JP2021107352A - 豚コレラの治療及び/又は予防剤 - Google Patents
豚コレラの治療及び/又は予防剤 Download PDFInfo
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- JP2021107352A JP2021107352A JP2019239164A JP2019239164A JP2021107352A JP 2021107352 A JP2021107352 A JP 2021107352A JP 2019239164 A JP2019239164 A JP 2019239164A JP 2019239164 A JP2019239164 A JP 2019239164A JP 2021107352 A JP2021107352 A JP 2021107352A
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- Prior art keywords
- swine fever
- classical swine
- compound
- therapeutic
- metal
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- ZNRVBINYQYCPPK-QTNFYWBSSA-L disodium (2S)-2-(dicarboxymethylamino)pentanedioate Chemical compound [Na+].[Na+].OC(=O)C(C(O)=O)N[C@H](C([O-])=O)CCC([O-])=O ZNRVBINYQYCPPK-QTNFYWBSSA-L 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 1
- 239000011706 ferric diphosphate Substances 0.000 description 1
- 235000007144 ferric diphosphate Nutrition 0.000 description 1
- VEPSWGHMGZQCIN-UHFFFAOYSA-H ferric oxalate Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O VEPSWGHMGZQCIN-UHFFFAOYSA-H 0.000 description 1
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 description 1
- 229940036404 ferric pyrophosphate Drugs 0.000 description 1
- 239000011640 ferrous citrate Substances 0.000 description 1
- 235000019850 ferrous citrate Nutrition 0.000 description 1
- 239000011773 ferrous fumarate Substances 0.000 description 1
- 235000002332 ferrous fumarate Nutrition 0.000 description 1
- 229960000225 ferrous fumarate Drugs 0.000 description 1
- 239000004222 ferrous gluconate Substances 0.000 description 1
- 235000013924 ferrous gluconate Nutrition 0.000 description 1
- 229960001645 ferrous gluconate Drugs 0.000 description 1
- 229960001604 ferrous succinate Drugs 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002506 iron compounds Chemical class 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- ATEAWHILRRXHPW-UHFFFAOYSA-J iron(2+);phosphonato phosphate Chemical compound [Fe+2].[Fe+2].[O-]P([O-])(=O)OP([O-])([O-])=O ATEAWHILRRXHPW-UHFFFAOYSA-J 0.000 description 1
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- APVZWAOKZPNDNR-UHFFFAOYSA-L iron(ii) citrate Chemical compound [Fe+2].OC(=O)CC(O)(C([O-])=O)CC([O-])=O APVZWAOKZPNDNR-UHFFFAOYSA-L 0.000 description 1
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 description 1
- 229940078795 lactoferrin Drugs 0.000 description 1
- 235000021242 lactoferrin Nutrition 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- PJJZFXPJNUVBMR-UHFFFAOYSA-L magnesium benzoate Chemical compound [Mg+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 PJJZFXPJNUVBMR-UHFFFAOYSA-L 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- BKJXSPNFVILSSW-UHFFFAOYSA-N n'-[2-(2-aminoethylamino)ethyl]ethane-1,2-diamine;iron Chemical compound [Fe].NCCNCCNCCN BKJXSPNFVILSSW-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 230000008520 organization Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- LQPLDXQVILYOOL-UHFFFAOYSA-I pentasodium;2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC(=O)[O-])CCN(CC([O-])=O)CC([O-])=O LQPLDXQVILYOOL-UHFFFAOYSA-I 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- OOTLZFANIDERRE-UHFFFAOYSA-K sodium butanedioic acid 2-hydroxypropane-1,2,3-tricarboxylate iron(2+) Chemical compound [Na+].[Fe+2].C(CC(O)(C(=O)[O-])CC(=O)[O-])(=O)[O-].C(CCC(=O)O)(=O)O OOTLZFANIDERRE-UHFFFAOYSA-K 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- KXFFQVUPQCREHA-UHFFFAOYSA-K sodium;2-hydroxypropane-1,2,3-tricarboxylate;iron(2+) Chemical compound [Na+].[Fe+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KXFFQVUPQCREHA-UHFFFAOYSA-K 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- GZXOHHPYODFEGO-UHFFFAOYSA-N triglycine sulfate Chemical compound NCC(O)=O.NCC(O)=O.NCC(O)=O.OS(O)(=O)=O GZXOHHPYODFEGO-UHFFFAOYSA-N 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- FUTVBRXUIKZACV-UHFFFAOYSA-J zinc;3-[18-(2-carboxylatoethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoate Chemical compound [Zn+2].[N-]1C2=C(C)C(CCC([O-])=O)=C1C=C([N-]1)C(CCC([O-])=O)=C(C)C1=CC(C(C)=C1C=C)=NC1=CC(C(C)=C1C=C)=NC1=C2 FUTVBRXUIKZACV-UHFFFAOYSA-J 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/12—Antivirals
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Abstract
Description
[項目1]
下記式(I)
で示される化合物又はその塩を含有する豚コレラの治療及び/又は予防剤。
[項目2]
R1及びR2が水素原子であることを特徴とする、項目1に記載の豚コレラの治療及び/又は予防剤。
[項目3]
さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする項目1又は2記載の豚コレラの治療及び/又は予防剤。
[項目4]
金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする項目3記載の豚コレラの治療及び/又は予防剤。
[項目5]
金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする項目3記載の豚コレラの治療及び/又は予防剤。
[項目6]
金属含有化合物が、鉄を含有する化合物であることを特徴とする項目3記載の豚コレラの治療及び/又は予防剤。
[項目7]
(1)下記式(I)
で示される化合物又はその塩を含有する豚コレラウイルスのタンパク質発現抑制剤。
[項目8]
R1及びR2が水素原子であることを特徴とする、項目1に記載の豚コレラウイルスのタンパク質発現抑制剤。
[項目9]
さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする項目1又は2記載の豚コレラウイルスのタンパク質発現抑制剤。
[項目10]
金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする項目9記載の豚コレラウイルスのタンパク質発現抑制剤。
[項目11]
金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする項目9記載の豚コレラウイルスのタンパク質発現抑制剤。
[項目12]
金属含有化合物が、鉄を含有する化合物であることを特徴とする項目9記載の豚コレラウイルスのタンパク質発現抑制剤。
[項目13]
前記豚コレラウイルスのタンパク質が、エンベロープタンパク質である、項目7〜12のいずれか1項に記載の豚コレラウイルスのタンパク質発現抑制剤。
[項目14]
下記式(I)
で示される化合物又はその塩を、薬学的許容される賦形剤と共に投与することを含む、豚コレラの治療及び/又は予防方法。
[項目15]
下記式(I)
で示される化合物又はその塩の、豚コレラの治療及び/又は予防における使用。
[項目16]
下記式(I)
で示される化合物又はその塩を、薬学的許容される賦形剤と共に投与することを含む、豚コレラウイルスのタンパク質発現抑制方法。
[項目17]
下記式(I)
で示される化合物又はその塩の、豚コレラウイルスのタンパク質発現抑制における使用。
本明細書において、複数の数値の範囲が示された場合、それら複数の範囲の任意の下限値および上限値の組み合わせからなる範囲も同様に意味する。
本発明の豚コレラの治療及び/又は予防剤、並びにウイルスタンパク質発現抑制剤の有効成分として用いられる化合物は、式(I)で示される化合物又はその塩(以下、これらを総称して「ALA類」ということもある)として例示することができる。δ−アミノレブリン酸とも呼ばれる5−ALAは、式(I)のR1及びR2が共に水素原子の場合であり、アミノ酸の1種である。5−ALA誘導体としては、式(I)のR1が水素原子又はアシル基であり、式(I)のR2が水素原子、直鎖若しくは分岐状アルキル基、シクロアルキル基、アリール基又はアラルキル基である、5−ALA以外の化合物を挙げることができる。
本発明の豚コレラの治療及び/又は予防剤に含有されるALA類と金属含有化合物または他の薬剤は、これらのうちのいずれか2つ以上を含む組成物としても、あるいは、それぞれを単独で含む組成物としても投与することできる。ALA類と金属含有化合物または他の薬剤とを、それぞれ単独で含む組成物を用いる場合、これらを同時に投与してもよく、また、別々に投与してもよい。好ましくは、ALA類と金属含有化合物または他の薬剤との投与が相加的効果、好ましくは相乗的効果を奏することができるように組み合わせて投与することができる。ALA類と金属含有化合物または他の薬剤をそれぞれ単独で含む組成物を別々に投与する場合、それらの投与間隔は、5分、10分、15分、20分、30分、45分、1時間、2時間、3時間、4時間、5時間、6時間、7時間、8時間、9時間、10時間、11時間、12時間等に設定できるが、これらに限定されない。
本発明の豚コレラの治療及び/又は予防剤並びにウイルスタンパク質発現抑制剤の剤型としては、上記投与経路に応じて適宜決定することができるが、注射剤、点滴剤、錠剤、カプセル剤、細粒剤、散剤、液剤、シロップ等に溶解した水剤、パップ剤、座薬剤等を挙げることができる。
本発明の豚コレラの治療及び/又は予防剤並びにウイルスタンパク質発現抑制剤の投与の量・頻度・期間としては、豚コレラを治療又は予防しようとする動物の種類、年齢、体重、症状等により異なるが、例えば豚に投与する場合、ALA類の投与量としては、5−ALAモル換算で、動物1頭当たり、0.01−200mg/体重kg/日、好ましくは0.5−100mg/体重kg/日、より好ましくは1−50mg/体重kg/日、さらに好ましくは5−30mg/体重kg/日を挙げることができ、特に予防剤として用いる場合は、低容量を継続して摂取することが望ましい。例えば予防剤サプリメントとして投与する場合には、0.1−10mg/体重kg/日、好ましくは0.5〜1mg/体重kg/日などの投与量で投与することができる。投与頻度としては、一日一回〜複数回の投与又は点滴等による連続的投与を例示することができる。治療剤または予防剤としての投与期間は、獣医等当該技術分野の専門家が既知の方法により決定することができる。
本発明の豚コレラの治療及び/又は予防剤並びにウイルスタンパク質発現抑制剤は、豚コレラの感染および/または発症を原因として生じる様々な症状の治療および予防に適用することができる。そのような症状として、発熱、食欲減退、急性結膜炎、便秘、下痢、全身リンパ節や各臓器の充出血、点状出血を例示することができるが、これらに限定されない。
本発明の豚コレラの治療及び/又は予防剤並びにウイルスタンパク質発現抑制剤は、豚、イノシシおよびこれらの近縁動物に投与することができる。
豚腎尿細管上皮細胞由来の株化細胞(SK−L細胞、In Vitro Cell Dev Biol Anim. 1998 Jan;34(1):53−7、農林水産省家畜衛生試験場より入手)を用いた。
Journal of Virology, 2019, Vol. 93, no. 22, e01191−19に基づいて、HiBitペプチドタグをコードする核酸を、ウイルスエンベロープタンパク質Ernsをコードする核酸の5‘側に挿入・融合させた豚コレラウイルスGPE−株(108.3TCID50/ml)を作成し、これを試験に用いた。
イーグルMEM培地に0.295%トリプトースフォスフェイトブロス、10mM N, N−bis (2−hydroxyethyl)−2−aminoethanesulfonic acid (BES)、0.292mg/ml L−グルタミン、10%ウマ血清を添加して培養液とした。
SK−L細胞を2セットの6穴プレートに、1穴(ウェル)あたり8.8x105個/mlの濃度で2mL分注した。細胞が90%のコンフルエンスに達した時点を試験開始点(0日目)として試験を開始した。
試験開始時点でプレートの2mLの培地を含むウェルあたり、moi(Multiplicity of Infection)=0.1となるように希釈したウイルス含有溶液を200μLずつ接種し、15分毎に軽く揺らした後、接種1時間後にウイルスを含む培地を除去し、新たに培地を2mLずつ加えた。
各ウェルから培地400μLを回収し、そのうち50μLをルシフェラーゼ測定に供し、代わりに下記の溶液を培地に加えた。
5−ALAとして、5−ALA塩酸塩を用いた。
培養開始24時間後(第1日目)、各ウェルから培地400μLを回収し、そのうち50μLをルシフェラーゼ測定に供し、代わりに下記の溶液を培地に加えた。
2日目から5日目まで、上記1日目と同様の方法で培地を交換して培養した。
なお、豚コレラウイルスについてはmoi=0.1接種で3日目が増殖のピークであることが判明しており(北海道大学、博士(獣医学)乙第5508号)、実験5日目の時点で試験を終了した。
試験開始後第0〜5日目から得られた培養液について、ルシフェラーゼアッセイを行ったところ、図1に示すとおり、5−ALAを添加した培地で培養した場合、ルシフェラーゼ活性が抑制されることが分かった。5−ALAに加えてSFCを添加した培地で培養した場合、更に強力なルシフェラーゼ活性抑制が得られ、5日目においてその抑制効果は、豚コレラウイルス免疫豚血清を添加した培地で培養した場合よりもさらに強力であった。
なお、細胞変性を目視によって観察したところ、第1群〜第6群の間で、細胞変性の程度に差異はなく、いずれの薬剤も細胞障害性を有しないことが確認できた。
当該試験により、5−ALAおよび5−ALA+SFCにより、ウイルスの増殖およびタンパク質発現が抑制されることが判明した。
Claims (13)
- R1及びR2が水素原子であることを特徴とする、請求項1に記載の豚コレラの治療及び/又は予防剤。
- さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする請求項1又は2記載の豚コレラの治療及び/又は予防剤。
- 金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする請求項3記載の豚コレラの治療及び/又は予防剤。
- 金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする請求項3記載の豚コレラの治療及び/又は予防剤。
- 金属含有化合物が、鉄を含有する化合物であることを特徴とする請求項3記載の豚コレラの治療及び/又は予防剤。
- R1及びR2が水素原子であることを特徴とする、請求項1に記載の豚コレラウイルスのタンパク質発現抑制剤。
- さらに、一種又は二種以上の金属含有化合物を含有することを特徴とする請求項1又は2記載の豚コレラウイルスのタンパク質発現抑制剤。
- 金属含有化合物が、鉄、マグネシウム、亜鉛、ニッケル、バナジウム、銅、クロム、モリブデン又はコバルトを含有する化合物であることを特徴とする請求項9記載の豚コレラウイルスのタンパク質発現抑制剤。
- 金属含有化合物が、鉄、マグネシウム又は亜鉛を含有する化合物であることを特徴とする請求項9記載の豚コレラウイルスのタンパク質発現抑制剤。
- 金属含有化合物が、鉄を含有する化合物であることを特徴とする請求項9記載の豚コレラウイルスのタンパク質発現抑制剤。
- 前記豚コレラウイルスのタンパク質が、エンベロープタンパク質である、請求項7〜12のいずれか1項に記載の豚コレラウイルスのタンパク質発現抑制剤。
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