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WO1991009595A1 - Compositions antivirales - Google Patents

Compositions antivirales Download PDF

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Publication number
WO1991009595A1
WO1991009595A1 PCT/US1990/007375 US9007375W WO9109595A1 WO 1991009595 A1 WO1991009595 A1 WO 1991009595A1 US 9007375 W US9007375 W US 9007375W WO 9109595 A1 WO9109595 A1 WO 9109595A1
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WO
WIPO (PCT)
Prior art keywords
phloroglucinol
compound
methylphloroglucinol
chch
alkylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1990/007375
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English (en)
Inventor
James Amigo Chan
John William Westley
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO1991009595A1 publication Critical patent/WO1991009595A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/335—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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom

Definitions

  • This invention is in the field of treatment of immune disorders associated with infection by Immunodeficiency Viruses, such as the Human Immunodeficiency Virus (HIV).
  • Immunodeficiency Viruses such as the Human Immunodeficiency Virus (HIV).
  • the etiologic agent of AIDS is the
  • HIV Human Immunodeficiency Virus
  • Immunodeficiency Viruses have been identified as etiologic agents in immune dysfunctions in other animals. These include the Simian Immuno- deficiency Virus (SIV). See, e.g., Hirsh et al., Cell 49: 307 (1987) and Kestler et al., Nature 331: 619 (1988). These viruses have been classified in the family, Retroviridae. These are RNA-containing enveloped, icosohedral viruses of about 150 nm diameter and have a coiled nucleocapsid within a core structure.
  • SIV Simian Immuno- deficiency Virus
  • Phloroglucinols are a class of trihydroxylic phenols which were identified as natural products having anthelminthic activity. The naturally occuring members of this class can be extracted from plants of the species Medicosma sessiliflora (formerly, Melicope sessiliflora) in the family Rustaceae, which are indigenous to Australia. Bowden et al., Brit. J. Pharmacol. 24: 714 (1965), report on the relative anthelminthic (Hymenolepis nana) activity of a variety of phloroglucinols and related compounds.
  • This invention is of a method for treating infection in an animal by an Immunodeficiency Virus, especially human immune disorders associated with infection by HIV and related human immunodeficiency viruses, by internally administering to the animal aneffective amount of phloroglucinol or a derivative of phloroglucinol which has the core trihydroxylic structure of phloroglucinol but has one or more of the protons in the hydroxyl groups or in the non-substitututed positions replaced.
  • This invention is also of certain novel phloroglucinols and of use of such novel phloroglucinols to treat infection by an Immunodeficiency Virus.
  • This invention is also of a pharmaceutical composition for the treatment of infection in an animal by an Immunodeficiency Virus comprising phloroglucinol or a derivative thereof as described above and hereinbelow.
  • the method of the invention is useful in alleviating immune disorders associated with infection by Immunodeficiency Viruses, several of which have now been isolated. These include the isolates which have been variously identified as HIV, HTLV-III, HIV-1, HIV-2, LAV and ARV and which are herein collectively referred to as HIV. See, references cited above. It is postulated that alleviation of the immune disorders is achieved by inhibition of direct infection of cells, especially lymphocytes, and by inhibition of syncytia formation. Alleviation of the immune disorders is manifested by normalization of T4 and T8 lymphocytes counts and of the T4:T8 lymphocyte ratio.
  • the compounds which are useful in the method of the present invention are phloroglucinol and derivatives of phloroglucinol which have the core trihydroxyl phenolic structure of phloroglucinol or in which the proton in one or more of the three hydroxyl groups is replaced, preferably by a lipophilic substituent such, i.e., a non-polar uncharged group such as an alkyl, alkenyl, alkyl aryl or alkenyl aryl group having 1 to 6 in-chain carbon atoms and one or more of the protons in the non-substituted positions are replaced by other moieties, preferably lipophilic moieties such as alkyl, alkenyl, alkyl aryl, alkenyl aryl, acyl or acyl aryl groups having 1 to 18 in-chain carbon atoms.
  • a lipophilic substituent such, i.e., a non-polar uncharged group such as an alkyl,
  • R 1 , R 3 and R 5 are the same or different and are -H, -R 7 H, R 7 Ar, -C(O)R 7 H or -C(O)R 7 Ar;
  • R 2 , R 4 and R 6 are the same or different and are -H, halogen, nitro, -R 8 H, -R 8 Ar, -C(O)R 8 H or
  • Ar is -toluyl, naphthyl, phenyl or pyridyl optionally substituted by -OH, halogen, -R 7 H or
  • R 1 , R 2 , R 3 , R 4 , R 5 and R groups are together C 2-4 alkylene, thereby forming a 5-, 6- or 7- member ring fused to the core phenolic ring, and one or more of such members are optionally substituted with -R 7 H, R 7 Ar, -C(O)R 7 H or -C(O)R 7 Ar.
  • the halogens are -Br, -F, -Cl and -I of which -F is the least preferred.
  • the compounds which are employed are those of Formula I in which R 1 , R 3 and R 5 are independently selected from -H or -CH 3 ;
  • R 2 is -R 8 H
  • R 4 and R 6 are -C(O)R 8 H or -C(O)R 8 Ar; and
  • Ar is phenyl; or
  • R 1 and R 2 , or R 2 and R 3 are C2 alkylene, thereby forming a five member ring fused to the core phenolic ring and one of the two carbon atoms is covalently bound to the R 2 position of a second compound which second compound otherwise has the structure of Formula I, i.e., has the structure of Formula I
  • R 1 ', R 3 ', R 4 ', R 5 ' and R 6 ' are as defined above for R 1 , R 3 , R 4 , R 5 and R 6 , respectively.
  • alkyl alkylene
  • alkenylene alkenylene
  • alkanol alkanol
  • acyl alkyl and other like terms encompass branched as well as linear carbon chains.
  • Phloroglucinol and the phloroglucinol derivatives which can be used in the method of the invention are synthesized by known technicrues.
  • preparation of phloroglucinol from trinitrobenzene or trinitrobenzoic acid is described by Pascoe, Chem. Products 18: 454 (1955). Briefly, trinitrobenzene or trinitrobenzoic acid is reduced in the presence of tin and hydrochloric acid and the solution is neutralized and boiled for 15-20 hours. See, The Merck Index of Chemicals and Drugs, Merck & Co., Inc., Rahway, New Jersey.
  • diacylated compounds of Formula I e.g., compounds of Formula I in which R 1 , R 3 and R 5 are the same and are -H or
  • R 4 and R 6 are the same and are -C(O)R 8 H;
  • R 2 is -H or -CH 3 ;
  • R 8 is C 1-18 alkylene. Specific examples of such compounds include the compounds listed in Table I.
  • the compounds which are preferred for use in the method of the invention are the compounds of Formula I in which
  • R 1 , R 3 and R 5 are -H;
  • R 2 is -H or -CH 3 ;
  • R 8 is C 4-8 alkylene, Specifically preferred among such compounds are Compounds 90592, 90621, 90649, 90655, 90666 and 90770.
  • phloroglucinol derivatives can be isolated from extracts of plants of the genus, Medicosma, especially, M. sessiliflora. This plant can be found in northeastern Queensland, Australia from Gap Creek south to the Boonjie logging area, in rain forest to gallery forest and from sea level to about 750 m above sea level.
  • the plant and its habitat are described by Hartley, Austrl. J. Bot. 33: 27 (1985), which is incorporated herein by reference. The plant is described as follows:
  • Branchlets subpersistently puberulent to glabrous, 2-4 mm wide at the internodes, not corky; terminal bud pubescent to glabrous.
  • Follicles sparsely pubescent toward the apex or glabrous, 6-10 mm long; placental endocarp subfleshy; seed(s) brownish black, sparsely tuberculate and minutely papillate.
  • a typical extraction procedure comprises soaking dried, pulverized leaves in an organic solvent and fractionating the extract, such as on a hydrophobic and/or hydrophilic column(s) and eluting with organic solvents, such as is described in the Examples, below.
  • Exemplary of the phloroglucinol derivatives which can be isolated from M. sessiliflora hexane or methyl ethyl ketone extracts are the compounds illustrated in Table III. As indicated in the Examples, below, not all of the natural product phloroglucinol derivatives have been demonstrated to have activity in an assay for inhibition of HIV infection, although all have been shown to inhibit syncytia formation. On the basis of -these assay results, among the single ring natural product-derived compounds, . the most preferred compound is Compound 104402; among the fused ring compounds, the compounds which are preferred for use in the method of the invention are 107923 and 107921.
  • Additional phloroglucinol derivatives can be prepared from the natural derivatives of phloroglucinol by standard chemical procedures. It appears to be desirable in preparing such derivatives, to retain hydroxyl or lower alkoxy, especially methoxy, groups in the hydroxyl positions of phlorogucinol, i.e., in the -OR 1 , -OR 3 and -OR 5 positions; to replace the hydrogens in the R 4 and R 6 positions with acyl groups, e.g., -C(O)R 8 H or
  • the compounds of Formula I can form salts with inorganic and organic cations which salts are non-toxic and otherwise pharmaceutically acceptable, which salts are included within the scope of the invention.
  • exemplary of such cations are magnesium, calcium, sodium, potassium and piperazine.
  • pro-drugs of phloroglucinol or phloroglucinol derivatives i.e., phloroglucinol or derivatives of phloroglucinol bound, usually covalently, to another chemical group, which may impart enhanced stability, reduced toxicity or targeted delivery and which may or may not be active in the prodrug form, and which is cleaved off in the body of the treated animal to produce the active phloroglucinol or phloroglucinol derivative.
  • compounds of Formula I are administered internally, e.g., parenteraliy, such as by intravenous, subcutaneous or intramuscular injection or infusion, orally, rectally, buccally, transdermally or by inhalation.
  • the compounds are typically administered in a pharmaceutically acceptable carrier or diluent selected on the basis of the route of administration.
  • useful carriers include, among others, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • Liquid carriers such as for oral, intranasal or parenteral administration include, among others, glycerin, syrup, peanut oil, olive oil, saline, dextrose and water, optionally bufferred with organic or inorganic salts, for example, acetates, adipates, succinates or citrates of ammonium, potassium or sodium.
  • excipients may be added to adjust tonicity or, especially in the case of a formulation to be lyophilized, stabilizers such as, for example, gelatin, polyvinylpyrrolidine, cellulose, acacia, polyethylene glycol, pyrrolidone or mannitol .
  • stabilizers such as, for example, gelatin, polyvinylpyrrolidine, cellulose, acacia, polyethylene glycol, pyrrolidone or mannitol .
  • the compounds can be combined in powder form with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol and molded into a suppository.
  • transdermal delivery the compounds can be combined with an oily preparation, gel, cream or emulsion and administered via a transdermal patch.
  • Formula I are administered to an animal, especially a human, who has been or is suspected of having been infected with an Immunodeficiency Virus, especially HIV, in an amount effective to inhibit progression of immune dysfunction and, preferably, to stabilize or improve the immune dysfunction.
  • the amount administered will vary depending upon a variety of factors including the stage of immune dysfunction progression and the age, weight and general health of the animal being treated. In general, it is expected that the method of the invention will be carried out by administering from about 1 to 500 mg/Kg/day, although in particular cases a physician may elect to administer even higher doses .
  • the effects of the method of the invention on immune disorders associated with infection by an Immunodeficiency Virus can be monitored by evaluating T4 and T8 cell counts and the T4/T8 ratio and the dosage rate and dose can be modified accordingly.
  • the presence of virus in the bodily fluids of the animal can be monitored by evaluation of presence of virus antigens, or of antibodies to virus antigens, in sera. It is expected that the method of the invention will be carried out over a lengthy period of time, e.g., several weeks to months, or for the treatment to be repeated periodically, due to the ability of Immunodeficiency Viruses to remain latent within the infected animal.
  • Encompassed within the method of the invention is co-administration or simultaneous administration of phloroglucionol or of derivatives of phloroglucinol with other pharmaceutically active agents, e.g., other agents which are also effective in inhibiting virus replication and syncytia formation, such as other nucleoside analogs such as AZT and ddC, HIV protease inhibitors and sCD4 and truncates thereof.
  • other pharmaceutically active agents e.g., other agents which are also effective in inhibiting virus replication and syncytia formation, such as other nucleoside analogs such as AZT and ddC, HIV protease inhibitors and sCD4 and truncates thereof.
  • other pharmaceutically active agents e.g., other agents which are also effective in inhibiting virus replication and syncytia formation, such as other nucleoside analogs such as AZT and ddC, HIV protease inhibitors and sCD4
  • Example 1 Diacyl Phloroglucinol Derivatives.
  • the compounds listed in Table IV, below, were tested in a HIV Infectivity Inhibition Assay substantially as follows. 100 uL of T4+ lymphocyte (AA5 or MOLT4 cells) stocks containing about 3 X 10 cells per mL were seeded on a 24 or 96 well plate. Then, to each well was added 100 uL of an HIV stock containing about 10 Infectious Units (which units are approximately equivalent to TCID D 50 units). Virus was allowed to adsorb to the cells for about an hour at 37 C in a CO 2 incubator. Then, appropriate dilutions of a phloroglucinol derivative were added to each well. Control wells were prepared in the same manner except that no phloroglucinol derivative was added.
  • HIV in the conditioned medium was concentrated by precipitation with polyethylene glycol.
  • the relative amounts of virus in the experimental and control wells was determined by assaying for reverse transcriptase activity in viral lysates and by an ELISA for p24 antigen. Results are reported in Table IV in which IC 50 means the concentration of the phloroglucinol derivative which resulted in a reduction of 50 % of reverse transcriptase activity and of p24 concentration relative to controls. "N.A.” means that no significant inhibition of infectivity was observed at the concentrations tested. Results reported in parentheses are the results of a second experiment.
  • Giant cells i.e., cells of at least 5-fold greater diameter than normal cells, were enumerated using an inverted microscope at 40X magnification. Control wells typically ave about 60 to 70 giant cells per well. Results are reported in Table V in which IC 50 is the concentration of each phloroglucinol derivative which resulted in a 50 % reduction in the number of giant cells, or syncytia, per well.
  • N.A indicates no detectable activity.
  • AZT is 5-azidothymidine; and
  • ddC is dideoxycytosine.
  • the methyl ethyl ketone extract (20 g) was chromatographed on silica gel 60 (230-400 mesh) in a Whatman Magnum 40 stainless steel column (4.7x47cm) (Whatman Chemica Separations, Inc., Clifton, New Jersey) in two 10g batches.
  • the column was eluted sequentially first with CH 2 Cl 2 (Solvent A), then with 0.2% H 2 O/1% CH 3 OH/CH 2 Cl 2 (Solvent B) finally with 0.2% H 2 O/2% CH 3 OH/CH 2 Cl 2 (Solvent C) at a flow rate of 50 ml/min while monitoring at 254 nm.
  • a second fraction (183 mg) was eluted from the silica column with Solvent B and crystallized from ET 2 O/CH 2 Cl 2 to give 38 mg. of compound 107924.
  • the mother liquor was separated by multiple injections on a Mer Lichrosorb silica gel 60 column (7 ⁇ m, 10x250mm) (EM Science, Cherry Hill, New Jersey) eluting with 0.1% HOAc/30 EtOAc/n-hexane at 4ml/min (800 psi) while monitoring at 335 nm.
  • Compound 107922 (50 mg) eluted at 7.5 min.
  • Compound 107925 (860 mg) eluted with 70% CH 3 OH/H 2 O and crystallized from CH 2 Cl 2 .
  • the major peak eluted with 70 to 75% CH 3 OH/H 2 O and gave 2 g of crude mixture.
  • the Solvent C elution from the silica gel column gave at least three additional bioactive fractions.
  • the first 220 mg fraction which on trituration with 30% ETOAc/n-hexane gave 55 mg of insoluble material which was compound 107921.
  • the next major fraction w ⁇ a 480 mg mixture which gave 84 mg of 107923 on crystallization from ethyl ether.
  • the third major bioactive fraction eluted from the silica gel column with Solvent C consisted of 225 mg of a crude mixture. Fractionation of the crude mixture on silica Bond-Elut (60 ml) with 0.1% HOAc/30% ETOAc/n-hexane gave a mixture containing compounds 107923 and 108189. A second elution with 0.1% HOAc/70% EtOAc/n-hexane gave another mixture which was further purified on a Merck Lichrosorb silica gel 60(10x250 mm) column eluting with 0.1% HOAc/70%EtOAc/n-hexane to give compound 108190 (7 mg). Provided below are analytical data for the above compounds. 104402 : IR(CH 2 Cl 2 )film)3600-3100(OH), 3300-2400 (hydrogen bonded hydroxyl), 1615cm -1 (hydrogen-bonded carbonyl);

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le phloroglucinol et les dérivés de phloroglucinol sont utiles dans le traitement des dysfonctionnements immunitaires associés à l'infection par un virus d'immunodéficience.
PCT/US1990/007375 1989-12-22 1990-12-14 Compositions antivirales Ceased WO1991009595A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45564789A 1989-12-22 1989-12-22
US455,647 1989-12-22

Publications (1)

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WO1991009595A1 true WO1991009595A1 (fr) 1991-07-11

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AU (1) AU6976191A (fr)
IE (1) IE904690A1 (fr)
PT (1) PT96331A (fr)
WO (1) WO1991009595A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121087A1 (fr) 2004-06-08 2005-12-22 A. Carlsson Research Ab Nouvelles phenylpiperidines/piperazines disubstitues utilisees comme modulateurs de neurotransmission de la dopamine
WO2009063440A1 (fr) * 2007-11-15 2009-05-22 Caudalie Compositions de dérivés polyphénoliques stilbeniques et leurs applications pour lutter contre les pathologies et le vieillissement des organismes vivants
CN107582545A (zh) * 2017-09-21 2018-01-16 中国农业科学院哈尔滨兽医研究所 绵马酚或其衍生物在制备用于预防和/或治疗由细菌引起的相关疾病的药物中的用途
US11439603B2 (en) * 2017-05-11 2022-09-13 Korea Food Research Institute Compositions for ameliorating, preventing or treating somnipathy including phloroglucinol as active ingredient and compositions for suppressing intolerance to or alleviating side effects of agonist at benzodiazepine binding site of GABA-A receptor including phloroglucinol as active ingredient
US12167996B2 (en) 2018-12-05 2024-12-17 Byotrol Limited Anti-viral composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3377241A (en) * 1963-06-12 1968-04-09 Smith Kline French Lab Certain diacyl derivatives of phloroglucinol as anthelmintics

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3377241A (en) * 1963-06-12 1968-04-09 Smith Kline French Lab Certain diacyl derivatives of phloroglucinol as anthelmintics
US3467715A (en) * 1963-06-12 1969-09-16 Smithkline Corp 2,4-diloweralkanoyl phloroglucinol derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ORGANIC CHEMISTRY, Volume 54, (1989), page 2098-2103, (CHON et al). *
JOURNAL OF PHARM. PHARMACOLOGY, Volume 17, page 239-242, (1965). *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121087A1 (fr) 2004-06-08 2005-12-22 A. Carlsson Research Ab Nouvelles phenylpiperidines/piperazines disubstitues utilisees comme modulateurs de neurotransmission de la dopamine
WO2009063440A1 (fr) * 2007-11-15 2009-05-22 Caudalie Compositions de dérivés polyphénoliques stilbeniques et leurs applications pour lutter contre les pathologies et le vieillissement des organismes vivants
FR2923717A1 (fr) * 2007-11-15 2009-05-22 Caudalie Compositions de derives polyphenoliques stilbeniques et leurs applications pour lutter contre les pathologies et le veillissement des organismes vivants
US11439603B2 (en) * 2017-05-11 2022-09-13 Korea Food Research Institute Compositions for ameliorating, preventing or treating somnipathy including phloroglucinol as active ingredient and compositions for suppressing intolerance to or alleviating side effects of agonist at benzodiazepine binding site of GABA-A receptor including phloroglucinol as active ingredient
CN107582545A (zh) * 2017-09-21 2018-01-16 中国农业科学院哈尔滨兽医研究所 绵马酚或其衍生物在制备用于预防和/或治疗由细菌引起的相关疾病的药物中的用途
US12167996B2 (en) 2018-12-05 2024-12-17 Byotrol Limited Anti-viral composition

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AU6976191A (en) 1991-07-24
IE904690A1 (en) 1991-07-17
PT96331A (pt) 1991-10-15

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