Classifications

• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to novel hydrazones of the general formula 1 , to a process for the manufacture of these hydrazones, to pharmaceutical compositions containing them and to their use in the treatment of microbial infections.
• Related hydrazones have been investigated previously, especially with regard to their potential as antitumor agents: see Antonini et al., J. Med. Chem. 1981 , 24, 1181 -1184.
• PIH Pyridoxal Isonicotinoyl Hydrazone
• azinyl and diazinyl hydrazones appear to act similarly: Easmon, J.; Heinisch, G.; P ⁇ rstinger, G.; Langer, T.; Oecker, J.K.; Grunicke, H.H.; Hofmann, J. J. Med. Chem., 1997, 40, 4420-4425.
• the inhibition of tumor growth seems to be linked to the iron (III) chelating property of PIH: Richardson, D.R. Antimicrob. Agents Chemother. 1997, 41, 2061 -2063.
• the assay comprises of three major components, purified enzyme I in catalytic amounts, Phosphoenol Pyruvate (PEP) as the phosphoryl donor substrate and purified HPr as the phosphoryl acceptor substrate.
• Phosphoenol Pyruvate Phosphoenol Pyruvate
• the assay couples the formation of pyruvate formed from PEP to lactate, catalyzed by lactate dehydrogenase.
• the disappearance of NADH, cofactor required by lactate dehydrogenase, is determined spectrophotometerically at 340 nm.
• the assay is done in a U-shaped microtiter plate format, and quantitation is done using microplate absorbance reader.
• the reaction is started by the addition of enzyme I (final concentration 0.75 ⁇ M).
• enzyme I final concentration 0.75 ⁇ M
• the compound is replaced by DMSO.
• NCLS National Committee for Clinical Laboratory Standards
• MIC Minimum Inhibitory Concentration
• na means not active at concentrations less than 128 ⁇ g/ml nt means not tested
• the present invention relates to novel hydrazones of the general formula 1 ,
• R 1 represents lower alkyl-carbonylamino; formylamino; amino; hydroxy;
• R 2 represents hydrogen; hydroxy; lower alkyl; fluoro; chloro;
• R 3 represents hydrogen; methyl; ethyl; isopropyl;
• R 11 represents hydrogen; hydroxy; lower alkyl; lower alkoxy; fluoro; chloro; amino;
• R 12 represents hydrogen; hydroxy; lower alkyl; lower alkoxy; fluoro; chloro; amino
• R 13 represents hydrogen; lower alkyl
• R 4 represents aryl; arylmethyl; indoyl methyl; mono-, di- or tri- substituted aryl, arylmethyl, which substituents may be lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, N- pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and which substituents may be the same or different;
• R 4 is not unsubstituted phenyl; phenylmethyl; 2-amino-phenyl; 2-hydroxy-phenyl; 4- chloro-phenyl;
• R 1 represents amino and R 2 , R 11 , R 12 and R 13 represent hydrogen and R 3 represents methyl, R 4 is not unsubstituted phenyl; 2-hydroxy-phenyl; case R 1 represents methyl-carbonylamino and R 2 , R 3 , R 11 , R 13 and R 1 represent hydrogen, R 4 is not 4-hydroxy-3-methoxy-phenyl;
• R 4 is not unsubstituted phenyl; 4-methyl-phenyl; 2-methyl- phenyl; 2-hydroxy-phenyl; 4-methoxy-phenyl; 4-chloro-phenyl; 2-chloro-phenyl; 2,4,6-trimethyl-phenyl;
• R 1 is hydroxy and R 2 , R 11 , R 12 and R 13 represent hydrogen and R 3 represents ethyl, R 4 is not unsubstitued phenyl or 2-hydroxy-phenyl;
• R 1 is hydroxy and R 2 , R 11 , R 12 and R 3 represent hydrogen and R 13 represents methyl, R 4 is not unsubstituted phenyl;
• R 4 is phenyl substituted with 2-trifluoromethyl, 3-thfluoromethyl, 3-methoxy or (2- amino-5-chloro);
• R 4 is not 2-chloro-phenyl
• R 4 is not unsubstituted phenyl; 2-hydroxy-phenyl; 2-chloro-phenyl; 4- hydroxy-3-methoxy-phenyl; 5-chloro-2-hydroxy-phenyl; 2-(3-hydroxy)-naphthyl; 2,4-dichloro-phenyl; 4-amino-3,5-dichloro-phenyl; 5-bromo-2-hydroxy-phenyl;
• R 1 , R 11 and R 12 represent hydroxy and R 2 and R 13 represent hydrogen and R 3 is methyl, R 4 is not unsubstituted phenyl;
• R 4 is not unsubstituted phenyl; 2-hydroxy-phenyl; 4-methoxy-phenyl; 4-hydroxy-3-methoxy-phenyl; 2,4-dichloro-phenyl; in case R 1 and R 12 represent hydroxy and R 2 , R 11 and R 13 represent hydrogen and R 3 is methyl, R 4 is not unsubstituted phenyl; 2-hydroxy-phenyl;
• R 4 is not 4-hydroxy-3-methoxy-phenyl
• R 1 is hydroxy and R 12 is methoxy and R 2 , R 11 and R 13 represent hydrogen and R 3 is methyl, R 4 is not unsubstituted phenyl;
• R 4 is not unsubstituted phenyl; 2-methyl-phenyl; 2-hydroxy-phenyl; 4- hydroxy-phenyl; 4-methoxy-phenyl; 4-chloro-phenyl; 5-chloro-2-hydroxy-phenyl; 2-hydroxy naphth-1 -yl; 3-hydroxy naphth-2-yl; 2,4-dichloro-phenyl; 3,4-dichloro- phenyl; 3,4,5-trihydroxy-phenyl; 5-bromo-2-hydroxy-phenyl;
• R 4 is not 2-hydroxy-phenyl; 5-chloro-2-hydroxy-phenyl; 3- hydroxy naphth-2-yl; 2-hydroxy-3,5-dichloro-phenyl; 5-bromo-2-hydroxy-phenyl; 3,5-dibromo-2-hydroxy-phenyl; N-pyrrolyl;
• R 1 is hydroxy and R 2 and R 3 represent methyl and R 11 , R 12 and R 13 represent hydrogen, R 4 is not unsubstituted phenyl;
• R 4 is not 4-chloro-phenyl; 2-naphthyl; 2-bromo-phenyl; 3-bromo- phenyl; 4-bromo-phenyl;
• R 1 is hydroxy and R 2 is fluoro and R 11
• R 12 and R 13 represent hydrogen and R 3 is methyl or ethyl
• R 4 is not 4-fluoro methyl
• R and R 12 represent hydroxy and R 11 is chloro
• R 3 and R 13 represent hydrogen and R 2 is n-butyl or (3-methyl)-butyl or n-pentyl, R 4 is not 4-amino-2- hydroxy-phenyl;
• R 1 and R 12 represent hydroxy and R 2 is ethyl or n-butyl or n-hexyl or (3- methyl)-butyl and R 3 , R 11 and R 13 represent hydrogen, R 4 is not unsubstituted phenyl, 4-amino-phenyl, 4-hydroxy-phenyl, 2-hydroxy-phenyl, 4-amino-2- hydroxy-phenyl,
• Preferred compounds are compounds of the formulae 2a-2e,
• R 3 , R 13 and R 4 have the meaning given in formula 1 and R 14 is hydrogen, lower alkyl , formyl or acetyl and R 16 is hydrogen, methyl, fluoro, chloro, hydroxy or ethyl and pharmaceutically acceptable salts thereof.
• Very preferred compounds are compounds of the formulae 3a-3e,
• R 4 has the meaning given in formula 1 and R 14 is hydrogen, lower alkyl , formyl or acetyl and R 16 is hydrogen, methyl, fluoro, chloro, hydroxy or ethyl and R 15 is hydrogen, methyl or ethyl and pharmaceutically acceptable salts thereof.
• R 4a-4f is Especially preferred compounds.
• R 15 represents hydrogen, methyl or ethyl and, R 17 , R 18 , R 19 , R 20 and, R 21 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, in case R 15 is methyl either one or two of the substituents R 17 , R 18 , R 19 , R 20 , R 21 represent N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy.
• R 15 represents hydrogen, methyl or ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, in case R 17 is N- pyrrolyl either one or two of the substituents R 18 , R 19 , R 20 , R 21 represent lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy.
• R 15 represents hydrogen, methyl or ethyl and R 17 , R 18 , R 9 , R 20 and R 21 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, in case R 15 is hydrogen and R 7 is chloro either one or two of the substituents R 18 , R 19 , R 20 , R 21 represents, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino or lower alkylendioxy.
• R 17 , R 18 , R 19 , R 20 and R 21 which may be the same or different, represent hydrogen, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, in case R 17 is hydrogen or hydroxy, either one or two of the substituents R 18 , R 19 , R 20 , R 2 represent N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy.
• R 15 represents hydrogen, methyl, ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy.
• R 15 represents hydrogen, methyl, ethyl and R 17 , R 18 , R 19 , R 20 and R 2 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, in case R 15 is hydrogen then at least one of the substituents R 17 , R 18 , R 19 , R 20 or R 21 represents pyrrolyl, trifluoromethyl, or lower alkylamino
• R 15 represents hydrogen, methyl or ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, lower alkylamino, lower alkylendioxy, with the proviso that one or two of the substituents R 17 , R 18 , R 19 , R 20 and R 21 represent trifluoromethyl or chloro.
• R 15 represents hydrogen, methyl or ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, lower alkylamino, lower alkylendioxy, N-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, with the proviso that one or two of the substituents R 17 , R 18 , R 19 , R 20 and R 21 represent N-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, in case R 17 represents N-pyrrolyl, at least one of the substituents R 18 , R 19 , R 20 of R 21 represents lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, lower alkylamino, lower alkylendioxy.
• R 15 represents hydrogen, methyl or ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, lower alkylamino, lower alkylendioxy, with the proviso that one or two of the substituents R 17 , R 18 , R 19 , R 20 and R 21 represent chloro or trifluoromethyl.
• R 17 , R 18 , R 19 , R 20 and R 21 which may be the same or different, represent hydrogen, lower alkyl, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, with the proviso that one or two of the substituents R 17 , R 18 , R 19 , R 20 and R 21 represent chloro, methoxy, methyl or trifluoromethyl.
• R 15 represents hydrogen, methyl, ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, with the proviso that one or two of the substituents R 17 , R 18 , R 19 , R 20 and R 21 represent chloro, methoxy, methyl of trifluoromethyl.
• R 15 represents hydrogen, methyl, ethyl and R 17 , R 18 , R 19 , R 20 and R 21 , which may be the same or different, represent hydrogen, N-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, lower alkyl, hydroxy, lower alkoxy, fluoro, chloro, bromo, trifluoromethyl, amino, lower alkylamino, lower alkylendioxy, with the proviso that in case R 15 is hydrogen at least one of the substituents R 17 , R 18 , R 19 , R 20 and R 21 represents N-pyrroly, 2-pyrrolyl, 3-pyrrolyl, trifluoromethyl or lower alkylamino.
• lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms.
• Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy.
• aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl rings which may be substituted with halogen, hydroxy, lower alkyl, lower alkoxy, or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, trifluoromethyl, lower alkylamino.
• salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methane sulfonic acid, p-toluene sulfonic acid and the like or in case the compound of formula 1 is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide etc.
• hydrohalogenic acids e.g. hydrochloric or hydrobromic acid
• an inorganic base like an alkal
• the described compounds can be used for the treatment of diseases which are associated with an infection by such type of pathogens. They are valuable anti- infectives.
• the compounds can be administered orally, rectaliy, parenterally, e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol.
• parenterally e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol.
• examples of applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
• Preferred applications are intravenous, intra-muscular, or oral administrations as well as eye drops.
• the dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1 - 50 mg / kg body weight per day are considered.
• the preparations with compounds of formula 1 can contain inert or as well pharmacodynamically active excipients like sulphonamides. Tablets or granules, for Example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
• compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectaliy in form of suppositories.
• enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectaliy in form of suppositories.
• These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.
• compositions may contain the compounds of formula 1 as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
• vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used.
• solutions and syrups e.g. water, polyols, saccharose, glucose etc. are used.
• injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc.
• Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats ), liquid or half-liquid polyols etc.
• compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti oxidants etc.
• the compounds of formula 1 may also be used in co-therapy with one or more other therapeutically used classes of antimicrobial substances, for example, beta- lactams e.g. penicillins and cephalosporins; glycopeptides; quinolones; tetracyclines; aminoglycosides; macrolides etc.
• beta- lactams e.g. penicillins and cephalosporins
• glycopeptides e.g. penicillins and cephalosporins
• glycopeptides e.g. quinolones; tetracyclines; aminoglycosides; macrolides etc.
• the dosage may vary within wide limits but should be adapted to the specific situation.
• the dosage given in oral form should daily be between about 3 mg and about 4 g, preferably between about 0.2 g and about 4 g, especially preferred between 0.2 g and 2 g per adult with a body weight of about 70 kg.
• the dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.
• the invention also relates to a process for the manufacture of compounds of formula 1 , which process comprises reacting a) equimolar amounts of an aromatic carboxylic acid hydrazide and an aromatic aldehyde at ambient temperature, until the respective hydrazone precipitates, (Method A), or b) equimolar amounts of an aromatic carboxylic acid hydrazide and an aromatic aldehyde at reflux temperature of the solvent, until the respective hydrazone precipitates (Method B).
• a preferred solvent in step B is ethanol.
• Example 3 (Method A) 1-Naphthoic acid hydrazide (1 mmol) and 2,5-dihydroxy-benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until N'-(2,5- dihydroxy-benzylidene)-naphthalene-1-carbohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 5 2-Amino-5-chloro benzoic acid hydrazide (1 mmol) and 2-hydroxy-benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 2- amino-5-chloro-N'-(2-hydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 9 3,4-Dichloro benzoic acid hydrazide (1 mmol) and 2,3,4-trihydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 3,4- dichloro-N'-(2,3,4-trihydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 11 4-Hydroxy benzoic acid hydrazide (1 mmol) and 2,5-dihydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 4- hydroxy-N'-(2,5-dihydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 19 2-Methylamino-benzoic acid hydrazide (1 mmol) and 2,5-dihydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 2- methylamino-N'-(2,5-dihydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 22 (Method A) 2-Methylamino-benzoic acid hydrazide (1 mmol) and 2-hydroxy acetophenone (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 2- methylamino-N'-[1-(2-hydroxy-phenyl)-ethylidene]-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 27 3-Methoxy benzoic acid hydrazide (1 mmol) and 2-hydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 3- methoxy-N'-(2-hydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 34 3-Trifluoromethyl benzoic acid hydrazide (1 mmol) and 2,5-dihydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 3-trifluoromethyl-N'-(2,5-dihydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 37 4-Chloro benzoic acid hydrazide (1 mmol) and 2,4-dihydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 3- chloro-N'-(2,4-dihydroxy-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 41 3,5-Bis-(trifluoromethyl)-benzoic acid hydrazide (1 mmol) and 2,3,4-trihydroxy benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 3,5-Bis-(trifluoromethyl)-N'-(2,3,4-trihydroxy-benzylidene)-benzo- hydrazide precipitated, which was filtered off and dried under vacuum.
• Example 43 3-Chloro-2-pyrrol-1-yl benzoic acid hydrazide (1 mmol) , of which the synthesis is described in examples 54-56, and 2-hydroxy-3,5-dichloro benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until 3-chloro-2- pyrrol-1-yl-N'-(2-hydroxy-3,5-dichloro-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.
• Example 48 (Method A) Benzoic acid hydrazide (1 mmol) and 2-hydroxy-3,5-dichloro benzaldehyde (1 mmol) were suspended in 15 ml of ethanol. The mixture was stirred until N'-(2- hydroxy-3,5-dichloro-benzylidene)-benzohydrazide precipitated, which was filtered off and dried under vacuum.

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• 2002
  • 2002-01-18 EP EP02722025A patent/EP1404644A2/de not_active Withdrawn

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