DE2037964C3 - 5-NHrofuranderlvate - Google Patents

Description

lose weight, it is

^ ^ ^^ _thus such antimicrobially effective

The invention relates to 5-nitrofuran derivatives of the general formula

Π P

In vtrgfShsversuche some of the found compounds were tested against known nitrofuran derivatives.

ΐή of the following table 1 a.nd d, e in v.tro against a deer of microorganisms obtained ear bones kuhc _. _r _ " _{t Die m} i _nl male Hemmkon / en-

according to the known series

-3-ac

Br

(D

in which A is an alkylene radical having 1 to 3 carbon atoms. X is a hydrogen atom, a hydroxyl or o-2-furfurylidene) 3y ve ^ binding E, derived from the British patent, , 05 007 known compound no. 6: ? [Nitro - 2 furyl] - N - (2 - hydroxyaryl) - nitrone used.

Tabel

Microorganism Tested connection

Example I.

3 3 IO

τ,

Example 2

0.1

0.3

1 0.3

Example 3

0.3

0.01

0.3

10

Staphylococcus aureus

Batilus subtitis

Escherichia coli

Salmonella typhimuriuin

Mycobacterium tuberculosis

Candida albicans

Trichophyton asteroides

Trichomonas vaginalis

The values given in the table mean: MIC = mcg / ml.

In further experiments, the effect on the infection with Salmonella lyphimurium in mice

Tested in vivo.

Ten mice from each group were infected intraperitoneally with 0.5 ml of a bacterial _{suspension containing 1000 LD 50} of Salmonella typhimurium. 6.25, 12.5, 25 and 50 mg / kg of the test compound were given Oral 2ma! administered for 4 days a day, the first treatment being immediately after infection. After observation over the course of 2 weeks, the effectiveness was determined by the survival value (surviving / test animals). The results obtained are shown in Table 11.

Example 4 kispicl 5 I. 0.03 0.1 0.3 1 0.3 1 10 10 1 10 10 I. 1

Example 6

0.3

I 10

30th

Connection Λ! Known)

HX)

30th

30th

30 KKl 100

30th

bond l ^; I known I

Dnsis

50 mg / kg ...

25 mg / kg ..

12.5 mg / kg.

6.25 mg / kg

example 1

10/10
9/10
3/10

Example 2

ED ₅₀ I 6.25

In the table:

6/10 3/10

= 9.5

2 037 964 link 5 Example 6 B.
(known) 3 4th D.
(bckannl) E. IO Table II 10. 10 7/10 5/10 2/10 10 / 10 ispie 1/10 C.
Ibekunnl) 2/10 4 / 9/10 5/10 4/10 2/10 1/10 1/10

Untreated control 0/10

17.7

<25

= 50

> 50

> 50

12.5

B = S-Nhro-I-furaldehydsemicarbaion,

C = S-nilro-i-furfurylidene aminoguanidine.

D - Anii-5-nitio-2-furaldoxime.

E = 'H> Nitriv2-furyl) -N- (2-hydrox) glyphyl> -nitrone.

The ED ₅₀ values were determined as the effective dose 50 according to the Behrens-Kiirber method. (Compare G. Kiirber. "Contribution to the collective treatment of pharmacological series experiments" Arch. Exp. Path. Pharm. 162, p. 480 [1931]).

Furthermore, the effect on, nit Trichomonas vaginalis infected mice tested in vivo.

Five to six mice in each group were injected intraperitoneally with 0.1 ml of a Protozoensuspension (Trichomonas vagina!.,) Containing 10 ⁷ cells infected orally and 125 and 250 mg / kg of the compound to be tested at one time one hour n ^ ch Infection administered. On the 7th day after infection, the mice were sacrificed and the presence of viable protozoa in the intraperitoneal cavity formed abscesses were examined by culturing. The results are shown in Table III.

Table III

link

dose

at at B. c: game 1 game 2 bckannl known 4/6 5/6 0/5 0/5 0/6 2/5 1/6

I) bckannl

1/5

250 mg / kg
125 mg / kg

62.5 mg / kg

The ratios in the table mean the number of mice without visible protozoa / examined Mice. The known compounds B. C and D correspond to those in Table II.

From the tests it can be seen that the tested compounds according to the invention particularly strong in vitro activities against gram-positive bacteria, such as Staphylococcus aureus and Mycobacterium tuberculosis, gram negative bacteria such as Eschcrichia coli, fungi such as Candida albicans and Trichophyton asteroides and protozoa such as Trichomonas vaginalis own.

The 5-nitrofuran derivatives of the general formula I given above are known per se Way prepared by a 5-nitrofuran compound of the formula

O ₁ N

CH = C-CHO

Br

with an N-substituted hydroxylamine of the general formula below

HO-N-AfX) _n (ΠΙ)

in which A (X) _{n have} the meaning given above. implements.

The reaction can be carried out at room temperature or by heating the reaction mixture to an increased level Temperature in the range of about 20 to about 100 ° C can be carried out. One can be in the presence of a Solvent work, preferably water. Methanol, ethanol, dioxane, tetrahydrofuran. Dimethyl sulfoxide and dimethylformamide. The condensation reaction can be accelerated by adding a catalytic amount of acetic acid be achieved.

The hydroxylamine to be used can be applied in free form or as a salt. The salt however, should be used with a sufficient amount of a base so that the Hydroxylamine is released from the salt. Inorganic bases are preferably used for this, such as sodium hydroxide, potassium carbonate and sodium bicarbonate, or organic bases such as sodium acetate, pyridine, triethylamine.

A compound of the general formula I. in which X is a hydroxyl group, can with Acetic acid or a reactive derivative thereof be converted into the acetyloxy compound in question.

This can also be carried out in the presence of a solvent.

The 5-nitrofuran derivatives according to the invention can be used for medicaments both in human medicine as well as for veterinary purposes, as well as for food and agriculture.

The 5-nitrofuran derivatives according to the invention are particularly effective in the treatment of bacterial

rial, fungi / iden or protozoal diseases. For treatment of both humans and animals, they can be used either topically, orally, or through Injection optionally in the form of powders, ointments, liquids or parenteral solutions together be used with customary inert TrügerstofTen or auxiliaries.

example 1

<i- [l-B.rom-2- (5-nitro-2-furyl) -viiiyl] -N- (2-acetyloxyethyl) nitrone (Connection 1)

To a solution of 2.46 g of a-bromo- / i- {5-nitro-2-furyl) acrolein and 500 ml of ethanol were 1.42 g of N - (2 - acetyloxyethyl) - hydroxylamine and 0.2 ml Glacial acetic acid added. The mixture was stirred at room temperature for about 2 hours, and then the obtained one Filtered off precipitate. This was crystallized from acetylnitrile, the "- [1-bromo-2- (5-nitro-2-furyl) -vinyl] -N- (2-acetyloxyethyl) -niUun obtained in the form of light yellow needles with a temperature of 131 to 133 C. became. The yield was 3.1 g.

Example 2

«- [1 -Bromo-2- (5-nitro-2-furyl) vinyl] -N-methylnitrone (Connection 2)

4.92 g of d-bromo- / i- (5-nitro-2-furyl) -acrolein were dissolved in 80 ml of ethanol at 65 ° C. with stirring. 2.16 g of N - methylhydroxylamine hydrochloride and 2.1 g of anhydrous sodium acetate was then added and the reaction mixture was at room temperature Stirred for 6 hours. The precipitate formed was filtered off and the filtrate was halved Volume concentrated under reduced pressure. The one obtained after cooling the concentrated filtrate Residue gave further crystals which were combined with the above precipitate. The crystals obtained were then recrystallized from ethanol, with 4.4 g of r <- [l-bromo-2- (5-nitro-2 - furyl) - vinyl] - N - methylnitron in the form of yellow fine needles with a temperature of 180 to 181 C (decomposition) were obtained.

Example 3

u- [1-Bromo-2- (5-nitro-2-furyl) vinyl] -N- (2-hydroxyethyl) nitrone (Connection 3)

To a solution of 3.14 g of u-bromo- / i- (5-nitro-2-furyl) -acrolein in 80 ml of ethanol was a solution of 1.20 g of N- (2-hydroxyethyl) hydroxylamine in 10% hydrochloric acid and 3.87 g sodium acetate were added with stirring. The mixture was then on Heated between 50 and 55 ° C. After about an hour, the reaction mixture was concentrated under reduced pressure and the residue extracted with chloroform, the extract washed with water and dried, whereupon the chloroform was distilled off. The remaining crystals were from a 2; 1 mixture (Weight) recrystallized from ethanol and hexane. where diis «- [1 -Bromi-2- (5-nitro-2-furyl) vinyl] -N- (2-hydroxyethyl) nitrone from 160 to 162 ° C. The yield was 3.2 g.

B e i s ρ i e 1 4

ii- [1-Bromo-2- (5-nitro-2-furyl) vinyl] -N- (2-hydroxypropyl) nitrone (Connection 4)

The procedure of Example 3 was carried out with the

so amendment is repeated, but that N- (2-hydroxypropyl) hydroxylamine was used in place of N- (2-hydroxyethyl) hydroxylamine. There were 3.13 g of green-yellow needles of a- [l-bromo-2- (5-nitro-2 - furyl) - vinyl] - N - (2 - hydroxypropyH - nitrone dated

Melting point 124-126 ° C.

Example 5

r £ - [1-Bromo-2- (5-nitro-2-furyl) vinyl] -N-0-methyl-2-hydroxyethyl) nitrone (Compound 5)

The procedure of Example 3 was followed with the modification repeats that each; also N- (l-methyl-2-hydroxyethyl) hydroxylamine was used in place of N- (2-hydroxyethyl) hydroxylamine. There were 2.9 g yellow needles of fi [l-bromo-2- (5-nitro-2-furyl | - V'nyl] -N- (I - methyl - 2 - hydroxyethyl 1 - nitrone \ um F. 191 to 193 "C obtained.

Example 6

u- [1-Bromo-2- (5-nitro -? - furyl) vinyl] -N- (1,3-dihydroxy-2-propyi) nitrone (Connection fti

The procedure of Example 3 was repeated with the modification that N- (1,3-dihydro \ vpropyl) -hydroxylamine was used instead of N- (2-hydroxyethyl) -hydroxylamine. 3.2 g of green-yellow needles of u- [l-bromo-2- (5-nitro-2 - furyl) - vinyl] - N - (1,3 - dihydroxy - 2 - propyl | - nitrone with a melting point of 186 to 187) were obtained 'C received.

Example 7

K- [1-Bromo-2- (5-nitro-2-furyl) vinyl] -N- (2-acetyloxyiithyl) nitrone (Connection! I

To a solution of 1.0 g of n- \ l-bromo-2- (5-nitro-2-furyl) vinyl] -N- (2-hydroxyethyl) -nw: on in SmI anhydrous pyridine, 1 ml of acetic anhydride was added with cooling and the mixture was stirred at room temperature for about 2 hours. Then water was added to the reaction mixture, and stirring was continued for 30 minutes to decompose the overcurrent of acetic anhydride. The then precipitated crystals were filtered off and washed with water. The raw crystals obtained were recrystallized from ethanol, whereby 1.5 g ./-1 1 - Bromo-2 - (5 -nitro- 2 -furyl) -vinyl] - N - (I - acciyloxyäthyllnitron *) in the form of yellow-orange needles from I 131 to 113 "C.

·) (Compound I).

Claims (1)

■ ψ- Claim: 5-nitrofuran derivatives of the general formula 1 C-CH = N-A (X). Br in which A is an alkylene radical with 1 to 3 carbon atoms, X is a hydrogen atom, a hydroxyl or acetyloxy group and π is an integer from 1 to 3 means. Acetyloxy group and η is an integer from 1 to 3. have excellent unti- mikÄte ^ Å and are known herein nitro ^O furandenva _e th superior. ^^ ^ ^ ■ · ^ η in terms of nitro-2-furfurylidene) amine compounds substituted P- ^N 'JJ_: activity known, but known. _a "" m, _n krobieller ^{Aia iv} _{either a unzulüssige} ; 1 in effectiveness, so that their use is limited to good ones of the nitrone type are from the British _with
sit Toxicity
by !