FI61887B - NYA KINOXALIN-1,4-DIOXIDE DERIVATIVES WITH VIKTOEKANDE VERKAN VAMT FOERFARANDE FOER DERAS FRAMSTAELLNING - Google Patents

Description

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jjSgA IBJ (11) UTLAGG N I NGSSKRI FT 61 GO / c Patent granted 11 10 1932 · 2λ5 (45) Patent raeddelat ^ (51) Kv.ik.3 / Int.a.3 c 07 D 241/52. AOi / 12, 405/12 // A 23 E 1/16 FINLAND —FINLAND (21) P »t * nttih» k.mu · - Pu «nt * n * 6knin | 753225 (22) H.k.mitplivi - ArwOknlripdag 17 · 11 · 7 5 (FI) (23) Alkuplivt - Glklghttid> g 17 · 11 · 7 5 (41) Come swans · ktl - Bllvic effwttllg 22.05 · 76

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Hungary-Hungary (HU) EE-2278 (Tl) EGYT Gyogyszervegyeszeti Gyär, 30, Kereszturi u., Budapest X,

Hungary-Hungary (HU) (72) Pal Benko, Budapest, Ildiko Simonek, Budapest, Laszlo Pallos, Budapest,

Jeno Koväcs, Budapest, Karoly Magyar, Budapest, Hungary-Hungary (HU) (7M Oy Jalo Ant-Wuorinen Ab (5 ^) New quinoxaline-1, U-dioxide derivatives with weight-increasing effect and method for their preparation - Nya quinoxalin-1 This invention relates to novel quinoxaline-1,4-dioxide derivatives of the general formula I: The present invention relates to novel quinoxaline-1,4-dioxide derivatives of the general formula I:

O

t

_ '.CH = N-NH-CO-R

or

OF

«1

O

wherein R represents a pyridyl, nitrofuryl or naphthylmethyl group.

The new compounds of the formula I have weight-increasing effects, as can be seen from the following experimental report: 618 8 7 2

The test report

The new weight-enhancing compounds of general formula I were compared with the compounds known from GB 1 058 047 and 1 202 770, namely 2- (enantoyl-hydrazono-formyl) -quinoxaline-1,4-dioxide (R = hexyl) and 2 - (methoxycarbonyl-hydrazono-formyl) -quinoxaline-1,4-dioxide (R = methoxy). The latter is the most effective of the substances marketed for a similar purpose (trade name Carbadox). The compound 2- (benzoyl-hydrazonoformyl) -quinoxaline-1,4-dioxide (R = phenyl) was further taken as a reference compound.

The weight gain-promoting effect of the new compounds and the reference compounds was studied in pigs. The feed used in each case contained 50 mg of quinoxaline-1,4-dioxide per kilogram. The animals were fed under identical conditions and also the amounts and compositions of feed were identical. The control group received the same feed without the addition of quinoxaline-1,4-dioxide.

The amount of feed needed to increase weight by one kilogram (feeding coefficient) was determined, as was the daily weight gain. The daily weight gain of the experimental group divided by the weight gain of the control group multiplied by 100 gives the characteristic weight gain of each additive in percent.

Since the weight gain effect depends on both the feeding factor and the daily weight gain, and since in animal husbandry it is important what amount of feed and at what time the animals reach their slaughter weight, a relationship between the above parameters was established. The percentage daily weight gain divided by the feeding coefficient is the feed utilization factor, which is a dimensionless figure. The higher the feed utilization factor, the more economical it is to raise animals. The following table summarizes the experimental feed utilization factors as well as the toxicities (determined in mice).

3 61 887 Meaning of R - Feed use Toxicity, po factor LD50 mg / kg

Known compounds: methoxy 66 4000 hexyl 53 4000 phenyl 66 4000

New compounds: 4-pyridyl 91 12000 5-nitrofuryl 91 14000 ____ ^ ynaphthylmethyl________________93, · 5__________13000_

Checks 50

It can be seen from the table that the new compounds have a significantly higher feed utilization factor. In addition, the new compounds are very low in toxicity, which is of great importance in the long-term feeding of animals.

The novel compounds of general formula I can be prepared according to the invention by reacting an aldehyde of general formula II

O

f

kA J

^ N

O

wherein Z represents an oxygen atom or a (O-alkyl) 2 - group, to react with an acid hydrazide of general formula III

R - CO - NH - NH2 III

where R is as defined above.

The starting materials of the general formulas II and III, i.e. 2-formyl-quinoxaline-1,4-dioxide and its diacetal, as well as the carboxylic acid hydrazides, can be prepared according to known methods (cf. e.g. Ber. 84_, 4771 (1951); Zh. Obshch. Him. 2J5, 161 (1955); BE Patent No. 669353; GB Patent No. 4,61887 to No. 1,058,047 (Compound II) and J. Zabiczky; "The Chemistry of Amides; Chapter 10, p. 515; Interscience Pub., 1970 (Compound III)).

A preferred way of carrying out the process according to the invention comprises reacting 2-formyl-quinoxaline-1,4-dioxide of the formula II with a small excess of carboxylic acid hydrazide in water in the presence of an acid.

If 2-formyl-quinoxaline-1,4-dioxide-diacetal is reacted with a carboxylic acid hydrazide, this reaction is preferably carried out in a protonated medium by boiling for a short time. The formation of a protonated medium can be ensured by the addition of acid. As the acid, a mineral acid such as hydrochloric, sulfuric and phosphoric acid can be generally used, but p-toluenesulfonic acid can be used for this purpose as well.

As the reaction medium, any solvent which does not react with the reagents or products and which is miscible with the acid used as a catalyst can be used. The reaction is preferably carried out in water.

Another preferred embodiment of the process, which is preferably used in the preparation of compounds of general formula I in a continuous process, comprises reacting the carboxylic acid hydrazide, after its preparation and without isolation, i.e. in the reaction mixture used for its preparation, with 2-formyl-quinoxaline-1,4 dioxide or acetal of the latter compound. This saves labor and equipment compared to a batch manufacturing process.

The novel compounds of the general formula I can be converted, as such or in combination with other compounds, or with acceptable carriers, diluents and / or other additives, into preparations which have a weight-increasing effect on improving the utilization of the feed.

As can be seen from the above experimental report, the new compounds have a valuable biological effect in that they maintain and increase the growth and feed utilization capacity of pigs, respectively, and this effect can be advantageously compared to the active ingredient of Mecadox Premix (Pfizer) used in saunas. ; at the same time, the toxicity of the compounds of general formula I is considerably lower than that of Carbadox.

The novel compounds of the invention and the process for their preparation are illustrated in the following examples. Example 1; 2- (1'-Naphthylacetyl) -hydrazonoformyl-quinoxaline-1,4-dioxide Dissolve 9.5 g (0.05 mol) of 2-formyl-quinoxaline-1,4-dioxide in 100 ml of water, containing 0.5 ml of concentrated hydrochloric acid and then 10.0 g (0.05 mol) of 1-naphthylacetic acid hydrazide are added to the solution. After stirring for 3 hours at room temperature, the suspension is filtered and the precipitate is washed with water and ethanol. In this way, 16.2 g (87%) of the title product with a melting point of 246-247 ° C are obtained.

Example 2: 2- (Nicotinoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide 7.55 g (0.05 mol) of nicotinic acid ethyl ester are dissolved in 60 g of ethanol, followed by dropwise addition of 2.6 g (0, 05 moles) of 96% hydrazine hydrate. The reaction mixture is boiled for 2 hours, then a warm solution of 9.5 g (0.05 mol) of 2-formyl-quinoxaline-1,4-dioxide and 1 ml of concentrated hydrochloric acid in 100 ml of methanol is added dropwise. The reaction mixture is allowed to cool to room temperature, then stirred for 2 hours at this temperature. The separated crystals are filtered and washed with methanol. In this way, 13.2 g (85.4%) of the title product with a melting point of 279 ° C are obtained.

Example 3: 2- (Isonicotinoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide 11.8 g (0.05 mol) of 2-formyl-quinoxaline-1,4-dioxide-dimethyl-acetal are suspended in 75 ml of water. Add 4 ml of concentrated hydrochloric acid to the suspension and boil for 10 minutes.

A suspension of 6.85 g (0.05 mol) of isonicotinic acid hydrazide in 50 ml of water is then added, heated to 60 ° C. The reaction mixture is allowed to cool to room temperature and stirred for a further 3 hours. The precipitate formed is filtered off and washed with water and ethanol. 14.4 g (93.2%) of product are obtained.

Claims (5)

6,61887 tetta, m.p. 268 ° C. Example 4: 2- (5 * -Nitro-2'-furanoyl) -hydrazono-formyl-quinoxaline-1,4-dioxide The title product with a melting point of 265 ° C is obtained in 82.6% yield as described in Example 3. 2-formyl-quinoxaline-1,4-dioxide-dimethylacetal and 5-nitrofuran-2-carboxylic acid hydrazide. New novel quinoxaline-1,4-dioxide derivatives having a weight-increasing effect, characterized in that their general formula I is O f ^ I „CH = N-NH-CO-R I 1 1 N Ψ 0 wherein R represents a pyridyl, nitrofuryl or naphthylmethyl group. A compound according to claim 1 wherein R is 4-pyridyl. The compound of claim 1, wherein R is 5-nitrofuryl. A compound according to claim 1 wherein R is 1-naphthylmethyl. Process for the preparation of quinoxaline-1,4-dioxide derivatives according to Claim 1, characterized in that the aldehyde of the general formula II is 618 8 7 7 0 t