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WO2019117733A1 - Utilisation de dérivés d'acétylène chez les ruminants - Google Patents

Utilisation de dérivés d'acétylène chez les ruminants Download PDF

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Publication number
WO2019117733A1
WO2019117733A1 PCT/NZ2018/050178 NZ2018050178W WO2019117733A1 WO 2019117733 A1 WO2019117733 A1 WO 2019117733A1 NZ 2018050178 W NZ2018050178 W NZ 2018050178W WO 2019117733 A1 WO2019117733 A1 WO 2019117733A1
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Prior art keywords
lower alkyl
formula
halo
compound
ruminant
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PCT/NZ2018/050178
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Inventor
Ian Kenneth Boddy
Robert Starr Ronimus
Michael Tavendale
Vincenzo Carbone
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Pastoral Greenhouse Research Ltd
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Pastoral Greenhouse Research Ltd
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Priority to AU2018383221A priority Critical patent/AU2018383221A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A23K20/111—Aromatic 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
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • 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
    • A23K20/116—Heterocyclic compounds
    • A23K20/132—Heterocyclic compounds containing only one nitrogen as hetero atom
    • 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
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    • A61K31/01—Hydrocarbons
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/02—Halogenated hydrocarbons
    • A61K31/035—Halogenated hydrocarbons having aliphatic unsaturation
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/11—Aldehydes
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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 acetylene derivatives in ruminants, in particular the use of phenyl acetylene derivatives in ruminants.
  • the use of such derivatives in ruminants is to inhibit methanogens to either reduce methane production in the rumen and/or to enhance productivity in the ruminant.
  • methane forming methanogens are members of the Archaea, and are quite different in a number of features compared to bacteria, fungi and protozoa.
  • Methanogens have a number of unusual and archaeal-specific features including cell wall structures, lipids, cofactors, and amino acid synthesis pathways as well as their signature energy metabolism that is linked to methane production. They represent only about 1-4% of the rumen microbial community. It is known that due to the unique metabolic pathways of methanogens and their low numbers that methanogen-specific inhibitors can be developed that do not adversely affect the fermentation of feed.
  • methane loss represents a loss of an energy source for the ruminant. It has been previously recognised that if one could inhibit or reduce the release of methane from ruminants that the impact of methane on the environment and atmosphere would be reduced and productivity gains might be achieved in the ruminants.
  • acetylene C2H4
  • Sprott et al. in Acetylene as an Inhibitor of Methanogenic Bacteria, J. of Gen. Microbiology (1982), 128, 2453- 2462.
  • Six pure cultures of methanogens were inhibited by low concentrations of dissolved acetylene, whilst other archaea and bacteria were not similarly inhibited or affected.
  • Elleway et al. in Archivfur Mikrobiologie (1971), 76, Issue 4, 277-291 that methane production by filtrates of rumen contents was found to be inhibited by acetylene.
  • acetylene is a gas, it is difficult to administer to the rumen of a ruminant. Furthermore, its effect is short lived and is therefore not suitable as a methane reducing agent.
  • Methanosarcina mazei At 4 mmol 1 1 propynoic acid caused further inhibition of (i) a pure culture of Methanobrevibacter ruminantium but had minimal further effects on (ii) a pure culture of
  • Methanobrevibacter ruminantium and Methanomicrobium mobile was greater than the inhibition previously reported by Ungerfeld et al. 2003 (Reproduction Nutrition Development 43, 189-202) in mixed ruminal cultures at 6 mmol I 1 .
  • Propynoic acid is a liquid, which is unstable to sunlight and has an odour similar to acetic acid or vinegar, which makes propynoic acid unsuitable for adding to feed or water supplies of ruminants.
  • the present invention provides the use of a compound of Formula I, Formula I wherein the - line optionally represents a double bond; and wherein each X independently represents -halo, -OFI, -CN, -NO2, -CECFI, -CFhihalo), -CFI(halo)2, - C(halo)3, -SH, -C1-C6 lower alkyl, -(C1-C6 lower alkyl)-OH, -NFI2, -NFI(C I -C 6 lower alkyl), -N(C I -C 6 lower alkyl)2, a 3-7 membered monocyclic cycloalkyl, a 3-6 membered monocyclic heterocycle; an -8-12 membered bicyclic; -O (C1-C6 lower alkyl), -S(Ci-C 6 lower alkyl), -SO-(Ci-C 6 lower alkyl), -S0 2 -(Ci-C)
  • the invention provides the use of a compound of Formula II,
  • each X independently represents -halo, -OH, -CN, -NO2, -CECH, -CH2(halo), -CH(halo)2, - C(halo)3, -SH, -C1-C6 lower alkyl, -(C1-C6 lower alkyl)-OH, -NH2, -NH(CI-C 6 lower alkyl), -N(CI-C 6 lower alkyl)2, a 3-7 membered monocyclic cycloalkyl, a 3-6 membered monocyclic heterocycle; an -8-12 membered bicyclic; -O (C1-C6 lower alkyl), -S(Ci-C 6 lower alkyl), -SO-(Ci-C 6 lower alkyl), -S0 2 -(Ci-C 6 lower alkyl), -C(0)-0(-Ci-C 6 lower alkyl), -C(0)0H; -C(0)-H, or -C
  • each X independently represents - halo, -OH, -CN, -N0 2 , -CECH, -SH, -Ci-C 6 lower alkyl, -(C C 6 lower alkyl)-OH, -NH 2 , -N H(CI-C 6 lower alkyl), -N(CI-C 6 lower alkyl ⁇ , a 3-7 membered monocyclic cycloalkyl, a 3-6 membered monocyclic heterocycle; -O (C1-C6 lower alkyl), -C(0)-0(-Ci-C 6 lower alkyl), -C(0)OH; -C(0)-H, or -C(0)-(Ci-C 6 lower alkyl); and wherein each -C1-C6 lower alkyl of X defined above may be further substituted by one or more substituents selected from -halo, -OH, -CN, -NO2, -CE
  • n is selected from 0, 1, 2 or 3.
  • n is selected from 0, 1 or 2.
  • n is selected from 1 or 2.
  • the X substituent is located in the para position.
  • the X substituents are located in the meta positions.
  • the X substituents are located in the ortho positions.
  • X is -OCH3 and n is 1.
  • X is -CN and n is 1.
  • X is— NH2 and n is 1.
  • -halo is -F or -Br.
  • X is -NO2 and n is 1.
  • X is a fused phenyl ring and n is 1. In another embodiment of the compound of Formula II X is a phenyl ring fused at the ortho and meta positions.
  • the compound of Formula II is l-ethynyl-4-nitrobenzene.
  • the compound of Formula II is 1-ethynyl-naphthylene. In one embodiment the compound of Formula I or II is selected from one or more of the following:
  • a compound of Formula I or Formula II as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 10%.
  • a compound of Formula I or Formula II as defined above is for reducing the formation of methane from the digestive actions of ruminants by at least 15%.
  • administration a route involving drenching, addition to feed, water source or pasture or manual administration of a bolus or a capsule.
  • the effective amount of at least one compound of Formula I or Formula II or a salt thereof is administered at least once-daily to the ruminant.
  • the effective amount of at least one compound of Formula I or Formula II or a salt thereof reduces the production of methane emanating from the ruminant by at least 10% per day.
  • the effective amount of at least one compound of Formula I or Formula II or a salt thereof reduces the production of methane emanating from the ruminant by at least 15% per day. In one embodiment the effective amount of at least one compound of Formula I or Formula II or a salt thereof reduces the production of methane emanating from the ruminant by at least 20% per day.
  • composition comprising at least one compound of Formula I or Formula II or a salt thereof for reducing the production of methane emanating from a ruminant, and the composition further including at least one agriculturally and an orally acceptable excipient .
  • composition is adapted for use as a feed additive.
  • composition is adapted for use as a ruminant lick.
  • composition is adapted to reduce the production of methane emanating from the ruminant by at least 10% per day.
  • composition is adapted to reduce the production of methane emanating from the ruminant by at least 15% per day. In one embodiment the composition is adapted to reduce the production of methane emanating from the ruminant by at least 20% per day.
  • the excipient may include one or more minerals and/or one or more vitamins.
  • the excipient may include one or more vitamins selected from vitamin A, vitamin D3, vitamin E, and vitamin K, e.g. vitamin K3, vitamin B12, biotin and choline, vitamin Bl, vitamin B2, vitamin B6, niacin, folic acid or the like.
  • the excipient may include one or more minerals selected from calcium, phosphorus, sodium, manganese, zinc, iron, copper, chlorine, sulfur, magnesium, iodine, selenium, and cobalt or the like.
  • composition may further include sunflower oil, electrolytes such as ammonium chloride, calcium carbonates, starch, proteins or the like.
  • composition may further include one or more anthelmintic.
  • the compounds of the present invention have potential for use in a ruminant to reduce the formation of methane without affecting microbial fermentation in a way that would be detrimental to the ruminant.
  • FIG. 1 shows a plot of inhibition of methane production by ENB using a 60 ml rumen in vitro assay system.
  • FIG. 2 shows a plot of the gas profile for three sheep (one control animal, two treatment animals) dosed twice-daily with feed with 1- ethynyl-4-nitrobenzene (ENB).
  • ENB 1- ethynyl-4-nitrobenzene
  • FIG. 3 shows a plot of the gas profile for one of the five sheep dosed once-daily with 4-ethynyl-anisole.
  • FIG. 4 shows a plot of the gas profile for one of the five sheep dosed once-daily with 4-ethynyl aniline.
  • FIG 5 shows a plot of the gas profile for the two cattle dosed with 1- ethynyl-4-nitrobenzene (ENB) provided in feed (Y-axis is g CFU and X-axis is the date).
  • ENB 1- ethynyl-4-nitrobenzene
  • FIG 6 shows a plot of the gas profile for a control cow with no inhibitor in the l- ethynyl-4-nitrobenzene (ENB) cattle trial.
  • ruminant as used herein is a mammal that is able to acquire nutrients from plant-based food by fermenting it in a specialized foregut (the rumen) prior to digestion, principally through microbial activity.
  • Representative examples of ruminants and other foregut fermenters include cattle, goats, sheep, giraffes, bison, moose, elk, yaks, water buffalo, deer, camels, alpacas, llamas, and antelope.
  • an effective amount refers to an amount of at least one compound of Formula I or Formula I I or a salt thereof that either reduces the production of methane emanating from the ruminant or improves ruminant performance.
  • ruminant performance refers to improving the productivity of the ruminant, such as increased muscle weight gain, milk yield or quality, wool growth or quality, surviving offspring per parturition, or the like.
  • Ci-Cg lower alkyl refers to a straight or branched chain, saturated hydrocarbon having from to 6 carbon atoms.
  • Representative Ci-Cg lower alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert butyl, pentyl, isopentyl, neopentyi, hexyl, isohexyl, neohexyl and the like.
  • the CrCg lower alkyl group may be further substituted, for example, by -halo, -OFI, -CN, -NO2, -CECFI, -SH, -C1-C6 lower alkyl, -(C1-C6 lower alkyl)- OFI, -NH2, -N FI(CI-C 6 lower alkyl), -N(CI-C 6 lower alkyl ⁇ , -O (C1-C6 lower alkyl), -S(Ci-C 6 lower alkyl), - SO-(Ci-C 6 lower alkyl), -S0 2 -(Ci-C 6 lower alkyl), -C(0)-0(-Ci-C 6 lower alkyl), -C(0)0H; -C(0)-H, or -C(O)- (C1-C6 lower alkyl).
  • C3-C7 monocyclic cydoalkyi is a 3-, 4-, 5-, 6-, or 7-membered saturated non-aromatic monocyclic cydoalkyi ring.
  • Representative C3-C7 monocyclic cydoalkyi groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cydoheptyl.
  • the C3-C7 monocyclic cydoalkyi group may be substituted with one or more of the following groups: -halo, -OFI, -CN, -NO2, -CECFI, -SH, -C1-C6 lower alkyl, -(C1-C6 lower alkyl)-OH, -N FI2, -NFI(CI-C 6 lower alkyl), -N(CI-C 6 lower alkyl ⁇ , -O (C1-C6 lower alkyl), -S(Ci-C 6 lower alkyl), -SO-(Ci-C 6 lower alkyl), -S0 2 -(Ci-C 6 lower alkyl), -C(0)-0(-Ci-C 6 lower alkyl), -C(0)0FI; -C(0)-H, or -C(0)-(Ci-C 6 lower alkyl).
  • 3- to 6-membered monocyclic heterocycle refers to: (i) a 3- or 4-membered non aromatic monocyclic cycloalkyl in which 1 of the ring carbon atoms has been replaced with an N, O or 5 atom; or (ii) a 5-, or 6-membered aromatic or non-aromatic monocyclic cycloalkyl in which 1-4 of the ring carbon atoms have been independently replaced with a N, O or S atom.
  • the non-aromatic 3- to 6-membered monocyclic heterocycles can be attached via one or more ring nitrogen, sulfur, or carbon atoms.
  • the aromatic 3- to 6-membered monocyclic heterocycles may be attached via one or more ring carbon atoms.
  • the 3- to 6-membered monocyclic heterocycie group may be substituted with one or more of the following groups-halo, -OH, -CN, -NO2, -CECH, -SH, -C1-C6 lower alkyl, -(C1-C6 lower alkyl)-OH, -IMH2, -NH(CI-C 6 lower alkyl), -N(CI-C 6 lower alkyl ⁇ , -O (C1-C6 lower alkyl), -S(Ci-C 6 lower alkyl), -SO-(Ci-C 6 lower alkyl), -S0 2 -(Ci-C 6 lower alkyl), -C(0)-0(-Ci-C 6 lower alkyl), -C(0)0H; -C(0)-H, or -C(0)-(Ci-C 6 lower alkyl).
  • a -8-12 membered bicyclic group refers to a 8 -12 membered aromatic or non-aromatic bicyclic in which one or both of the rings of the bicyclic ring system optionally have 1 to 3 of the ring carbon atoms has been optionally replaced with a N, O or S atom or a carbonyl - C(O) group. Included in this class are 3-6 membered monocyclic heterocydes, as defined above, that are fused to a benzene ring.
  • 8- to 12-membered bicyclic heterocydes include napbtha!eny!, benzimieazolyl, benzofurany!, henzothiofurany!, benzothiopheny!, benzoxazolyl, benzthiazo!yl, benztriazolyl, benztetrzolyl, benzisoxazolyl, benzisothiazolyl, benzimieazo!iny!, cinno!iny!, decahydroquino!iny!, IH-indazoly!, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofurany!, isoindazo!y!, isoindo!yl, isoindo!iny!, isoquino!inyl, naphthyr!einyl, octahydroisoquino!inyl, pbtha!azinyl,
  • a salt thereof is a salt of an acid or a basic nitrogen atom.
  • Illustrative salts include, but are not limited, to sodium salt, potassium salt, lithium salt, calcium salt, ammonium salt, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, and the like.
  • anthelmintic means a compound that expels parasitic worms (helminths) and other internal parasites from the body of the ruminant by either stunning or killing them and without causing significant damage to the host.
  • the one or more anthelmintic may be selected from benzimidazoles, including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, and flubendazole; abamectin, diethylcarbamazine, ivermectin, suramin, pyrantel pamoate, levamisole, salicylanilides (eg niclosamide), nitrazoxanide, praziquantel, octadepsipeptides (eg emodepside), aminoacetonitrile derivatives (eg monepantel), spiroindoles (eg derquantel), pelletierine sulphate and artemisinin.
  • the compounds of the present invention were screened for initial in vitro activity using a fully automated incubation system for the measurement of total gas production and gas composition (methane and hydrogen).
  • the system used is described in detail in the paper by Muetzel et al.
  • the system in this specification is referred to as the rumen in vitro system or RIV.
  • the RIV system provides a relatively simple tool for determining the rate and production of methane and also whether the rate and production of methane is inhibited or reduced by a particular compound or feed.
  • Rumen in vitro assays utilise rumen fluid from donor animals (typically either sheep or cattle) which is typically combined with a buffer and then incubated in sealed fermentation vessels at 39 °C for either 24 or 48 h.
  • donor animals typically either sheep or cattle
  • a buffer typically combined with a buffer and then incubated in sealed fermentation vessels at 39 °C for either 24 or 48 h.
  • These assays systems have been well-characterised and used by the scientific community over the last two decades (Rymer et al. 2005). The system that has been used here to characterise the effects of inhibitors on methane production and gas production, and the formation of H2, was described by Muetzel et al. 2014.
  • Rumen in vitro assay systems reflect what can occur in the rumen in vivo, but only short-term, due to their short incubation times (typically not exceeding 48 h) which is limited by its buffering capacity and the fact that it is a closed system.
  • ENB for example, was tested using the 60 mL rumen in vitro assay system at 100 mM, 70 mM and 30 mM final concentrations and compared to a positive control with 30 mM BES (see Figure 1 for the effect on methane production). A negative control, with no added inhibitor (but with DMF) was also included. ENB produced BES-like effects with approximately 25% inhibition at 30 mM at 24 h. At 70 mM and 100 mM, inhibition levels were approximately 49% and 68% at 24 h, respectively.
  • Other compounds of Formula I and Formula II were tested in the RIV using the same method described above for ENB. All the compounds were either sourced from commercially available stockists or synthesised by chemical synthesis companies. It can be seen from the results of the RIV experimentation tabulated below and the subsequent results of the in vivo testing that is described below that the RIV results for the compounds of Formula I and II are somewhat predictive of in vivo activity.
  • the toxicity of ENB was tested in mice under a contract research arrangement and no adverse effects were observed. It should be noted that the 300 mg/kg concentration used for the toxicity testing in mice for ENB was significantly higher (circa 19-fold) than that used for the sheep trials.
  • mice testing used two groups with three mice (Female Swiss mice, non-pregnant) for each compound, all at approximately 8-9 weeks of age. On the day of testing, food was withdrawn 1-2 hours prior to dosing. Following fasting, the animals were weighed and the test substances administered. Access to food was resumed 1-2 hours after administration of ENB. ENB was administered in a single dose by oral gavage in corn oil (maximum of 0.3 ml per dose) at the selected dose and the time recorded. The mice were observed individually after dosing at least once during the first 30 minutes, periodically over the first 24 hours, with special attention given to the first 4 hours, and then daily thereafter for a total of 14 days. The mice were weighed every seven days (0, 7 and 14 days).
  • the trial was approved by the Grasslands Animal Ethics Committee and the use of ENB in animals was approved by the New Zealand Food Safety Authority, as required under ACVM legislation.
  • Five sheep were used for the ENB trial treatment group and a control group with five untreated animals.
  • Three further animals were dosed in the trial to determine if there were any adverse health effects caused by dosing with ENB (one animal was dosed first for two days and observed, then two new animals were dosed for two days and observed). This pre-testing was a condition of the AEC approvals (in addition to the mice toxicity testing).
  • the animals received a general purpose diet (GP) at 1.5 x maintenance energy requirements throughout the trials consisting of 500 g hay, 100 g soy bean meal, 290 g barley, 100 g molasses and 10 g mineral mix. During the time in the respiration chambers the animals had free access to water, with the feed offered twice a day at approximately 9:00 and 16:00 h in equal amounts. Feed refusals were weighed.
  • GP general purpose diet
  • SCFA samples were thawed and centrifuged (20,000 g, 10 min, 4 °C) and 800 pi of the supernatant was collected into a crimp cap glass vial. SCFA were analysed using a HP 6890 gas chromatograph (Attwood et al., 1998). Ammonia was analysed from the SCFA sample using a downscaled nitroprusside method (Weatherburn 1967).
  • the 10 animals entered the methane respiratory chambers for four days. On the start of the third day in the chambers, five animals were dosed with ENB in sunflower oil and five control animals were given only oil.
  • the five ENB-treated animals continued to be administered ENB orally in feed twice daily through to the end of the experiment (total of 16 days dosing). After 10 days in pens, all animals were re introduced into crates again for two days and then placed in the chambers for two days.
  • mice toxicity tests were required for all compounds according to the standardised toxicity testing method OECD 423.
  • the initial target concentration for the two acetylene containing compounds for mice testing was 300 mg/kg of live weight. The compounds were not expected to be toxic based on their chemistries.
  • a liquid acetylene derivative, 4-ethynyl-anisole is considered to be non-toxic according to Regulation (EC) No. 1272/2008 and is not classified as dangerous according to Directive 67/548/EEC.
  • mice at a Crown Research Institute in New Zealand No adverse effects were noted at 300 mg/kg for 4-ethynyl-anisole. However, after dosing with 4- ethnyl-aniline the mice were observed to be lethargic and panted for 1-2 hours. No further effects were noted. It should be noted that the 300 mg/kg concentration used for mice testing for 4-ethynyl- aniline was significantly higher (25.6-fold) than that used for the sheep trial. The 300 mg/kg mice dosing for 4-ethynyl-anisole was also higher than that used for the sheep trials (22.7-fold).
  • the two acetylene derivative compounds were each tested at a rumen target concentration 10-fold higher levels in sheep (i.e. target rumen concentration of 1.0 mM for the acetylene derivatives).
  • the trials were approved by the Grasslands Animal Ethics Committee, and the use of the compounds in animals by the New Zealand Food Safety Authority, as required under ACVM legislation.
  • Eight sheep were used for each of the three trials. Each sheep was used as its own control (ie the first day in chambers without any added inhibitor was the control day). Three animals being dosed while in pens to determine if there were any adverse health effects due to dosing with the compounds (one animal was dosed first and observed, then two animals dosed and observed). This pre-testing was a condition of the AEC approval (as well as the mice toxicity testing). Five animals were then used for the treatment period with three days in chambers (Day 1, control day with no dosing; Day 2 and Day 3, with once-daily dosing).
  • the other components were (g per 100 g dry matter): crude protein (16.9); lipid ( ⁇ 1); ash (3.0); acid detergent fibre (23.1); neutral detergent fibre (50.5); soluble sugars and starch (24.9); and metabolisable energy (10.1 MJ/kg dry matter).
  • FIG. 2 A typical gas profile from the treatment period (Day 3) in the chambers for one of the five sheep dosed once-daily with 4-ethynyl-anisole is shown in Fig. 2 below.
  • Dosing with 4-ethynyl-anisole produced a rapid and near-total reduction in methane emissions, however, the effect was observed only for a limited number of hours post feeding (approximately six hours; up to approximately nine hours if the secondary peak is included) possibly due to washout or degradation of the product. Methane emissions did not recover to those observed before dosing (after feeding) in the respective animal controls.
  • 4-ethynyl-aniline was dosed as a suspension in sunflower oil and produced a rapid and near-total reduction in methane emissions. Methane emissions recovered over the next 24 hours after dosing, but not to pre-dosing levels. Overall reductions for Day 2 and 3 were on average 38% and 27%, respectively.
  • the dosing with 4-ethynyl- aniline almost entirely negated the typical large methane emissions that occur after feeding and it was associated with a large spike in H2.
  • VFAs Volatile fatty acids
  • methane emissions were measured in open circuit respiration chambers as described in Chapter 1 of the technical manual on respiration chamber design (Pinares- Patifio et al., 2012). During methane measurements dry matter intake (DMI, kg/d) was recorded, from the weight difference of feed offered and refused.
  • DMI dry matter intake
  • Rumen samples from stomach tubing were immediately subsampled for short chain fatty acid (SCFA) analysis (1.8 ml). The samples were centrifuged (20,000 g, 10 min, 4 °C). An aliquot of 0.9 ml of the supernatant was collected into 0.1 ml of internal standard (19.8 mM ethylbutyrate in 20% v/v phosphoric acid) for SCFA analysis and stored at -20 °C.
  • SCFA short chain fatty acid
  • SCFA samples were thawed and centrifuged (20,000 g, 10 min, 4 °C) and 800 pi of the supernatant was collected into a crimp cap glass vial.
  • SCFA were analysed using a HP 6890 gas chromatograph (Attwood et al., 1998). Ammonia was analysed from the SCFA sample using a downscaled nitroprusside method (Weatherburn, 1967).
  • the two-day cattle trial used the cattle chambers at the New Zealand Ruminant Methane Measurement Centre facility, AgResearch, Palmerston North according to standard procedures (Pinares-Patino et al., 2012). Three animals were used for the cattle trial with ENB.
  • the animals were pre-adapted to feed (GP diet) for at least 10 days.
  • Three cattle (one control, two treatment) were checked for their background methane emissions in chambers for one day, followed by dosing for two days in the treated animals (ENB). Their rumens were sampled prior to entering the chambers and after they were released. ENB was added to feed just prior to the experiment starting by first adding to soy meal and then to the bulk GP diet. The animals were in chambers for a total of three days.
  • Table 6 Total short chain fatty acid production and composition of cattle fed ENB compared to a control group.
  • ENB when tested in cattle over two days, produced reductions in methane yield of circa 20%. These reductions were similar to those observed in the previous 16-day sheep trial for ENB. ENB dosing also caused an obvious increase in H2 emissions (a positive indicator of successful inhibition of methanogens). There were no apparent toxicity effects and no feed refusals.
  • Pinares-Patifio CS Hunt C, Martin R, West J, Lovejoy P, Waghorn GC. (2012) Chapter 1: New Zealand Ruminant Methane Measurment Centre, AgResearch, Palmerston North. In Technical Manual on Respiration Chamber Design'. Vol. 2013. (Eds. CS Pinares-Patifio and GC Waghorn). (Ministry of Agriculture and Forestry, Wellington, New Zealand).

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Abstract

La présente invention concerne l'utilisation d'un composé de formule I ou de formule II ou d'un sel de celui-ci pour réduire la formation de méthane provenant des actions digestives de ruminants et/ou pour améliorer les performances des ruminants.
PCT/NZ2018/050178 2017-12-14 2018-12-14 Utilisation de dérivés d'acétylène chez les ruminants Ceased WO2019117733A1 (fr)

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CN112920418A (zh) * 2021-01-26 2021-06-08 南京林业大学 一种新型的含溴未配位基团的蜂窝状二维金属有机多面体骨架化合物及其合成方法和应用

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CA3201057A1 (fr) 2020-12-08 2022-06-16 Mark Christopher LAY Ameliorations apportees a des dispositifs et des methodes d'administration de substances aux animaux
WO2024006531A1 (fr) 2022-07-01 2024-01-04 Arkea Bio Corp. Compositions et procédés pour réduire les émissions de gaz atmosphérique délétères à partir d'écosystèmes inondés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110036470A (ko) * 2009-10-01 2011-04-07 강원대학교산학협력단 반추동물의 메탄가스 생성 저감용 사료 및 저감 방법
WO2012091115A1 (fr) * 2010-12-29 2012-07-05 キッセイ薬品工業株式会社 Dérivé d'acétylène et application pharmaceutique associée
US20170105958A1 (en) * 2011-05-26 2017-04-20 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ruminants, and/or to improve ruminant performance

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110036470A (ko) * 2009-10-01 2011-04-07 강원대학교산학협력단 반추동물의 메탄가스 생성 저감용 사료 및 저감 방법
WO2012091115A1 (fr) * 2010-12-29 2012-07-05 キッセイ薬品工業株式会社 Dérivé d'acétylène et application pharmaceutique associée
US20170105958A1 (en) * 2011-05-26 2017-04-20 Dsm Ip Assets B.V. Use of a feed composition for reducing methane emission in ruminants, and/or to improve ruminant performance

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112920418A (zh) * 2021-01-26 2021-06-08 南京林业大学 一种新型的含溴未配位基团的蜂窝状二维金属有机多面体骨架化合物及其合成方法和应用
CN112920418B (zh) * 2021-01-26 2022-03-29 南京林业大学 一种新型的含溴未配位基团的蜂窝状二维金属有机多面体骨架化合物及其合成方法和应用

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