WO2011070133A1 - Nitrooxy alkanoic acids and derivatives thereof in feed for reducing methane emission in ruminants, and/or to improve ruminant performance - Google Patents

Nitrooxy alkanoic acids and derivatives thereof in feed for reducing methane emission in ruminants, and/or to improve ruminant performance Download PDF

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Publication number
WO2011070133A1
WO2011070133A1 PCT/EP2010/069338 EP2010069338W WO2011070133A1 WO 2011070133 A1 WO2011070133 A1 WO 2011070133A1 EP 2010069338 W EP2010069338 W EP 2010069338W WO 2011070133 A1 WO2011070133 A1 WO 2011070133A1
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Prior art keywords
nitrooxy
ethyl
hydrogen
acid
independently
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PCT/EP2010/069338
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English (en)
French (fr)
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Stephane Duval
Maik Kindermann
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Dsm Ip Assets B.V.
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Priority to US13/514,165 priority Critical patent/US8784871B2/en
Priority to CN201080056411.2A priority patent/CN102781252B/zh
Priority to EP10790939.2A priority patent/EP2509435B1/en
Priority to AU2010329869A priority patent/AU2010329869B2/en
Priority to JP2012542556A priority patent/JP5786221B2/ja
Priority to BR112012014004-3A priority patent/BR112012014004B1/pt
Priority to KR1020127017869A priority patent/KR101794363B1/ko
Priority to NZ600516A priority patent/NZ600516A/en
Publication of WO2011070133A1 publication Critical patent/WO2011070133A1/en
Priority to US14/159,576 priority patent/US9365489B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • 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
    • A23K20/105—Aliphatic or alicyclic compounds
    • 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
    • A23K20/174—Vitamins
    • 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
    • A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P60/00—Technologies relating to agriculture, livestock or agroalimentary industries
    • Y02P60/20—Reduction of greenhouse gas [GHG] emissions in agriculture, e.g. CO2
    • Y02P60/22—Methane [CH4], e.g. from rice paddies

Definitions

  • the present invention relates to the use of at least one nitrooxy alkanoic acid and/or derivative thereof for reducing the production of methane emanating from the digestive activities of ruminants, and/or to improve the ruminant performance.
  • the present invention also relates to animal feed or animal feed composition and feed additives comprising these above mentioned compounds.
  • feed or feed composition means any compound, preparation, mixture, or composition suitable for, or intended for intake by an animal.
  • a ruminant is a mammal of the order Artiodactyla that digests plant-based food by initially softening it within the animal's first stomach, known as the rumen, then regurgitating the semi-digested mass, now known as cud, and chewing it again.
  • the process of again chewing the cud to further break down plant matter and stimulate digestion is called "ruminating". Ruminating mammals include cattle, goats, sheep, giraffes, American Bison, European bison, yaks, water buffalo, deer, camels, alpacas, llamas, wildebeest, antelope, pronghorn, and nilgai.
  • domestic cattle, sheep and goat are the more preferred species.
  • most preferred species are domestic cattle.
  • the term includes all races of domestic cattle, and all production kinds of cattle, in particular dairy cows and beef cattle.
  • methane is also a greenhouse gas, which is many times more potent than CO2. Its concentration in the atmosphere has doubled over the last century and continues to increase alarmingly. Ruminants are the major contributors to the biogenic methane formation, and it has been estimated that the preven- tion of methane formation from ruminants would almost stabilize atmospheric methane concentrations.
  • the assessment of the Kyoto protocol places increased priority in decreasing methane emissions as part of a multi-gas strategy.
  • the most effective ad- ditives currently used for reducing the formation of methane contain antibiotics which diminish the proliferation of microorganisms providing hydrogen (H 2 ) to the methanogenes.
  • H 2 hydrogen
  • the effect of antibiotics on the formation of methane has some disadvantages because of rapid adaptation of the microflora and/or resistance development leading to a complete loss of the intended effect within a short period of time (2 to 3 weeks).
  • Non antibiotic products leading to reduction of methane emission when tested using an in vitro rumen simulation model have recently been published (WO2010072584).
  • the amount required to produce a moderate reduction of methane emission are not compatible with the ruminant feed industry cost constraints.
  • a number of natural plant extracts Garlic WO2009150264, yucca, cinnamon, rhubarb(7) have been described in the scientific literature as potent solutions to reduce methane emission in ruminants based on in vitro experiments.
  • none of these made it to a commercial product because of side effects (residues in milk), or lack efficacy, when tested in vivo.
  • such substances may also contribute to improve ruminant performance by improving the feed conversion ratio, reducing feed intake, improving weight gain, and/or improving carcass, or milk yield.
  • the present inventors surprisingly found that the compounds specified herein after have a great potential for use in animal feed in order to essentially reduce the for- mation of methane without affecting microbial fermentation in a way that would be detrimental to the host animal.
  • the compounds of the present invention have also a great benefit regarding overall animal performance as measured by feed conversion ratio, feed intake, weight gain, carcass yield, or milk yield. Said compounds are also more stable than those described in the prior art, safer for the animal and human, lead to persistent methane reduction effect, they do not affect palatability, they can be produced at industrial scale at a cost compatible with the animal nutrition industry, and above all, they do not provoke accumulation of any metabolite in the milk or meat of the treated animal.
  • the addition of at least one nitrooxy alkanoic acid and/or derivative thereof according to the invention is highly effective in decreasing methane formation in in vitro experiments without affecting total VFA production, and in decreasing overall methane production in vivo. Therefore, the present invention provides the use of at least one nitrooxy alkanoic acid and/or derivative thereof as defined by formula (I) as an active compound in animal feeding for reducing the formation of methane emanating from the digestive activities of ruminants and/or for improving ruminant performance.
  • the invention further provides a method for reducing the production of methane emanating from the digestive activities of ruminants and/or improving ruminant animal performance, comprising orally administering a sufficient amount of at least one nitrooxy alkanoic acid and/or derivative thereof as defined by formula (I) to the animal.
  • nitrooxy alkanoic acids and/or derivatives thereof are defined by the following formula (I)
  • n is comprised between 0 and 23, preferably between 0 and 9, and wherein, if n ⁇ 0, the carbon chain is a linear, a cyclic, or a branched linear or cyclic aliphatic carbon chain which may be mono- or polyunsaturated and in any isomeric form,
  • X is independently O, NH, or N-R3, wherein if R1 ⁇ H, X-R1 - represents an ester or a secondary amide derivative,
  • R1 is independently, hydrogen or a saturated straight, cyclic or branched chain of an alkyl or alkenyl group containing 1 to 10, preferably 1 to 5 carbon atoms,
  • R2 is independently, hydrogen or a saturated straight or branched chain of an alkyl or alkenyl group containing 1 to 23, preferably 1 to 9 carbon atoms, and
  • R3 is independently, hydrogen or a saturated straight, cyclic or branched chain of an alkyl or alkenyl group containing 1 to 10, preferably 1 to 5 carbon atoms. It is to be understood in the above definition of compounds of formula (I) that when n > 2, the carbon chain can be linear or branched at any position along the carbon chain. In addition, the carbon chain can be branched by multiple branches at different positions along the carbon chain. Moreover, when n > 4, the aliphatic carbon chain may form a cyclic moiety. This cycloalkyl-carboxylate moiety can carry the nitrooxy moiety at position 2, 3, 4, and it can also be branched at multiple positions by any aliphatic groups. The branched aliphatic groups are preferably, methyl, ethyl or propyl .
  • a preferred alkyl group is methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, pentyl, neopentyl, hexyl, cyclohexyl, and 2-ethyl-hexyl and octyl .
  • any alkyl or alkenyl group con- taining three or more carbon atoms can be straight chain, branched, or cyclic.
  • preferred esters according to the present invention are methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, pentyl, neopentyl, hexyl, 2- ethyl-hexyl and octyl.
  • preferred amide derivatives are methyl-amide, ethyl-amide, propyl-amide, butyl-amide, pentyl-amide, dimethyl-amide, diethylamide, and methyl-ethyl-amide.
  • more preferred derivatives of formula (I) are derivatives, wherein
  • n is comprised between 0 and 23, preferably between 0 and 9, and wherein, if n ⁇ 0, the carbon chain is a linear, a cyclic, or branched linear or cyclic aliphatic carbon chain which may be mono- or polyunsaturated and in any isomeric form,
  • X is independently O, NH, or N-R3, wherein if R1 ⁇ H, X-R1 - represents an ester or a secondary amide derivative, and
  • R1 , R2, and R3 are all three independently a hydrogen, a methyl, or an ethyl group.
  • n is comprised between 0 and 23, preferably between 0 and 9, and wherein, if n ⁇ 0, the carbon chain is a linear, a cyclic, or branched linear or cyclic aliphatic carbon chain which may be mono- or polyunsaturated and in any isomeric form,
  • X is independently O, NH, or N-R3, wherein if R1 ⁇ H, X-R1 - represents an ester or a secondary amide derivative, and
  • R2 is a hydrogen
  • n is comprised between 0 and 23, preferably between 0 and 9, and wherein, if n ⁇ 0, the carbon chain is a linear, a cyclic, or branched linear or cyclic aliphatic carbon chain which may be mono- or polyunsaturated and in any isomeric form,
  • X is oxygen (O), wherein if R1 ⁇ H, X-R1 - represents an ester, and
  • R2 is a hydrogen
  • more preferred derivatives of formula (I) are selected from the group consisting of: nitrooxy ethanoic acid, 3-nitrooxy propionic acid, 4- nitrooxy butanoic acid, 5-nitrooxy pentanoic acid, 6-nitrooxy hexanoic acid, 7- nitrooxy heptanoic acid, 2-nitrooxy-cyclohexylcarboxylic acid, 3-nitrooxy- cyclohexylcarboxylic acid, 4-nitrooxy-cyclohexylcarboxylic acid, 8-nitrooxy octanoic acid, 9-nitrooxy nonanoic acid, 10-nitrooxy decanoic acid, 1 1 -nitrooxy undecanoic acid, methyl -nitrooxy ethanoate, methyl-3-nitrooxy propionate, methyl-4-nitrooxy butanoate, methyl -5-nitrooxy pentanoate, methyl-6-nitrooxy hexanoate, methyl-7- nitrooxy heptanoate, methyl-2-
  • most preferred derivatives or of formula (I) for all the embodiments of the present invention are selected from the group consisting of: ethyl-nitrooxy-ethanoate, 3-nitrooxy propionic acid, methyl-3- nitrooxy propionate, ethyl-3-nitrooxy propionate, ethyl-2-nitrooxy propanoate, 4- nitrooxy butanoic acid, ethyl-4-nitrooxy-butanoate, ethyl-3-nitrooxy-butanoate, 5- nitrooxy pentanoic acid, ethyl-5-nitrooxy pentanoate, 2,2-dimethyl-3-nitrooxy propi- onic acid, 6-nitrooxy hexanoic acid, ethyl-6-nitrooxy hexanoate, 8-nitrooxy octanoic acid, ethyl-8-nitrooxy octan
  • Even more preferred derivatives or of the formula (I) are selected from the group consisting of: 3-nitrooxy propionic acid, methyl-3-nitrooxy propionate, ethyl-3- nitrooxy propionate, ethyl-4-nitrooxy-butanoate, ethyl-3-nitrooxy-butanoate, 5- nitrooxy pentanoic acid, ethyl-5-nitrooxy pentanoate, 6-nitrooxy hexanoic acid, ethyl- 6-nitrooxy hexanoate, ethyl-4-nitrooxy-cyclohexylcarboxylate, 8-nitrooxy octanoic acid, ethyl-8-nitrooxy octanoate, 1 1 -nitrooxy undecanoic acid, ethyl-1 1 -nitrooxy un- decanoate, 5-nitrooxy-pentanoic amide, and 5-nitrooxy-N-methyl-pentanoic amide.
  • salts of the nitrooxy alkanoic acids also comprises salts of the nitrooxy alkanoic acids.
  • Preferred cations for salt preparation may be selected from the group consisting of sodium (Na+), potassium (K+), lithium (Li+), magnesium (Mg2+), calcium (Ca2+), barium (Ba2+), strontium (Sr2+), and ammonium (NH4+). Salts may also be prepared from an alkali metal or an alkaline earth metal.
  • the compounds of the present invention can be manufactured in principle according to synthetic methods known per se for nitrooxy alkanoic acids, esterifications or amidations. In all these cases appropriate methods to purify the product (compounds of formula (I)) can be chosen by those skilled in the art, i.e. by column chromatography, or the compound of formula (I), can be isolated and purified by methods known per se, e.g. by adding a solvent such as diethyl-ether or ethyl acetate to induce the separation of the crude product from the mixture after reaction, and drying over Na2SO 4 of the collected crude product.
  • a solvent such as diethyl-ether or ethyl acetate
  • Methane emission by ruminants can easily be measured in individual animals in metabolic chambers by methods known in the art (Grainger et al., 2007 J. Dairy Science; 90: 2755-2766). Moreover, it can also be assessed at barn level by an emerging technology using laser beam (McGinn et al., 2009, Journal of Environmental Quality; 38: 1796-1802). Alternatively, methane produced by a dairy rumi- nant can also be assessed by measurement of VFA profiles in milk according to WO 2009/156453.
  • Ruminant performance can be assessed by methods well known in the art, and is usually characterized by feed conversion ratio, feed intake, weight gain, carcass yield, or milk yield .
  • the present invention also relates to the use of at least one nitrooxy alkanoic acid and/or derivative thereof in combination with at least one additional active substance which shows similar effects with regard to methane formation in the rumen and which is selected from the group consisting of diallyl disulfide, garlic oil, allyl isothio- cyanate, deoxycholic acid, chenodeoxycholic acid and derivatives thereof.
  • yeasts for example yeasts, essential oils, and ionophores like Monensin, Rumensin.
  • diallyl disulfide, garlic oil, allyl isothiocyanate deoxycholic acid, chenodeoxycholic acid and derivatives thereof are independently administered in dosage ranges of for example 0.01 to 500 mg active substance per kg feed (ppm).
  • ppm active substance per kg feed
  • the present invention also relates to the use of at least one nitrooxy alkanoic acid and/or derivative thereof, wherein the methane production in ruminants calculated in liters per kilogram of dry matter intake is reduced by at least 10 % when measured in metabolic chambers.
  • methane reduction is at least 15 %, more preferably, at least 20 %, even more preferably, at least 25 %, most preferably, at least 30 %.
  • Alternative methane emission measurements may also be used like using a laser beam or for dairy ruminants, correlating methane production to the VFA profile in milk.
  • the present invention also relates to the use of at least one nitrooxy alkanoic acid and/or derivative thereof, wherein the ruminant feed conversion ratio is reduced by least 1 % when measured in conventional performance trial .
  • the feed conversion ratio is reduced by at least 2 %, more preferably, by at least 2.5 %, even more preferably, by at least 3 %, most preferably, by at least 3.5 %.
  • the present invention also relates to the use of at least one nitrooxy alkanoic acid and/or derivative thereof, wherein the amount of the at least one active compound as defined in formula (I) administered to the ruminant animal is from 1 mg to 10 g per kg of feed, preferably from 10 mg to 1 g per Kg of feed, more preferably, from 50 mg to 500 mg per kg of feed.
  • nitrooxy alkanoic acids and derivatives thereof need not be that pure; it may e.g. include other compounds and derivatives.
  • the compounds of the present invention are useful as compounds for feed additives and animal feed compositions for ruminants, and accordingly are useful as the active ingredients in such feed to reduce methane formation in the digestive tract of the animal, and or to improve ruminant performance.
  • the compounds may be incorporated in the feed by methods known per se in the art of feed formulation and processing.
  • compositions i.e. feed addi- tives and animal feed compositions containing compounds as herein above defined.
  • the normal daily dosage of a compound according to the invention provided to an animal by feed intake depends upon the kind of animal and its condition. Normally this dosage should be in the range of from about 1 mg to about 10 g, preferably from about 10 mg to about 1 g, more preferably, 50 mg to 500 mg compound per kg of feed.
  • the at least one nitrooxy alkanoic acid and/or derivative thereof may be used in combination with conventional ingredients present in an animal feed composition (diet) such as calcium carbonates, electrolytes such as ammonium chloride, pro- teins such as soya bean meal, wheat, starch, sunflower meal, corn, meat and bone meal, amino acids, animal fat, vitamins and trace minerals.
  • Diet animal feed composition
  • electrolytes such as ammonium chloride
  • pro- teins such as soya bean meal, wheat, starch, sunflower meal, corn, meat and bone meal
  • amino acids animal fat, vitamins and trace minerals.
  • compositions of the invention are the following:
  • An animal feed additive comprising (a) at least one compound selected from table 1 and (b) at least one fat-soluble vitamin, (c) at least one water-soluble vitamin, (d) at least one trace mineral, and/or (e) at least one macro mineral;
  • An animal feed composition comprising at least one compound selected from table 1 and a crude protein content of 50 to 800 g/kg feed.
  • premixes are examples of animal feed additives of the invention.
  • a premix designates a preferably uniform mixture of one or more micro-ingredients with diluents and/or carrier. Premixes are used to facilitate uniform dispersion of micro-ingredients in a larger mix.
  • the premix of the invention contains at least one fat-soluble vitamin, and/or at least one water soluble vitamin, and/or at least one trace mineral, and/or at least one macro mineral.
  • the premix of the invention comprises the at least one compound according to the invention together with at least one additional component selected from the group consisting of fat-soluble vitamins, water-soluble vitamins, trace minerals, and macro minerals.
  • the premix comprises the active ingredients of the invention together with at least one additional component selected from the group consisting of fat- soluble vitamins, water-soluble vitamins, and trace-minerals.
  • fat-soluble vitamins are vitamin A, vitamin D3, vitamin E, and vitamin K, e.g. vitamin K3.
  • water-soluble vitamins are vitamin B12, biotin and choline, vitamin B1 , vitamin B2, vitamin B6, niacin, folic acid and panthothenate, e.g. Ca-D- panthothenate.
  • trace minerals are manganese, zinc, iron, copper, selenium, and cobalt.
  • Examples of macro minerals are calcium, phosphorus and sodium.
  • the ruminant diet is usually composed of an easily degradable fraction (named concentrate) and a fiber-rich less readily degradable fraction (named hay, forage, or roughage).
  • Hay is made of dried grass, legume or whole cereals.
  • Grasses include among others timothy, ryegrasses, fescues.
  • Legumes include among others clover, lucerne or alfalfa, peas, beans and vetches.
  • Whole cereals include among others barley, maize (corn), oat, sorghum.
  • Other forage crops include sugarcane, kales, rapes, and cabbages.
  • root crops such as turnips, swedes, mangles, fodder beet, and sugar beet (including sugar beet pulp and beet molasses) are used to feed ruminants.
  • tubers such as potatoes, cassava and sweet potato.
  • Silage is an ensiled version of the fiber-rich fraction (e.g. from grasses, legumes or whole cereals) whereby material with a high water content is treated with a controlled anaerobic fermentation process (naturally-fermented or additive treated).
  • Concentrate is largely made up of cereals (such as barley including brewers grain and distillers grain, maize, wheat, sorghum), but also often contain protein-rich feed ingredients such as soybean, rapeseed, palm kernel, cotton seed and sunflower.
  • Cows may also be fed total mixed rations (TMR), where all the dietary components, e.g. forage, silage and concentrate, are mixed before serving.
  • TMR total mixed rations
  • a premix is an example of a feed additive which may comprise the active compounds according to the invention.
  • the compounds may be administered to the animal in different other forms.
  • the compounds can also be included in a bolus that would be placed in the rumen and that would release a defined amount of the active compounds continuously in well defined dosages over a specific period of time.
  • the present invention further relates to a method for reducing the production of methane emanating from the digestive activities of a ruminant animal and/or for improving ruminant animal performance comprising orally administering a sufficient amount of at least one active compound as defined in formula (I) with preferred embodiments described for the derivatives.
  • the invention further relates to a method as described above, wherein the active compound is administered to the animal in combination with at least one addi- tional active substance selected from the group consisting of diallyl disulfide, garlic oil, allyl isothiocyanate, deoxycholic acid, chenodeoxycholic acid and derivatives thereof.
  • at least one addi- tional active substance selected from the group consisting of diallyl disulfide, garlic oil, allyl isothiocyanate, deoxycholic acid, chenodeoxycholic acid and derivatives thereof.
  • the invention also relates to a method as described above, wherein the ruminant animal is selected from the group consisting of: cattle, goats, sheep, giraffes, American Bison, European bison, yaks, water buffalo, deer, camels, alpacas, llamas, wildebeest, antelope, pronghorn, and nilgai, and more preferably from the group consisting of: cattle, goat and sheep.
  • the invention also relates to a method as described above, wherein the amount of the at least one active compound as defined in formula (I) administered to the ruminant animal is from about 1 mg to about 10 g per kg feed, preferably from about 10 mg to about 1 g, more preferably from 50 mg to 500 mg compound per kg of feed.
  • the invention also relates to a method as described above, wherein the methane production in ruminants calculated in liters per kilogram of dry matter intake is reduced by at least 10 % when measured in metabolic chambers.
  • methane reduction is at least 15 %, more preferably, at least 20 %, even more preferably, at least 25 %, most preferably, at least 30 %.
  • Alternative methane emission meas- urements may also be used like using a laser beam or for dairy ruminants, correlating methane production to the VFA profile in milk.
  • the invention also relates to a method as described above, wherein the ruminant feed conversion ratio is reduced by least 1 % when measured in conventional per- formance trial.
  • the feed conversion ratio is reduced by at least 2 %, more preferably, by at least 2.5 %, even more preferably, by at least 3 %, most preferably, by at least 3.5 %.
  • the present invention is further described by the following examples which should not be construed as limiting the scope of the invention.
  • HFT Hohenheim Forage value Test
  • Feed is given into a syringe with a composition of rumen liquor and an appropriate mixture of buffers.
  • the solution is incubated at 39°C. After 8 hours the quantity (and composition) of methane produced is measured and put into a formula for conversion.
  • the feed stuff is sieved to 1 mm - usually TMR (44 % concentrate, 6 % hay, 37 % maize silage and 13 % grass silage) - and weighed exactly into 64 syringes. 4 of these syringes are the substrate controls, which display the gas production without the effect of the tested compounds. 4 other syringes are positive control, in which bromoethane sulfonate has been added to 0.1 mM.
  • the components are mixed in a Woulff bottle in following order:
  • the completed solution is warmed up to 39°C followed by the addition of 1 .83 ml sodium salt solution and the addition of reduction solution at 36 °C.
  • the rumen liquor is added, when the indicator turns colourless.
  • the diluted rumen fluid (24 ml) is added to the glass syringe.
  • the syringes are then incubated for 8 hours at 39 °C under gentle agitation. After 8 hours, the volume of gas produced is measured, and the percentage of methane in the gas phase is determined by gas chromatography.
  • the food fermented was artificial TMR (44 % concentrate, 6 % hay, 37 % maize silage and 13 % grass silage).
  • the compounds produced as described in examples 3 to 20 were added to the fermentation syringes to a concentration of 2 to 0.01 % of dry matter (DM). The results are presented in the following table.
  • Methane reduction effect resulting from the average of two experiments with some compounds according to the present invention (a minus sing followed by an integer in the column effect on methanogenesis (%) means a reduction in methane produced when compared to control; no value means that the concentration was not tested)
  • Example 2 In vivo test for methane inhibition 1. Material and methods
  • the experimental design consisted of a cross-over design with 2 sheep per treatment in each period.
  • the trial consisted in 3 consecutive periods of: 14 days of adaptation to the dose plus three consecutive days of methane measurements in chambers. This 14 days adaptation phase was established as the period necessary for wash out between different doses assayed in consecutive periods.
  • rumen contents samples were collected two hours after the morning feeding, sub sampled and immediately frozen prior DNA extraction and determination of volatile fatty acids and ammonia nitrogen concentration.
  • Experimental animals were randomly allocated in three sub-groups of 2 animals and were assigned one of the three treatments (control, dose 1 and dose 2).
  • the 3 sub-groups started the adaptation period with a gap of three days so they had the same number of adaptation days prior to methane measurement in the chambers.
  • Each animal was held in cages with constant access to fresh water.
  • the diet provided to the animals consisted of alfalfa hay chopped at 15 to 20 cm and concentrate in a proportion 1 :1 at approximately 1 .1 times the energy requirements maintenance level (Prieto et al, 1990) plus mineral-vitamin supplement. Fresh matter intake was monitored daily for each animal throughout the trial.
  • the diet was provided to animals in two equal meals at 9.00 h and 14.00 h.
  • the additive was provided twice a day through the ruminal cannula at the same time as the diet.
  • the doses were 50 (dose 1 ) and 500 (dose 2) mg/animal per day.
  • dose 1 dose 1
  • dose 2 dose 2 mg/animal per day.
  • the higher dose was reached after 3 days of gradual increases (50, 200 and 500 mg), so the whole adaptation period was consequently extended for 3 more days.
  • rumen samples analysis Samples of rumen contents were freeze-dried and thoroughly mixed by physical disruption using a bead beater (Mini-bead Beater; BioSpec Products, Bartlesville, OK, USA) before DNA extraction, which was performed from approximately 50 mg sample using the QIAamp® DNA Stool Mini Kit (Qiagen Ltd, West Wales, UK) following the manufacturer's instructions with the modification that a higher tempera- ture (95 °C) was used for lysis incubation. DNA samples were used as templates for quantitative real-time PCR (qPCR) amplification. The numbers of total bacteria, total protozoa and total methanogenic archaea were quantified by Real Time - PCR (qPCR).
  • qPCR quantitative real-time PCR
  • the amplifications mixture contained 1 1 .5 ⁇ 2X RT-PCR su- permix BioRad (Bio-Rad Laboratories Inc., Hercules, CA, USA), 0.4 ⁇ of each primer (50 pmol) and 0.5 ⁇ of sample in a final volume of 23 ⁇ .
  • the amplification efficiency was evaluated for each pair of primers with the following program: 5 min cycle at 95 °C, 40 cycles at 95 °C for 15 s, 60 °C for 30 s, 72 °C for 55 s and, 75 °C during 6 s for fluorescent emission measures.
  • the melting curve was built by increasing temperature from 55 °C to 95 °C and reading were taken every 5 °C.
  • Amplification of each target group was carried out with the following program: 5 min cycle at 95 °C, 40 cycles at 95 °C for 15 s, 15 s at 60 °C and 72 °C for 45 s (includ- ing the fluorescence emission measuring) and a melting curve with a set point temperature of 45 °C and end temperature of 95 °C.
  • the qPCR standards consisted of the plasmid pCR®4-TOPO (InvitrogenTM, Carlsbad, CA, USA).
  • PCR product obtained using the respective set of primers was purified and then cloned into PCR® 4-TOPO® plasmid (InvitrogenTM, Carlsbad, CA, USA) to produce recombinant plasmids.
  • a single colony, verified for the expected insert using PCR, was grown in solid media with antibiotics and X-gal overnight. Afterwards, a screening of transformed E. coli colonies was done and some of the positive ones were randomly selected. After check- ing the presence of the inserted fragment in the colonies by PCR, massive culture of positive colonies was done in liquid media overnight.
  • Plasmids belonging to these cultures were extracted using the Pure LinkTM Miniprep kit (InvitrogenTM, Carlsbad, CA, USA) and then sequenced to verify the presence of the fragment inserted.
  • the number of 16S rRNA gene copies present in the plasmid extracts was calculated using the plasmid DNA concentration and the molecular mass of the vector with the insert.
  • the concentrated plasmid was serially diluted (10-fold) to provide a range of 10 8 to 10 2 copies. Serially diluted samples were used to generate a standard curve.
  • Volatile fatty acids were analysed by gas chromatography and ammonia N concentration by colorimetry according to (Cantalapiedra-Hijar et al. Journal of Animal Science. 87, 622-631 , 2009). Statistical analysis
  • Ethyl-3-nitrooxy propionate appears as a strong inhibitor of methanogenesis, voking a shift in the metabolic pathways involved in H 2 transferring.

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US13/514,165 US8784871B2 (en) 2009-12-11 2010-12-10 Nitrooxy alkanoic acids and derivatives thereof in feed for reducing methane emission in ruminants, and/or to improve ruminant performance
CN201080056411.2A CN102781252B (zh) 2009-12-11 2010-12-10 饲料中用于减少反刍动物甲烷散发和/或改善反刍动物性能的硝基氧烷酸及其衍生物
EP10790939.2A EP2509435B1 (en) 2009-12-11 2010-12-10 Nitrooxy alkanoic acids and derivatives thereof in feed for reducing methane emission in ruminants, and/or to improve ruminant performance
AU2010329869A AU2010329869B2 (en) 2009-12-11 2010-12-10 Nitrooxy alkanoic acids and derivatives thereof in feed for reducing methane emission in ruminants, and/or to improve ruminant performance
JP2012542556A JP5786221B2 (ja) 2009-12-11 2010-12-10 反芻動物のメタン排出を減少させ、および／または反芻動物の能力を改善するための、飼料中のニトロオキシアルカン酸およびその誘導体
BR112012014004-3A BR112012014004B1 (pt) 2009-12-11 2010-12-10 uso de pelo menos um ácido nitróxi alcanóico, e/ou seu derivado e composição de ração ou aditivo de ração os compreendendo, bem como método para reduzir a produção de metano que emana das atividades digestivas de um animal ruminante e/ou para melhorar o desempenho de animais ruminantes
KR1020127017869A KR101794363B1 (ko) 2009-12-11 2010-12-10 반추동물에서의 메탄 방출을 감소시키고/감소시키거나 반추동물 수익성을 개선시키기 위한 사료중의 니트로옥시 알칸산 및 이의 유도체
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WO2014013068A1 (de) 2012-07-20 2014-01-23 Dr. Eckel Gmbh Kombination zur reduzierung der methanemissionen in der wiederkäuerfütterung
US20140088161A1 (en) * 2011-05-26 2014-03-27 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ruminants, and/or to improve ruminant performance
WO2015018726A1 (en) * 2013-08-07 2015-02-12 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ru-minants, and/or to improve ruminant performance
WO2017137489A1 (en) * 2016-02-12 2017-08-17 Dsm Ip Assets B.V. Anti-methanogenic compositions and uses thereof
EP3238720A1 (en) * 2016-04-29 2017-11-01 DSM IP Assets B.V. Anti-methanogenic compositions and uses thereof
WO2018091643A1 (en) * 2016-11-18 2018-05-24 Dsm Ip Assets B.V. Powderous formulations
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WO2019206892A1 (en) * 2018-04-25 2019-10-31 Dsm Ip Assets B.V. Novel dicarboxylic acid diesters
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CN106165771A (zh) * 2016-07-20 2016-11-30 南京农业大学 2,2双甲基‑3‑(硝基氧基)丙酸的应用
AU2018222469B2 (en) * 2017-02-14 2023-06-08 Dsm Ip Assets B.V. Storage-stable formulations
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US10154981B2 (en) * 2011-05-26 2018-12-18 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ruminants, and/or to improve ruminant performance
US20140088161A1 (en) * 2011-05-26 2014-03-27 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ruminants, and/or to improve ruminant performance
WO2013144786A1 (en) * 2012-03-26 2013-10-03 Dsm Ip Assets B.V. Use of para nitro amino derivatives in feed for reducing me-thane emission in ruminants
CN104202999A (zh) * 2012-03-26 2014-12-10 帝斯曼知识产权资产管理有限公司 对硝基氨基衍生物在饲料中减少反刍动物甲烷排放的用途
CN104202999B (zh) * 2012-03-26 2016-11-16 帝斯曼知识产权资产管理有限公司 对硝基氨基衍生物在饲料中减少反刍动物甲烷排放的用途
EP2644038A1 (en) * 2012-03-26 2013-10-02 DSM IP Assets B.V. Use of para nitro amino derivatives in feed for reducing meth-ane emission in ruminants
WO2014013068A1 (de) 2012-07-20 2014-01-23 Dr. Eckel Gmbh Kombination zur reduzierung der methanemissionen in der wiederkäuerfütterung
WO2015018726A1 (en) * 2013-08-07 2015-02-12 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ru-minants, and/or to improve ruminant performance
US10440975B2 (en) 2014-06-02 2019-10-15 Cj Cheiljedang Corporation Feed additive composition for reducing methane gas produced by ruminant animals
WO2017137489A1 (en) * 2016-02-12 2017-08-17 Dsm Ip Assets B.V. Anti-methanogenic compositions and uses thereof
EP3238720A1 (en) * 2016-04-29 2017-11-01 DSM IP Assets B.V. Anti-methanogenic compositions and uses thereof
WO2018091643A1 (en) * 2016-11-18 2018-05-24 Dsm Ip Assets B.V. Powderous formulations
AU2017360025B2 (en) * 2016-11-18 2022-06-09 Dsm Ip Assets B.V. Powderous formulations
WO2019206892A1 (en) * 2018-04-25 2019-10-31 Dsm Ip Assets B.V. Novel dicarboxylic acid diesters
US11987539B2 (en) 2018-04-25 2024-05-21 Dsm Ip Assets B.V. Dicarboxylic acid diesters
WO2020011992A1 (en) * 2018-07-12 2020-01-16 Dsm Ip Assets B.V. Continuous production of an adsorption product of a nitrooxy-functional organic compound
US11758925B2 (en) 2018-07-12 2023-09-19 Dsm Ip Assets B.V. Continuous production of an adsorption product of a nitrooxy-functional organic compound
EP4302609A3 (en) * 2018-07-12 2024-03-13 DSM IP Assets B.V. Continuous production of an adsorption product of a nitrooxy-functional organic compound

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