TW200407115A - Organic compounds - Google Patents

Abstract

The provision of animal feed pellets is described, which pellets comprise, as antibiotic, a pleuromutilin derivative in stabilised form, namely in the form of microspherules. The pleuromutilin derivatives in question have the general formula I, wherein R1 is ethyl or vinyl, there is either a double bond or a single bond between carbon atoms 1 and 2, Ra and Rb are each independently of the other hydrogen or halogen, and T is a short or long-chain organic radical.

Description

200407115 发明 、 Invention description :::::: ":; ...:. :::::::::::::::::::::::; ::;.; ^:; ≫ | ::: |. :::::::; ::: v '; · :::: v; ^;'. Y;:;-;- -:,:; F :: 'III:;-::! ::: > · ί: · :::: ;; :: .. i:' :; f: l :::::::: : '; ::::::; :::;. :: ;; :: ;; :: ^; i ::: fi ::! ::: ^'; :: :: 0; i: iv 1ί ::::-::!-::-; ...- :: i:;: i: l: ^ ::!: ^; '::: ...: M; !: Η ;: ^ :: ;;;;; :::!: ;;;;;;;!;;: I: ^: ;; :::: '. [Technical Field to which the Invention belongs] This The invention is related to the provision of animal feed pellets comprising pleuromutilin derivatives in a stabilized form as antibiotics. The invention also relates to the preparation of stabilized pleuromutilin derivatives, the preparation of such animal feed particles, and the use of the method for controlling infectious diseases in animals. Pleuromutilin derivatives are to be understood below as compounds comprising the macrocyclic fragment of the following formula (I) as a feature:

Where Ri is ethyl or vinyl; there are double or single bonds between carbon atoms 1 and 2, Ra and Rb are each independently hydrogen or halogen; and τ is a short or long chain organic group, which is relatively It is preferably as defined below. In some announcements, the terms pleuromutilin, valnemulin, Q tiamulin, and Q mutilin) are used synonymously. The term pleuromutilin will be used consistently here. [Prior art] Pleuromutilin is the most modern and effective antibiotic currently used in veterinary medicine. Their most well-known representatives include Tiamutin® (active substance: tamarind) as described below, and more recently Econor (g) 200407115 (active substance: valnarin). Both of these substances can be used very successfully in animals to combat the full range of infectious bacterial diseases of the respiratory organs and digestive tract, and even in the case of problems, where high-dose mixtures of traditional antibiotics are at best only possible with many active substances When used in the form (because resistance has now developed), both substances can also show their full effect. Pleuromutilin's range of activity includes, for example, pathogens such as Streptococcus aureus, Staphylococcus aureus (), Arthritidis arthritis (M. k) , Bovine mastitis mold (M. mountain \), Bovine nose mold (M · Z ^ Wr / z / nb), Mycobacterium spp. 57? _), Canine mold (M. canis), cat Mycoplasma (M ·, fermented mycoplasma (M ·, chicken mold (M. ga // z_MrWm), chicken septiceomyces (M. gallisepticum), granular mycelium (M · gM / zw / arwm), human mycoplasma (M.), mycoplasma hyorhinis (m_ 办 〇 カ · —), actinomyces lei (Xci / ⑽, turkey mycoplasma (M. meleagridis), neurolysin M. neurolyticum, M. pneumoniae and M. hyopneumoniae. In addition, WO 98/01 127 shows the significant activity of valinomycin against the disease syndrome, the disease Symptom groups can occur anywhere in captive animals, for example, for transportation purposes, in highly confined spaces (increased stocking densities) 'resulting' animals are highly stressed In the meantime, the most common pathogens that play a decisive role in 200407115 are Mycoplasma hyopneumoniae, Treponema hyodysenteriae (heart rpW / and (formerly known as Treponema) hyodys enter iae), Treponema pallidum (heart), intracellular Lawsonia intracellularis, Mycoplasma gallisepticum, Pasteurella multocida (), Actinobacillus pleuropneumoniae (Actinobacillus (Haemophilus)) and Haemophilus parasuis (// · par like w / s), accompanied by respiratory diseases and other infections, usually occur together and lead to complex clinical conditions. All herd animals (such as cattle, sheep and pigs) and poultry are affected. In today's large-scale livestock farming, such as pigs, cattle, horses, sheep, and poultry, the above-mentioned animal diseases cannot be eliminated by the administration of antibiotics, because these diseases will spread rapidly through the entire fauna, and (unless passed through Treatment) will cause unbearable losses. Therefore, there is a great demand for effective antibiotics, which can be used before a large number of herds are affected Rapidly increasing the control of infectious diseases in animals. Although pleuromutilin meets all expectations of efficacy as antibiotics, they do have the common disadvantage that cannot be underestimated, that is, the instability of their administration forms, Because they are easy to handle, they are particularly important in veterinary medicine. As disclosed in WO 01/41758, pleuromutilin, especially in the form of a free base, is particularly unstable, which obviously results in them being added with acid. It is used in the form of a salt, preferably the hydrochloride 'is usually in the form of an injection solution. Acid addition salts have storage stability of up to 5 years at room temperature. In the case of animals, oral administration is by far the equivalent of 200407115, and can only be used to a limited extent, even in the form of feed supplements. Although in the human case, antibiotics can be administered in a wide variety of administration forms, such as lozenges, dragees, emulsions, injectable solutions, and the like, as they may depend on the self-discipline of the human patient and his or her desire to recover , But in the case of animals, there are quite a few practical issues that need to be addressed quickly. ^ In animals, there must be natural preparations for oral pharmaceutical preparations. Of course, a single animal or a small number of animals can be compulsorily treated, and antibiotics must be administered to the animal by choking or injection. However, such a coercive method is unacceptable for large animal populations, as it is labor-intensive, requires a veterinarian to appear in each individual case, and ultimately results in high costs, which will not pass through meat and dairy products. Consumers, because of competition. Therefore, in large-scale livestock breeding, simple and reliable forms of dosing are still being sought, so that the animal's breeder can operate as independently as possible, or even fully automatically, and keep costs within acceptable limits . One way to meet these factors is to administer precise doses of antibiotics, which are contained in dry animal feed, i.e. in so-called feed pellets. At present, domestic animals and productive livestock (for example, pigs, but also cattle, sheep, and poultry) are usually kept in animal buildings equipped with the most modern, fully automated feeding systems. In such an example, the feed is fully and automatically distributed according to the age and weight of the animal, and is delivered to each animal, and is loaded into its feed trough at a precisely scheduled time and amount every day. Such feed pellets are often used in such fully automated systems. A pellet is a plant- and / or animal-based, compact, highly compressed, concentrated dry feed that can be enriched with additives such as proteins, vitamins, and minerals. Such feed pellets are simple synthetic, mass-producible, round or long pellets, pellets, or depending on the manufacturing method 'are uniformly-shaped fragments formed in rods, which match the type and age of the animal' and range It ranges from a few millimeters (for poultry) to about 1 cm (for fully grown pigs and cattle). Commercial feed mills produce feed pellets by grinding organic ingredients, mixing the ingredients in the desired composition, and finally compressing the pellets into pellets; the pellets are bagged and shipped to animal breeders, and then the They fit into the distribution system. A clear advantage of such particles is that they are easy to handle due to their uniformity, mass productivity, and storage stability. They can be easily and completely emptied from the container, rationed, transported via conveyor belts or tubes, and given to each animal in precise amounts. In addition, the pellets take up less space than fresh feed, and most importantly, the pellets can be eaten happily by animals without any problems. Therefore, it is advantageous not only to add protein and other nutrients (for example, vitamins and minerals) to the granules, but also to add antibiotics when needed. This is actually happening, but in the case of the pleuromutilin-type active ingredients discussed here, there are special dilemmas that are illustrated, these dilemmas are specific to the substance type and will be further described below explain in detail. It has been found that pleuromutilin is somewhat unstable during the preparation of feed pellets, 200407115, especially when in contact with feed materials, especially plant and animal fibers, which results in considerable losses as early as during the preparation process . In the preparation of feed pellets, the dried animal and plant-derived organic raw materials are ground, and the additives, vitamins, trace elements, antibiotics (in the case of pleuromutilin derivatives) are thoroughly mixed, etc., which is the essence The ground is homogenized and then moistened with about 5 to 10% by weight of water or steam, and at a high temperature of about 60 to 80 ° C, preferably 65 to 75 ° C, at about 1 to 100 仟 bar (kbar ) Pressure, usually 25 to 100 bar, and compressed into particles. Fixed high temperatures (e.g. 100 ° C) have a negative tendency and can drastically reduce the viscosity of the particles. Local short-term temperature peaks of up to 20 ° C within the press (so-called flashing), on the contrary, will not cause problems. In the press, the residence time of the pellets is about 5 to 180 seconds, preferably 10 to 90 seconds, and especially depending on the size of the particles. Although pleuromutilin in its pure form can be very tolerant of such temperatures itself, and can be stored at room temperature for even months without any measurable Loss of active ingredients, but under pressure and when animal or plant fiber is thoroughly mixed in the feed, and at general high temperatures, they will decompose quite quickly. It is shown that contact with the fiber can actually catalyze the decomposition Process. Even if the high-pressure and high-temperature periods are maintained as technically as possible and the final particles are cooled directly to room temperature immediately after the compression process, 1/4 to 1/3 of the active ingredient will still be lost. Even if degraded The product will not have an adverse effect on the animals being treated, but the inevitable loss of active ingredients will still inevitably lead to a substantial increase in the cost of the final product. Pleuromutilin, which is still intact in the granules, is 12 200407115, which has less storage stability than, for example, pure active ingredients. Even at room temperature, the degradation of the active ingredients in the final granules will continue. 3 After a few months, the content of the active ingredient has dropped to less than 60%. To date, this relative instability also means that the active ingredient in the form of feed pellets can be administered in the exact dose, which can only be performed for about 4 to 6 weeks after the pellets are prepared Therefore, animal breeders have so far been forced to use only fairly freshly prepared pellets. They cannot store a proper amount of pellets in the long-term and must issue new production orders to feed mills about every 4 to 6 weeks to supply Fresh feed with guaranteed antibiotic content. Although this is technically feasible, it involves a high degree of logistical planning and causes feed factories to repeatedly execute small orders, which are not necessarily suitable for their production plans, which would Leading to inconvenient waiting times, and in particular additional particle costs. Therefore, for the above reasons, more effort Forces have been directed towards stabilized pleuromutilin, which allows them to withstand high temperatures and pressures during particle preparation without loss of active substances, and when present in the form of final particles, also has long-term storage suitable for practical use. Stability. Failed attempts at such stabilization include, for example: (1) reducing the surface area of active ingredients by compressing them into granules, trying a wide variety of particle sizes; (2) sealing these active ingredient particles In very diverse protective layers, such as gelatin or various sugars and coatings; (3) Encapsulating active ingredients in porous materials, such as various cellulose, starch, silicic acid or zeolites, with or without other And (4) chemical modification of the basic macrocyclic structure of the active ingredient. Although in some cases the chemical modification has resulted in improved stability of the compound itself, it has also resulted in a loss of activity of 13 200407115. However, none of these attempts have resulted in significantly less loss of active ingredients in compressed pellets or produced measurably improved storage stability. Surprisingly, however, a user-friendly method of administering feed pellets in a form that no longer shows the disadvantages of the above-mentioned active ingredients has been successfully achieved. Surprisingly, pleuromutilin 'can now be stably truncated, which not only can withstand the undamaged particle preparation, but also survive a long enough storage period. [Summary of the Invention] Although the present invention is described below with reference to a specific embodiment of pleuromutilin, it is clearly and equally applicable to Tiamutin® / Tiamulin and other cuts having the basic macrocyclic structure of formula (I) shown at the beginning Pleuromutilin derivatives. In the context of the present invention, the pleuromutilin of the following formula (I) is preferred: a oh

Where h is ethyl or vinyl; (A) has a single bond between carbon atoms 1 and 2; Ra and Rb are H; and T is one of the following (a) to (i) groups: (a) -CH2 -OH; (b) 14 200407115

(C)-(CH2-X) m- (CH2) n-N (R2) (R3), where X is -ο-, -S-, -ΝΗ- or

m is 0 or η is an integer from 2 to 5; 1 and R3 are each independently a CV6 alkyl group, or together with the nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclic ring containing _8_, -0_S -N (R4) as a heteromolecular part, where R4 is Cr6 or Cw, and Y and Z are each independently -0- or -S-; (d) · 0Η24-((: Η2νΝ (I15) (I16), wherein k is an integer from 2 to 5; and R and R6 are each independently a Ci.6 alkyl group; (e) -CH2-SC (CH3) 2-CH2-NH-C (0) -R7, wherein R7 is a CV6 alkyl group substituted with -NH2, or a saturated 5-membered heterocyclic ring containing one or two heteroatoms selected from -S_ and -NH-; (f) -CH2- SC (CH2) rR8, where 1 is 0 or 1, and 118 is a group

Where K is Η, Cw alkylsulfonium, _NH2,-

CH0, -N (R9) (R10), S- (CH2) q-N (R9) (R1〇) or 忑 ⑹-Laixin, G is oxygen or sulfur, rule 9 and above. Each independently is fluorene, cv6 alkyl, cv6 alkylsulfonium, Ci-6 hydroxyalkyl, CV6 dihydroxyalkyl, or unsubstituted or substituted cv6 alkyl sulfonium; () Together with the nitrogen atom to which they are bonded, an unsubstituted or substituted Duncan group is formed, in which the second nitrogen 15 200407115 atom is substituted by a substituent selected from the group radical 1 Ci. And c "two-base

Is fluorene, Nii 11 alkyl or OV6 alkyl carbonyl; Q 'is as defined above; Cl. 6 alkynyl, galidine or Na 9) (Rl °), I and CH N 3 CH2a,' ChBi ·, -CH2SCN, -CH2-NH2, -CKC〇 Collar, · wo, — ^; and "Lu N (Rl5) (Rl6), where Rl5 and R" are the same or different, H; unsubstituted or Substituted, straight or branched, saturated a == C1.6 hydrocarbyl; unsubstituted or substituted, saturated or unsaturated white aromatic unsubstituted ring-substituted; and unsubstituted or substituted; or 1 " 5 And the nitrogen atoms bound to them ^ 3_ to 8_ member ring 'which does not contain other _xuanmei containing other heteroatoms selected from the _ series; or k is one of the above groups, r16 疋 -s 〇2r17, -c (0) Ri8, _0_u 戦 is the choice of free unsubstituted forward lean, straight _ branch _, _ or unsaturated C1-6 warp group; unsubstituted or substituted, saturated or unsaturated c Yanyuan Group; unsubstituted Qing ⑽ unsubstituted simple substituted fangqi ==: — 6 _ group; and unsubstituted or substituted cardiyl amine: leg into _ group; r18 is _ free H; face generation Qing =

Chain or branched, saturated or unsaturated hydrocarbon groups; unsubstituted or L, saturated or unsaturated _c3_8 scale groups; unsubstituted bridging heterocyclic and unsubstituted or substituted aryl groups; R is I9 / 乂 K2. Is quotient or different, and is a free, unsubstituted, substituted, saturated or unsaturated Ci_6 hydrocarbon group of 16 200407115; unsubstituted or substituted, saturated or unsaturated C3_8 cycloalkyl group; unselected A substituted or substituted heterocyclic ring; and a group of unsubstituted or substituted aryl groups; or together with the nitrogen atom to which they are bonded to form a 3- to 8-membered ring group, which may include optional free_N- , _〇_, and other heteroatoms in the group they are composed of; (B) there are double bonds between carbon atoms 1 and 2; Ra and Rb are Η; and T is the following (i) group: (1)- CH ^ CO-R ^ 'wherein R12 is an unsubstituted or substituted nitrogen-containing 5- or 6-membered heterocyclic ring, unsubstituted or substituted aryl or group _Ch2_Ri3, Ri3 is halogen or -SR14, and R14 is Aminoalkyl, or unsubstituted or substituted nitrogen-containing 5- or 6-membered heterocyclic ring, or unsubstituted or substituted aryl, the substituent of the heterocyclic ring or aryl is 1 to 3 choices. , CN, N02, N3, Carboxyl, Cu ^ Tt: Carbyl, Cu-oxy-(^ _ 6-coated, Di-TV-Cu alkylamino, C16 fluorenylamino, (^ _6fluorenylcarbonyl) Amine, Cr6 hydrazone Groups in the group consisting of methyl, c1-6 aminocarbamidine, mono- and dimerylcarbamidine, Ci-6methoxyoxycarbonyl, alkylsulfonium, CV6 alkylsulfinylfluorene, and benzyl; (C ) Has a single bond between carbon atoms 1 and 2; and Ra is Η, OH or F, and Rb is Η; or Ra is Η and Rb is F; and T is the following U) group: (k) _CH2- CO-R12, where R12 is as defined in the (i) group; including physiologically tolerable acid addition salts and quaternary ammonium salts. Free compounds of formula (I) can be converted by known methods They are acid addition salts, and vice versa. Among the acid addition salts, the best is the HC1 17 200407115 salt. The quaternary ammonium salts can be prepared similarly by a method known per se. Unless otherwise different Definition, otherwise the definition of the substituent is based on the definition generally understood by ordinary chemists. Within the scope of the above formula (I), the alkyl group itself or as a part of the substituent, according to the number of carbon atoms, is methyl, Ethyl, n-propyl, isopropyl, n-butyl, second-butyl, third-butyl, isobutyl, etc. "Halogen" is fluorine, chlorine, bromine or iodine Preferred are fluorine, chlorine or bromine, and especially chlorine. Preferred saturated or unsaturated 5- or 6-membered heterocycles, including those containing one or more heteroatoms, suitable heteroatoms are in particular Sulfur and nitrogen. A particularly preferred subgroup of such heterocycles is those containing 1, 2 or 3 nitrogen atoms and no other heterogeneous components. Among these, the unsaturated 5_ or 6- is particularly emphasized. A membered heterocyclic ring, which contains a nitrogen atom as a heterocomponent, for example, 卩 tt steep, 卩 ft slightly or 5,6_ dihydropyridine. Suitable unsaturated 5- or 6-membered heterocyclic rings containing two nitrogen atoms are, for example, imidazole, pyridin and pyrimidine. Such rings may also have one or more fused benzene rings. Typical examples are benzimidazole, quinoline, isoquinoline, and peptide farming. A suitable 5- or 6-membered heterocyclic ring containing three nitrogen atoms is, for example, 1,2,4-triazole. Other preferred heterocyclic groups include a nitrogen atom and a sulfur atom. These include, for example, various thiazoles, 4,5-dihydrothiazoles, and benzothiazoles. A typical example of a heterocyclic ring containing two nitrogen atoms and one sulfur atom is 1,3,4-thiadiazole. An aryl or aryl group, especially a phenyl or naphthyl group, may be unsubstituted unless specifically defined, or may carry up to four identical or different substituents, and is freely chosen from 0H, Nitro, amine, cyano, halogen, C ^ 6 alkyl, Cu alkyloxy, Cuyl-Culyl, mono-jy-Cu alkylamine 18 200407115, di-7V-cv6 alkyl Amine group, fluorenyloxy group, (γ6 fluorenylamino group, Cl_6 fluorenylcarbonylamino group, cv6 aminoformamidine, mono- and dialkylcarbamidine, c fluorenylamino group, Ch6 sulfonylsulfonium group , Cv6, sulfinylsulfenium, and benzyl. Unless specifically defined otherwise, suitable substituents are the same as heterocyclic substituents, and the heterocycles are also the same or different groups, and One or more substitutions. Heterocyclics with particular emphasis are: 3-pyridyl, 4-pyridyl, pyrimidin-2-yl, 1,3,4-_azole-2-yl, benzothiazole-2- , 2H-1,2,4-triazol-3-yl, azabicycloheptyl, azabicyclooctyl, and pyridinyl. The present invention is particularly related to compounds of formula (I), in which I Is vinyl; between carbon atoms 1 and 2 Single bond; Ra and Rb are hydrogen or halogen, preferably hydrogen; and T is as defined by formula (I); including its physiologically tolerable acid addition salts and quaternary ammonium salts. Particularly preferred is Pleuromutilin derivatives of formula (I), wherein: the heart is a vinyl group; there is a single bond between carbon atoms 1 and 2;

Ra and Rb are hydrogen; and T is -CH2-S- (CH2) kN (R5) (R6), where k is an integer from 2 to 5; and R5 and R6 are each independently an alkyl group; including their physiologically acceptable Resistant acid addition salts and quaternary ammonium salts. Within the scope of this group, pleuromutilin derivatives are particularly preferred, where T is -CH2-S- (CH2) 2-N (C2H5) (C2H5) ο Also preferred is formula (I) A pleuromutilin derivative, wherein: I is a vinyl group; there is a single bond between carbon atoms 1 and 2;

Ra and Rb are hydrogen; and Τ is -CH2-S_C (CH3) 2_CH2-NH- 19 200407115

C (0) -R7 'wherein R7 is a Cl_6 alkyl group substituted with -nh2, or a saturated 5-membered heterocyclic ring containing one or two heteroatoms selected from _S_ and _NH-; including its Physiologically tolerable acid addition salts and quaternary ammonium salts. Within this group, the pleuromutilin derivative of formula (I) is preferred, where T is -CH2-SC (CH3) 2-CH2-NH-C (0) -R7, where R7 is Ci-6 alkyl substituted with -NH2, and especially pleuromutilin derivatives, where T is -ch2-s_c (ch3) 2-ch2-nh_c (o) _ch (nh2) -ch (ch3) 2. In the context of the invention, particularly preferred are therefore the compounds tamarin and valanirol, especially valanirol, as it has a wide range of activities. As mentioned above, both substances are commercially available. The chemical structures of these two better substances are as follows:

Tiamutin® / Tiamutin Econor® / Varimex R R 5 \ N—C——C—S—C—— C2h {H2 H2 H2 H3C R? H3) —C—C——N—C—C ——S—C—— H3C Plant H 76 H H2 l H2 The compound of formula (I) is described in detail in the literature, for example, in the reference materials provided below: The compound of formula (I), its center and A Is as defined in formula (I), and τ is as defined in (a) ethnic group, which has been separated by Kavanagh et al. 20 200407115 and described in / Voc · dcW. Xin C 37: 570-574 (1951). This compound is the basic representative of the types of substances discussed here (ie pleuromutilin). It is shown in U.S. Patent No. 4,247,542 that the structure of pleuromutilin was discovered later, and is characterized in that Y in the above formula (I) is -CH2-OH. The same U.S. patent also illustrates compounds of formula (I) where Ri is vinyl; there is a single bond between carbon atoms 1 and 2; Ra and Rb are Η; and T is -CH2_ / 3, D-pyran Glycans. Compounds of formula (I), where h and A are as defined in formula (I), and T is as defined in group (b), are described in U.S. Patent No. 4,129,721. Compounds of formula (I), wherein Ri and A are as defined in formula (I), and T is as defined in (c) group, are described in US Patent No. 4,148,890. The compound of formula (I), its center and A are as defined in formula (I), and T is as defined in (d) group, which is described in US Patent No. 3,919,290, including the substance that has been specifically mentioned several times Miao Su, which is available under the trade name Tiamutin®. The compound of formula (I), its center and A are as defined in formula (I), and T is as defined in group (e), which is described in European patent 0 153 277, which includes already mentioned several times and may also Vanisole is known from WO 98/01 127. The compound of formula (I), its center and A are as defined in formula (I), and T is as defined in group (f), and is described in US Patent No. 4,428,953. 21 200407115 A compound of formula (I), wherein 1 and A are as defined in formula (I), and T is as defined in group (g) 'are described in US Patent No. 3,979,423. Compounds of formula (I), wherein Ri and A are as defined in formula (I), and T is as defined in group (h), are described in WO 97/25309. The compound of formula (I), whose center and B are as defined in formula (I), and T is as defined in group (i), are described in WO 01/14310. The compound of formula (I), its center and B are as defined in formula (I), and T is as defined in group (k), as described in WO 01/14310. It will be understood that the individual examples specifically mentioned in the above references are included in the preferred embodiments of the present invention. [Embodiment] The literature discloses a series of tests involving adding a drug (including tamarind) to animal feed, but these tests cannot solve the technical problems constituting the present invention. Some of these references will be briefly discussed as follows: European Patent 0 165 5W is about providing feed supplements including zinc bacitracin after mixed feeds or when pelleted, which have improved stability and extended storage . Improved stability is achieved by providing a polymeric outer layer to feed additives including zinc bacitracin. Polymers such as polysaccharides, polyacrylic acid, fats, fat-like compounds or waxes are used as the outer layer. Derwent Announcement 26.04.1991 XP002197610 [Japanese Patent No. 03101619 A, SDS Biotech Co., Ltd.] is a bitter-free veterinary medicine in the form of granules composed of a zeolite carrier and tamarind. 22 200407115 13.02.1988 Derwent Announcement XP002198060 [Japanese Patent 63 033330 A 'Daban KK], is an oral antibacterial dosing form, especially tamarind, which, based on sodium polyacrylate, leads to improved absorption of active ingredients. The dosing form consists of powder, which can also be compressed into granules or lozenges and mixed in animal feed. European patent 0 707 798 describes a method for preparing a feed comprising a pharmacologically active substance. This method is characterized in that the pharmacologically active substance is applied individually or in a mixture of suitable herbal colloidal preparations, in the form of sprayable colloids, and is applied to the actually prepared feed. European patent application 0 658 313 describes particles composed of a core and an outer layer. The core is composed of organic (especially vegetable) or inorganic materials' and has a diameter of 100 to 800 microns. The outer layer is composed of water-soluble polymers including active ingredients, which polymers dissolve in water-soluble substrates, especially gastric fluids. The active ingredient is incorporated into or adhered to the outer layer. During manufacturing, the core is first prepared. The core surface is treated with an acid 'and then sprayed with an aqueous solution of the active ingredient. The goal is to prepare fine particles that can be mixed with animal feed without any difficulty. In contrast to the present invention, the granules described in the reference material do not cause any significant stabilization of the active ingredient and are therefore not suitable for providing animal feeds including pleuromutilin derivatives. Contrary to the present invention, the active ingredient is released in the stomach. Surprisingly, it has now been discovered that pleuromutilin derivatives can be enclosed in microspheres by methods known per se; these microspheres can be introduced into dry animal feed and compressed under high pressure and high temperature to form Feed pellets 23 200407115, and then dried again, so far there has been no unavoidable loss of active ingredients. In addition, the stability of this newly obtained active ingredient in the pellets results in extremely high storage stability in the final feed. At room temperature, such feed pellets can now be stored stably for several months, which means that the active ingredient content can actually remain fixed. The active material enclosed in the microspheres not only leads to an unexpected improvement in stability, but also has other advantages quite independently: in contrast to pure active materials, the microspheres do not cause the formation of dust and do not form lumps. It is obviously mass-producible and protects the active substance from unwanted external influences. For example, unintentional inhalation or contact with the skin or eyes can be avoided during the procedure. Because they are embedded in microspheres, active substances that are not approved for human use can be handled simply and safely without the need for special protection measures. Since the microspheres actually show no adhesion to the surface of the device, and do not form lumps or hard skins, nor do they stick together in any other way, for example, devices used in feed mills can be almost There are no technical difficulties to manage; simple vacuum cleaners are usually sufficient. In addition, the use of these microballoons also yields other advantages in use. When antibiotics are administered orally, a decrease in appetite can be observed in sensitive human patients, which increases during treatment. Depending on the severity of the case, the physician will then switch to other forms of administration, such as injections or suppositories, to bypass the stomach. In animals, the same effects were observed in individual cases. Decreased appetite reflects a refusal to eat enough food. In addition, the feed is less metabolizable and the desired weight gain does not occur. Since animals like 24 200407115 eat less feed, oral treatment is risky. In the case of animals, conversion to a suppository is not the preferred choice, and injection will have the disadvantages described, and excluding these methods is the goal of the present invention. When the microspheres of the present invention were orally used, the excessive sensitivity and related feed rejection were not observed, which is presumed to be related to the fact that the microspheres are an acid-resistant substrate. Studies of bioavailability have shown that microspheres can pass through the stomach intact and release actives only in the alkaline medium of the small intestine. When using (a) feed granules comprising free valimir hydrochloride or commercially available Econor®, and (b) feed pellets prepared according to Example 2, which include valimir salt enclosed in microspheres Acid, and when conducting a comparative feed test on piglets, blood samples were taken from test animals every hour and the concentration of vanicumin present in the plasma was measured. It was found in Example (a) that after 2-3 hours Before reaching its maximum level, the concentration of the active ingredient rises rapidly. After 8-10 hours, the curve then decreases again and approaches zero. In Example (b), due to the presence of microspheres, the increase in active ingredient concentration begins after a delay of about 1-2 hours, reaches its maximum level after about 3-4 hours, and decreases after about 10-12 hours To 0. As a result, although Example (b) has a slight delay in establishing effective blood levels, this does not have a negative effect on the treatment. This new method can make effective use of the gentle administration of the stomach, and makes oral treatment more effective. If necessary, the microspheres of the present invention can dissolve and release the active ingredient as early as possible in an acidic medium in the stomach by an additive such as sodium bicarbonate. However, in many cases this is not needed. 25 200407115 In the context of the present invention, microspheres (or "microspheres") are understood to be tiny, mostly spherical polymeric matrix particles having an average size of about 1 micron to about 5000 microns, typically 50 Micrometers to 3000 micrometers. Pleuromutilin derivatives are embedded in them. Therefore, they are fairly small spheres including a complete polymeric matrix, where the active ingredients in solid or liquid form are highly dispersed, not just coated. It can be described as a special example of encapsulation. The method for preparing microspheres in the present invention is known per se; similarly, the material used for encapsulation and the pleuromutilin derivative used are also known. However, the microspheres first prepared in this way, as well as feed pellets including these microspheres, and their oral use to combat infectious diseases in animals are novel. Microspheres can be prepared similar to the methods described in the references mentioned below:

Shigeru Goto et al., J. Microencapsulation 3 (4): 293 · 305 (1986);

Shigeru Goto et al.].] ^ 1 (^ € ^ 11. &Amp; 卩 81111 狂 1 ^ 〇11 3 (4): 305.3 16 (1986) or US Patent No. 3,714,065 (corresponding to German Patent 2 105 039). The main objective of the present invention in the preparation of microspheres or the oral use of pleuromutilin is less than the provision of novel feed pellets including pleuromutilin derivatives stabilized in the form of microspheres. During or during storage, no significant loss of active ingredients was experienced. The present invention is to provide stabilization of active substances in feed pellets. The present invention hopes to assist 26 200407115 to solve existing technical problems and provide their methods, This allows the storage of feed pellets including pleuromutilin for a considerable period of time and administration to domesticated animals and productive livestock without the need for substantial personnel, time and logistical costs. In the final analysis, not only Saves time and money, and also significantly increases the safety and reliability of practical use. Microspheres are advantageously prepared in a two-phase system, which Consists of a first organic or organic-aqueous phase, and a second oil phase. The organic or organic-aqueous phase is a solution or dispersion of a polymeric component suitable for forming microspheres, a solvent, and a truncated flank to be enveloped The oil phase is a dispersion of mono-, di- or tri-aluminum stearate, sodium stearate, calcium stearate or magnesium stearate in suitable fats, most advantageously liquid Rockwell or silicone oil. However, other, for example, non-ionic emulsifiers or dispersants (eg, sorbitan monooleate (Span-80®)) can also be used. The volume of the oil phase advantageously exceeds that of the organic Phases are several times the volume. The two phases are closely mixed together by vigorous stirring, or even homogenized under high pressure or with the help of a static mixer. Tiny polymeric particles are formed in the process. Tiny The spheres contain the active ingredients in a highly dispersed form and will not dissolve in the reaction mixture, allowing them to be separated, decanted, and dried by decantation or filtration. The two-phase agitation is also important for the formation of microspheres. Generally, Say, A stirring device with a propeller-shaped stirrer can be used to stir at a relative speed of at least 100 revolutions per minute (rpm) to about 1500 revolutions per minute to ensure vigorous mixing of the two phases and rapid formation of microspheres. Of course, it can also be used Static mixer 27 200407115 In detail, the preparation of microspheres is performed by the following steps: (a) Preparation of a polymer solution suitable for the formation of a matrix of microspheres, the polymer is selected from shellac and cellulose, Acrylic or methacrylic acid, cis-butadiene anhydride, polyvinylpyrrolidone, or polyvinyl alcohol-based polymers are made by dissolving shellac or polymer in organic solvents. Oil or silicone oil has low affinity and has a dielectric constant of about 10 to about 40, and water can be added if appropriate; (b) introducing pleuromutilin derivatives into shellac or polymer solution, while Stir to form a first organic phase that is immiscible with paraffin oil or silicone oil; (c) Stir the first phase by vigorous stirring (for example, using a static mixer or High pressure homogenizer) and introduce it into the second oil phase composed of paraffin oil or silicone oil, and continue to stir the resulting mixture until the microspheres including the pleuromutilin derivative are evaporated or removed 0 (d) Microspheres are separated until formation, and can be rinsed and dried if appropriate. Shellac is well known in the pharmaceutical industry for the preparation of outer layers of sugar-coated tablets of neutral taste. Suitable raw materials for cellulose-based polymers are, for example, cellulose acetate peptidate or cellulose acetate N, N-di-n-butylhydroxypropyl ether. Suitable raw materials for acrylic or methacrylic-based polymers are, for example, methacrylate / methacrylic copolymer, 2-methyl-5-vinyl-pyridine / methacrylate / methacrylic acid Copolymer, methacrylic acid 28 200407115 methyl / methacrylic acid copolymer, methyl methacrylate / methacrylic acid copolymer, methyl methacrylate / cis butadiene anhydride copolymer or methacrylic acid Ester / cis-butadiene anhydride copolymer. A suitable raw material for a cis-butanedioic acid-based polymer is, for example, a vinyl methyl ether / cis-butanedioic anhydride copolymer or a styrene / cis-butanedioic anhydride copolymer. In the context of the present invention, an acrylic- or methacrylic-based polymer is particularly preferred as the outer membrane of the microspheres. Most advantageously, a commercially available product is used for its preparation. Such products are polymerized products of acrylic acid and acrylate having a low content of a quaternary ammonium group. Commercially available products, such as Eudragit® E, L, or S (available from R6hm, Darmstadt 'Germany) are very suitable. Eudragit® E is a cationic polymer of dimethylaminoethyl methacrylate and neutral methacrylate. Eudragit® L and S are anionic copolymers of methacrylic acid and methyl methacrylate. A suitable starting material for polyvinylpyrrolidone-based polymers is, for example, polyvinylpyrrolidone. A suitable raw material for the polyvinyl alcohol-based polymer is, for example, polyvinyl alcohol itself. The oil phase is used in a relatively large amount such that the volume ratio of the organic phase to the oil phase is in the range of approximately 1:20 to 5:10. Normally, the process is performed at room temperature or slightly higher temperature, that is, a temperature range of about 20 ° C to 45 ° C. However, room temperature is perfectly adequate. The organic solvent suitable for the first organic phase is, for example, a solvent which is not mixed with the oil phase as much as possible and is easily volatile. 29 200407115 Organic solvents having a dielectric constant of 10 to 40 are very suitable. Many such solvents are shown by way of example in the table below. Solvent permittivity Solvent permittivity methanol 32.6 phenol 9.8 ethanol 24.3 acetone 20.7 isopropanol 18.7 acetic acid 9.7 butanol 17.1 acetic anhydride 20.7 benzyl alcohol 13.1 nitromethane 35.9 ethylene glycol 37.7 ethylenediamine 14.2 propylene glycol 35.0 ethylene glycol acetic acid Ether 16 may be used as a pure solvent or a mixture of such solvents, for example, an acetone-ethanol mixture (1: 1). A very small amount of water is added to achieve very good results, i.e. from about 1 to 5 parts by volume of water and 10 to 50 parts by volume of organic solvent. The preferred is an acetone-water mixture (approximately 30: 1). It has proven advantageous to use mono-, di-, or preferably tri-aluminum stearate, sodium stearate, stearic acid before use. Calcium, magnesium stearate or other non-ionic emulsifiers or dispersants (eg, sorbitan monooleate (Span-80®)) are added to the second oil phase while vigorously agitating to make it homogeneous A dispersion was formed. Such additions can promote the extremely rapid formation of very uniformly sized microspheres. As a result, the formed microspheres can be prevented from bonding to each other during preparation. When the first phase including the polymer and the pleuromutilin derivative is composed of a mixture of acetone-water, and the two phases are combined by stirring at a rotation speed of 800 to 1,000 rpm, Microspheres having a uniform size of 500 to 1000 micrometer 30 200407115 meters can be obtained. Pleuromutilin and stearate are advantageously used in a weight ratio of 0.5: 1 to 10: 1, preferably about 1: 1. The microspheres can be washed with, for example, diethyl ether, light petroleum or n-hexane, methylcyclopentane, or preferably washed with cyclohexane. The solvent was removed most gently under vacuum at room temperature. It goes without saying that the solvent is removed with as little residue as possible. The microspheres obtained by the above method have a fairly strong polymer coating. In order to achieve greater ductility, 3 to 10% by weight of a plasticizer can be added to the organic phase based on the polymer. Suitable plasticizers are triacetin, acetylated monoglycerides, glycerol, polyethylene glycol (eg, PEG 400 or PEG 600), peptidic acid esters (eg, diethyl peptidate or peptidic acid) Dibutyl ester), citrates (e.g., triethyl citrate, acetotriethyl citrate, tributyl citrate or acetotributyl citrate) and vegetable oils (e.g., 'castor oil, rapeseed oil Or sunflower oil). It is appropriate to add about 4 to 10% triethyl citrate. However, in general, the addition of plasticizers is not necessary because it has been found that the higher the plasticizer ratio, the lower the storage stability of the final feed pellets. Therefore, the addition of a plasticizer tends to violate the desired stability improvement, however, this does not mean that the plasticizer 'cannot be added, especially in a relatively small amount. Plasticizers reduce the glass transition temperature. In our experiments, when the glass transition temperature is below about 100-150 °°, the 'active ingredient is no longer protected during the preparation of feed pellets. Feed pellets are usually manufactured by feed mills. Grated mash is generally used as a substrate. Add other ingredients (such as fats and white matter from plants and animals) to the substrate. Mix all ingredients in a honing or mixing device 31 200407115, intimately mix together, sprinkle with water or steam, and extrude at high temperature through a circular nozzle with a diameter of about 2 to 15 mm (also Is suppression). During this pressing process, the wet material is compacted and leaves the nozzle in the form of a relatively rigid strip, which is cut at the nozzle outlet by a cutting device into pieces of the desired length, for example, about 5 to 25 mm length. The resulting still warm particles are air-dried as they are to be transported, or they are placed on a conveyor belt, passed through a heating chamber, and dried at about 80 to 120 ° C. The final particles are rod or cylindrical; they have a fairly smooth surface and can be easily mass produced without breaking or forming dust. They generally have a density of about 1.2 grams per cubic centimeter. In general, the method for preparing the stabilized feed pellets of the present invention is exactly the same as the method for preparing normal feed pellets without added additives. Prior to the pressing process, however, the microspheres are closely mixed with organic, ground and homogenized feed ingredients, moistened with about 5 to 10% by weight of water or steam, and at about 60 to 80 ° The high temperature of C, preferably 65 to 75 ° C, is compressed into feed pellets. The excellent homogenization is most advantageously achieved when the microspheres are first closely mixed with a relatively small portion of the remaining feed ingredients, due to the so-called premix (premix) with a relatively high proportion of microspheres ). A portion of the premix is then mixed with other feed materials to form a further topical mixture, and in a final step, the portion of the mixture is diluted with additional feed materials to a final concentration. Dilution results in a particularly uniform dispersion of the encapsulated active ingredient in the particles. The pine pine is cooled to room temperature 'and packed in a paper bag or other suitable container 32 200407115 for storage or shipping to the end consumer. No special warnings are required, as the granules have maximum storage stability and include the active ingredient in the form of a coating, which protects the active ingredient from environmental influences. No active ingredient is exposed to the outside from these storable particles. Surprisingly, the measurement of the amount of active ingredient before and after compression into granules has shown that the use of microspheres for granulation does not result in any measurable loss of active ingredient. [Example] Example 1: Preparation of varnishol hydrochloride microspheres coated with a certain acrylic resin. Weight of varnishol hydrochloride (active substance) 12.5 g of excipient Eudragit® L 100 * 37.5 grams of aluminum monostearate, 11.25 grams of water, 9.4 grams of acetone, 303.1 milliliters of light liquid stone gangue, 1250 milliliters, and a total weight of 1,351.94 grams. * Eudragit® is a product of R0hm. It is composed of butyl methacrylate, 2-dimethylaminoethyl methacrylate and methyl methacrylate copolymer. Step 1: Disperse Eudragit in 100 ml of acetone in a glass beaker at room temperature while stirring (800 rpm, 5 minutes, magnetic stirring 33 200407115). The dispersion was continuously stirred under the same conditions and water was added. After 10 minutes, the polymer was completely dissolved. While continuing to stir, add the active substance (in this case, valimirin) in several portions. After another 10 minutes, a clear solution was obtained. Step 2: In a 2-liter reactor equipped with a 3-blade propeller stirrer (1000 rpm), disperse aluminum monostearate in light liquid paraffin at room temperature. After 10 minutes, the dispersion was homogeneous. Step 3: After adding the solution obtained in step 1 to the dispersion obtained in step 2 at room temperature, continue to stir (1000 rpm). After the emulsion is formed, continue to stir at 800 rpm for 24 hours at room temperature (or the emulsion can also be heated to 40 ° C under a pressure of 200 mbar for 1 hour, and then Pressure and temperature were maintained for another 2 hours). In these two examples, microspheres (microspheres), that is, microcapsules composed of methacrylic resin, and the active substance is enclosed therein. Step 4 = After turning off the stir bar, sink the microspheres to the bottom of the reactor, and pour the upper layer of stone ballast and aluminum monostearate as completely as possible. The microspheres were washed several times with a cyclohexane (three times / Buchner funnel / fabric filter), and excess cyclohexane was removed in vacuo. Example 2: Preparation of feed pellets for pig breeding, feed, 80 grams of active substance (vanimellin) was added to 3,920 grams of traditional, ground and homogenized dry piglet feed, Mix intimately with a spiral stirrer. In this way, 4,000 grams of a premix was obtained. Add 4,000 grams of the premix to a 100-liter screw stirrer and add another 36 kg of traditional, ground and homogenized dry piglet feed, and similarly intimately mix 34 200407115. The resulting 40 kg of topical mixture is then mixed into another 360 kg of traditional, ground and homogenized dry piglet feed, transferred to an extruder, and at a pressure of 68-72 ° C and a pressure of 10-100 bar , Compressed into rod-shaped feed pellets about 10 mm long and about 6 mm wide. During the compression process, steam (2 bar, 136 ° C) was used. The dwell time in the heating section of the extruder is set at about 75 seconds. Fill the final granules into each 25 kg bag. Example 3: Stability test of a feed mixture including free active ingredients, commercially available coated active ingredients, or active ingredients embedded in microspheres: According to Preparation Example 2, three types of piglet feed Granules A, B and C are prepared using different pre-treated active ingredients, but the same amount of active ingredients. Type A granules include commercially available Econor® 50% (active ingredient: valnemulin), where the active ingredient is coated with hydroxypropyl methylcellulose (HPMC). The B-type particles include pure active ingredient vanillin in the form of the hydrochloride, and the C-type particles include microspheres prepared in Preparation Example 1, which include the embedded vanillin hydrochloride. In order to measure the stability, three types of feed pellets were prepared according to Preparation Example 2, and a 50-gram sample was taken from each of the first samples immediately after preparation. Nine samples were sampled for type A, nine samples were sampled for type B, and for type C, three different batches of feed pellets were prepared, which were slightly different from each other in the composition of the feed material. Nine samples were also taken for each batch. All samples were quickly tested and analyzed to determine the complete vaniulin content in each sample. The remaining feed is divided into two equal parts ’and transferred to two climate chambers for practical long-term research. The climatic chamber (I) is 35 200407115 at 25 ° C and 60% relative humidity, which simulates the normal storage environment at room temperature. The climate chamber (II) is a high temperature of 40 ° C and a high relative humidity of 75%, which simulates a long-term storage period. At 1-month intervals, 3 samples were taken from each climatic chamber and each type and batch of feed pellets, 50 grams each, and the complete vaniulin content was determined. For different climatic conditions, the mean radon and related standard deviations are listed in Tables 1 and 2 below. Table 1: The relative pano data at 25 ° C / 60% is expressed as [% vanicumin / (standard deviation)], measured immediately after granulation, measured after 1 month, measured after 2 months, and measured after 6 months. A Type: Econor® 50%, HPMC 98.36% / (9.28) 76.68% / (2.56) 70.54% / (1.38) 37.31% / (1.39) Type B: vanisulin hydrochloride 78.38% / (8.66) 43.55% / (15.37) 47.30% / (1.00) 26.62% / (0.87) Type C: Vanimolin in microspheres 102.93% / (6.49) 99.69% / (3.18) 99.20% / (2.11) 96.22% / (3.91 ) Table 2: Phases at 40 ° C / 75%. The data is expressed as [% vanicumin / (standard deviation)]. Immediately after measuring 1 month after granulation, after 2 months and after 6 months. Measurement type A: Econor® 50%, HPMC 98.36% / (9.28) 38.72% / (2.28) 25.35% / (1.13) 6.83% / (0.96) Type B: vanisulin hydrochloride 76.38% / (8.66) 34.65% / (15.98) 15.33% / (0.24) 9.14% / (0.90) Type C: Vanimolin in microspheres 102.93% / (6.49) 96.42% / (1.74) 89.12% / (3.19) 79.10% / (6.62) Tables 1 and 2 show fairly clearly that in A, B and C feed pellets 36 200407115 The varnishes present in the granules have different stability. Pure vanillin (Type B) is clearly the most rapidly degraded and has experienced a loss of about 21% during granulation. At normal room temperature, after 2 months, the content of vanisulin in Type B dropped to less than 50%, and in the case of high temperature of 40 ° C, it even dropped to less than 20%. In the case of type A vanillin coated with HPMC, the degradation of vanillin is somewhat reduced, but it is still quite large. Negligible losses of approximately 1% of the active ingredients during granulation can be ignored, but after 2 months storage at 25 ° C results in a significant loss of approximately 30%, and at 40 ° C, even approximately 76%. In contrast, C-type feed pellets with active ingredients embedded in microspheres showed significantly less active ingredient loss. After 2 months at 25t, the loss is only about 1%, and at a high temperature of 40 ° C, only about 11%. Even after 6 months, almost 80% of the active ingredient was still present in the C-type case, while in the other two cases, the active ingredient content was reduced to less than 10%. In feed pellets, the apparent stabilization of the active ingredient can never be predicted, especially if microspheres are incorporated into the uncompressed feed, which does not cause any stabilization. In uncompressed feed, the unprotected vanillin and the vanillin in the microspheres function in exactly the same way and cause the same loss. Note: As of the filing date of this application, this trial is still incomplete; further data will be available within these months.

Claims (1)

200407115 Scope of patent application 1. A stabilized pleuromutilin derivative of formula (I) ... Its center is ethyl or vinyl, there are double or single bonds between carbon atoms 1 and 2, Ra and Rb are each independently hydrogen or halogen, and τ is a short or long chain organic group, where the formula (I) The compound is enclosed in a microsphere. 2. A pleuromutilin derivative stabilized in a microsphere encapsulated in a microsphere according to item 1 of the scope of patent application, wherein in formula (I): h is ethyl or vinyl; (A) at carbon atom 1 and There is a single bond between 2; Ra and 111) are 11; and τ is one of the following (a) to (i) groups: (a) -CH2-OH; (c)-(CH2-X) m- (CH2) nN (R2) (R3), where χ is _〇_, I -NH · or; 111 is 0 or 1; η is an integer from 2 to 5 38 200407115 r2 and r3 are each independently a CV6 alkyl group, or together with a nitrogen atom to which they are bonded, form a 5- or 6-membered heterocyclic ring, which contains -S-, -0, or -N (R4)-as a hetero Molecular part, where R4 is CV6 alkyl or (^ _6hydroxyalkyl, and γ and Z are each independently -0- or -S-; (d) -CH2-S- (CH2) kN (R5) ( R6), where k is an integer from 2 to 5; and 1 and R6 are each independently a CV6 alkyl group; (e) -CH2-SC (CH3) 2-CH2-NH-C (0) -R7, where R7 is · NH2 substituted CV6 alkyl, or a saturated 5-membered heterocyclic ring, which contains one or two heteroatoms selected from -S- and -NH-; (f) -CH2-SC (CH2) rR8, Where 1 is 0 or 1, and R8 is a group , Where K is H, Ci_6 alkylsulfonium, -NH2, CHO, -N (R9) (R10), S- (CH2) qN (R9) (R10) or -C (G) -NHRn, G is oxygen Or sulfur 'R9 and Rig are each independently H, Cu, or Ci-6, sulfofluorene, cv6 hydroxyalkyl, cv6 dihydroxyalkyl, or unsubstituted or CV6 alkylsulfonium substituted with cN6 alkylsulfonium ; Or r9 and R1Q together with the nitrogen atom to which they are bonded form an unsubstituted or substituted morphinyl group, wherein the second nitrogen atom is selected from the group consisting of CV6 alkyl, hydroxyalkyl, and CV6 dihydroxyalkyl Rn is alkyl or Cm alkylcarbonyl; Q is fluorene, -NH2, -CF3, (V6 alkyl, pyridyl, or -N (R9) (R1 (}), R9 and Rio are as The above definitions; (g) -CH3, -CH2C, -CH2Br, -CH2SCN, -CH2-NH2, -CH2_N3, -CO-OH, -CH2-OCOCH3 or one; 39 200407115 (h) -n (r15) ( r16), where Ri5 and Ri6 are the same or different, and are free to choose, unsubstituted or substituted, linear or branched, saturated or unsaturated Cw hydrocarbon group, unsubstituted or substituted, saturated or unsaturated Cm ring courtyard group 'unsubstituted or substituted heterocyclic ring and unsubstituted or substituted In the group consisting of phenyl groups; or ri5 and Ri6 together with the nitrogen atom to which they are bonded form a 3- to 8-membered ring, which does not contain other heteroatoms or contains a group selected from the _N_, -〇-, and -s- series Other heteroatoms; or Ri5 is one of the above groups, and r16 is _so2r17, -c (o) r18, _〇_Ri9, or N (Ri9) (R2 ()); Ri7 is freely unsubstituted or substituted , Linear or branched, saturated or unsaturated Cw hydrocarbyl, unsubstituted or substituted, saturated or unsaturated cycloalkyl, unsubstituted or substituted heterocyclic ring, unsubstituted or substituted aryl, unsubstituted In the group consisting of unsubstituted or substituted amino amines and unsubstituted or substituted aryl amines; R18 is freely selected, unsubstituted or substituted, linear or branched, saturated or unsaturated (^ _6 Hydrocarbon group, unsubstituted or substituted, saturated or unsaturated C3_8 cycloalkyl, unsubstituted or substituted heterocyclic ring and unsubstituted or substituted aryl group; R19 and r2Q are the same or different, and are Select free unsubstituted or substituted, linear or branched, saturated or unsaturated CV6 hydrocarbyl, unsubstituted or substituted , Saturated or unsaturated C3_8 cycloalkyl, unsubstituted or substituted heterocycles and unsubstituted or substituted aryl groups; or together with the nitrogen atom to which they are bonded to form a 3- to 8-membered ring group , Which may include, as necessary, other heteroatoms in the group consisting of _N_, _〇_, and -S-; (B) a double bond between carbon atoms 1 and 2; Ra and Rb are H; and T Is the following (i) ethnic group: 200407115 (i) _ch2_co_r1 ?, I ^, I, and R12 are unsubstituted or substituted nitrogen-containing 5-or 6-membered heterogeneous, unsubstituted or accompanying #, Λ A substituted square group or group -ch2_r13, r13 is halogen or -SRi4, and Ru is an amine group, or an unsubstituted or substituted group containing 5-6 members, or unsubstituted or aryl groups, The substituent of the heterocyclic or aryl group is 1 to 3 free radicals, CN, no2, &, Cw alkyl, CV6 alkoxy, Ci 6 alkoxy_Ci 6 alkyl, dialkyl Amine, c "6-Aminoamino, Ci-6-Aminocarbonylamino, 6-Amino, Cw aminoformamidine, mono- and di-6-alkylaminoformamidine, ci-6-Aminocarbonyl, alkylsulfonium Ci 6 alkylsulfinium And a benzyl group; (C) there is a single bond between carbon atoms 1 and 2; and Ra is Η, OH or F, and Rb is Η; or Ra is η and Rb is f; And τ is the following (k) group: (k) -ch2-co-r12, where Ri2 is as defined by the ⑴ group; including its physiologically tolerable acid addition salts and quaternary ammonium salts. 3. The pleuromutilin derivative stabilized in a microsphere according to item 2 of the scope of the patent application, where I is a vinyl group; there is a single bond between carbon atoms 1 and 2; Ra and Rb are hydrogen or halogen And T is as defined by formula (I); including its physiologically tolerable acid addition salts and quaternary ammonium salts. 4. The pleuromutilin derivative stabilized in a microsphere according to item 3 of the scope of the patent application, where: h is vinyl; there is a single bond between carbon atoms 1 and 2; Ra and Rb are hydrogen; And τ is _CH2-S- (CH2) kN (R5) (R6), where k is an integer of 200 to 115,200,115115; and 1 and R6 are each independently a Cw alkyl group; including their physiologically tolerable acids Addition salts and quaternary ammonium salts. 5. A pleuromutilin derivative stabilized in a microsphere according to item 4 of the scope of the patent application, where T is · CH2-S- (CH2) 2-N (C2H5) (c2h5). 6. The pleuromutilin derivative stabilized in a microsphere and enclosed in a microsphere according to item 3 of the scope of patent application, wherein: I is a vinyl group; there is a single bond between carbon atoms 1 and 2; Ra and Rb are Η; And T is -CH2-SC (CH3) 2_CH2-NH_C (0) _R7, where R7 is a C ^ 6 alkyl substituted with -NH2, or a saturated 5-membered heterocyclic ring containing one or two selected from -S- and -NH- heteroatoms; including their physiologically tolerable acid addition salts and quaternary ammonium salts. 7. The pleuromutilin derivative stabilized in a microsphere according to item 6 of the scope of the patent application, where: R! Is vinyl; there is a single bond between carbon atoms 1 and 2; Ra and Rb are Η And τ is -ch2-sc (ch3) 2-ch2_nh_c (o) _r7, where R7 is a CV6 alkyl substituted with -NH2; including physiologically tolerable acid addition salts and quaternary salts. 8. The pleuromutilin derivative stabilized in a microsphere according to item 7 of the scope of the patent application, where: h is vinyl; there is a single bond between carbon atoms 1 and 2; Ra and Rb are b; And 42 200407115 T is -ch2, sc (ch3) 2-ch2-nh-c (o) -ch (nh2) -ch (ch3) 2; including its physiologically tolerable acid addition salts and quaternary ammonium salt. 9. The pleuromutilin derivative stabilized in a microsphere according to any one of claims 1 to 8 of the scope of application for a patent, wherein the microsphere is composed of a polymer suitable for microsphere formation, the polymer It is a group consisting of free shellac and polymers based on cellulose, acrylic or methacrylic acid, cis-butanedioic anhydride, polyvinylpyrrolidone, or polyvinyl alcohol. 10. Preparations include, for example, patent applications A method of truncating the microspheres of a pleuromutilin derivative according to any one of items 1 to 9, the method comprising: (a) preparing a polymer solution suitable for the formation of a matrix of microspheres, the polymer being selected free shellac And polymers based on cellulose, acrylic or methacrylic acid, cis-butadiene anhydride, polyvinylpyrrolidone, or polyvinyl alcohol, this is achieved by dissolving shellac or polymer in organic Among solvents, the solvent has low affinity for paraffin oil or silicone oil, and has a dielectric constant of about 10 to about 40, and water can be added if appropriate; (b) pleuromutilin The organism is introduced into the shellac or polymer solution and stirred at the same time, so that a first organic phase that is immiscible with stone oil or silicone oil is formed; (c) the first phase is introduced to the In the second oil phase composed of paraffin oil or silicone oil, the resulting mixture is continuously stirred until microspheres including pleuromutilin derivatives are formed after the solvent is evaporated or removed. 43 200407115 (d) Separate the microspheres and, if appropriate, rinse and dry them. U · —Animal feed pellets, in addition to ground dry plant- and / or animal p-based feeds, with or without additives such as proteins, vitamins and minerals, and including an effective amount such as A stabilized pleuromutilin derivative according to any one of items i to 9. 12. The animal feed pellets according to item 11 of the scope of the patent application are methods for treating infectious diseases in domestic animals and productive livestock. 13 · —The use of pleuromutilin derivatives stabilized in microspheres as claimed in any of claims 1 to 9 in the scope of patent application, which is used to prepare infections for domestic animals and productive livestock Animal feed pellets for sexually transmitted diseases. 14. A method for preparing an animal feed pellet comprising a stabilized pleuromutilin derivative as in any one of claims i to 9 of the scope of patent application, the method comprising The stabilized pleuromutilin derivative of any of 9 items is intimately mixed with organic, ground and homogenized feed ingredients, moistened with about 5 to 10% by weight of water or steam, and It is compressed into sticks at a high temperature of about 60 to 80 ° C, and the sticks are divided into feed pellets. First, the drawing 200407115 Lu, (a), the designated representative of this case is: Figure _ (b), the representative symbols of this representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the features that can best show the invention Chemistry 0 Rb