JPH0417958B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to ether, ester, urethane and other derivatives of the animal growth promoter known as M.139603. The derivatives are effective in reducing the proportion of methane produced by rumen fermentation and increasing the proportion of propionic acid in the ruminal fluid of the rumen, thus Other compounds are believed to have growth-promoting properties in animals, reducing methane concentrations and increasing propionic acid concentrations in the rumen of the rumen, e.g. This results in increased growth rates when fed to ruminants.
well known. The compound known as M.139603, a metabolite obtained from the aerobic culture of Steptomyces longisporoflavus, is described and claimed in UK Patent Application No. 7922511 and has the structure, R ¹ = methyl group, R ² = hydroxymethyl group. According to the invention the formula: [Wherein, M ⁺ is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is a formyl or hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is Derivatives of M.139603 having 3 to 7 carbon atoms are obtained. The details of R ¹ , R ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are, for example, 1 to 1 when it is an alkyl group or a group having an alkyl moiety.
Such alkyl groups have 3 carbon atoms, or such groups have 1 to 3 carbon atoms in the alkyl portion. Particular optional substituents of R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are optionally substituted phenyl, naphthyl or phenylalkyl groups, For example, halogen atoms, nitro,
cyano or hydroxy group, or e.g. 8
Alkyl, alkoxy, halogenoalkyl, halogenalkoxy, alkylamino, dialkylamino or alkanoylamino groups such as groups having up to 4 carbon atoms, preferably up to 4 carbon atoms. Particulars of R ⁷ are, when it is an alkenyl or alkynyl group, such groups having, for example, 2 or 3 carbon atoms. Detailed cations M ⁺ include, for example, sodium, lithium, potassium, calcium, magnesium,
Zinc, ammonium, mono-, di-, tri- and tetra-alkylammonium ions (in which case alkyl each has 1 to 10 carbon atoms), and mono-, di- and tri-(hydroxyalkyl) ammonium ions (in this case the hydroxyalkyl each have 1 to 10 carbon atoms). Particular compounds according to the invention which are good for increasing the proportion of propionic acid in the rumen fluid of the rumen are those in which R ¹ is a hydrogen atom and R ² is a hydroxymethyl group; R ¹ is a methyl group; and R ² is a formyl group; R ¹ is a methyl group and R ^{2 is a methoxymethyl group; R 1 is} a methyl group and R ² is a propargyloxymethyl group; R ¹ is methyl and R ² is a benzoyloxymethyl group; R ¹ is a methyl group and R ² is a 2-bromobenzoyloxymethyl group; R ¹ is a methyl group and R ² is a chloroacetoxymethyl group; R ¹ is a methyl group and R ² is an ethoxalyloxymethyl group; and R ¹ is a methyl group and R ² is an N-methylthiocarbamoyloxymethyl group. . The compounds according to the invention can be prepared by methods known per se for the preparation of chemically similar compounds. The following method is thus obtained as another embodiment of the invention: (a) For compounds such that R ² is a group of the formula -CH ₂ OR ⁷ as defined above, with the proviso that R ¹ represents the above, R ² is a hydroxymethyl group)
A compound of the formula: R ⁷ Z, where R ⁷ is as defined above and Z is a leaving group, for example a halogen atom such as chlorine or bromine, or a mesyl or tosyl group, and a strong base. (b) R ¹ is other than a hydrogen atom and R ² is of the formula -CH ₂ O;・COR ⁸ or −CH ₂ O.CO.
For compounds of the formula COR ⁹ , where R ¹ is an alkyl or optionally substituted phenylalkyl group and R ² is a hydroxymethyl group, a compound of the formula: ^R8 .
Acylating agents, acid anhydrides derived from carboxylic acids of COOH or R ⁹ CO.COOH, where R ⁸ and R ⁹ represent the aforementioned, for example acyl halides, such as chlorides, bromides or iodides. (c) R ¹ is other than a hydrogen atom and R ² is of the formula: -CH ₂ O.COR ⁸ or -CH ₂ O.CO.
For compounds of the formula COR ⁹ , where R ¹ is an alkyl or optionally substituted phenyl or phenylalkyl group, and R ² is a hydroxymethyl group, Formula: R ⁸ .COOH or R ⁹ CO.COOH (however,
R ⁸ and R ⁹ are as defined above) in the presence of a carbodiimide, such as dicyclohexylcarbodiimide; (d) R ² is of the formula -CH ₂ O.COR ⁸ , , R ⁸ is a hydroxyalkyl group), where R ² is a hydroxyalkyl group.
(e) reacting a compound of CH ₂ O.COR ⁸ (in which R ⁸ is a (t ^- alkoxy)-alkyl group) with an acid, e.g. ethanolic hydrogen chloride; For compounds of ^the formula: _-CH2O.COR8 , where ^R8 is an alkylaminoalkyl or dialkylaminoalkyl group, the corresponding aminoalkyl compound is converted to an alkyl halide, e.g. bromide. ( ^f ) Reacting with ^alkyl or ^alkyl _iodide ; (g) where R ² is of the formula —CH ₂ O.COR ⁸ (wherein R ⁸ is carbamoylalkyl, N-alkylcarbamoylalkyl or N,N-dialkylcarbamoylalkyl group), the corresponding carboxyalkyl or alkoxycarbonylalkyl compound (h) R ² is of the formula -CH ₂ O.CO.COR ⁹ , where R ⁹ is an amino, mono- or dialkylamino group; ), the corresponding compound (wherein R ⁹ is a hydroxy or alkoxy group) is reacted with ammonia or a mono- or di-alkylamine, respectively; (i) R ² is For compounds having the formula: -CH ₂ O.CX.NR ¹⁰ R ¹¹ (wherein R ¹⁰ is a hydrogen atom and X and R ¹¹ represent the above), the formula (however, R ² is a hydroxymethyl group) with an isocyanate or isothiocyanate of the formula R ¹¹ .NCX, where R ¹¹ and X are as defined above; (j) R ² is a group of the formula: -CH ₂ O.CX.NR ¹⁰ R ¹¹ (wherein, X represents the above, and one or both of R ¹⁰ and R ¹¹ is other than a hydrogen atom) , a corresponding compound (provided that one or both of R ¹⁰ and R ¹¹ is a hydrogen atom), a halogen compound R ¹⁰ , a halide, or R ¹¹ , a halide (provided that one of R ¹⁰ and R ¹¹ is a hydrogen atom) or both are other than hydrogen atoms; (k) for compounds where R ² is a formyl group, the corresponding compound (wherein R ² is a hydroxymethyl group); For example, by oxidizing with activated manganese dioxide; (l) For compounds in which R ² is a hydroxyiminomethyl group, the corresponding compound (however,
(n) for compounds in ^{which R 1 is} a hydroxy group and R ² is a hydroxymethyl group, Streptomyces longisporoflavus (Streptomyces longisporoflavus)
NCIB11426 or its variants or mutants are cultivated in an aqueous nutrient medium with an assimilable carbon source under shaking aerobic conditions at a temperature of 22-32°C, and the fermentation mixture is mixed with a water-immiscible organic solvent. The product with R _F =0.43 was extracted from this organic extract by thin layer chromatography to a thickness of 0.25 mm.
silica plate (Merck's “Kieselgel60F−
254"-trademark) with a volumetric mixture of diethyl ether, methanol and formic acid 95:4:1. The microorganism Steptomyces longisporoflavus (S.
longisporoflavus) NCIB 11426 has been transferred to the National Industrial Bacteria Repository (the
Collection of Industrial Bacteria, Ministry
of Agriculture, Fisheries and Food, Torry
Research Station, 135 Abbey Road;
Aberdeen AB9 8DG, Scotland) is a known microorganism. As mentioned above, this compound has the effect of increasing the proportion of propionic acid in the rumen fluid of the rumen, in particular increasing the proportion of propionic acid at the expense of methane and/or acetic acid. This is known to be a desirable effect in terms of nutritional intake in ruminants. This is because propionic acid is
It is a significantly more effective precursor of glucose than acetic acid, from which animals derive their energy and boost; the portion of an animal's food intake that is converted to methane is easily lost from the animal, with methane being This is because it is excreted by It is therefore believed that the modulation of rumen metabolism achieved by the compounds according to the invention is a most beneficial effect and increases the growth rate and efficiency of food conversion in ruminants. ing. According to another embodiment of the invention, therefore, in order to increase the efficiency of food conversion in a domestic ruminant, the compound according to the invention is administered orally to the animal as described above. The present invention provides a method for use in livestock farming of ruminant animals. In the method of the invention, the compound according to the invention is
Advantageously administered orally to ruminants as a supplement to their normal diet, i.e. mixed with salt dissolved in drinking water or dissolved in whole milk or skimmed milk for young animals, e.g. lambs or calves. be done. The compound according to the invention can be used in such a way that each treated animal receives 1 kg of body weight per day of the compound according to the invention.
It is incorporated into food, feed mass, salt, drinking water, whole milk and skimmed milk to such an extent that the intake amount is 0.01 mg to 30 mg, preferably 0.01 mg to 10 mg per serving. The compounds according to the invention can be prepared in slow release formulations so that the ruminant absorbs the same amount of the compounds according to the invention every day.
It can be selectively administered to ruminants in the form of intraruminal pellets or pills. The ruminant can receive the compound according to the invention for substantially all of its growth time, or only for a part of its growth time, for example early on and/or up to slaughter. Due to the increased growth rate achieved by carrying out the method of the invention,
Ruminants raised for meat may be brought to market weight or slaughter weight with a shorter than normal growing time, or heavy ruminants may be produced at the end of the normal growing time. Due to the improved efficiency of food conversion achieved by carrying out the method of the present invention, treated animals can achieve any desired weight and outperform untreated animals grown to the same weight. Less food consumption is required. No trace of toxic effects of the compounds according to the invention is observed at optimal growth-promoting contents. According to another embodiment of the invention, compositions are obtained consisting of a compound according to the invention and an edible, non-toxic diluent or carrier in solid or liquid form. Suitable liquid diluents or carriers are, for example, drinking water, whole milk or skimmed milk. Suitable solid, edible, non-toxic diluents or carriers include, for example, conventional nutritionally balanced ruminant feeds, such as cereal products such as coarse barley flour, corn flour or wheat flour, nuts, etc. Products and actual products, such as pulverized nut cake or cottonseed cake with the hull removed, or extracted cottonseed cake with small amounts, such as feathers, seaweed, coarse bone meal, fine bone meal, choyoke, salt, urea, molasses, vitamins. and trace minerals; or it can be an inert solid diluent or carrier of zero energy value, such as kaolin, talc, calcium carbonate, terra alba, It can be attapulgus clay, crushed oyster shells or crushed coalstone; or it can be starch or lactose. The composition according to the invention may be in the form of a feed added for direct feeding to ruminants, in which case it contains 5 ppm of the compound according to the invention.
~3000 ppm in admixture with conventional ruminant feed; or the composition according to the invention may be diluted with conventional ruminant feed to obtain an added feed suitable for direct feeding. Such premixes contain from 0.3% w/w to 50% w/w of the compound according to the invention.
% in a conventional nutritionally balanced ruminant feed, mixed with an inert solid diluent of zero energy value, such as ground limestone, or mixed with starch or lactose. According to another embodiment of the invention, the compound according to the invention is homogeneously mixed with a solid, edible, non-toxic diluent or carrier.
A method for producing a solid composition according to the invention is obtained. Advantageously, the compound of formula is diluted continuously with a diluent or carrier in two or more successive steps to ensure uniform mixing. The present invention is illustrated in detail by the following examples, but the present invention is not limited thereby: Example 1 M.139603 (1.0 g) was mixed with dichloromethane (40 ml).
and then add acetyl chloride (5 ml) to this solution.
was added and the mixture was left in a stoppered flask at room temperature over the weekend. This solution is then filtered and
The filtrate was evaporated to dryness. The resulting rubber was tested by thin layer chromatography (TLC), which showed that about 90% of the new product was formed. Dissolve this rubber in a small amount of acetone, and apply this solution to two preparative TLC plates (Merck ART5717-
40 cm x 20 cm x 2 mm), and this plate was developed with chloroform/methanol/formic acid (90:5:5). Two bands, R _F =0.46 and 0.54, were separated from this plate and eluted with ethyl acetate/methanol (95:5), each yielding a new product 490
mg, and 320 mg of a mixture of new product and starting material M.139603. The mixed material with R _F = 0.46 was repurified in a similar manner, yielding 192 mg of speckled product.
combining this material with the previously eluted product;
A total of 682 mg of M.139603 acetate was produced with an NMR spectrum in deuterochloroform as illustrated in FIG. Similarly, using 2-bromobenzoyl chloride instead of acetyl chloride, the following was obtained; M.139603 2-bromobenzoate (, R ¹ =
_CH3 , ^R2 = _CH2O.CO (2 _{- BrC6H4} )). Analysis result: Calculated value for C ₄₂ H ₅₆ O ₉ BrNa.2H ₂ O: C,
59.8%; H, 7.1%. Actual value: C, 59.7%; H,
6.8%. Mass Spectrum Accurate mass measurement result for molecular ion: Calculated value for C ₄₂ H ₅₆ O ₉ ⁷⁹ BrNa:
806.2988; Actual value: 806.3006. Example 2 M.139603 (0.624 g,
Add ethoxalyl chloride (0.5 ml, 4.5 mmol) to a stirred solution of the sodium salt (1.0 mmol);
This mixture was stirred at room temperature for 64 hours. The solvent was evaporated under reduced pressure and the residue was treated with a 50% solution containing sodium bicarbonate to destroy excess acid chloride. The mixture was diluted with water and extracted twice with ether, the combined ether extracts were washed with water, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure to dryness. This residue was chromatographed on silica gel (Merck 7734) using toluene-acetone (4:1) as eluent. The appropriate fractions were evaporated to give the ethoxalyl ester of M.139603 (, R ¹ = CH ₃ , R ² = CH ₂ O.
CO.COOC ₂ H ₅ ) was formed as white bubbles.
Calculated values for C ₃₉ H ₅₇ O ₁₁ Na: C, 64.6%; H,
7.9%. Actual value: C, 64.8%; H, 8.1%. Mass spectrum Accurate mass measurement results for molecular ions:
Calculated _{for C39H57O11Na} : _724.3799 ; Found: 724.3796. Similarly, the following ester derivatives of M.139603 were obtained from the sodium salt of M.139603 and the appropriate acid halide. The structure was confirmed by mass spectroscopy and precise mass measurements of the molecular ions.

【table】

Table Example 3 To a stirred solution of the sodium salt of M.139603 (1.0 g, 1.60 mmol) in toluene (10 ml) was added succinic anhydride (0.18 g, 1.8 mmol) and triethylamine (0.26 ml, 1.9 mmol). . The mixture was heated at reflux for 20 hours, then cooled and the solvent was evaporated under reduced pressure. The remaining gum was dissolved in ether (100ml) and this solution was extracted with saturated sodium carbonate solution (2 x 100ml). The combined aqueous extracts were acidified with 2N hydrochloric acid and extracted with ether (2 x 70ml), the combined ethereal extracts were dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The remaining gum was purified by chromatography on silica gel (Merck 7734) using ethyl acetate as eluent. The appropriate fractions were combined and concentrated under reduced pressure to give the monosuccinyl ester of M.139603 (, R ¹ = CH ₃ , R ² = CH ₂ O.CO.
CH ₂ CH ₂ COOH) was formed as white bubbles. Analysis result: Calculated value for C ₃₉ H ₅₇ O ₁₁ Na ² H ₂ O: C,
61.6%; H, 8.0%. Actual value: C, 61.3%; H,
7.8%. Mass spectrum Accurate mass measurement result of molecular ion; calculated value for C ₃₉ H ₅₇ O ₁₁ Na:
724.3799; Actual value: 724.3810. Example 4 To a stirred solution of the sodium salt of M.139603 (312 mg, 0.5 mmol) in toluene (2 ml) was added methyl isocyanate (0.18 ml, 3.0 mmol) and
After heating the solution at 100° C. for 2 hours, the solvent was evaporated under reduced pressure. This residue was purified by chromatography on silica gel (Merck 7734) using ethyl acetate as eluent. Appropriate fractions were combined and concentrated under reduced pressure to remove the N of M.139603.
-methyl carbamoyl ester (, R ¹ = CH ₃ ,
R ² =CH ₂ O.CONH.CH ₃ ) was formed as white bubbles. Analytical results: Calculated for _C37H56Na11 / _2H2O : C, 62.7%; _H , 8.3%; N, 2.0%. Actual values: C, 62.7%; H, 8.3%; N, 1.8%. Mass spectrum Accurate mass measurement results for molecular ions:
Calculated _{for C37H56NO9Na} : _681.3853 ; found: 681.3825. Similarly, the following urethane and thiourethane derivatives of M.139603 were obtained from the sodium salt of M.139603 and the appropriate isocyanate or isothiocyanate. The structure was confirmed by mass spectroscopy and precise mass measurements of the molecular ions.

[Table] Example 5 M.139603 (95mg) was dissolved in ethyl acetate (10ml), and phenyl isocyanate (30μ
) was added. The course of the reaction was followed by TLC and was shown to be essentially complete after standing overnight. Next, this solution was added to a preparative TLC plate (Merck
ART5717, 20 cm x 20 cm x 2 mm) and developed with chloroform/methanol/formic acid (90:5:5). Two bands R _F =0.48 and 0.58 were separated and eluted from the silica with ethyl acetate/methanol (95:5). band containing product
R _F =0.58 was evaporated to dryness to give a colorless gum having a weight of 87 mg, which was then crystallized from ether,
N-phenylcarbamoyl ester of M.139603 (, R ¹ = CH ₃ , R ² = CH ₂ O.CO.NHPh),
In this case, the ester first melted at 160-165°C, then solidified again and melted again at 203-205°C. Example 6 M.139603 (0.624 g, 1.0
mmol) of sodium salt was added. After stirring the solution at room temperature for 1 hour, methyl iodide (0.14 ml, 2.2 mmol) was added to it and stirring was continued for a further 2 hours. This reaction mixture was mixed with water (100 ml).
This aqueous solution was diluted with ether (2 x 50 ml).
Extracted with. The combined ether extract was diluted with water (2 x 50
ml), dried (anhydrous magnesium sulfate),
and concentrated under reduced pressure to yield an oil that solidified on standing. Furthermore, this oil is dried under reduced pressure,
M.139603 Methyl ether (, R ¹ = CH ₃ , R ² =
CH ₂ OCH ₃ ) was formed as white bubbles. Analysis result: Calculated value for C ₃₆ H ₅₅ O ₈ NalHO: C, 65.9
%; H, 8.7%. Actual value: C, 66.1%; H, 9.0%.
Mass spectrum accurate mass measurement of molecular ion: Calculated for C ₃₆ H ₅₅ O ₈ Na: 638.3795; Observed: 638.3795. Similarly, the following ether and carbonate derivatives of M.139603 were obtained from the sodium salt of M.139603 and the appropriate alkyl, alkynyl or aryl bromide. Extraction was carried out using ethyl acetate instead of ether and the product was further purified by chromatography on silica gel (Merck 7734) using ethyl acetate as eluent. The structure was confirmed by mass spectroscopy and precise mass measurements of the molecular ions.

[Table] Example 7 In petroleum ether (boiling point: 60-80℃) (40ml)
Activated manganese dioxide (3.2 g) was added to a stirred solution of the sodium salt of M.139603 (0.40 g, 0.64 mmol). After stirring this solution for 20 hours at room temperature,
The reaction mixture was filtered and the filtrate was concentrated under reduced pressure and dried. This residue was chromatographed on silica gel (Merck 7734) using ethyl acetate as eluent and the appropriate fractions were concentrated under reduced pressure to obtain the M.139603 aldehyde (, R ¹ =
CH ₃ , R ² =CHO) was produced as white bubbles.
Analysis result: Calculated value for C ₃₅ H ₅₁ O ₈ NaH ₂ O:
C, 65.6%; H, 8.3%. Actual value: C, 65.9%;
H, 8.5%. Mass spectrum Accurate mass measurement results for molecular ions: Calculated values for C ₃₅ H ₅₁ O ₈ Na:
622.3482; Actual value: 622.3431. Example 8 Sodium acetate (0.10 g, 1.22 mmol) is added to a stirred solution of the sodium salt of M.139603 aldehyde (0.10 g, 0.16 mmol) in ethanol (5 ml).
and hydroxylamine hydrochloride (0.10 g, 1.44 mmol) were added. 1/2 of this mixture under reflux
After heating for an hour, cooling and filtering, the filtrate was concentrated under reduced pressure and dried. This residue was chromatographed on silica gel (Merck 7734-trademark) using acetone/petroleum ether (1:1) at 60-80°C as eluent, the appropriate fractions were concentrated under reduced pressure, and M. 139603 Aldehyde oxime (,
R ¹ =CH ₃ , R ² =CH=NOH) were generated as bubbles. Analytical results: Calculated for _{C35H52O8NNa1 / 2H2O} : C, 65.0%; H, 8.2%; _N , 2.2%. Actual values: C, 65.1%; H, 8.6%; N, 2.3%. Mass spectrum Accurate mass measurement results for molecular ions:
Calculated _{for C35H52O8NNa} : _637.3561 ; Found: 637.3591. Example 9 Streptomyces longisporoflavus as described in GB 2027013A
The mother liquor from the crystals of M.139603 obtained by fermentation of NCIB11426 was collected on a preparative thin layer chromatography (PTLC) plate (Merck ART5717, 40 cm x 20 cm).
2 mm) using ether/glacial acetic acid (98:2) as eluent.
The band at R _F = 0.40, corresponding to M.139603, was discarded, but the second band at R _F = 0.23 was separated from the plate and eluted with ethyl acetate/methanol (95:5), resulting in a viscous A brown oil was produced. This substance was dissolved in a solvent system of chloroform/methanol/formic acid (90:5:5).
Further purification was performed by repeated PTLC using . The band, R _F =0.33, was separated from the plate and the product, dimethyl-M.139603 (, R ¹ =H,
^R2 = _CH2OH ) as petroleum ether (boiling point 60-80℃)
(melting point 156-158°C). Example 10 A premix suitable for dilution in ruminant feed is the ethoxalyl ester of M.139603 10.
It can be obtained by incorporating 25, 50, 100 or 250 mg into crushed limestone. The same premix can be obtained using equivalent amounts of any other compound according to the invention. Example 11 An animal feed suitable for direct feeding to ruminants is prepared by intimately mixing 500 g of the premix obtained as described in Example 10 with 999.5 mg of typical cattle feed. M.139603 per tonne, depending on the concentration of active ingredient used.
A ruminant feed containing 10, 25, 50, 100 or 250 g of the ethoxalyl ester of or any other compound according to the invention is obtained. Suitable cattle feeds are:

[Table]

【table】

[Table] Example 12 Preventing methane production in the rumen of ruminants and increasing the ratio of propionate to acetate and butyrate (P/A+B) in the volatile fatty acids (VFA) produced The ability of the compounds according to the present invention to inhibit the entire digestive process at the same time is demonstrated by: rumination from two meat steers fed the same hay and concentrate diet. The rumen fluid of the stomach is collected on a conventional substrate. The sample extraction time was standardized to be as long as possible, and the rumen fluid from two ruminants was
Store at base 50. The rumen fluid containing large particulate matter is removed by filtering through four layers of muslin cloth. Next, this filtrate was mixed with the rumen fluid of an artificial rumen (GLBales et al., “Journal of
Dairy Science”, 1976, Volume 59, Page 1850,
(produced in the same manner as described above (however, acetic acid was omitted)) in a volume ratio of 1:3, and the pH of this mixture was adjusted to 6.9 to 7.0 with a saturated aqueous sodium carbonate solution. Aliquots (50 ml) of this mixture are distributed into 100 ml round bottom flasks containing dry ground hay (0.5 g) and the entire flask is used to test the test compound at the detailed concentration. The test compound is added as a solution in ethanol to a round bottom flask, which is flushed with carbon dioxide gas, sealed with a suba-seal, and incubated at 39°C for 15-16 hours. After 1 hour, a fine bore needle is inserted through the suba-seal, the gas pressure is reduced and the needle is withdrawn 30 minutes before the end of the incubation. The fermentation is then stopped by placing ice in the flask and after cooling for 15 minutes the gas above the liquid is analyzed for methane by chromatography. The flask contents are then filtered through a pre-dried and weighed glass funnel, the glass funnel is oven dried and the difference in weight of digested hay is determined. (Empty flasks containing no hay are treated similarly and non-cellulose residue is measured). Measure the net VFA (acetate, propionate, and butyrate) generated during incubation by comparing three samples of the filtrate with the pre-incubated concentrations of VFA measured by gas chromatography. do. The following results were obtained (including a negative control without test compound):

【table】 [Brief explanation of drawings]

FIG. 1 is an NMR spectrum of an example of a derivative of M.139603 according to the invention in deuterochloroform.

Claims (1)

[Claims] 1 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is derivatives of M.139603 having 3 to 7 carbon atoms. 2 R ¹ , R ² , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ is each an alkyl group having 1 to 3 carbon atoms, or an alkyl moiety having 1 to 3 carbon atoms; or R ⁷ is an alkenyl or alkynyl group having 2 or 3 carbon atoms. 3 The substituent of R ¹ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ is
phenyl which each of these substituents may be substituted,
if it is a naphthyl or phenylalkyl group, it is a halogen atom, a nitro, cyano or hydroxy group or an alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, alkylamino, dialkylamino or alkanoylamino group having up to 8 carbon atoms; The derivative according to claim 1, which is 4 M is sodium, lithium, potassium, calcium, magnesium, zinc, ammonium,
mono-, di-, tri- or tetraalkylammonium ions (in which case each alkyl has 1 to 10 carbon atoms), or mono-,
2. A derivative according to claim 1, which is a di-, tri- or tri-(hydroxyalkyl)ammoniumoin, in which each hydroxyalkyl has from 1 to 10 carbon atoms. 5 R ¹ is a hydrogen atom and R ² is a hydroxymethyl group; R ¹ is a methyl group and R ² is a formyl group; R ¹ is a methyl group and R ² is a methoxymethyl group; R ¹ is a methyl group and R ² is a propargyloxymethyl group; R ¹ is a methyl group and R ² is a benzoyloxymethyl group; R ¹ is a methyl group and R ² is a 2- is a bromobenzoyloxymethyl group; R ¹ is a methyl group and R ² is a chloroacetoxymethyl group; R ¹ is a methyl group and R ² is an ethoxalyloxymethyl group; or R 1 is a methyl group and R ² is an ethoxalyloxymethyl group; The derivative according to claim 1, which is a methyl group and R ² is an N-methylthiocarbamoyloxymethyl group. 6 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], for the compound in which R ² is a group of the above formula: -CH ₂ OR ⁷ , the formula (with the proviso that R ¹ represents the above, R ² is a hydroxymethyl group)
is reacted with a compound of the formula: R ⁷ Z (wherein R ⁷ is as defined above and Z is a leaving group) in the presence of a strong base.
Method for producing derivatives of M.139603. 7 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], wherein R ¹ is other than a hydrogen atom and R ²
is the above formula: -CH ₂ O.COR ⁸ or -CH ₂ O.CO.
For compounds of the formula COR ⁹ , where R ¹ is an alkyl or optionally substituted phenylalkyl group and R ² is a hydroxymethyl group, a compound of the formula : ^R8.COOH
or an acylating agent, acid anhydride or mixed anhydride derived from a carboxylic acid of R ⁹ CO.COOH (wherein R ⁸ and R ⁹ represent the above); Method for producing derivatives of M.139603. 8 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], wherein R ¹ is other than a hydrogen atom and R ²
is the above formula: -CH ₂ O.COR ⁸ or -CH ₂ O.CO.
For compounds of the formula COR ⁹ , where R ¹ is an alkyl or optionally substituted phenyl or phenylalkyl group,
R ² is a hydroxymethyl group),
Formula: R ⁸ .COOH or R ⁹ CO.COOH (however, R ⁸ and
A process for producing a derivative of the formula M.139603, characterized in that it is reacted with a carboxylic acid (R ⁹ represents one of the above) in the presence of a carbodiimide. 9 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], in which R ² is a group of the formula: -CH ₂ O.COR ⁸ (wherein R ⁸ is a hydroxyalkyl group); For certain compounds, the formula (where R ² is the formula: −
CH ₂ O・COR ⁸ (in which case R ⁸ is a (t-alkoxy)-alkyl group) is reacted with an acid,
Method for producing derivatives of M.139603. 10 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], wherein R ² is of the formula: -CH ₂ O・COR ⁸ (wherein R ⁸ is an alkylaminoalkyl or dialkylaminoalkyl group). A process for producing derivatives of the formula M.139603, which comprises reacting a corresponding aminoalkyl compound with an alkyl halide for a compound such as a group of 11 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], in which R ² is a group of the formula: -CH ₂ O・COR ⁸ (wherein R ⁸ is an alkoxycarbonyl alkyl group) of the formula M.139603, characterized in that the corresponding carboxyalkyl compound is reacted with a diazoalkane or the corresponding salt of the carboxyalkyl compound is reacted with an alkyl halide. Method for producing derivatives. 12 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], wherein R ² is of the formula: -CH ₂ O.COR ⁸ (wherein R ⁸ is carbamoylalkyl, N-alkylcarbamoylalkyl, or N,N-dialkylcarbamoylalkyl group), the corresponding carboxyalkyl or alkoxycarbonylalkyl compound is reacted with ammonia or a mono- or di-alkylamine, respectively. A method for producing a derivative of formula M.139603. 13 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], in which R ² is of the formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹
is an amino, monoalkylamino or dialkylamino group, the corresponding compound (wherein R ⁹ is a hydroxy or alkoxy group) is treated with ammonia or mono-
or a dialkylamine, respectively. 14 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], in which R ² is of the formula: -CH ₂ O.CX.NR ¹⁰ R ¹¹ (provided that
R ¹⁰ is a hydrogen atom, and X and R ¹¹ represent the above ^- mentioned groups. : A process for producing a derivative of the formula M.139603, characterized in that it is reacted with an isocyanate or isothiocyanate of R ¹¹ .NCX (wherein R ¹¹ and X represent the above). 15 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is 3 to 7 carbon atoms], in which R ² is of the formula: -CH ₂ O.CX.NR ¹⁰ R ¹¹ (provided that
X represents the above-mentioned group, and one or both of R ¹⁰ and R ¹¹ is other than a hydrogen atom), and the corresponding compound (however,
One or both of R ¹⁰ and R ¹¹ is a hydrogen atom)
is reacted with a halogen compound R ¹⁰ .halide or R ¹¹ .halide (provided that one or both of R ¹⁰ and R ¹¹ is other than a hydrogen atom), M.139603 of the formula Method for producing derivatives of. 16 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is In the process for producing a derivative of M.139603 having 3 to 7 carbon atoms], for a compound in which R ² is a formyl group, the corresponding compound (provided that R ² is a hydroxymethyl group) A process for producing a derivative of formula M.139603, characterized in that the oxidation of 17 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is In the method for producing a derivative of M.139603 having 3 to 7 carbon atoms, for a compound in which R ² is a hydroxyiminomethyl group, the corresponding compound (with the proviso that
M.139603 of the formula, characterized in that R ² is a formyl group) is reacted with hydroxyamine.
Method for producing derivatives of. 18 Formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is In the process for producing ^a derivative ^of M.139603 having 3 to 7 carbon atoms, Streptomyces spp. Streptromyces Longisporoflavus
NCIB11426 or its variants or mutants are cultivated in an aqueous nutrient medium with an assimilable carbon source under shaking aerobic conditions at a temperature of 22-32°C, and the fermentation mixture is mixed with a water-immiscible organic solvent. The product with R _f =0.43 was extracted from the organic extract by thin layer chromatography on a 0.25 mm thick silica plate (“Kieselgel 60F-254”-trademark from Merck) in a volume ratio of 95:4:1. A process for the preparation of derivatives of the formula M.139603, characterized in that they are isolated by elution with a mixture of diethyl ether, methanol and formic acid. 19. In a composition for use in ruminant livestock farming to increase the efficiency of food conversion in farmed ruminants, the formula: [wherein M is an alkali metal, alkaline earth metal, ammonium, alkylammonium or hydroxyalkylammonium cation; R ¹ is a hydrogen atom or a methyl group; R ² is formyl or a hydroxyiminomethyl group; or is a group of the formula: -CH ₂ OR ⁷ (wherein R ⁷ is an alkyl, alkenyl, alkynyl, alkoxycarbonyl or alkylaminoalkyl group, or an optionally substituted phenylalkyl group); or : _-CH2O・^COR8 (However, ^R8 is alkyl, cycloalkyl, (cycloalkyl)alkyl, halogenoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, N-alkylcarbamoylalkyl,
N,N-dialkylcarbamoylalkyl or an optionally substituted phenyl, naphthyl or phenylalkyl group; or Formula: -CH ₂ O.CO.COR ⁹ (wherein R ⁹ is amino , mono- or di-alkylamino, alkoxy or optionally substituted phenyl, naphthyl or phenylalkyl group);
or Formula: -CH ₂ O・CX.NR ¹⁰ R ¹¹ (However, X is an oxygen or sulfur atom, R ¹⁰ and R ¹¹ may be the same or different, and each represents a hydrogen atom, an alkyl group, or an optionally substituted phenyl, naphthyl or phenylalkyl group; or R ¹ is a hydrogen atom, R ² is a hydroxymethyl group, and each alkyl, alkenyl or alkynyl group is 6 in each radical having up to 6 carbon atoms and having an alkyl moiety, the alkyl moiety has 1 to 6 carbon atoms, and the cycloalkyl group or the cycloalkyl moiety of the (cycloalkyl)alkyl group is for use in ruminant livestock farming, characterized in that it consists of a derivative of M.139603 having 3 to 7 carbon atoms] and an edible non-toxic diluent or carrier in solid or liquid form Composition of.