WO2017061532A1 - ピリミジン化合物 - Google Patents
ピリミジン化合物 Download PDFInfo
- Publication number
- WO2017061532A1 WO2017061532A1 PCT/JP2016/079756 JP2016079756W WO2017061532A1 WO 2017061532 A1 WO2017061532 A1 WO 2017061532A1 JP 2016079756 W JP2016079756 W JP 2016079756W WO 2017061532 A1 WO2017061532 A1 WO 2017061532A1
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- WIPO (PCT)
- Prior art keywords
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- carbon atoms
- substituted
- alkyl group
- hydrogen atom
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- 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
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- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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- 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
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- 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 a compound useful as a vaccine adjuvant, a production method thereof, a pharmaceutical composition containing the compound, and use of the compound as a vaccine adjuvant.
- a vaccine comprising a protein derived from a protein produced by a microorganism or a partial peptide thereof can be produced by chemical synthesis or genetic recombination techniques, it is excellent in terms of vaccine safety and production method.
- subunit vaccines composed of partial peptides tend to have lower efficacy of immunostimulation than live vaccines and inactivated vaccines. Therefore, in order to enhance the immunogenicity of the epitope and improve the immunostimulatory activity of the vaccine, a preventive or therapeutic method using an adjuvant and an antigen in combination has been studied.
- An adjuvant is an additive that enhances a humoral immune response and / or a cellular immune response to an antigen.
- TLR Toll-like Receptor
- TLR7 and TLR8 a small molecule that mimics a single-stranded RNA of a virus, which is a natural ligand, is known as an activator.
- synthetic compounds such as pyrimidine compounds (see Patent Documents 1 and 2) and imidazoquinoline compounds (see Patent Document 3) have been reported.
- TLR7 and / or TLR8 Activation of TLR7 and / or TLR8 with the agonist induces Th1 cells via a TLR / MyD88-dependent signaling pathway and activates dendritic cells (DC).
- DC dendritic cells
- T-cell co-stimulatory molecules CD80, CD86, CD40
- inflammatory cytokines including type I interferon (particularly IFN ⁇ ), TNF ⁇ , IL-6 or IL-12 are produced.
- TLR7 and / or TLR8 agonists are known to have activities such as activating B cells and stimulating NK cells to promote IFN ⁇ production.
- TLR7 / TLR8 agonists such as Resiquimod or Imiquimod has been reported (see Non-Patent Document 2). From the above, development of a new vaccine adjuvant that activates TLR7 and / or TLR8 is required.
- squalene is an oily substance used as an oil component in an oil-in-water or water-in-oil emulsion formulation
- MF59 is mentioned as an adjuvant containing squalene, and is used as an adjuvant for influenza vaccines (See Non-Patent Documents 3, 4 and 5).
- Examples of the complex of a TLR7 / 8 agonist and another substance include a vaccine adjuvant in which a fatty acid and an imidazoquinoline compound are covalently linked (see Patent Documents 4, 5, and 6 and Non-Patent Document 6), fatty acid glycerides And the imidazoquinoline compound complex (see Patent Document 7), fatty acid glyceride and adenine compound complex (see Patent Document 8), and phospholipid and adenine compound complex (see Patent Document 9) Yes.
- the complex (refer patent document 10) through the polyethyleneglycol of fatty acid glyceride and an adenine compound is also known.
- no TLR7 / 8 agonist / squalene complex was known.
- the present invention provides a compound useful as a vaccine adjuvant, a production method thereof, and a composition containing the compound.
- TLR7 Toll-like Receptor 7
- X represents a methylene, oxygen atom or NR 7 (R 7 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms); R 1 and R 2 independently represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms; When the alkyl group is substituted, it may be substituted with the same or different 1 to 4 substituents selected from a hydroxy group and a halogen atom, R 3 represents an alkyl group having 1 to 6 carbon atoms, R 4 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof according to [1]; [3] Or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein all are single
- a pharmaceutical composition comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof; [11] The pharmaceutical composition according to [10], further comprising an antigen; [12] The pharmaceutical composition according to [11], wherein the antigen is a pathogen-derived antigen or a tumor antigen; [13] The pharmaceutical composition according to [11] or [12], wherein the antigen is a peptide or protein; [14] A vaccine adjuvant comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof; [15] The compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof used as a vaccine adjuvant; [16] A method of enhancing an antigen-specific immune response in a mammal, comprising administering the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof;
- the alkyl group When the alkyl group is substituted, it may be substituted with the same or different 1 to 4 substituents selected from a hydroxy group and a halogen atom, When the 4- to 8-membered nitrogen-containing saturated heterocyclic ring or the 5- to 8-membered nitrogen-containing saturated heterocyclic ring is substituted, a methyl group, ethyl group, propyl group, hydroxymethyl group, hydroxyethyl group, carbonyl group, hydroxy group May be substituted with the same or different 1 to 4 substituents selected from a group and a halogen atom, p represents an integer of 1 to 6, q and q ′ independently represent an integer of 0 to 4, r represents an integer of 0 to 5, r ′ represents an integer of 1 to 5, the sum of r and r ′ is 5 or less, and when Y 2 is a single bond, r ′ represents an integer of 2 or more.
- R 8 represents a hydrogen atom or an amino-protecting group.
- X represents methylene
- R 1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms which may be substituted with a hydroxy group
- R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
- R 3 represents an alkyl group having 1 to 3 carbon atoms
- R 4 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms
- Y 1 represents a single bond or methylene
- Y 2 represents a single bond or —C (O) —
- L represents a linear alkylene having 2 or 3 carbon atoms
- R 5 and R 6 independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R 5 together with R 6 contains a
- a nitrogen-saturated heterocycle may be formed, and when the 5- to 8-membered nitrogen-containing heterocycle is substituted, it is substituted with the same or different 1 to 4 substituents selected from a hydroxy group and a halogen atom Or a pharmaceutically acceptable salt thereof according to [19].
- the present invention has made it possible to provide an adjuvant that enhances a specific immune response to an antigen useful as a vaccine.
- FIG. 2 is a graph showing the production amount of OVA-specific IgG when immunized with OVA in mice administered with the compounds of Examples 1 to 5 intramuscularly. It is a graph which shows the result of having quantified OVA specific IgG1 and IgG2c in the immune mouse
- the vertical axis represents the plasma OVA-specific IgG2c / IgG1 ratio. It is a graph which shows the ratio of the OVA specific multifunctional CD4 positive T lymphocyte in the spleen cell of the mouse
- the concept of the present invention has the following physiological activity. Any optically active or racemic form is included. Synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art (for example, synthesis from optically active starting materials or resolution of racemates). The physiological activity can be evaluated using standard experimental techniques described below.
- the compound represented by the above formula (1) may be in an unsolvated form or a solvated form (for example, a hydrate).
- a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1). .
- the form of the compound represented by the formula (1) is not particularly limited, and it may be indefinite or present as a specific crystal.
- the compound represented by the formula (1) obtained as a crystal or a pharmaceutically acceptable salt thereof may have a crystal polymorphism, and the compound of the present invention includes all crystal forms.
- examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.
- examples of “linear alkylene” include linear alkylene having 1 to 6 carbon atoms. Specific examples of the linear alkylene include, but are not limited to, methylene, ethylene, n-propylene, and n-butylene.
- Examples of the “alkyl group” include linear or branched alkyl groups having 1 to 6 carbon atoms.
- alkyl group examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.
- Cycloalkane includes 4- to 8-membered cycloalkane. Specific examples include cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane, and preferably cyclopentane, cyclohexane, or cycloheptane.
- the “divalent group of cycloalkane” is not particularly limited, and specific examples include a divalent group capable of bonding to an adjacent atom on a different carbon atom of the cycloalkane.
- alkoxy group examples include linear or branched alkoxy groups having 1 to 6 carbon atoms. Specific examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxyl, butoxy, isobutoxy, tert-butoxy, pentoxy or isopentoxy.
- “4- to 8-membered nitrogen-containing saturated heterocycle” includes at least 2 nitrogen atoms selected from 2 or 3 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom Examples thereof include 4- to 8-membered nitrogen-containing saturated heterocycles containing 1 to 3 heteroatoms in the ring. Specific examples include azetidine, pyrrolidine, piperidine, perhydroazepine, imidazolidine, piperazine, morpholine, thiomorpholine, and perhydro-1,4-diazepine. Examples of the “5- to 8-membered nitrogen-containing saturated heterocyclic ring” include 5- to 8-membered nitrogen-containing saturated heterocyclic rings described above.
- X represents a methylene, oxygen atom, sulfur atom, SO, SO 2 or NR 7 (R 7 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms).
- R 7 preferably represents a hydrogen atom or a methyl group.
- X preferably represents methylene.
- R 1 preferably represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. Specific examples of R 1 include a methyl group, an ethyl group, a propyl group, and a butyl group.
- R 2 represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms.
- R 2 preferably include a hydrogen atom, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, or a hydroxyethyl group.
- R 3 preferably represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or an alkylthio group having 1 to 4 carbon atoms, and more preferably 1 to 4 carbon atoms.
- R 3 are preferably a methyl group, an ethyl group, a propyl group, or a butyl group, and more preferably a methyl group.
- R 4 is preferably a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a hydroxy group or a halogen atom, and more preferably a hydrogen atom or A methoxy group etc. are mentioned.
- Y 1 is preferably a single bond, — (CR 9 R 10 ) p —, or — (CR 9 R 10 ) r —O— (CR 9 ′ R 10 ′ ) r ′ — ( R 9 , R 10 , R 9 ′ and R 10 ′ each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
- R 9 , R 10 , R 9 ′ and R 10 ′ are preferably independently a hydrogen atom or a methyl group, more preferably a hydrogen atom.
- Y 1 more preferably represents a single bond or — (CR 9 R 10 ) p —.
- p preferably represents an integer of 1 to 4, more preferably 1, 2 or 3.
- Y 1 is —CH ⁇ CH— (CR 9 R 10 ) q —, or
- Q and q ′ preferably independently represent an integer of 0 to 3, more preferably 0 or 1.
- r preferably represents an integer of 0 to 3, Preferably represents an integer of 1 to 4.
- the sum of r and r ′ is 5 or less, more preferably r represents 0 or 1, and r ′ represents 1 or 2.
- Y 1 represents a single bond or — (CR 9 R 10 ) p —
- Y 2 represents a single bond or —C (O)-(carbonyl).
- a preferred embodiment includes an embodiment in which Y 1 represents a single bond and Y 2 represents —C (O) —.
- a preferred embodiment includes an embodiment in which Y 1 represents — (CR 9 R 10 ) p —, and Y 2 represents a single bond.
- R 9 and R 10 preferably independently represent a hydrogen atom or a methyl group, more preferably a hydrogen atom.
- p preferably represents an integer of 1 to 4, more preferably 1, 2 or 3.
- L in the formula (1) specifically represents a linear alkylene having 2 to 4 carbon atoms, more preferably a linear alkylene having 2 or 3 carbon atoms, and more preferably ethylene.
- L in the formula (1) represents a divalent group of a 4- to 8-membered cycloalkane, and more preferably represents a divalent group of a 5- or 6-membered cycloalkane.
- Specific examples of the divalent group include the following divalent groups.
- R 5 and R 6 in the formula (1) specifically represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 3 carbon atoms, preferably independently a hydrogen atom. Or an alkyl group having 1 to 3 carbon atoms, more preferably independently a hydrogen atom or a methyl group, and still more preferably a hydrogen atom.
- the alkyl group When the alkyl group is substituted, it may be substituted with the same or different 1 to 4 substituents selected from a hydroxy group and a halogen atom.
- either one of R 5 and R 6 in formula (1) is bonded to any carbon atom in L to form a 4- to 8-membered nitrogen-containing saturated heterocyclic ring.
- a 4- to 6-membered nitrogen-containing saturated heterocyclic ring may be formed.
- Specific examples of the 4- to 8-membered nitrogen-containing saturated heterocycle formed by R 5 bonding to any carbon atom in L include the following.
- R 6 represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms.
- R 6 is, as any nitrogen-containing saturated heterocyclic 4- to 8-membered to form bound to the carbon atom in L, and specifically may be exemplified by the following.
- R 5 represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms.
- R 5 and R 6 in formula (1) may be taken together to form a substituted or unsubstituted 5- to 8-membered nitrogen-containing saturated heterocycle, preferably 5 or A 6-membered nitrogen-containing saturated heterocyclic ring may be formed.
- the nitrogen-containing saturated heterocyclic ring is represented by the following formula:
- the nitrogen-containing saturated heterocyclic ring represented by these is mentioned.
- One of R 5 and R 6 is a 4- to 8-membered nitrogen-containing saturated heterocyclic ring formed by bonding to any carbon atom in L, or 5 formed by combining R 5 and R 6 together.
- Preferred examples of the substituent in the case where the ⁇ 8-membered nitrogen-containing saturated heterocyclic ring is substituted include the same or different 1 to 4 substituents selected from a hydroxy group and a halogen atom.
- m preferably represents 1.
- X represents methylene
- R 1 represents an alkyl group having 1 to 4 carbon atoms
- R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a hydroxy group
- R 3 represents an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms
- R 4 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
- Y 1 represents a single bond or — (CR 9 R 10 ) p —
- Y 2 represents —C (O) —
- L represents a linear alkylene having 2 to 6 carbon atoms
- R 5 and R 6 independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or either R 5 or
- a 4- to 8-membered nitrogen-containing saturated heterocyclic ring may be formed, or R 5 may be combined with R 6 to form a substituted or unsubstituted 4- to 8-membered nitrogen-containing saturated heterocyclic ring; m represents 0 or 1, preferably 1.
- X represents methylene
- R 1 represents an alkyl group having 1 to 4 carbon atoms
- R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a hydroxy group
- R 3 represents an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms
- R 4 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
- Y 1 represents-(CR 9 R 10 ) p- Y 2 represents a single bond
- L represents a linear alkylene having 2 to 6 carbon atoms
- R 5 and R 6 independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or either R 5 or R 6 is bonded to any carbon atom in L
- a 4- to 8-membered nitrogen-containing saturated heterocycle may be formed, or R 5 may be combined with R 6 to form a substituted or unsubstituted 4- to 8-membered nitrogen-containing saturated heterocycle; m represents 0 or 1, preferably 1.
- X represents methylene
- R 1 represents an alkyl group having 1 to 4 carbon atoms
- R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a hydroxy group
- R 3 represents an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms
- R 4 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms
- Y 1 represents a single bond and Y 2 represents —C (O) —
- Y 1 represents — (CR 9 R 10 ) p — and Y 2 represents a single bond
- L represents a linear alkylene having 2 to 6 carbon atoms
- R 5 and R 6 independently represent a hydrogen atom or an alkyl group
- Suitable compounds of the present invention include the following compounds or pharmaceutically acceptable salts thereof: (4E, 8E, 12E, 16E, 20E) -N- ⁇ 2-[ ⁇ 4-[(2-Amino-4- ⁇ [1-hydroxyhexane-3-yl] amino ⁇ -6-methylpyrimidine-5- Yl) methyl] benzyl ⁇ (methyl) amino] ethyl ⁇ -4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaenamide; (4E, 8E, 12E, 16E, 20E) -1- (4- ⁇ 4-[(2-Amino-4- ⁇ [1-hydroxypentan-2-yl] amino ⁇ -6-methylpyrimidin-5-yl ) Methyl] -3-methoxybenzyl ⁇ piperazin-1-yl) -4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,
- the present invention includes a composition obtained by combining a plurality of the above compounds.
- examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) include an acid addition salt or a base addition salt of the compound represented by the formula (1).
- examples of the acid addition salt include acid addition salts with inorganic or organic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, citric acid, maleic acid and the like).
- examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, ammonium salt and the like.
- the compound represented by the formula (1) can be produced by the following production method using a known compound as a raw material. Each compound used as a raw material compound may be used as a salt. These production methods are merely examples, and can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.
- Compound (1) can be produced by reacting compound (3) with compound (2) in an inert solvent using a condensing agent, if necessary, in the presence of a base.
- the base is not particularly limited as long as it is used by those skilled in the art as a base in an organic chemical reaction.
- the amount of the base used is usually 0.1 to 100 equivalents relative to compound (3), preferably 1 to 5 equivalents.
- the condensing agent include those described in Experimental Chemistry Course (edited by Chemical Society of Japan, Maruzen) Vol.
- phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide
- carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC ⁇ HCl) and dicyclohexylcarbodiimide (DCC);
- 2 Combinations of disulfides such as 2,2'-dipyridyl disulfide and phosphines such as triphenylphosphine
- Phosphorus halides such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl); Azo Combinations of azodicarboxylic acid diesters such as
- the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; ketone solvents such as acetone; aprotic solvents such as acetonitrile, N, N′-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc., and mixtures thereof It may be.
- ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
- hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene
- the reaction temperature is not particularly limited, but is preferably selected from the range of about ⁇ 70 ° C. to 100 ° C., more preferably 0 ° C. to 40 ° C.
- a halogenating reagent for example, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosphorus pentachloride and the like
- compound (1) can also be produced by reacting with compound (2) in an inert solvent, if necessary, in the presence of a base.
- the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform Halogenated hydrocarbon solvents such as dichloroethane; ester solvents such as ethyl acetate and isopropyl acetate; ketone solvents such as methyl ethyl ketone and acetone; acetonitrile, N, N′-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.
- ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
- hydrocarbon solvents such as hexane, heptane,
- aprotic solvents examples include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene.
- Organic bases such as pyridine, dimethylaminopyridine, and picoline.
- the halogenating reagent can be used in an amount of 0.1 to 100 equivalents, preferably 0.8 to 3 equivalents, relative to compound (3).
- the reaction temperature is not particularly limited, but is preferably selected from the range of about ⁇ 30 ° C. to 60 ° C.
- Compound (3) can be produced according to a method well known to those skilled in the art (see Org. Biomol. Chem. 2011, 9, 4367).
- Compound (2a) can be synthesized from compound (4) and compound (5a) according to the method described in the method for producing compound (1).
- Compound (4) can be produced according to methods well known to those skilled in the art (for example, methods described in International Publication Pamphlet Nos. WO2009 / 067081 and WO2010 / 133885).
- X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined above, and Y 1 represents — (CR 9 R 10 ) p —, —CH ⁇ CH- (CR 9 R 10 ) q- or
- Q 1 and Q 2 are either (1) Q 1 represents —Y 1 NHR 5 and Q 2 represents CHO, or (2) Q 1 Represents —Y 1 ′ —CHO (wherein Y 1 ′ does not exist or represents alkylene, —Y 1 ′ — (CR 9 R 10 ) — corresponds to —Y 1 —), and Q 2 represents -Represents CH 2 NHR 5 ]
- Compound (2b) can be produced by condensing compound (6) and compound (5b) under the conditions of reductive amination reaction well known to those skilled in the art.
- the compound (2b) is reacted with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent in the presence or absence of an acid such as acetic acid.
- a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
- a solvent in the presence or absence of an acid such as acetic acid.
- Compound (6) can be produced according to a method well known to those skilled in the art (for example, the methods described in International Publication Pamphlet Nos. WO2010 / 133885, WO2012 / 066635, and WO2012 / 0666336).
- X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined above, and Y 1 is — (CR 9 R 10 ) p —, —CH ⁇ CH- (CR 9 R 10 ) q- ,
- Compound (7) can be produced according to a method well known to those skilled in the art (see International Publication Pamphlet Nos. WO2010 / 133885, WO2012 / 0666336, etc.).
- the leaving group LG of the compound (8) is not particularly limited as long as it is a leaving group well known to those skilled in the art, and a halogen atom, an alkylsulfonyloxy group, an arylsulfonyloxy group, or the like can be appropriately used.
- Compound (8) is obtained by, for example, reacting compound (7) with methanesulfonyl chloride, p-toluenesulfonyl chloride or the like in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, sodium carbonate or potassium carbonate.
- a base such as triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, sodium carbonate or potassium carbonate.
- the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 120 ° C.
- Compound (2b) can be produced by reacting compound (8) with compound (5a) in the presence of a base in an inert solvent.
- the base is not particularly limited as long as it is used as a base in a normal reaction.
- Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine; sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, And inorganic bases such as sodium hydride.
- the base With respect to the use amount of the base, it can be generally used 0.1 to 100 equivalents, preferably 1 to 3 equivalents, relative to compound (8).
- the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; acetonitrile, N , N′-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide and the like, and a mixture thereof may be used.
- the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 120 ° C.
- L is a substituted or unsubstituted alkylene having a carbon number of 2 ⁇ 6
- Compound (2b) can be produced using compound (9) and compound (5c) by a method similar to step 2 described in production method 3 for compound (2).
- Compound (9) can be produced according to a method well known to those skilled in the art (see International Publication Pamphlet Nos. WO2010 / 133885, WO2012 / 0666336, etc.).
- L ′ represents a substituted or unsubstituted alkylene group having 1 to 5 carbon atoms
- Y 1 is a single bond, — (CR 9 R 10 ) p —, —CH ⁇ CH— (CR 9 R 10 ) q —,
- the present invention includes a production intermediate in the production method. Specifically, the formula (2):
- R 1 and R 2 independently represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and when the alkyl group is substituted, the following groups: A hydroxy group, a halogen atom and an alkoxy group having 1 to 6 carbon atoms, May be substituted with the same or different 1 to 4 substituents selected from R 3 represents an alkyl group, alkoxy group or alkylthio group having 1 to 6 carbon atoms having 1 to 6 carbon atoms having 1 to 6 carbon atoms, R 4 represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a cyano group, Y 1 is a single bond
- R 9 , R 10 , R 9 ′ and R 10 ′ are each independently a hydrogen atom or 1 to Represents an alkyl group of 4), Y 2 represents a single bond or -C (O)-, L represents a substituted or unsubstituted divalent group of a straight-chain alkylene having 2 to 6 carbon atoms or a 4- to 8-membered cycloalkane;
- the linear alkylene or cycloalkane is substituted, the following group: May be substituted with the same or different 1 to 4 substituents selected from an alkyl group having 1 to 5 carbon atoms, a hydroxy group and a halogen atom, Any one methylene group in the linear alkylene in L may be replaced by a carbonyl group;
- R 5 and R 6 independently represent a hydrogen atom, a substituted or unsubstituted
- the alkyl group When the alkyl group is substituted, it may be substituted with the same or different 1 to 4 substituents selected from a hydroxy group and a halogen atom, When the 4- to 8-membered nitrogen-containing saturated heterocyclic ring or the 5- to 8-membered nitrogen-containing saturated heterocyclic ring is substituted, a methyl group, ethyl group, propyl group, hydroxymethyl group, hydroxyethyl group, carbonyl group, hydroxy group May be substituted with the same or different 1 to 4 substituents selected from a group and a halogen atom, p represents an integer of 1 to 6, q and q ′ independently represent an integer of 0 to 4, r represents an integer of 0 to 5, r ′ represents an integer of 1 to 5, the sum of r and r ′ is 5 or less, and when Y 2 is a single bond, r ′ represents an integer of 2 or more.
- R 8 represents a hydrogen atom or an amino-protecting group.
- the protecting group for R 8 is not particularly limited, and examples thereof include groups commonly used as amino-protecting groups. Specifically, carbamates such as t-butoxycarbonyl group, benzyloxycarbonyl group and 9-fluorenylmethyloxycarbonyl group, sulfones such as benzyl group and nosyl group, imides such as phthalimide, etc. Can do.
- any production process of the present invention if it is necessary to protect a specific functional group (such as a hydroxyl group or an amino group) in a reaction reagent with a protecting group, it can be appropriately performed by a method well known to those skilled in the art at an appropriate stage. Alternatively, protection / deprotection with more protecting groups can be performed.
- a specific functional group such as a hydroxyl group or an amino group
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound represented by formula (1) as defined above or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.
- the pharmaceutical composition can be used as an adjuvant for maintaining or enhancing the immunostimulatory activity of an active ingredient having immunostimulatory activity. That is, the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of inducing or enhancing an antigen-specific antibody, specifically an antigen-specific IgG, more specifically a Th1-type antigen-specific IgG (for example, IgG2c).
- the compound of the present invention or a pharmaceutically acceptable salt thereof induces or enhances CD4 positive (ie, MHC class 2 restricted) and / or CD8 positive (ie, MHC Class 1 restricted) T lymphocytes.
- the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of inducing or enhancing MHC-restricted antigen-specific T lymphocytes.
- the compound of the present invention or a pharmaceutically acceptable salt thereof has an activity of inducing or enhancing memory T lymphocytes, specifically CD8 positive effector memory T lymphocytes.
- the compound of the present invention or a pharmaceutically acceptable salt thereof induces systemic inflammatory mediator when administered to a mammal, that is, interferon- ⁇ , interferon- ⁇ , IL-6 or IP-10 in blood. It has the characteristic that the effect
- the pharmaceutical composition can contain an antigen.
- the antigen include a tumor antigen protein, or a tumor antigen peptide derived from the tumor antigen protein (eg, NY-ESO-1, MAGE-3, WT1, or Her2 / neu), an antibody hypervariable region, a pathogen-derived antigen, such as a virus.
- proteins derived from pathogens such as bacteria, partial peptides thereof, and the like, and complexes of these antigens and carriers are also included in the category of antigens in the present specification.
- Such complexes include those in which an antigen (including but not limited to proteins and peptides) is chemically cross-linked with a carrier protein and a linker well known to those skilled in the art, and the antigen is a virus-like particle. Examples include those contained in (Virus-like Particle; VLP). Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a drug for treating or preventing cancer or infectious diseases such as viruses or bacteria when used in combination with the antigen.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as an adjuvant for assisting the immunostimulatory action in other therapeutic methods for inducing an immunological or immune response.
- Specific therapies include, for example, ex-vivo and in-vivo approaches to increase the immunogenicity of a patient's tumor cells (eg, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor) ), Approaches to reduce T cell anergy, approaches using transfected immune cells (eg, cytokine transfected dendritic cells), approaches using cytokine transfected tumor cell lines, immunosuppressive cells (eg, regulatory properties) Examples include an approach for reducing the function of T cells, bone marrow-derived suppressor cells, or IDO (indoleamine 2,3-dioxygenase) -expressing dendritic cells), radiotherapy that induces an immune response, and the like.
- cytokines such as interleuk
- Examples of the route of administration of the pharmaceutical composition include parenteral administration, specifically, intravascular (for example, intravenous), subcutaneous, intradermal, intramuscular, nasal, and transdermal administration.
- parenteral administration specifically, intravascular (for example, intravenous), subcutaneous, intradermal, intramuscular, nasal, and transdermal administration.
- the pharmaceutical composition of the present invention may contain a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
- Examples of the form of the pharmaceutical composition of the present invention include an injection or nasal solution, or a lyophilized preparation prepared by lyophilizing the solution.
- an injectable solution for example, an emulsion containing an aqueous solution and an oily composition, a liposome preparation, an active ingredient and / or a compound represented by formula (1) or a pharmaceutically acceptable salt thereof is dissolved or dispersed in water.
- Aqueous solution preparation or aqueous suspension, or active ingredient and / or oily solution preparation or oil suspension obtained by dissolving or dispersing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof in oil, etc. Is mentioned.
- an emulsion containing an aqueous solution and an oily composition, a liposome preparation, or an active ingredient and / or a compound represented by formula (1) or a pharmaceutically acceptable salt thereof is dissolved in water.
- examples thereof include a dispersed aqueous solution preparation or an aqueous suspension.
- examples of the aqueous solution, aqueous solution preparation or aqueous suspension include distilled water for injection, an aqueous buffer or aqueous suspension containing an appropriate buffer, a pH regulator, a stabilizer, an isotonic agent or an emulsifier. Can be mentioned.
- oily compositions, oily solution preparations, and oily suspensions include compositions containing vegetable oils, animal fats, hydrocarbons, fatty acid esters, and the like, and more specifically, include squalene, squalane and the like.
- a composition As the emulsion, an oil-in-water emulsion or a water-in-oil emulsion can be used.
- the oil used in the oil-in-water emulsion is not particularly limited as long as it is a component that can dissolve or uniformly disperse the compound represented by the formula (1) (or a pharmaceutically acceptable salt thereof).
- the oil used in the water-in-oil emulsion is not particularly limited as long as it is a component that can dissolve or uniformly disperse the compound represented by the formula (1) (or a pharmaceutically acceptable salt thereof).
- examples include fats and oils, animal fats and oils, hydrocarbons, and fatty acid esters.
- an oil-in-water emulsion containing 0.1 to 10% by weight of squalene can be mentioned.
- One embodiment includes an oil-in-water emulsion containing 0.001 to 1% by weight of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, and 1 to 10% by weight of squalene.
- the oil-in-water emulsion may further contain one or more surfactants or buffers.
- surfactant examples include polysorbates, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycols, polyhydric alcohol fatty acid esters, fatty acid esters, and the like, which maintain a uniform emulsified state.
- the surfactant include polysorbates, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycols, polyhydric alcohol fatty acid esters, fatty acid esters, and the like, which maintain a uniform emulsified state.
- the surfactant include polysorbates, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycols, polyhydric alcohol fatty acid esters, fatty acid esters, and the like, which maintain a uniform emulsified state.
- the buffer include phosphates and organic acid salts.
- excipients When preparing a lyophilized preparation, excipients can be added as appropriate.
- the excipient include sugars, sugar alcohols, amino acids, sodium chloride, and the like, and are not particularly limited as long as they are components and blending ratios suitable for forming a good freeze-dried cake or freeze-dried powder. For example, 0.1 to 20% mannitol and the like can be mentioned.
- the pharmaceutical composition of the present invention may further contain other additives, and examples of the additives include surfactants, antioxidants, preservatives, soothing agents and the like.
- the compound of the formula (1) or a pharmaceutically acceptable salt thereof can be administered simultaneously with the antigenic substance (immunogen) or at a time difference, and the dosage is usually 5 to 5000 mg / m for a warm-blooded animal.
- 2 body surface area
- a unit dose ranging from about 0.1 ng / kg to 100 mg / kg, which usually results in a prophylactically or therapeutically effective dose.
- Unit dosage forms such as injections, tablets or capsules usually contain, for example, 1 ng to 250 mg of active ingredient.
- a dose in the range of 1 ng to 50 mg / kg per day is used.
- the daily dose will also need to be varied depending on the host treated, the particular route of administration and the severity of the illness being treated.
- the optimum dose can be determined by a practitioner who treats individual patients or warm-blooded animals.
- treatment is used in a sense that includes alleviating, in whole or in part, any or some or all of the symptoms of a disease, or preventing or delaying the progression of a disease state. .
- prevention refers to primary prevention (preventing the onset of disease) or secondary prevention (preventing recurrence for patients whose symptoms have been alleviated or the disease has been cured after the onset of the disease). , Used to mean recurrence prevention).
- the compound of the present invention or a pharmaceutically acceptable salt thereof has immunoadjuvant activity in vitro or in vivo, it is useful as a vaccine adjuvant for maintaining or enhancing the immunogenicity of an antigen.
- the compound of the present invention or a pharmaceutically acceptable salt thereof maintains or improves the action of an immunostimulatory substance (immunostimulatory substance), that is, a substance that induces an antigen-specific immune response, which is a therapeutic or preventive agent for diseases.
- an immunostimulatory substance that is, a substance that induces an antigen-specific immune response, which is a therapeutic or preventive agent for diseases.
- a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof and a substance that enhances an antigen-specific immune response (also referred to as an antigen) is also an embodiment of the present invention.
- the antigen is not particularly limited, and examples thereof include an antigen protein, an antigen peptide (partial peptide) derived from the antigen protein, and a complex of these and a carrier.
- a compound of the invention or a pharmaceutically acceptable salt thereof is treated or prevented by administering in combination with a tumor antigen protein or tumor antigen peptide for cancer immunotherapy.
- cancer include bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, ovarian cancer, pancreas, intestine and colon cancer, gastric cancer, skin cancer and brain tumor, bone marrow (including leukemia) And malignant diseases (such as Hodgkin lymphoma and non-Hodgkin lymphoma) that affect the lymphoproliferative system.
- treatment or prevention of cancer includes prevention of metastatic disease and tumor recurrence, and prevention and treatment of paraneoplastic syndromes).
- the antigen is not particularly limited, but for example, MAGE (Science, 254: p1643 (1991)), gp100 (J. Exp. Med., 179: p1005 (1994)), MART-1 (Proc. Natl. Acad. Sci. USA, 91: p3515 (1994)), tyrosinase (J. Exp. Med., 178: p489 (1993)), MAGE-related proteins (J. Exp. Med., 179: p921 (1994)), ⁇ -Catenin (J. Exp. Med., 183: p1185 (1996)), CDK4 (Science, 269: p1281 (1995)), HER2 / neu (J. Exp.
- MAGEA3 peptide 168-176 (Coulie PG et al., Immunol. Rev. 188: 33 (2002)), gp100 peptide 209-217 (Rosenberg SA et al., Nat. Med. 4: 321 (1998)), gp100 peptide 280-288 (Phan GQ et al., Proc. Natl. Acad. Sci. USA 100: 8372 (2003)), Melan-A peptide 27-35 (Cormier JN et al., Cancer J. Sci. Am.
- the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered in combination with an active ingredient of an infectious disease preventive vaccine to produce various infectious diseases such as genital warts, common warts, plantar warts. , Hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, smallpox, human immunodeficiency virus (HIV), human papilloma virus (HPV), RS virus, norovirus, cytomegalovirus (CMV), chickenpox Viral diseases such as herpes virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, parainfluenza; bacterial diseases such as tuberculosis, mycobacterium avium, leprosy; mycosis, chlamydia, candida, aspergillus, cryptococcus marrow Membitis, Pneumocystis carini, Cryptosporidium Can prevent histoplasm
- the active ingredient of the infectious disease prevention vaccine is not particularly limited, and examples include substances derived from microorganisms and pathogens such as bacteria, fungi, protozoa, and viruses that cause infectious diseases. Examples include antigen peptides (partial peptides), polysaccharides, lipids, and combinations thereof, or combinations of substances and carriers derived from the microorganisms and pathogens.
- the viral antigen peptide derived from the viral antigen is not particularly limited.
- influenza matrix protein peptide 58-66 (Jager E et al., Int. J. Cancer 67:54 (1996)), HPV16 E7 peptide 86 -93 (van Driel WJ et al., Eur. J. Cancer 35: 946 (1999)), HPV E7 peptide 12-20 (Scheibenbogen C et al., J. Immunother 23: 275 (2000)), HPV16 E7 peptide 11-20 (Smith JWI et al., J. Clin. Oncol.
- the carrier used in the present invention is a substance that chemically and / or physically binds an antigenic protein or antigenic peptide.
- examples thereof include proteins and lipids, and are not particularly limited.
- CRM197 Vaccine. 2013
- KLH Cancer Immunol Immunother. 2003 Oct; 52 (10): 608-16
- virus-like particles PoS ONE 5 (3): e9809
- liposomes J Liposome Res. IV 2004; 14 (3-4): 175-89.
- the antigenic protein can be prepared by cloning a cDNA encoding the antigenic protein and expressing it in a host cell according to a basic book such as Molecular Cloning 2nd Edt., Cold Spring Harbor Laboratoy Press (1989).
- the synthesis of the antigen peptide can be performed according to a method used in normal peptide chemistry.
- the synthesis method is described in literature (Peptide Synthesis, Interscience, New York, 1966; The Proteins, Vol. 2, Academic Press Inc., New York, 1976). The method is mentioned.
- the present invention further provides a kit comprising: a) a compound represented by formula (1), or a pharmaceutically acceptable salt thereof; b) an antigen; and c) a container or device for containing the unit dosage forms of a) and b) together or independently.
- the antigen is not particularly limited as long as it is an antigen that can be used as an active ingredient of a vaccine.
- the antigen protein described above or an antigen peptide (partial peptide) derived from the antigen protein, and the like and a carrier A composite etc. are mentioned.
- One aspect of the present invention provides the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof, for the manufacture of a vaccine adjuvant. Moreover, as one aspect of the present invention, use of a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof as a vaccine adjuvant in the manufacture of a vaccine for the treatment of a disease or condition I will provide a.
- treatment, prevention or prevention of a disease comprising the step of administering a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof together with an antigen to a patient.
- a method comprising the step of administering a compound represented by formula (I) as defined above or a pharmaceutically acceptable salt thereof together with an antigen to a patient.
- Example 1 (4E, 8E, 12E, 16E, 20E) -N- ⁇ 2-[ ⁇ 4-[(2-Amino-4- ⁇ [(3S) -1-hydroxyhexane-3-yl] amino ⁇ -6-methyl Pyrimidin-5-yl) methyl] benzyl ⁇ (methyl) amino] ethyl ⁇ -4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaenamide
- Process 1 Dissolve methyl 4- (2- (ethoxycarbonyl) -3-oxobutyl) benzoate (3.56 g, 12.8 mmol) and guanidine carbonate (4.61 g, 25.6 mmol) in methanol (23 ml) and heat to reflux Stirred for 7 hours.
- the reaction solution was allowed to cool, 30 ml of water and acetic acid (0.660 ml, 11.5 mmol) were added, and the precipitated solid was collected by filtration.
- the obtained solid was suspended in THF and stirred for 1 hour under heating and refluxing, and the reaction solution was allowed to cool and then collected. This solid was washed with THF and dried to obtain the desired product (1.62 g, 46%).
- Process 2 The compound obtained in Step 1 (1.62 g, 5.93 mmol) and N, N, N ′, N′-tetramethyl-1,3-propanediamine (1.41 ml, 8.89 mmol) were suspended in THF (24 ml). 2-mesitylenesulfonyl chloride (1.94 g, 8.89 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
- Step 6 (S) -4-((2-Amino-4-((1-hydroxyhexane-3-yl) amino) -6-methylpyrimidin-5-yl) methyl) benzaldehyde (0.28 g, 0.82 mmol) in chloroform ( 8 mL), t-butyl (2- (methylamino) ethyl) carbamate (0.29 g, 1.6 mmol), acetic acid (0.23 mL, 4.1 mmol) and sodium triacetoxyborohydride (0.52 g, 2.5 mmol). ) was added. After stirring overnight at room temperature, water was added and the mixture was extracted with ethyl acetate.
- Step 7 (S) -t-Butyl (2-((4-((2-amino-4-((1-hydroxyhexane-3-yl) amino) -6-methylpyrimidin-5-yl) methyl) benzyl) ( Methyl) amino) ethyl) carbamate (0.150 g, 0.29 mmol) was dissolved in chloroform (4 mL), and hydrogen chloride (4M cyclopentyl methyl ether solution (2.2 ml, 8.80 mmol)) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure.
- Example 4 4-[(2-Amino-4- ⁇ [(2S) -1-hydroxypentan-2-yl] amino ⁇ -6-methylpyrimidin-5-yl) methyl] -N- (2- ⁇ [(4E, 8E, 12E, 16E, 20E) -4,8,12,17,21,25-hexamethylhexacosa-4,8,12,16,20,24-hexaenoyl] amino ⁇ ethyl) -3-methoxybenzamide
- mice C57BL / 6 mice were given an initial mixture of ovalbumin (OVA) (1 mg / mL) and the compound of the above example (0.1 mg / mL) (100 ⁇ L / mouse) intramuscularly in the gastrocnemius muscle. Two weeks later, an equal volume of the same mixture was intramuscularly administered to the gastrocnemius muscle for booster immunization. One week after the booster immunization, heart blood was collected under isoflurane inhalation anesthesia, plasma was collected by centrifugation, and the OVA-specific IgG level in the plasma was determined by ELISA using mouse anti-ovalbumin IgG ELISA kit (Alpha Diagnostic). (See FIG. 1).
- OVA ovalbumin
- OVA-specific IgG1 and IgG2c values in the plasma of the immunized mice were quantified by ELISA. That is, after adding an OVA solution (SIGMA) to a 96-well plate, blocking with 1% skim milk (Wako Pure Chemical Industries), adding a plasma sample diluted with a phosphate buffer, and then using a secondary antibody A goat anti-mouse IgG1 (Jackson) or IgG2c (Southern Bio) was added, and after adding SureBlue TM TMB microwell peroxidase substrate (KPL), the product of the enzyme reaction was measured with a microplate reader (see FIG. 2). .
- SIGMA OVA solution
- skim milk Wako Pure Chemical Industries
- KPL SureBlue TM TMB microwell peroxidase substrate
- All compounds of Examples 1-5 induced OVA specific IgG more strongly compared to the negative control group.
- the compounds of Example 1 and Example 4 induced significant OVA-specific IgG production relative to the negative control group.
- the compounds of Example 1 and Example 4 are significantly more effective than the negative control group in the ratio of IgG2c, which is one of Th1-type IgG, to IgG1, which is one of Th2-type IgG, among OVA-specific antibodies. Increased to
- Test Example 2 Spleen cells of the mouse of Test Example 1 were prepared and cultured overnight after adding OVA and Brefeldin A (eBioscience). The cells were collected, stained with APC-labeled anti-mouse CD3e antibody, FITC-labeled anti-mouse CD4 antibody, and Fixable Viability Dye eFluor (registered trademark) 450 (eBioscience), and then fixed with Fixation / Permeabilization buffer (eBioscience). The cells were stained with antibody cocktail PerCP-Cy5.5-labeled anti-IFN- ⁇ antibody, PE-Cy7-labeled anti-IL-2 antibody, and PE-labeled TNF- ⁇ (eBioscience) after treatment with Permeabilization buffer (eBioscience).
- the above spleen cells were divided into antibody cocktail eFluor450-labeled anti-mouse CD3e antibody, Alexa Fluor647-labeled anti-mouse CD8 antibody, PE-Cy7-labeled anti-mouse CD44 antibody, PerCP-Cy5.5-labeled anti-mouse CD62L antibody and Fixable Viability Dye520 (eBioscience). Stained with Data acquisition and analysis were performed using FACS Cant II (BD Biosciences) and FLOWJO software (TreeStar). The results are shown in FIG.
- Example 1 and Example 4 are proportions of OVA-specific multifunctional CD4-positive T lymphocytes, proportion of MHC-restricted OVA-specific CD8-positive T lymphocytes, and proportion of CD8-positive effector memory T lymphocytes. was significantly increased compared to the negative control group.
- the compound of the present invention is useful as an adjuvant for enhancing the immunostimulatory action used by adding to a vaccine preparation.
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Abstract
Description
アジュバントは、抗原に対する液性免疫応答及び/又は細胞性免疫応答を高める添加剤であり、アラム(Alum)、サポニン(saponin)等がワクチンアジュバントとして用いられている。
最近になって、Toll様受容体(Toll-like Receptor; TLR)が微生物に対する生体の防御機構の一つである、自然免疫の賦活に重要な役割を果たしており、モノホスホリルリピッドA (MPL)、CPG ODN等が、TLRを介して免疫賦活作用を示していることが判明した。
ヒトで特定されている既知の13のTLRのうち、5つは細菌の構成成分の認識に関連し(TLR1, 2, 4, 5, 6)、他の4つ(TLR3, 7, 8, 9)は細胞質区画に拘束され、ウイルスRNA(TLR3,7,8)と非メチル化DNA(TLR9)の認識にも関与すると言われる(非特許文献1を参照)。
TLR7及びTLR8の場合、その作動薬(Activator)として、天然リガンドであるウイルスの一本鎖RNAを模倣した低分子が知られている。例えば、ピリミジン化合物(特許文献1及び2を参照)及びイミダゾキノリン化合物(特許文献3を参照)等の合成化合物が報告されている。
また、TLR7及び/又はTLR8作動薬(Activator)は、DC活性化に加えて、B細胞を活性化し、さらにNK細胞を刺激してIFNγ産生を促すなどの活性が知られており、ワクチンアジュバント活性を有することが期待される。実際に、Resiquimod又はImiquimodなどのTLR7/TLR8作動薬のアジュバント活性が報告されている(非特許文献2を参照)
以上のことから、TLR7及び/又はTLR8を活性化する、新たなワクチンアジュバントの開発が求められている。
一方、スクワレンは、水中油型もしくは油中水型エマルション製剤における油成分として用いられている油状物質であり、スクワレンを含有するアジュバントとして、MF59が挙げられ、インフルエンザワクチンのアジュバントとして用いられている(非特許文献3、4及び5を参照)。
TLR7/8作動薬と他の物質との複合体としては、脂肪酸とイミダゾキノリン化合物を共有結合で連結させたワクチンアジュバント(特許文献4、5、6及び非特許文献6を参照)や、脂肪酸グリセリドとイミダゾキノリン化合物の複合体(特許文献7を参照)、脂肪酸グリセリドとアデニン化合物の複合体(特許文献8を参照)、リン脂質とアデニン化合物の複合体(特許文献9を参照)が知られている。また、脂肪酸グリセリドとアデニン化合物のポリエチレングリコールを介した複合体(特許文献10を参照)も知られている。
しかしながら、TLR7/8作動薬とスクワレン類の複合体は全く知られていなかった。
〔1〕 式(1):
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、前記アルキル基が置換されている場合には、以下の群:
ヒドロキシ基、ハロゲン原子、炭素数1から6のアルコキシ基、
から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基、炭素数1~6のアルコキシ基又は炭素数1~6のアルキルチオ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基又はシアノ基を表し、
Y1は、単結合、-(CR9R10)p-、-CH=CH-(CR9R10)q-、
Y2は、単結合又は-C(O)-を表し、
Lは、置換もしくは無置換の炭素数2~6の直鎖アルキレン又は4~8員のシクロアルカンの二価基を表し、
前記直鎖アルキレン又はシクロアルカンが置換されている場合には、以下の群:
炭素数1~5のアルキル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
L中の直鎖アルキレンにおける任意の1つのメチレン基はカルボニル基で置き換えられてもよく、
R5及びR6は、独立して水素原子、置換もしくは無置換の炭素数1~6のアルキル基を表すか、あるいは、R5もしくはR6のどちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成しているか、又は、R5及びR6が一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、
前記アルキル基が置換される場合、ヒドロキシ基、ハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
前記4~8員の含窒素飽和ヘテロ環又は前記5~8員の含窒素飽和ヘテロ環が置換される場合、メチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、カルボニル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
mは0又は1を表し、
pは1~6の整数を表し、
q及びq’は独立して、0~4の整数を表し、
rは0~5の整数を表し、r’は1~5の整数を表し、r及びr’の和が5以下であり、Y2が単結合の場合、r’は2以上の整数を表し、
で示される、化合物又はその薬学上許容される塩;
〔2〕Xは、メチレン、酸素原子又はNR7(R7は水素原子又は炭素数1~3のアルキル基を表す)を表し、
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、
前記アルキル基が置換されている場合には、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表す、〔1〕に記載の化合物又はその薬学上許容される塩;
〔3〕
〔4〕Y1は、単結合、-(CR9R10)p-(R9及びR10は独立して水素原子又は炭素数1~4のアルキル基を表す)を表し、Y2は単結合又は-C(O)-を表す、〔1〕~〔3〕のいずれかに記載の化合物又はその薬学上許容される塩;
〔5〕Y1は、単結合を表し、Y2は-C(O)-を表す、〔4〕に記載の化合物又はその薬学上許容される塩;
〔6〕Y1は、-(CR9R10)p-(R9及びR10は独立して水素原子又は炭素数1~4のアルキル基を表す)を表し、pは1~3の整数を表し、Y2は単結合を表す、〔4〕に記載の化合物又はその薬学上許容される塩;
〔7〕Y1は、-(CR9R10)r-O-(CR9’R10’)r’-を表し(R9、R10、R9’及びR10’は独立して水素原子又は炭素数1~4のアルキル基を表す)、r及びr'は独立して、0、1又は2を表す、〔3〕に記載の化合物又はその薬学上許容される塩;
〔8〕Lが、炭素数2又は3の直鎖アルキレンを表す、〔1〕~〔7〕のいずれかに記載の化合物又はその薬学上許容される塩;
〔9〕Xは、メチレンを表し、
R1は水素原子、又はヒドロキシ基で置換されていてもよい炭素数1~3のアルキル基を表し、
R2は、水素原子、又は炭素数1~6のアルキル基を表し、
R3は、炭素数1~3のアルキル基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表し、
Y1は、単結合又はメチレンを表し、
Y2は、単結合又は-C(O)-を表し、
Lは、炭素数2又は3の直鎖アルキレンを表し、
R5及びR6は、独立して水素原子又は炭素数1~3のアルキル基を表すか、あるいは、R5は、R6と一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、前記5~8員の含窒素飽和ヘテロ環が置換されている場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
mは0又は1を表し、
〔10〕〔1〕~〔9〕のいずれかに記載の化合物又はその薬学上許容される塩を含む医薬組成物;
〔11〕更に、抗原を含む〔10〕に記載の医薬組成物;
〔12〕抗原が、病原体由来抗原又は腫瘍抗原である、〔11〕に記載の医薬組成物;
〔13〕抗原が、ペプチド又はタンパク質である、〔11〕又は〔12〕に記載の医薬組成物;
〔14〕〔1〕~〔9〕のいずれかに記載の化合物又はその薬学上許容される塩を含む、ワクチンアジュバント;
〔15〕ワクチンアジュバントとして用いられる、〔1〕~〔9〕のいずれかに記載の化合物又はその薬学上許容される塩;
〔16〕〔1〕~〔9〕のいずれかに記載の化合物又はその薬学上許容される塩を哺乳動物に投与することを含む、哺乳動物における抗原特異的免疫反応を増強させる方法;
〔17〕〔1〕~〔9〕のいずれかに記載の化合物又はその薬学上許容される塩を哺乳動物に投与することを含む、哺乳動物の免疫応答能を向上させる方法;
〔18〕〔1〕~〔9〕のいずれかに記載の化合物又はその薬学上許容される塩の、ワクチンアジュバントの製造のための使用;
〔19〕式(2):
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、前記アルキル基が置換されている場合には、以下の群:
ヒドロキシ基、ハロゲン原子及び炭素数1から6のアルコキシ基、
から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基、炭素数1~6のアルコキシ基又は炭素数1~6のアルキルチオ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基、炭素数1~6のアルコキシ基、又はシアノ基、を表し、
Y1は、単結合、-(CR9R10)p-、-CH=CH-(CR9R10)q-、
Y2は、単結合又は-C(O)-を表し、
Lは、置換もしくは無置換の炭素数2~6の直鎖アルキレン又は4~8員のシクロアルカンの二価基を表し、
前記直鎖アルキレン又はシクロアルカンが置換されている場合には、以下の群:
炭素数1~5のアルキル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
L中の直鎖アルキレンにおける任意の1つのメチレン基はカルボニル基で置き換えられてもよく、
R5及びR6は、独立して水素原子、置換もしくは無置換の炭素数1~6のアルキル基を表すか、あるいは、R5もしくはR6のどちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成しているか、又は、R5及びR6が一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、
前記アルキル基が置換される場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
前記4~8員の含窒素飽和ヘテロ環又は前記5~8員の含窒素飽和ヘテロ環が置換される場合、メチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、カルボニル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
pは1~6の整数を表し、
q及びq’は独立して、0~4の整数を表し、
rは0~5の整数を表し、r’は1~5の整数を表し、r及びr’の和が5以下であり、Y2が単結合の場合、r’は2以上の整数を表し、
R8は、水素原子又はアミノ基の保護基を表す。]
で示される、化合物又はその薬学上許容される塩;及び
〔20〕式(2)において、Xはメチレンを表し、
R1は、水素原子又はヒドロキシ基で置換されていてもよい炭素数1~3のアルキル基を表し、
R2は、水素原子又は炭素数1~6のアルキル基を表し、
R3は、炭素数1~3のアルキル基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表し、
Y1は、単結合又はメチレンを表し、
Y2は、単結合又は-C(O)-を表し、
Lは、炭素数2又は3の直鎖アルキレンを表し、
R5及びR6は、独立して、水素原子、炭素数1~3のアルキル基を表すか、あるいは、R5は、R6と一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、前記5~8員の含窒素飽和ヘテロ環が置換されている場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよい、〔19〕に記載の化合物又はその薬学上許容される塩。
また、式(1)で表される化合物のいずれか1つ又は2つ以上の1Hを2H(D)に変換した重水素変換体も式(1)で表される化合物に包含される。
「直鎖アルキレン」としては、炭素数1~6の直鎖アルキレンが挙げられる。直鎖アルキレンとして具体的には、メチレン、エチレン、n-プロピレン又はn-ブチレンが挙げられるがこれらに限定されない。
「アルキル基」としては、炭素数1~6の直鎖もしくは分枝のアルキル基が挙げられる。アルキル基として具体的には、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル又はtert-ブチルが挙げられるがこれらに限定されない。
「シクロアルカン」としては、4~8員のシクロアルカンが挙げられる。具体的には、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン又はシクロオクタンが挙げられ、好ましくは、シクロペンタン、シクロヘキサン又はシクロヘプタンが挙げられる。
「シクロアルカンの二価基」としては特に限定は無いが、具体的には、前記シクロアルカンの異なる炭素原子上で隣接する原子と結合可能な二価基を挙げることができる。
「5~8員の含窒素飽和ヘテロ環」としては、上記4~8員の含窒素飽和ヘテロ環のうち、5~8員のものを挙げることができる。
当該含窒素飽和ヘテロ環が置換される場合の置換基として、好ましくは、メチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、カルボニル基、ヒドロキシ基又はハロゲン原子、更に好ましくはヒドロキシ基又はハロゲン原子が挙げられ、同一もしくは異なる1~4個の置換基で置換されていてもよい。
式(1)において、R1は、好ましくは、水素原子又は炭素数1~4のアルキル基を表す。具体的なR1としては、メチル基、エチル基、プロピル基又はブチル基が挙げられる。
式(1)において、R2は、水素原子、又は置換もしくは無置換の炭素数1~4のアルキル基を表す。ここで前記アルキル基が置換されている場合の置換基として具体的にはヒドロキシ基が挙げられる。具体的なR2として、好ましくは、水素原子、メチル基、エチル基、プロピル基、ヒドロキシメチル基又はヒドロキシエチル基等が挙げられる。
式(1)において、R3は、好ましくは、炭素数1~4のアルキル基、炭素数1~4のアルコキシ基又は炭素数1~4のアルキルチオ基を表し、更に好ましくは、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表す。具体的なR3として、好ましくは、メチル基、エチル基、プロピル基又はブチル基、更に好ましくはメチル基が挙げられる。
式(1)において、Y1は、好ましくは、単結合、-(CR9R10)p-、又は-(CR9R10)r-O-(CR9’R10’)r’-(R9、R10、R9’及びR10’は独立して水素原子又は炭素数1~4のアルキル基を表す)を表す。ここでR9、R10、R9’及びR10’は好ましくは独立して水素原子又はメチル基を表し、更に好ましくは水素原子を表す。Y1は、更に好ましくは、単結合又は-(CR9R10)p-を表す。
式(1)において、Y1が-(CR9R10)p-を表す場合、pは、好ましくは1~4の整数を表し、更に好ましくは、1、2又は3を表す。
式(1)において、Y1が-CH=CH-(CR9R10)q-、又は
式(1)において、Y1が-(CR9R10)r -O-(CR9’R10’)r’-を表す場合、rは、好ましくは0~3の整数を表し、r’は好ましくは1~4の整数を表す。ここでr及びr’の和は5以下であり、更に好ましくはrは0又は1を表し、r’は1又は2を表す。
好ましい態様として、Y1が単結合を表し、Y2が-C(O)-を表す態様が挙げられる。
好ましい態様として、Y1が-(CR9R10)p-を表し、Y2が単結合を表す態様が挙げられる。ここでR9及びR10は好ましくは独立して水素原子又はメチル基を表し、更に好ましくは水素原子を表す。また、pは好ましくは1~4の整数を表し、更に好ましくは、1、2又は3を表す。
R5及びR6は、どちらか一方が、L中の任意の炭素原子と結合して形成する4~8員の含窒素飽和ヘテロ環、又はR5及びR6が一緒になって形成する5~8員の含窒素飽和ヘテロ環が置換されている場合の置換基として、好ましくは、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基が挙げられる。
式(1)において、
Xは、メチレンを表し、
R1は炭素数1~4のアルキル基を表し、
R2は、水素原子、炭素数1~3のアルキル基、又は、ヒドロキシ基で置換された炭素数1~3のアルキル基を表し、
R3は、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基を表し、
Y1は、単結合又は-(CR9R10)p-を表し、
Y2は、-C(O)-を表し、
Lは、炭素数2~6の直鎖アルキレンを表し、
R5及びR6は、独立して水素原子又は炭素数1~3のアルキル基を表すか、あるいは、R5もしくはR6は、どちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成するか、又はR5は、R6と一緒になって置換もしくは無置換の4~8員の含窒素飽和ヘテロ環を形成してもよく、
mは0又は1、好ましくは1を表し、
Xは、メチレンを表し、
R1は炭素数1~4のアルキル基を表し、
R2は、水素原子、炭素数1~3のアルキル基、又はヒドロキシ基で置換された炭素数1~3のアルキル基を表し、
R3は、炭素数1~3のアルキル基、又は炭素数1~3のアルコキシ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基を表し、
Y1は、-(CR9R10)p-を表し、
Y2は、単結合を表し、
Lは、炭素数2~6の直鎖アルキレンを表し、
R5及びR6は、独立して水素原子又は炭素数1~3のアルキル基を表すか、あるいは、R5もしくはR6は、どちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成しているか、又はR5は、R6と一緒になって置換もしくは無置換の4~8員の含窒素飽和ヘテロ環を形成してもよく、
mは0又は1、好ましくは1を表し、
Xは、メチレンを表し、
R1は炭素数1~4のアルキル基を表し、
R2は、水素原子、炭素数1~3のアルキル基、又は、ヒドロキシ基で置換された炭素数1~3のアルキル基を表し、
R3は、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基を表し、
Y1が単結合を表しY2が-C(O)-を表すか、又はY1が-(CR9R10)p-を表しY2が単結合を表し、
Lは、炭素数2~6の直鎖アルキレンを表し、
R5及びR6は、独立して水素原子又は炭素数1~3のアルキル基を表し、
mは0又は1、好ましくは1を表し、
(4E,8E,12E,16E,20E)-N-{2-[{4-[(2-アミノ-4-{[1-ヒドロキシヘキサン-3-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]ベンジル}(メチル)アミノ]エチル}-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエンアミド;
(4E,8E,12E,16E,20E)-1-(4-{4-[(2-アミノ-4-{[1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-3-メトキシベンジル}ピペラジン-1-イル)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン-1-オン;
(4E,8E,12E,16E,20E)-1-(4-{4-[(2-アミノ-4-{[1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-3-メトキシベンゾイル}ピペラジン-1-イル)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン-1-オン;
4-[(2-アミノ-4-{[1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-N-(2-{[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエノイル]アミノ}エチル)-3-メトキシベンズアミド;及び
4-[(2-アミノ-4-{[1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-N-(2-{[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエノイル](メチル)アミノ}エチル)-3-メトキシベンズアミド。
又は、
(4E,8E,12E,16E,20E)-N-{2-[{4-[(2-アミノ-4-{[(3S)-1-ヒドロキシヘキサン-3-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]ベンジル}(メチル)アミノ]エチル}-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエンアミド;
(4E,8E,12E,16E,20E)-1-(4-{4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-3-メトキシベンジル}ピペラジン-1-イル)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン-1-オン;
(4E,8E,12E,16E,20E)-1-(4-{4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-3-メトキシベンゾイル}ピペラジン-1-イル)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン-1-オン;
4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-N-(2-{[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエノイル]アミノ}エチル)-3-メトキシベンズアミド;及び
4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-N-(2-{[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエノイル](メチル)アミノ}エチル)-3-メトキシベンズアミド。
原料化合物として用いられる化合物は、それぞれ塩として用いてもよい。尚、これらの製造方法は単なる例示であり、有機合成に習熟している者の知識に基づき、適宜、他の方法で製造することができる。
式(1)で表される化合物又はその塩は、例えば下記に示す方法によって製造される。
塩基としては、有機化学反応において塩基として当業者が使用するものであれば特に限定されないが、例えば、N-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、1,8-ジアザビシクロ[4.3.0]ノナ-5-エン、1,4-ジアザビシクロ[5.4.0]ウンデカ-7-エン、ピリジン、ジメチルアミノピリジン、ピコリン等の有機塩基;炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム等の無機塩基等が挙げられる。塩基の使用量としては、化合物(3)に対して通常0.1~100当量用いることができるが、好ましくは、1~5当量である。
縮合剤としては、実験化学講座(日本化学会編、丸善)22巻に記載されているもの等が挙げられる。例えば、シアノリン酸ジエチル、ジフェニルホスホリルアジド等のリン酸エステル類;1-エチル-3-(3-ジメチルアミノプロピル)-カルボジイミド塩酸塩(WSC・HCl)、ジシクロヘキシルカルボジイミド(DCC)等のカルボジイミド類;2,2'-ジピリジルジスルフィド等のジスルフィド類とトリフェニルホスフィンのようなホスフィン類の組み合わせ;N,N'-ビス(2-オキソ-3-オキサゾリジニル)ホスフィニッククロリド(BOPCl)等のリンハライド類;アゾジカルボン酸ジエチル等のアゾジカルボン酸ジエステルとトリフェニルホスフィン等のホスフィンの組み合わせ;2-クロロ-1-メチルピリジニウムヨーダイド等の2-ハロ-1-低級アルキルピリジニウムハライド類;1,1'-カルボニルジイミダゾール(CDI);ジフェニルホスホリルアジド(DPPA);ジエチルホスホリルシアニド(DEPC);2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム テトラフルオロボレート(TBTU)、2-クロロ-1,3-ジメチルイミダゾリジニウム テトラフルオロボレート(CIB)等のテトラフルオロボレート類;2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート(HBTU)、ベンゾトリアゾール-1-イルオキシトリス(ジメチルアミノ)ホスホニウム ヘキサフルオロホスフェート(BOP)、ベンゾトリアゾール-1-イルオキシトリス(ピロリジノ)ホスホニウム ヘキサフルオロホスフェート(PYBOP)、2-(7-アザ-1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート(HATU)等のホスフェート類等が挙げられる。
不活性溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、1,4-ジオキサン、1,2-ジメトキシエタン等のエーテル系溶媒;ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒;ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化炭化水素系溶媒;アセトン等のケトン系溶媒;アセトニトリル、N,N’-ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチルホスホルアミド等の非プロトン性溶媒等が挙げられ、これらの混合物であってもよい。反応温度は、特に限定されないが、好ましくは約-70℃~100℃の範囲から選択され、さらに好ましくは0℃~40℃である。
また、化合物(3)を、ハロゲン化試薬(例えば、1-クロロ-N,N,2-トリメチルプロペニルアミン、オキシ塩化リン、三塩化リン、塩化チオニル、五塩化リン等が挙げられる。)を用いて、酸ハライドに導いた後、不活性溶媒中、必要に応じて塩基の存在下、化合物(2)と反応させることにより、化合物(1)を製造することもできる。
不活性溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、1,4-ジオキサン、1,2-ジメトキシエタン等のエーテル系溶媒;ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒;ジクロロメタン、クロロホルム、ジクロロエタン等のハロゲン化炭化水素系溶媒;酢酸エチル、酢酸イソプロピル等のエステル系溶媒;メチルエチルケトン、アセトン等のケトン系溶媒;アセトニトリル、N,N’-ジメチルホルムアミド、ジメチルスルホキシド、ヘキサメチルホスホルアミド等の非プロトン性溶媒が挙げられる。塩基としては、例えば、N-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、1,8-ジアザビシクロ[4.3.0]ノナ-5-エン、1,4-ジアザビシクロ[5.4.0]ウンデカ-7-エン、ピリジン、ジメチルアミノピリジン、ピコリン等の有機塩基が挙げられる。ハロゲン化試薬は、化合物(3)に対して、0.1~100当量用いることができるが、好ましくは、0.8~3当量用いることができる。反応温度は、特に限定されないが、好ましくは約-30℃~60℃の範囲から選択される。
化合物(3)は、当業者に周知の方法(Org. Biomol. Chem. 2011, 9, 4367を参照)に従って製造することができる。
化合物(2)においてY2が-C(O)-を表す化合物(2a)又はその塩は、下記に示す方法で製造することができる。
化合物(2a)は、化合物(4)と化合物(5a)から、化合物(1)の製造方法に記載の方法に従って、合成することができる。
化合物(4)は、当業者に周知の方法(例えば、国際公開パンフレット第WO2009/067081号、同第WO2010/133885号に記載の方法)に従い製造することができる。
化合物(2)においてY2が単結合を表す化合物(2b)は、例えば以下の式で表される製造方法により、製造することができる。
化合物(2b)は、化合物(6)と化合物(5b)を、当業者に周知されている還元的アミノ化反応の条件によって縮合することにより製造することができる。具体的には、溶媒中、アルデヒド化合物及びアミン化合物を酢酸等の酸存在下又は非存在下、トリアセトキシ水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム等の還元剤と反応させることにより、化合物(2b)を製造することができる。
化合物(6)は、当業者に周知の方法(例えば、国際公開パンフレット第WO2010/133885号、同第WO2012/066335号、同第WO2012/066336号に記載の方法)に従い製造することができる。
化合物(2b)又はその塩は、下記に示す方法でも製造することができる。
化合物(7)は、当業者に周知の方法(国際公開パンフレット第WO2010/133885号、同第WO2012/066336号等を参照)に従い製造することができる。化合物(8)の脱離基LGは、当業者に周知されている脱離基であれば特に限定はなく、ハロゲン原子又はアルキルスルホニルオキシ基、アリールスルホニルオキシ基等を適宜用いることができる。化合物(8)は、例えば、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン、ジメチルアミノピリジン、炭酸ナトリウム、炭酸カリウム等の塩基存在下に、化合物(7)を塩化メタンスルホニル、塩化p-トルエンスルホニル等と反応させることにより、製造することができる。反応温度は、特に限定されないが、好ましくは約0℃~120℃の範囲から選択される。
化合物(2b)は、化合物(8)を不活性溶媒中、塩基存在下で化合物(5a)と反応させることにより製造することができる。
塩基としては、通常の反応において塩基として使用されるものであれば特に限定されないが、例えば、N-メチルモルホリン、トリエチルアミン、ジイソプロピルエチルアミン、トリブチルアミン、1,8-ジアザビシクロ[4.3.0]ノナ-5-エン、1,4-ジアザビシクロ[5.4.0]ウンデカ-7-エン、ピリジン、ジメチルアミノピリジン等の有機塩基;炭酸水素ナトリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水素化ナトリウム等の無機塩基等が挙げられる。塩基の使用量としては、化合物(8)に対して通常0.1~100当量用いることができるが、好ましくは、1~3当量用いることができる。
不活性溶媒としては、例えば、テトラヒドロフラン、ジエチルエーテル、1,4-ジオキサン、1,2-ジメトキシエタン等のエーテル系溶媒;ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素系溶媒;アセトニトリル、N,N’-ジメチルホルムアミド、N-メチルピロリドン、ジメチルスルホキシド等の非プロトン性溶媒が挙げられ、これらの混合物であってもよい。反応温度は、特に限定されないが、好ましくは約0℃~120℃の範囲から選択される。
化合物(2b)又はその塩は、下記に示す方法でも製造することができる。
化合物(2b)は、化合物(9)と化合物(5c)を用い、化合物(2)の製造方法3に記載されている工程2と同様の方法によって、製造することができる。
化合物(9)は、当業者に周知の方法(国際公開パンフレット第WO2010/133885号、同第WO2012/066336号等を参照)に従い製造することができる。
化合物(2c)又はその塩は、例えば下記に示す方法で製造することができる。
化合物(2c)は、化合物(9)と化合物(5d)を用い、化合物(1)の製造方法に記載されている方法によって、製造することができる。
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、前記アルキル基が置換されている場合には、以下の群:
ヒドロキシ基、ハロゲン原子及び炭素数1から6のアルコキシ基、
から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基、炭素数1~6のアルコキシ基又は炭素数1~6のアルキルチオ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基又はシアノ基を表し、
Y1は、単結合、-(CR9R10)p-、-CH=CH-(CR9R10)q-、
Y2は、単結合又は-C(O)-を表し、
Lは、置換もしくは無置換の炭素数2~6の直鎖アルキレン又は4~8員のシクロアルカンの二価基を表し、
前記直鎖アルキレン、又はシクロアルカンが置換されている場合には、以下の群:
炭素数1~5のアルキル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
L中の直鎖アルキレンにおける任意の1つのメチレン基はカルボニル基で置き換えられてもよく、
R5及びR6は、独立して水素原子、置換もしくは無置換の炭素数1~6のアルキル基を表すか、あるいは、R5もしくはR6のどちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成しているか、又は、R5及びR6が一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、
前記アルキル基が置換される場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
前記4~8員の含窒素飽和ヘテロ環又は前記5~8員の含窒素飽和ヘテロ環が置換される場合、メチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、カルボニル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
pは1~6の整数を表し、
q及びq’は独立して、0~4の整数を表し、
rは0~5の整数を表し、r’は1~5の整数を表し、r及びr’の和が5以下であり、Y2が単結合の場合、r’は2以上の整数を表し、
R8は、水素原子又はアミノ基の保護基を表す。]
で示される、化合物又はその塩が挙げられる。
式(2)中R8における保護基としては、特に限定はなく、アミノ基の保護基として汎用される基が挙げられる。具体的には、t-ブトキシカルボニル基、ベンジルオキシカルボニル基、9-フルオレニルメチルオキシカルボニル基等のカーバメート類、ベンジル基、ノシル基等のスルホン類、フタルイミド等のイミド類等を例示することができる。
本発明の任意の製造工程において、反応試薬における特定の官能基(ヒドロキシル基又はアミノ基等)を保護基で保護する必要があれば、適宜当業者に周知の方法で、適当な段階で、1又はそれ以上の保護基による保護・脱保護を行うことができる。
当該医薬組成物は、免疫賦活活性を有する有効成分の免疫賦活活性を維持もしくは増強するためのアジュバントとして用いることができる。
すなわち、本発明の化合物又はその薬学上許容される塩は、抗原特異的抗体、詳しくは抗原特異的IgG、さらに詳しくはTh1型抗原特異的IgG(例えばIgG2c)を誘導又は亢進する活性を有する。
また、本発明の化合物又はその薬学上許容される塩は、CD4陽性(すなわち、MHC class 2拘束性)及び/又はCD8陽性(すなわち、MHC Class 1拘束性)Tリンパ球を誘導又は亢進する活性を有する。
また、本発明の化合物又はその薬学上許容される塩は、MHC拘束性抗原特異的なTリンパ球を誘導又は亢進する活性を有する。
また、本発明の化合物又はその薬学上許容される塩は、メモリーTリンパ球、詳しくはCD8陽性エフェクターメモリーTリンパ球を誘導又は亢進する活性を有する。
また、本発明の化合物又はその薬学上許容される塩は、哺乳動物に投与された場合、全身性炎症性メディエーター誘導、すなわち血中のインターフェロン-α、インターフェロン-γ、IL-6又はIP-10等の濃度を上昇させる作用が、同投与量のスクワレン構造を含まない化合物よりも低いという特徴を有する。
当該医薬組成物は抗原を含有し得る。当該抗原としては、腫瘍抗原タンパク質、又は当該腫瘍抗原タンパク質由来の腫瘍抗原ペプチド(例えばNY-ESO-1、MAGE-3、WT1又はHer2/neu)、抗体の超可変領域、病原体由来抗原、例えばウイルスもしくは細菌等の病原体由来のタンパク質又はその部分ペプチド等が挙げられ、さらにこれらの抗原と担体との複合体等も本明細書における抗原の範疇に含まれる。このような複合体としては、抗原(タンパク質、ペプチドが挙げられるがこれらに限定されない)が担体となるタンパク質と当業者に周知のリンカーを介して化学的に架橋されたもの、抗原がウイルス様粒子(Virus-like Particle;VLP)に含まれるもの等が挙げられる。従って、本発明の化合物又はその薬学上許容される塩は、前記抗原と組合せて用いることで、癌又はウイルスもしくは細菌等の感染症の治療又は予防のための薬剤として有用である。
注射用液剤としては、例えば水性の溶液及び油状組成物を含むエマルション、リポソーム製剤、有効成分及び/又は式(1)で表される化合物又はその薬学上許容される塩を水に溶解又は分散させた水性溶液製剤もしくは水性懸濁液剤、又は有効成分及び/又は式(1)で表される化合物又はその薬学上許容される塩を油に溶解又は分散させた油性溶液製剤もしくは油性懸濁液剤等が挙げられる。
点鼻用液剤としては、例えば水性の溶液及び油状組成物を含むエマルション、リポソーム製剤、又は有効成分及び/又は式(1)で表される化合物又はその薬学上許容される塩を水に溶解又は分散させた水性溶液製剤もしくは水性懸濁液剤等が挙げられる。
ここで水性の溶液、水性溶液製剤もしくは水性懸濁液剤としては、注射用蒸留水、適宜緩衝剤、pH調節剤、安定化剤、等張化剤又は乳化剤を含む水溶液もしくは水性懸濁液等が挙げられる。
油状組成物、油性溶液製剤もしくは油性懸濁液剤としては、植物性油脂、動物性油脂、炭化水素類、脂肪酸エステル類等を含む組成物が挙げられ、更に具体的にはスクワレン、スクワラン等を含む組成物が挙げられる。
エマルションとしては、水中油型エマルション、又は、油中水型エマルションを用いることができる。水中油型エマルションに用いられる油としては、式(1)で示される化合物(又はその薬学上許容される塩)を、溶解又は均一に分散できる成分であれば特に限定はされないが、植物性油脂、動物性油脂、炭化水素類、脂肪酸エステル類等が挙げられ、好ましくはスクワレン、スクワラン等が挙げられる。油中水型エマルションに用いられる油としては、式(1)で示される化合物(又はその薬学上許容される塩)を、溶解又は均一に分散できる成分であれば特に限定はされないが、植物性油脂、動物性油脂、炭化水素類、脂肪酸エステル類等が挙げられる。
具体的には、0.1~10重量%のスクワレンを含む水中油型エマルションが挙げられる。一態様として、0.001~1重量%の式(1)で表される化合物又はその薬学上許容される塩、及び1~10重量%のスクワレンを含む水中油型エマルションが挙げられる。当該水中油型エマルションは更に1又は複数の界面活性剤又は緩衝剤を含んでいてもよい。当該界面活性剤としては、ポリソルベート類、ポリオキシエチレン硬化ヒマシ油類、ポリオキシエチレンポリオキシプロピレングリコール類、多価アルコール脂肪酸エステル類、脂肪酸エステル類等が挙げられ、均一な乳化状態を維持するのに適切な成分、配合比率であれば特に限定はされないが、例えば、0.1~5重量%のポリソルベート80、0.1~5重量%のトリオレイン酸ソルビタン(例えばSpan 85(登録商標))等が挙げられる。また、緩衝剤としてはリン酸塩、有機酸塩等が挙げられる。
本発明の化合物もしくはその薬学上許容される塩、及び抗原特異的免疫反応を増強させる物質(抗原ともいう)を含む医薬組成物も、本発明の一態様である。当該抗原としては、特に限定はないが、抗原タンパク質又は該抗原タンパク質に由来する抗原ペプチド(部分ペプチド)、さらにこれらと担体との複合体が挙げられる。
癌抗原に由来する腫瘍抗原ペプチドとしては、特に限定はないが、例えば、MAGEA3ペプチド168-176(Coulie PG et al.,Immunol. Rev. 188:33(2002))、gp100ペプチド209-217(Rosenberg SA et al., Nat. Med. 4:321(1998))、gp100ペプチド280-288(Phan GQ et al., Proc. Natl. Acad. Sci. USA 100:8372(2003))、Melan-Aペプチド27-35(Cormier JN et al., Cancer J. Sci. Am. 3:37(1997))、Melan-Aペプチド26-35、Tyrosinaseペプチド1-9、Tyrosinaseペプチド368-376、gp100ペプチド280-288、gp100ペプチド457-466(Jager E et al., Int. J. Cancer 67:54(1996))、HER-2ペプチド369-384、HER-2ペプチド688-703、HER-2ペプチド971-984(Knutson KL et al., J. Clin. Invest. 107:477(2001))、MAGE-A12ペプチド170-178(Bettinotti MP et al., Int. J. Cancer 105:210(2003))等が挙げられる。
a)式(1)で示される化合物、又はその薬学上許容し得る塩;
b)抗原;および
c)前記a)及びb)の単位投与形態を合わせて又は独立して入れるための容器もしくはデバイス。
ここで、抗原としては、ワクチンの有効成分として用いられ得る抗原であれば特に限定はないが、上述の抗原タンパク質又は該抗原タンパク質に由来する抗原ペプチド(部分ペプチド)等、さらにこれらと担体との複合体等が挙げられる。
また、本発明の一態様として、疾患又は状態の処置のためのワクチンの製造における、ワクチンアジュバントとしての、上で定義した式(I)で示される化合物、又はその薬学上許容し得る塩の使用を提供する。
EtOAc:酢酸エチル
NMP:N-メチルピロリジノン
TEA:トリエチルアミン
MS検出器:LCMS-IT-TOF
HPLC:Shimadzu Nexera X2 LC 30AD
カラム:Kinetex 1.7u C18 100A New column 50×2.1mm
流速:1.2ml/min
測定波長:254nm
移動層:A液;0.1%ギ酸水溶液
B液;アセトニトリル
タイムプログラム:
ステップ 時間(分)
1 0.01-1.40 A液:B液=90:10~5:95
2 1.40-1.60 A液:B液=5:95
3 1.61-2.00 A液:B液=99:1
(4E,8E,12E,16E,20E)-N-{2-[{4-[(2-アミノ-4-{[(3S)-1-ヒドロキシヘキサン-3-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]ベンジル}(メチル)アミノ]エチル}-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエンアミド
1H-NMR (400 MHz, DMSO-d6) δ2.00 (3H, s), 3.71 (2H, s), 3.82 (3H, s), 6.35(1H, br), 7.31 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz).
1H-NMR (400 MHz, DMSO-d6) δ2.20 (3H, s), 2.29 (3H, s), 2.48 (6H, s),3.84 (3H, s), 3.88 (2H, s), 6.35 (1H, br), 7.08 (2H, s), 7.19 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz).
1H-NMR (CDCl3) δ 0.73 (t, J = 7.2Hz, 3H), 0.90-1.76 (m, 6H), 2.41 (s, 3H), 3.49-3.61 (m, 2H), 3.69-3.87 (m, 2H), 3.90 (s, 3H), 4.24 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H).
1H-NMR (CD3OD) δ 0.78 (t, J = 7.2Hz, 3H), 1.03-1.76 (m, 6H), 2.18 (s, 3H), 3.41-3.48 (m, 2H), 3.76-3.88 (m, 2H), 4.23 (m, 1H), 4.55 (s, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H).
1H-NMR (CD3OD) δ 0.70 (t, J = 7.2Hz, 3H), 1.05-1.77 (m, 6H), 2.20 (s, 3H), 3.42-3.50 (m, 2H), 3.90-4.03 (m, 2H), 4.32 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 9.93 (s, 1H).
1H-NMR (CDCl3) δ 0.66 (t, J = 7.2Hz, 3H), 0.91-1.77 (m, 6H), 1.40 (s, 9H), 2.12 (s, 3H), 2.26 (s, 3H), 2.39-2.44 (m, 2H), 3.15-3.46 (m, 4H), 3.43 (s, 2H), 3.61-3.86 (m, 2H), 4.05(m, 1H), 4.67-4.77 (br, 2H), 4.91-5.01 (br, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H).
1H-NMR (CDCl3) δ 0.71 (t, J = 7.2Hz, 3H), 0.92-1.83 (m, 27H), 1.95-2.08 (m, 20H), 2.18-2.32 (m, 10H), 2.46 (t, J = 6.0 Hz, 2H), 3.28-3.43 (m, 4H), 3.46 (s, 2H), 3.64-3.81 (m, 2H), 4.10 (m, 1H), 4.48-4.58 (br, 2H), 5.06-5.17 (m, 6H), 5.94-6.04 (br, 1H), 7.06 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H). ESI: [M+H]+ 852.6
(4E,8E,12E,16E,20E)-1-(4-{4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-3-メトキシベンジル}ピペラジン-1-イル)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン-1-オン
公知化合物である(S)-4-((2-アミノ-4-((1-ヒドロキシペンタン-2-イル)アミノ)-6-メチルピリミジン-5-イル)メチル)-3-メトキシベンズアルデヒド(0.10 g, 0.28 mmol)、t-ブチル ピペラジン-1-カルボキシレート(0.13 g, 0.71 mmol)及び(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン酸(72 mg, 0.15 mmol)から実施例1工程6および7と同様の方法により目的物(96 mg, 23 %(2工程))を得た。
1H-NMR (CDCl3) δ 0.77 (t, J = 7.2Hz, 3H), 1.00-1.44 (m, 4H), 1.57-1.65 (m, 21H),1.88-2.04 (m, 20H), 2.23-2.38 (m, 11H), 3.38-3.74 (m, 6H), 3.44 (s, 2H), 3.67 (s, 2H), 3.88 (s, 3H), 4.00 (m, 1H), 4.77-4.87 (br, 2H), 5.03-5.11 (m, 6H), 6.79 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H). ESI: [M+H]+ 879.6
(4E,8E,12E,16E,20E)-1-(4-{4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-3-メトキシベンゾイル}ピペラジン-1-イル)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン-1-オン
MS (ESI+): [M+H]+ 543.4
(S)-tert-ブチル 4-(4-((2-アミノ-4-((1-ヒドロキシペンタン-2-イル)アミノ)-6-メチルピリミジン-5-イル)メチル)-3-メトキシベンゾイル)ピペラジン-1-カルボキシレート (200 mg, 0.369 mmol)をクロロホルム(3.0 ml)に溶解し、4M塩酸-シクロペンチルメチルエーテル溶液 (3 ml, 12.0 mmol)を加えて、室温で1時間撹拌した。反応溶液にトルエンを加えて減圧濃縮した。得られた残渣を、(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエン酸(166 mg, 0.355 mmol)、1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム 3-オキシド ヘキサフルオロホスファート(202 mg, 0.532 mmol)およびN,N-ジイソプロピルエチルアミン(0.185 ml, 1.065 mmol)のN,N-ジメチルホルムアミド(5 ml)溶液に加えて、室温で6時間撹拌した。反応溶液に水を加えてクロロホルムで抽出し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ(クロロホルム/メタノール20/1)で精製することにより、表題の化合物(159 mg, 50%)を得た。
1H-NMR (CDCl3) δ 0.83 (t, J = 7.3Hz, 3H), 1.15-1.48 (m, 4H), 1.58-1.68 (m, 21H), 1.94-2.15 (m, 20H), 2.25-2.32 (m, 2H), 2.32 (s, 3H), 2.40-2.48 (m, 2H), 3.37-3.80 (m, 12H), 3.93 (s, 3H), 3.99-4.05 (m, 1H), 4.65 (brs, 2H), 4.80 (br, 1H), 5.07-5.18 (m, 6H), 6.86 (dd, J = 7.8, 1.4 Hz, 1H), 6.97-7.00 (m, 2H). MS (ESI+): [M+H]+ 893.6
4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-N-(2-{[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエノイル]アミノ}エチル)-3-メトキシベンズアミド
1H-NMR (CDCl3) δ 0.81 (t, J = 7.3Hz, 3H), 1.07-1.40 (m, 4H), 1.47 (s, 9H), 2.32 (s, 3H), 3.37-3.45 (m, 3H), 3.52-3.57 (m, 2H), 3.63-3.67 (m, 1H), 3.74 (s, 2H), 3.97 (s, 3H), 3.97-4.03 (m, 1H), 4.58 (br, 2H), 4.75-4.77 (br, 1H), 4.97-4.99 (br, 1H), 6.95-6.98 (m, 1H), 7.22-7.23 (m, 1H), 7.27-7.31 (br, 1H), 7.47-7.49 (m, 1H).
1H-NMR (CDCl3) δ 0.81 (t, J = 7.3Hz, 3H), 1.07-1.46 (m, 4H), 1.55-1.70 (m, 21H), 1.90-2.10 (m, 20H), 2.26-2.30 (m, 4H), 2.33 (s, 3H), 3.38-3.44 (m, 1H), 3.46-3.58 (m, 4H), 3.62-3.67 (m, 1H), 3.74 (s, 2H), 3.97 (s, 3H), 3.97-4.03 (m, 1H), 4.54-4.57 (br, 2H), 4.76-4.79 (br, 1H), 5.06-5.15 (m, 6H), 6.10-6.14 (br, 1H), 7.00 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.41 (br, 1H), 7.45 (d, J = 1.6 Hz, 1H). MS (ESI+): [M+H]+ 867.6.
4-[(2-アミノ-4-{[(2S)-1-ヒドロキシペンタン-2-イル]アミノ}-6-メチルピリミジン-5-イル)メチル]-N-(2-{[(4E,8E,12E,16E,20E)-4,8,12,17,21,25-ヘキサメチルヘキサコサ-4,8,12,16,20,24-ヘキサエノイル](メチル)アミノ}エチル)-3-メトキシベンズアミド
1H-NMR (CDCl3) δ 0.84 (t, J = 7.3Hz, 3H), 1.07-1.41 (m, 4H), 1.43 (s, 9H), 2.31 (s, 3H), 2.91 (s, 3H), 3.39-3.44 (m, 1H), 3.45-3.55 (m, 2H), 3.56-3.61 (m, 2H), 3.62-3.67 (m, 1H), 3.73 (s, 2H), 3.96 (s, 3H), 3.97-4.02 (m, 1H), 4.55-4.59 (br, 2H), 4.74-4.78 (br, 1H), 6.94-6.97 (m, 1H), 7.21-7.24 (m, 1H), 7.47-7.50 (m, 2H).
1H-NMR (CDCl3) δ 0.80 (t, J = 7.3Hz, 3H), 1.06-1.45 (m, 4H), 1.56-1.68 (m, 21H), 1.90-2.09 (m, 20H), 2.21-2.31 (m, 2H), 2.33 (s, 3H), 2,37-2.43 (m, 2H), 3.08 (s, 3H), 3.37-3.45 (m, 1H), 3.55-3.69 (m, 5H), 3.73 (s, 2H), 3.96 (s, 3H), 3.97-4.03 (m, 1H), 4.55-4.58 (br, 2H), 4.77-4.80 (br, 1H), 5.06-5.14 (m, 6H), 7.00 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 1.2 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.53-7.55 (br, 1H). MS (ESI+): [M+H]+ 881.6
C57BL/6マウスにオボアルブミン(OVA)(1mg/mL)と上記実施例の化合物(0.1mg/mL)の等量混合液(100μL/マウス)を腓腹筋に筋肉内投与し初回免疫とした。さらに2週間後に等量の同混合液を腓腹筋に筋肉内投与し追加免疫とした。追加免疫から1週間後、イソフルラン吸入麻酔維持下において心臓採血を行い遠心分離により血漿を回収し、血漿中のOVA特異的IgG値をマウス抗オボアルブミンIgG ELISAキット(Alpha Diagnostic)を用いてELISAにて定量した(図1を参照)。
また、上記免疫マウス血漿中のOVA特異的IgG1およびIgG2c値をELISA法によって定量した。すなわち、96ウェルプレートにOVA溶液(SIGMA)を添加した後、1 % スキムミルク (和光純薬工業)にてブロッキングを行い、リン酸緩衝液を用いて希釈した血漿サンプルを添加後、2次抗体であるヤギ抗マウスIgG1(Jackson)もしくはIgG2c(Southern Bio)を添加し、SureBlueTM TMBマイクロウェルペルオキシダーゼ基質(KPL)添加後、酵素反応の生成物をマイクロプレートリーダーにて測定した(図2を参照)。
実施例1~5の全ての化合物は、陰性対照群と比較してより強くOVA特異的IgGを誘導した。特に実施例1と実施例4の化合物は、陰性対照群に対する有意なOVA特異的IgG産生を誘導した。さらに、実施例1と実施例4の化合物は、OVA特異的抗体の中でもTh1型IgGの一つであるIgG2cのTh2型IgGの一つであるIgG1に対する比率を、陰性対照群と比較して有意に増加させた。
試験例1のマウスの脾臓細胞を調製し、OVAとブレフェルジンA (eBioscience)を添加後一晩培養した。細胞を回収し、APC標識抗マウスCD3e抗体、FITC標識抗マウスCD4抗体、およびFixable Viability Dye eFluor(登録商標)450(eBioscience)で染色後、Fixation/Permeabilization buffer(eBioscience)で固定した。細胞をPermeabilization buffer (eBioscience)処置後、抗体カクテルPerCP-Cy5.5標識抗IFN-γ抗体、PE-Cy7標識抗IL-2抗体、およびPE標識TNF-α (eBioscience)で染色した。FACS Cant II(BD Biosciences)およびFLOWJO ソフトウェア (TreeStar)を用いてデータ取り込みおよび解析を行った。結果を図3に示した。
また、上記脾臓細胞を、eFluor450標識抗マウスCD3e抗体、Alexa Fluor(登録商標)647標識抗マウスCD8抗体、PE標識H-2Kb OVA Tetramer -SIINFEKL (MBL)およびFixable Viability Dye eFluor520(eBioscience)で染色した。FACS Cant II(BD Biosciences)およびFLOWJOソフトウェア(TreeStar)を用いてデータ取り込みおよび解析を行った。結果を図4に示した。
更に、上記脾臓細胞を、抗体カクテルeFluor450標識抗マウスCD3e抗体、Alexa Fluor647標識抗マウスCD8抗体、PE-Cy7標識抗マウスCD44抗体、PerCP-Cy5.5標識抗マウスCD62L抗体およびFixable Viability Dye520(eBioscience)で染色した。FACS Cant II(BD Biosciences)およびFLOWJO ソフトウェア (TreeStar)を用いてデータ取り込みおよび解析を行った。結果を図5に示した。
実施例1と実施例4の化合物は、OVA特異的多機能性のCD4陽性Tリンパ球の割合、MHC拘束性OVA特異的CD8陽性Tリンパ球の割合、およびCD8陽性エフェクターメモリーTリンパ球の割合を陰性対照群と比較して有意に増加させた。
Claims (20)
- 式(1):
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、前記アルキル基が置換されている場合には、以下の群:
ヒドロキシ基、ハロゲン原子、炭素数1から6のアルコキシ基、
から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基、炭素数1~6のアルコキシ基又は炭素数1~6のアルキルチオ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基又はシアノ基を表し、
Y1は、単結合、-(CR9R10)p-、-CH=CH-(CR9R10)q-、
Y2は、単結合又は-C(O)-を表し、
Lは、置換もしくは無置換の炭素数2~6の直鎖アルキレン又は4~8員のシクロアルカンの二価基を表し、
前記直鎖アルキレン又はシクロアルカンが置換されている場合には、以下の群:
炭素数1~5のアルキル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
L中の直鎖アルキレンにおける任意の1つのメチレン基はカルボニル基で置き換えられてもよく、
R5及びR6は、独立して水素原子、置換もしくは無置換の炭素数1~6のアルキル基を表すか、あるいは、R5もしくはR6のどちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成しているか、又は、R5及びR6が一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、
前記アルキル基が置換される場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
前記4~8員の含窒素飽和ヘテロ環又は前記5~8員の含窒素飽和ヘテロ環が置換される場合、メチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、カルボニル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
mは0又は1を表し、
pは1~6の整数を表し、
q及びq’は独立して、0~4の整数を表し、
rは0~5の整数を表し、r’は1~5の整数を表し、r及びr’の和が5以下であり、Y2が単結合の場合、r’は2以上の整数を表し、
で示される、化合物又はその薬学上許容される塩。 - Xは、メチレン、酸素原子又はNR7(R7は水素原子又は炭素数1~3のアルキル基を表す)を表し、
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、
前記アルキル基が置換されている場合には、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表す、請求項1に記載の化合物又はその薬学上許容される塩。 - Y1は、単結合、-(CR9R10)p-(R9及びR10は独立して水素原子又は炭素数1~4のアルキル基を表す)を表し、Y2は単結合又は-C(O)-を表す、請求項1~3のいずれかに記載の化合物又はその薬学上許容される塩。
- Y1は、単結合を表し、Y2は-C(O)-を表す、請求項4に記載の化合物又はその薬学上許容される塩。
- Y1は、-(CR9R10)p-(R9及びR10は独立して水素原子又は炭素数1~4のアルキル基を表す)を表し、pは1~3の整数を表し、Y2は単結合を表す、請求項4に記載の化合物又はその薬学上許容される塩。
- Y1は、-(CR9R10)r-O-(CR9’R10’)r’-を表し(R9、R10、R9’及びR10’は独立して水素原子又は炭素数1~4のアルキル基を表す)、r及びr'は独立して、0、1又は2を表す、請求項3に記載の化合物又はその薬学上許容される塩。
- Lが、炭素数2又は3の直鎖アルキレンを表す、請求項1~7のいずれかに記載の化合物又はその薬学上許容される塩。
- Xは、メチレンを表し、
R1は水素原子、又はヒドロキシ基で置換されていてもよい炭素数1~3のアルキル基を表し、
R2は、水素原子、又は炭素数1~6のアルキル基を表し、
R3は、炭素数1~3のアルキル基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表し、
Y1は、単結合又はメチレンを表し、
Y2は、単結合又は-C(O)-を表し、
Lは、炭素数2又は3の直鎖アルキレンを表し、
R5及びR6は、独立して水素原子又は炭素数1~3のアルキル基を表すか、あるいは、R5は、R6と一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、前記5~8員の含窒素飽和ヘテロ環が置換されている場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
mは0又は1を表し、
- 請求項1~9のいずれかに記載の化合物又はその薬学上許容される塩を含む医薬組成物。
- 更に、抗原を含む請求項10に記載の医薬組成物。
- 抗原が、病原体由来抗原又は腫瘍抗原である、請求項11に記載の医薬組成物。
- 抗原が、ペプチド又はタンパク質である、請求項11又は12に記載の医薬組成物。
- 請求項1~9のいずれかに記載の化合物又はその薬学上許容される塩を含む、ワクチンアジュバント。
- ワクチンアジュバントとして用いられる、請求項1~9のいずれかに記載の化合物又はその薬学上許容される塩。
- 請求項1~9のいずれかに記載の化合物又はその薬学上許容される塩を哺乳動物に投与することを含む、哺乳動物における抗原特異的免疫反応を増強させる方法。
- 請求項1~9のいずれかに記載の化合物又はその薬学上許容される塩を哺乳動物に投与することを含む、哺乳動物の免疫応答能を向上させる方法。
- 請求項1~9のいずれかに記載の化合物又はその薬学上許容される塩の、ワクチンアジュバントの製造のための使用。
- 式(2):
R1及びR2は、独立して、水素原子又は置換もしくは無置換の炭素数1~6のアルキル基を表し、前記アルキル基が置換されている場合には、以下の群:
ヒドロキシ基、ハロゲン原子及び炭素数1から6のアルコキシ基、
から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
R3は、炭素数1~6のアルキル基、炭素数1~6のアルコキシ基又は炭素数1~6のアルキルチオ基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~6のアルキル基又は炭素数1~6のアルコキシ基、シアノ基、を表し、
Y1は、単結合、-(CR9R10)p-、-CH=CH-(CR9R10)q-、
Y2は、単結合又は-C(O)-を表し、
Lは、置換もしくは無置換の炭素数2~6の直鎖アルキレン又は4~8員のシクロアルカンの二価基を表し、
前記直鎖アルキレン又はシクロアルカンが置換されている場合には、以下の群:
炭素数1~5のアルキル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
L中の直鎖アルキレンにおける任意の1つのメチレン基はカルボニル基で置き換えられてもよく、
R5及びR6は、独立して水素原子、置換もしくは無置換の炭素数1~6のアルキル基を表すか、あるいは、R5もしくはR6のどちらか一方が、L中の任意の炭素原子と結合して4~8員の含窒素飽和ヘテロ環を形成しているか、又は、R5及びR6が一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、
前記アルキル基が置換される場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
前記4~8員の含窒素飽和ヘテロ環又は前記5~8員の含窒素飽和ヘテロ環が置換される場合、メチル基、エチル基、プロピル基、ヒドロキシメチル基、ヒドロキシエチル基、カルボニル基、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよく、
pは1~6の整数を表し、
q及びq’は独立して、0~4の整数を表し、
rは0~5の整数を表し、r’は1~5の整数を表し、r及びr’の和が5以下であり、Y2が単結合の場合、r’は2以上の整数を表し、
R8は、水素原子又はアミノ基の保護基を表す。]
で示される、化合物又はその薬学上許容される塩。 - Xはメチレンを表し、
R1は、水素原子又はヒドロキシ基で置換されていてもよい炭素数1~3のアルキル基を表し、
R2は、水素原子又は炭素数1~6のアルキル基を表し、
R3は、炭素数1~3のアルキル基を表し、
R4は、水素原子、ハロゲン原子、ヒドロキシ基、炭素数1~3のアルキル基又は炭素数1~3のアルコキシ基を表し、
Y1は、単結合又はメチレンを表し、
Y2は、単結合又は-C(O)-を表し、
Lは、炭素数2又は3の直鎖アルキレンを表し、
R5及びR6は、独立して、水素原子、炭素数1~3のアルキル基を表すか、あるいは、R5は、R6と一緒になって置換もしくは無置換の5~8員の含窒素飽和ヘテロ環を形成してもよく、前記5~8員の含窒素飽和ヘテロ環が置換されている場合、ヒドロキシ基及びハロゲン原子から選択される同一もしくは異なる1~4個の置換基で置換されていてもよい、請求項19に記載の化合物又はその薬学上許容される塩。
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