DE1545605A1

DE1545605A1 - Process for the preparation of new 5-nitrofuran derivatives

Info

Publication number: DE1545605A1
Application number: DE19621545605
Authority: DE
Inventors: Achelies Dr Med Johann Daniel; Haack Dr Phil Erich; Berger Dr Phil Herbert; Voemel Dr Med Wolfgang
Original assignee: Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1962-03-28
Filing date: 1962-03-28
Publication date: 1970-03-12

Description

Verfahren zur Herstellung neuer 5-Nitrofuran-Derivate 5-Nitrofuran-Derivate der allgemeinen Formel in welcher R1 und R2 Wasserstoff, Amino-, Acylamino-, Hydroxy-oder Alkoxygruppen bedeuten und X und Y eine Methingruppe oder ein Stickstoffatom vorstellen, wobei aber mindestens eines der beiden Symbole Stickstoff sein soll, sind bislang in der Literatur nicht beschrieben.Process for the preparation of new 5-nitrofuran derivatives 5-nitrofuran derivatives of the general formula in which R1 and R2 are hydrogen, amino, acylamino, hydroxy or alkoxy groups and X and Y represent a methine group or a nitrogen atom, but at least one of the two symbols should be nitrogen, have not yet been described in the literature.

Es wurde gefunden, daß diese Verbindungen hervorragende germistatische Eigenschaften aufweisen. Im Vergleich zu bekannten Nitrofuran-Derivaten ergibt sich insbesondere eine verbesserte Wirksamkeit gegenüber Staphylococcus aureus, Escherichia coli und Streptococcus aureus sowie auch gegenüber Pilzen.These compounds have been found to be excellent germistatic Have properties. In comparison to known nitrofuran derivatives results in particular an improved effectiveness against Staphylococcus aureus, Escherichia coli and Streptococcus aureus as well as against fungi.

Das erfindungsgemäße Verfahren zur Herstellung der neuen 5-Nitrofuran-Derivate ist dadurch gekennSeichnet, daß man 5-Nitrofurfurol bzw. dessen Diacetat mit Verbindungen der allgemeinen Formel in welcher X, Y, R1 und R2 die oben angegebene Bedeutung haben, kondensiert, wobei man gegebenenfalls die Substituenten R1 und R2 auch erst nach erfolgter Kondensation durch Acylierung, Alkylierung oder Verseifung einführt bzw. freisetzt.The process according to the invention for the preparation of the new 5-nitrofuran derivatives is characterized in that 5-nitrofurfurol or its diacetate is mixed with compounds of the general formula in which X, Y, R1 and R2 have the meanings given above, condensed, with the substituents R1 and R2 also being introduced or released only after the condensation has taken place by acylation, alkylation or saponification.

B e i s p i e 1 e 1.) l- (5-Nitro-2-furyl')-2- (4-pyrimidyl)-äthylen 0, 48 g 4-Methyl-pyrimidin erhitzt man mit 0, 92 g Eisessig, 1, 05 g Acetanhydrid und 0, 72 g 5-Nitro-2-fural 1 Stunde auf 130° (Badtemperatur) ; nach dem Erkalten wird mit Wasser versetzt, mit Natriumbicarbonat neutralisiert, abgesaugt und mit Wasser gewaschen. Das erhaltene Rohprodukt kocht man 3mal mit Benzol aus (zunächst mit 30 ml, dann 2mal mit je 15 ml) und dampft die klare Benzolloesung ein. Der RUckstand liefert nach Umkristallisation aus 8, 5 ml Dioxan 0, 45 g 1- (5-Nitro-2-furyl)-2- (4-pyrimidyl)-athylen vom Fp. 223-224°. Ex. 1 e 1.) 1- (5-Nitro-2-furyl ') - 2- (4-pyrimidyl) -ethylene 0.48 g of 4-methyl-pyrimidine are heated with 0.92 g of glacial acetic acid and 1.05 g of acetic anhydride and 0.72 g of 5-nitro-2-fural 1 hour at 130 ° (bath temperature); after cooling is mixed with water, neutralized with sodium bicarbonate, filtered off with suction and with Water washed. The crude product obtained is boiled 3 times with benzene (initially with 30 ml, then twice with 15 ml each) and evaporates the clear benzol solution. The residue after recrystallization from 8.5 ml of dioxane gives 0.45 g of 1- (5-nitro-2-furyl) -2- (4-pyrimidyl) ethylene with a melting point of 223-224 °.

In analoger Weise erhält man die folgenden Verbindungen : 1-(5-Nitro-2-furyl)-2-(5-acetamido-4-pyrimidyl)-äthylen vom Fp. 233-234°, 1- (5-Nitro-2-furyl)-2- (2, 6-dimethoxy-4-pyrimidyl)-äthylen vom Fp. 207-208°, 1-(5-Nitro-2-furyl)-2-(2,6-bis-acetamido-4-pyrimidyl)-äthylen vom Fp. 282-284° (Zers.). The following compounds are obtained in an analogous manner: 1- (5-Nitro-2-furyl) -2- (5-acetamido-4-pyrimidyl) -ethylene of melting point 233-234 °, 1- (5-nitro-2-furyl) -2- (2,6-dimethoxy-4-pyrimidyl) -ethylene from Mp. 207-208 °, 1- (5-nitro-2-furyl) -2- (2,6-bis-acetamido-4-pyrimidyl) -ethylene from M.p. 282-284 ° (dec.).

2.) 1- (5-Nitro-2-furyl-)-2- (4, 6-diacetamido-2-triazyl)-athylen 7, 05 g 5-Nitro-2-fural kocht man mit 10, 45 g 2-Methyl-4, 6-diacetamido-triazin und 5 ml Acetanhydrid 3 Stunden unter RUckflub (Badtemperatur 190°) ; dann wird im Vakuum eingedampft und der Rückstand mit Isopropyläther angerieben. Das Ungeloeste kocht man mit 200 ml Eisessig, trennt vom Ungeloesten ab und läßt das Filtrat kristallisieren ; dieses Kristallisat und der in Eisessig ungeloest gebliebene Rückstand werden aus Dioxan umkristallisiert. Auf diese Weise erhält man 6 g 1- (5-Nitro-2-furyl)-2- (4, 6-diacetamido-2-triazyl)-äthylen vom Fp. 260-262° ; aus der Dioxan-und der Eisessigmutterlauge koennen durch Einengen noch weitere 1, 5 g vom Fp. 260-262° erhalten werden.2.) 1- (5-Nitro-2-furyl -) - 2- (4, 6-diacetamido-2-triazyl) -ethylene 7.5 g of 5-nitro-2-fural are boiled with 10.45 g of 2-methyl-4,6-diacetamido-triazine and 5 ml of acetic anhydride for 3 hours under reflux (bath temperature 190 °); Then it will be evaporated in vacuo and the residue rubbed with isopropyl ether. The unsolved it is boiled with 200 ml of glacial acetic acid, the undissolved material is separated off and the filtrate is allowed to crystallize ; this crystallizate and the residue left undissolved in glacial acetic acid become recrystallized from dioxane. In this way, 6 g of 1- (5-nitro-2-furyl) -2- are obtained (4, 6-diacetamido-2-triazyl) ethylene with a melting point of 260-262 °; from the dioxane and glacial acetic mother liquor A further 1.5 g with a melting point of 260-262 ° can be obtained by concentration.

3.) l-(5-Nitro-2-furyl)-2-(5-acetamido-2-pyrimidyl)-äthylen<' 2, 2 g 5-Amino-2-methyl-pyrimidin erhitzt man mit 7, 5 ml Acetanhydrid 15 Min. unter RUckfluß (160° Badtemperatur), gibt dann 3 g 5-Nitro-2-furfural zu und hdlt weitere 4 Std. auf dieser Temperatur ; nun trägt man erneut 1, 3 g Nitrofurfural ein und hält 4 Std. unter RUckfluß. Man gibt dann anschließend noch 1 g Nitrofurfural zu md erhitzt abermals 4 Std. unter Rückfluß. Der erkaltete Ansatz wird abgesaugt, der Filterrückstand erschoepfend mit einer Mischung von Dioxan-Toluol (1 : 2) heiß extrahiert und der Eindampfrückstand der vereinigten Extrakte aus Dioxan umkristallisiert.3.) 1- (5-Nitro-2-furyl) -2- (5-acetamido-2-pyrimidyl) ethylene <'2, 2 g of 5-amino-2-methyl-pyrimidine are heated with 7.5 ml of acetic anhydride for 15 min Reflux (160 ° bath temperature), then 3 g of 5-nitro-2-furfural are added and more 4 hours at this temperature; now one enters again 1, 3 g of nitrofurfural and refluxes for 4 hours. Then 1 g of nitrofurfural is then added md refluxed again for 4 hours. The cooled approach is sucked off, the filter residue exhaustively with a mixture of dioxane-toluene (1: 2) hot extracted and the residue from evaporation of the combined extracts recrystallized from dioxane.

Aus der eingeengten Dioxan-Mutterlauge wird weiteres Kristallisat erhalten ; insgesamt fallen so 1, 1 g Kristalle vom Fp. 262-263° (Aufschäumen) an. Further crystals are formed from the concentrated dioxane mother liquor obtain ; a total of 1.1 g of crystals with a melting point of 262 ° -263 ° (foaming) is obtained.

C12HlON404 (274) : Ber. C 52,55%; H 3,65 %; N 20,45 % ; Gef. C 52, 18% ; H 3, 96 % ; N 20, 33 %. C12HlON404 (274): Ber. C 52.55%; H 3.65%; N 20.45%; Found C 52, 18%; H 3, 96%; N 20.33%.

9 g dieser Acetylverbindung loest man in 30 ml einer Mischung aus 15 ml Wasser und 15 ml konz. Schwefelsäure bei Raumtemperatur, erwärmt 30 Minuten auf 40°C, gibt dann 30 ml Wasser zu und hält anschließend 2 Stunden auf 40°. Nach dem Erkalten macht man in Gegenwart von EiswUrfeln mit konz. wässriger Ammoniakloesung alkalisch (pH ca. 10), saugt das dabei ausgeschiedene Material ab, wäscht mit Wasser und trocknet im Vakuum. Das so erhaltene Rohprodukt (9 g) kocht man nach Pulverisierung wiederholt mit je 100 ml einer Mischung aus Dioxan-Toluol (1 : 1) aus und saugt dabei jeweils das schwarze, ungeloest gebliebene Material ab, während die vereinigten klaren Filtrate im Vakuum eingedampft werden. Den erhaltenen Rückstand (6, 1 g) loest man in 250 ml heißem Dioxan, trennt von wenig ungeloestem Material ab, versetzt das klare Filtrat mit 160 g Aluminiumoxyd (nach Brockmann), ruhrt 45 Minuten gut durch, saugt das Aluminiumoxyd ab, wäscht mit Dioxan gut \ nach und dampft das Filtrat im Vakuum ein, wobei 3, 4 g roter RUokstand verbleiben, den man zur weiteren Reinigung nach Pulverisierung wiederholt mit Isopropanol auskocht. Der ungeloest gebliebene Anteil zersetzt sich ab 220° und stellt das 1-(5-Nitro-2-furyl)-2-(5-amino-2-pyrimidyl)-äthylen vor. 9 g of this acetyl compound are dissolved in 30 ml of a mixture 15 ml of water and 15 ml of conc. Sulfuric acid at room temperature, heated for 30 minutes to 40 ° C, then add 30 ml of water and then hold at 40 ° for 2 hours. To the cooling is done in the presence of ice cubes with conc. aqueous ammonia solution alkaline (pH approx. 10), sucks off the precipitated material and washes with water and dries in a vacuum. The crude product thus obtained (9 g) is boiled after pulverization repeatedly with 100 ml of a mixture of dioxane-toluene (1: 1) and sucks each time the black, unresolved material was removed, while the unified clear filtrates are evaporated in vacuo. The residue obtained (6.1 g) dissolved in 250 ml of hot dioxane, separated from a little undissolved material, added the clear filtrate with 160 g of aluminum oxide (according to Brockmann) stirs well for 45 minutes through, sucks off the aluminum oxide, washes well with dioxane \ after and the filtrate is evaporated in vacuo, 3.4 g of red residue remaining, the for further purification after pulverization, it is repeatedly boiled with isopropanol. The remaining undissolved portion decomposes from 220 ° and provides 1- (5-nitro-2-furyl) -2- (5-amino-2-pyrimidyl) -ethylene before.

C10H8N4O3 (232) Ber. C 51,70 % ; H 3,45 %; Gef. C 52,00 % ; H 3,97 %.C10H8N4O3 (232) Calc. C 51.70%; H 3.45%; Found C 52.00%; H 3.97 %.

Durch Behandlung des 1-(5-Nitro-2-furyl)-2-(5-amino-2-pyrimidyl)-äthylens mit Methylisocyanat in Pyridin erhält man das 1- (5-Nitro-2-furyl)-2- (5-methylcarbamoyl-amido-2-pyrimidyl)-äthylen vom Fp. 255° (Zers.).By treating 1- (5-nitro-2-furyl) -2- (5-amino-2-pyrimidyl) -ethylene methyl isocyanate in pyridine gives 1- (5-nitro-2-furyl) -2- (5-methylcarbamoyl-amido-2-pyrimidyl) -ethylene of m.p. 255 ° (decomp.).

C12H11N5O4 (289) Ber. C 49,80 %; H 3,81 %; N 24,23 %; Gef. c 49,80 %; H 3,98 %; N 23,39 %; 0, 72 g 1- (5-Nitro-2-furyl)-2- (5-acetamido-2-pyrimidyl)-athylen erhitzt man 1 1/2 Std. mit 10, 8 ml einer Mischung aus Dioxan und 5n-Salzsäure (1, : l) auf 100°C, dampft dann im Vakuum fast zur Trockne, reibt den Rückstand mit 2n-Salzsäure an, saugt das erhaltene Kristallisat t (0, 65 g) ab und kristallisiert aus einer Mischung von Wasser, Athanol und 2n Salzsäure (13 : 6 : 1) ) unter Verwendung von Aktivkohle um. Man erhält 0, 4 g 1-(5-Nitro-2-furyl)-2-(5-hydroxy-2-pyrimidyl)-äthylen vom Fp. 232-234° (Aufschäumen). Die Substanz loest sich in tuberschüssiger ln-Salzsäure, ebenso in wässriger Natronlauge, wässriger Ammoniak oder wässriger Sodaloesung (unter tiefer Orangefärbung).C12H11N5O4 (289) calc. C 49.80%; H 3.81%; N 24.23%; Found c 49.80 %; H 3.98%; N 23.39%; 0.72 g of 1- (5-nitro-2-furyl) -2- (5-acetamido-2-pyrimidyl) -ethylene it is heated for 1 1/2 hours with 10.8 ml of a mixture of dioxane and 5N hydrochloric acid (1, : l) to 100 ° C, then evaporates almost to dryness in vacuo, rubs the residue with it 2N hydrochloric acid, the crystals obtained are filtered off with suction (0.65 g) and crystallized from a mixture of water, ethanol and 2N hydrochloric acid (13: 6: 1)) using of activated charcoal. 0.4 g of 1- (5-nitro-2-furyl) -2- (5-hydroxy-2-pyrimidyl) ethylene are obtained of m.p. 232-234 ° (foaming). The substance dissolves in excess tubular hydrochloric acid, also in aqueous sodium hydroxide solution, aqueous ammonia or aqueous soda solution (under deep orange color).

C10H7N3O4 (233) : Ber. C 51,5 %; H 3,05 %; N 18,0 %; Gef. C 51,59 %; H 3,43 %; N 18,04 %.C10H7N3O4 (233): calc. C 51.5%; H 3.05%; N 18.0%; Found C 51.59 %; H 3.43%; N 18.04%.

Durch Behandlung dieser Verbindung mit Diazomethan in Äther erhält man das 1- (5-Nitro-2-furyl)-2- (5-methoxy-2-pyrimidyl)-äthylen vom Fp. 185-187°. ~ ~~ C11H9N3O4 (247) : Ber. C 53,40 %; H 3,65 $; N 17,00 %; Gef. C 53,50 %; H 3,77 %; N 17,09 %.By treating this compound with diazomethane in ether it is obtained the 1- (5-nitro-2-furyl) -2- (5-methoxy-2-pyrimidyl) -ethylene of melting point 185-187 °. ~ ~~ C11H9N3O4 (247): Calc. C 53.40%; H $ 3.65; N 17.00%; Found C 53.50%; H 3.77 %; N 17.09%.

Claims

P atent claim Process for the preparation of new 5-nitrofuran derivatives of the general formula in which R1 and R2 are hydrogen, amino, acylamino, hydroxy or alkoxy groups and X and Y represent a methine group or a nitrogen atom, but at least one of the two symbols should be nitrogen, characterized in that, 5-nitrofurfurol or Its diacetate with compounds of the general formula in which X, Y, R1 and R2 have the meanings given above, condensed, with the substituents Ri and R2 also being introduced or released only after the condensation has taken place by acylation, alkylation or saponification.

Comparative experiments HB 121 = 1- (5-nitro-2-furyl) -2- (4-pyrimidyl) -ethylene HB 254 = 1- (5-nitro-2-furyl) -2- (5-acetamido-4-pyrimidyl) ethylene <HB 267 = 1- (5-nitro-2-furyl) -2- (2,6-dimethoxy-4-pyrimidyl) -ethylene HB 272 = 1- (5-nitro-2-furyl) -2- (2, 6-bis-acetamidD-4-pyrimidyl) -ethylene HB 146 = 1- (5-nitro-2-furyl) -2- (4, 6-diacetamido-2-triazyl) -ethylene ' HB 232 = 1- (5-nitro-2-furyl) -2- (5-acetamido-2-pyrimidyl) ethylene HB 253 = 1- (5-nitro-2-furyl) -2- (5-amino-2 pyrimidyl) ethene HB 250 = 1- (5-nitro-2-furyl) -2- (5-methylcarbamoyl-amido-2-pyrimidyl) -ethylep-HB 233 1- (5-nitro-2-furyl) -2- (5-hydroxy-2-pyrimidyl) ethylene HB 249 = 1- (5-nitro-2-furyl) -2- (5-methoxy-2- pyrimidyl) ethylene A = 5-nitrofurfurol-semioarbazon ["PURACIN"] B = N- (5-nitro-2-furfurylidene) -3-amino-oxazolidone-2 ["FUROXONE"] C = N- (5-nitro-2-furfurylidene) -1-amino-hydantoin ["FURADANTIN"] D = 5-nitro-2-furfuryl methyl ether ["FURASPOR"] carrying out the Experiments: The testing of the substances was carried out in the usual serial dilution test with carried out in liquid nutrient medium. To gain a broader base of assessment and with regard to the dependence of the inhibition values on the strength of the germination 3 to 5 different culture dilutions were made for each type of germ. the Nitrofuran compounds were made with the aid of solubilizing organic solvents brought into aqueous solution. Each individual experiment was run in parallel Control dilution series show a germistatic intrinsic effect of the organic solvents locked out. These control dilution series contained the same solvent concentrations like the actual test series, but no nitrofuran compounds. In the The minimum germistatic concentration given in the tables is the lowest concentration of the tested compounds, each of which is the bacterial or. Fungal growth complete suppressed.

Table 1: Effect against Staphylococcus aureus absolutely germistatic Substance minimum concentration (µg / ml) HB 232 0.125 HB 250 0.125 HB 253 0.25 HB 254 0.5 HB 272 0.25 HB 146 0.5 A 8 B 1 C 8

Table 2: Action against Streptococcus pyogenes, Aronson absolutely germistatic Substance minimum concentration (µg / ml) HB 232 0.125 HB 250 0.062 HB 253 0.25 HB 254 1 HB 272 0.062 HB 146 2 A4 B 8 C 4

Table 3: Activity against Escherichia coli absolutely germistatic Substance minimum concentration (µg / ml) HB 232 0.031 HB 249 0.062 HB 250 0.031 HB 253 0, 062 HB 267 0, 062 A 8 B 0.25 C 8

Table 4: Action against Proteus vulgaris absolutely germistatic Substance minimum concentration (µg / ml) HB 232 8 ' HB 249 16 HB 250 8 HB 253 16 HB 121 8 HB 272 8 A 128 64 c 256 C ..

Table 5: Activity against Pseudomonas aeruginosa absolutely germistatic Substance minimum concentration (ug / ml) HB 232 0.5 HB 249 2 HB 250 0.25 HB 253 1 -HB 146 32 A 128 B 64 C 256

Table 6: Action against fungi @ Candida Microsporum Trichophyton Aspergillus Substance albicans gypseum mentagrophytes niger HB 232-32 ~ ~ HB 233 - 32 32 - HB 121 8 2 2 4 D 64128 128 128

As can be seen from the tables above, the new nitrofurans are superior to commercial products A, B and C in terms of their bacteriostatic effectiveness. The high effectiveness of the new compounds against Escherichia coli and Pseudomonas aeruginosa is particularly striking. This finding is all the more surprising since most of the known chemotherapeutic agents and antibiotics are little or no effective against these microorganisms.

As a result of this specificity of action of the new nitrofuran compounds these represent a valuable enrichment of the pharmaceutical treasure because with them a reliable control of the microorganisms caused by the mentioned, otherwise difficult. curable wound and urinary tract infections can be carried out.

The very high effectiveness of the new compounds should also be emphasized towards mushrooms; this finding is also very surprising and therapeutic significant, especially since the nitrofuran preparation against fungal infections available on the market "Furaspor" (D) is much weaker.

The toxicity of the new nitrofurans is about the same order of magnitude like that of the known compounds, e.g. Sometimes it is also considerably lower. In the table below are the data of two characteristic compounds The present application is compared with the data of the known nitrofurans.

Table 7: Acute toxicity Substance LD 50 per os (mg / kg mouse) HB 232> 2000 HB 249> 2000 A 230 B 1280 C 250 DN 430