JPH0558912A - Method for controlling propagation rate of vertebrate animal by composition containing peripheral dopamine activating substance and said composition - Google Patents

Abstract

PURPOSE: To obtain the composition comprising a peripheral dopaminergic substance such as an ergoline derivative, a carrier and a vehicle and useful for completely reducing the propagation of rodents such as mice, rats and rabbits. CONSTITUTION: The subject composition comprises a peripheral dopaminergic substance, especially an ergoline derivative of formula I [R1 , R2 are each methyl, ethyl, isopropyl or dimethylaminopropyl (R1 and R2 are simultaneously not dimethylaminopropyl, respectively); R3 is propyl, allyl; R4 is H, Cl, Br] or its acid adduct salt, especially 1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'- allylergoline-8'β-carbonyl)-urea, a vehicle and a carrier, e.g. grains such as wheat, corn, barley, oats, rye, rice or soybean in the form of seeds or their flour, or chopped dry fruits or vegetables. The compound of formula I is obtained by reacting a compound of formula II with a carbodiimide of formula III.

Description

Detailed Description of the Invention

[0001] The present invention relates to a method for suppressing the reproductive rate of vertebrates by a composition containing one or more peripheral long-acting dopamine agonist type D-2 and the composition.

The use of known rodenticides such as warfarin and many warfarin-like products, 4-hydroxy-coumarin derivatives, is based on the very strong anticoagulant activity of the oral antivitamin K type. This activity causes lethal internal hemorrhage in rodents. The main drawback of the known rodenticides is that they can also kill domestic animals, such as cats, dogs or other pets, who might feed on bait of these compounds.

The object of the present invention is to avoid the above-mentioned drawbacks of the known rodenticides, to make them highly fertile and directly or indirectly human,
The present invention provides a composition for use in a method for suppressing or even eliminating the survival rate of newborn vertebrates that cause significant harm to livestock animals and / or the environment.

More specifically, the object of the present invention is to provide a completely new method for drastically reducing the reproduction of some mammals, especially rodents such as mice, rats, rabbits and the like. ..

According to the invention, the above-mentioned object is to propagate vertebrates using a composition which is characterized in that it comprises one or more peripheral dopamine agonists together with customary carriers and excipients. Achieved by controlling the rate.

Furthermore, the present invention is characterized in that a composition comprising one or more peripheral dopamine agonists together with conventional carriers and excipients is applied to the area where the vertebrate develops. It is intended to provide a method for suppressing animal reproduction.

Finally, the present invention provides the use of a peripheral dopaminergic agent to control vertebrate fertility.

The method of the present invention, described in detail below, consists essentially of adequately suppressing the luteinizing hormone endocrine secretion in female rodents from pre-puberty to postpartum. It differs from the usual hormonal contraceptives used to inhibit the excessive fertility of certain vertebrates, such as pigeons.

This appropriate inhibition is achieved by feeding the animals with a diet containing the potent peripheral dopamine agonist type D-2, which has a very long lasting effect.

With the proper dosage of the feed or the active ingredient in the feed, the following three objectives, leading to a drastic reduction or elimination of progeny that can be derived from each female rodent, are achieved: Can have an effect.

(A) Delay the onset of fertility in female rodents, resulting in a shorter fertility period.

(B) Even when mating during the fertility period of the animal, it exerts an inhibitory effect on implantation.

(C) whether lactation is reduced or totally suppressed even after delivery, resulting in reduced survival.
Or eradicate all littermates by dying.

In other words, without having to kill the rodent with a toxic substance such as a 4-hydroxy-coumarin derivative,
The three effects reported above may substantially reduce the rodent population according to the invention. The use of the above toxic substances represents a hidden hazard to humans, livestock animals and the environment.

Examples of dopamine agonists used within the scope of the present invention include Bromocriptine (German Patent No. 19 26 045), Pergolide (US).
-A-4166 186) and Lislide (Semonsky)
Coll. Czech. Chem. Comm. 25, p. 1922, 1960).

These are short-acting dopamine agonists or give central agonist activity, the latter
So-called "state dependent learning"
It immediately alerts the presence of the active ingredient in the feed or feed and is characterized in that it is completely unsuitable for administration to rodents.

Accordingly, preferred dopamine agonists according to the present invention have the following structural formula (I):

[0018]

[Chemical 4]

(Wherein R ₁ and R ₂ independently represent a methyl-, ethyl-, isopropyl-, dimethylaminopropyl-group, provided that both R ₁ and R ₂ are dimethylaminopropyl. R ₃ represents a propyl- or allyl-group, and R ₄ represents a hydrogen-, chlorine-, or bromine-atom), or an ergoline derivative or an addition salt with a usual organic or inorganic acid. ..

A particularly preferred dopamine agonist is cabergoline, ie 1-ethyl-3-
(3′-dimethylaminopropyl) -3- (6′-allyl ergoline-8′β-carbonyl) -urea.

The ergoline derivatives of general formula (I), their process of preparation and their pharmaceutical use as antihypertensive, antiprogestin and antitumor agents are already described in US Pat.
It is known from 526892. However, the patent does not describe the use of the present invention for controlling the reproductive rate of vertebrates. According to the description of said US patent, the ergoline derivative of general formula (I) is an acid having the following general formula (II):

[0022]

[Chemical 5]

And a carbodiimide having the following general formula (III):

[0024]

[Chemical 6]

(In these formulas, R ₁ , R ₂ , R ₃ and R
₄ has the meaning given above).

The reaction is carried out in a solvent such as tetrahydrofuran, dimethylformamide or dioxane, optionally in the presence of an organic base such as pyridine or triethylamine.
Suitably it is carried out at a temperature of 50 to 100 ° C. for 5 to 24 hours. When the reaction is complete, the product can be isolated and produced by the following conventional methods such as chromatography and / or crystallization. The intermediate acids of general formula (II) are known compounds or may be prepared from the corresponding esters by saponification reactions. The intermediate ester in which R3 is a propyl- or allyl-group is described by AM Crider et al., Journal of Pharmac.
eutical Sciences, Vol.70, No.12, pp.1319-1321 (198
Manufactured by 1). It can be prepared from the corresponding 6-nor-derivative.

The formation of the desired pharmaceutically acceptable salts with customary organic or inorganic acids is carried out by known methods, for example by reaction with suitable acids.

A preferred compound within the class of Structural Formula I of the present invention is 1-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-allyl ergoline-8'β-carbonyl) -urea. , Non-proprietary generic name "Cabelgoline"
Is.

Cabergoline can be used both as the free base and as addition salts with customary organic or inorganic acids.

When a single oral administration of 100 micrograms per 1 kg of body weight (100 mcg / kg of body weight) to female rats, the action of inhibiting luteinizing hormone endocrine remains remarkably high even 72 hours or more after administration.

Therefore, the long-acting anti-prolactinic effect of cabergoline.
It is quite suitable as a surprising method to drastically reduce the reproductive rate of rodents according to the three effects described above, from preconception, during the prepartum stage, and up to the neonatal stage. It also gives a purpose. At the same time, this method is absolutely safe for humans, for livestock animals (even if they happen to eat cabergoline-containing feed), and for the environment. ..

In fact, it is well known from the literature that the acute toxicity of cabergoline in animals is very low.

For example, the LD ₅₀ (semi-lethal dose) by oral administration is 350 mg / kg body weight in male mice and 200 in female mice.
mg / kg body weight. LD _{50 in} rats is 4 in males
The dose is 00 mg / kg body weight and 350 mg / kg body weight for females.

Another advantage of the compositions and methods of the present invention is 4
While the toxic effect of -hydroxy-coumarin is irreversible, the inhibitory effect of luteinizing hormone caused by compounds of structural formula I, especially cabergoline, is completely reversible. Discontinuing administration of the above compounds restores the normal physiological state in a dose-dependent manner, but some days after administration.

Another significant effect of the compositions and methods of the invention of reliably eradicating rodents is that the active ingredient at the doses used in the feed or feed confers only a peripheral effect, while the central nervous system. Is shown by the fact that it totally avoids any effect on. As a result of this property, so-called "state-dependent learning" does not take place, ie the animal becomes vigilant and immediately notices that "dangerous" active ingredients are "present" in the feed or feed, resulting in It is possible to avoid that the animal refuses to eat any more. It is clear that this is an effect superior to that of conventional rodenticides and to peripheral activity as well as other centrally active dopamine agonists.

Ordinary organic acids such as tartaric acid, citric acid or methanesulfonic acid or inorganic acids such as phosphoric acid, sulfuric acid or hydrochloric acid, dissolved in water or in a suitable polar organic solvent such as ethanol or acetone and water. Cabergoline as an addition salt with or as a free base or other compound of the general formula (I) is wheat, corn, barley,
Rodents consisting of oats, rye, rice, soybean seeds or cereals in the form of flour, or all other rodent-attractive carriers such as chopped dried fruits or vegetables, such as apples or carrots It is used by being impregnated with a usual feed or feed for use. Appropriate excipients may be added to increase palatability.

The cabergoline as salt may be dissolved in the drinking water provided to the animal.

Whatever the mode of administration (feed / bait, drinking water) used, cabergoline 0.0005-0.
It is blended in a proportion in the range of 05 wt%.

Within the scope of the present invention, it is preferred to make the bait from the grain flour described above, suitably impregnated with pelletized and dried cabergoline. The average weight is 0.5 to 2.0 g and the content of cabergoline is 0.0005 to 0.05% by weight, based on the dry weight of the pellets.

Cabergoline as the free base is MI
It can be advantageously dissolved in neutral oils such as GLYOL® (manufactured by DYNAMIT NOBEL). The best type of neutral oil, fractionated coconut oil fatty acids C ₈ -C meeting the purpose
MIGLYOL 812, which is a triglyceride of ₁₀ (“caprylic / capric triglyceride”). A preferred concentration is 50 micrograms of cabergoline per ml of solution. The oily solution thus obtained can be suitably used for impregnating feed or feed.

[0041]

The following examples are intended to illustrate the invention, but not to limit its scope.

Example 1 500 g of wheat flour and 500 g of soybean flour were suspended in a sufficient amount of water under stirring to prepare a uniform porridge. 5 mg of cabergoline as the free base was then added with stirring in the form of the diphosphate dissolved in a small amount of water. If desired, a few drops of edible aroma attractant for rodents may be added.

The porridge is left to stir for 10 minutes and then subjected to a suitable pellet-forming machine and the pellets obtained are kept at 45 ° C.
Dried "under vacuum".

The product pellets prepared for administration to rodents, weighing 0.5 to 2.0 g, contain cabergoline in a proportion of 0.0005%, ie 1 g of composition contains about 5 micrograms of active ingredient. ..

In order to examine the effect of reducing the survival rate of rodent pups of the pellets thus obtained, 1 to 3 days after the birth of children per group, breastfeeding was performed.
Three groups of 5 Wistar rats were used. The animals were fed "optionally" with the above pellets except drinking water. After 5 days many pups died.

Example 2 Results obtained by testing in young female rats of the prepubertal stage show that they are sexually mature at 25 mcg / kg body weight / day of the “oral” test dose. Proved to significantly delay Furthermore, administration of cabergoline at 25 mcg / kg body weight / day for 10 days in an “oral” test dose prior to mating of adult female rats always completely inhibited fertility. The same administration to pregnant rats interrupted their gestation after about 10 days, while control rats delivered normally.

Example 3 Adult Female Rats (Sprague Dawley) Having a Second Delivery
Fifteen were randomly divided into 3 groups of 5 each. One group served as a control and the other two groups were treated with different doses of cabergoline. The dose is 25m for animals in the previous group starting the day after delivery.
cg / kg body weight / day, 100m for animals in the latter group
Cg / kg body weight / day was administered.

Rats (Altromin MT® of parenting) rearing cabergoline with a standard diet in pellet form.
The firm Rieper, Bolzano). Food and water were provided ad libitum after the drug pellets were completely depleted.

The survival rate of the pups at the dose of 25 mcg / kg body weight / day was calculated based on the mortality rate on the 14th day after feeding and 7 after feeding.
It was assessed by the significant decrease in body weight gain on days 14, 14 and 21. With this administration,
60% died within the second week of lactation.

With 100 mcg / kg body weight / day, 100% of the mice died within the first week of lactation.

[0051]

[Table 1]

Claims (15)

[Claims] 1. A composition for controlling the reproductive rate of vertebrates, which comprises one or more peripheral dopamine agonists together with conventional carriers and excipients. 2. A peripheral dopamine agonist is represented by the following general formula (I): (In the formula, R ₁ and R ₂ independently represent a methyl-, ethyl-, isopropyl-, dimethylaminopropyl-group, provided that both R ₁ and R ₂ are not dimethylaminopropyl; R ₃ represents a propyl- or allyl-group, and R ₄ represents a hydrogen-, chlorine-, or bromine-atom), an ergoline derivative or an addition salt with a usual organic or inorganic acid. Claim 1
The composition according to. 3. The ergoline derivative is 1-ethyl-3-
(3′-dimethylaminopropyl) -3- (6′-allyl ergoline-8′β-carbonyl) -urea, or an addition salt with an ordinary organic acid or inorganic acid The composition according to claim 2. 4. Wheat, corn, barley, oats,
Grains in the form of rye, rice and soybean seeds or flour, or chopped dried fruits or vegetables, and optionally suitable excipients added to increase palatability, and further 1-ethyl- 3- (3'-dimethylaminopropyl) -3- (6'-allyl ergoline-8
4. The composition according to claim 3, characterized in that it is in the form of a feed or bait containing 0.0013 to 0.05% by weight, based on the total weight of the composition, of'β-carbonyl) -urea or an addition salt thereof. 5. The composition according to any one of claims 1 to 4, wherein the vertebrate is a rodent. 6. Inhibition of vertebrate reproduction, characterized in that a composition comprising one or more peripheral dopamine agonists together with conventional carriers and excipients is applied to the area where vertebrates develop. Method. 7. The peripheral dopamine agonist is represented by the general formula:
(I): [Chemical formula 2] (In the formula, R ₁ and R ₂ independently represent a methyl-, ethyl-, isopropyl-, dimethylaminopropyl-group, provided that both R ₁ and R ₂ are not dimethylaminopropyl; R ₃ represents a propyl- or allyl-group, and R ₄ represents a hydrogen-, chlorine-, or bromine-atom), an ergoline derivative or an addition salt with a usual organic or inorganic acid. Claim 6
The method described in. 8. The ergoline derivative is 1-ethyl-3-
(3'-Dimethyl-aminopropyl) -3- (6'-allyl ergoline-8'β-carbonyl) -urea or an addition salt with a usual organic acid or inorganic acid. The method described in. 9. Wheat, corn, barley, oats,
Grains in the form of rye, rice and soybean seeds or flour, or chopped dried fruits or vegetables, and optionally suitable excipients added to increase palatability, and further 1-ethyl- 3- (3'-dimethylaminopropyl) -3- (6'-allyl ergoline-8
9. The method according to claim 8, which comprises applying a feed or feed containing 0.003 to 0.05% by weight of the β-carbonyl) -urea or an addition salt thereof, based on the total weight of the composition. 10. The method according to any one of claims 6 to 9, wherein the vertebrate is a rodent. 11. A method for suppressing the reproductive rate of a vertebrate,
Use of peripheral dopamine agonists. 12. A peripheral dopamine agonist is represented by the general formula:
(I): [Chemical Formula 3] (In the formula, R ₁ and R ₂ independently represent a methyl-, ethyl-, isopropyl-, dimethylaminopropyl-group, provided that both R ₁ and R ₂ are not dimethylaminopropyl; R ₃ represents a propyl group or an allyl group, and R ₄ represents a hydrogen-, chlorine-, or bromine-atom)
Use according to claim 11, characterized in that it is an ergoline derivative having or an addition salt with a common organic or inorganic acid. 13. The ergoline derivative is 1-ethyl-3.
13. An addition salt with-(3'-dimethylaminopropyl) -3- (6'-allyl ergoline-8 '?-Carbonyl) -urea or a usual organic acid or inorganic acid. Use as described in. 14. Wheat, corn, barley, oats, rye, grains in the form of seeds or flour of wheat and soybeans, or dried fruits or vegetables in chopped form, and optionally added to increase palatability. 1-ethyl-3- (3'-dimethylaminopropyl) -3- (6'-allyl ergoline-8) containing appropriate excipients
14. Use according to claim 13, characterized in that a feed or bait containing'β-carbonyl) -urea or an addition salt thereof in an amount of 0.0005 to 0.05% by weight, based on the total weight of the composition, is applied. 15. Use according to any one of claims 11 to 14, characterized in that the vertebrate is a rodent.