CA1077056A - Derivatives of pleuromutilin and compositions - Google Patents
Derivatives of pleuromutilin and compositionsInfo
- Publication number
- CA1077056A CA1077056A CA260,231A CA260231A CA1077056A CA 1077056 A CA1077056 A CA 1077056A CA 260231 A CA260231 A CA 260231A CA 1077056 A CA1077056 A CA 1077056A
- Authority
- CA
- Canada
- Prior art keywords
- mutilin
- fumaric acid
- deoxy
- solution
- fumarate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
ABSTRACT
A new neutral fumarate salt of a derivative of the antibiotic plueromutilin -14-deoxy-14-[(2-diethylaminoethyl)-mercaptoacetoxy]mutilin neutral fumarate- has been found whose physical properties made bulk manufacture more repro-ducible, simplify formulation and provide advantages in the administration of the substance.
A new neutral fumarate salt of a derivative of the antibiotic plueromutilin -14-deoxy-14-[(2-diethylaminoethyl)-mercaptoacetoxy]mutilin neutral fumarate- has been found whose physical properties made bulk manufacture more repro-ducible, simplify formulation and provide advantages in the administration of the substance.
Description
GC144a ~07705~;
Pleuromutilin (also now known as pleuromulin) is an antibiotic produced by cultures of the basidiomycete Pleurotus mutilis. The antibiotic has antibacterial activity. A group of new derivatives of pleuromutilin having antibacterial activity is described in German Offenlegungschrift 2,248,237 (April 12, 1973). One of these derivatives in particular, 14-deoxy-14-[(2-diethyl-aminoethyl)mercaptoacetoxy]mutilin (known generically as tiamutilin or tiamulin), as the hydrogen fumarate salt, 1~ has been found to be very active against microorganisms such as Streptococci, Staphylococci and Mycoplasmas and particularly useful in veterinary medicine. See Antimicrobial Agents and Chemotherapy, May 1975, pages 507-516, 517-S21. This substance, however, causes difficulties in manufacture, formulation and administration.
Research on the substance has now demonstrated that the formation of the neutral fumarate salt provides a material at least equally active on a weight basis but which has markedly different physical properties which overcome the more serious disadvantages of the hydrogen fumarate.
~ GC144a This invention relates to the new compound 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate and to compositions containing it.
[See Hodgin et al., Eur. J. Biochem. 47, 527-533 (1974?
for the structure and this system of nomenclature.~
This compound can also be named as the 14-(2-diethyl-aminoethyl)thioacetate ester of mutilin, neutral fumaratesalt. By neutral fumarate salt is meant the salt containing one moie of fumaric acid and two moles of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin, i.e., both acid groups of the fumaric acid are neutralized.
[For conveneince, 14-deoxy-14-[(2-diethylaminoethyl)-mercaptoacetoxy]mutilin is referred to hereinafter for brevity as mutilin derivative.] This is distinguished from the hydrogen fumarate discussed in the two articles in Antimicrobial Agents and Chemotherapy, supra, which contains one mole of fumaric acid and one mole of mutilin derivative.
The mutilin derivative is difficult to isolate from the impurities and by products found in the reaction mixture in which it is produced. Tiamutilin forms few readily isolatable salts. One of these is the salt with fumaric acid. It has been found, however, that even the previously used hydrogen furamate requires numerous steps for isolation and purification involving formation of a non-aqueous solvent adduct and employment of several solvents in large amounts which must then be GC144a ~077056 disposed of.
By forming the neutral fumarate under conditions as described below, a reproducible, readily crystallizable salt is formed in one step.
The new neutral fumarate lS produced from the mutilin derivative(produced as described in German Offenlegungsschrift
Pleuromutilin (also now known as pleuromulin) is an antibiotic produced by cultures of the basidiomycete Pleurotus mutilis. The antibiotic has antibacterial activity. A group of new derivatives of pleuromutilin having antibacterial activity is described in German Offenlegungschrift 2,248,237 (April 12, 1973). One of these derivatives in particular, 14-deoxy-14-[(2-diethyl-aminoethyl)mercaptoacetoxy]mutilin (known generically as tiamutilin or tiamulin), as the hydrogen fumarate salt, 1~ has been found to be very active against microorganisms such as Streptococci, Staphylococci and Mycoplasmas and particularly useful in veterinary medicine. See Antimicrobial Agents and Chemotherapy, May 1975, pages 507-516, 517-S21. This substance, however, causes difficulties in manufacture, formulation and administration.
Research on the substance has now demonstrated that the formation of the neutral fumarate salt provides a material at least equally active on a weight basis but which has markedly different physical properties which overcome the more serious disadvantages of the hydrogen fumarate.
~ GC144a This invention relates to the new compound 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate and to compositions containing it.
[See Hodgin et al., Eur. J. Biochem. 47, 527-533 (1974?
for the structure and this system of nomenclature.~
This compound can also be named as the 14-(2-diethyl-aminoethyl)thioacetate ester of mutilin, neutral fumaratesalt. By neutral fumarate salt is meant the salt containing one moie of fumaric acid and two moles of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin, i.e., both acid groups of the fumaric acid are neutralized.
[For conveneince, 14-deoxy-14-[(2-diethylaminoethyl)-mercaptoacetoxy]mutilin is referred to hereinafter for brevity as mutilin derivative.] This is distinguished from the hydrogen fumarate discussed in the two articles in Antimicrobial Agents and Chemotherapy, supra, which contains one mole of fumaric acid and one mole of mutilin derivative.
The mutilin derivative is difficult to isolate from the impurities and by products found in the reaction mixture in which it is produced. Tiamutilin forms few readily isolatable salts. One of these is the salt with fumaric acid. It has been found, however, that even the previously used hydrogen furamate requires numerous steps for isolation and purification involving formation of a non-aqueous solvent adduct and employment of several solvents in large amounts which must then be GC144a ~077056 disposed of.
By forming the neutral fumarate under conditions as described below, a reproducible, readily crystallizable salt is formed in one step.
The new neutral fumarate lS produced from the mutilin derivative(produced as described in German Offenlegungsschrift
2,248,237) by adding one mole of fumaric acid to two moles of mutilin derivative. The mutilin derivative is preferably dissolved in a solvent in which the final product is insoluble, e.g., isobutyl acetate (which is preferred), butanol, ethyl acetate, methyl isobutyl ketone, xylene or the like. The fumaric acid can be added as a solid but it is preferably added as a concentrated solution in dimethylformamide.
By adding the fumaric acid to the solution of mutilin derivative the neutral fumarate is formed in high yield in the form of well developed prisms. When the order of addition is reversed, i.e., the mutilin derivative is added to the fumaric acid then the tendency is to form the hydrogen fumarate salt. The crystalline neutral fumarate product is isolated by filtration or centrifugation, washing with the same solvent and drying.
According to the preferred method, the crude mutilin derivative,as the free base, in the reaction mixture is extracted into isobutyl acetate, a solution containing fumaria acid in dimethylformamide is added to the isobutyl acetate solution in a proportion of one mole of fumaric acid to two moles of mutilin derivative at room temperature.
The precipitated crystalline product is then isolated by filtering or centrifuging.
GC14~a .
The neutral fumarate is obtained in crystalline form which has properties distinct from the hydrogen fumarate.
A comparison of properties of the neutral fumarate and hydroyen fumarate is as follows:
Property Neutral llydrogen fumarate fumarate Molecular weight 1103.5 609.8 Melting point, C 137-138 147-1~9 Solubility in Water at 25 C, 380 70 g/ltr pH of Saturated Solution 4.9 3.3 Bulk Density gm/cc 0.5 0.27 HygroscopiOity at 70% r.h. none none and 25 C
Residual Solvents traces traces Volatiles in Wet Cake, <10 >30 % w/w Active Base in Salt,% w/w 89.5 ~1.0 Crystal Porm Stout Prisms Thin Plates and needles The new neutral fumarate of this invention overcomes various disadvantages encountered with thc known hydrogen fumarate in various areas. In manufacturing, the hydrogen fumarate has a tendency to form polymorphs and solvates which make it difficult to reliably reproduce acceptable crystals on a bulk manufacturing scale. No solvates of the neutral fumarate have been encountered in manufacturing so reproducible results are consistently obtained.
The hydrogen fumarate which is obtained in the form of fine crystals shows a tendency to disperse into the atmosphere and cause the handlers to sneeze, thus providing a hazard to the manufacturing workcrs. Thc neutral fumaratc is 1077056 GC144a characterized by large crystal size and high bulk density and does not display this tendency. The large prisms in which the neutral fumarate forms are easily obtained in pure form during manufacture and are easy to handle.
The amount of volatiles retained in the wet cake after production of the salt/as seen from the table, is greater than 30% in the case of the hydrogen fumarate compared with less than 10% (usually about 8%) for the neutral fumarate.
This makes it easier to work up the neutral fumarate, requiring less washing of the cake to remove impurities.
From the point of view of formulation, the high bulk density of the neutral fumarate simplifies formulation work, especially in tablets and capsules. The product is useful in preparing injectable compositions, particularly for larger animals like pigs and cattle, and also to produce concentrates for dilution with drinking water in automatic proportioning devices like "Auto-Medic" used in administering medicaments to poultry.
The higher pH of the neutral fumarate in solution is an advantage from the point of view of irritation at the site of injection since it is known that such irritation occurs more fre-quently as the pH decreases. In addition, the local tolerance on injection is improved when the neutral fumarate is used.
The neutral fumarate is at least as active as the hydrogen fumarate in vitro and in vivo on a weight basis.
The product is thus useful as an antibacterial agent, particularly in veterinary medicine, for the treatment of a variety of infections particularly against pathogenic gram positive bacteria such as Streptococci and Staphylococci as well as Mycoplasma and Treponema. Some gram positive 1077056 GC144a organisms such as Shigella, Klebsiella and Escherichia coli are also responsive to this substance.
The neutral fumarate of 14-deoxy-14-[(2-diethylamino-ethyl)mercaptoacetoxy]mutilin is useful for the treatment of swine dysentery (due to Treponema _yodysenteriae), enzootic pneumonia of pigs, atrophic rhinitis in pigs, mycoplasmosis, chronic respiratory disease in poultry (CRD), air sac disease, infectious synovitis, fowl cholera, bovine pneumonia, respiratory infections of horses, sheep, dogs, cats, etc.
The substance can be administered orally in drinking water or in feed compositions or parenterally in physiologically acceptable vehicle or carrier such as water, which is the preferred carrier, aqueous ethanol solutions, naturally occurring vegetable oil or physiologically acceptable modified naturally occurring oils or synthetic oils. Effective doses lie in the range of 1 to 50 mg/kg, preferably about 5 to 20 mg/kg.
Compositions containing the 14-deoxy-14-[(2-diethylaminoethyl~-mercaptoacetoxy]mutilin neutral fumarate, dependiny on the intended use and mode of administration as discussed below, can contain abouto-oo2 to 20~ by weight of active substance.
The preferred mode of administration is by intramuscular injection. The vehicle can be sterile water for injection, aqueous ethanol solutions, naturally occurring vegetable oil solutions, e.g., corn oil, sesame oil, coconut oil, cottonseed oil and the like, or synthetic oil solutions, e.g., ethyl oleate, fractionated coconut oil, etc.
The drug is administered utilizing sufficient material in about 5 to 10 ml. of vehicle, providing conccntra-tions of about-5 to 20% (weight/vol.). The dosage is in general administered 1 to 2 times daily for 5 to 10 days.
GC144a ~(~7705G
Other substances can be included in the formulations as required to produce a stable composition of pharmaceutical elegance. For example, the composition can include preservatives like phenol, chlorobutanol, methyl paraben, propylaraben or benzyl alcohol, antioxidants like sllT
(butylated hydroxytoluene), sH~ (butylated hydroxyanisole), buffering agents, etc. as required by conventional pharmaceutical practice in formulating drug compositions, especially for veterinary use.
The neutral fumarate of this invention can also be administered by other methods. For example, it can be administered to poultry for the treatment of Mycoplasma infections in the drinking water. The active material is dissolved in the water for the poultry at a concentration of about 0.002 to 2~, preferably about 0.005 to 0.05% (wt/vol).
Treatment is usually continued for about 7 to 10 days.
Concentrates for liquid proportioning devices containing 2 ounces per gallon for mixing with 128 gallons water provide a 0.016% solution.
The medicament can also be administered by incorporating the substances in animal feed compositions, e.g., swine starter rations, grower and finisher rations, starter and finisher rations for broiler chickens and turkeys, layer rations, etc. Such compositions are generally prepared as concentrated feed premixes (containing about 50 to 500 gm., preferably 50 to 250 gm. of medicament per pound of premix material) which are then incorporated in the bulk animal eed material resulting in a concentration of about 50 to 500 (jm.
of neutral fumarate per ton of feed compositioJl.
1077056 GC144a The following examples are illustrative of thc invention.
~xample 1 Pre aration of 14-Deox -1~-[(2-diethvlaminoethyl)mercapto-P Y, acetoxy]mutilin Neutral Fumarate From Pleuromutilin Tosyla~c Pleuromutilin tosylate~(53.3 grams) and ~-diethylamino-ethanethiol hydrochloride (18.7 grams) are stirred with acetone (160 ml.) in an ice bath. After cooling to +5 C, a methanolic solution of sodium methylate (50 ml. of a 25~ solution) is added in one portion. The temperature rises rapidly to about 30 C. The mixture is again cooled to 20 C. and isobutyl acetate (250 ml.) and water (250 ml.) are added. The batch is equilibrated and the layers are allowed to separate. The aqueous layer is discarded. The organic layer is stirred with water (100 ml.) and sufficient dilute HCl to lower the pH to 6.5. The aqueous phase, containing disulfide impurities, is again discarded. The organic phase is then extracted with 1 N E~Cl (100 ml.), followed by water (25 ml.). The combined aqueous layers are made basic with lN NaOH (105 ml.) to a pH above 8 in the presence of fresh isobutyl acetate (150 ml.). The mixture is equilibrated, the phases are allowed to separate and the aqueous layer is discarded. The organic layer is dried over MgSO4 and is polish filtered. The filtrate contains the desired mutilin derivative as the free base. Titration indicates a yield of about 92-94 mole~, based upon the pleuromutilin tosylate input.
The equivalent amount of fumaric acid (5.3 grams) is dissolved in dimethylformamide (17.5 ml.). About 10~ of this solution is added with stirring to the solution of GC144a the free base from above. Crystallizatioll is allowed to proceed for about lO minutes, in the presence of some secds of the desired product. Subsequently, the remainder of the fumaric acid solution is added and the crystallizat~on is completed by stirring for two hours at room temperature.
The crystals are collected on a filter and are washed with fresh isobutyl acetate (about 50 Ml.). Drying furnishes pure 14-deoxy-14[(2-diethylaminoethyl)mercapto-acetoxy]mutilin neutral fumarate (37 cJrams, correspondiny to 67 mole %, based upon the pleuromutilin tosylate input).
Most of the mutilin derivative remaining in the mother .
liquors (about 22 mole %, based upon the pleuromutilin tosylate input) is recovered by washing the liquid with aqueous sodium hydroxide to remove fumaric acid, followed by extraction into aqueous hydrochloric acid at a pH below 2. This acidic extract is then returned into a subsequent batch for a substantial overall yield increase.
Example 2 A solution of the free base of the mutilin derivative in isobutyl acetate is prepared as described in Example l.
The solution is heated to about 60-70 C. and the equivalent amount of solid fumaric acid (5.3 grams) is added in one portion with efficient agitation. The fumaric acid dissolves gradually and the characteristic prismatic crystals of the desired product separate. The mixture is allowed to cool to room temperature and the crystallization is completed by stirring for two more hours. The crystals are collected on a filter and are washed with fresh isobutyl ace~ate (75 ml.).
Drying furnishes pure 14-deoxy-14-[(2-dietllylaminoethyl)mercai)to-acetoxy]mutilin neutral fumarate (4G.3 yrams or 84 mole %, GC144a ~077056 based upon the pleuromutilin tosylate charged).
Example 3 14-Deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin is produced as described in Example 1 and the mixture is worked up to the aqueous acidic extract. For the subsequent back-extraction, ethyl acetate (200 ml.) is substituted for the isobutyl acetate. The extract is dried and filtered as described in ~xample 1. Titration indicates the presence of about 92 mole % of the free base of the mutilin derivative in the filtrate.
The equivalent amount of fumaric acid is added as a solid to the stirred filtrate at reflux temperature. The fumaric acid dissolves quickly and the neutral fumarate salt separates in the form of prismatic crystals. The mixture is cooled to room temperature and crystallization is completed by stirring for two additional hours. Filtration, washing with fresh ethyl acetate (50 ml.) and dryiny furnishes pure 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate (42.4 grams or 77 mole %, based upon the pleuromutilin tosylate input).
Example 4 A 10% multiple dose solution is prepared by dissolviny 1 kg. of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin neutral fumarate in 10 liters of a 50% solution ofaqueous ethanol at room temperature. The solution is bottled in 100 ml. multi-dose bottles. This solution is administered intramuscularly to pigs infected with swine dysentery in 1 to 10 ml. dosaqes (10 mg/kg) once daily for five days.
10770S6 GC144a Examplc 5 1 kg. of 14-deoxy-14[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin neutral fumarate is mixed with 5 liters of ethyl oleate under sterile conditions until thoroughly suspended. S mg. of a mixture of methyl paraben and propyl paraben (10:1) are added.
The 20% oil suspension is bottled in 100 ml. multiple dose bottles for intramuscular injection.
Example 6 500 gm. of 14-deoxy-14-[(2-diethylaminoethyl)mercapto-acetoxy]mutilin neutral fumarate are suspended in 10 liters of fractionated coconut oil (Neobee 20) and 100 mg. of benzyl alcohol are added under sterile condltions. The 5~ suspension is subdivided into sterile vials each containing 5 ml. for intramuscular injection.
~ mple 7 An aqueous concentrate for use in a liquid proportioning device like "Auto-Medic" is prepared by dissolying 6 k~. oE
14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mu~ilin neutral fumarate in 100 gal. of water. 3.78 kg. of benzyl alcohol are added. The solution is bottled in 1 gal.
bottles. The contents of one bottle are placed in a liquid proportioning device adjusted to mix with 128 gal. of water to provide a .0125% concentration drinking water solution for administration to broiler chickens infected with CRD.
GC144a l'xarnple 8 .
A feed premix is prepared by thoroucJhly admixiny 10 kg.
of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate with 100 lb. of soybean meal. The mixture is subdivided into packages each containing 100 gm. o~
active ingredient per lb. of premix. Two lbs. of premix is added to one ton of feed to provide a medicated feed containing 200 gm. per ton.
Example 9 A swine starter ration is admixed consistiny of the following ingredients Lbs Corn meal 1315 Wheat midds 100 Soybean 405 Menhaden meal 40 Dried Whey 50 Calcium phosphate 30 Salt 10 Molasses 50 To the swine starter ration is added 100 gm of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy~mutilin neutral fumarate and the mixture is thoroughly blended.
The feed composition contains 100 gm. of activ,e medicament per ton of feed. The medicated feed composition is fed to 5 to 8 week old pigs infected with Treponema hvodysenteriae for 14 days. ^
.. . .
1~77056 GC144a E:xample 10 A swine starter ration is prepared containing the following ingredients:
Lbs Corn meal 1311 Wheat midds 100 Soybean 405 Menhaden meal 40 Dried Whey 50 Calcium phosphate 30 Salt 10 Molasses 50 Mineral Mix 2 Vitamin Mix 2 The mineral mix is made up in the followiny proportions:
Gm Copper 5 4 Iron 68.0 Manganese 18.2 Zinc 45.4 Iodine 0.2 The vitamin mix is made up in the following proportions:
Vitamin A 3000 IU
Vitamin D 1000 IU
Vitamin E 20 IU
Vitamin B12 20 1i(3 ;
Riboflavin 3 ~lg ~clntotl~en.ic (~ O ~ r ~o770s6 GC144a Niacin 20 mg Choline . 200 mg The feed composition including vitamin and mineral mixes is thoroughly admixed with 200 gms. of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate providing a medicated feed composition containing 200 gm. of active ingredient per tOIl of feed. Pigs infected with Treponema hyodysenteriae are permitted to feed ad libitum on this feed composition for 14 days.
By adding the fumaric acid to the solution of mutilin derivative the neutral fumarate is formed in high yield in the form of well developed prisms. When the order of addition is reversed, i.e., the mutilin derivative is added to the fumaric acid then the tendency is to form the hydrogen fumarate salt. The crystalline neutral fumarate product is isolated by filtration or centrifugation, washing with the same solvent and drying.
According to the preferred method, the crude mutilin derivative,as the free base, in the reaction mixture is extracted into isobutyl acetate, a solution containing fumaria acid in dimethylformamide is added to the isobutyl acetate solution in a proportion of one mole of fumaric acid to two moles of mutilin derivative at room temperature.
The precipitated crystalline product is then isolated by filtering or centrifuging.
GC14~a .
The neutral fumarate is obtained in crystalline form which has properties distinct from the hydrogen fumarate.
A comparison of properties of the neutral fumarate and hydroyen fumarate is as follows:
Property Neutral llydrogen fumarate fumarate Molecular weight 1103.5 609.8 Melting point, C 137-138 147-1~9 Solubility in Water at 25 C, 380 70 g/ltr pH of Saturated Solution 4.9 3.3 Bulk Density gm/cc 0.5 0.27 HygroscopiOity at 70% r.h. none none and 25 C
Residual Solvents traces traces Volatiles in Wet Cake, <10 >30 % w/w Active Base in Salt,% w/w 89.5 ~1.0 Crystal Porm Stout Prisms Thin Plates and needles The new neutral fumarate of this invention overcomes various disadvantages encountered with thc known hydrogen fumarate in various areas. In manufacturing, the hydrogen fumarate has a tendency to form polymorphs and solvates which make it difficult to reliably reproduce acceptable crystals on a bulk manufacturing scale. No solvates of the neutral fumarate have been encountered in manufacturing so reproducible results are consistently obtained.
The hydrogen fumarate which is obtained in the form of fine crystals shows a tendency to disperse into the atmosphere and cause the handlers to sneeze, thus providing a hazard to the manufacturing workcrs. Thc neutral fumaratc is 1077056 GC144a characterized by large crystal size and high bulk density and does not display this tendency. The large prisms in which the neutral fumarate forms are easily obtained in pure form during manufacture and are easy to handle.
The amount of volatiles retained in the wet cake after production of the salt/as seen from the table, is greater than 30% in the case of the hydrogen fumarate compared with less than 10% (usually about 8%) for the neutral fumarate.
This makes it easier to work up the neutral fumarate, requiring less washing of the cake to remove impurities.
From the point of view of formulation, the high bulk density of the neutral fumarate simplifies formulation work, especially in tablets and capsules. The product is useful in preparing injectable compositions, particularly for larger animals like pigs and cattle, and also to produce concentrates for dilution with drinking water in automatic proportioning devices like "Auto-Medic" used in administering medicaments to poultry.
The higher pH of the neutral fumarate in solution is an advantage from the point of view of irritation at the site of injection since it is known that such irritation occurs more fre-quently as the pH decreases. In addition, the local tolerance on injection is improved when the neutral fumarate is used.
The neutral fumarate is at least as active as the hydrogen fumarate in vitro and in vivo on a weight basis.
The product is thus useful as an antibacterial agent, particularly in veterinary medicine, for the treatment of a variety of infections particularly against pathogenic gram positive bacteria such as Streptococci and Staphylococci as well as Mycoplasma and Treponema. Some gram positive 1077056 GC144a organisms such as Shigella, Klebsiella and Escherichia coli are also responsive to this substance.
The neutral fumarate of 14-deoxy-14-[(2-diethylamino-ethyl)mercaptoacetoxy]mutilin is useful for the treatment of swine dysentery (due to Treponema _yodysenteriae), enzootic pneumonia of pigs, atrophic rhinitis in pigs, mycoplasmosis, chronic respiratory disease in poultry (CRD), air sac disease, infectious synovitis, fowl cholera, bovine pneumonia, respiratory infections of horses, sheep, dogs, cats, etc.
The substance can be administered orally in drinking water or in feed compositions or parenterally in physiologically acceptable vehicle or carrier such as water, which is the preferred carrier, aqueous ethanol solutions, naturally occurring vegetable oil or physiologically acceptable modified naturally occurring oils or synthetic oils. Effective doses lie in the range of 1 to 50 mg/kg, preferably about 5 to 20 mg/kg.
Compositions containing the 14-deoxy-14-[(2-diethylaminoethyl~-mercaptoacetoxy]mutilin neutral fumarate, dependiny on the intended use and mode of administration as discussed below, can contain abouto-oo2 to 20~ by weight of active substance.
The preferred mode of administration is by intramuscular injection. The vehicle can be sterile water for injection, aqueous ethanol solutions, naturally occurring vegetable oil solutions, e.g., corn oil, sesame oil, coconut oil, cottonseed oil and the like, or synthetic oil solutions, e.g., ethyl oleate, fractionated coconut oil, etc.
The drug is administered utilizing sufficient material in about 5 to 10 ml. of vehicle, providing conccntra-tions of about-5 to 20% (weight/vol.). The dosage is in general administered 1 to 2 times daily for 5 to 10 days.
GC144a ~(~7705G
Other substances can be included in the formulations as required to produce a stable composition of pharmaceutical elegance. For example, the composition can include preservatives like phenol, chlorobutanol, methyl paraben, propylaraben or benzyl alcohol, antioxidants like sllT
(butylated hydroxytoluene), sH~ (butylated hydroxyanisole), buffering agents, etc. as required by conventional pharmaceutical practice in formulating drug compositions, especially for veterinary use.
The neutral fumarate of this invention can also be administered by other methods. For example, it can be administered to poultry for the treatment of Mycoplasma infections in the drinking water. The active material is dissolved in the water for the poultry at a concentration of about 0.002 to 2~, preferably about 0.005 to 0.05% (wt/vol).
Treatment is usually continued for about 7 to 10 days.
Concentrates for liquid proportioning devices containing 2 ounces per gallon for mixing with 128 gallons water provide a 0.016% solution.
The medicament can also be administered by incorporating the substances in animal feed compositions, e.g., swine starter rations, grower and finisher rations, starter and finisher rations for broiler chickens and turkeys, layer rations, etc. Such compositions are generally prepared as concentrated feed premixes (containing about 50 to 500 gm., preferably 50 to 250 gm. of medicament per pound of premix material) which are then incorporated in the bulk animal eed material resulting in a concentration of about 50 to 500 (jm.
of neutral fumarate per ton of feed compositioJl.
1077056 GC144a The following examples are illustrative of thc invention.
~xample 1 Pre aration of 14-Deox -1~-[(2-diethvlaminoethyl)mercapto-P Y, acetoxy]mutilin Neutral Fumarate From Pleuromutilin Tosyla~c Pleuromutilin tosylate~(53.3 grams) and ~-diethylamino-ethanethiol hydrochloride (18.7 grams) are stirred with acetone (160 ml.) in an ice bath. After cooling to +5 C, a methanolic solution of sodium methylate (50 ml. of a 25~ solution) is added in one portion. The temperature rises rapidly to about 30 C. The mixture is again cooled to 20 C. and isobutyl acetate (250 ml.) and water (250 ml.) are added. The batch is equilibrated and the layers are allowed to separate. The aqueous layer is discarded. The organic layer is stirred with water (100 ml.) and sufficient dilute HCl to lower the pH to 6.5. The aqueous phase, containing disulfide impurities, is again discarded. The organic phase is then extracted with 1 N E~Cl (100 ml.), followed by water (25 ml.). The combined aqueous layers are made basic with lN NaOH (105 ml.) to a pH above 8 in the presence of fresh isobutyl acetate (150 ml.). The mixture is equilibrated, the phases are allowed to separate and the aqueous layer is discarded. The organic layer is dried over MgSO4 and is polish filtered. The filtrate contains the desired mutilin derivative as the free base. Titration indicates a yield of about 92-94 mole~, based upon the pleuromutilin tosylate input.
The equivalent amount of fumaric acid (5.3 grams) is dissolved in dimethylformamide (17.5 ml.). About 10~ of this solution is added with stirring to the solution of GC144a the free base from above. Crystallizatioll is allowed to proceed for about lO minutes, in the presence of some secds of the desired product. Subsequently, the remainder of the fumaric acid solution is added and the crystallizat~on is completed by stirring for two hours at room temperature.
The crystals are collected on a filter and are washed with fresh isobutyl acetate (about 50 Ml.). Drying furnishes pure 14-deoxy-14[(2-diethylaminoethyl)mercapto-acetoxy]mutilin neutral fumarate (37 cJrams, correspondiny to 67 mole %, based upon the pleuromutilin tosylate input).
Most of the mutilin derivative remaining in the mother .
liquors (about 22 mole %, based upon the pleuromutilin tosylate input) is recovered by washing the liquid with aqueous sodium hydroxide to remove fumaric acid, followed by extraction into aqueous hydrochloric acid at a pH below 2. This acidic extract is then returned into a subsequent batch for a substantial overall yield increase.
Example 2 A solution of the free base of the mutilin derivative in isobutyl acetate is prepared as described in Example l.
The solution is heated to about 60-70 C. and the equivalent amount of solid fumaric acid (5.3 grams) is added in one portion with efficient agitation. The fumaric acid dissolves gradually and the characteristic prismatic crystals of the desired product separate. The mixture is allowed to cool to room temperature and the crystallization is completed by stirring for two more hours. The crystals are collected on a filter and are washed with fresh isobutyl ace~ate (75 ml.).
Drying furnishes pure 14-deoxy-14-[(2-dietllylaminoethyl)mercai)to-acetoxy]mutilin neutral fumarate (4G.3 yrams or 84 mole %, GC144a ~077056 based upon the pleuromutilin tosylate charged).
Example 3 14-Deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin is produced as described in Example 1 and the mixture is worked up to the aqueous acidic extract. For the subsequent back-extraction, ethyl acetate (200 ml.) is substituted for the isobutyl acetate. The extract is dried and filtered as described in ~xample 1. Titration indicates the presence of about 92 mole % of the free base of the mutilin derivative in the filtrate.
The equivalent amount of fumaric acid is added as a solid to the stirred filtrate at reflux temperature. The fumaric acid dissolves quickly and the neutral fumarate salt separates in the form of prismatic crystals. The mixture is cooled to room temperature and crystallization is completed by stirring for two additional hours. Filtration, washing with fresh ethyl acetate (50 ml.) and dryiny furnishes pure 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate (42.4 grams or 77 mole %, based upon the pleuromutilin tosylate input).
Example 4 A 10% multiple dose solution is prepared by dissolviny 1 kg. of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin neutral fumarate in 10 liters of a 50% solution ofaqueous ethanol at room temperature. The solution is bottled in 100 ml. multi-dose bottles. This solution is administered intramuscularly to pigs infected with swine dysentery in 1 to 10 ml. dosaqes (10 mg/kg) once daily for five days.
10770S6 GC144a Examplc 5 1 kg. of 14-deoxy-14[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin neutral fumarate is mixed with 5 liters of ethyl oleate under sterile conditions until thoroughly suspended. S mg. of a mixture of methyl paraben and propyl paraben (10:1) are added.
The 20% oil suspension is bottled in 100 ml. multiple dose bottles for intramuscular injection.
Example 6 500 gm. of 14-deoxy-14-[(2-diethylaminoethyl)mercapto-acetoxy]mutilin neutral fumarate are suspended in 10 liters of fractionated coconut oil (Neobee 20) and 100 mg. of benzyl alcohol are added under sterile condltions. The 5~ suspension is subdivided into sterile vials each containing 5 ml. for intramuscular injection.
~ mple 7 An aqueous concentrate for use in a liquid proportioning device like "Auto-Medic" is prepared by dissolying 6 k~. oE
14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mu~ilin neutral fumarate in 100 gal. of water. 3.78 kg. of benzyl alcohol are added. The solution is bottled in 1 gal.
bottles. The contents of one bottle are placed in a liquid proportioning device adjusted to mix with 128 gal. of water to provide a .0125% concentration drinking water solution for administration to broiler chickens infected with CRD.
GC144a l'xarnple 8 .
A feed premix is prepared by thoroucJhly admixiny 10 kg.
of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate with 100 lb. of soybean meal. The mixture is subdivided into packages each containing 100 gm. o~
active ingredient per lb. of premix. Two lbs. of premix is added to one ton of feed to provide a medicated feed containing 200 gm. per ton.
Example 9 A swine starter ration is admixed consistiny of the following ingredients Lbs Corn meal 1315 Wheat midds 100 Soybean 405 Menhaden meal 40 Dried Whey 50 Calcium phosphate 30 Salt 10 Molasses 50 To the swine starter ration is added 100 gm of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy~mutilin neutral fumarate and the mixture is thoroughly blended.
The feed composition contains 100 gm. of activ,e medicament per ton of feed. The medicated feed composition is fed to 5 to 8 week old pigs infected with Treponema hvodysenteriae for 14 days. ^
.. . .
1~77056 GC144a E:xample 10 A swine starter ration is prepared containing the following ingredients:
Lbs Corn meal 1311 Wheat midds 100 Soybean 405 Menhaden meal 40 Dried Whey 50 Calcium phosphate 30 Salt 10 Molasses 50 Mineral Mix 2 Vitamin Mix 2 The mineral mix is made up in the followiny proportions:
Gm Copper 5 4 Iron 68.0 Manganese 18.2 Zinc 45.4 Iodine 0.2 The vitamin mix is made up in the following proportions:
Vitamin A 3000 IU
Vitamin D 1000 IU
Vitamin E 20 IU
Vitamin B12 20 1i(3 ;
Riboflavin 3 ~lg ~clntotl~en.ic (~ O ~ r ~o770s6 GC144a Niacin 20 mg Choline . 200 mg The feed composition including vitamin and mineral mixes is thoroughly admixed with 200 gms. of 14-deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin neutral fumarate providing a medicated feed composition containing 200 gm. of active ingredient per tOIl of feed. Pigs infected with Treponema hyodysenteriae are permitted to feed ad libitum on this feed composition for 14 days.
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 14-deoxy-14-[(2-diethylamino-ethyl)mercaptoacetoxy]mutilin neutral fumarate characterized by reacting two moles of 14-deoxy-14[(2-diethylaminoethyl)-mercaptoacetoxy]mutilin with one mole of fumaric acid.
2. A process according to claim 1 wherein the fumaric acid is added to said mutilin derivative which is dissolved in a solvent.
3. A process according to claim 1 wherein the fumaric acid is added to a solution of the mutilin derivative wherein the solvent is selected from the group consisting of isobutyl acetate, butanol, ethyl acetate, methyl isobutyl ketone and xylene.
4. A process according to claim 1 wherein the fumaric acid is added to a solution of the mutilin derivative in isobutyl acetate.
5. A process according to claim 1 wherein a solution of fumaric acid in dimethylformamide is added to a solution of the mutilin derivative in isobutyl acetate.
6. 14-Deoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]-mutilin neutral fumarate whenever prepared by the process of claim 1.
7, The compound of claim 1, whenever prepared by the process of claim 2.
8. The compound of claim 1, whenever prepared by the process of claim 3.
9. The compound of claim 1, whenever prepared by the process of claim 4.
10. The compound of claim 1, whenever prepared by the process of claim 5.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61808775A | 1975-09-30 | 1975-09-30 | |
| US05/709,983 US4086359A (en) | 1975-09-30 | 1976-07-30 | Derivatives of pleuromutilin and compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077056A true CA1077056A (en) | 1980-05-06 |
Family
ID=27088148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA260,231A Expired CA1077056A (en) | 1975-09-30 | 1976-08-31 | Derivatives of pleuromutilin and compositions |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS6029383B2 (en) |
| AT (1) | AT350835B (en) |
| CA (1) | CA1077056A (en) |
| CH (1) | CH595339A5 (en) |
| DE (1) | DE2643672C2 (en) |
| FR (1) | FR2326186A1 (en) |
| GB (1) | GB1547437A (en) |
| IE (1) | IE44428B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2526019A1 (en) * | 1982-04-28 | 1983-11-04 | Sandoz Sa | NOVEL DERIVATIVES OF PLEUROMUTILINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
-
1976
- 1976-08-31 IE IE1943/76A patent/IE44428B1/en not_active IP Right Cessation
- 1976-08-31 CA CA260,231A patent/CA1077056A/en not_active Expired
- 1976-09-23 GB GB39543/76A patent/GB1547437A/en not_active Expired
- 1976-09-28 DE DE2643672A patent/DE2643672C2/en not_active Expired
- 1976-09-29 AT AT722976A patent/AT350835B/en not_active IP Right Cessation
- 1976-09-29 CH CH1230476A patent/CH595339A5/xx not_active IP Right Cessation
- 1976-09-30 JP JP51118409A patent/JPS6029383B2/en not_active Expired
- 1976-09-30 FR FR7629398A patent/FR2326186A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2326186B1 (en) | 1978-11-17 |
| DE2643672C2 (en) | 1986-07-24 |
| GB1547437A (en) | 1979-06-20 |
| CH595339A5 (en) | 1978-02-15 |
| DE2643672A1 (en) | 1977-04-07 |
| JPS5244221A (en) | 1977-04-07 |
| AT350835B (en) | 1979-06-25 |
| JPS6029383B2 (en) | 1985-07-10 |
| IE44428B1 (en) | 1981-12-02 |
| ATA722976A (en) | 1978-11-15 |
| IE44428L (en) | 1977-03-30 |
| FR2326186A1 (en) | 1977-04-29 |
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