AU621587B2

AU621587B2 - Use of thiazoles for improving performance in animals

Info

Publication number: AU621587B2
Application number: AU30095/89A
Authority: AU
Inventors: John Francis Quirke; Manfred Reiffen; Eckhard Rupprecht; Mario Sommer
Original assignee: Boehringer Ingelheim Vetmedica GmbH; Boehringer Ingelheim Vetmedica Inc
Current assignee: Boehringer Ingelheim Vetmedica GmbH
Priority date: 1988-02-20
Filing date: 1989-02-20
Publication date: 1992-03-19
Anticipated expiration: 2009-02-20
Also published as: DE3805382A1; DK72889D0; KR890012648A; EP0330017A2; JPH01249721A; EP0330017A3; AU3009589A; DK72889A

Description

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AUSTRALIA

2 71 5 8 7h 1 PATENTS ACT 1952 62158,0 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: SComplete Specification Lodged: SAccepted: c Lapsed: Published: Priority: R A Related Art: TO BE COMPLTED BY APPLICANT BOEHRINGER INGELBHEIM VETMEDICA GMBH Name of Applicant: Address of Applicant: Actual Inventors: Address for Service: of D-6507 Ingelheim am Rhein, Federal Republic of Germany MANFRED REIFFEN, ECKHARD RUPPRECHT, JOHN FRANCIS QUIRKE and MARIO SOMMER CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Complete Specification for the invention entitled: "USE OF THIAZOLES FOR IMPROVING PERFORMANCE IN ANIMALS".

The following statement is a full description of this invention, including the best method of performing it known to us:m nr la 21L 53 777 Use of thiazoles for improving performance in animals This invention relates to the use of thiazoles for improving growth performance in animals, to grokzo_ performance-enhancing agents containing these compounds and to processes for preparing said agents.

EP-A-239815 describes inter alia thiazoles of formula O Ot 0 0 o re 0000 ego' 00 4r o 0O 000 o 00C 0 0 0 00 0 4.i C

C

4 4.

OR

3

R

4 R1 CH CH 2 N CH CH 2

S

(I)

wherein represents a halogen atom, a (C 1 3 )-alkyl group or a trifluoromethyl group, represents a hydrogen atom and

R

3 and R 4 represents a hydrogen atom or a (C 1 3 )-alkyl group optionally substituted by a hydroxy group in the 2- or 3-position, or together represent an ethylene group or a [(C1- 3 )-alkoxy]-carbonylmethylene group; and represents a methoxy group substituted by a group selected from carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, 04.

hydroxymethyl, alkoxymethyl, aminomethyl and alkylaminomethyl groups, or a 2-carboxy-l-methyl-ethenyl or 2-alkoxycarbonyl-l-methyl-ethenyl group, wherein in each case the alkyl or alkoxy part may contain from 1 to 3 carbon atoms, and all the optical isomers and diastereoisomers thereof, and the acid addition salts thereof.

These compounds have valuable pharmacological properties, namely an effect on metabolism, particularly the effect of lowering blood sugar and reducing body fat, and the effect of lowering the atherogenic beta-lipoproteins VLDL and LDL, whilst some of these compounds also have an anabolic effect.

We have now surprisingly found that the thiazoles of formula I hereinabove may also be used as growth performance enhancers in animals, particularly in order for the animals to achieve higher daily weight gains and improved feed utilisation in animal nutrition. The compounds have been found useful most q notably in the fattening of animals such as sheep, pigs, cattle (calves, oxen, bulls, heifers, and cows), buffalo, rabbits and poultry (pigeons, chickens, turkeys, o. guinea-fowl, pheasants, quails, ducks, and geese).

00 0 Hence, viewed from one aspect, the present invention provides a method of enhancing growth performance in an animal which comprises administering to said animal an effective amount of a compound of formula I as defined above, an optical isomer and/or diastereomer thereof or a physiologically acceptable acid S addition salt thereof.

Physiologically acceptable acid addition salts of the compounds of formula I may be formed, for example, with the following acids: hydrochloric, r J

EF

-3hydrobromic, sulphuric, phosphoric, acetic, oxalic, malonic, fumaric, maleic, succinic, ascorbic, malic, tartaric, lactic, citric, benzoic, methanesulphonic, toluenesulphonic, phthalic, naphthalenesulphonic, nicotinic, palmitic and embonic acid.

Examples of compounds which may be used according to the invention include those wherein R represents a fluorine, chlorine or bromine atom, a trifluoromethyl, methyl, ethyl,

CE

0 a n-propyl or isopropyl group; cct R3 Rrepresents a hydrogen atom and R represents a hydrogen atom, a methyl, c C C ethyl, n-propyl, isopropyl, 2-hydroxyethyl or 3-hydroxy-n-propyl group, or Act r C R and R together represent an ethylene, methoxycarbonylmethylene, ethoxycarbonylmethylene, C n-propoxycarbonylmethylene or isopropoxycarbonylmethylene group; and represents a 2-hydroxy-ethoxy, 2-methoxyethoxy, 2-ethoxy-ethoxy, 2-n-propoxyethoxy, 2-amino-ethoxy, 2-methylaminoethoxy, 2-isopropylamino-ethoxy, carboxymethoxy, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, n-propoxycarbonylmethoxy, aminocarbonylmethoxy, methylaminocarbonylmethoxy, 2-carboxy-l-methyl-ethenyl, 2-methoxycarbonyl-l-methyl-ethenyl, 2ethoxycarbonyl-1-methyl-ethenyl or 2-A isopropoxycarbonyl-l-methyl-ethenyl group.

Preferred compounds of formula I are those wherein 6. -4- R 1 represents a chlorine atom or a trifluoromethyl group; R 3 represents a hydrogen atom and R 4 represents a hydrogen atom, a methyl group or a 2-hydroxyethyl group, or Rand R 4 together represent an ethylene or methoxvcarbonylmethylene group; and tCC C Rrepresents a methoxy group substituted C C CC C by a group selected from carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, hydroxymethyl and CC ethoxymethyl groups, or a 2-carbomethoxyc 1-methyl-ethenyl group, C C the optical isomers and diastereoisomers thereof C I15 and the physiologically acceptable acid addition g salts thereof.

a 0 0 Examples of particularly preferred compounds of formula I include the following: CCt C C C C C (4-Carbomethoxymethoxyphenyl) -1-methylethyl>cc 20 2 -hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethylamine, 4 -Aminocarbonylmethoxyphenyl) -1-methylethyll- 2 -hydroxy-2- (2-trifluoromethyl-thiazol-4-yl)etyaiie 4 -Methylaminocarbonylmethoxyphenyl) -1-methylethyl]- 2-hydroxy-2- (2-trifluoromethyl-thiazol-4-yl) ethylamine, (4-Carbomethoxymethoxyphenyl) -1-methylethyl]- 2- 2 -trifluoromethyl-thiazol-4-yl)morpholine, Methyl (4-carbomethoxymethoxyphenyl)-l-methylethyl]- (2-trifluoromethyl-thiazol-4-yl) -2--oxazolidine carboxylate, (4-Carbomethoxymethoxyphenyl) -1-methylethyl]- N-methyl-2-hydroxy- 2- (2-trifluoromethyl-thiazol- 4-yl)-ethylamine, (4-Carbomethoxymethoxyphenyl) -l-methylethyl]- N- (2-hydroxy-ethyl)-2-hydroxy-2- (2-trifluoromethylthiazol-4-yl) ethylarnine, t (4 -(2-Hydr o xy-ethoxy ph eny) -1-mTe th y 1eth vl1 -2-(2-trifluoromethyl--thiazol-4-yl)morpholine, (C N-[2-(4-Carboxymethoxyphenyl)-l-methylethyll-2- (2-trifluoromethyl-thiazol-4-yl)morpholine, (4-Carbomethoxymethoxyphenyl)-l-methylethyl]- 2-hydroxy-2-(2-chloro-thiazol-4-yl)ethylamine, N- (2-EtidoXY- ethyl) phenyl) -1-methylethyl] 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethylamine, and Cr CC C (C Methyl 3-[2-(4-(2-carbomethoxy-l-methylethenyl)phenyt)- (2-trifluoromnethyl-thiazol-4yl) -2-oxazolidine-carboxylate.

By way of example, effec of the compound 2- (4-carboxymethoxyphenyl) -1methylethenyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine was tested.

1) 2 groups of 7 lambs, in which each animal was /j ~kept separately, were given identical food and 6 6 f, 0 0 o e a water ad libitum. One group was additionally given 8 ppm of the above-mentioned compound. During the 33 day test period, weight gain and food consumption were determined by comparison with the control group.

The results are shown in Table 1: Table 1 Concentration Deviation 10 of test com- from control pound in ppm in 0 8 Starting weight in kg 35.6 35.6 Final weight in kg 41.0 43.9 Weight gain in g/day 164.0 258.0 57.3 Food uptake in g/day 1530.0 1598.0 4.4 Feed utilisation (kg gain/kg feed) 0.107 0.161 50.5 2) 2 groups of 12 lambs were given identical food and water ad libitum. One group was additionally given 8 ppm of the compound mentioned above. During the 42-day test period, the weight gain and parameters of carcass quality were determined by comparison with the control.

0 0oo a 0 d0 0 o o4o 0 00 0000

C

0 CCC 0I CC 0 CC The results are shown in Table 2: fi i i; ii i; 7 Table 2 Concentration Deviation of test com- from control pound in ppm in 0 8 Starting weight in kg 34.8 33.2 Final weight in kg 47.4 46.6 Weight gain g/day 306.0 320.0 4.6 oThickness of fat on back (mm) 1.87 1.78 4.8 SCarcass composition: S- Fat 17.3 16.1 6.9 a 15 Meat 68.3 69.1 1.2 Sa, Bone 14.4 14.8 2.8 Weight of the musculus longissimus dorsi in g 303.0 324.0 6.9 20 3) 2 groups of 10 pigs, in which each animal was fed separately, were given identical food and water "o ad libitum. One group was additionally given 8 ppm of the compound mentioned above. During the 33 day test period, weight gain, feed consumption t 25 and carcass quality were determined by comparison with the control group.

The results are shown in Table 3: ii i I ::lr L i 8 Table 3 Concentration of test compound in ppm 0 8 Deviation from control in C cc Cs C C C CP C

C

rC C r CC Starting weight in kg Final weight in kg Weight gain g/day Feed utilisation (kg feed/kg gain) 40 Carcass yield in Weights of different parts in kg Shoulder Ribs 45 Ham Surface area of rear muscle (cm 2 64.6 96.5 749.0 3.18 76.3 9.27 7.11 7.16 31.9 65.6 97.6 754.0 3.17 77.2 9.48 7.25 7.46 0.7 0.3 1.2 2.3 4.2 32.3 1.3 CC c C C- The compounds of formula I, the enantiomers and distereomers thereof, and the physiologically acceptable acid addition salts thereof will hereinafter be referred to as "the active substances".

In view of the results shown in the Tables, the active substances mentioned above may be used as performance enhancers in animals for promoting and accelerating growth, milk and wool production; for improving feed utilisation and the quality of the slaughtered carcasses; and for increasing the meat-to-fat ratio. The active substances may be used in farm animals, animals for breeding, and also in animals kept for pleasure and as pets.

Farm animals and animals for breeding include mammals 9 such as cattle, pigs, horses, sheep, goats, rabbits, hares, deer, fur animals such as mink and chinchilla, poultry such as hens, geese, ducks, turkeys, fish such as carp, trout, salmon, eels, tench and pike, and reptiles such as snakes and crocodiles.

Animals kept for pleasure and as pets include mammals such as dogs and cats, birds such as parrots, canaries, fish such as ornamental fish and aquarium fish, e.g. goldfish.

1 0 The active substances may be used, irrespective o o of the sex of the animal, throughout all the growth 0000 phases and performance phases. The active substances 001 are preferably used during the intensive growth 0000and performance phase. The intensive growth and 0 0 15 performance phase typically lasts from one month to 10 years, depending on the type of animal.

g The quantity of active substance administered to the animals in order to achieve the desired effect 0 may vary considerably because of the favourable properties of the active substances. The quantity of active substance administered will preferably o00o be about 0.001 to 50 mg/kg, more particularly 0.01 S~ to 5 mg/kg of body weight per day. The proper quantity of active substance and suitable duration of administration will depend particularly on the type of animal, its age, sex and state of health and on the method of keeping and feeding the animals, and may readily be determined by anyone skilled in the art.

The active substances may be administered to the animals by conventional methods. The method of administration will depend particularly on the type of animal, its behaviour and state of health.

i

UL

The active substances may be administered in a single dose. However, they may also be administered temporarily or continuously throughout the entire growth phase of the animal or during part only of it. In the event of continuous administration, the substance may be given one or more times a day at regular or irregular intervals.

The substances may be administered orally or parenterally in suitable formulations or in pure form. Oral preparations include powders, tablets, granules, drenges, boli and feed substances, premixes for feeds, formulations for administering in drinking water.

The oral preparations may contain the active substance in concentrations of from 0.01 ppm to 100%, preferably from 0.01 ppm to e Parenteral formulations may be injections in the t' form of solutions, emulsions, suspensions and implants.

S' R The active substances may be present in the preparations either on their own or combined with other active substances, mineral salts, trace elements, vitamins, proteins, colourings, fats or flavourings.

0 0 O The concentration of the active substances in the feed will normally be about 0.01 to 500 ppm, preferably 0.1 to 50 ppm.

The active substances may be added to the feed as they are or in the form of premixes or feed concentrates.

Thus, viewed from another aspect, the invention provides animal feeds, and premixes for preparing said animal feeds, containing at least one compound of formula I as defined hereinbefore, or an optical

S;

-11isomer or diastereomer thereof, or an acid addition salt thereof together with one or more extenders, diluents and/or excipients.

Viewed from a further aspect, the invention provides growth performanceenhancing compositions for animals, comprising at least one compound of formula I as defined hereinbefore, or an optical isomer or diastereomer thereof, or an acid addition salt thereof in admixture with one or more extenders, diluents and/or excipients.

The invention also provides a process for preparing growth performanceenhancing compositions for animals, wherein at least one compound of formula I as defined hereinbefore, or an optical isomer or diastereomer thereof, or an acid addition salt thereof is mixed with one or more extenders, diluents, nutrients and/or excipients.

i r i The feeds according to the invention may contain in addition to the active substance and optionally in addition to a conventional vitamin/mineral mixture, for t, example, in the case of pigs for fattening, barley, wheat flour, broad beans, shredded rape extract and edible fat and for broilers maize, soya flour, meat meal, edible fat and soya oil, for cattle shredded sugar beet, maize gluten, malt germs, soya bean meal, wheat and molasses and for lambs barley, soya bean flour, maize and molasses. To this feed is added an active substance as defined hereinbefore, most preferably N-[2-(4-carboxymethoxyphenyl)-l-methylethenyl]-2-(2- S trifluoromethyl-thiazol-4-yl)morpholine, in a concentration of 0.01 to 500 ppm, preferably 0.1 to 50 ppm, the mixing preferably being carried out in the form of S a preliminary mixing of active substance. This premix contains, for example, mg of active substance to every 10 g, conveniently in 9.99 g of corn starch.

CCCa t The Examples which follow are intended to illustrate the invention without narrowing its scope in any way: t D E i 1 groups, or a 2-carboxy-1-methyl-ethr E, r 2 -alkoxycarbonyl-l- /2 ll' f: I Example 1 Complete feed II for fattening pigs Barley 370 g Wheat flour 200 g Manioc flour 135 g Broad beans 100 g Shredded rape extract 100 g Edible fat 65 g Lysine-rich mineral feed for pigs 20 g Active substance premix 10 g These components in the quantities specified produce 1 kg of feed after careful mixing. The 10 g of active substance premix may contain, for example, 10 mg of active substance and 9.99 g of corn starch.

Example 2 3 Fattening feed II for broilers Maize 625 g Soya flour 260 g Meat meal 40 g Edible fat 25 g Soya oil 17 g Bicalcium phosphate 12 g Calcium carbonate 6 g Vitamin/mineral mixture 5 g Active substance premix 10 g These components in the quantities specified yield 1 kg of feed when thoroughly mixed.

The 10 g of active substance premix may contain, b4IA 4 for example, 10 mg of active substance and 9.99 g A of corn starch.

Example 3 Build-up feed for cattle Shredded sugar beet 600.0 g Maize gluten 100.0 g Malt germs 50.0 g Soya flour 35.0 g Wheat 110.0 g Molasses 60.0 g Edible phosphates 12.0 g Calcium carbonate 2.5 g Salt 5.0 g Minerals 10.0 g I 4 Vitamin premix 5.5 g These components in the quantities specified will yield 1 kg of feed after thorough mixing.

The 10 g of active substance premix may contain, for example, 10 mg of active substance and 9.99 g of corn starch.

Example 4 Fattening feed for lambs Barley 690 g Soya flour 100 g Maize 150 g Molasses 30 g Vitamin/mineral mixture 20 g Active substance premix 10 g These components in the quantities specified yield 1 kg of feed when carefully mixed together.

A The 10 g of active substance premix may contain, e3 I6i L for example, 10 mg of active substance and 9.99 g of corn starch.

0 04 00 4 00 C0 0 0 to~Q

Claims

1. A method of enhancing growth performance in an animal which comprises administering to said animal an effective amount of a compound of formula I OR 3 N R CH CH 2 S Rq CH 3 N -CH CH 2 R (I) wherein r r i' c C Ct C C *54 (CCC C C R represents a halogen atom, a (Cl 3 )-alkyl group or a trifluoromethyl group, R 3 represents a hydrogen atom and R4 represents a hydrogen atom or a (C 1 )-alkyl group optionally substituted by a hydroxy group in the 2- or 3-position, or R 3 and R 4 together represent an ethylene group or a [(C 1 3 )-alkoxy]- carbonylmethylene group; and R5 represents a methoxy group substituted by a group selected from carboxy, alkoxy-carbonyl, aminocarbonyl, alkylaminocarbonyl, hydroxymethyl, alkoxymethyl, aminomethyl and alkylaminomethyl groups, or a 2-carboxy-l-methyl-ethenyl or 2-alkoxycarbonyl-1- methyl-ethenyl group, wherein in each case the alkyl or alkoxy part may contain from 1 to 3 carbon atoms, an optical isomer and/or diastereoisomer thereof, or an acid addition salt thereof.

2. A method as claimed in claim 1, characterised in that in the compound of formula I R, represents a chlorine atom or a trifluoromethyl group; R 3 represents a hydrogen atom and R4 represents a hydrogen atom, a methyl group or a 2-hydroxyethyl group, or R 3 and R 4 together represent an ethylene group or methoxycarbonylmethylene grbup; and r i' I -16- R 5 represents a methoxy group substituted by a group selected from carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, hydroxymethyl and ethoxymethyl groups, or a 2-carbomethoxy-l-methyl-ethenyl group.

3. A method as claimed in claim 1, wherein the compound of formula I is N- [2-(4-carboxymethoxyphenyl)-l-methyl-ethenyl]-2-(2-trifluoromethyl-thiazol-4- yl)morpholine, an optical isomer thereof, a diastereoisomer thereof or a physiologically acceptable acid addition salt thereof.

4. Animal feeds and premixes for preparing the animal feeds for use in the method of claim 1, which include at least one compound of formula I as defined in any one of claims 1 to 3, or an optical isomer or diastereoisomer thereof, or an acid addition salt thereof together with one or more extenders, diluents, nutrients and/or excipients.

A growth performance-enhancing composition tor animals, comprsin at least one compound of formula I as defined in any one of claims 1 or an S optical isomer or diastereoisomer thereof, or an acid additi salt thereof, in S admixture with one or more extenders, diluents, nutrie and/or excipients.

6. A process for preparing a growth perfor ce-enhancing composition for animals, wherein at least one compoun formula I as defined in any one of claims 1 to 3, or an optical isomer fdiastereoisomer thereof, or an acid addition salt thereof is mixed wit ne or more extenders, diluents, nutrients and/or excipients.

7. A pr ss as claimed in claim 6 substantially as hereinbefore described and withreference to any one of the Examples. S DATED this 12th day of November 1991. ctt BOEHRINGER INGELHEIM VETMEDICA GmbH By their Patent Attorneys: CALLINAN LAWRIE C L IAn\-v I !i 1