FR2608046A1 - Zootechnical compositions containing a 6-amino-7-hydroxy-4,5,6,7-tetrahydroimidazo[4,5,1-jk][1]benzazepin-2(1 H)-one derivative - Google Patents

Abstract

The zootechnical compositions contain as active principle at least one compound of formula I: in which R represents a hydrogen atom or an optionally substituted alkyl radical and the wavy lines mean that the hydroxyl at position 7 and the amino radical at position 6 are of transconfiguration, or one of its addition salts with organic or inorganic acids. The compositions of the invention promote weight gain in livestock.

Description

 The present invention relates to zootechnical compositions containing a derivative of 6-amino 7-hydroxy 4,5,6,7tetrahydro imidazo / 4,5,1-j-k / / 1 / benzazepin 2 (1H) one.

dans laquelle R représente un atome d'hydrogène, un radical alcoyle, linéaire ou ramifie renfermant de 1 à 8 atomes de carbone, éventuellement substitué par un radical hydroxy, par un radical phényle ou par un radical phényloxy ou un radical cycloalcoyle renfermant de 3 à 7 atomes de carbone, ou un radical 4-pipéridinyle dont l'atome d'azote porte éventuellement un substituant alcoyle renfermant de 1 à 4 atomes de carbone et les traits ondulés signifient que l'hydroxyle en position 7 et le radical amino en position 6 sont de configuration trans ou un de ses sels d'addition avec les acides minéraux ou organiques.The subject of the invention is zootechnical compositions containing as active principle at least one compound of general formula CI)

in which R represents a hydrogen atom, an alkyl radical, linear or branched containing from 1 to 8 carbon atoms, optionally substituted by a hydroxy radical, by a phenyl radical or by a phenyloxy radical or a cycloalkyl radical containing from 3 to 7 carbon atoms, or a 4-piperidinyl radical whose nitrogen atom optionally carries an alkyl substituent containing from 1 to 4 carbon atoms and the wavy lines mean that the hydroxyl in position 7 and the amino radical in position 6 are of trans configuration or one of its addition salts with mineral or organic acids.

In the general formula (I) and in what follows, the term alkyl radical, linear or branched, containing from 1 to 8 carbon atoms, denotes, for example, an n-pentyl, n-butyl, n-propyl radical, 2,2-dimethylpropyl or preferably an isopropyl, ethyl or methyl radical;
the term cycloalkyl radical containing 3 to 7 carbon atoms denotes a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyctoheptyl radical;
the addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosDhoric, acetic, formic, propionic, benzoic, malic, fumaric, succinic, tartaric, citric acids , oxalicue, glyoxylic, aspartic, alkane sulfonic, such as es methane or ethane sulfonic, arylsulfonic, such as benzene or paratoluene sulfonic and arylcarboxylic acids.

 Among the products of the invention, mention may be made of those corresponding to formula I in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms as well as their addition salts with mineral acids or organic.

 The products of formula I are products known for their antihypertensive and hypotensive activity (see on this subject, European patent 0107569). We have just discovered that these products made it possible to improve weight gain and the quality of meat in farm animals such as cattle and pigs, as shown by the test results set out below in the experimental part. .

 A more particular subject of the invention is the zootechnical compositions containing as active principle (6RS, trans) 6-Ci-methylethyl) amino 7-hydroxy 4,5,6,7-tetrahydro imidazo / 5,4,1-jk / / 1 / benzazepin-2- (1H) -one as well as its addition salts with mineral or organic acids and in particular its hydrochloride.

 This product is described in example 14 of the aforementioned patent, it will hereinafter be called product P1.

dans laquelle X représente un atome d'hydrogène, un radical alcoyle saturé ou insaturé renfermant de 1 à 6 atomes de carbone dont l'un des atomes de carbone peut être remplacé par un atome d'oxygène ou X représente un radical acyle dérivé d'un acide carboxylique renfermant de 1 à 18 atomes de carbone, pour une utilisation simultanée, séparée ou etalée dans le temps.The subject of the invention is also associations characterized in that they contain
a) a zootechnical composition defined above,
b) a zootechnical composition containing as active ingredient a steroid of formula (A)

in which X represents a hydrogen atom, a saturated or unsaturated alkyl radical containing from 1 to 6 carbon atoms, one of the carbon atoms of which can be replaced by an oxygen atom or X represents an acyl radical derived from a carboxylic acid containing from 1 to 18 carbon atoms, for simultaneous, separate or spread over time use.

 The products of formula A are known products described in particular in French patents 1,380,414 and 1,492,985 as well as in Belgian patent 696,084.

 Among the preferred products of formula A, mention may be made of 3-oxo 17 beta-acetoxy estra 4,9,11-triene.

It was found that particularly interesting results were obtained, by using associations containing
a) a zootechnical composition containing, as active principle, a product of formula I defined above,
b) a zootechnical composition containing as active principle a product of formula A defined as above,
c) a zootechnical composition containing as active ingredient zeranol, for simultaneous, separate or spread over time use.

 The results obtained are quite remarkable, when the product of formula I used is (6RS, trans) 6 (1-methylethyl) amino 7-hydroxy 4,5,6,7-tetrahydro imidazo / 5,4,1- jk / / 1 / benzazepin-2- (1H) one, or one of its addition salts with organic or mineral acids, and the product of formula A is 3-oxo 17 beta-acetoxy estra 4.9 , 11-triéne.

The subject of the invention is also the associations containing
a) a zootechnical composition containing as active principle a product of formula I defined above,
b) a zootechnical composition containing as active ingredient a product of formula A defined above,
c) a zootechnical composition containing, as active principle, estradiol, for simultaneous, separate or spread over time use.

As a particular association of the invention, associations can be used, characterized in that they contain
a) a zootechnical composition containing as active principle, a product of formula I defined above,
b) a zootechnical composition containing as active principles
b1) a product of formula A defined as above,
b2) zeranol or estradiol, for simultaneous or spread over time, and in particular combinations containing
a) a zootechnical composition containing as active ingredient the (6RS, trans) 6- (1-methylethyl) amino 7-hydroxy 4,5,6,7-tetrahydro imidazo / 5,4,1-jk / / 1 / benzazepin- 2- (1H) - one or one of its addition salts with organic or mineral acids,
b) a zootechnical composition containing as active principles
b1) 3-oxo 17 beta-acetoxy will be 4,9,11-triene,
b2) zeranol.

 The products of formula I are preferably administered to animals by the oral route, in the form of tablets, granules or powders distributed in food and prepared according to conventional methods of manufacturing such products. The products of formula I can be administered parenterally.

 The products of formula I can also be incorporated into food compositions in combination with a nutritional mixture suitable for animal feed.

 The nutrient mixture may vary according to the animal species, it may contain cereals, sugars, soya meal, peanut and sunflower seeds, meal of animal origin, for example, fish meal, synthetic amino acids, mineral salts, vitamins and antioxidants.

 For their administration to cattle, the products of formula A, zeranol and estradiol can be deposited in the form of an implant at the base of the ear. These implants can also be administered in the neck of animals or in the gluteal muscles. They are deposited, for example, from 20 days to 4 months before slaughter, preferably from 1 to 3 months before it.

 The products of formula A, zeranol and estradiol, can also be either injected in the form of solutions or suspensions, or ingested.

 The compositions or associations of the invention thus show interesting anabolic properties and more particularly protein anabolic properties.

These properties make the zootechnical compositions of the invention suitable for use as veterinary drugs, in particular for increasing general organic resistance to attacks of all kinds, for combating growth retardation, weight loss, general organic disorders linked to a state of senescence and also to fight on a secondary basis against infectious, parasitic and nutritional diseases.

 The usual dosage can be, for example, from 10 to 1000 mcg of products of formula I per kg of animal weight and per day administered orally, the products of formula I can be administered in the form of zootechnical compositions containing from 1 to 300 mg of product of formula I, in the form of an implant, for example.

 Zeranol can be administered in the form of zootechnical compositions containing 10 to 100 mg of zeranol, in the form of an implant for example.

Estradiol can be administered in the form of zootechnical compositions containing from 0.05 to 50 mg of estradiol.

One can cite as particularly interesting the combination of the compositions containing from 0.5 to 100 mg of product of formula I, for example, from 5 to 25 mg of product of formula I and of implants containing from 5 to 50 mg of trembolone acetate (or 3-oxo 17 beta-acetoxy estra 4,9,11-triene) and from 10 to 50 mg of zeranol.

 The following examples illustrate the invention without, however, limiting it.

Example 1
Tablets containing
Product P1 5 mg
Excipient qs for a 100 mg finished tablet.

 (detail of excipient: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc).

EXAMPLE 2
Granules containing 25 mg of product P1 were prepared for a daily dose of granules.

Example 3 associations:
We have prepared associations containing
a) granules of product P1
25 mg of active ingredient for a daily dose of
granules and,
b) P implants containing
trembolone acetate 20 mg
zeranol 36 mg.

Example 4:
The test was carried out on pigs.

The animals are divided into 4 lots
- a control batch (receiving only food),
- a batch receiving 250 mcg / kg of product P1 in its food per day,
- a batch receiving 250 mcg / kg of product P1 in its food per day and to which a P2 implant has been implanted (see example 3),
- a batch receiving only the P2 implant in addition to its food.

The product P1 is given in food,
product P2 is administered as an implant in the subcutaneous tissue behind the ear.

 All animals receive the same food for 90 days.

The results are collated in the following table
Witnesses Lot 1 Lot 2 Lot 3
Number of animals 10 10 10 10
Number of days
fattening medium 28 28 28 28
Average weight at
implantation in KG 82.00 81.80 81.80 81.80
Average weight at
slaughter in KG 103.00 103.90 107.60 103.30
Weight gain in KG 21.00 22.10 25.80 21.50
Weight gain
daily average in KG 0.750 0.789 0.921 0.768
Conclusion: 1) All the treated lots have a growth superior to that of the control lot.

2) The batch which received the product P1 and the implant
P2 has an exceptional growth far superior to the addition of the effects caused by the products P1 and P2 administered separately.

Claims (3)

1) The compositions. zootechnics containing as active principle at least one compound of general formula Le (I):

 in which R represents a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by a hydroxy radical, by a phenyl radical or by a phenyloxy radical or a cycloalkyl radical containing from 3 to 7 carbon atoms, or a 4-piperidinyl radical, the nitrogen atom of which optionally carries an alkyl substituent containing 1 to 4 carbon atoms and the wavy lines mean that the hydroxyl in position 7 and the amino radical in position 6 are of trans configuration or one of its addition salts with mineral or organic acids. 2) The zootechnical compositions defined in claim 1 containing as active principle at least one compound of formula I in which R represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 5 carbon atoms or one of its salts addition with mineral or organic acids. 3) The zootechnical compositions containing as active ingredient:  - (6RS, trans) 6- (1-methylethyl) amino 7-hydroxy 4,5,6,7-tetrahydro imidazo / 5,4,1-jk / / 1 / benzazépin-2- (1H) - one thus as its addition salts with mineral or organic acids and in particular its hydrochloride.