DE2611733A1 - SUBSTITUTED 5,6-DIALKOXYINDAZOLE- 3-CARBONIC ACID HYDRAZIDES, PHARMACEUTICALS CONTAINING SUCH AND METHOD OF MANUFACTURE THE SAME - Google Patents

Description

DR.STEPHAN G. BESZEDES PATENT ADVOCATE

806 DACHAU near MÖNCHEN

BOX 1168

AM HEIDEWEG 2

TELEPHONE: DACHAU 4371 Postal checking account Munich (BLZ 700 100 80)

Account no. 1368 71

Bank account No. 90 637 at the Kreis- und Stadtsparkasse Dachau-Indersdorf (BU 700 515 40)

P 901

description

for patent application

EGYT GYOGYSZERVEGYESZETI GYAR

Budape st, Hungary

concerning

Substituted ^ e-dialkoxyindazole - ^ - carboxylic acid hydrazides, medicaments containing them and processes for the preparation thereof

The invention relates to new substituted 5 * 6-dialkoxyindazole-3-carboxylic acid hydrazides including their optically active isomers, medicaments containing such, especially such with a bacterial growth inhibiting or antimicrobial and fungicidal effect, as well as a method for producing the same.

The invention relates to substituted 5 »6-dialkoxyindazole-3-carboxylic acid hydrazides the general formula

609841/0985

■ x

R ,, for alkyl radicals, preferably with 1 "to 4 carbon atoms , stand,

Ho is hydrogen or an alkyl having 1 to 4 carbon atoms means and

X represents oxygen or sulfur,

with the further proviso that, in the event that

R ^ are methyl radicals and R _{2 is} hydrogen,

X represents only sulfur,

as well as their optically active isomers. The invention includes all possible stereoisomers of the compounds according to the invention and their mixtures.

The alkyl radicals represented by R ^ are preferably such with 1 or 2 carbon atoms.

It is also preferred that the alkyl radical which R ₂ can represent is one having 1 or 2 carbon atoms.

- 3 609841/0985

Furthermore, according to the invention, drugs "or Disinfectants which contain 1 or more of the compounds according to the invention as active ingredients or active ingredients, optionally together with customary carriers and / or auxiliaries and / or diluents included.

As already mentioned, the compounds according to the invention have valuable pharmacological ones, in particular those which inhibit bacterial growth and fungicidal, properties.

Thus, the compounds according to the invention prevent or inhibit the multiplication of microorganisms even in low concentrations. Therefore, they are able to benefit advantageously
in the form of common pharmaceutical preparations (such as powders or ointments) to eliminate or avert infections caused by bacteria and fungi.

To illustrate the bacterial growth inhibiting respectively The minimum inhibitory concentrations (MIO) of compounds according to the invention and have an antibacterial effect known comparative compounds recognized as having good effects against the following microorganisms:

Escherichia coli

Staphylococcus aureus ATCG 6538

Staphylococcus aureus SG 5 ^ 1

Staphylococcus epidermis OKI 891

The nutrient medium containing different concentrations of the compounds investigated was treated with equal amounts of
investigated microorganisms ^{incubated at 37 0} G for 24 to 48 hours, whereupon the values of the minimum inhibitory concentrations
were determined by turbidity measurements (turbidimetrically). as

B ο 9 ·> U 1 / M 9 8 '■■

Comparative compounds were the known N "- (5-nitro-2- -furfurylidene) -1-aminohydantoin ^ Kitrofurantoin ^, 5-nitrofurfurolsemicarbazone and D-Threo-i-p-nitroph.enyl-2-dichloroacetylaminopropanol-1,5 (Chloramphenicol) is used.

The results are compiled in Table 1 below.

B Π 9 B 4 1 / f) 9 8 h

Tabel

link Meanings of the sym K ₂ JL Minimum inhibitory concentration E. ccüi Staphylococcus Staphylococcus Staphylococcus at description bole in the in aureus aureus epidermis game Formula I.
■ T "» f ^ "» - ^ pg / cnr ATCC 6538 SG 511 OKI 891 No. H S (0) 5,6-Mmethoxyindazole-3- 0.3 11.0 7.8 31.2 -carboxylic acid- (5 '-nitrotban- 1 -2'-ylidene) hydrazide CH ₅ or [or 5,6-di- 2 methoxyindazole-3-carbon- CpH _n - 0 acid- (5'-nitrofurfur-2'- 1.9 1.9 1.9 1.9 -ylidene) hydrazide] 1-ethyl-5,6-dimethoxy- OH, 5 indazole-3-carboxylic acid - (5'-nitrofurfur-2 - -ylidene) hydrazide

O3 O CD CO

CO co

Table 1 continued

at
game
No. link
description Meanings of the sym
bole in the ormel I
R ₂ X Minimum inhibitory concentration
in
^ Ug / cm ⁵ E. coli Staphylococcus
aureus
ATCC 6538 Staphylococcus
aureus
SG 511 Staphylococcus
epidermis
OKI 891 4th 5,6-diethoxyindazole-3-
-carboxylic acid- (5'-nitrofur-
for 2'-ylidene) hydrazide H 0 0.4 0.9 0.9 3.9 3 5,6-diethoxyindazole-3-
-carboxylic acid ~ (5'-nitrothen-
-2'-ylidene) hydrazide "C ₂ H ₅ H S. 0.9 15.6 ■ 31.2 15.6 NC 5-nitro-2-furfurylidene) -
-1-aminohydantoin
[Nitrofurantoin]
f reference substance ^ C ₂ H ₅ 15.6 3.9 3.9 6.0

β *

ro CD

OJ to

Continued ^- UHK. Of table 1

at
game link
description Meanings of the sym
bole in the ormel I
R ₂ X Minimum heme concentration
in
jig / cm * E. coli Staphylococcus
aureus
ATCC 6538 Siaphylococcus
aureus
SG 511 Staphylococcus
epidermis
OKI 891 No. ^R 1 3.9 0.3 0.3 0.3 5-nitrofurfural
semicarbazone
{Comparison substance] 3.9 3.9 7.8 3.9 D-threo-1-p-nitrophenyl-
-2-dichloroacetylamino-
propanol-1,3
[Chloramphenicol]
{Comparison substancej

Note: toxicity of the compounds according to the invention with intraperitoneal and

oral administration to mice: at doses of 1,500 mg / kg not fatal
Effect during a 48-hour observation period

From the ot) igen Table 1 it can be seen that the fiction according to compounds are superior to all comparison compounds with regard to at least 1 microorganism examined. The measured values of the minimum inhibitory concentration were 0.2 to 2.0 ^

The conversion of the compounds according to the invention in Medicinal preparations can be used in a manner known per se with the help of the usual in the preparation of pharmaceutical preparations Carriers and / or auxiliaries and / or diluents take place.

The invention also relates to a method for production of the compounds according to the invention, which thereby is marked that

a) a 5 »6-DiaTkoxyindazol-3-carboxylic acid hydrazide of general formula

0 H

Il I

C-N-NH,

wherein R ^ and R2 are as defined above, with an aldehyde of the general formula

= 0

III, - 9 -

h 0 9 ft Z. 1 / M 9 f < f.

wherein X is as defined above and Y is hydrogen or a nitro group, is ^{reacted at a temperature of 20 to 200 0} C, preferably 4-0 to 150 ⁰ C, and, if Y is hydrogen, the product obtained is separated off and is nitrided in a known manner or

a 5> 6-dialkoxyindazole-3-carboxylic acid hydrazide the general formula

0 H

C-N-NH,

II

wherein R ,. and R ~ ^w ^ - ^e are defined above, with an aldehyde derivative of the general formula

IV

wherein X is as defined above and R ^ represent alkylcarbonyl having 1 to 6 carbon atoms, is reacted in the presence of an aqueous mineral acid at a temperature of 20 to 100 ° C, preferably 40 to 80 ⁰ C,

and, if appropriate, the compound of the formula I obtained

- 10 -

B0 9841/0985

- ίο -

through fractional crystallization to practically, pure cis- and trans isomers is cleaved.

Preferably, for the implementation according to variant a) of the process according to the invention, the 5,6-dialkoxyindazole-3-carboxylic acid hydrazide of the formula II in a mineral acid in an amount of at least 1 Mo! equivalent aqueous solution used.

The nitration, which may be carried out, is advantageously carried out in a mixture of concentrated sulfuric acid and nitric acid at a temperature of 0 to 10 ° C .

The aldehyde derivative of the formula IV is preferably one in which R _{1 represents} acetyl radicals.

Appropriately, the implementations of the ^ ö indazole-3-carboxylic acid hydrazides of the formula II in a solvent and / or diluents carried out. For this purpose, primarily lower (1 to 6 carbon atoms) mono- or polyhydric aliphatic ^ alcohols, their ethers and cyclic ethers and also lower alkanecarboxylic acids, their Esters and amides or mixtures thereof can be used.

The 5 »6-dialkoxyindazole-3- used as starting materials -Carboxylic acid hydrazides of the formula II can for the most part have been prepared in a known manner (Hungarian patent specification 161 840), but partly they are new connections, their production is described in the examples. The compounds of Ibrmeln m and IV are commercially available.

The invention is not intended to be limiting in light of the following Examples to be understood are explained in more detail.

B O 9 8 4 1 / O 9 8 5

- 11 Example 1

There were 18 g (0.075 mol) of 5,6-dimethoxyindazole-3- carboxylic acid hydrazide and 10 g (0.088 mol) thiophene-2-aldehyde in 200 cnr ethanol for 2 hours with stirring respectively Shake heated to the boil. The reaction mixture, cooled to room temperature, gave 24.2 g (97% of theory) 5,6-Dimethoxyindazole-3-carboxylic acid (then-2'-ylidene) hydrazide obtained with a melting point of 269 C.

5 g (0.015 mol) of this product were dissolved in 15 cnr concentrated sulfuric acid. Then a mixture of 1 enr 98% strength nitric acid and 5 cm concentrated sulfuric acid was added dropwise at a temperature of 0 to 5 ° C. with stirring or shaking. The stirring or shaking was continued for a further 2 hours at a temperature of around 20 ^° C. and the reaction mixture was poured onto 100 g of crushed ice. The precipitated product was filtered and washed acid-free with water. After drying, 5 »4 g (100% of theory) of 5» 6-diinethoxyindazole-3-carboxylic acid (5'-nitrothen-2'-ylidene) hydrazide were obtained. Its melting point is not characteristic (carbonization in the capillary tube at about 250 ⁰ O).

Example 2

A 10 η sulfuric acid was added to a suspension of 3.6 g (0.015 mol) of 5 »6- dimethoxyindazole-3-carboxylic acid hydrazide in 50 cur of water until the substance had dissolved. A solution of 4 g (0.0155 mol) of 5-nitrothiophene-2-aldehyde diacetate in 15 cubic centimeters of hot ethanol was then added. The reaction mixture was stirred or shaken for 1 to 2 hours at 60 to 7O ⁰ C and then cooled and filtered, whereby 5 »4 g of one with the compound of the by-

- 12 -

- 12 -

Game 1 identical product were obtained. Yield: 100% of theory.

The trans modification (melting point: over 300 ° C.) of the above substance was obtained by recrystallization from dimethylformamide. When the mother liquor was diluted with water, another fraction, which essentially consisted of the cis modification (melting point: about 200 ^° C.), was obtained,

Using the methods described in Examples 1 and 2 The further compounds compiled in Table 2 below were also used, for example manufactured:

- 13 -

κ /, 1 / i] ⁽ iK5

- 13 Table 2

at link Meanings of E ₁ E ₂ Sym- Enamel the end game description bole in the O ₂ H ₅ H Point prey No. Formula I. CJE ₁ - 2 5 H X CD
(-} 3 S. CO
OC 5,6-diethoxyindazole-3-carboxylic acid- (5 · -nitrothen-2'- O ₂ H ₅ approximately 97% ■ Ρ-
1 4th -ylidene) hydrazide 0 150 ⁰ G cc 5,6-I) ethoxyindazole-3-carboxylic acid (5 ^l -nitrorurfur-. approximately 87% co
in 5 -2'-ylidene) hydrazide ο 250 ⁰ C 1-ethyl-5,6-dimethoxyindazole-3-carboxylic acid (5'-nitro- approximately 88% furfur-2'-ylidene) hydrazide 290 ⁰ C

The "in the preparation of the compound of Example 5 Starting compound used 1-ethyl-5,6-dimetho: xyindazol-3- -carboxylic acid hydrazide has been obtained as follows:

22 g (0.1 mol) of 5,6-dimethoxyindazole-3-carboxamide in 100 cnr dimethylformamide were stirred or shaken and the mixture was given a 50% suspension of Ψ.8 g (0.1 mol) of sodium hydride in mineral oil added. The solution obtained was ^{cooled to 0} ° C., whereupon 16 g of ethylgodide were added at this temperature. After stirring or shaking at 50 ° C. for 2 hours, the reaction mixture was poured into 500 ml of water. Thus 18 g (72% of theory) of 1-ethyl-5,6-dimethoxyindazol-3-carboxamide with a melting point of 177 ⁰ G (after recrystallization from ethanol).

This compound was heated to boiling with 50 cm ^ 100% hydrazine hydrate for 5 hours, after which the solution was concentrated under reduced pressure. Thus, 17 g of 1-ethyl -5,6-dimetho3iyindazol-3-carboxylic acid having a melting point of 140 ⁰ C. Yield: 95% <ier theory.

Claims

0 9841/0 985

Claims (6)

Claims Substituted 5, ö-dialkoxyindazole-J-carboxylic acid hydrazide of the general formula H C wherein R _{7 represents} alkyl radicals, preferably with 1 "to 4 carbon atoms, R ₂ denotes hydrogen or an alkyl radical having 1 to 4 · carbon atoms and X represents oxygen or sulfur, with the further proviso that, in the event that R ^ stand for methyl radicals and Rp is hydrogen means, X represents only sulfur, B 0 9 H A 1/0 9 B 5 - 16 as well as their optically active isomers. 2.) 5> 6-dialkoxyindazole-3-carboxylic acid hydrazide according to claim. 1, characterized in that the alkyl radicals for which E ^ are those with 1 or 2 carbon atoms are. 3.) 5 »6-Malkoxyindazol-3-carboxylic acid hydrazide according to claim 1 or 2, characterized in that the alkyl radical for which Rp can stand is one with 1 or Is carbon atoms. 4-.) Medicines, characterized by a content of 1 or more compounds according to claim 1 or 2 as an active ingredient or active ingredients, optionally together with customary carriers and / or auxiliaries and / or diluents. 5 ·) Disinfectants, characterized by a content of 1 or more compounds according to claim. 1 or as an active ingredient or active ingredients, if appropriate together with the usual carriers and / or auxiliaries and / or diluents. 6.) Process for the preparation of the compounds according to claim 1 to 3 »characterized in that one a) a 5 »6-dialkoxyindazole-3-carboxylic acid hydrazide the general formula - 17 - B 0 9 8 k 1 / Π ^c i 8 wherein R. and R ^ ^yf ^ - ^{e in} & ^βη claims 1 to 3 are defined, with an aldehyde of the general formula III wherein X is as defined in claim 1 and X is hydrogen or a nitro group, at a temperature of 20 to 200 ⁰ G, preferably 40 to 150 ⁰ C, and reacting, in the case that Y is hydrogen, the resulting
The product is separated off and nitrated or in a manner known per se b) a 5 _i 6-dialkoxyindazole-3-carboxylic acid hydrazide of the general formula - 18 - 809841/0 985 II N-H, wherein R ^, and Rp as in claims 1 to 3 are set with an Aldehydd erivat the general formula IV wherein X is as defined in claim 1 and R ^ are alkylcarbonyl radicals having 1 to 6 carbon atoms, in the presence of an aqueous mineral acid at a temperature of 20 to "100 ⁰ G, preferably 40 to 80 ⁰ O, reacted and optionally the resulting compound of IOrmel I cleaves to practically pure cis and trans isomers by fractional crystallization. 6 09841/0985 7.) Method according to claim 6 a), characterized in that that the 5 »6 ~ dialkoxyindazole-3-carboxylic acid hydrazide of the formula II in a mineral acid in an amount of at least 1 molar equivalent containing aqueous Solution sets in. 809841 / Ü 985 ORIGINAL