WO2019054379A1 - Dérivé d'acide oléanolique - Google Patents

Dérivé d'acide oléanolique Download PDF

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WO2019054379A1
WO2019054379A1 PCT/JP2018/033663 JP2018033663W WO2019054379A1 WO 2019054379 A1 WO2019054379 A1 WO 2019054379A1 JP 2018033663 W JP2018033663 W JP 2018033663W WO 2019054379 A1 WO2019054379 A1 WO 2019054379A1
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group
compound
ring
salt
acid
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PCT/JP2018/033663
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English (en)
Japanese (ja)
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哲夫 鳴海
香澄 荻原
吉村　和久
恵嘉 原田
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国立大学法人静岡大学
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to oleanolic acid derivatives.
  • HIV human immunodeficiency virus
  • cART multiple drug combination therapy
  • anti-HIV drugs include nucleic acid reverse transcriptase inhibitors (NRTIs) that inhibit reverse transcription of HIV RNA, non-nucleic acid reverse transcriptase inhibitors (NNRTIs), and protease inhibitors that inhibit the activity of proteases
  • NRTIs nucleic acid reverse transcriptase inhibitors
  • NRTIs non-nucleic acid reverse transcriptase inhibitors
  • protease inhibitors that inhibit the activity of proteases
  • PI integrase inhibitors
  • INSTI integrase inhibitors
  • drugs that inhibit HIV entry into target cells HIV entry inhibitors
  • HIV entry inhibitor it is linked to the existing licensed drug, peptide fusion inhibitor (T-20) which binds to the envelope protein (Env) gp41 of HIV virus particle and the receptor protein CCR5 on the host cell Development of new HIV entry inhibitors different from CCR5 inhibitors (Marabiroc).
  • a betulinic acid derivative (IC9564) consisting of 3 units of betulinic acid, an amidooctyl linker and a statin has been reported (for example, Non-Patent Document 1).
  • An object of the present invention is to provide novel compounds having anti-HIV activity.
  • the inventors of the present invention conducted intensive studies and found that a compound based on the structure of oleanolic acid (oleanolic acid derivative) had anti-HIV activity, and completed the present invention.
  • Ring C is a hydrocarbon ring or a heterocyclic ring, and the hydrocarbon ring and the heterocyclic ring have a substituent selected from the group consisting of a hydroxy group, an oxo group, a hydroxyimino group and a C 1-6 alkoxy group
  • R 1 is a hydroxy group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxy group substituted with a halogen atom, or a C 1-6 alkyl ester group
  • R 2 is —OH or a group represented by the following formula (II), (In Formula (II), * represents a bond
  • X is a C 1-6 alkylene group which may have a substituent selected from the group consisting of a hydroxy group and a C 1-6 alkyl group .
  • Z 1 is a C 1-10 alkylene group
  • the C ring may be a cyclohexane ring or a cyclohexene ring, and the cyclohexane ring and the cyclohexene ring may have a hydroxy group or an oxo group.
  • the present invention also provides a compound represented by the following formula (Ia), (Ib), (Ic), or (Id) or a salt thereof.
  • the present invention provides a complex comprising cyclodextrin and the above-described compound or a salt thereof incorporated in cyclodextrin.
  • the present invention also provides a pharmaceutical composition comprising the above compound or a salt thereof or the above complex.
  • the present invention provides a pharmaceutical composition which is a combination of the above compound or a salt thereof or the above complex with an anti-HIV antibody. These pharmaceutical compositions can be used as anti-HIV drugs.
  • novel compounds having anti-HIV activity can be provided.
  • a portion where the steric structure in the structural formula is clearly defined indicates a structure as clearly shown, and a portion where the steric structure is not clearly defined otherwise is a stereoisomer.
  • the body may be included, and one isomer or a mixture thereof may be used.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group and an n-propyl group, Examples thereof include isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl groups.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkoxy group means an oxy group to which a C 1-6 alkyl group is bonded, and examples thereof include a methoxy group, an ethoxy group, a 1-propyloxy group, 2- A propyloxy group, 1-butyloxy group, 2-methylpropyloxy group, 1-methylpropyloxy group, 1,1-dimethylethoxy group and the like can be mentioned.
  • C 1-6 alkoxy group substituted by a halogen atom means a group in which one or more hydrogen atoms in the C 1-6 alkoxy group are substituted by a halogen atom, for example Fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 1,2-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-tri And fluoroethoxy, 1-fluoropropoxy, 2-fluoropropoxy, 3-fluoropropoxy, 3-chloropropoxy and the like.
  • alkylene group means a divalent group derived by removing an arbitrary hydrogen atom from the alkyl group and "C 1-10 alkylene group” means a carbon number of It means 1 to 10 alkylene groups.
  • C 1-10 alkylene group for example, methylene group, ethylene group, 1,2-propylene group, n-propylene group, 1,2-butylene group, 1,3-butylene group, n-butylene group, 2, Examples thereof include a 3-butylene group, an n-pentylene group, an n-hexylene group, an n-heptylene group, an n-octylene group, an n-nonylene group, an n-decylene group, and an n-dodecylene group.
  • heteroatom means an oxygen atom, a nitrogen atom, or a sulfur atom.
  • heteroalkylene group means a group in which at least one carbon atom of the alkylene group is substituted with a hetero atom.
  • hetero C 2-7 alkylene group means a C 2-7 hetero alkylene group.
  • One embodiment of the present invention is a compound represented by the general formula (I) (hereinafter, also referred to as “compound (I)”) or a salt thereof.
  • the C ring is a hydrocarbon ring or a heterocyclic ring, and the hydrocarbon ring and the heterocyclic ring are selected from the group consisting of a hydroxy group, an oxo group, a hydroxyimino group and a C 1-6 alkoxy group
  • R 1 has a substituent
  • R 1 is a hydroxy group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxy group substituted with a halogen atom, or a C 1-6 alkyl ester group
  • R 2 is -OH or a group represented by the following formula (II)
  • Z 1 is a C 1-10 alkylene group or a hetero C 2-7 alkylene group containing 1 to 3 hetero atoms.
  • * represents a bond
  • * represents a
  • the C ring is a hydrocarbon ring or a heterocycle.
  • the hydrocarbon ring and the heterocyclic ring may be a saturated ring or an unsaturated ring.
  • the hydrocarbon ring and the heterocyclic ring may be a 5- to 8-membered ring or a 6- to 7-membered ring.
  • the hydrocarbon ring and the heterocyclic ring in the C ring have a substituent selected from the group consisting of a hydroxy group, an oxo group, a hydroxyimino group, and a C 1-6 alkoxy group.
  • the number of the substituents in the C ring may be one or two, and may be one.
  • the hydrocarbon ring and the heterocyclic ring in the C ring may have a hydroxy group or an oxo group.
  • a cyclohexane ring or a cyclohexene ring having the above-mentioned substituent, or an ⁇ -caprolactone ring or an ⁇ -caprolactam ring can be mentioned.
  • the C ring may be a cyclohexane ring or a cyclohexene ring having the above substituent, may be a cyclohexane ring or a cyclohexene ring having a hydroxy group or an oxo group, and may be a cyclohexane ring having a hydroxy group or an oxo group, It may be a cyclohexane ring having a hydroxy group.
  • the compound (I) is a compound represented by the following general formula (i-1), (i-2) or (i-3) (compound (i-1), compound (i-2) or compound (i-) 3)).
  • R 1 , Z 1 and R 2 are as defined above.
  • the compound (i-3) may be a compound (compound (i-3a) or compound (i-3b)) represented by the following general formula (i-3a) or (i-3b).
  • R 1 , Z 1 and R 2 are as defined above.
  • the compound (I) may be the compound (i-1) or the compound (i-3), or may be the compound (i-1) or the compound (i-3a), from the viewpoint of excellent anti-HIV activity.
  • the compound (I) may be the compound (i-1) from the viewpoints of being excellent in anti-HIV activity and pharmacokinetics (in terms of facilitating maintenance of effective blood concentration, etc.).
  • R 1 may be a hydroxy group, a halogen atom, a C 1-6 alkoxy group, a C 1-6 alkoxy group substituted by a halogen atom, or a C 1-6 alkyl ester group.
  • R 2 may be a group represented by the above general formula (II).
  • the general formula (II) X is, C 1-6 alkyl group having hydroxy group, or a C 1-6 alkyl group having a hydroxy group and a C 1-6 alkyl group.
  • R 2 may be a group represented by the following formula (IIa).
  • R 2 may be a group represented by the following formula (IIb).
  • Z 1 is a C 1-10 alkylene group or a hetero C 2-7 alkylene group containing 1 to 3 heteroatoms.
  • the heteroatoms in the hetero C 2-7 alkylene group containing one to three heteroatoms do not bond directly to the nitrogen atom of —CO—NH— of general formula (I).
  • Z 1 When Z 1 is a C 1-10 alkylene group, Z 1 may be n-pentylene group, n-hexylene group, n-heptylene group, n-octylene group or n-nonylene group, and n-heptylene group , N-octylene group or n-nonylene group, and n-heptylene group.
  • Z 1 When Z 1 is a hetero C 2-7 alkylene group containing 1 to 3 heteroatoms, Z 1 may be, for example, a group represented by the following formula (III).
  • the hetero C 2-7 alkylene group When Z 1 is a hetero C 2-7 alkylene group containing two or more hetero atoms, the hetero C 2-7 alkylene group may contain only hetero atoms of the same kind, and nitrogen, oxygen and sulfur And may contain two or more hetero atoms selected from the group consisting of In formula (III), Y is a hetero atom, and n and m are each independently an integer of 1 to 3.
  • Z 1 is, for example, -CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -or -CH 2 -CH 2 -NR Z1 -CH 2 -CH 2 -NR Z1 -CH 2- It may be.
  • R Z1 represents a hydrogen atom or a C 1-6 alkyl group. R Z1 may be the same or different.
  • the C ring is a cyclohexane ring or a cyclohexene ring
  • the cyclohexane ring and the cyclohexene ring have an oxo group or a hydroxy group
  • R 1 is a hydroxy group
  • R 2 is the above Z 1 is a group represented by the formula (IIb)
  • Z 1 is an n-heptylene group. That is, the compound (I) may be a compound represented by the following formula (Ia), (Ib), (Ic) or (Id).
  • the salt of compound (I) may be any pharmaceutically acceptable salt, and the salt of compound (I) may be, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
  • compound (I) has one or more isomers, such as tautomers, optical isomers, stereoisomers, positional isomers, rotational isomers, etc.
  • isomers such as tautomers, optical isomers, stereoisomers, positional isomers, rotational isomers, etc.
  • either one or both isomers are also compounds of the present invention. Is included.
  • an optical isomer is present in compound (I)
  • an optical isomer resolved from a racemate is also encompassed in compound (I).
  • Compound (I) may be a crystal, and a single crystal or a mixture of crystal forms is encompassed in compound (I).
  • Compound (I) may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non hydrate etc.), both of which are encompassed in compound (I) Ru.
  • compound (I) of the present embodiment is described below.
  • R 1 is a hydroxy group
  • compound (I) can be produced, for example, by the following method.
  • R a , R b and R c represent a protecting group.
  • R a is, for example, an acetyl group
  • R b is a trimethylsilyl (TMS) group
  • R c is a tert-butyl group.
  • L is, for example, a halogen atom.
  • Step 1 is a step of producing a compound (2-1) by reacting the compound (1-1) with the compound (1-2).
  • the compound (1-1) can be produced by using commercially available oleanolic acid as a starting material.
  • an oxidant such as 3-chloroperbenzoic acid (mCPBA) can be used to synthesize a compound (1-1) or a precursor of the compound (1-1) in which a cyclohexane ring having an oxo group in the C ring is formed.
  • the compound C ring is cyclohexane ring having an oxo group as a starting material, the reduction reaction of the carbonyl group with a reducing agent such as LiAlH 4, Beckmann rearrangement type reaction, or by subjecting the Baeyer-Villiger oxidation type reaction, ring C
  • a compound (1-1) or a precursor thereof each of which is a cyclohexane ring, an ⁇ -caprolactam ring or an ⁇ -caprolactone ring having a hydroxy group.
  • the compound (1-2) may be one obtained by synthesizing a commercially available compound or a commercially available compound as a raw material.
  • a specific reaction condition of the step 1 for example, the reaction condition shown in the production example described later can be mentioned.
  • Step 2 is a step of producing a compound (3-1) by reacting the compound (2-1) with the compound (2-2).
  • the compound (2-2) may be one obtained by synthesizing a commercially available compound or a commercially available compound as a raw material.
  • the compound may be produced according to the method described in The Journal of Organic chemistry, 2008, 73, 9228-9234 it can.
  • Specific reaction conditions of Step 2 include, for example, the reaction conditions shown in the production examples described later.
  • Step 3 is a step (deprotection step) of producing a compound (4-1) by deprotecting the protective group of the compound (3-1).
  • the deprotecting conditions may be appropriately selected according to the type of protecting group. For example, when R c is a tert-butyl group (t-butyl group) and R a is an acetyl group, compound (3-1) is stirred in the presence of methanol and potassium carbonate, and then aqueous sodium hydroxide solution The acetyl and t-butyl groups can be deprotected by stirring in the presence to produce compound (4-1).
  • the reaction conditions shown in the production examples described later can be mentioned.
  • R 1 is a halogen atom, C 1-6 alkoxy groups, when manufacturing a C 1-6 alkoxy group or a C 1-6 alkyl ester group, compound substituted with a halogen atom (I), the compound of the above Step 1 instead of oR a group in (1-1), a halogen atom, C 1-6 alkoxy group, step 1 to a compound having a C 1-6 alkoxy group or a C 1-6 alkyl ester group substituted with a halogen atom It can manufacture by using as a raw material. In this case, the deprotection step (step 3) may not be performed.
  • Compound (I) or a salt thereof can be made into a pharmaceutical composition by adding a pharmaceutically acceptable additive, if necessary. Since the compound (I) has anti-HIV activity and its cytotoxicity is suppressed, the pharmaceutical composition containing the compound (I) or a salt thereof can be used as an anti-HIV drug. In addition, compound (I) can be used as an HIV entry inhibitor because it inhibits HIV cell entry.
  • the pharmaceutical composition of the present embodiment mixes Compound (I) or a salt thereof with a pharmaceutically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, the method described in the Japanese Pharmacopoeia etc.) It can be used as a pharmaceutical composition.
  • the pharmaceutical composition of the present embodiment includes, for example, tablets, pills, powders, granules, capsules, troches, syrups, solutions, emulsions, suspensions, controlled release formulations, aerosols, films, injections, It can be administered orally or parenterally as an instillation, a percutaneous absorption-type preparation, an ointment, a lotion, a patch, a suppository, a pellet, a nasal agent, a pulmonary agent, and an eye drop.
  • the content of the compound (I) or a salt thereof in the pharmaceutical composition according to the present embodiment can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the dosage of the pharmaceutical composition of the present embodiment varies depending on the degree of symptoms, age, sex, body weight, dosage form / type of salt, specific type of disease, etc., and can be administered without causing unacceptable side effects. It is not limited unless the maximum dose of drug is exceeded.
  • the dose may be, for example, 30 ⁇ g to 10 g, 100 ⁇ g to 5 g, or 100 ⁇ g to 1 g when orally administered to an adult (body weight 60 kg) in an amount of Compound (I) or a salt thereof,
  • the administration interval may be, for example, once or several times (eg, 2 to 6 times) daily, may be administered once every two days, or may be once weekly. It may be administered once in January.
  • the pharmaceutically acceptable carrier that may be used for producing the pharmaceutical composition of the present embodiment
  • various organic or inorganic carrier substances commonly used as a pharmaceutical material may be mentioned.
  • fillers, binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents, and the like may be mentioned.
  • additives such as conventional preservatives and antioxidants can be appropriately used in appropriate amounts.
  • Excipients include, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid.
  • lubricant for example, magnesium stearate, calcium stearate, talc, colloidal silica can be mentioned.
  • binder for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium can be mentioned.
  • Disintegrants include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, L-hydroxypropylcellulose.
  • solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
  • suspending agents examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc .; for example, polyvinyl alcohol, polyvinyl pyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
  • tonicity agents include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
  • the buffer examples include buffers such as phosphate, acetate, carbonate, citrate and the like.
  • the soothing agent includes, for example, benzyl alcohol.
  • preservatives include p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid and sorbic acid.
  • Antioxidants include, for example, sulfites, ascorbic acid and ⁇ -tocopherol.
  • compound (I) or a salt thereof can be used in combination with an anti-HIV antibody.
  • the anti-HIV antibody may be a polyclonal antibody or a monoclonal antibody.
  • the animal from which the anti-HIV antibody is derived may be a mouse (mouse antibody, chimeric antibody, humanized antibody, human antibody etc.).
  • the anti-HIV antibody may be an HIV neutralizing antibody.
  • the compound (I) can increase the sensitivity of HIV to an HIV neutralizing antibody, and thus is useful as a pharmaceutical composition comprising a combination of the compound (I) or a salt thereof and an HIV neutralizing antibody.
  • HIV neutralizing antibody for example, V2 apex (PGDM1400, which recognizes the V2 sugar chain region at the tip of gp120 trimer, which is the envelope protein (Env) located on the outermost side of HIV virus particle.
  • V2 apex PGDM1400, which recognizes the V2 sugar chain region at the tip of gp120 trimer, which is the envelope protein (Env) located on the outermost side of HIV virus particle.
  • V3-high mannose patch (10-1074, PGT-128, 2G12 etc) that recognizes the sugar chain at the V3 base
  • CD4bs VRC01, 3BNC117, etc.
  • gp120 / 41 interface 35O22, PGT151, 8ANC 195 etc.
  • MPER 10E8, 2F5, 4E10 etc.
  • the above-mentioned anti-HIV antibody can be obtained by Polymun Scientific, Creative biolab, etc., except KD-247.
  • composition which is a combination of Compound (I) or a salt thereof and an anti-HIV antibody of the present embodiment
  • the compound (I) or a salt thereof and the anti-HIV antibody At the time of administration, compound (I) or a salt thereof and the anti-HIV antibody may be administered simultaneously to the administration subject, or may be administered at a time-delayed interval.
  • the administration mode of the combination pharmaceutical composition of the present embodiment may be such that Compound (I) or a salt thereof and an antibody are combined at the time of administration.
  • a dosage form for example, administration of a single preparation obtained by simultaneously formulating Compound (I) or a salt thereof and an antibody, (2) Compound (I) or a salt thereof and an antibody Co-administration of the two formulations obtained by separately formulating the same formulation by the same administration route, (3) the same administration route of the two formulations obtained by separately formulating the compound (I) or a salt thereof and an antibody Administration with time lag, (4) co-administration of two formulations obtained by separately formulating compound (I) or a salt thereof and an antibody by different administration routes, (5) compound (I) Or administration of the two preparations obtained by separately formulating the salt and the antibody with different administration routes with different administration routes (for example, administration of the combined drug after administration of the compound of the present embodiment or a salt thereof And the like) and the like.
  • the time lag may differ depending on the active ingredient to be administered, the dosage form, and the administration method. For example, within one month, one week, two days, one minute to one day, ten minutes to six hours, or fifteen minutes to three hours after administration of compound (I) or a salt thereof. The method of administration is mentioned.
  • Compound (I) or a salt thereof can be used in combination with cyclodextrin.
  • Compound (I) or a salt thereof may be used as a complex in which compound (I) or a salt thereof is included in cyclodextrin because HIV activity is further improved and cytotoxicity is further reduced. That is, as one embodiment of the present invention, there is provided a complex comprising cyclodextrin and compound (I) or a salt thereof incorporated in cyclodextrin.
  • the cyclodextrin may, for example, be ⁇ -cyclodextrin, ⁇ -cyclodextrin or ⁇ -cyclodextrin.
  • the number of cyclodextrin molecules per molecule of compound (I) or a salt thereof may be 1 to 2, and may be 2.
  • Oleanolic acid derivatives (described later) according to methods known from oleanolic acid (methods described in Org. Lett., 2013, 15, 1622-1625, and Bioorg. Med. Chem., 2008, 16, 8697-8705) Compounds A-1, B-1, C-1, C-1 'and D-1) were synthesized.
  • Production Example 3-4 (3S, 4S) -N '-[N- [3 ⁇ , 12 ⁇ -diacetoxyoleanane-28-oil] -8-aminooctanoyl] -4-amino-3-hydroxy-6- Synthesis of methyl heptanoic acid t-butyl ester
  • the title compound (17.9 mg, yield: 66%) was synthesized using C-4 (20.9 mg, 29.8 ⁇ mol) by the same method as in Production Example 1-3.
  • Production Example 5-2 (3S, 4S) -N '-[N- [3 ⁇ -Acetoxyoleano-12-ene-28-Oil] -8-aminooctanoyl] -4-amino-3-hydroxy-6 -Methyl heptanoic acid tert-butyl ester synthesis Using D-2 (101 mg, 0.158 mol), the title compound (130 mg, yield: 97%) was synthesized by the same method as in Production Example 1-3.
  • Test Example 1 Evaluation Test of Anti-HIV Activity
  • the anti-HIV activity and the compounds of Examples 1 to 4 synthesized (compounds A, B, C and C ′) and the compounds of Reference Examples 1 to 2 (compound D and IC9564) Cytotoxicity was evaluated by the following method. The results are shown in Table 1. In Table 1, "ND" means not detectable.
  • TZM-bl cells obtained from the US NIH AIDS Research and Reference Reagent Program
  • TZM-bl cells are cell lines in which the ⁇ -galactosidase and luciferase genes have been incorporated into the HIV-1 long terminal repeat (LTR) sequence of the parent strain JC-53 cells.
  • HIV-1 infection can be detected with a luminescent signal proportional to the expression level of ⁇ -galactosidase.
  • the quantification of ⁇ -galactosidase was performed using a Beta-GloTM assay system (Promega).
  • the virus strains are CCR5 (R5) tropic virus YU2 strain (obtained from the US NIH AIDS Research and Reference Reagent Program), and CX4 (X4) tropic virus NL4.
  • CCR5 R5 tropic virus YU2 strain
  • CX4 X4 tropic virus NL4.
  • Three strains of 3 strains obtained from the US NIH AIDS Research and Reference Reagent Program
  • 89.6 strains of amphotropic virus obtained from the US NIH AIDS Research and Reference Reagent Program
  • TZM-bl cells (1 ⁇ 10 4 cells) were cultured with 100 TCID 50 of virus strain and dilution series drug.
  • ⁇ -galactosidase activity was measured with a luminometer according to the attached instruction of Beta-GloTM assay to compare drug sensitivity.
  • the IC 50 value is the concentration at which HIV infection of TZM-bl cells was inhibited by 50%. Since LTR is a transcriptional regulatory region, this assay system can detect viral infection up to the process of viral DNA transcription in the HIV life cycle.
  • TZM-bl cells obtained from the US NIH AIDS Research and Reference Reagent Program
  • ATP ATP-activated glutathione
  • TZM-bl cells obtained from the US NIH AIDS Research and Reference Reagent Program
  • ATP ATP-activated phosphatidylcholine
  • dilution series drugs dilution series drugs
  • the amount of ATP production was measured with a luminometer to quantify the proliferation rate and the survival rate of the cells.
  • the CC 50 value is the concentration at which TZM-bl cells are mock infected and the survival rate reaches 50%.
  • compound C ′ which is a diastereomer of compound C, also exhibited anti-HIV activity and was shown to have lower cytotoxicity as compared to IC9564.
  • Test Example 2 Combined Effect with HIV-1 Neutralizing Antibody Using the amphipathic virus 89.6 strain and TZM-bl cells, the combined effect of Compound A or Compound D and HIV-1 neutralizing antibody is evaluated. did. The combined effect was evaluated according to the method described in Eur. J. Biochem., 1981, 115, 207-216, J. Biol. Chem., 2012, 287, 15076-15086 and the like. The IC 50 was measured by the same method as in Test Example 1. The results are shown in Table 2. In addition, b12, 2G12, 2F5, 4E10, 447-52D, and KD247 were used as HIV-1 neutralizing antibodies (hereinafter also referred to as "NAb"). Hereinafter, the compound and NAb are also referred to as "inhibitors". The ratio of compound to NAb (compound: NAb) approximates the ratio of IC 50 values for each inhibitor alone.
  • DRI Dose reduction index
  • CI Combination index
  • Test Example 3 Combined Effect with Cyclodextrin (CD)
  • complex A in which Compound A is included in ⁇ -cyclodextrin ( ⁇ -CD) was obtained by the following method.
  • a 50% aqueous ethanol solution (10 mL) was added to compound A (38.6 mg, 0.05 mmol) and ⁇ -cyclodextrin (113.4 mg, 0.1 mmol), and the mixture was stirred at room temperature for 24 hours. Then, water (10 mL) was added to the residue obtained by evaporating the solvent under reduced pressure, and the mixture was lyophilized to quantitatively obtain a mixture of a white solid containing complex A.
  • SI Selectivity Index
  • compound A was improved in water solubility and anti-HIV activity by inclusion in cyclodextrin (CD).
  • Test Example 4 Pharmacokinetic (PK) Evaluation A pharmacokinetic test was conducted on Compound A and Compound C according to the following method. The test substance was made into a 100 mM solution using DMSO, and this solution was adjusted to 2 mM using PBS. As animals for pharmacokinetic evaluation, mice (strain: Crlj: CD1 (ICR), source: Japan Charles River Co., Ltd., gender: male, age: 7 weeks old (upon arrival), number of animals used: 24) )It was used. The breeding conditions were room temperature 24 ⁇ 3 ° C., humidity 50 ⁇ 20%, ventilation (10-25 times / 1 hour), and lighting 12 hours (8: 00-20: 00).
  • the animals used had free access to MF (Oriental Yeast Co., Ltd.) as feed.
  • the animals used were fasted from 17:00 on the day before administration.
  • the day of administration was fed after completion of blood collection 4 hours after administration.
  • Autoclaved sterile tap water was placed in a water bottle and allowed to be consumed freely by the animals used.
  • the autoclaved cages were used and the animals were reared at 3 animals / cage.
  • the animals used were observed daily for 7 days or more after the arrival of the animals until the end of the quarantine and acclimation. The weight was also measured on the date of arrival and on the end of quarantine and acclimation. Animals in good health after quarantine and habituation were used for the study.
  • Grouping of the animals used was carried out by weight stratified random sampling method using body weight at the time of test substance administration. Four animals were used in each group.
  • the cage was labeled with a test number, an animal number, a test period, and the like.
  • the administration was performed by intraperitoneal administration (IP) using a needle and a syringe.
  • IP intraperitoneal administration
  • the dose was 30 mg / 10 mL / kg.
  • Blood is collected 5 minutes, 1 minute and 8 hours after administration, 10 minutes, 2 hours and 24 hours after administration, or 30 minutes after administration (pre) and 4 days after administration It took place at a later time. Blood was drawn under fasting. The blood collection site was jugular vein, and the blood collection volume was 30 ⁇ L. Blood treatment was carried out by heparin sodium treatment, and centrifugation conditions were 6,000 rpm, 15 minutes, 4 ° C. conditions. Samples obtained by blood collection were stored under ice-cooling until centrifugation, and after plasma collection, they were stored frozen at -20 ° C or lower.

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Abstract

La présente invention concerne un composé représenté par la formule (I) ou un sel de celui-ci. [Dans la formule (I), le cycle C est un cycle hydrocarboné, etc. ; le cycle hydrocarboné, etc., a un groupe substituant choisi dans le groupe constitué par des groupes hydroxyle, des groupes oxo, des groupes hydroxyimino, et des groupes alcoxy en C 1-6 ; R1 représente un groupe hydroxy, etc. ; R2 représente, entre autres, un groupe représenté par la formule (II) (dans la formule (II), * représente une liaison, et X représente un groupe alkylène en C1-6 qui peut avoir un groupe substituant choisi dans le groupe constitué par des groupes hydroxyle et des groupes alkyle en C1-6) ; et Z1 est un groupe alkylène en C1-10, etc.]
PCT/JP2018/033663 2017-09-14 2018-09-11 Dérivé d'acide oléanolique WO2019054379A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114874281A (zh) * 2022-01-27 2022-08-09 贵州医科大学 一种齐墩果酸衍生物及其制备方法与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009553A1 (fr) * 1990-11-21 1992-06-11 Hokkaidosugar Co., Ltd. Composition de triterpene pentacyclique, soluble dans l'eau, et production de cette composition
CN1724556A (zh) * 2005-03-11 2006-01-25 南京大学 齐墩果酸及其衍生物、制法及用途
JP2010504921A (ja) * 2006-09-27 2010-02-18 ウニヴェルジタ カルロヴァ ウ プラゼ，プリーロドヴェデカー ファクルタ 水不溶性の五環性テルペノイドおよび四環性テルペノイドの可溶性処方物の調製方法、五環性テルペノイドまたは四環性テルペノイドの可溶性処方物、およびこの可溶性処方物を含んだ薬学的組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009553A1 (fr) * 1990-11-21 1992-06-11 Hokkaidosugar Co., Ltd. Composition de triterpene pentacyclique, soluble dans l'eau, et production de cette composition
CN1724556A (zh) * 2005-03-11 2006-01-25 南京大学 齐墩果酸及其衍生物、制法及用途
JP2010504921A (ja) * 2006-09-27 2010-02-18 ウニヴェルジタ カルロヴァ ウ プラゼ，プリーロドヴェデカー ファクルタ 水不溶性の五環性テルペノイドおよび四環性テルペノイドの可溶性処方物の調製方法、五環性テルペノイドまたは四環性テルペノイドの可溶性処方物、およびこの可溶性処方物を含んだ薬学的組成物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
MA, C. ET AL.: "CHEMICAL MODIFICATION OF OLEANENE TYPE TRITERPENES AND THEIR INHIBITORY ACTIVITY AGAINST HIV-1 PROTEASE DIMERIZATION", CHEM. PHARM. BULL., vol. 48, no. 11, 2000, pages 1681 - 1688, XP001208133 *
OGIHARA, KASUMI ET AL., ABSTRACTS OF THE 138TH ANNUAL CONFERENCE OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 1 February 2018 (2018-02-01) *
WEI, Y. ET AL.: "Synthesis and evaluation of A-seco type triterpenoids for anti-HIV-1protease activity", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, 2009, pages 4112 - 4120, XP026394760 *
YAKUGAKU ZASSHI, vol. 124, no. 8, 2004, pages 519 - 529 *
YU , F. ET AL., JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, 2013, pages 4300 - 4319 *
ZHANG, Y. ET AL.: "Synthesis and activity of oleanolic acid derivatives, a novel class of inhibitors of osteoclast formation", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 15, 2005, pages 1629 - 1632, XP004771159 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114874281A (zh) * 2022-01-27 2022-08-09 贵州医科大学 一种齐墩果酸衍生物及其制备方法与应用
CN114874281B (zh) * 2022-01-27 2023-09-26 贵州医科大学 一种齐墩果酸衍生物及其制备方法与应用

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