EP0793654A1 - Derives antibacteriens de dibenzimidazol - Google Patents

Derives antibacteriens de dibenzimidazol

Info

Publication number
EP0793654A1
EP0793654A1 EP95934584A EP95934584A EP0793654A1 EP 0793654 A1 EP0793654 A1 EP 0793654A1 EP 95934584 A EP95934584 A EP 95934584A EP 95934584 A EP95934584 A EP 95934584A EP 0793654 A1 EP0793654 A1 EP 0793654A1
Authority
EP
European Patent Office
Prior art keywords
dibenzimidazol
compounds
phenol
hydroxyphenyl
formula
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Withdrawn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
EP95934584A
Other languages
German (de)
English (en)
Inventor
Walter Haesler
Yu-Hua Ji
Werner Leupin
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.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
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
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0793654A1 publication Critical patent/EP0793654A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the invention relates to dibenzimidazole derivatives.
  • it relates to 2,2'-bis-substituted 6,6'-dibenzi ⁇ jidazoles of the general formula
  • R 1 and R 2 can be the same or different and C6H4 3 -, C6H3 (OH) R - or heterocyclyl,
  • R 3 is hydroxy, amino, lower alkoxy or cyano and R 4 is halogen, lower alkyl or lower alkoxy, and pharmaceutically acceptable salts of compounds of the general formula I.
  • the compounds of formula I and their pharmaceutically acceptable salts show very good antibacterial activity, especially against Gram-positive pathogens such as Staphylococcus and Enterococcus faecalis. They also show good activity against Helicobacter pylori.
  • Symmetrical bis-benzimidazoles have been described in the literature as starting materials for the preparation of polybenzimidazoles (J. Org. Chem., 42, 3485-3491 [1977]).
  • the present invention relates to compounds of general formula I and pharmaceutically acceptable salts thereof for use as therapeutic agents, in particular as agents against bacterial pathogens; Medicaments containing one or more compounds of general formula I or pharmaceutically acceptable salts thereof; the use of these compounds in combating or preventing diseases which are caused by bacterial pathogens and in the preparation of medicaments for the indications mentioned; as well as the new compounds of formula I, their pharmaceutically acceptable salts and the preparation of the new compounds and salts.
  • lower alkyl used in the present description expediently denotes those having up to 7, preferably up to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- Butyl and the like.
  • Halogen means chlorine, bromine, fluorine or iodine.
  • lower alkoxy denotes a lower alkyl radical bonded via an oxygen atom.
  • heterocyclyl means a 5- or 6-membered unsaturated ring having at least one heteroatom such as 0, S or N, for example furyl, pyranyl, thienyl, pyrrolyl or pyridyl.
  • R 1 and R 2 are identical or different and are C ⁇ HiR 3 - or C6H3 (OH) R 4 -, R 3 and R 4 have the meaning given above are particularly preferred for use as therapeutic active substances and wherein a substituent preferably occupies a 4- or optionally a 3-position on the phenyl ring.
  • Hydroxy group is in the 4-position on the phenyl ring.
  • the following compounds are particularly preferred for use as therapeutic agents:
  • the symmetrically substituted compounds of the formula I in which R 1 and R 2 have the same meaning can be prepared by using the compound of the formula
  • the asymmetrically substituted compounds of the formula I in which R 1 and R 2 do not have the same meaning can be prepared according to the invention by reacting the compound of the formula II simultaneously with two different reactive compounds which provide the radicals R 1 and R 2 .
  • R 1 has the meaning given above, with a reactive agent which provides the radicals R 1 or R 2 .
  • Both the symmetrically substituted compounds and the unsymmetrically substituted compounds of the formula I can, if desired, be converted into a pharmaceutically acceptable salt.
  • the procedure is such that the 3,3'-diamine-benzidine is mixed with twice the amount of the reactive derivative in a solvent, e.g. Ethanol is reacted for several hours at the boiling point of the solvent used.
  • a solvent e.g. Ethanol
  • Na2S2 ⁇ s or nitrobenzene are particularly suitable as additives for the preparation of the compounds of the formula I if aldehydes are used as reactive derivatives. If acids, esters, anhydrides, alkylimides or acyl halides are used, HC1 (J. Chem. Soc, 2393-2399, [1928]), polyphosphoric acid (J. Amer.
  • Unsymmetrically substituted dibenzimidazoles can be prepared in a similar manner.
  • the compound 4- [2 '- (4-ethoxyphenyl) -6,6'-dibenzimidazol-2-yl] phenol is thus obtained, for example, by reacting 3,3'-diaminobenzidine with 4-hydroxybenzaldehyde and 4-ethoxy-benzaldehyde in ethanol and addition of Na2S2 ⁇ s after stirring for several hours at reflux.
  • reaction solution also contains the corresponding symmetrical compounds.
  • Symmetrically or asymmetrically substituted dibenzimidazole derivatives can also be obtained by using a compound of the formula with an above-mentioned reactive compound which provides the radical Rl or R 2 .
  • the implementation is analogous to the process described above.
  • the pharmaceutically acceptable salts can be prepared according to known
  • the free bases of the formula I can be converted, for example, into the corresponding salts using the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p -Toluenesulfonic acid and the like.
  • Preferred salts are the hydrochlorides derived from the basic compounds of formula I, e.g. with a methanolic HC1 solution.
  • the starting compounds required for the preparation of the compounds of formula I are known commercial products, e.g. the compound II, or can be easily prepared by methods known per se.
  • Amino-3'-nitro-benzidine with a reactive compound which provides the radical R 1 is obtained by subsequently hydrogenating the nitro group of the isolated intermediate to give the amino group.
  • the hydrogenation is carried out according to methods described in the literature, for example with
  • the compound III obtained can then, as described, be reacted with a further compound which provides the radical R 1 or R 2 to give the dibenzimidazoles of the formula I.
  • All reactive compounds required for the preparation of the compound I, which contain the radicals R 1 or R 2 are known compounds and / or can be prepared in an analogous manner by processes described in the literature.
  • ethyl imide ester of 4-hydroxybenzoic acid can be prepared as follows:
  • the minimum inhibitory concentration (MIC) of the substances examined against gram-positive and gram-negative strains was determined using standard agar methods. The compounds were dissolved in a small amount of dimethyl sulfoxide, diluted with water and incorporated in liquefied DST agar at 50 ° C. The agar plates thus produced were used in the experiment immediately afterwards. The test concentrations were between 128 and 0.06 ⁇ g ml.
  • the bacterial vaccine solutions were prepared from pre-cultures incubated overnight, diluted and applied to the agar surface using an inoculation device (Denley A400). The plates were incubated at 35 ° C for 20 hours. The MIC was determined as the lowest substance concentration that prevents visible growth. A barely visible cloudiness and that
  • the antibacterial activities against Helicobacter pylori were carried out analogously to the method described above, with the following changes:
  • the compounds were incorporated in Müller-Hinton agar with 5% sheep blood additive.
  • the test concentrations were between 10 and 0.1 ⁇ g ml.
  • the preincubation time was 5 days, the incubation time 4 days for H. pylori K 1585 and 7 days for H. pylori PN 81.
  • the products according to the invention can be used as medicaments, for example in the form of pharmaceutical preparations, which they or their salts are mixed with a pharmaceutical, organic or inorganic inert carrier material suitable for parenteral or enteral application, such as water, gelatin,
  • the pharmaceutical preparations can be in solid form, e.g. as tablets, tablets, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions.
  • the compounds of the formula I and their salts are preferably suitable for parenteral administration and are preferably prepared for this purpose as lyophilisates or dry powder for dilution with conventional agents such as water or isotonic saline.
  • the dosage of the compounds of general formula I and the pharmaceutically acceptable salts thereof with bases can vary within wide limits and is of course to be adapted to the individual circumstances and the pathogen to be controlled in each individual case.
  • medicaments containing a compound of the general formula I or a pharmaceutically acceptable salt thereof are also a process for the preparation of such medicaments, which is characterized in that one or more compounds of the general formula I or pharmaceutically acceptable salts thereof and optionally one or more other therapeutically valuable substances in a pharmaceutical dosage form.
  • Ampoules for intramuscular administration are produced in the usual way:
  • a lyophilisate of 1 g of 4- [2 '- (4-hydroxyphenyl) -6,6'-dibenzimidazol-2-yl] phenol hydrochloride (1: 2) is prepared in the usual manner and
  • the lyophilisate is treated with 2.5 ml of 2% lidocaine hydrochloride solution.
  • Example B Tablets of the following composition are produced in the usual way: mg / tablet
  • Capsules of the following composition are produced: mg / kg gel
  • the active ingredient, milk sugar and corn starch are first mixed in a mixer and then in a shredder. You bring the mixture back into the mixer, add the talc and mix thoroughly. The mixture is filled into hard gelatin capsules by machine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dibenzimidazoles connus et nouveaux de la formule (I) dans laquelle R<1> et R<2> peuvent être identiques ou différents et désignent C6H4R<3>-, C6H3(OH)R<4>- ou hétérocyclyle, R<3> désigne hydroxy, amino, alcoxy inférieur ou cyano et R<4> désigne halogène, alkyle inférieur ou alcoxy inférieur. L'invention concerne des sels de composés de la formule (I), utilisables sur le plan pharmaceutique et qui ont une action antibactérienne, notamment à l'égard du Staphylococcus, de l'Enterococcus et de l'Heliobacter pylori.
EP95934584A 1994-11-17 1995-11-02 Derives antibacteriens de dibenzimidazol Withdrawn EP0793654A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH345994 1994-11-17
CH3459/94 1994-11-17
PCT/CH1995/000255 WO1996016042A1 (fr) 1994-11-17 1995-11-02 Derives antibacteriens de dibenzimidazol

Publications (1)

Publication Number Publication Date
EP0793654A1 true EP0793654A1 (fr) 1997-09-10

Family

ID=4256402

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95934584A Withdrawn EP0793654A1 (fr) 1994-11-17 1995-11-02 Derives antibacteriens de dibenzimidazol

Country Status (9)

Country Link
US (1) US5824698A (fr)
EP (1) EP0793654A1 (fr)
JP (1) JPH09512831A (fr)
AU (1) AU3696495A (fr)
BR (1) BR9509671C1 (fr)
CA (1) CA2204639A1 (fr)
FI (1) FI972090A0 (fr)
MX (1) MX9703634A (fr)
WO (1) WO1996016042A1 (fr)

Cited By (1)

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US7482743B2 (en) 2001-08-24 2009-01-27 Semiconductor Energy Laboratory Co., Ltd. Luminous device

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GB9908828D0 (en) * 1999-04-16 1999-06-16 Univ Reading The Compounds
CA2371728C (fr) * 1999-06-11 2009-06-02 Neorx Corporation Complexe a forte dose de radionucleides destine a la suppression de la moelle osseuse
US7094885B2 (en) 1999-07-11 2006-08-22 Neorx Corporation Skeletal-targeted radiation to treat bone-associated pathologies
US6403652B1 (en) 2000-06-30 2002-06-11 Colgate-Palmolive Company Method and composition
JP2004536034A (ja) 2001-01-08 2004-12-02 ネオルクス コーポレイション 治療的および診断的化合物、組成物および方法
EP1458416A1 (fr) 2001-12-13 2004-09-22 Dow Global Technologies Inc. Traitement de l'osteomyelite avec des produits radiopharmaceutiques
KR100629060B1 (ko) 2004-08-11 2006-09-26 주식회사 엘지화학 새로운 벤즈이미다졸계 화합물
DE102005017508A1 (de) * 2005-04-15 2006-10-19 Basf Ag Verfahren zur Gewinnung einer basischen Aminosäure aus einer Fermentationsbrühe II
GB0821913D0 (en) * 2008-12-02 2009-01-07 Price & Co Antibacterial compounds
BR112012030621B1 (pt) 2010-06-01 2020-10-27 Summit (Oxford) Limited compostos para o tratamento de doença associada a clostridium difficile
WO2011151617A1 (fr) 2010-06-01 2011-12-08 Summit Corporation Plc Composés pour le traitement d'une maladie associée à clostridium difficile
GB2480813A (en) * 2010-06-01 2011-12-07 Summit Corp Plc Compounds for the treatment of clostridium difficile-associated disease
GB2480814A (en) * 2010-06-01 2011-12-07 Summit Corp Plc Compounds for the treatment of clostridium difficile-associated disease
WO2011151619A1 (fr) 2010-06-01 2011-12-08 Summit Corporation Plc Composés destinés au traitement d'une maladie associée à clostridium difficile
WO2011151620A1 (fr) * 2010-06-01 2011-12-08 Summit Corporation Plc Composés pour le traitement d'une maladie associée à clostridium difficile
WO2011151618A2 (fr) 2010-06-01 2011-12-08 Summit Corporation Plc Composés pour le traitement d'une maladie associée à clostridium difficile
US9079935B2 (en) 2012-08-13 2015-07-14 The Board Of Regents Of The Nevada System Of Higher Education On Behalf Of The University Of Nevada, Las Vegas Reducing risk of contracting Clostridium-difficile associated disease
US20180000793A1 (en) 2015-02-06 2018-01-04 Ernesto Abel-Santos Inhibiting Germination of Clostridium Perfringens Spores to Reduce Necrotic Enteritis
AU2020315188A1 (en) 2019-07-17 2022-02-10 Summit (Oxford) Limited Process for the preparation of ridinilazole and crystalline forms thereof
GB202100471D0 (en) 2021-01-14 2021-03-03 Summit Oxford Ltd Preparation of antibacterial compounds

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US5412059A (en) * 1993-04-05 1995-05-02 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Polybenzimidazoles via aromatic nucleophilic displacement

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US7482743B2 (en) 2001-08-24 2009-01-27 Semiconductor Energy Laboratory Co., Ltd. Luminous device

Also Published As

Publication number Publication date
FI972090A (fi) 1997-05-15
US5824698A (en) 1998-10-20
MX9703634A (es) 1997-08-30
BR9509671C1 (pt) 2000-04-18
FI972090A0 (fi) 1997-05-15
JPH09512831A (ja) 1997-12-22
AU3696495A (en) 1996-06-17
BR9509671A (pt) 1997-10-28
WO1996016042A1 (fr) 1996-05-30
CA2204639A1 (fr) 1996-05-30

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