NO118066B - - Google Patents

Description

Process for the production of new microbiologically active 4-substituted 2-(5-nitro-2-furyl)-quinazolines.

where R denotes hydrogen, lower alkyl, hydroxy (lower) alkyl, lower alkoxyalkyl or amino, and R-^ denotes hydroxy (lower)

alkyl, lower alkoxyalkyl or morpholinopropyl.

The method according to the invention is characterized by a compound with the formula

is reacted with a compound with the formula

where R and R-^ each have the meaning indicated above.

When carrying out the reaction, it is convenient to combine the reacting substances in the presence of a solvent such as dimethylformamide and to add heat to the reaction mixture to speed up the reaction. When the reaction is finished, an inert solvent is conveniently added, in which the desired end product has a low solubility, e.g. water or light petrol to the solution to provide a separation of solid matter which is recovered by filtration, and when necessary purified to obtain the desired end product.

The above-mentioned compounds are particularly distinguished for their ability to inhibit the growth of microorganisms.

Representative of the very powerful antibacterial effect of the present compounds is the effect provided by the compound 4-/"bis-(2-hydroxyethyl)-amino7-2-(5-nitro-2-furyl)-quinazoline with a broad spectrum against gram-positive and gram-negative organisms by the common dilution series technique In the following table, 4-/~bis-(2-hydroxyethyl)-amino7-2-(5-nitro-2-furyl)-quinazoline (compound A) is compared with the known compound 6-chloro-2-(5-nitro-2-furyl)-cinchoninic acid (compound B) with regard to its inhibitory effect on microorganisms.

These compounds are thus suitable for mixing with suitable carriers in the form of powders, suspensions, ointments, spray preparations or the like in order to prevent and eradicate bacterial infections.

The new compounds can also be used to neutralize body infections in animals caused by Staphylococcus aureus. Through peroral administration in a dose of 50-200 mg/kg to mice, which are fatally infected with this bacterium, the animals are prevented from dying.

For the preparation of the above-mentioned compounds, the following compound can be used, namely 4-chloro-2-(5-nitro-2-furyl)-quinazoline, with the formula:

This can take place by reacting 5-nit.ro-2-furoyl-chloria with o-aminobenzamide, e.g. in the following way:

Example A.

a. 2-(S-nitro-2-furyl)-4-(3H)-quinazolinone.

o-Aminobenzamide (6.6 g or 0.05 mol) is dissolved in rj0 crn^ dimethylformamide and any insoluble material is filtered off. 510 g (0.05 mol) of calcium carbonate is added to the solution. Without stirring, 8.75 g (0.05 ml) of 5-nitrofuroyl chloride in 20 cm 3 of aimethylformamide are added. The mixture is heated on a hot plate for 1 hour. The insoluble material consisting of calcium chloride and unreacted calcium carbonate is filtered off. On cooling, the filtrate gives 3>9g of product (yield 30%)« This can be recrystallized from tiO crn-^ aimethylformamide.

Analysis calculated for 012HyW^O^: C 56.03, H 2.74, N 16.34.

Found: C 55.9<0>, H 3.00, N 16.31.

b. 4-chloro-2-(5-nitro-2-furyl)-quinazoline.

A 5 liter three-necked flask equipped with a stirrer, thermometer and condenser is charged with 159 S (0.766 mol) of phosphorus pentachloride and 790 ml of phosphorus oxychloride. The stirred mixture is mixed with 198 g (0.77 mol) of compound mentioned under point a in small portions at room temperature. The mixture is refluxed for 1 hour. It cooled to room temperature, diluted with about 3 1 light petrol, cooled well and filtered. The product (208 g) is purified by extraction according to Soxhlet with toluene. The toluene solution is cooled and filtered. The product is obtained in the form of long, yellow needles, which melt at 196.5~198.5°C in a yield of 106 g.

Analysis calculated for C^^CIN^: C 52.28, H 2.19, Cl 12.86, Found: G 52.38, H 2.14, Cl 12.79.

The invention will be explained in more detail with the help of some examples.

Example 1.

4-/~2-Hydroxyethyl(2-hydroxy-propylJamino/-2-(5~nitro-2-furyl)-quinazoline.

A 1 liter three-necked flask equipped with a stirrer is charged with 30 g (0.11 mol) of the compound according to Example Ab and 26.5 g (0.221 mol) of isopropanolethanolamine in 750 ml of dimethylformamide. The solution is heated on a steam bath for 1 hour. It is diluted with water until a solid begins to separate. The mixture is cooled, the product is collected by filtration and recrystallized from isopropyl alcohol (Darco). The product is separated in the form of yellow plates, which melt at 1965 - 1966°C (corr.), in a yield of 18 g (46%).

Analysis calculated for C-^H^N^O^: C 56.98, H 5.06, N 15.64. Found: C 57.14, N 5.25, N 15.65. Example 2.

4-bis(2-hydroxypropyl)amino-2-(5-nitro-2-furyl)-quinazoline.

A 1 liter three-necked flask equipped with a stirrer is charged with 40 g (0.145 mol) of the compound prepared according to Example Ab, and 40 g (0.3 mol) of 1,1-iminodi-2-propanol in 500 ml of dimethylformamide. The solution is heated on a steam bath for 2 hours. It is diluted with water until a solid begins to separate out. The mixture is cooled, the crude product is collected by filtration and recrystallization from isopropyl alcohol. The product separates in the form of yellow needles which melt at 179 - 170°C (corr.) in a yield of 39 g (73%).

Analysis calculated for C^gHggN^O^: C 58.06, H 5.41, N 15.05.

Found: C 57.94, H 5.55, N 14.81. Example 3»

4-butyl(2-hydroxyethyl)-amino-2-(5-nitro-2-furyl)-quinazoline.

A 1 liter three-necked flask equipped with a stirrer is charged with 40 g (0.145 mol) of the compound prepared according to Example Ab, and 36 g (0.3 mol) of N-butylethanolamine in 500 ml of dimethylformamide. The solution is heated on a steam bath with stirring for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled, the yellow solid is collected by filtration and recrystallized from isopropyl alcohol. The product is recovered in the form of yellow needles which melt at 120 - 121°C (corr.) in a yield of 39 g (75°/°).

Analysis calculated for C^H^N 0 : G 60.66, H 5.66, N 15.72.

Found: C 60.76, N 5.76, N 15.76. Example 4.

4- bis-(2- hydroxyethyl)- amino- 2-( 5- nitro- 2- furyl)- quinazoline.

A 500 ml three-necked flask fitted with a stirrer is added

30.2 g (0.11 mol) of the compound according to example Ab and 20.3 g (0.25 mol) diethanolamine in 300 ml dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled,

and the crude product is collected by filtration and recrystallization from ethanol. The product is separated in the form of yellow plates, which melt at 162.5 - 164.5°C (corr.), in a yield of 22 g (569b).

Further recrystallization from ethanol gives a yellow solid, melting at 167 - 168°C (corr.).

Analysis calculated for C-^H^N^O^: C 55.8l, H 4.68, N 16.27-

Found: C 55.90, H 4.75, N 16.36. Example 5»

4-(2-Hydroxyethyl)-methylamino7-2-(5-nitro-2-furyl)-quinazoline.

A mixture of 50 g (0.182 mol) of the compound according to example Ab and 34 g (0.45 mol) N-methylethanolamine in 1 liter of benzene is refluxed for 1 hour. A solid, brown substance is obtained by cooling the mixture. The substance is suspended in cold water and made basic with an aqueous sodium hydroxide solution. The crude brown solid is collected by filtration and recrystallized from dilute aqueous dimethylformamide to a product in the form of brown plates melting at 151-152°C (corr.), in a yield of 40 g (70%).

Analysis calculated for C^H^N^: C 57.32, H 4.49, N 17.03.

Found. C 57.25, H 4.56, N 18.01.

Example 6.

4-(2-Methoxyethyl)-amino-2-(5-nitro-2-furyl)-quinazoline.

A 2 liter three-necked flask equipped with a stirrer, cooler and stopper is charged with 40 g (0.145 mol) of the compound according to example Ab and 22.56 (0.3 mol) of 2-methoxyethylamine in 1 liter of benzene. The mixture is refluxed for 1 hour. The cooled mixture is diluted with light petrol. The crude product is collected by filtration and recrystallized from methyl alcohol. The product is separated in the form of yellow needles which melt at 155-157°C in a yield of 26 g (57%).

Further recrystallizations from methyl alcohol increase the melting point to 160 - 162°C (corr.).

Analysis calculated for C-^H-^N^O^: G 57.32, H 4.49, N 17.83.

Found: G 57.30, H 4.bl, N 17.74.

Example 7.

4-(3-Methoxypropylamino)-2-(5-nitro-2-furyl)-quinazoline.

A 1 liter three-necked flask fitted with a stirrer is added

35 g (0.127 mol) of the compound according to example Ab and 23.1 g (0.26 mol) of methoxypropylamine in 500 ml of dimethylformamide. The solution is heated on a steam bath for 2 hours. It is diluted with water until a solid begins to separate. The mixture is cooled, the crude product is collected by filtration and recrystallized from isopropyl alcohol. The product separates in the form of yellow plates melting at 143-145°^

(corr.), in a yield of 33 g (82%).

Analysis calculated for: C^H^N^O^: C 58.53, N 4.91, N 17.07

Found: C 58.68, H 4.80, N 16.67. Example 8.

4-bis(2-ethoxyethyl)amino-2-(5-nitro-2-furyl)-quinazoline.

A 2 liter three-necked flask with a stirrer is added to 35 S

(0.127 mol) of the compound according to example Ab and 42 g (0.26 mol) of diethoxyethylamine in 1 liter of dimethylformamide. The solution is heated on a steam bath with stirring for 2 hours. The solution is diluted with water until the solid begins to separate. The mixture is cooled, the crude product is collected by filtration and recrystallized from isopropyl alcohol. The product separates out in the form of yellow needles which melt at 60 - 61°C (corr.) in a yield of 40 g (79%).

Analysis calculated for<C>20<H>24N4°5: ° 59.99, H 6'04"' N 13»99

Found; C 60.03, H 5.85, N 14.13.

Example Q.

4-(2-hydroxyethyl)amino-2-(5-nitro-2-furyl)-quinazoline.

A solution of the compound from example Ab (30.2 g, 0.11 mol) and 15 g (0.25 mol) of 2-ethanolamine in 800 ml of dimethylformamide is heated on a steam bath for 2 hours. The solutions are diluted with water until the solid begins to separate. The mixture is cooled and filtered, obtaining a light yellow solid. Upon recrystallization from ethanol, the product is obtained in a yield of 31 g (94%)« (Melting point 221 - 223°C).

Analysis calculated for clzj.H12N4°4: C H4.03, N 18.66.

Found: C 56.05, H 4.41, N 18.48.

Example 10.

4-/3-(4-morpholino)propyl7-amino-2-(5-nitro-2-furyl)-quinazolineT dihydrochloride.

A 2 liter three-necked flask equipped with a stirrer, cooler and

cork is added to 30.2 g (0.11 mol) of the compound from example Ab and 36 g (0.25 mol) 3_aminoP1''C)Pylmorpholine in 750 ml of benzene and refluxed for 1 1/2 hours. The mixture is cooled and diluted with light petrol. A yellow solid is collected by filtration, slurried in cold water and basified with a sodium hydroxide solution. The free base melting at 164 - 166°C is collected by filtration in a yield of 42 g (100%). Upon recrystallization from ethanol, a product is obtained in the form of yellow disks which melt at 170 - 171.5°C (corr.).

Analysis calculated for C-^Hg-^N^O^: C 59.52, H 5.52, N 18.27.

Found: C 59.69, H 5.50, N 18.28.

The free base (40 g, 0.104 mol) is dissolved in 500 ml of glacial acetic acid and anhydrous hydrogen chloride is bubbled into the solution until saturation. The mixture is cooled and diluted with anhydrous ether. A yellow, firm

substance is collected by filtration and recrystallized from ethanol to a hydrochloride in the form of a yellow solid melting at 211-213°C

in a yield of 30 g (63.5%).

Analysis calculated for C-^H^N^O^HCl: C 50.00, N 5.08, Cl 15.34, Found: C 50.07, N 5.02, Cl 15.07. Example 11.

4-(3-hydroxypropylamino)-2-(5-nitro-2-furyl)-quinazoline.

A 1 liter three-necked flask fitted with a stirrer is added

35 g (0.127 mol) of the compound from example Ab and 19.5 g (0.26 mol) of 3-aminopropanol in 500 ml of dimethylformamide. The mixture is heated on a steam bath with stirring for 1 hour. The solution is diluted with water and cooled. The brown product is collected by filtration and recrystallized from acetonitrile. The product separates in the form of yellow plates which melt at 108 - 183°C (Corr.) in a yield of 22 g (55%). Analysis calculated for C^H^N^O^: C 57.32, H 4.49»N 17.83. Found: C 57.55, N 4.50, N 17.8l. Example 12.

4-[1-(2-hydroxyethyl)-hydrazino-7-2-(S-nitro-2-furyl)-quinazoline.

A 1 liter three-headed flask equipped with a stirrer is added

40 g (0.45 mol) of the compound from example Ab and 28.5 g (22.8 g, 0.3 mol) of 80% hydroxyethylhydrazine in 500 ml of dimethylformamide. The mixture is left for 15 minutes. The temperature approaches approx. 40°C. The solution is then heated to bO°C. It is diluted with water and the mixture is cooled. The solid is collected by filtration to give 43 g (94%), 34 g of this product is recrystallized from nitromethane to give yellow needles melting at 186 - 188°C (corr. ) in a 28 g yield.

By further recrystallization of nitromethane, the melting point is increased to 190 - 191°C (corr.).

Analysis calculated for C-^H^N^O^: C 53.33, H4.16, N 22.22

Found: C 53.33, H 4.29, N 22.43-Example 13-4-(2-hydroxyethyl)isopropylamino7-2-(5-nitro-2-furyl)quinazoline.

A 1 liter three-necked flask fitted with a stirrer is added

35 g (0.127 mol) of the compound from example Ab and 25 g (0.242 mol) of M-isopropylethanolamine in 500 ml of dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with water until a solid separates and the mixture is cooled. The product is collected by filtration and recrystallized from isopropyl alcohol.

It separates in the form of yellow plates which melt at I48 - 150°C i

a yield of 21 g (48%).

With continued recrystallization from isopropyl alcohol, the melting point increases to 157 - 158°C (corr.).

Analysis calculated for C^H-j^N^O^: C 59.64, H 5.30, N 16.37. Found: C 59.70, N 5.38, N 16.50.

Claims (4)

1. Control device for automatic indication of erroneous connection establishment and separation of these from establishment as a result of blockages, as well as blocking of switching devices with errors in signaling equipment in automatic telecommunications systems, where controls of the switching devices are checked by receipt sig- nals or response signals that are given when a connection phase has begun and/or ended, characterized in that the control device is designed to, when an acknowledgment signal has not been received that control signals have been sent, automatically maintain the connection until the body where an error occurs, regardless of whether the call is terminated from the preceding body (so-called locking), and that the automatic retention ceases when an acknowledgment signal is received, and that a timer is arranged which, after a fixed or adjustable time that is greater than the average waiting time for blocked calls, marks that the body with an error has been connected during the establishment and gives an alarm to the monitoring staff or to recording bodies. 2. Device according to claim 1, characterized in that devices (R4) which, depending on an acknowledgment signal, cancel the hold, are connected to the timing device (T-10m, R7) in such a way that the devices for canceling the hold are rendered ineffective when the time device kicks in function for error indication, so that the retention is maintained if an acknowledgment signal is received after the time setting has entered the function for error indication. 3. Device according to claim 1 or 2, characterized in that the timing device affects the devices for retaining engaged voter bodies with a certain time delay, so that the retention comes into operation after a time that exceeds the normal establishment time, but is shorter than the time, after which the timing device comes into operation for fault indication. 4. Device according to one or more of the preceding claims, where the device is part of a register which can be connected to voter bodies controlled by the register by means of a register connection device (RFV) and which comprises a relay (R2) which is affected by calls from a calling line and thereby ends a holding current circuit for the register connection device, characterized in that the devices which effect retention of engaged selector devices include a device (R6) for establishing another holding current circuit for the register connection device, which holding current circuit is independent of the first-mentioned holding current circuit. German Patent No. 881,071, 881,691, 903,349, 286,814.