WO2019151241A1 - Aldh2活性化剤 - Google Patents
Aldh2活性化剤 Download PDFInfo
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- WO2019151241A1 WO2019151241A1 PCT/JP2019/002955 JP2019002955W WO2019151241A1 WO 2019151241 A1 WO2019151241 A1 WO 2019151241A1 JP 2019002955 W JP2019002955 W JP 2019002955W WO 2019151241 A1 WO2019151241 A1 WO 2019151241A1
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- Prior art keywords
- compound
- methoxymethyl
- methyl
- fluoro
- group
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- 0 COCc1cc(N)c(CNC(c2c(*)cccc2*)=O)cc1* Chemical compound COCc1cc(N)c(CNC(c2c(*)cccc2*)=O)cc1* 0.000 description 1
- CXEWREITGADCOJ-UHFFFAOYSA-N OCc(cc(c(Br)c1)F)c1F Chemical compound OCc(cc(c(Br)c1)F)c1F CXEWREITGADCOJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
Definitions
- the present invention relates to an ALDH2 activator.
- Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies endogenous or exogenous aldehydes such as acetaldehyde and 4-hydroxynonenal, which are harmful to the living body, by oxidation. Therefore, compounds that activate ALDH2 are expected to have various medicinal effects as listed in Patent Document 1.
- ALDH2 N-[(2H-1,3-benzodioxol-5-yl) methyl] -2,6-dichlorobenzamide (hereinafter referred to as “Alda-”) described in Patent Document 2 is used. 1 ”) is reported in various non-clinical stages (for example, Non-Patent Document 1 and Non-Patent Document 2).
- Alda-1 is concerned with problems in promoting clinical development.
- the challenge is the production of reactive metabolites.
- reactive metabolites can generally cause serious hematologic toxicity and liver damage (Non-patent Document 3).
- Clozapine a therapeutic agent for schizophrenia, is an example of a drug that causes severe hematologic toxicity and liver damage. It may produce a large amount of reactive metabolites in an in vitro test using a matrix derived from human liver. It has been reported (Non-Patent Documents 4 and 5).
- Test Example 2 below Alda-1 is a compound that produces a reactive metabolite comparable to clozapine. Therefore, a compound that has an activation effect on ALDH2 and that does not generate more reactive metabolites is desired.
- the problem to be solved by the present invention is to provide a compound having an ALDH2 activating action and a small amount of a reactive metabolite produced.
- a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof [Wherein, X and Y are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and the C 1-6 alkoxy group represents a C 1-6 May be substituted with an alkoxy group, Z and W are the same or different and each represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group.
- [5] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein Y is a chlorine atom, a bromine atom or a methyl group.
- Y is a chlorine atom, a bromine atom or a methyl group.
- Z is a hydrogen atom, a fluorine atom or a methyl group.
- W is a hydrogen atom or a fluorine atom.
- a method for treating radiation dermatitis comprising administering the compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof to a patient.
- a method for treating osteoporosis comprising administering the compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof to a patient.
- a method for treating Fanconi anemia comprising administering the compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof to a patient.
- a method for treating inflammatory pain comprising administering the compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof to a patient.
- a method for activating ALDH2 wherein the compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof is administered to a patient.
- the present invention it is possible to provide a compound having an ALDH2 activating action and a small amount of reactive metabolite produced. That is, the compound according to the present invention has applicability as an ALDH2 activator.
- the term “compound according to the present invention” means a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
- the compound represented by the formula (1) may be referred to as “compound (1)”.
- the compound according to the present invention shows the structure as clearly shown for the part in which the three-dimensional structure in formula (1) is clearly defined, and the part in which the other three-dimensional structure is not clearly specified May include stereoisomers, and may be one of the isomers or a mixture thereof.
- crystal polymorphism may exist, but is not limited to a specific crystal form, and may be a single substance or a mixture of any of the crystal forms.
- Such compounds include amorphous forms and solvates such as anhydrides and hydrates.
- halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, 1 -Propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl Group, 1-hexyl group, 2-hexyl group, 3-hexyl group and the like.
- C 1-6 alkoxy group means a group in which an oxygen atom is bonded to the terminal of the above-defined “C 1-6 alkyl group”.
- Specific examples include, for example, a methoxy group, Ethoxy group, 1-propyloxy group, 2-propyloxy group, 2-methyl-1-propyloxy group, 2-methyl-2-propyloxy group, 1-butyloxy group, 2-butyloxy group, 1-pentyloxy group 2-pentyloxy group, 3-pentyloxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group and the like.
- X in the compound represented by the formula (1) is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and the C 1-6 alkoxy group is a C 1-6 alkoxy group. May be substituted.
- X is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an isopropyl group or a methoxymethoxy group.
- Y in the compound represented by the formula (1) is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and the C 1-6 alkoxy group is a C 1-6 alkoxy group. May be substituted.
- Y is preferably a chlorine atom, a bromine atom or a methyl group.
- Z in the compound represented by the formula (1) is a hydrogen atom, a halogen atom or a C 1-6 alkyl group, preferably a hydrogen atom, a fluorine atom or a methyl group.
- W in the compound represented by the formula (1) is a hydrogen atom, a halogen atom or a C 1-6 alkyl group, preferably a hydrogen atom or a fluorine atom.
- the “pharmaceutically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound represented by the general formula (1) and is pharmaceutically acceptable.
- examples thereof include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, and the like.
- inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like
- organic acid salts include acetate, succinate, and fumarate.
- examples include sulfonates such as sulfonates.
- the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt and the like, and preferable examples of organic base salt Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.
- Preferred examples of the acidic amino acid salt include aspartate and glutamate, and preferred examples of the basic amino acid salt include arginine salt, lysine salt, ornithine salt and the like.
- the compound represented by the formula (1) can be produced by the method described below. Moreover, the manufacturing method of the compound represented by Formula (1) is not limited to the said method, A person skilled in the art may improve and manufacture based on normal knowledge.
- Step 1 This step is a step of obtaining compound (1) by reacting compound (2) with compound (3).
- a commercially available product can be used as it is, or it can be produced from a commercially available product by a known method.
- the compound (2) can also be produced using the method described in Step A-1 and the like described later.
- the compound (3) a commercially available product can be used as it is, or it can be produced from a commercially available product by a known method.
- the compound (3) can also be produced by using the production examples in the examples or the method described in the step 2 or 4 described later. This step can be performed under the same conditions as those usually used described in the following documents.
- a known method for example, J. Org. Med. Chem. , 34 (1), 227-234 (1991), J. Am. Med. Chem. 37 (7), 999-1014 (1994).
- the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate examples include dichloromethane, chloroform, DMF, toluene, xylene and the like.
- CDI N, N′-carbonyldiimidazole
- Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate
- WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride)
- DCC N, N-dicyclohexylcarbodiimide
- diethylphosphoryl cyanide PyBOP (benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexa Fluorophosphate) and the like
- PyBOP benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexa Fluorophosphate
- Compound (2) can be used in an amount of 1 equivalent to an excess amount relative to compound (3). If necessary, an organic base such as triethylamine or diisopropylamine may be added in an amount from 1 equivalent to an excess amount relative to the compound (3).
- the reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited, but is preferably from ice cooling to the reflux temperature of the solvent.
- the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
- this process can also use the acylation reaction which is a method well-known to those skilled in the art. Examples of the base used in the acylation reaction include triethylamine, pyridine, potassium carbonate, diisopropylethylamine and the like.
- the reaction temperature is not particularly limited, but is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from ⁇ 20 ° C. to room temperature.
- the solvent used in the acylation reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, ether, toluene, dichloromethane and the like.
- Step 2 the cyano compound (4) is subjected to a reduction reaction to obtain the compound (3).
- This step is not particularly limited as long as it is a reduction method known to those skilled in the art.
- lithium aluminum hydride or a mixture thereof with aluminum chloride a metal catalyst such as Raney nickel, palladium, platinum or cobalt boride is used.
- reduction by catalytic hydrogenation Preferably, a reduction reaction using alane prepared from aluminum chloride and lithium aluminum hydride is used.
- Step 3 the leaving group L 3 in the compound (5) by replacing the methoxy group, to give compound (4).
- the reaction can be carried out under the same conditions as those usually used for the reaction for converting a leaving group into a methoxy group.
- a methoxylating agent For example, sodium methoxide, its methanol solution, etc. are mentioned.
- the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
- methanol is used.
- the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from 0 ° C. to the reflux temperature of the solvent.
- the reaction time is not particularly limited, but is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours.
- Step 4 by condensation reaction using a transition metal, to obtain a compound (3) by converting the leaving group L 2 of the compound (6) to an aminomethyl group derivative, then deprotection of the protecting group of the amine It is.
- the reaction can be carried out under the same conditions.
- the organometallic catalyst used in this reaction is not particularly limited, but preferably palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), (dibenzylideneacetone) palladium (0 ) And the like.
- the amount of the organometallic catalyst used is about 0.001 to 0.5 equivalent relative to the starting material.
- the aminomethyl derivative to be a condensation partner is not particularly limited, but sodium [(1,3-dioxoisoindoline-2-yl) methyl] trifluoroborate is preferable.
- the amount of the aminomethyl derivative to be used is not particularly limited, but is usually 1 to 5 equivalents relative to compound (6).
- the solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferred examples include 1,4-dioxane, water, or a mixture thereof.
- the ligand to be used is not particularly limited, but XPhos or SPhos is preferable.
- Such a base or salt is not particularly limited, but preferably lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like.
- the reaction temperature is not particularly limited, but is usually from ice-cooling to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent, for example.
- the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
- the conditions for deprotecting the protecting group on the subsequent amino group are not particularly limited. However, when the protecting group is phthalic acid, there is no particular limitation, but preferably a deprotecting agent such as ethylenediamine or hydrazine hydrate is used. Addition may give good results.
- the protecting group is phthalic acid
- further addition of solvent may give good results.
- the solvent to be added is not particularly limited as long as it does not inhibit the reaction, but preferred examples include methanol, ethanol, 1-propanol, 2-propanol and 1-butanol.
- the reaction temperature is not particularly limited, but is usually from ice-cold to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent, for example.
- the reaction time is not particularly limited, but when the protecting group is phthalic acid, it is usually 0.5 to 96 hours, preferably 1 to 48 hours.
- Step 5 This step is a step of obtaining the compound (6) by converting the hydroxyl group of the compound (7) into a methoxy group.
- the reaction can be carried out under the same conditions as those usually used in the reaction for converting a hydroxyl group to a methoxy group.
- a methylating agent Preferably, a methyl iodide, a dimethyl sulfate, etc. are mentioned, for example.
- the base to be used is not particularly limited as long as it does not inhibit the reaction, and preferred examples include sodium hydride.
- the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, DMF, DMSO, NMP and the like.
- the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from 0 ° C. to 50 ° C.
- the reaction time is not particularly limited, but is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours.
- This step is a step of obtaining compound (7) by a reduction reaction of compound (8).
- the alcohol compound (7) can be obtained from the carboxylic acid compound (8) by a method known to those skilled in the art.
- the reducing agent used in the reaction include borane dimethyl sulfide complex and borane tetrahydrofuran complex.
- the reaction temperature is not particularly limited, but is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from ⁇ 20 ° C. to room temperature.
- the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, ether and the like.
- compound (2-1) in which Y is a C 1-6 alkoxy group which may be substituted with a C 1-6 alkoxy group can also be synthesized by the following method. It can.
- X is as defined above, L 4 represents a leaving group as in L 1 to L 3 , R 1 represents a C 1-6 alkyl group, and R 2 represents a C 1-6 alkoxy]
- a C 1-6 alkyl group which may be substituted with a group is shown.
- Compounds (2-1), (2-2), (2-3), (2-4), (2-5) and (2-6) used in this step may be commercially available products. It can also be produced from commercially available products by methods known to those skilled in the art, and can also be produced using the methods described in the production examples in the examples.
- Step A-1 This step is a step of obtaining the compound (2-1) by hydrolysis of the ester moiety of the compound (2-2).
- the method for synthesizing compound (2-1) by hydrolysis of the ester moiety of compound (2-2) is a synthesis method known to those skilled in the art, and is not particularly limited.
- a hydrous solvent using a base or a salt The reaction in is mentioned.
- a base or salt Preferably lithium hydroxide or its hydrate, sodium hydroxide, potassium hydroxide etc. are mentioned.
- the solvent used for this reaction will not be specifically limited if it does not inhibit reaction, Preferably, tetrahydrofuran, a dioxane, methanol, ethanol, water, or its mixture is mentioned, for example.
- the reaction temperature is not particularly limited, but is usually ice-cold to the reflux temperature of the solvent, and preferably, for example, room temperature to the reflux temperature of the solvent.
- the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
- Step A-2 This step is a step of obtaining compound (2-2) by etherification reaction of compounds (2-3) and (2-4).
- the method of synthesizing the compound (2-2) by etherification of the compounds (2-3) and (2-4) is a synthesis method known to those skilled in the art.
- the amount of (2-3) used is Although not particularly limited, it is usually 1 to 5 equivalents relative to compound (2-4).
- the solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferred examples include tetrahydrofuran, DMF, DMSO, NMP and the like.
- the base or salt to be used is not particularly limited, but preferred examples include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium hydride and the like.
- the reaction temperature is not particularly limited, but is usually from ice-cooling to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent, for example.
- the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
- Step A-3 This step is a step of obtaining the compound (2-4) from the compound (2-5).
- the method of synthesizing the hydroxylated compound (2-4) by the Sandmeyer reaction of the compound (2-5) can be carried out under the same conditions as those usually used described in the following documents.
- the reaction can be carried out under the same conditions.
- a heating reflux reaction in an aqueous solvent using sodium nitrite and sulfuric acid can be used.
- Step A-4 This step is a step of obtaining the compound (2-5) from the compound (2-6).
- the method of synthesizing compound (2-5) by reducing the nitro compound of compound (2-6) is a synthesis method known to those skilled in the art.
- a noble metal catalyst such as Raney nickel, palladium, ruthenium, rhodium or platinum is used.
- Examples include catalytic hydrogenation to be used, reduction reaction using a stoichiometric amount of iron (0), tin (II) chloride, titanium (III) chloride, and the like.
- Preferable examples include a reduction reaction with iron under neutral conditions using ammonium chloride.
- the target compound in each step can be collected from the reaction mixture according to a conventional method.
- the above is a representative example of the production method of compound (1), but the raw material compound and various reagents in the production of compound (1) may form solvates such as salts and hydrates. Also, it can be changed depending on the starting material, the solvent used and the like, and is not particularly limited as long as the reaction is not inhibited.
- the solvent to be used is not particularly limited as long as it varies depending on starting materials, reagents and the like, and can dissolve the starting material to some extent without inhibiting the reaction.
- compound (1) When compound (1) is obtained as a free form, it can be converted into a salt or a solvate that may be formed by compound (1) according to a conventional method.
- compound (1) When compound (1) is obtained as a salt or solvate, it can be converted to the free form of compound (1) according to a conventional method.
- various isomers for example, geometric isomers, optical isomers, rotational isomers, stereoisomers, tautomers, etc.
- compound (1) or intermediates can be obtained by conventional separation means such as crystals. It can be purified and isolated by using an analysis, a diastereomeric salt method, an enzyme resolution method, and various chromatography (for example, thin layer chromatography, column chromatography, gas chromatography, etc.).
- the pharmaceutical composition according to the present invention can be produced by mixing a pharmaceutically acceptable additive with compound (I) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition according to the present invention can be produced according to a known method such as the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.
- the pharmaceutical composition according to the present invention can be appropriately administered to a patient according to its dosage form.
- the dose of the pharmaceutical agent according to the present invention usually varies depending on symptoms, age, sex, weight, etc., and may be an amount sufficient to produce a desired effect. For example, in the case of an adult, about 0.1 to 5000 mg (preferably 0.5 to 1000 mg) per day is used once a day or a plurality of days or divided into 2 to 6 times a day. .
- the compounds according to the invention also include isotope-labeled compounds of compound (1), which have an atomic mass or mass different from the atomic mass or mass number in which one or more atoms are normally found in nature. Identical to compound (1) except that it is replaced by a number atom.
- the isotopes that can be incorporated into the compound (1) are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine or chlorine, and 2 H, 3 H, 11 C, 14 C, 18 F , 35 S, 123 I, 125 I and the like.
- the compound (1) containing the above isotopes and / or other isotopes or a pharmaceutically acceptable derivative (for example, a salt) thereof is included in the compounds according to the present invention.
- the isotope-labeled compounds according to the present invention for example, compounds incorporating radioactive isotopes such as 3 H and 14 C, are useful for pharmaceutical or substrate tissue distribution assays.
- the isotopes 3 H and 14 C are considered useful because of their ease of preparation and detection.
- the isotopes 11 C and 18 F are considered useful in PET (positron emission tomography), and the isotope 125 I is considered useful in SPECT (single photon emission computed tomography), all useful in brain imaging. It is.
- isotope-labeled compound of compound (1) is uniformly obtained by performing the procedures disclosed in the following examples, using readily available isotope-labeled reagents in place of non-isotopically labeled reagents. Can be prepared.
- Compound (1) can be used as a chemical probe for capturing a target protein of a bioactive low molecular weight compound. That is, the compound (1) is different from the structural part essential for the expression of the activity of the compound in the J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5, 2003, p492-498 or International Publication No. 2007/139149, etc., can be converted into affinity chromatography, photoaffinity probe, etc. by introducing a labeling group, a linker and the like.
- Examples of the labeling group and linker used for the chemical probe include groups shown in the following groups (1) to (5).
- Photoaffinity labeling groups for example, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group and nitro group
- chemical affinity groups for example, alpha carbon atom is halogen
- Proteins such as ketone groups, carbamoyl groups, ester groups, alkylthio groups, Michael acceptors (eg, ⁇ , ⁇ -unsaturated ketone groups, ⁇ , ⁇ -unsaturated ester groups), and oxirane groups substituted with atoms Labeling group
- (2) a cleavable linker such as —SS—, —O—Si—O—, monosaccharide (glucose group, galactose group, etc.) or disaccharide (lactose etc.), and oligopeptide cleavable by
- the compound according to the present invention can be produced, for example, by the methods described in the following production examples and examples. However, these are illustrative, and the compound according to the present invention is not limited to the following specific examples in any case.
- HATU 520 mg, 1.4 mmol
- Example 9 2-Chloro-N- ⁇ [3-fluoro-4- (methoxymethyl) phenyl] methyl ⁇ -6- (methoxymethyl) benzamide Hydroxylation to a mixture of methyl 2-chloro-6- (methoxymethyl) benzoate (220 mg, 0.95 mmol), methanol (0.6 mL), and water (0.6 mL) described in Preparation Example 9-1 at room temperature Lithium monohydrate (40 mg, 0.95 mmol) was added, and the mixture was stirred at 50 ° C. overnight. The reaction mixture was evaporated under reduced pressure.
- N-dimethylformamide 5 mL was added N, N-diisopropylethylamine (0.40 mL, 2.4 mmol) and [3-fluoro-4-4 described in Preparation Example 1-2 under ice-cooling.
- (Methoxymethyl) phenyl] methanamine 240 mg, 1.4 mmol was added sequentially.
- HATU 540 mg, 1.4 mmol was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and the solvent was distilled off under reduced pressure.
- Example 11 N- ⁇ [3-Fluoro-4- (methoxymethyl) phenyl] methyl ⁇ -2,6-dimethylbenzamide
- N-dimethylformamide 0.3 mL
- N, N-diisopropylethylamine 0.068 mL, 0.40 mmol
- [3-fluoro-4- (methoxymethyl) phenyl] methanamine 34 mg, 0.20 mmol) described in Production Example 1-2 were sequentially added.
- Example 12 2-Chloro-N- [3-fluoro-4- (methoxymethyl) benzyl] -6-isopropylbenzamide 2-chloro-N- [3-fluoro-4- (methoxymethyl) benzyl-6- (prop-1-en-2-yl)] benzamide (20 mg, 0.059 mmol) described in Preparation Example 12-1. Palladium-fibroin (25 mg, 0.0059 mmol) was added to a mixture of methanol (1 mL) and tetrahydrofuran (0.5 mL), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Hydrogen in the reaction system was replaced with nitrogen, and the reaction mixture was filtered using filter paper.
- a commercially available ALDH2 enzyme (manufactured by ATGen Inc.) was dissolved in ALDH assay Buffer so as to be 1 ⁇ g / mL, and 10 ⁇ L thereof was dissolved. 2. 10 ⁇ L of 30 ⁇ M or 3 ⁇ M compound solution prepared using ALDH assay Buffer (containing 3% DMSO) 3. 10 ⁇ L of Reaction Mix consisting of ALDH assay Buffer 7.82 ⁇ L, PicoProbe 0.55 ⁇ L, Substrate Mix 0.27 ⁇ L, and Acetaldehyde 1.36 ⁇ L
- the compound according to the present invention is more reactive than clozapine and comparative compounds, which are known to exhibit severe hepatotoxicity and hepatotoxicity through the formation of reactive metabolites. It was shown that the amount of sex metabolites produced was small.
- Example 1 Stimulate the mouse vertically for 6 seconds until the filament bends, and score the escape response of the mouse in 3 stages (0: no response or startle response (shift without lifting the foot), 1: lift the foot, 2: lift the foot Lick or shake). Stimulation was performed 10 times, and the total value (escape score) of 10 scores was calculated.
- the compound (Example 1) was dissolved in DMSO / 5% glucose injection solution (1: 1 volume ratio), and a compound dose of 12 mg / kg (Vehicle group does not contain the compound) and a dose of 5 mL / kg 15 minutes before the injection of carrageenan, 30 minutes and 150 minutes after the injection of carrageenin, a total of 3 doses were administered subcutaneously to the back of the neck.
- Carrageenin was prepared as a 1.5% solution using physiological saline and subcutaneously administered to the left hind limb plantar at 7 ⁇ L / body.
- Wilcoxon rank sum test was performed comparing the Vehicle group and the Example 1 group. The significance level was 5%, and it was calculated separately for less than 5% (p ⁇ 0.05) and less than 1% (p ⁇ 0.01).
- the commercially available statistical program SAS SYSTEM SAS Software Release 9.1.3; SAS Institute Japan Ltd
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Abstract
Description
そのため、ALDH2を活性化する化合物は、特許文献1に列挙されるような多様な薬効が期待されている。ALDH2を活性化する化合物の中で、特許文献2に記載のN-[(2H-1,3-ベンゾジオキソール-5-イル)メチル]-2,6-ジクロロベンズアミド(以下、「Alda-1」と称す)は、非臨床段階において、多様な薬効が報告されている(例えば、非特許文献1および非特許文献2)。
したがって、ALDH2の活性化作用を有し、かつ、反応性代謝物をより生成させない化合物が望まれている。
すなわち、本発明は、以下[1]から[32]に関する。
[1]下式(1)で表される化合物またはその薬剤学的に許容できる塩。
ZおよびWは同一または相異なって、水素原子、ハロゲン原子またはC1-6アルキル基を意味する。]
[2]ハロゲン原子が、フッ素原子、塩素原子または臭素原子である、[1]に記載の化合物またはその薬剤学的に許容できる塩。
[3]C1-6アルキル基が、メチル基またはイソプロピル基である、[1]または[2]に記載の化合物またはその薬剤学的に許容できる塩。
[4]Xが、水素原子、フッ素原子、塩素原子、臭素原子、メチル基、イソプロピル基またはメトキシメトキシ基である、[1]ないし[3]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[5]Yが、塩素原子、臭素原子またはメチル基である、[1]ないし[4]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[6]Zが、水素原子、フッ素原子またはメチル基である、[1]ないし[5]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[7]Wが、水素原子またはフッ素原子である、[1]ないし[6]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[8]下記から選択される一の化合物またはその薬剤学的に許容できる塩:
(1)2,6-ジクロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(2)2,6-ジクロロ-N-{[3,6-ジフルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(3)2,6-ジクロロ-N-[4-(メトキシメチル)ベンジル]ベンズアミド、
(4)2,6-ジクロロ-N-{[4-(メトキシメチル)-3-メチルフェニル]メチル}ベンズアミド、
(5)2-ブロモ-6-クロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(6)2-クロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(7)2-ブロモ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(8)2-ブロモ-6-フルオロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(9)2-クロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}-6-(メトキシメチル)ベンズアミド、
(10)2-クロロ-6-フルオロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(11)N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}-2,6-ジメチルベンズアミド、
(12)2-クロロ-N-[3-フルオロ-4-(メトキシメチル)ベンジル]-6-イソプロピルベンズアミドおよび
(13)2,6-ジフルオロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド。
[9]下式で表される2,6-ジクロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミドまたはその薬剤学的に許容できる塩。
[13]放射線皮膚炎治療剤である、[12]に記載の医薬組成物。
[14]骨粗鬆症治療剤である、[12]に記載の医薬組成物。
[15]ファンコニ貧血治療剤である、[12]に記載の医薬組成物。
[16]炎症性疼痛治療剤である、[12]に記載の医薬組成物。
[17]ALDH2活性化剤である、[12]に記載の医薬組成物。
[18][1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩を患者に投与する、放射線皮膚炎の治療方法。
[19][1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩を患者に投与する、骨粗鬆症の治療方法。
[20][1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩を患者に投与する、ファンコニ貧血の治療方法。
[21][1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩を患者に投与する、炎症性疼痛の治療方法。
[22][1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩を患者に投与する、ALDH2活性化方法。
[23]放射線皮膚炎の治療に使用される、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[24]骨粗鬆症の治療に使用される、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[25]ファンコニ貧血の治療に使用される、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[26]炎症性疼痛の治療に使用される、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[27]ALDH2の活性化に使用される、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[28]放射線皮膚炎治療剤を製造するための、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[29]骨粗鬆症治療剤を製造するための、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[30]ファンコニ貧血治療剤を製造するための、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[31]炎症性疼痛治療剤を製造するための、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[32]ALDH2活性化剤を製造するための、[1]ないし[11]いずれかに記載の化合物またはその薬剤学的に許容できる塩。
[工程1]
本工程は、化合物(2)と化合物(3)とを反応させることにより、化合物(1)を得る工程である。
化合物(2)は、市販品をそのまま用いることもできるし、市販品から公知の方法で製造することもできる。更に、化合物(2)は、後述する工程A-1等に記載の方法を用いて製造することもできる。
化合物(3)は、市販品をそのまま使うこともできるし、市販品から公知の方法で製造することもできる。更に、化合物(3)は、実施例中の製造例、または、後述する工程2または工程4に記載の方法等を用いて製造することもできる。
本工程は、以下の文献に記載された通常用いられる条件と同様の条件で行うことができる。公知の方法として、例えば、J.Med.Chem.,34(1),227-234(1991),J.Med.Chem.,37(7),999-1014(1994)等が挙げられる。
なお、本工程は、当業者に公知の方法であるアシル化反応を用いることもできる。アシル化反応に使用される塩基としては、例えばトリエチルアミン、ピリジン、炭酸カリウム、ジイソプロピルエチルアミン等が挙げられる。
反応温度は、特に限定されないが、通常、-78℃~溶媒の還流温度であり、好ましくは-20℃~室温である。
アシル化反応に使用される溶媒としては、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好適には、例えば、テトラヒドロフラン、エーテル、トルエン、ジクロロメタン等があげられる。
本工程は、シアノ化合物(4)を還元反応に付し、化合物(3)を得る工程である。
本工程は、当業者に公知の還元方法であれば、特に制限はないが、例えば、水素化アルミニウムリチウムやその塩化アルミニウムとの混合物、ラネーニッケル、パラジウム、白金あるいはホウ化コバルト等の金属触媒を使用する接触水素化による還元等が挙げられる。好ましくは、塩化アルミニウムと水素化リチウムアルミニウムから調製されるアランを用いた還元反応等が挙げられる。
本工程は、化合物(5)の脱離基L3をメトキシ基に置換することで、化合物(4)を得る工程である。
脱離基をメトキシ基に変換する反応に通常用いられる条件と同様の条件で反応を行うことができる。メトキシ化剤としては、特に限定されないが、例えばナトリウムメトキシドやそのメタノール溶液等が挙げられる。反応に使用する溶媒としては、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好ましくは、例えばメタノール等が挙げられる。反応温度は、通常、-78℃~溶媒の還流温度であり、好ましくは0℃~溶媒の還流温度である。反応時間は、特に限定されないが、通常、5分~48時間であり、好ましくは5分~12時間である。
本工程は、遷移金属を用いた縮合反応により、化合物(6)の脱離基L2をアミノメチル基誘導体に変換し、その後アミンの保護基を脱保護することにより化合物(3)を得る工程である。
アミノメチル化の条件としては,例えばOrg.Lett.,14(11),2818-2821(2012)に記載の反応条件と同様の条件で反応を行うことができる。具体的には、本反応に用いられる有機金属触媒としては特に限定されないが、好ましくは、例えば酢酸パラジウム(II)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、(ジベンジリデンアセトン)パラジウム(0)等の金属触媒を挙げることができる。有機金属触媒の使用量は、出発原料に対して約0.001~0.5当量である。縮合相手となるアミノメチル誘導体は、特に限定されないが、好ましくはナトリウム [(1,3-ジオキソイソインドリン-2-イル)メチル]トリフルオロボレート等が挙げられる。アミノメチル誘導体の使用量は、特に限定されないが、通常、化合物(6)に対して1~5当量である。本反応に用いられる溶媒は、反応を阻害しないものであれば特に限定されないが、好ましくは、例えば1,4-ジオキサン、水、またはその混合物等を挙げることができる。用いる配位子としては、特に限定はされないが、好ましくはXPhosあるいはSPhosが挙げられる。かかる塩基或いは塩としては特に限定はされないが、好ましくは炭酸リチウム、炭酸ナトリウム、炭酸カリウム、あるいは炭酸セシウム等が挙げられる。反応温度は特に限定されないが、通常、氷冷~溶媒の還流温度であり、好ましくは、例えば、室温~溶媒の還流温度である。反応時間は、特に限定されないが、通常、0.5~48時間であり、好ましくは0.5~24時間である。
引き続くアミノ基上の保護基を脱保護する条件に関しては、特に限定はされないものの、保護基がフタル酸である場合、特に限定はされないが、好ましくはエチレンジアミンやヒドラジン水和物等の脱保護剤の添加が良好な結果を与えることがある。また、保護基がフタル酸である場合、溶媒のさらなる添加が良好な結果を与えることがある。添加する溶媒としては、反応を阻害しないものであれば特に限定はされないものの、好ましくは、メタノール、エタノール、1-プロパノール、2-プロパノールあるいは1-ブタノールが挙げられる。反応温度は、特に限定されないが、通常氷冷~溶媒の還流温度であり、好ましくは、例えば、室温~溶媒の還流温度である。反応時間は、特に限定されないが、保護基がフタル酸である場合、通常、0.5~96時間であり、好ましくは1~48時間である。
本工程は、化合物(7)の水酸基をメトキシ基に変換することにより化合物(6)を得る工程である。
水酸基をメトキシ基に変換する反応において通常用いられる条件と同様の条件で反応を行うことができる。メチル化剤としては、特に限定されないが、好ましくは、例えばヨウ化メチルやジメチル硫酸等が挙げられる。用いる塩基は反応を阻害しない限りにおいて特に限定されないが、好ましくは、例えば水素化ナトリウム等が挙げられる。反応に使用する溶媒としては、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好ましくは、例えばテトラヒドロフラン、DMF、DMSO、NMP等が挙げられる。反応温度は、通常、-78℃~溶媒の還流温度であり、好ましくは0℃~50℃である。反応時間は、特に限定されないが、通常、5分~48時間であり、好ましくは5分~12時間である。
本工程は、化合物(8)の還元反応により化合物(7)を得る工程である。
当業者に公知の方法によりカルボン酸化合物(8)からアルコール化合物(7)を得ることができる。反応に使用される還元剤としては、例えばボラン ジメチルスルフィド錯体、ボラン テトラヒドロフラン錯体等が挙げられる。反応温度は特に限定されないが、通常、-78℃~溶媒の還流温度であり、好ましくは-20℃~室温である。反応に使用される溶媒は、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好ましくは、例えば、テトラヒドロフラン、エーテル等があげられる。
本工程は、化合物(2-2)のエステル部位の加水分解により化合物(2-1)を得る工程である。
化合物(2-2)のエステル部位の加水分解により化合物(2-1)を合成する方法は、当業者に公知の合成法であり、特に限定されないが、例えば、塩基或いは塩を用いた含水溶媒中での反応が挙げられる。用いる塩基或いは塩としては、特に限定はされないが、好ましくは水酸化リチウム或いはその水和物、水酸化ナトリウム、水酸化カリウム等が挙げられる。本反応に用いられる溶媒は、反応を阻害しないものであれば特に限定されないが、好ましくは、例えばテトラヒドロフラン、ジオキサン、メタノール、エタノール、水或いはその混合物が挙げられる。反応温度は特に限定されないが、通常、氷冷~溶媒の還流温度であり、好ましくは、例えば、室温~溶媒の還流温度である。反応時間は、特に限定されないが、通常、0.5~48時間であり、好ましくは0.5~24時間である。
本工程は、化合物(2-3)と(2-4)のエーテル化反応により化合物(2-2)を得る工程である。
化合物(2-3)と(2-4)のエーテル化により化合物(2-2)を合成する方法は、当業者に公知の合成法であり、例えば、(2-3)の使用量は、特に限定されないが、通常、化合物(2-4)に対して1~5当量である。本反応に用いられる溶媒は、反応を阻害しないものであれば特に限定されないが、好ましくは、例えば、テトラヒドロフラン、DMF、DMSO、NMP等を挙げることができる。用いる塩基或いは塩としては特に限定はされないが、好ましくは炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、水素化ナトリウム等が挙げられる。反応温度は特に限定されないが、通常、氷冷~溶媒の還流温度であり、好ましくは、例えば、室温~溶媒の還流温度である。反応時間は、特に限定されないが、通常、0.5~48時間であり、好ましくは0.5~24時間である。
本工程は、化合物(2-5)から化合物(2-4)を得る工程である。
化合物(2-5)をSandmeyer反応にて水酸化化合物(2-4)を合成する方法は、以下の文献に記載された通常用いられている条件と同様の条件で行うことができる。公知の方法として、例えばJ.Org.Chem.,42(12),2053-2058(1977),J.Med.Chem.,47(4),871-887(2004)に記載の反応条件と同様の条件で反応を行うことができる。好ましくは、例えば、亜硝酸ナトリウムと硫酸を用いる、水溶媒下での加熱還流反応等が挙げられる。
本工程は、化合物(2-6)から化合物(2-5)を得る工程である。
化合物(2-6)のニトロ化合物を還元して化合物(2-5)を合成する方法は、当業者に公知の合成法であり、例えばラネーニッケル、パラジウム、ルテニウム、ロジウムまたは白金等の貴金属触媒を使用する接触水素化や、鉄(0)や塩化スズ(II)、塩化チタン(III)等を化学量論量用いる還元反応等が挙げられる。好ましくは、例えば、塩化アンモニウムを用いる中性条件下での鉄による還元反応等が挙げられる。
(1)光親和性標識基(例えば、ベンゾイル基、ベンゾフェノン基、アジド基、カルボニルアジド基、ジアジリジン基、エノン基、ジアゾ基およびニトロ基等)および化学親和性基(例えば、アルファー炭素原子がハロゲン原子で置換されたケトン基、カルバモイル基、エステル基、アルキルチオ基、マイケル受容体(例えば、α,β-不飽和ケトン基、α,β-不飽和エステル基)、およびオキシラン基等)等のタンパク質標識基、
(2)-S-S-、-O-Si-O-、単糖(グルコース基、ガラクトース基等)または二糖(ラクトース等)等の開裂可能なリンカー、および酵素反応で開裂可能なオリゴペプチドリンカー、
(3)ビオチン、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等のフィッシングタグ基、
(4)125I、32P、3H、14Cなどの放射性標識基;フルオレセイン、ローダミン、ダンシル、ウンベリフェロン、7-ニトロフラザニル、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等の蛍光標識基;ルシフェリン、ルミノール等の化学発光基;ランタノイド金属イオン、ラジウムイオン等の重金属イオン等の検出可能なマーカーまたは
(5)ガラスビーズ、ガラスベット、マイクロタイタープレート、アガロースビーズ、アガロースベッド、ポリスチレンビーズ、ポリスチレンベッド、ナイロンビーズ、ナイロンベッド等の固相担体と結合させる基等。
上記(1)~(5)からなる群より選択される標識基等を上記文献に記載の方法等に準じて化合物(1)に導入して調製されるプローブは、新たな創薬ターゲットの探索等に有用な標識タンパクの同定のためのケミカルプローブとして用いることができる。
略語
SPhos:2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル
HATU: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ェート
DMSO:ジメチルスルホキシド
1H-NMR Spectrum (CDCl3) δ (ppm):3.40 (s, 3 H), 4.51 (s, 2 H), 4.67 (d, J=5.86 Hz, 2 H), 6.07 (br. s., 1 H), 7.10 - 7.15 (m, 1 H), 7.18 (dd, J=7.81, 1.56 Hz, 1 H), 7.24 - 7.29 (m, 1 H), 7.31 - 7.34 (m, 2 H), 7.36 - 7.41 (m, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.41 (s, 3 H), 4.45 - 4.50 (m, 2 H), 7.21 - 7.26 (m, 1 H), 7.28 - 7.32 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.40 (s, 3 H), 3.87 (s, 2 H), 4.51 (s, 2 H), 6.99 - 7.14 (m, 2 H), 7.35 (t, J = 7.61 Hz,1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.42 (s, 3 H), 4.48 (s, 2 H), 4.67 (d, J = 5.86 Hz, 2 H), 6.38 (br. s, 1 H), 7.07 - 7.16(m, 2 H), 7.18 - 7.28 (m, 1 H), 7.29 - 7.34 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):1.89 (br. s,1 H), 4.72 (d, J = 3.12 Hz, 2 H), 7.23 - 7.31 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.42 (s, 3 H), 4.45 (s, 2 H), 7.10 - 7.37 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.41 (s, 3 H), 3.87 (s, 2 H), 4.48 (s, 2 H), 7.03 - 7.14 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.35 (s, 3 H), 4.42 (s, 2 H), 4.64 (d, J=5.50 Hz, 2 H), 6.09 (br. s., 1 H), 7.19 - 7.26(m, 1 H), 7.26 - 7.32 (m, 4 H), 7.32 - 7.41 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):2.32 (s, 3 H), 3.39 (s, 3 H), 4.43 (s, 2 H), 4.65 (d, J=5.86 Hz, 2 H), 5.95 (br. s., 1 H),7.19 - 7.23 (m, 2 H), 7.24 - 7.27 (m, 2 H), 7.28 - 7.33 (m, 3 H).
1H-NMR Spectrum (CDCl3) δ (ppm):2.33 (s, 3 H), 3.45 (s, 3 H), 4.47 (s, 2 H), 7.44 - 7.51 (m, 3 H).
Mass spectrum (ESI) m/z: 166 (M+H) +
1H-NMR Spectrum (CDCl3) δ (ppm):3.41 (s, 3 H), 4.51 (s, 2 H), 4.68 (d, J=5.86 Hz, 2 H), 6.01 (d, J=4.69 Hz, 1 H), 7.15(dd, J=10.54, 1.17 Hz, 1 H), 7.17 - 7.22 (m, 2 H), 7.35 - 7.42 (m, 2 H), 7.48 -7.51 (m, 1 H), 7.48 - 7.51 (m, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.41 (s, 3 H), 4.51 (s, 2 H), 4.66 (d, J=5.86 Hz, 2 H), 6.54 (br. s., 1 H), 7.09 (dd,J=10.54, 1.56 Hz, 1 H), 7.16 (dd, J=7.81, 1.56 Hz, 1 H), 7.31 - 7.43 (m, 4 H),7.69 - 7.73 (m, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.41 (s, 3 H,) 4.51 (s, 2 H), 4.65 (d, J=5.86 Hz, 2 H), 6.31 (br. s., 1 H), 7.10 (dd,J=10.54, 1.56 Hz, 1 H), 7.17 (dd, J=7.81, 1.56 Hz, 1 H), 7.26 - 7.31 (m, 1 H),7.34 - 7.38 (m, 1 H), 7.38 - 7.41 (m, 1 H), 7.58 (ddd, J=9.18, 7.81, 1.37 Hz, 2 H).
1H-NMRSpectrum (CDCl3) δ (ppm):3.41 (s, 3H), 4.51 (s, 2 H), 4.67 (d, J=6.25 Hz, 2 H), 6.07 (br. s., 1 H), 7.07 - 7.14(m, 2 H), 7.18 (d, J=8.20 Hz, 1 H), 7.22 - 7.29 (m, 1 H), 7.37 - 7.42 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.41 (s, 3 H), 3.46 (s, 3 H), 4.51 (s, 2 H), 4.69 (d, J=6.25 Hz, 2 H), 5.22 (s, 2 H), 6.05(br. s., 1 H), 7.04 - 7.10 (m, 2 H), 7.15 - 7.28 (m, 3 H), 7.38 (t, J=7.61 Hz, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.47 (s, 3 H)3.46 - 3.48 (m, 3 H) 3.95 (s, 3 H) 5.19 (s, 2 H) 7.03 - 7.06 (m, 1 H) 7.06 -7.09 (m, 1 H) 7.24 -7.29 (m, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.40 (s, 3 H), 4.51 (s, 2 H), 4.67 (d, J=6.25 Hz, 2 H), 6.11 (br. s., 1 H), 7.05 (td,J=8.49, 0.98 Hz, 1 H), 7.10 (d, J=10.54 Hz, 1 H), 7.16 (d, J=7.81 Hz, 1 H),7.21 - 7.24 (m, 1 H), 7.29 - 7.35 (m, 1 H), 7.39 (t, J=7.81 Hz, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):2.31 (s, 6H), 3.41 (s, 3 H), 4.51 (s, 2 H), 4.63 (d, J=5.86 Hz, 2 H), 5.94 (br. s., 1 H),7.01 (d, J=8.20 Hz, 2 H), 7.08 (dd, J=10.35, 1.76 Hz, 1 H), 7.13 - 7.18 (m, 2 H), 7.39 (t, J=7.61 Hz, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):1.22 (d,J=6.70 Hz, 6 H), 3.04 (dt, J=13.60, 6.95 Hz, 1 H), 3.39 (s, 3 H), 4.49 (s, 2 H), 4.64 (d, J=5.86 Hz, 2 H), 5.95 (br. s., 1 H), 7.05 - 7.12 (m, 1 H), 7.16(dd, J=7.95, 1.22 Hz, 1 H), 7.20 (td, J=6.73, 1.22 Hz, 1 H), 7.22 - 7.30 (m, 2H), 7.37 (t, J=7.64 Hz, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):, 2.04 (s, 3 H), 3.38 (s, 3 H), 4.49 (s, 2 H), 4.58 (d, J=6.11 Hz, 2 H), 5.02 (br. s., 1 H), 5.16 (t, J=1.53 Hz, 1 H), 5.95 (br. s., 1 H), 7.07 (d, J=10.39 Hz, 1 H), 7.09 -7.16 (m, 2 H), 7.21 - 7.32 (m, 2 H), 7.32 - 7.42 (m, 1 H).
1H-NMR Spectrum (CDCl3) δ (ppm):3.39 (s, 3 H), 4.49 (s, 2 H), 4.64 (d, J=5.89 Hz, 2 H), 6.29 (br. s., 1 H), 6.91 - 6.98 (m, 2 H), 7.05 (dd, J=10.65, 1.59 Hz, 1 H), 7.13 (dd, J=7.93, 1.59 Hz, 1 H), 7.32 - 7.41 (m, 2 H).
1H-NMR Spectrum (CDCl3) δ (ppm):4.24 (s, 4 H), 4.57 (d, J=5.47 Hz, 2 H), 5.94 (br. s., 1 H), 6.81 - 6.92 (m, 3 H), 7.21 -7.33 (m, 3 H).
1H-NMR Spectrum (DMSO-d6) δ (ppm):3.78 (s, 3 H), 4.37 (d, J=6.11 Hz, 2 H), 7.07 - 7.14 (m, 1 H), 7.14- 7.20 (m, 1 H), 7.37 -7.43 (m, 1 H), 7.47 (s, 1 H), 7.48 (s, 1 H), 9.07-9.17 (m, 1 H).
(アルデヒドデヒドロゲナーゼ2(ALDH2)によるアセトアルデヒドの酸化速度に対する化合物の効果)
アルデヒドデヒドロゲナーゼ2(ALDH2)によるアセトアルデヒドの酸化速度に対する化合物の効果は、当技術分野で公知の方法により実施した。詳細には、市販のPicoProbeTM Aldehyde dehydrogenase Activity Assay Kit(BioVision Inc.製)を用い、商品の取扱説明書を参考にして試験を実施した。384-ウェルプレートの各ウェルに、以下の試薬を順次ピペットにより添加した。
2.ALDH assay Bufferを用いて調製した30μMまたは3μMの化合物溶液を10μL(3%DMSOを含む)
3.ALDH assay Buffer 7.82μL,PicoProbe 0.55μL,Substrate Mix 0.27μL、およびAcetaldehyde 1.36μL、で構成されるReaction mixを10μL
蛍光の検出では、excitationが535nm、emissionが587nmの波長を用いた。
表1には化合物を添加しない場合のアセトアルデヒドの酸化速度を100とした時の、化合物添加による酸化速度を示している。化合物濃度が10μMの値は、比較例1化合物を「175」として補正し、化合物濃度が1μMの値は、比較例1化合物を「137」として補正した。結果として、本発明にかかる化合物が、比較例化合物と同様に、アセトアルデヒドの酸化速度を増加させることが示された。
(反応性代謝物生成量の比較)
化合物の反応性代謝物の生成能の評価は、以下の方法で実施した。100mMリン酸緩衝液(pH7.4)に1mg/mLの濃度のヒト肝ミクロソーム、0.2mmol/Lの化合物および0.1mmol/LのRI標識した捕捉剤を加え、最後に1mmol/LのNADPHを添加して、Cytochrome P450(CYP)依存的な代謝を開始した。37℃で60分間インキュベーションした後に、反応液(0.1mL)と等量のアセトニトリルを添加して、代謝反応を停止した。遠心分離した上清に0.8mLの水を添加した後、0.5mLをラジオディテクターにつないだHPLCに注入し、反応性代謝物とRI標識した捕捉剤の共有結合体のRI強度を定量的に分析した。
結果を表2に示す通り、本発明にかかる化合物が、反応性代謝物の生成を介して重篤な血液毒性および肝毒性を示す事が知られているクロザピンや比較例化合物と比べて、反応性代謝物の生成量が少ないことが示された。
(カラゲニンにより誘発される疼痛の抑制効果)
本実験は,Science Translational Medicine 6, 251ra118 (2014).を参考にして実施した。動物は雄C57BL/6Jマウス(日本チャールス・リバー),7週齢を使用した。足底部に機械刺激アロディニアを誘発するため、カラゲニンをマウスの左後肢足底に皮下投与した。誘発180分後の機械的刺激に対する逃避反応を、左後肢の足底面への上行曲げ力(0.16グラム)のvon Freyフィラメントを用いて測定した。フィラメントが曲がるまで垂直に6秒間マウスを刺激し、マウスの逃避反応を3段階スコア化(0:無反応または驚愕反応(足を引きあげずにずらす)、1:足を引き挙げる、2:足を舐めるまたは振る)した。刺激は10回行い,10回のスコアの合計値(逃避スコア)を算出した。
化合物(実施例1)をDMSO/5%ブドウ糖注射液(1:1の体積比)に溶解し、12mg/kgの化合物投与量(Vehicle群は化合物含まない)および5mL/kgの投与液量でカラゲニンを注入する15分前,カラゲニンを注入してから30分および150分後の計3回同量を頸背部皮下に投与した。カラゲニンは,生理食塩液を用いて1.5%溶液を調製し,左後肢足底に7μL/bodyで皮下投与した。
有意差検定は、Vehicle群と実施例1群の比較をWilcoxonの順位和検定を行った。有意水準は5%とし、5%未満(p<0.05)と1%未満(p<0.01)に分けて算出した。有意差検定には、市販の統計プログラムSAS SYSTEM(SAS Software Release 9.1.3;SAS Institute Japan Ltd)を使用した。
表3に示す通り、本発明にかかる化合物が、カラゲニンにより誘発される疼痛を抑制することが示された。
Claims (17)
- ハロゲン原子が、フッ素原子、塩素原子または臭素原子である、請求項1に記載の化合物またはその薬剤学的に許容できる塩。
- C1-6アルキル基が、メチル基またはイソプロピル基である、請求項1または2に記載の化合物またはその薬剤学的に許容できる塩。
- Xが、水素原子、フッ素原子、塩素原子、臭素原子、メチル基、イソプロピル基またはメトキシメトキシ基である、請求項1ないし3いずれか一項に記載の化合物またはその薬剤学的に許容できる塩。
- Yが、塩素原子、臭素原子またはメチル基である、請求項1ないし4いずれか一項に記載の化合物またはその薬剤学的に許容できる塩。
- Zが、水素原子、フッ素原子またはメチル基である、請求項1ないし5いずれか一項に記載の化合物またはその薬剤学的に許容できる塩。
- Wが、水素原子またはフッ素原子である、請求項1ないし6いずれか一項に記載の化合物またはその薬剤学的に許容できる塩。
- 下記から選択される一の化合物またはその薬剤学的に許容できる塩:
(1)2,6-ジクロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(2)2,6-ジクロロ-N-{[3,6-ジフルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(3)2,6-ジクロロ-N-[4-(メトキシメチル)ベンジル]ベンズアミド、
(4)2,6-ジクロロ-N-{[4-(メトキシメチル)-3-メチルフェニル]メチル}ベンズアミド、
(5)2-ブロモ-6-クロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(6)2-クロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(7)2-ブロモ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(8)2-ブロモ-6-フルオロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(9)2-クロロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}-6-(メトキシメチル)ベンズアミド、
(10)2-クロロ-6-フルオロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド、
(11)N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}-2,6-ジメチルベンズアミド、
(12)2-クロロ-N-[3-フルオロ-4-(メトキシメチル)ベンジル]-6-イソプロピルベンズアミドおよび
(13)2,6-ジフルオロ-N-{[3-フルオロ-4-(メトキシメチル)フェニル]メチル}ベンズアミド。 - 請求項1ないし11いずれか1項に記載の化合物またはその薬剤学的に許容できる塩を含む医薬組成物。
- 放射線皮膚炎治療剤である、請求項12に記載の医薬組成物。
- 骨粗鬆症治療剤である、請求項12に記載の医薬組成物。
- ファンコニ貧血治療剤である、請求項12に記載の医薬組成物。
- 炎症性疼痛治療剤である、請求項12に記載の医薬組成物。
- ALDH2活性化剤である、請求項12に記載の医薬組成物。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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AU2019214670A AU2019214670A1 (en) | 2018-01-31 | 2019-01-29 | ALDH2 activator |
KR1020207017801A KR20200115474A (ko) | 2018-01-31 | 2019-01-29 | Aldh2 활성화제 |
CN201980006700.2A CN111566082A (zh) | 2018-01-31 | 2019-01-29 | Aldh2活化剂 |
EP19746574.3A EP3747862A1 (en) | 2018-01-31 | 2019-01-29 | Aldh2 activator |
BR112020014237-9A BR112020014237A2 (pt) | 2018-01-31 | 2019-01-29 | Ativador de aldh2 |
JP2019569127A JPWO2019151241A1 (ja) | 2018-01-31 | 2019-01-29 | Aldh2活性化剤 |
MX2020006628A MX2020006628A (es) | 2018-01-31 | 2019-01-29 | Activador de aldehido deshidrogenasa 2 (aldh2). |
RU2020121490A RU2020121490A (ru) | 2018-01-31 | 2019-01-29 | Активатор aldh2 |
CA3085992A CA3085992A1 (en) | 2018-01-31 | 2019-01-29 | Aldh2 activator |
IL275883A IL275883A (en) | 2018-01-31 | 2020-07-06 | activates ALDH2 |
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JP2018-015512 | 2018-01-31 | ||
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US (1) | US10406126B2 (ja) |
EP (1) | EP3747862A1 (ja) |
JP (1) | JPWO2019151241A1 (ja) |
KR (1) | KR20200115474A (ja) |
CN (1) | CN111566082A (ja) |
AU (1) | AU2019214670A1 (ja) |
BR (1) | BR112020014237A2 (ja) |
CA (1) | CA3085992A1 (ja) |
IL (1) | IL275883A (ja) |
MX (1) | MX2020006628A (ja) |
RU (1) | RU2020121490A (ja) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022092310A1 (ja) | 2020-11-02 | 2022-05-05 | 株式会社アークメディスン | 化合物、アルデヒドデヒドロゲナーゼ2活性化剤、医薬組成物、並びに治療及び/又は予防薬 |
WO2023204292A1 (ja) * | 2022-04-22 | 2023-10-26 | 株式会社アークメディスン | 化合物、アルデヒドデヒドロゲナーゼ2活性化剤、医薬組成物、並びに治療及び/又は予防薬 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022092310A1 (ja) | 2020-11-02 | 2022-05-05 | 株式会社アークメディスン | 化合物、アルデヒドデヒドロゲナーゼ2活性化剤、医薬組成物、並びに治療及び/又は予防薬 |
KR20230104589A (ko) | 2020-11-02 | 2023-07-10 | 앨커메디신, 인크. | 화합물, 알데히드 디히드로게나아제 2 활성화제, 의약 조성물 및 치료 및/또는 예방약 |
JP7479725B2 (ja) | 2020-11-02 | 2024-05-09 | 株式会社アークメディスン | 化合物、アルデヒドデヒドロゲナーゼ2活性化剤、医薬組成物、並びに治療及び/又は予防薬 |
WO2023204292A1 (ja) * | 2022-04-22 | 2023-10-26 | 株式会社アークメディスン | 化合物、アルデヒドデヒドロゲナーゼ2活性化剤、医薬組成物、並びに治療及び/又は予防薬 |
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EP3747862A1 (en) | 2020-12-09 |
MX2020006628A (es) | 2020-09-14 |
JPWO2019151241A1 (ja) | 2021-01-28 |
BR112020014237A2 (pt) | 2020-12-08 |
CA3085992A1 (en) | 2019-08-08 |
RU2020121490A (ru) | 2022-02-28 |
AU2019214670A1 (en) | 2020-07-09 |
CN111566082A (zh) | 2020-08-21 |
KR20200115474A (ko) | 2020-10-07 |
IL275883A (en) | 2020-08-31 |
US10406126B2 (en) | 2019-09-10 |
US20190231720A1 (en) | 2019-08-01 |
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