Preparation of 2-bromo-5-(2-bromo-2-nitrovinyl)-furan and its use as microcide

Abstract: An obtention and purification procedure of 1-(5-bromophur-2-il)-2-bromo-2-nitroethane is proposed, with a reaction from 1-(fure-2-il)-2-nitroethane with appropriate output and high purity, guaranteeing its use as active principle in the human and veterinary medical-pharmaceutical industry. The product demonstrates effectiveness in "in vitro" tests, in experimentation animals and in humans against negative gram, positive gram bacteria, superior bacteria, escotobacteria, monomorphic gemant fungi and monomorphic filamentose fungi. The microcide action of the product has been proven with numerous examples, as the active principle of several formulas being developed for human and veterinary use for the treatment of several ailments.

Description: The following invention relates human and animal health in general with a product which has an extensive microcide activity, and which has been evaluated "in vitro", in experimental and stock animals and in humans with a wide number of gram positive bacteria (more than 500 strains), gram negative (more than 1500 strains), fungi (more than 500 strains) and other microorganisms (more than 100 strains). This substance was described in the international literature by author Z.N. Nazarova during 1972. The first time was in an article "Synthesis of some furyl-nitro-olefins with potential biological activity" together with the author G.F. Potemkin in the review Khim. Farm. Zh. 6 (10); 5-8 (1972), the second in an article "Physicochemical properties and reactivity of furyl-nitro-olefins" together with authors M.G. Gruntfest, G.F. Potemkin, Yu. V. Kolodyazhnyi, V. Zverev and O.A. Osipov in the review Zh. Org. Khim 8(2); 404-11 (1972). In the first article the synthesis routes used by the author were covered and in the second chemical-physical studies of a wide range of substituted furyl-nitro-olefins were described, and the calculation of dipolar moments, some data from infra-red and ultraviolet spectra and certain theoretical studies about these systems were included. Neither of the two articles published reported any specific biological actions of the product. The obtention procedures described by the author in the first article are the following: A solution of 0.03 moles of bromine in 20 ml of chloroform is added to a solution of 0.015 moles of β-furyl-nitro-olefins in 50 ml of chloroform with constant agitation and a temperature of 0°C for 30 minutes. The solution is left for 3-4 hours, at a temperature of 20-25°C, after which the solvent is distilled at room temperature. The residue obtained is β-(5-bromofur-2-yl)-α,β-dibromo-nitroethane in the form of a pale yellow oil, which decomposes if stored or distilled. A solution of 3.4 g of potassium hydroxide in 50 ml of water with energetic shaking and a temperature of 20-25°C was added to 5.3 g of the oil obtained. The precipitate formed is separated, washed with water to obtain a neutral medium, dried in the drier and then recrystallized twice in hexane. The reported yield was 27 g (64%), melting temperature of 94-95°C, yellow crystals. Another proposed method consists in: To a solution of 0.01 moles of 5-bromofurfural and 0.01 moles bromonitromethane in 30 ml of methanol chilled in a mixture of ice and salt, one adds, drop by drop, whilst shaking constantly for 30 minutes, a solution of 0.02 moles of potassium hydroxide in 3 moles of water and little by little the cold mixture is poured into 3.2 ml of concentrated hydrochloric acid and 12 ml of water. After 30 minutes the precipitate is separated, washed with water to obtain a neutral medium, purified with a steam washed distillation and subsequently recrystallized with alcohol. The reported yield in this case was 76.8%, with a melting temperature of 88-89°C. The author states that the product obtained by both routes are identical, bearing in mind the infra-red (IR) and ultraviolet (UV) spectrums and the thin layer chromatography. The invention is defined in the claims. The proposed procedure for making the compound used in the present invention produces greater yield and higher purity rates and the same consists in the reaction of 2-(2-nitro-vinyl)-furan, with bromine in a molar ratio, which oscillates between 1:2 and 1:2.6, using non polar solvents such as: carbon disulphide or carbon tetrachloride, being shaken between 1 and 6 hours, and controlling the temperature between 20 and 60°C. The solvent is then separated by simple atmospheric pressure distillation, the majority of the possible excess bromine is eliminated during this operation, as well as part of the hydrogen bromide formed. Subsequently, both neutralization and dehydrobromination is carried out, simultaneously, using a tertiary amine, and a temperature control in the range of 20-70°C. At the end of this stage of the experiment the product precipitates into a yellow mass, which is dissolved in a hot polar solvent and the same precipitates from the solution after some hours of resting. Yields higher than 90% are achieved on the scales reported by Z.N. Nazarova and in the scale of 5.5 moles never less than 63%. The purity obtained in small scales are always higher than 90% and in the larger scales never less than 75%, the reduction being caused by the fact that up until now a total drying process has not been completed on doing analysis. The purity of the raw product is determined by gas chromatography and HPLC. The crude product undergoes a purification process which consists in dissolving it in a polar solvent such as: ethanol, isopropanol or methanol at a temperature of between 25 and 70°C and immediately adding a finely divided adsorbent product and maintaining it in agitation for 10 to 60 minutes. It is then filtered, the solution is left to rest for some hours and the product finally crystallizes into yellow crystals which are separated by filtration, dried and packed. The pure product is of a purity which oscillates between 98 and 100%, the established limit by pharmacopoeia for using active principles as medicaments. The main impurity which appears in the synthesis is the 2- bromo-5-(2-nitro-vinyl)-furan and its content oscillates between 0.1 and 1.99%. The product obtained is thus in the form of yellow crystals and has a melting temperature of 88-89°C. The advantages of this new procedure are varied and stem from the fact that the complete synthesis process can be carried out in an organic phase which avoids losses and greatly reduces the high number of operations needed by the presence of the water phase. This has made it possible to scale the reaction starting from the scale of 0.015 moles reported by Z.N. Nazarova to 5.5 moles, i.e. a scale which is 366 times greater, good results being obtained; the use of tertiary amine means that the pH of the reaction medium can be neutralized simultaneously and the dehydrobromination reaction can be carried out without resins forming, which had always occurred with the method described in the literature. Z.N. Nazarova does not report on the purity of the product obtained after purification, and what is striking is that the results obtained in the condensation of 5-bromofurfural with bromonitromethane are 76.8% and the reported melting temperature is 88-89°C and by means of bromination of the 2-(2-nitrovinyl)furan the result is 64% and the melting temperature is 94-95°C, in spite of always obtaining a mixture of the two components. On reproducing this technique in a laboratory, using the latter method in the same scale described by the author, apart from obtaining very low yield, there always appeared to be a considerable concentration of impurity described by us, i.e. of 2-bromo-5-(2-nitro-vinyl)-furan. Using the procedure described by ourselves, the purity obtained is always guaranteed, to be above 98% and the limits of impurity previously described are maintained below 2%, which means, on applying good production practices, a reliable active principle may be supplied for the creation of finished medicative forms in human and veterinary medicine. The component obtained using the procedure described in this invention shows a mass spectrum with peaks in m/e=297, corresponding to the molecular ion and also shows peaks M+2 and M+4 characteristic for the presence of two atoms of bromine in the structure. This peak (M + =297) corresponds to the global formula C 6 H 3 NO 3 Br 2 , which also fulfills the nitrogen rule. In the IR spectrum of this compound, registered in solid state (KBr disc, the bands of the nitro group appear at 1507 cm -1 and 1306 cm -1 and correspond to the antisymmetrical and symmetrical stretching vibration of the mentioned group. Another band of interest is that which appears at 1618 cm -1 , corresponding to the stretching vibrations of Carbon-Carbon double bonds. The presence of a high electronic conjugation in the molecule is proven by the UV spectrum where a band of great intensity appears (lgE=4.09) at 371 nm when the spectrum is registered using a methanolic solution. The assignation of this band corresponds to a transition π→π* was undertaken with the register of the UV spectrum in solvents of different polarities where a notable hypsochromic shift occurred when the dielectric constant of the medium was reduced. The 1 H-NMR spectrum was registered using CDCl 3 as a solvent and only three signals with chemical shifts of 6.63, 7.39 and 8.50 ppm were observed, each one with the same relative intensity, which corresponds to a single proton, when the overall formula is taken into consideration. The assignations of these signals are carried out using the tables of additive increments for chemical shifts. The values calculated were of 6.59 for a proton linked to carbon 3 of the furan ring. The chemical shift which appears at 8.50 ppm is characteristic for a high shielded olefin proton. From the calculation of the chemical shift for a proton linked to a double bond with a nitro and a bromine in β-position, it could be determined that this proton stays in trans position with respect to the bromine and in cis position with respect to the nitro, corresponding to a Z-configuration for the substituting groups (chemical shift for Z is 8.48 and for E is 7.70 ppm). All the carbon atoms in the molecules from the 13 C-NMR spectrum were expected to be of sp2 type, as was expected from the previous data. The crystallographic study was carried out for this compound determining that the same had an ortorhomboidal structure and the spacial configuration was checked for the previously established atoms. From this complete structural analysis it was concluded that the compound in question is the (Z)-2-bromo-5-(2-bromo-2-nitro-vinyl)-furan. The antimicrobial sensitivity was first evaluated "in vitro" using the serial dilution method for bacteria and fungi. Other growth methods in agar cultures were included for other species. The liquid and solid mediums used were Mueller-Hinton, Tryptona Soya, Sabouraud Dextrosa, Sabouraud Maltose and other mediums in accordance with the cultural demands of the micro-organisms valued. The temperature and incubation period was adjusted to conditions and characteristics of the micro-organisms used. The Minimal Inhibitory Concentration (MIC) was calculated in terms of MIC 50 and MIC 90 in µg/ml. EXAMPLES OF OBTENTION PROCEDURE Example 1 In the following table some examples of synthesis are presented according to the procedure proposed, using the same scale reported by Z.N. Nazarova. Molar relation Time (h) Temperatures (°C) Yield (%) Purity (%) 1:2 4 50 80.4 98.0 1:2:5 3 45 85.0 98.8 1:2:5 4 40 93.0 99.5 1:2:5 5 50 86.2 98.2 Some results using a scale 366 times higher than the published in the literature were reported. Example 2 No. Synthesis Raw Yield (%) %Purity Pure Product %Impurity 1 63.05 98.34 1.66 2 66.11 98.99 1.01 3 71.01 98.65 1.35 4 66.72 98.81 1.19 5 71.93 99.54 0.46 Note: The quantitative purity was obtained with gas chromatography. Example 3 IN VITRO ASSAYS CONDUCTED WITH THE CORRESPONDING VALUES OF MINIMAL INHIBITORY CONCENTRATIONS (MIC) AGAINST THE FOLLOWING MICROORGANISMS. 1. Of importance in human and animal health MIC 50 values MIC 90 values µg/ml µG/ml Bacteria 1.1 Gram Negative 1.1.1. Family: Pseudomonadaceae Pseudomonas aerguinosa 07.84 14.97 Pseudomonas maltophila 29.73 45.06 1.1.2. Family: Enterobacteriaceae Escherichia coli 07.53 15.97 Enterobacter spp. 05.30 17.16 Klebsiella spp. (including K. pneumoniae) 10.99 21.34 Proteus mirabilis 9.36 24.15 Proteus vulgaris 05.95 19.75 Proteus morganii 03.13 10.15 Proteus rettgeri 02.78 09.92 Enterobacter aglomerans ("in vivo" tests) Salmonella typhimurium 07.43 17.68 Salmonella enteritidis 06.86 11.50 Salmonella oxford 04.42 05.83 Salmonella dublin 04.38 05.73 Salmonella choleraesuis 05.57 10.51 Salmonella thyphi 02.50 10.00 Serratia marcescens 05.03 10.95 1.1.3. Family: Brucellaceae Pasteurella haemolytica 03.72 05.63 Pasteurella multocida 03.59 09.47 Haemophilus influenzae 03.51 39.23 Moracella bovis 02.63 05.08 1.1.4. Family: Neisseriaceae Neisseria meningitidis 01.84 03.47 1.2. Gram Positive 1.2.1. Family: Micrococaceae Staphylococcus aureus 05.91 12.94 Staphylococcus albus 10.25 19.84 Sarcina lutea 01.56 04.43 1.2.2. Family: Lactobacillaceae Streptococcus agalactiae 01.99 04.55 Streptococcus pyogenes 01.86 04.42 1.2.3. Family: Corynebacteriaceae Corynebacterium pyogenes 03.56 05.59 Listeria monocytogenes 03.13 05.44 1.2.4. Family: Bacillaceae Bacillus subtilis 02.27 05.08 Bacillus alvei 02.21 05.08 1.3. Superiors 1.3.1. Family: Treponemataceae Leptospira canicola 09.36 15.39 Leptospira pomona 08.84 11.66 1.3.2. Family: Spirillaceae Vibrio cholerae ser. Inabu 05.87 17.68 1.4. Escotobacterias 1.4.1. Family: Mycoplasmataceae Mycoplasma bovigenitalium 50.00 Fungi 1.5. Monomorphic budding fungi 1.5.1. Family: Cryptococcaceae Candida albicans 03.11 07.95 Candida parasilosis 03.56 06.93 Candida tropicalis 02.78 05.29 Candida pseudotropicalis 01.92 03.56 Candida zeyfanoide 01.92 03.56 Candida glabrata ("in vivo" tests) Candida stellatoidea 01.92 03.56 Candida guilliermondi 01.92 02.84 Candida krusei 01.92 02.84 Candida sp. ("in vivo" tests) Malassezia furfur ("in vivo" tests) 1.6. Monomorphic Filamentous Fungi 1.6.1. Family: Moniliaceae Aspergillus sp. 16.21 48.30 Trichophyton rubrum 13.80 24.03 Trichophyton mentagrophytes 17.68 40.61 Microsporum canis 07.91 40.61 Microsporum gypseum 12.50 20.78 Epidermophyton floccasum 12.50 1.6.2. Family: Tuberculariaceae Fusarium sp. 50.00 Reproduction and experimental treatment studies have been carried out for bacterial and fungus infections in various laboratory animal species such as: rats, mice, guinea-pigs, hamster, rabbits and dogs, using different formulations of the active principle which is the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan. In toxicological studies in animals of experimentation, necessary to guarantee effectiveness studies about which reference is made in this descriptive record, it was proven that the Lethal Average Dose (LD 50 ) taken orally of 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan using a tragacant gum as the vehicle was of 1731.4 and 1835.8 mg/kg of body mass for mice OF1 females and male, respectively and of 1515.5 and 1857 mg/kg of body mass for female and male Sprague Dawley rats respectively. By percutaneous route, applying the product in the interscapular region (approximately in an area of 10% of the animal) the quantities of 0.2 ml/10 g of body mass for mice OF1, the LD 50 was 9.8% and 12.1% in females and males, respectively, and 14.7 and 15.8% for female and male Sprague Dawley rats, respectively, applying the product in the interscapular region of 0.2 ml/10 g of body mass. Moreover, the anatomopathological elements and the clinical events were characterized during the experiments. In ophthalmic irritability studies it was proven that for concentrations lower than 1.25% no irritating effects were made on the eye structure. Chronic studies of 2-bromo-5-(2-bromo-nitro-vinyl)-furan were made on Sprague Dawley rats. The haematological, haemochemical and histopathological studies revealed that the target product applied externally for a period of six months did not lead to any major problems in the different organs and tissues analysed. Example 4 The "in vivo" effectiveness of four ointments of 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan was evaluated at 1, 0.5, 0.25 and 0.125% in hydrophislous ointment applying it on 2 cm 2 of burns provoked to guinea-pigs and subsequently infected with Pseudomonas aeruginosa by a burn wound in an area of 2 cm 2 , using positive and negative control groups. It was found that the effective dose 50 (ED 50 )was achieved with the concentration of 0.125% (Table N°1). Example 5 The effectiveness of two oil formulations was checked of 0.05% for the experimental treatment of eye infections by Pseudomonas aeruginosa in New Zealand Rabbits through the erosion and instillation method. The effectiveness of treatments was tested clinically and microbiologically, observing significant differences with the control group (not treated) (Table No. 2 and 2.1.). Post inoculation clinical and microbiological evaluation Group Secretions Hyperemia Edam Ulcer Bacteriolo-gical Exam I 6/6 6/6 6/6 6/6 6 (+) II 6/6 6/6 6/6 6/6 6 (+) III 6/6 6/6 6/6 6/6 6 (+) IV 6/6 6/6 6/6 6/6 6 (+) Legend: I. Treated with ointment of 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan at 0.05% for 8 days II. Treated with ointment of 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan at 0.05% for 4 days III. Treated with eye drops of 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan at 0.05% for 4 days IV. Control (inoculated without treating) The effectiveness of three oil formulations were also tested, at 0.15, 0.2, 0.25% and a control with placebo in mice experimentally infected using implanted sponge method, inoculated with Pseudomonas aeruginosa and Staphylococcus aureus. Recuperation of the animal was between 3 and 4 days of treatment (Tables No. 3 and 3.1). Proportions with letters which are not common differ statistically for (p< 0.05). Read: n = Accumulated from recuperated animals Tr = Recuperation time in days (weighted average) ((n1±1)+((n2-n1)±2)+((n3-n2)±3((n4-n3)±4)/n I, II, III: treated with 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan. Effectiveness of treatment in mice inoculated with Pseudomonas aeruginosa. Group Formula (%) n Average Weight Sex Accumulated clinical recuperation (days) I Tr (days) 3 5 7 n % n % n % I 0.15 10 22.6 H 8 80.0a 10 100.0a 10 100.0 3.43.4 II 0.2 10 22.9 H 8 80.0a 10 100.0a 10 100.0 4.24.6 III 0.25 10 22.8 H 5 50.0a 9 90.0a 10 100.0 IV 0 Control 10 23.6 H 4 40.0a 8 80.0bc 10 100.0 Proportions with letters which are not common differ statistically for (p< 0.05). Read: n = Accumulated from recuperated animals Tr = Recuperation time in days (weighted average) ((n1±1) + ((n2-n1) ±2)+((n3-n2)±3((n4-n3)±4)/n I,II, III: treated with 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan. Example 6 The effectiveness of the active principle against bacterial eye diseases in: 9435 animal eyes affected with queratoconjunctivitis; 8093 of cattle and 1342 of other species (sheep, rabbits, dogs, horses, pigs, cats, guinea-pigs and birds). The results showed a rising clinical recuperation to 89,6%, oscillating between 74 and 91% (Table No 4). In some cases the result of the medicament was compared with others habitually used for these treatments. Summary of results of clinical tests of G-1 ointments in the external treatment of eye infections in animals. Species Sufferings Applied formulations G-1 ointment Queraforte spary Chloran-fenicol-(U) Chloran-fenicol-(I) n P± Re(%) n P± Re (%) n P± Re (%) n P± Re (%) Cows (PE) 1 36 2.9a 100.0a 36 3.2ab 97.2ab - - - 36 3.1ab 80.6ba Dogs 2,3,4, 91 2.9a 93.4a 20 5.4c 25.0c 28 7.3b 81.5a - - - Rabbits 2 and 5 42 3.0a 88.1a 29 3.5a 80.6a 22 3.2a - - - - Sheep 3 12 3.4a 75.0a 11 3.7a 72.7a - - - - - - Horses 2 and 4 46 3.7a 95.7a 22 4.2b 90.9a - - - - - - Pigs 2 and 4 16 3.6a 75.0a 13 3.8a 76.9a - - - - - - Cats 2 10 3.2a 90.0a 8 3.4a 87.5a - - - - - - Cattle (E) 1 1830 3.1a 85.0a 285 3.1a 82.1a 164 3.4a 86.6a - - - Guinea-pig 6 27 4.3 74.1b - - - - - - - - - Birds >> 21 2.8 85.7a - - - - - - - - - (*) >> 6124 89.60 - - - - - - - - - Proportions with letters not in common differ statistically for (p< 0.01) Read: 1 = Bovine infectious queratoconjunctivitis (PE) = small scale or clinical test in conditions controlled on a small scale (U) = ointment (I) = injectable n = number of eyes treated P± = Average of treatment for clinical recuperation (weighted average) Rc = clinical recuperation 2 = conjunctivitis 3 = Querratitis 4= Queratoconjunctivitis 5= Blefaritis 6= general eye infection 7= clinical extension or test compared in conditions of extension (*) = Massive application in therapeutic survey in the new different animal species (G-1) = refers to 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan Example 7 The active principle was administered in a dose of 5-10 mg/kg of body mass by intramuscular route in bulls affected with piocianosis Pseudomonas aeruginosa. The animals clinically recuperated without any allergic reactions to the medicament being detected. Bactericide levels in serum were tested from 1 to 24 hours post-treatment and the bacteriological tests carried out in the semen at 3,7,14,21 and 28 days were negative at germ, no alterations being detected in seminal parameters established as quality control in the establishments of artificial insemination of the country. In clinical tests no allergic reactions were detected in animals (Table No.5). Subsequent studies carried out with frozen semen of treated bulls demonstrated the absence of cytotoxicity and variations in morphological characteristic of spermatozoid. Effectiveness of treatment with 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan on Artificial Insemination Stud Bulls affected by Pseudomonas aeruginosa. No. Ill animals No. Treatments per animal Recuperated percentage of effectiveness 25 5 21 84% Legend: G-1 = refers to 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan Example 8 The active principle in a concentration of 0.1 % is applied by intracisternal route daily for three consecutive days in femal oxes clinically affected by mastitis of morbid catarrh purulen course types, in which the isolated micro-organisms were Streptococcus agalactiae and Staphylococcus aureus. As a control medicament the mammary infusion of neomicine was used. Clinical recuperation of the affected parts was 98.25% for the infusion of G-I and 100% for the control medicament (Table No. 6). Clinical recuperation of the affected parts of clinical mastitis Treatment Recuperated Total n % G-I 56 98.25 57 Neomicine 12 100 12 Totals 68 98.55 69 Legend: G-1 = refers to 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan Example 9 The active principle was used in an oil solution at 1.5% for the treatment of septic puerperal metritis in female oxes. The treatment consisted in applying 40 ml for three consecutive days at intervals of 24 hours from the diagnosis of the disease process. Treatment was compared with intrasoric tetracyclin. 27 females were treated with a total of 20 (74.1%) with total recuperation with an average clinical treatment-recuperation interval (T-R) of 17.7 days. With the tetracycline, of the 19 animals treated, 13 recuperated (68.4%) and the T-R was 39 days. Indices of insemination were 1.09 ± 0.30 for the new formula and of 1.78 ± 1.99 days for the tetracycline with significant statistical differences (p<0.01) (Table No. 7). Clinical recuperation of septic puerperal metritis using G-1. Antibiotic Application route Total females treated Recuperated n % T-R IIA G-1 at 1.5% oil solution Intrauterine route 27 20 74.1 17.7 1.091±0.30a Tetracycline Abdominal aorta route 19 13 68.4 39 1.78± 1.99b Proportions with letters no in common differed statistically for (p<0.01). Legend: T-R = Average of treatment interval of clinical recuperation HA = Artificial insemination index G-1 = Refers to 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan. Example 10 A cream was developed which was subjected to clinical tests in Phase III in 386 patients in four hospitals. In the first piodermitis effectiveness was of 89.2% comparable with that of Gentamicin. In the candidiasis in skin effectiveness was 79.3% in versicolour pityriasis of 88.0% in dermatomycosis of 76.9% in onicomicosis by Candida of 32.6% and in onicomicosis by dermatophitos 42.9%, its effectiveness being comparable to that of Ketoconazol. The studies on the active principle and pharmaceutical forms indicate that they combine a strong antibacterial and antifungal action of wide spectrum, with a toxicity similar to that presented by many medicaments which may currently be found on the market (Tables No.8 and 8.1). Effectiveness of treatment Pathologies G-1 cream Control a b % Patients a Cured b % Primary Piodermitis 37 33 89.2 37 36 97.3 Versicolour pityriasis 25 22 88.0 30 26 86.7 Skin candidiasis 29 23 79.3 28 24 85.7 Dermatomycosis 39 30 76.9 31 29 93.5 Onicomicosis by Candida 46 15 32.6 30 14 46.7 Onicomocosis by dermatofitos 28 12 42.9 26 8 30.8 Cured and improved Patients Primary Piodermitis 37 34 91.9 37 37 100.0 Versicolour pityriasis 25 24 96.9 30 28 93.3 Skin candidiasis 29 25 86.2 28 24 85.7 Dermatomycosis 39 34 87.2 31 29 93.5 Onicomicosis by Candida 46 33 71.7 30 20 66.7 Onicomocosis by dermatofitos 28 20 71.4 26 12 46.2 Legend: a = Total of cases included b = Patients recuperated G-1 = Refers to the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan Stay in days of cured patients (average) Pathologies Cream G-1 Control Primary Piodermitis 52.2 43.1 Versicolour pityriasis 50.9 57.6 Skin candidiasis 120.4 120.9 Dermatomycosis 126.1 124.6 Onicomicosis by Candida 167.7 291.4 Onicomicosis by 253.2 305.7 dermatofitos Read: G-1 = Refers to the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan

Claims: 2-Bromo-5-(2-bromo-2-nitro-vinyl)-furan for use as medicament in human and veterinary medicine. 2-Bromo-5-(2-bromo-2-nitro-vinyl)-furan as claimed in claim 1, wherein the purity of this compound is at least 98 %. Use of 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan for the manufacture of a medicament for the treatment of microbian infections caused by gram negative, gram positive bacteria, superior bacteria and scotobacteria. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by gram negative bacteria from genera of the family Pseudomonadaceae such as Pseudomonas. Use of the 2-bromo-5-(2-bromo-2-vitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by gram negative bacteria from genera of the family Enterobacteriaceae such as Escherichia, Proteus, Salmonella, Klebsiella, Serratia and Enterobacter. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by bacteria from aerobic and microaerophile genera of the familiy Brucellaceae such as Pasteurella, Haemophilus and Moraxella. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by bacteria from genera of the family Neisseriaceae such as the genus Neisseria. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by bacteria from genera of the family Micrococcaceae such as Staphylococcus and Sarcina. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by bacteria from genera of the family Lactobacillaceae such as the genus Streptococcus. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by genera of asporogenous gram positive bacilli of the family Corynebacteriaceae such as Corynebacterium and Listeria. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by genera of endosporogenous gram positive bacilli of the family Bacillaceae such as the genus Bacillus. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by genera of the higher bacteria from the family Treponemataceae such as Leptospira. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by genera of the higher bacteria from the family Spirillaceae such as Vibrio. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 3, for the manufacture of a medicament for the treatment of infections caused by Scotobacteria from the family Mycoplasmataceae. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 1, for the manufacture of a medicament for the treatment of infections caused both by budding monomorphic fungi and filamentous monomorphic fungi. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 15, for the manufacture of a medicament for the treatment of infections caused by budding monomorphic fungi from the family Cryptococcaceae such as Candida and Malassezia. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 15, for the manufacture of a medicament for the treatment of infections caused by filamentous monomorphic fungi including dermatophytes. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 15, for the manufacture of a medicament for the treatment of infections caused by filamentous monomorphic genera from the family Moniliaceae such as Aspergillus, Trichophytum, Microsporum and Epidermophytum. Use of the 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 15, for the manufacture of a medicament for the treatment of infections caused by filamentous monomorphic genera from the family Tuberculariaceae such as Fusarium sp. A pharmaceutical composition containing the active substance 2-bromo-5-(2-bromo-2-nitro-vinyl)-furan, according to claim 1, in an appropriate dosage form. The pharmaceutical composition of claim 20, wherein the composition contains a carrier, excipient, diluent or adjuvant.

Inventors: CARTA FUENTES ANA DEL CARMEN, CASTANEDO CANCIO NILO RAMON, CUESTA MAZORRA MARIO, DELGADO LASVAL MARIA SOLEDAD, ESTRADA ROGER ERNESTO, GOIZUETA DOMINGUEZ RAMON DONAT, GONZALEZ FEITOT JOSEFA, GONZALEZ GARCIA ORAIDA, LUGO FARINAS ESTELA, MARTINEZ DEL PINO ANTONIO RAFA, PEREZ DONATO JORGE ANTONIO, SILVEIRA PRADO ENRIQUE ANTONIO, ZARRALUQUI OFELIA NAVIA, CARTA FUENTES, ANA DEL CARMEN, CASTANEDO CANCIO, NILO RAMON, CUESTA MAZORRA, MARIO, DELGADO LASVAL, MARIA SOLEDAD, ESTRADA ROGER, ERNESTO, GOIZUETA DOMINGUEZ, RAMON DONATO, GONZALEZ FEITOT, JOSEFA, GONZALEZ GARCIA, ORAIDA, LUGO FARINAS, ESTELA, MARTINEZ DEL PINO, ANTONIO RAFAEL, PEREZ DONATO, JORGE ANTONIO, SILVEIRA PRADO, ENRIQUE ANTONIO, ZARRALUQUI, OFELIA NAVIA, ESTRADA ROGER, ERNESTO, CALLE 14 ESCALERA 315 APTO, Gonzàlez Feitot, Josefa, Gonzàlez Garcia, Oraida, Pèrez Donato, Jorge Antonio
Applicants: CT DE BIOACTIVOS QUIMICOS DE L, CENTRO DE BIOACTIVOS QUIMICOS DE LA UNIVERSIDAD CENTRAL DE LAS VILLAS
Application year: 1995
Main classification: C07D307
IPC codes: A61P17, A61K31, A61P31, C07D307, A01N43, C07C201, C07C205