WO1999043689A1 - Nouveaux derives de kdn et medicaments les contenant sous forme de principes actifs - Google Patents

Nouveaux derives de kdn et medicaments les contenant sous forme de principes actifs Download PDF

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Publication number
WO1999043689A1
WO1999043689A1 PCT/JP1999/000926 JP9900926W WO9943689A1 WO 1999043689 A1 WO1999043689 A1 WO 1999043689A1 JP 9900926 W JP9900926 W JP 9900926W WO 9943689 A1 WO9943689 A1 WO 9943689A1
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Prior art keywords
group
compound
kdn
reaction
derivative
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PCT/JP1999/000926
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English (en)
Japanese (ja)
Inventor
Kimio Furuhata
Haruki Yamada
Takayuki Nagai
Katsumi Ajisaka
Original Assignee
Meiji Milk Products Co., Ltd.
The Kitasato Institute
Priority date (The priority date 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 date listed.)
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Application filed by Meiji Milk Products Co., Ltd., The Kitasato Institute filed Critical Meiji Milk Products Co., Ltd.
Priority to AU26415/99A priority Critical patent/AU2641599A/en
Publication of WO1999043689A1 publication Critical patent/WO1999043689A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/02—Acyclic radicals
    • C07H7/027—Keto-aldonic acids

Definitions

  • the present invention relates to a novel KDN derivative or a salt thereof useful for prevention and treatment of viral diseases such as influenza, and a medicament containing the same.
  • Influenza is a respiratory infection that spreads every year from winter to spring. When infected with the influenza virus, symptoms typically begin to appear after one to two days, such as runny nose, chills, fever, pain, malaise, and loss of appetite. These symptoms generally resolve in about a week, but in high-risk groups, such as the elderly and patients with underlying medical conditions, infants, and pregnant women, death often occurs with complications such as pneumonia and bronchitis. The danger of reaching is high.
  • Vaccination a preventive measure against influenza infection, cannot be expected to be effective against new types of viruses.
  • the anti-influenza drugs Aman Yujin and Liman Yujin give long-term side effects to the nervous system such as insomnia, dizziness and lack of concentration.
  • the types have drawbacks such as being ineffective and the emergence of drug-resistant viruses.
  • GG-167 sialidase
  • GS4 1 with a structure similar to GG-167 0 4 (US Pat. Nos. 5,763,483) have been developed and are undergoing extensive clinical trials.
  • Sialidase is a spike-like glycoprotein that protrudes from the surface of virus particles.
  • GG-167 and GS410 specific inhibitors of sialidase, are expected to be effective as therapeutic and prophylactic agents against all types of influenza.
  • the present inventors have conducted intensive studies to develop a novel antiviral agent.
  • a novel sialic acid derivative 2-keto-3-dexoxy-D-glycerose-D-galacto-mononurosonic acid (KDN)
  • KDN 2-keto-3-dexoxy-D-glycerose-D-galacto-mononurosonic acid
  • the present invention relates to the general formula (1)
  • R 1 is a lower alkyl group, indicates a lower alkenyl group or a lower Ararukiru group
  • R 2 and R 3 shows the same or different and have good hydrogen atom or a group -S_ ⁇ 3 H (Here, R 2 and R 3 are not both hydrogen atoms)
  • the present invention also provides a medicament comprising a KDN derivative represented by the above general formula (1) or a salt thereof as an active ingredient.
  • the present invention relates to a KDN derivative represented by the above general formula or a salt thereof and a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a KDN derivative represented by the above general formula or a salt thereof as a medicament.
  • the present invention provides a method for treating a virus of a disease characterized by administering an effective amount of a KDN derivative represented by the above general formula or a salt thereof.
  • FIG. 1 shows the anti-influenza virus activity (in vitro) for compound 2 and compound 3.
  • FIG. 2 shows the toxicity of Compound 2 and Compound 3 on MDCK cells.
  • FIG. 3 shows the therapeutic effect of compound 2 on influenza infection in mice.
  • the KDN derivative of the present invention is represented by the general formula (1).
  • the lower alkyl group represented by 1, is found include alkyl groups having 1 to 8 carbon atoms, specifically a methyl group, Echiru group, n - propyl group, an isopropyl group, n - Bed butyl group, sec- butyl Group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, etc., of which methyl group, ethyl group, n-propyl group, n —Butyl groups are preferred.
  • Examples of the lower alkenyl group represented by R 1 include an alkenyl group having 2 to 4 carbon atoms, specifically, a vinyl group, an aryl group, an isopropyl group, a 2-butenyl group, and a 1,3-butane group.
  • a phenyl group, a 2-pentenyl group and the like are preferred, and an aryl group is particularly preferred.
  • the aralkyl group represented by R 1 includes an aralkyl group having an alkyl moiety having 1 to 3 carbon atoms, and specifically, a phenylalkyl group such as a benzyl group, a phenyl group, and a 2-phenylpropyl group. Benzyl groups are particularly preferred. Good.
  • Examples of the salt of the KDN derivative (1) of the present invention include a base addition salt formed with respect to a free sulfonic acid group and a carboxyl group, for example, a salt with an alkali metal such as sodium, potassium and lithium. The ability to do so, sodium salt is particularly preferred.
  • the KDN derivative represented by the general formula (1) of the present invention can be synthesized by, for example, the following route using 3-dexoxy D-glycose mono-galacto-2-nonuloviranosonic acid as a starting material.
  • X represents a halogen atom (a chlorine atom, a bromine atom, etc.)
  • Y represents a lower alkyl group (a methyl group, an ethyl group, etc.)
  • Z represents an acetyl group (an acetyl group, a benzoyl group, etc.).
  • M represents a hydrogen atom or an alkali metal atom (sodium, potassium, etc.), and R 1 represents the same group as described above.
  • compound (G) was synthesized in 6 steps from 3-Doxy-D-glycerol / S—D-galacto-2-nonuloviranosanoic acid (A) by reaction 1 and
  • Step 1 is to convert 2-, 3-pi-2,3-dioxin-D-glycerone; 5-D-galact-1-2-nonuloviranosanoic acid (A) into a carboxylic acid ester, and then to the 4, 5, and 7-positions.
  • This is the step of acylating the hydroxyl group of the compound to form a 0-acyl derivative, and further introducing a halogen atom at the 2-position.
  • Esterification of the carboxylic acid is carried out by a known method usually known as an esterification reaction.
  • a dehydrating agent such as dicyclohexyl carboxylic acid (DCC), P-toluenesulfonic acid, and sulfuric acid.
  • DCC dicyclohexyl carboxylic acid
  • P-toluenesulfonic acid P-toluenesulfonic acid
  • sulfuric acid sulfuric acid.
  • carboxylic acid is converted into a reactive derivative (eg, acid halide, acid anhydride, mixed acid anhydride, active ester, etc.), it is reacted with an alcohol, or the carboxylic acid is converted into an alkali metal salt (eg, sodium, potassium, etc.). , Cesium salts, etc.) and then reacting with an alkyl halide.
  • an alkali metal salt eg, sodium, potassium, etc.
  • the acylation reaction can be carried out by any reaction usually used for acylation of a hydroxyl group.
  • acylating reagent for example, acyl chloride or acid anhydride is used, and the presence of a base such as N, N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, pyridine, sodium carbonate, carbonated lime, etc.
  • the reaction can be carried out at ⁇ 70 to 100 ° C. under or in the absence of.
  • the introduction of a halogen atom is carried out when introducing a chlorine atom, for example, by saturating hydrogen chloride in an appropriate solvent or by adding hydrochloric acid in the presence of zinc chloride, and when introducing a bromine atom, introducing hydrogen bromide. It can be carried out by using an acid or a mixture thereof with sulfuric acid.
  • Step - 2 2-position group of the compound (B) - introducing OR 1, a reaction for producing ⁇ Gurikoshido body (C).
  • the compound (B) was dissolved in an alcohol corresponding to R 1, sodium acetate, Natoriumu benzoic acid, the presence of a heavy metal salt catalyst such as silver triflate or silver oxide, stirred at room temperature ⁇ 5 0 ° C Can be performed.
  • a heavy metal salt catalyst such as silver triflate or silver oxide
  • Step-3 is a reaction for deacylation of compound (C) using an appropriate base to produce compound (D).
  • the base used here is not particularly limited as long as it does not affect other functional groups, but is preferably an alkali metal methoxide such as sodium methoxide and potassium methoxide.
  • the solvent used include lower alcohols such as methanol and ethanol, and methanol is preferred.
  • the reaction temperature is usually from 10 to 50 ° C, and the reaction time is usually from 15 minutes to 10 hours, preferably from 1 to 2 hours.
  • Step 14 is a reaction for producing a compound (E) by introducing an isopropylidene group into the compound (D).
  • acetone 2-methoxypropene
  • 2,2-dimethoxypropane 2,2-dimethoxypropane
  • an acid such as P-toluenesulfonic acid is used as a catalyst.
  • solvent used examples include non-protonic solvents such as acetone and N, N-dimethylformamide, and acetone is particularly preferred.
  • the reaction temperature is usually from 10 to 5 (TC, preferably from 10 to 30 ° C.
  • the reaction time is usually from 15 minutes to 10 hours, preferably from 1 to 5 hours. is there.
  • Step-15 is a reaction for producing a compound (F) by acylating a hydroxyl group in the compound (E). This reaction can be carried out by a method similar to the acylation method shown in Step 11.
  • Step 16 is a reaction for removing the isopropylidene group of the compound (F) to produce the compound (G).
  • An acid is used in this reaction, and the acid is not particularly limited as long as it is used in a usual reaction, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid are used.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, and phosphoric acid are used.
  • examples thereof include acids or organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and acetic acid and trifluoroacetic acid are preferred.
  • the reaction temperature is usually 0 to 80 ° C, preferably 50 to 60 ° C.
  • the reaction time is generally 15 minutes to 10 hours, preferably 1 to 5 hours.
  • the compound R 3 in R 2 is Kiichi S_ ⁇ 3 H is hydrogen atom can be prepared by the method shown in Reaction one 3.
  • the 9-position hydroxyl group of the compound (G) is protected by benzylation or the like to give a compound (J), and then the 8-position hydroxyl group is sulfated to give a compound (K).
  • the compound (L) of the present invention can be synthesized by elimination of the protecting group, deacylation at the 4-, 5-, and 7-positions and hydrolysis of the carboxylic acid ester.
  • the compound wherein R 2 is a hydrogen atom and R 3 is a group —S 0 3 H can be produced by the method shown in Reaction 14.
  • the hydroxyl group at the 9-position of the compound (G) is silylated to give a compound (M), and then the hydroxyl group at the 8-position is protected by, for example, benzylation to give a compound (N).
  • the 9-position silyl group is eliminated to give compound (0), and the 9-position hydroxyl group is sulfated to form a compound (P).
  • the 8-position hydroxyl protecting group is eliminated, and the 4- and 5-positions are removed.
  • the compound (Q) of the present invention can be synthesized by performing deacylation at the 7-position and hydrolysis of the carboxylic acid ester.
  • any known protecting group can be used.
  • an acryl group such as an acetyl group or a benzoyl group
  • an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group
  • a benzyl group a group having a benzyl group.
  • Hydroxy group silylation includes tert-butyldimethylsilyl group, tert-lo
  • a butyldiphenylurinyl group or the like can be mentioned.
  • tert-butyldimethylsilyl halide is added in the presence of a base such as imidazole, triethylamine, and 4- (N, N-dimethylamino) pyridine. It can be carried out by reacting.
  • the removal of the protecting group for the hydroxyl group and the decomposition of the carboxylic acid ester can be carried out by known base hydrolysis.
  • the reaction can be performed by reacting with an aqueous alkaline solution such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous sodium carbonate solution at room temperature to 5 (TC).
  • an aqueous alkaline solution such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, or an aqueous sodium carbonate solution at room temperature to 5 (TC).
  • Sulfur esterification can be carried out by ordinary methods, and it is a mild sulfonation reagent known as sulfur trioxide / pyridine complex, sulfur trioxide / trimethylamine complex, sulfur trioxide / dimethylforma It is preferable to use a mid complex or the like.
  • the reaction solvent include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and cyclobenzene; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; acetonitrile; Aprotic polar solvents such as N, N-dimethylformamide can be used.
  • the reaction temperature is usually from 0 to 60 ° C, preferably from 10 to 30 ° C.
  • the reaction time is generally 1 to 60 hours, preferably 24 to 48 hours.
  • the KDN derivative represented by the general formula (1) of the present invention is a sialic acid derivative, it does not have a sialidase inhibitory action such as GG-167 and GS410 as described above.
  • GG-167 and GS410 sialidase inhibitory action
  • the KDN derivative of the present invention is not limited to use as an anti-influenza drug. That is, a person skilled in the art would conceive of using the KDN derivative for drug screening for the treatment or prevention of viral diseases other than influenza, as well as for various other diseases, and an assay for implementing the method.
  • the system can be easily set based on known techniques. Therefore, the present invention provides such a switch.
  • the invention also encompasses a pharmaceutical use invention relating to a KDN derivative obtained by cleaning.
  • the KDN derivative of the present invention can be administered orally or parenterally (for example, intranasal administration) to animals and humans as it is or together with a conventional pharmaceutical carrier.
  • the KDN derivative of the present invention may be used in various dosage forms, for example, orally administered drugs such as powders, granules, tablets, dragees, capsules, ampoules, etc., and pharmaceutical preparations such as subcutaneous, intramuscular or intravenous injections, suppositories, etc. It can be.
  • KDN derivatives alone or their derivatives and excipients
  • fillers binders
  • wetting agents disintegrants
  • surfactants lubricants
  • dispersants buffers
  • preservatives flavoring agents
  • the medicament of the present invention thus obtained varies depending on the age, weight, symptoms, and administration route of the patient, but is generally 0.6 to 30 Omg / day, preferably It is 5 to 20 Omg / day, and it is usually preferable to administer it in 3 to 4 times a day.
  • Methyl (benzyl 4,5,7-tri-0-acetyl-3-dexoxy D-glycerol H-D-galacto 2-nonuloviranoside) netrate (100 mg.
  • Powder Molecular 'Sieves 4A 200mg
  • zirconium trioxide / trimethyl complex 32mg, 0.33ml
  • Methyl (benzyl 4,5,7-tree-acetyl-3-deoxy-D-glycethone-1-galatato-2-nonuloviranoside) net obtained in Reference Example 6 (220 mg, 0.44 mmoi) was passed through an argon stream.
  • Medium DMF (2mL) was added and dissolved, cooled to 0 ° C, imidazole (120mg, 1.77moi), tert-butyldimethylsilyl chloride
  • Compound 2 (Example 2) and Compound 3 (Example 3) were dissolved in dimethyl sulfoxide (DMSO), and diluted with water so that the final concentration of DMSO was 1% ( ⁇ / ⁇ ). I shouted.
  • the positive control, ribulin was dissolved in water.
  • DMSO diluted with water to a final concentration of 1% ( ⁇ / ⁇ ) was used.
  • Compound 2 (Example 2) was used as a physiological saline solution (1 mgZniL), and administered twice a day for 4 days before, 4 hours after and 4 days after virus inoculation under pentobarbital anesthesia at a dose of lmgZkg per day.
  • the mice were administered intranasally.
  • physiological saline was intranasally administered instead of the compound 2 solution.
  • the survival rate of the mice was observed for 21 days after infection with the influenza virus, and the in vivo anti-inffluenza virus activity of Compound 2 was evaluated by comparison with the control group.
  • the results are shown in Figure 3. The following is clear from FIG.
  • mice in the control group which received saline intranasally began to die on day 8 of virus inoculation, and the survival rate from day 9 to day 21 was 40%.
  • mice administered compound 2 nasally had a 70% survival rate from day 8 to day 18, and 60% of mice survived on day 21.
  • increased survival rates and prolonged survival days were observed. From these results, compound 2 has an excellent therapeutic effect on influenza infection and is useful as an antiviral agent.
  • Compound 2 (Example 2) is 10% (W / W), benzalkonium chloride is 0.04% (W / W), phenylethyl alcohol is 0.40% (W / W), Prepare an aqueous solution so that the purified water is 89.56% (W / W).
  • Compound 2 is 10% (W / W), benzalkonium chloride is 0.04% (W / W), polyethylene glycol 400 is 10.0% (W / W) An aqueous solution is prepared so that propylene glycol is 30% (WW) and purified water is 39.96% (WZW).
  • Formulation Example 3 A dry powder is prepared so that compound 2 (Example 2) is 40% (W / W) and lactose is 60% (W / W).
  • Formulation Example 4 Compound 2 (Example 2) Air port so that force is 0% (WZW), lecithin is 0.5% (W / W), freon 11 is 34.5%, freon 12 is 55%. Prepare a sol. Industrial applicability
  • novel KDN derivative of the present invention has excellent antiviral activity and low toxicity, and thus is useful as a therapeutic or preventive agent for viral infections, especially influenza infections.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

Dérivés de KDN représentés par la formule générale (I), sels de ceux-ci et agents antiviraux les contenant sous forme de principe actif. Dans ladite formule (I), R1 représente alkyle inférieur, aralkyle ou alcényle inférieur; R2 et R3 peuvent être identiques ou différents et représentent chacun hydrogène ou -SO¿3?H, à condition que R?2 et R3¿ ne représentent pas des atomes d'hydrogène en même temps. Ces composés ont une excellente activité antivirale et ne présentent pas de cytoxoticité.
PCT/JP1999/000926 1998-02-27 1999-02-26 Nouveaux derives de kdn et medicaments les contenant sous forme de principes actifs WO1999043689A1 (fr)

Priority Applications (1)

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AU26415/99A AU2641599A (en) 1998-02-27 1999-02-26 Novel kdn derivatives and drugs containing the same as the active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6187998 1998-02-27
JP10/61879 1998-02-27

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WO1999043689A1 true WO1999043689A1 (fr) 1999-09-02

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997043296A1 (fr) * 1996-05-16 1997-11-20 Nissin Food Products Co., Ltd. Nouveaux composes a activite antivirale

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997043296A1 (fr) * 1996-05-16 1997-11-20 Nissin Food Products Co., Ltd. Nouveaux composes a activite antivirale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHAN T.-H., ET AL.: "SYNTHESIS OF PHOSPHONIC ACID ANALOGUES OF SIALIC ACIDS (NEU5AC AND KDN) AS POTENTIAL SIALIDASE INHIBITORS.", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62., no. 11., 1 January 1997 (1997-01-01), US, pages 3500 - 3504., XP002920579, ISSN: 0022-3263, DOI: 10.1021/jo961891p *

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