AU637518B2

AU637518B2 - Zootechnical compositions containing a beta-adrenergic

Info

Publication number: AU637518B2
Application number: AU82424/91A
Authority: AU
Inventors: Jean Andre Grandadam
Original assignee: Roussel Uclaf SA
Current assignee: Hoechst Roussel Vet SA France
Priority date: 1986-12-11
Filing date: 1991-08-14
Publication date: 1993-05-27
Anticipated expiration: 2007-12-10
Also published as: AU616390B2; AU8242491A; AU8240587A

Description

Is 630/01 281/1918 Regulation 3.2

AUSTRALIA

Patents Act 1990 ORIGINAiL COM[PLETE SPECIFICATION STANDARD PATENT

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*3 Invention Title: ZOOTECHNICAL COMPOSMTONS CONTAINING

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S S 4* S S 0 *4 A BETA-ADRENERGIC The following statement is a full description of this invention, including the best method of performing it known to me:- 0

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The present invention is concerned with new zootechnical compositions containing a beta-adrenergic.

The subject of the invention is zootechnical compositions comprising a weight increasing effective amount of at least one compound selected from the group consisting of compounds of general formula (I) H K-R wherein. R is selected from the group consisting of hydrogen, cycloalkyl of 3 to 7 carbon atoms, 4-piperidinyl with the nitrogen optionally substituted by alkyl of 1 S to 4 carbon atoms, and linear or branched alkyl of 1 to 8 carbon atoms optionally substituted by -OH or phenyl or phenoxy; and the wavy lines indicate that the 7-hydroxy and 6-amino have the trans configuration, and their non-toxic, S? pharmaceutically acceptable acid addition salts; and an inert carrier.

The beta-adrener-ics are a family of medicaments well known in human medicine. Certain of these beta-adrenergics have been described as offering S anabolising properties in the animal (see on this subject, patents Nos. Me 3234995 and EP 103830).

In the general formula and in what follows 25' the term linear or branched alkyl radical of 1 to 8 carbon atoms designates, for example, an n-pentyl, n-butyl, n-propyl, or 2,2-dimethylpropyl, radical, or, preferably, an isopropyl, ethyl or methyl radical; the term cycloalkyl radical of 3 to 7 carbon atoms designates a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

The addition salts with mineral or organic acids can be, for example, the salts formed with the following acids -2ha; ii hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonic such as methane or ethane sulphonic, arylsulphonic such as benzene or paratoluene sulphonic, and aryl carboxylic.

The products with the formula are products known for their antihypertensive activity and hypotensive (see, in this respect, European patent 0107569).

The invention has particularly as its subject zootechnical compositions containing at least one compound answering to the general formula in which R represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon o atoms, as well as their addition salts with non-toxic pharmaceutically acceptable mineral or organic acids, and an inert carrier.

More particularly, the subject of the invention is the zootechnical compositions containing, as active compound, (6RS,trans) 6-(1-methyl-ethyl)-amino- .15. 7-hydroxy-4,5,6,7-tetrahydro-imidazo-[5,4,1-j-k]-[1]-benzazepin-2-(1H)-one, as well as its addition salts with non-toxic pharmaceutically acceptable mineral or organic acids, particularly its hydrochloride.

This compound is described in example 14 of the previously mentioned patent.

Among the preferred zootechnical composition of the invention, there can also be cited zootechnical composition, characterized in that they contain salbutamol as beta-adrenergic with the formula

S

H

O

1 H0o C/-oH- OH-/,V,-NH-c(cH,) 3 -3- Salbutamol is a known product salbutamol or albuterol is alpha [(tertbutylamino)-methyl]-4-hydroxy-n-xylene-alpha,alpha'-diol, known for its activity on the beta-2-receptors of the smooth bronchial muscle and marketed as a medicament for the treatment of asthma see on this subject, for example, item 206 of the new edition of the Merck Index or the items "VENTOLIN", pages 1585, 1586, 1587 of the VIDAL Dictionary, 61st edition (1985).

As beta-adrenergic, there can also be cited cimaterol, a product with the formula

CA/

OH

clembuterol, a product with the formula

"CH

as wclembuteroll as, the products described in the formulpatents already cited, (ME 3,234,995 and

H

EP 103,830).

The subject of the invention is also particularly the zootechnical compositions containing salbutol as active principle. The zootechnical compositions I according to the invention enable the increase in weight and the quality of the meat to be improved in farm animals such as cattle, and sheep, notably lambs, pigs or poultry.

The invention also has as its subject the zootechnical compositions defined above intended for administration to the pig and those intended for administration to the calf.

Finally, a subject of the invention is the zootechnical compositions defined above intended for administration to poultry.

The beta-adrenergics are preferably administered to the animals by oral route, in the form of tablets, granules or powders distributed in the foodstuffs and prepared according to the standard manufacturing processes for such products.

The beta-adrenergics can be administered by parenteral route.

The beta-adrenergics can equally be incorporated in the alimentary compositions in combination with a nutritional mixture adapted for animal alimentation.

The nutritional mixture can vary according to the animal species: .15. it can contain cereals, sugars, soya-cake grains, pea-nuts and sunflower seeds, So meals of animal origin, for example, fish-meals, synthetic amino acids, mineral salts, vitamins and anti-oxidants.

The zootechnical compositions of the invention also show interesting anabolising properties and more particularly, protein anabolising properties.

These properties make the zootechnical compositions of the invention suitable for use as veterinary medicaments, particularly in order to increase the general organic resistance to aggressions of every sort, to combat retardations of growth, emaciation, general organic disorders connected with a senescent state and also to combat in a secondary way infectious, parasitic and nutritional diseases.

The usual posology can be, for example, from 10 to 1000 mcg of betaadrenergic per Kg of animal weight and per day, administered by oral route. The i beta-adrenergics can be administered in the form of zootechnical compositions containing from 1 to 500 mg of beta-adrenergics in the form of an implant, for example.

The following examples illustrate the invention without, however, limiting 1~ n m In the following examples, the hydrochloride of (6RS,trans) 6-(1methylethyl)-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo-[5,4,1-j-k][l]-benzazepin-2- (1H)-one will be called product Pi.

Example 1 Tablets have been prepared containing Product P1 5 mg Excipient q.s. for a tablet finished at 100 mg (Detail of excipient lactose, wheat starch, treated starch, rice starch, magnesium stearate, talc).

Example 2 G Granules have been prepared containing 25 mg of product P 1 for a daily dose of granules.

Example 3 Combinations.

Combinations have been prepared containing *5s, a) granules of product P 1 mg of active principle for a daily dose of granules and, b) P 2 implants containing S trenbolone acetate 20 mg called 36 m g Example 4 Tablets have been prepared containing Salbutamol 5 mg Excipient sufficient for a tablet finished at 100 mg (detail of excipient lactose, wheat starch, treated starch, rice starch, magnesium stearate, talc).

Example 5 Granules have been prepared containing 25 mg of salbutamol for a daily dose of granules.

Example 6: Combinations.

Granules have been prepared containing a) granules of salbutamol, -6i Ai mg of active principle for a daily dose of granules, and b) implants containing trenbolone acetate 20 mg implants containing called 36 mg Example 7: A trial has been made with pigs.

The animals were divided into 4 lots a control lot (only receiving foodstuff) one lot receiving 250 mcg/Kg of product P 1 per day in its food.

one lot receiving 250 mcg/Kg of product P 1 per day in its food and which had received a P 2 implant.

one lot receiving only the P 2 implant in addition to its food.

The product P 1 was given in the foodstuff, the mixture P 2 ,,as administered in the form of an implant in the sub-cutaneous tissue behind the ear.

All the animals received the same foodstuff during 90 days.

1*5, The results are assembled in the following table C1-al ols Lot 1 Lot 2 Lot 3 Q Number of animals 10 10 10 0S Average number of days 28 28 28 28 of fattening Average weight at 82.00 81.80 81.80 81.80 implantation in Kg.

Average weight at 103.00 103.90 107.60 103.30 slaughter in Kg.

Gain of weight in Kg. 21.00 22.10 25.80 21.50 Average daily weight 0.750 0.789 0.921 0.768 gain in Kg.

-i7r Conclusion: 1) All of the lots treated have a growth greater than that of the control lot.

2) The lot which received the product P 1 and the implant P 2 has an exceptional growth much greater than the sum of the effects caused by the products P 1 and P2 administered separately.

Example 8 A trial has been made with pigs.

The animals were divided into 4 lots one lot receiving 0.25 mg/Kg of salbutamol per day in its food, one lot receiving 0.25 mg/Kg of salbutamol per day in its food and to which an implant P 2 has been made (see Example 3)1, one lot receiving only the implant P2 in addition to its food.

The salbutamol was given in the food.

The product P 2 was given in the form of an implant in the sub-cutaneous tissue behind the ear.

All the animals received the same food during 90 days.

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-8- -'lli- i i i i The results are assembled in the following table

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treatment controls called 36 mg salbutamol salbutamol trenbolone 0.25 mg 0.25 mg acetate 20 mg called 36 mg trenbolone acetate 20 mg time in days of treatment before 54 54 54 slaughter Lot No. I II IV V No. of animals 9 9 9 9 Average weight on day of treatment 61.67 61.67 61.67 61.56 (Kg) Average weight at the end of trial (Kg) 103.22 105.67 106.22 104.44 Average weight gain 41.56 44.00 44.56 42.89 (Kg) Average weight gain 0.770 0.815 0.825 0.794 per day, (Kg)_ Cold carcase weight 80.22 82.82 84.89 82.49 (Kg) Food consumed (Kg) 130.17 129.79 129.21 130.02 Consumption index 3.14 2.96 2.92 3.05 CONCLUSION Example 9 The combinations bring very good rearing results.

A trial has been carried out on calves.

The animals were divided into 2 lots of calves of male sex.

The treatments were arranged according to the following scheme Lot I or control lot did not receive any product Lot II lot receiving 0.1 mg/Kg of live weight of salbutamol.

-9- The trials took place over three periods: -one experimental period of 85 days -one experimental period of 34 days S one subsequent period of 15 days.

Weights were measured every 15 days.

The animals received a rationed foodstuff through the duration of the trial.

The results obtained are summarized in the following table e g.

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n.ee Lot Number I II Number of animals 9 Number of days of fattening 34 34 Average weight on the day of treatment (Kg) 140.22 141.50 Average weight at the end of the trial (Kg) 179.00 185.40 Mean gain in weight (Kg) 38.78 43.90 Average daily weight gain (Kg) 1.141 1.291 Foodstuff consumed (Kg) 81.90 82.00 Consumption index 2.11 1.87 Example 10 A trial was carried out on entire male lambs and female lambs.

The animals were divided into three lots one lot received 0.2 mg/Kg of product P 1 (lot 1) one lot received 0.4 mg/Kg of product P 1 (lot 2) one control lot did not receive any treatment.

The product P 1 was given in the foodstuff.

The foodstuff was constituted of granules given in rationed quantities and Sof hay supplied at will.

A cear improvement in the weight gain and in the structure of the animals in lots 1 and 2 was determined.

ii

Claims

1. A zootechnical composition comprising a weight increasing effective amount of at least one compound selected from the group consisting of compounds of formula (I) H b. wherein R is selected from the group consisting of hydrogen, cycloalkyl of 3 to 7 carbon atoms, 4-piperidinyl with the nitrogen optionally substituted by alkyl of 1 to 4 carbon atoms, and linear or branched alkyl of 1 to 8 carbon atoms optionally S. 16 substituted by -OH or phenyl or phenoxy; and the wavy lines indicate that the 7- hydroxy and 6- amino have the trans configuration, and their non-toxic, pharmaceutically acceptable acid addition salts; and an inert carrier.

2. A cdmposition as claimed in Claim 1 wherein R is hydrogen or alkyl of 1 to 5 carbon atoms.

3. A composition as claimed in Claim 1 wherein the active compound is selected from the group consisting of (6RS, trans) 6-(1-methyl ethyl)-amino-7- hydroxy-4,5,6,7-tetrahydroimidazo[5,4,1-j-k][1]-benzazep 2-(1H)-one, and its non-toxic, pharmaceutically acceptable acid addition salts.

4: A method of increasing the weight of pigs comprising administering to pigs a weight increasing effective amount of a zootechnical composition as claimed in Claim 1.

5. A method of increasing the weight of calves comprising administering to calves a weight increasing effective amount of a zootechnical composition as claimed in Claim 1. i

6. A method of increasing the weight of poultry comprising administering to poultry a weight increasing effective amount of a zootechnical composition as 11 1 *EW claimed in Claim 1.

7. A method as claimed in any one of Claims 4 to 6 wherein the beta- adrenergic is orally administered at a daily dose of between 10 and 1000 mg/kg of the animal.

8. A method as claimed in any one of Claims 4 to 6 wherein the beta- adrenergic is administered by parenteral route.

9. A zootechnical composition as claimed in any one of Claims 1 to 3 substantially as hereinbefore disclosed with reference to any one of Examples 1, 2, 3, 4, 5, 7 (Lot 8 (Lot 9 and

10. A method as claimed in any one of Claims 4 to 8 substantially as S hereinbefore disclosed. O O.. DATED this 14th day of August, 1991. ROUSSEL-UCLAF By its Patent Attorneys CALLINAN LAWRIE S •I -12- i ABSTRACT Zootechnical compositions comprising a weight increasing effective amount of at least one compound selected from the group consisting of compounds of formula (I) H,.,R .0*0 a e g Sc.. a 0e a 'r 4 0O 4a C 8S 0 S SO 4* wherein R is selected from the group consisting of hydrogen, cycloalkyl of 3 to 7 carbon atoms, 4-piperidinyl with the nitrogen optionally substituted by alkyl of 1 to 4 carbon atoms, and linear or branched alkyl of 1 to 8 carbon atoms optionally substituted by -OH or phenyl or phenoxy; and the wavy lines indicate that the 7-hydroxy and 6- amino have the trans configuration, and their non-toxic, pharmaceutically acceptable acid addition salts; and an inert carrier, and methods of increasing weight using said zootechnical compositions.