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WO2014200213A1 - Dérivé de tétracycline, sels pharmaceutiquement acceptables de celui-ci, ou composition pharmaceutique pour prévenir ou traiter des maladies virales contenant un stéréoisomère de dérivé de tétracycline en tant que substance active - Google Patents

Dérivé de tétracycline, sels pharmaceutiquement acceptables de celui-ci, ou composition pharmaceutique pour prévenir ou traiter des maladies virales contenant un stéréoisomère de dérivé de tétracycline en tant que substance active Download PDF

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Publication number
WO2014200213A1
WO2014200213A1 PCT/KR2014/004767 KR2014004767W WO2014200213A1 WO 2014200213 A1 WO2014200213 A1 WO 2014200213A1 KR 2014004767 W KR2014004767 W KR 2014004767W WO 2014200213 A1 WO2014200213 A1 WO 2014200213A1
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WIPO (PCT)
Prior art keywords
dimethylamino
tetrahydroxy
dioxo
acetyl
tetrahydrotetracene
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/KR2014/004767
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English (en)
Korean (ko)
Inventor
권두한
송재형
장미진
간수흐행흐테왕
오세량
이형규
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Korea Research Institute of Bioscience and Biotechnology KRIBB
Original Assignee
Korea Research Institute of Bioscience and Biotechnology KRIBB
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Priority claimed from KR1020140063452A external-priority patent/KR101660815B1/ko
Application filed by Korea Research Institute of Bioscience and Biotechnology KRIBB filed Critical Korea Research Institute of Bioscience and Biotechnology KRIBB
Publication of WO2014200213A1 publication Critical patent/WO2014200213A1/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
    • A61K31/65—Tetracyclines
    • 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
    • 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
    • A61P31/12—Antivirals
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • compositions for the prevention or treatment of viral diseases containing tetracycline derivatives, pharmaceutically acceptable salts thereof or stereoisomers thereof as active ingredients
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of a viral disease containing a tetracycline derivative, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as an active ingredient.
  • ⁇ iris is a small particle (less than 0.1 ⁇ m on average) that is smaller than bacteria and cannot be filtered by a bacterial filter (0.22 ⁇ ⁇ ) .
  • It is a substance necessary for survival and contains only nucleic acid (DNA or RNA) and a small number of proteins. It is a living thing that depends on.
  • Hepatitis one of the viral diseases, is mainly known as five types of A, B, (:, D, and E. Of these five types, hepatitis B, C, and D is mainly found in the blood of virus-infected patients.
  • hepatitis A and E are orally infected through contaminated water or food
  • hepatitis A is the most frequent hepatitis among the five types of viral hepatitis. This figure is diagnosed as due to a more high 673 ⁇ 4 to 83% of hepatitis type a.
  • oral infection is the main route of infection, it is resistant to acid and can easily penetrate the body through acid in the stomach.
  • Conjunctivitis, meningitis, or foot-and-mouth virus in animals belong to this group of viruses, unlike rotavirus, which has a large number of serotypes. Only serotypes are known to exist
  • Hepatitis A Tens of millions of people with hepatitis A occur worldwide each year. Hepatitis A may be prevented by a vaccine, but vaccination does not begin until at least 4 weeks. Infection with the hepatitis A virus causes little clinical manifestation. Only 103 ⁇ 4–15% of these develop acute hepatitis and most recover within six months. However, 0.5% leads to death of liver function. Although this hepatitis A is a fatal disease, no effective treatment for hepatitis A is currently being developed.
  • herpes simplex virus HSV infects mucosal cells such as the mouth and lip genitals, causing edema and shingles. The herpes simplex virus, type 1 and 2, is spread by skin contact.
  • acyclovir and balacyclovir are active against herpes simplex virus.
  • acyclovir and balacyclovir are less effective and are discharged to the body within 3 hours, so the intervals between doses are very short, making them less useful as therapeutic agents. There is a problem that this is possible.
  • respiratory syncytial virus is a virus that causes bronchitis, especially in infants and children.
  • Cell fusion virus infections Repetitive symptoms of respiratory syncytial virus infection can be aggravated, and the number of respiratory syncytial virus infections is increasing in adulthood.
  • Respiratory syncytial virus is an influenza virus (orthomyxoviridae) and other viruses and does not carry the neuraminidase gene. On the other hand, it has an F protein that fusions host cells.
  • respiratory cell fusion viruses have not been developed to date, including antiviral agents and vaccines (Non-Patent Document 1).
  • Tetracycline meanwhile, is a genus
  • Polyketide antibiotic produced by Actinobacter ia of Streptomyces It is an oral antibiotic widely used in Gram-positive and Gram-negative bacterial infections.
  • the antimicrobial action of tetracycline binds to the 30S subunit of bacterial ribosomes and interferes with the conjugation of ionized aminoacyl-tRNAs while inhibiting the synthesis of new amino acids in the peptide chain, thereby inhibiting protein synthesis.
  • protein synthesis is not inhibited by tetracycline, so it is safe.
  • Conventional research on the antiviral activity of tetracycline has been actively conducted.
  • Patent Document 1 studies on the prevention or treatment of inflammatory diseases including pathological reactions, such as viral phenotypic disease, sepsis, rheumatoid arthritis and autoimmune diseases, acute cardiovascular diseases using tetracycline or an analog thereof.
  • pathological reactions such as viral phenotypic disease, sepsis, rheumatoid arthritis and autoimmune diseases, acute cardiovascular diseases using tetracycline or an analog thereof.
  • Patent Document 2 the invention regarding the pharmaceutical composition which has a trefoil protein as an active ingredient, and the tetracycline derivative has antiviral activity with respect to the herpes virus contained as an auxiliary antimicrobial agent was disclosed (patent document 2).
  • An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of a viral disease containing a tetracycline derivative, a pharmaceutically acceptable salt thereof or a stereoisomer thereof as an active ingredient.
  • Another object of the present invention is to provide an external preparation for the prevention or treatment of a viral disease containing a tetracycline derivative, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient.
  • Still another object of the present invention is to provide a health functional food composition for preventing or ameliorating a viral disease containing a tetracycline derivative, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease containing a tetracycline derivative represented by Formula 1 as an active ingredient:
  • R 1 (In Formula 1, R 2) R 2) R 3, R 4 ( 5, 6, 7, R 8, 9 and Rio are as defined in the specification).
  • the present invention provides a tetracycline derivative represented by the following formula (1) as an active ingredient to provide an external preparation for the prevention or treatment of viral diseases:
  • the present invention provides a health functional food composition for preventing or improving a viral disease containing a tetracycline derivative represented by Formula 1 as an active ingredient:
  • the tetracycline derivatives according to the present invention not only have excellent antimicrobial activity, but, unlike the conventionally used antimicrobial agents, hepatitis A virus, herpes simplex virus type 1, herpes simplex virus type 2, and herpes virus 3 It has excellent selective antiviral activity against virus of type and respiratory syncytial virus, which is viral such as viral hepatitis A, herpes simplex, shingles, stomatitis, chickenpox, crop, capillary bronchitis, bronchitis, pneumonia Pharmaceutical compositions for the prevention or treatment of diseases can be usefully used.
  • Figure 2 is a graph showing the antiviral ability of each of the tetracycline derivatives of Preparation Examples 1 to 5 for herpes simplex type 1
  • 5 is a graph showing the weight change when the tetracycline derivative of Preparation Example 1 and Comparative Example 7 were administered to a herpes-infected animal.
  • 6 is a graph showing the antiviral activity of each concentration of the tetracycline derivative of Preparation Example 1, the compounds of Comparative Examples 1 to 3 and the cell survival rate of the tetracycline derivative of Sezo Example 1 by concentration.
  • the present invention provides a pharmaceutical composition for preventing or treating a viral disease containing a tetracycline derivative represented by the following Chemical Formula 1, a salt thereof, or a stereoisomer thereof as an active ingredient:
  • R 2 and R 3 are each independently hydrogen; Hydroxy; alkyl of d-Cs; Amino unsubstituted or substituted with one or more d-Cs alkyl; Or can form an unsubstituted alkenyl together with the carbon atom to which they are attached;
  • R 4 is hydrogen or alkyl of C-C 6 ;
  • R 5 is hydrogen; Amino substituted with straight or branched chain alkyl of one or more d-Cs; Nitro; Cyano; Or aminocarbonyl unsubstituted or substituted with d-Ce straight or branched alkyl;
  • R 6 is hydrogen; Hydroxy; Or carbonyl with carbon to which R 6 is bonded;
  • R 7 is hydrogen; Aminocarbonyl unsubstituted or substituted with aminoalkylene substituted with one or more dC 6 alkyl; Or may form together with the carbon atom to which R 7 is attached an alkenyl substituted with one or more hydroxy or alkylamino of Ci_C 6 ;
  • R 8 is hydrogen, hydroxy, or halogen
  • R 9 and Rio are hydrogen; Hydroxy; Or can form carbonyl together with the carbon to which they are bonded; and
  • R 2 and R 3 are independently of each other hydrogen; Hydroxy; alkyl of d-Cs; Amino unsubstituted or substituted with one or more Ci-Ce alkyl; Or together with the carbon atoms to which they are attached form an unsubstituted alkenyl;
  • R 4 is hydrogen or alkyl of dC 6 ;
  • R 5 is hydrogen; Amino or nitro substituted with one or more straight or branched chain alkyls of dC 6 ;
  • R 6 is hydrogen; Hydroxy; Or carbonyl together with the carbon to which R 6 is bonded;
  • R 7 is hydrogen; Unsubstituted aminocarbonyl; Or may form together with the carbon atom to which R 7 is attached an alkenyl substituted with one or more hydroxy or alkylamino of d-Ce;
  • R 8 is hydrogen or hydroxy
  • R 9 and silver hydrogen; Hydroxy; Or together with the carbon to which they are attached form carbonyl; And
  • rr ⁇ is a single or double bond, and at least one is a single bond when ⁇ is adjacent to each other. More preferably,
  • R 2 and R 3 are each independently hydrogen; Methyl; Hydroxy; Or together with the carbon atoms to which they are attached form an unsubstituted methylene;
  • R 4 is hydrogen
  • R 5 is dimethylamine; ⁇ is hydroxy; Or carbonyl together with the carbon to which R 6 is bonded;
  • R 8 is hydroxy
  • Rg and Rio are hydroxy; :In addition! Can form carbonyl with these 0- bonded carbons; And Is a single or double bond, and when is neighboring at least one is a single bond.
  • Preferred examples of the tetracycline derivative represented by Chemical Formula 1 according to the present invention include the following compounds.
  • the tetracycline derivative of 1-102 may be prepared by purchasing from Sigma, or may be prepared by referring to the synthesis methods known from US Patents "US 8,106,225” and “US 4,849, 136". More preferable examples of the tetracycline derivative represented by Chemical Formula 1 according to the present invention include the following compounds.
  • tetracycline derivative represented by Formula 1 can be used in the form of a pharmaceutically acceptable salt.
  • salts acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and Obtained from non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically harmless salts include sulfate, pyrosulfate, Bisulfate, sulfite, bisulfite, nitrate, phosphate monohydrogen phosphate, dihydrogen phosphate metaphosphate, pyrophosphate chloride, bromide iodide, fluoride, acetate, propionate decanoate, caprylate , Acrylate, formate isobutyrate, caprate, heptanoate, propionic acid, oxalic acid malonic acid, succinic acid, suverate, sebacate, fumarate, maleate butyne-1,4_dioate, nucleic acid-1,6- Dionic acid, benzoic acid, chlorobenzoic acid methylbenzoic acid, dynitrobenzoic acid, ⁇ -hydroxybenzoate mesoxybenzoic acid, phthalic acid, terephthalate, benzenesulfonic acid, toluenesulfonic acid
  • the acid addition salt according to the present invention is a conventional method, for example, by dissolving a derivative of formula (1) in an excess of an aqueous solution of an acid, the salt is a water-soluble organic solvent, for example methanol, ethanol, acetone or aceto It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from this mixture and then drying or by suction filtration of the precipitated salts.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate.
  • the metal salt it is pharmaceutically suitable to prepare lithium, sodium, potassium or calcium salts.
  • the silver salts mentioned herein are obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • the virus that causes the viral disease according to the present invention is a virus of the genus hepavirus (hepavi rus) of picornaviridae, a herpesviridae virus or paramyxoviride (ar amyxovir idae) ⁇ 1 is a virus of the genus pneumovi rus.
  • the viral disease according to the present invention refers to a disease caused by respiratory syncytial virus, hepatitis A virus, herpes simplex virus type 1, herpes simplex virus type 2, herpes virus type 3 and the like.
  • the viral disease include hepatitis A caused by the hepatitis A virus; Diseases such as herpes simplex, shingles and stomatitis caused by herpes simplex virus type 1, herpes simplex virus type 2 or herpes virus type 3; Or diseases such as crop, capillary bronchitis, bronchitis, pneumonia caused by respiratory syncytial virus, but are not limited thereto.
  • the pharmaceutical composition according to the present invention is penicillin (penicillin), cephalosporin (cephalosporin), agu 1 noglycolide 1 (aminogl ycos i . De), benzoyl peroxide, povidone iodine (povi done iodine), azeaic acid (aze 1 ai c acid), retinoids (ret inoid), clindamycin (clindamycin) and erythromycin may be further included one or more selected from the group consisting of .
  • the tetracycline derivative according to the present invention is a hepatitis A virus, herpes simplex virus type 1, herpes simplex virus It was found to have selectively antiviral activity against type 2 and respiratory cell fusion viruses (see Table 2 of Experimental Example 1).
  • the tetracycline derivative according to the present invention compared with hygromycin B, nomobiocin and geneticin which have been used as a conventional antimicrobial agent against hepatitis A virus.
  • herpes simplex virus type 1 herpes simplex virus type 2 and respiratory syncytial virus had a good virus growth inhibition of 81.49 ⁇ 15.19%, 81.49 ⁇ 1.83% and 84.2 ⁇ 29.4% at 100 yg / ml, respectively It confirmed (refer FIG. 2, FIG. 3, Table 4 of Experimental Example 3, and FIG. 6, Table 7 of Experimental Example 6).
  • preparation examples 2, 3 and 7 according to the present invention were respectively 111.73 ⁇ 1.01% and 105.21 ⁇ 0.90% at 100 yg / ml. , 93/75 ⁇ 0.29%, it was confirmed that it has a good virus growth inhibitory ability (see Fig. 4, Table 5 of Experimental Example 4).
  • Fig. 4, Table 5 of Experimental Example 4 As a result of evaluating the antiviral activity in the herpes-infected animals, in case of Preparation Example 1 and Comparative Example 7 according to the present invention ⁇ antiviral to herpes virus The activity was shown to be excellent (see FIG. 5, Table 6 of Experimental Example 5).
  • the tetracycline derivative represented by Formula 1 according to the present invention has an excellent antiviral activity selectively against hepatitis A virus, herpes simplex virus and respiratory cell fusion virus, unlike antibacterial agents generally used. .
  • the tetracycline derivative according to the present invention not only has excellent antibacterial activity but also has excellent antiviral activity against hepatitis A virus, herpes simplex virus and respiratory cell fusion virus, viral hepatitis A, herpes simplex, subject It can be usefully used as a pharmaceutical composition for the prevention or treatment of viral diseases such as herpes, stomatitis, chicken pox, crop capillary bronchitis, bronchitis, pneumonia.
  • viral diseases such as herpes, stomatitis, chicken pox, crop capillary bronchitis, bronchitis, pneumonia.
  • tetracycline derivatives of the present invention can be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. It is manufactured by.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellose, sodium carboxymethylcellose and / or polyvinylpyridane, optionally starch, agar, alginic acid or its sodium salt. Disintegrating or boiling mixtures such as and / or absorbents, colorants, flavors, and sweeteners.
  • the pharmaceutical composition comprising the tetracycline derivative of Formula 1 as an active ingredient may be administered parenterally, and the parenteral administration may be by injection of subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the tetracycline derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a laxative to prepare a parenteral dosage form into a solution or suspension, which is administered in a 3 ⁇ 4ple or vial unit. It can be manufactured in a mold.
  • the composition may be sterile and / or contain preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of combination, granules, It may be formulated according to the formulation or coating method.
  • the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0,001-100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day.
  • the present invention is tetracycline represented by the following formula (1)
  • the viral disease according to the present invention As defined in Formula 1). At this time, the viral disease according to the present invention
  • diseases include herpes simplex virus type 1, herpes
  • Herpes Simplex Virus Type 1 Herpes Simplex Bar
  • Solvents and bases may be included in addition to tetracycline derivatives. remind
  • the solvent can use what is generally used as a solvent of the external preparation.
  • polyethylene glycol having a molecular weight of .200-600 Dipropylene glycol, benzyl alcohol, polyoxyethylene sorbitan fatty acid ester,
  • the base may be one commonly used as a base for external preparations, in particular oil-based bases. Specific examples include petrolatum, squalane, paraffin, liquid paraffin, microcrystalline wax, carnauba wax, and bleached beeswax. have.
  • the external preparation according to the present invention may further include an absorption promoter, an anti-separation agent, water, a colorant, a copulation agent, a preservative, an antioxidant, a stabilizer, and / or a feeling improver.
  • the absorption accelerator plays a role of further improving the absorbency of the active ingredient to the skin
  • the separation inhibitor serves to maintain stability by preventing separation of the compounding ingredients (particularly solvents and absorption promoters) of the external preparation according to the present invention. Carry on.
  • absorption accelerator those generally used as absorption accelerators for external preparations may be used, and specifically, isopropyl myristate, ethyl myristic acid, octylate dodecyl palmitate isopropyl, Isostearyl palmitate isopropyl isopropyl stearate, butyl stearate, ethyl oleate, diisopropyl oleic acid diisopropyl, diethyl sebacinate, diethyl adipate diethyl propyl adipate, diethyl phthalate have.
  • anti-separation agent those commonly used as anti-separation agents for external preparations may be used.
  • polyethylene glycol having a molecular weight of 1000-50000 polyoxyethylene hardened castor oil, stearic acid, oleic acid, sorbitan monostearate, Sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate and glycerin fatty acid ester.
  • glycerin fatty acid esters include glycerin monostearate, diglyceryl isostearic acid, and polyglycerinolec glycerol.
  • water may be further included because it serves to suppress the decomposition of the active ingredient.
  • the colorant may include, for example, iron trioxide, yellow trioxide, carmine, caramel, ⁇ -carotene, titanium oxide, talc, riboflavin sodium, yellow aluminum lake, and the like.
  • methyl paraben, propyl paraben, chlorobutanol, benzyl alcohol, 2-phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are mentioned,
  • sulfite, ascorbic acid, Acid, tocopherol, and the like are mentioned.
  • polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 60 lights can be mentioned.
  • the compounding quantity of the external component which concerns on this invention can be suitably set in the range which does not impair the effect of this invention, it is preferable that it is the following range (it shows the weight 3 ⁇ 4 with respect to the formulation amount):
  • the tetracycline derivative of this invention 0.001-0.5 wt%
  • Solvent 30 wt%
  • Base 40-70 wt%
  • Absorption accelerator 5-20 wt%
  • Separation inhibitor 10-25 wt%
  • Water 0.1-5 wt%.
  • the solvent, the absorption accelerator and the total amount thereof are preferably 20-40% by weight.
  • the external preparation according to the present invention may be prepared according to a general preparation method of the external preparation. That is, an ointment can be manufactured as follows. First, a mixed solution is prepared by heating and dissolving a compound represented by Chemical Formula 1 as an active ingredient, a pharmaceutically acceptable salt thereof, or an isomer thereof in a solvent at a temperature of 7 ° C ( 80 ° C).
  • the present invention provides a dietary supplement for the prevention or improvement of a viral disease containing a tetracycline derivative represented by the following Chemical Formula 1, a salt thereof, or a stereoisomer thereof as an active ingredient.
  • a viral disease containing a tetracycline derivative represented by the following Chemical Formula 1, a salt thereof, or a stereoisomer thereof as an active ingredient.
  • Rl, R 2 , 3, 4 5, 6 > 7, 8, 9 Rio are as defined in Formula 1.
  • Virus virus or paramyxoviride of the genus Hepavirus (herpavir) of the virus (picornaviridae), herpesvir idae causing the viral disease according to the present invention Is a virus of the genus pneumov ir us.
  • the hepatitis A virus of the piconaviridae include hepatitis A virus, etc.
  • the herpesvir idae virus may include the herpes simplex virus type 1, the herpes simplex virus type 2 and the herpes virus type 3, and the paramyxovir idae.
  • Pneumovi rus virus is a respiratory syncytial virus.
  • the viral disease according to the present invention refers to a disease caused by respiratory syncytial virus, hepatitis A virus, herpes simplex virus type 1, herpes simplex virus type 2, herpes virus type 3 and the like.
  • the viral disease include hepatitis A caused by the hepatitis A virus; Diseases such as herpes simplex, shingles and stomatitis caused by herpes simplex virus type 1, herpes simplex virus type 2 or herpes virus type 3; Or Crop, capillary bronchitis, bronchitis, or pneumonia, which are caused by respiratory syncytial virus, but are not limited thereto.
  • the pharmaceutical composition according to the present invention is penicillin, cephalosporin, aminoglycoside benzoyl peroxide, povidone iodine, ' azelaic acid (aze 1). ai c aci d), retinoid (r et inoi d) clindamycin (cl indamycin) and erythromycin in, may further comprise one or more auxiliary additives selected from the group.
  • the tetracycline derivative according to the present invention is a hepatitis A virus, a herpes simplex virus type 1, harpe It was found to have selectively antiviral activity against S simplex virus type 2 and respiratory cell fusion viruses (see Table 2 of Experimental Example 1).
  • the tetracycline derivative according to the present invention is compared with hygromycin B, nomobiocin and geneticin, which have been used as antibacterial agents against hepatitis A virus.
  • herpes simplex virus type 1 herpes simplex virus type 2 and respiratory cell fusion virus were found to have excellent viral growth inhibition of 81.49 ⁇ 15.19% 81.49 ⁇ 1.83% and 84.2 ⁇ 29.4% at 100 yg / ml, respectively.
  • preparation examples 2, 3 and 7 according to the present invention were respectively 111.73 ⁇ 1.
  • Example 1 and Comparative Example 7 according to the present invention were shown to have excellent antiviral activity against the herpes virus (Fig. 5 of Table 5, Table 6 Reference).
  • the tetracycline derivative represented by Formula 1 according to the present invention has an excellent antiviral activity selectively against hepatitis A virus, herpes simplex virus and respiratory cell fusion virus, unlike antibacterial agents generally used. .
  • the tetracycline derivative according to the present invention not only has excellent antimicrobial activity but also has excellent antiviral activity against hepatitis A virus, herpes simplex virus and respiratory syncytial virus, viral hepatitis A, herpes simplex, subject It can be usefully used as a health functional food composition for the prevention or improvement of viral diseases such as herpes, stomatitis, chickenpox, crop, capillary bronchitis, bronchitis, pneumonia.
  • viral diseases such as herpes, stomatitis, chickenpox, crop, capillary bronchitis, bronchitis, pneumonia.
  • the health functional food composition according to the present invention comprises the tetracycline derivative for the purpose of preventing or improving viral diseases such as viral hepatitis A herpes simplex, shingles, stomatitis, chickenpox, crop, capillary bronchitis, bronchitis, pneumonia, It can be added to dietary supplements such as beverages.
  • viral diseases such as viral hepatitis A herpes simplex, shingles, stomatitis, chickenpox, crop, capillary bronchitis, bronchitis, pneumonia, It can be added to dietary supplements such as beverages.
  • Examples of foods to which the above substances can be added include dairy products, including soups, meats, sausages, breads, biscuits, rice cakes, chocolates, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, Beverages, alcoholic beverages and vitamin complexes, dairy products, dairy products, and the like, and all of the health functional foods in the ordinary sense.
  • the tetracycline derivative of the present invention may be added to a food as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention or improvement).
  • the amount of the compound in the health food can be added at 0.1 to 90 parts by weight of the total food weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks.
  • natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides such as conventional sugars such as dextrin, cyclodextrin and the like, and Xili, Sorbi, Erie, etc.].
  • natural flavoring agents for example, tautin stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.
  • the proportion of said natural carbohydrates is generally about 1 g to 20 g, preferably 5 g to 12 g per 100 g of the composition of the present invention.
  • Tetracycline of the present invention in addition to the various nutrients, vitamins, minerals (electrolytes), synthetic flavors, such as flavoring agents, coloring and neutralizing agents (cheese, chocolate, etc.) and salts thereof, alginic acid and salts thereof, organic acids, protective properties It may contain a colloid pH adjuster, stabilizer, preservative, glycerin alcohol, carbonation agent used in carbonated drinks.
  • the tetracycline derivative of the present invention may contain for the preparation of fruit juice and fruit juice beverage beverage.
  • tetracycline derivatives of the invention can be used independently or in combination.
  • the proportion of such additives is not so critical, but it is common for the tetracycline derivatives of the invention to be selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight.
  • Dioxo-1,4,4a, 5,5a, 6, 11, 12a-octahydrotetracene-2-carboxamide was purchased from Sigma and prepared.
  • Tetracycline derivatives according to the invention (4S, 4aS, 5aS, 12aS) -4, gbis (dimethylamino) -3,10,12,12a-tetrahydroxy-1,11-dioxos 1,2 3, 4, 4a, 5, 5a, 6, 11, 12a ⁇ decahydrotetracene-2-carboxamide was purchased from Sigma and prepared.
  • Preparation Example 6 Preparation of Tetracycline Derivatives 6
  • Tetrahydroxy-2- (hydroxy (pyridin-1-ylmethylamino) methylene) -6-methyl-4a, 5, 5a, 6 ⁇ tetrahydrotetracene-1, 3, 12 (2H, 4H, 12aH) -trion was purchased from Sigma and prepared.
  • Compound 8 ′ 102 according to the present invention may be prepared from Sigma, or prepared by reference to the synthesis methods known from US Pat. Nos. US 8,106,225 and US 4,849,136.
  • Hygromycin B hygromycin B which is well known as an antimicrobial agent, was purchased from Sigma and prepared.
  • Novobiocin previously known as an antimicrobial agent, was purchased from Sigma and prepared.
  • Erythromycin previously known as an antimicrobial agent, was purchased from Sigma and prepared.
  • Ampicillin previously known as an antimicrobial agent, was purchased from Sigma and prepared.
  • Streptomycin previously known as an antimicrobial agent, was purchased from Sigma and prepared. Comparative Example 7 Preparation of Control Virus 1
  • Aciclovir previously known as a herpes virus infection, was purchased from Sigma and prepared.
  • Famciclovir formerly known as a herpes virus infection, is used by Sigma Purchased and prepared.
  • Pennciclovir which is well known as a herpes virus infection, was purchased from Sigma. Table 1 below shows the chemical structural formulas of the compounds prepared in Preparation Examples 1-7.
  • rhinoviruses type 2 and 3 enterovirus malformations, swine epidemic diarrheal virus, hepatitis A virus, influenza virus (Inf A (A / PR) )
  • Herpes simplex type 1 virus HSV-1
  • herpes simplex type 2 virus HSV-2
  • varicella zoster virus VZV
  • respiratory syncytial virus RSV A2
  • HeLa, Vero, Frh4k, MDCK and Hep2 cells were cultured in each 96-well plate, and HeLa cells contained rhinoviruses type 2 and 3 (RhinoV-2 and -3); Vero cells include enterovirus malformations, swine pandemic diarrheal virus and herpes simplex virus type 1; Frhk4 cells include hepatitis A virus; MDCK cells include influenza virus; Hep2 cells were infected with a respiratory syncytial virus at a dose of 100TCID50, and then the individual compounds of Comparative Example 1 and Comparative Example 3, which are used as antibacterial agents against microorganisms such as tetracycline derivatives of Preparation Example 1, conventional bacteria, and bear yeast Three wells of each virus were administered to a final concentration of 0.1-100 yg / ml.
  • each well was designated as a virus-free group (A), each drug treatment group (B), virus treatment group (C), virus and drug treatment group (D), the cell survival of each drug treatment group (%) It was derived using Equation 1.
  • the virus growth inhibitory ability ( ⁇ of each drug administration group was calculated by the following Equation 2. The experiment was repeated three times under the same conditions to obtain an average value and a standard deviation, and the formula at 100 ⁇ g / ml concentration of tetracycline Based on the formula of 2 to calculate the antiviral capacity value for each virus, the results are shown in Table 2 below.
  • conductor is type A herpes sl ⁇ ⁇
  • the antiviral activity against ns-1 type 1 and respiratory syncytial virus is superior. More specifically, the prepared tetracycline derivative is 55.77% for hepatitis A virus, 84.23% for herpes simplex virus type 1 and respiratory cells. It was found to have a virus inhibition of 70.74% for the fusion virus. On the other hand, in the case of the compound of Comparative Example 3, the overall antiviral effect was remarkable, and in the case of the compound of Comparative Example 7, which was conventionally used as a therapeutic agent for respiratory syncytial virus, 94.91% of the virus inhibition rate was observed only for the precellular fusion virus. The virus inhibition rate for the remaining viruses was found to be significantly lower.
  • the tetracycline derivative according to the present invention has an excellent antiviral effect selectively against hepatitis A virus, herpes simplex type 1 and respiratory syncytial virus.
  • hepatitis A virus was purchased from the American Cell Line Bank (ATCC) for this experiment. Stored at -70 ° C and used.
  • Hep-2 and Frhk 4 cells used to measure the activity of hepatitis A virus were purchased from the American Cell Line Bank (ATCC), respectively.
  • the tetracycline derivative according to the present invention has excellent antiviral activity against hepatitis A virus. More specifically, when the hygromycin B, Novobiocin and Geneticin of Comparative Examples 1 to 3, which have conventionally been used for the same antimicrobial use as tetracycline derivatives, are treated, their IC 50 values range from 0.1 to 100 ⁇ . In addition, the antiviral activity of the antimicrobial agents was 4.18 ⁇ 1.55% and 31.5 ⁇ , respectively, in the range of 0.1 to 100 Ug / ml. It can be seen that it has a significantly lower maximum virus proliferation efficiency of 1.33% and 9.32 ⁇ 2.05%.
  • the tetracycline derivative according to the present invention can be seen that the 50% proliferation inhibitory concentration (IC 50 ) for hepatitis A virus shows excellent antiviral activity as 88.2 ⁇ 1.51 ⁇ g / ml.
  • the tetracycline derivative according to the present invention has an antiviral activity of at least 2.6-fold and at most 34-fold, which is 55.8 ⁇ 0.91% at a concentration of 100 ⁇ g / ml against hepatitis A virus. It can be seen that.
  • the tetracycline derivatives according to the present invention were found to be cytotoxic at concentrations higher than the antiviral effective amount.
  • the tetracycline derivative according to the present invention has excellent antiviral activity against hepatitis A virus, unlike antimicrobial agents commonly used in the past. have. Accordingly, the tetracycline derivatives, pharmaceutically acceptable salts thereof and stereoisomers thereof according to the present invention have excellent antiviral activity against hepatitis A virus and are safe for the human body, thus preventing or treating viral hepatitis A. It can be usefully used.
  • herpes simplex virus 1 herpes simplex virus type 2
  • Vero cells used to measure activity of type 1 and herpes simplex virus type 2 were also purchased from the American Cell Line Bank (ATCC).
  • ATCC American Cell Line Bank
  • the present inventors cultured Vero cells in 96-well plates, and then the solution containing either herpes simplex virus type 1 or herpes simplex virus type 2 To the tetracycline derivatives prepared in Preparation Examples 1 to 7 after infection with a dose of TCID50, respectively, Comparative Examples 1, 2 and 4 and 4
  • the tetracycline derivative according to the present invention is herpes simplex virus 1 It can be seen that the antiviral activity against herpes simplex virus type 2 is excellent. More specifically, when the concentration of the tetracycline derivative according to the present invention is 100 yg / ml was confirmed to have a virus growth inhibition of at least about 50% for each of the herpes simplex virus type 1 and herpes simplex virus type 2. In particular, the tetracycline derivatives prepared in Preparation Examples 1 and 2 were found to have an excellent virus growth inhibitory ability of at least 70% of herpes simplex virus type 1 and at least about 503 ⁇ 4 of herpes simplex virus type 2.
  • virus growth inhibitory ability against herpes simplex virus type 1 and herpes simplex virus type 2 It can be seen that the inhibitory ability of virus growth is significantly reduced to less than 503 ⁇ 4 at 0.1 to 100 ug / ml. From this, it can be seen that the tetracycline derivative according to the present invention has excellent antiviral activity against herpes simplex virus, unlike antimicrobial agents generally used in the prior art.
  • the tetracycline derivatives, pharmaceutically acceptable salts thereof and stereoisomers thereof according to the present invention have excellent antiviral activity against the herpes virus, and therefore, for the prevention or treatment of herpes virus-related diseases such as herpes simplex, shingles, stomatitis, etc. It can be usefully used as a composition.
  • the antiviral activity against the varicella zoster virus also called herpes virus type 3 of the tetracycline derivative according to the present invention
  • the following experiment was performed.
  • Vero cells Cultured in 96-well plates and infected with varicella zoster virus at a dose of 100TCID50 the tetracycline derivatives of Preparation Examples 2, 3 and 7 and conventionally used as an antimicrobial agent against microorganisms such as bacteria, gourds and yeasts.
  • the compounds of Comparative Examples 7-9 were administered to six wells each with a final concentration of 0.1-100 / ml.
  • Six days after administration the cytopathic effect of each well due to Varicella zoster virus infection was measured and measured as follows.
  • Each well was designated as a virus-free group (A), each drug treatment group (B), virus treatment group (C), virus and drug treatment group (D), the cell survival rate (%) of each drug administration group It was derived using Equation 1.
  • the virus growth inhibition capacity (3 ⁇ 4) of each drug administration group was calculated by the above equation (2). The experiment was repeated three times under the same conditions to obtain an average value. And standard deviation were obtained, and the antiviral ability value for the herpesvirus was calculated based on the formula of Equation 2 at a concentration of 100 ⁇ g / ml of tetracycline.
  • the tetracycline derivative of the present invention has excellent antiviral activity against varicella zoster virus. More specifically, the concentration of the tetracycline derivative according to the invention was confirmed to have a virus inhibition of at least about 90% against the varicella zoster virus having a concentration of 100 ⁇ g / ml. Particularly, the tetracycline derivatives prepared in Preparation Examples 2 and 3 were found to have a virus growth inhibitory ability of about 100% or more with respect to varicella zoster virus. The same antimicrobial agent used as the tetracycline derivative was used as the conventional antibacterial agent.
  • the herpes simplex type 1 virus was infected with the dose of 10000TCID50 on the sole of the hind limb of BALB ⁇ Bagg's Albino) / C mouse, a kind of three-week-old Albino mouse.
  • Compound lOOy g of Example 1 and Comparative Example 7 were orally administered daily, and the body weight and hind limb movement of the mice were measured and compared.
  • ⁇ ⁇ ⁇ f group is not infected with the virus, infected group is infected with herpes type 1 virus, Preparation Example 1 is infected with herpes type 1 virus and administered Preparation Example 1 ,
  • mice corresponding to the administration group 1 and Comparative Example 7 were found to have some hind limbs. Therefore, tetracycline derivatives, pharmaceutically acceptable salts thereof and stereoisomers thereof according to the present invention have excellent antiviral activity against herpes virus, and thus, related to herpes virus such as herpes simplex, shingles, stomatitis, chickenpox, etc. It can be usefully used as a pharmaceutical composition for the treatment of diseases.
  • the respiratory cell fusion virus was purchased from the American Cell Line Bank (ATCC) for the present experiment, and the culture activity was measured and stored at 70 ° C.
  • respiratory cell fusion Hep-2, Frhk 4 and Vero cells used to measure virus activity were also purchased from the American Cell Line Bank (ATCC), respectively.
  • the tetracycline derivative according to the present invention has excellent antiviral activity against respiratory syncytial virus. More specifically, the tetracycline derivative of Preparation Example 1 according to the present invention was found to exhibit a virus growth inhibition of 84.2 ⁇ 29, 4% at 100 pg / ml, IC 50 value of 64.6 ⁇ 3.01 antiviral in a small amount It can be seen that the activity is valid. In addition, it can be seen that the cytotoxicity is very low through no change in the number of Hep-2 cells.
  • tetracycline derivatives, pharmaceutically acceptable salts thereof and stereoisomers thereof according to the present invention have excellent antiviral activity against herpes simplex virus, thereby preventing diseases related to respiratory syncytial virus such as crop, capillary bronchitis, bronchitis and pneumonia.
  • it may be usefully used as a therapeutic pharmaceutical composition.
  • the derivative according to the present invention may be formulated in various forms according to the purpose. Formulation Examples for the Compositions of the Invention
  • ⁇ formulation was prepared by mixing the above ingredients and filling into an airtight cloth.
  • the compound of Formula 1 according to the present invention 100 mg corn starch 100 mg lactose 100 mg stearic acid magnesium 2 mg After the above components were mixed, tablets were prepared by tableting according to a conventional method for preparing tablets.
  • Compound of Formula 1 according to the present invention 100 mg corn starch 100 mg lactose 100 mg magnesium stearate 2 mg After the above components were mixed, the capsules were prepared by filling in gelatin capsules according to the conventional method for preparing capsules.
  • 1.5 g glycerin 1 g xylyl per compound 1 of Formula 1 according to the present invention was prepared so that 0.5 g of the above components were mixed and 4 g per ring according to a conventional method.
  • composition (b) an oil phase raw material (composition (b)) was accurately weighed and dissolved in an oil phase auxiliary tank by heating to 75 ° C.
  • the raw material (composition ( c )) of the water phase was weighed and poured into an emulsification tank, heated and dissolved at 75 ° C., and then the composition (a) was added thereto.
  • ⁇ ⁇ gun is stirred at a temperature of about 25 ° C while stirring at 3500 rpm and Pedal Mixer 100 rpm to finish and mature the external ointment. It was.
  • the compounds of the present invention can be prepared in various forms according to the purpose. Examples of health functional preparations for the compositions of the present invention are illustrated below.
  • Preparation Example 2 Preparation of Dairy Products
  • Brown rice, barley, rice, and jujube were alphanized by a known method, and then dried and roasted to prepare a powder having a particle size of 60 mesh.
  • Black beans, black sesame seeds, and perilla were also steamed and dried in a known manner, and then roasted to prepare a powder having a particle size of 60 mesh.
  • the health functional food composition of the present invention was concentrated under reduced pressure in a vacuum concentrator to obtain a dry powder.
  • the grains, seeds, and dry powders of the compound of Formula 1 according to the present invention were prepared by blending the following ratios. Cereals (34 parts by weight brown rice, 19 parts by weight barley 20 parts by weight), seeds (7 parts by weight perilla, 8 parts by weight black soybeans 7 parts by weight) tetracycline derivative (2 parts by weight),
  • Compound of the chemical process 1 according to the present invention 100 mg vitamin complex amount vitamin A acetate 70 y vitamin E 1.0 mg vitamin B1 0.13 mg vitamin B2 0.15 mg vitamin B6. 0.5 mg Vitamin B12 0.2 U g Vitamin C 10 mg Biotin 10 ug Nicotinamide.
  • composition ratio of the vitamin and mineral mixtures described above is a suitable composition suitable for a relatively healthy functional food, but the composition ratio may be arbitrarily modified, and the composition may be arbitrarily modified. After mixing, the granules may be prepared and used for preparing a health functional food composition according to a conventional method.
  • citric acid 100 mg sugar sugar 100 mg plum concentrate 2 mg taurine 100 mg Uniform name 1
  • composition ratio is a relatively suitable composition for a preferred beverage in a preferred embodiment
  • compounding ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, usage.
  • tetracycline derivatives not only have excellent antimicrobial activity, but, unlike the conventionally used antimicrobial agents, hepatitis A virus, herpes simplex virus type 1, herpes simplex virus type 2, and herpes virus Selective antiviral activity against type 3 and respiratory syncytial viruses, so viral diseases such as viral hepatitis A, herpes simplex, shingles, stomatitis, cropping, capillary bronchitis, bronchitis, pneumonia caused by these viruses
  • viral diseases such as viral hepatitis A, herpes simplex, shingles, stomatitis, cropping, capillary bronchitis, bronchitis, pneumonia caused by these viruses
  • Pharmaceutical compositions for the prophylaxis or treatment of can be useful.

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Abstract

La présente invention concerne un dérivé de tétracycline, des sels pharmaceutiquement acceptables de celui-ci, ou une composition pharmaceutique pour prévenir ou traiter des maladies virales contenant, en tant que substance active, un stéréoisomère du dérivé de tétracycline. Le dérivé de tétracycline selon la présente invention il présente une excellente activité antibactérienne, et contrairement aux agents antibactériens existants et couramment utilisés, a une activité antibactérienne supérieure spécifique contre le virus de l'hépatite A, l'herpès simplex de type 1, l'herpès simplex de type 2, le virus varicelle-zona, et le virus syncitial respiratoire, et peut donc être utile dans la composition pharmaceutique pour prévenir ou traiter des maladies virales causées par les virus ci-dessus, telles que l'hépatite A, l'herpès simplex, la stomatite, la varicelle, le croup, la bronchiolite, la bronchite et la pneumonie.
PCT/KR2014/004767 2013-06-13 2014-05-28 Dérivé de tétracycline, sels pharmaceutiquement acceptables de celui-ci, ou composition pharmaceutique pour prévenir ou traiter des maladies virales contenant un stéréoisomère de dérivé de tétracycline en tant que substance active Ceased WO2014200213A1 (fr)

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KR20130067800 2013-06-13
KR10-2013-0067800 2013-06-13
KR1020140063452A KR101660815B1 (ko) 2013-06-13 2014-05-27 테트라싸이클린 유도체, 이의 약학적으로 허용가능한 염 또는 이의 입체이성질체를 유효성분으로 함유하는 바이러스성 질환의 예방 또는 치료용 약학적 조성물
KR10-2014-0063452 2014-05-27

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5834450A (en) * 1994-02-17 1998-11-10 Pfizer Inc. 9- (substituted amino) -alpha-6-deoxy-5-oxy tetracycline derivatives, their preparation and their use as antibiotics
US6384081B2 (en) * 1998-10-09 2002-05-07 Charles L. Berman Treatment of diseases of the eye characterized by the formation of metalloproteinase
WO2002072532A1 (fr) * 2001-03-13 2002-09-19 Paratek Pharmaceuticals, Inc. Composes de tetracycline substitues en position 7,9
US20090325909A1 (en) * 2003-09-26 2009-12-31 The Johns Hopkins University Suppression of HIV replication and prevention and treatment of HIV
EP2327409A1 (fr) * 2001-07-13 2011-06-01 Paratek Pharmaceuticals, Inc. Tetracycline avec activité pharmacéutique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5834450A (en) * 1994-02-17 1998-11-10 Pfizer Inc. 9- (substituted amino) -alpha-6-deoxy-5-oxy tetracycline derivatives, their preparation and their use as antibiotics
US6384081B2 (en) * 1998-10-09 2002-05-07 Charles L. Berman Treatment of diseases of the eye characterized by the formation of metalloproteinase
WO2002072532A1 (fr) * 2001-03-13 2002-09-19 Paratek Pharmaceuticals, Inc. Composes de tetracycline substitues en position 7,9
EP2327409A1 (fr) * 2001-07-13 2011-06-01 Paratek Pharmaceuticals, Inc. Tetracycline avec activité pharmacéutique
US20090325909A1 (en) * 2003-09-26 2009-12-31 The Johns Hopkins University Suppression of HIV replication and prevention and treatment of HIV

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