US20030044851A1 (en) * 1998-06-16 2003-03-06 Human Genome Sciences, Inc. Secreted protein HCEJQ69
WO2000015207A2 (fr) * 1998-09-15 2000-03-23 Naeja Pharmaceutical Inc. Therapie combinee pour le traitement des inflammations, utilisant un ou plusieurs inhibiteurs d'elastase et un ou plusieurs agents antibacteriens
WO2003061767A1 (fr) * 2002-01-25 2003-07-31 Atopic Pty Ltd Techniques et compositions destines au traitement de l'asthme et de troubles associes
WO2004048525A2 (fr) * 2002-11-21 2004-06-10 Genentech, Inc. Therapie de maladies ou troubles benins a l'aide d'anticorps anti-erbb2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MONTGOMERY, MEGAN J. ET AL: "Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY , 45(12), 3468-3473 CODEN: AMACCQ; ISSN: 0066-4804, 2001, XP008041750 *
STRATTON, CHARLES W.: "Nonantibiotic effects of macrolide antibiotics: suppression of the bacterial glycocalyx of Pseudomonas aeruginosa isolates from patients with cystic fibrosis", INFECTIOUS DISEASE AND THERAPY , 21(EXPANDING INDICATIONS FOR THE NEW MACROLIDES, AZALIDES, AND STREPTOGRAMINS), 91-100 CODEN: IDTHER; ISSN: 1043-2981, 1997, XP008041756 *

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