WO2012023582A1 - Composé 4-isopropylphényl glucitol - Google Patents

Composé 4-isopropylphényl glucitol Download PDF

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Publication number
WO2012023582A1
WO2012023582A1 PCT/JP2011/068674 JP2011068674W WO2012023582A1 WO 2012023582 A1 WO2012023582 A1 WO 2012023582A1 JP 2011068674 W JP2011068674 W JP 2011068674W WO 2012023582 A1 WO2012023582 A1 WO 2012023582A1
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group
mmol
compound
esi
substituted
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PCT/JP2011/068674
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English (en)
Japanese (ja)
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浩行 柿沼
陽平 小橋
円 川村
史康 塩澤
由紀 岩田
憲一 川部
翔一 黒田
まこと 濱田
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大正製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 4-isopropyl having an inhibitory activity specific to sodium-dependent glucose cotransporter 1 (hereinafter abbreviated as “SGLT1” where appropriate) involved in the absorption of glucose and galactose in the small intestine. It relates to phenyl glucitol compounds.
  • Blood glucose level is one of the biomarkers of metabolic syndrome, and diabetes is diagnosed when fasting blood glucose is 126 mg / dL or more. Even if the fasting blood glucose level is normal, a glucose tolerance abnormality (or postprandial hyperglycemia) is diagnosed when the blood glucose level for 2 hours after meal is 140 to 200 mg / dL.
  • impaired glucose tolerance increases the risk of cardiovascular disorders (see Non-Patent Documents 1 and 2).
  • exercise therapy and drug treatment suppress the transition from impaired glucose tolerance to type 2 diabetes and significantly suppress the onset of hypertension (see Non-Patent Document 3).
  • suppressing postprandial hyperglycemia is important for suppressing the onset of diabetes and metabolic syndrome, and the demand for drugs that control postprandial hyperglycemia is increasing.
  • ⁇ -glucosidase inhibitors that inhibit saccharide hydrolase and delay sugar absorption from the small intestine have been widely used as postprandial hyperglycemia-improving agents. Development of drugs to improve blood glucose is also underway.
  • SGLT1 Sodium-dependent glucose cotransporter 1
  • SGLT1 is frequently expressed in the small intestinal epithelium of mammals.
  • SGLT1 is known to depend on sodium in the small intestine and to control the active transport of glucose and galactose. Accordingly, pyrazole derivatives that inhibit SGLT1 activity to suppress glucose absorption derived from meals and can be used for prevention or treatment of postprandial hyperglycemia have been reported (see Patent Documents 1 to 6). ).
  • sodium-dependent glucose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose once filtered by the glomerulus is reabsorbed via SGLT2 (non-patent document). Reference 4).
  • Non-Patent Document 5 As a feature of SGLT2 inhibitor, it has an excellent effect of lowering blood glucose as needed, but it has a low effect of correcting postprandial hyperglycemia like SGLT1 inhibitor. There is also a report on a C-phenyl glucitol derivative that simultaneously inhibits SGLT2 activity in addition to SGLT1 activity (see Patent Document 7).
  • a cationic drug having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is hydrophobically bound to a phospholipid, and is taken into a lysosome and accumulated in organs throughout the body. It is known that As typical examples, chloroquine caused retinal damage, and perhexiline had changes in the lungs and cerebellum, causing neuropathy (see Non-Patent Document 6).
  • the drug is rapidly excreted from the body after exhibiting a medicinal effect.
  • a drug having no problem of persistence in the body is desired.
  • An object of the present invention is to provide a 4-isopropylphenyl glucitol compound or a salt thereof exhibiting a SGLT1 inhibitory action with a wide safety range between a medicinal amount and toxicity and an amount of occurrence of side effects, and a medicament containing them.
  • R 1 is a hydrogen atom or a “C 1-4 alkyl group optionally substituted with a hydroxyl group or a halogen atom”
  • R 2 and R 3 are the same or different and are a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group, Or R 2 and R 3 together with the adjacent carbon atom form a C 3-6 cycloalkane ring
  • R 4 and R 5 are the same or different and are a hydrogen atom, a methyl group or a hydroxymethyl group, Or R 4 and R 5 together with the adjacent carbon atom form a C 3-6 cycloalkane ring or a 4-6 membered heterocyclo ring
  • n is 0 or 1
  • R 6 is a hydrogen atom, “a piperidyl group optionally substituted with a benzyl group” or “same or different, and is a hydroxyl group, amino group, carbamoyl group, ureido group,
  • Carbonyl group (the C 1-6 alkylaminocarbonyl group is substituted with 1 to 3 groups selected from an amino group, a C 2-7 alkoxycarbonyl group, a carbamoyl group, a diC 1-4 alkylamino group and a hydroxyl group.
  • C 2-7 alkanoylamino group (the C 2-7 alkanoylamino group may be substituted with an amino group), C 1-6 alkylsulfonylamino group, diC 1-4 alkylamino group, A phenyl group (the phenyl group may be substituted with a hydroxyl group), a C 1-6 alkyl group substituted with 1 to 3 groups selected from a pyridyl group and a piperidyl group; R 7 is a hydrogen atom or a C 1-4 alkyl group, Or R 6 and R 7 together with an adjacent nitrogen atom are a “C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a C 2-7 alkoxycarbonyl group or a hydroxyl group), a carbamoyl group, and A piperazine ring optionally substituted with one group selected from a C 2-7 alkanoyl group (the C 2-7 alkanoyl group may be substituted with an amino group)
  • R 1 is a hydrogen atom or a “C 1-4 alkyl group optionally substituted with a hydroxyl group or a halogen atom”
  • R 2 and R 3 are the same or different and are a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group, Or R 2 and R 3 together with the adjacent carbon atom form a C 3-6 cycloalkane ring
  • R 4 and R 5 are the same or different and are a hydrogen atom, a methyl group or a hydroxymethyl group, Or R 4 and R 5 together with the adjacent carbon atom form a C 3-6 cycloalkane ring or a 4-6 membered heterocyclo ring
  • n is 0 or 1
  • R 6 is a hydrogen atom, “a piperidyl group optionally substituted with a benzyl group” or “same or different, and is a hydroxyl group, amino group, carbamoyl group, ureido group,
  • Carbonyl group (the C 1-6 alkylaminocarbonyl group is substituted with 1 to 3 groups selected from an amino group, a C 2-7 alkoxycarbonyl group, a carbamoyl group, a diC 1-4 alkylamino group and a hydroxyl group.
  • C 2-7 alkanoylamino group (the C 2-7 alkanoylamino group may be substituted with an amino group), C 1-6 alkylsulfonylamino group, diC 1-4 alkylamino group, A phenyl group (the phenyl group may be substituted with a hydroxyl group), a C 1-6 alkyl group substituted with 1 to 3 groups selected from a pyridyl group and a piperidyl group; R 7 is a hydrogen atom or a C 1-4 alkyl group, Or R 6 and R 7 together with an adjacent nitrogen atom are a “C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a C 2-7 alkoxycarbonyl group or a hydroxyl group), a carbamoyl group, and A piperazine ring optionally substituted with one group selected from a C 2-7 alkanoyl group (the C 2-7 alkanoyl group may be substituted with an amino group)
  • R 6 is a C 3-5 alkyl group substituted with one hydroxyl group, or A C 5 alkyl group substituted with one diC 1-4 alkylamino group
  • R 7 is a hydrogen atom
  • R 1 is a hydrogen atom
  • R 2 and R 3 are methyl groups
  • 4 and R 5 are methyl groups
  • n is 0.
  • W is a single bond or a methylene group (CH 2 ), the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3): (5) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein W represents a carbonyl group (C ⁇ O). (6) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3) or (5), wherein Y represents a C 1-4 alkylene group.
  • R 1 represents a hydrogen atom
  • R 2 and R 3 represent a methyl group
  • R 4 and R 5 represent a methyl group
  • n represents 0, and
  • R 6 represents “C 3- substituted with one hydroxyl group.
  • R 7 is a hydrogen atom
  • W is a carbonyl group (C ⁇ O)
  • a pharmaceutical composition comprising the 4-isopropylphenyl glucitol compound according to any one of (1) to (11) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a sodium-dependent glucose cotransporter 1 (SGLT1) activity inhibitor comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (11) as an active ingredient.
  • a postprandial hyperglycemia improving drug comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (11) as an active ingredient.
  • a preventive or therapeutic agent for diabetes comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (11) as an active ingredient.
  • a preventive or therapeutic agent for diabetes comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (11) as an active ingredient.
  • n is normal, “i” is iso, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” "" Indicates ortho, “m” indicates meta, and “p” indicates para.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-4 alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a tert-butyl group.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1-6 carbon atoms. Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, and an isohexyl group.
  • C 3-6 cycloalkane ring means a cyclic alkane having 3-6 carbon atoms.
  • a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring are mentioned.
  • the “4- to 6-membered heterocyclo ring” is a 4- to 6-membered group consisting of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or the same or different, and 1 to 5 carbon atoms. It means a monocyclic saturated heterocyclic ring. Examples thereof include an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a tetrahydrothiopyran ring, a pyrrolidine ring, and a piperidine ring.
  • C 2-7 alkanoyl group means a carbonyl group having “a linear or branched alkyl group having 1 to 6 carbon atoms”. Examples include acetyl group, propionyl group, n-butyryl group, isobutyryl group, n-valeryl group, isovaleryl group, and pivaloyl group.
  • C 1-6 alkylamino group means an amino group having one “C 1-6 alkyl group” as a substituent. Examples thereof include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, and an n-butylamino group.
  • the “di-C 1-4 alkylamino group” means an amino group having the same or different two “C 1-4 alkyl groups” as the substituent. Examples include a dimethylamino group, a diethylamino group, a di (n-propyl) amino group, a di (isopropyl) amino group, an ethylmethylamino group, and a methyl (n-propyl) amino group.
  • C 2-7 alkoxycarbonyl group means a group in which a “linear or branched alkoxy group having 1 to 6 carbon atoms” and a carbonyl group are bonded. Examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
  • C 1-6 alkylaminocarbonyl group means a group in which the above “C 1-6 alkylamino group” is bonded to a carbonyl group.
  • a methylaminocarbonyl group is mentioned.
  • the “C 2-7 alkanoylamino group” means a group in which the above “C 2-7 alkanoyl group” and an amino group are bonded.
  • an acetamide group can be mentioned.
  • C 1-6 alkylsulfonylamino group means a group in which the sulfonyl group to which the above “C 1-6 alkyl group” is bonded is bonded to an amino group.
  • An example is a methanesulfonamide group.
  • C 1-6 alkylaminocarbonylamino group means a group in which a carbonyl group to which the above “C 1-6 alkylamino group” is bonded is bonded to an amino group.
  • An example is a methylaminocarbonylamino group.
  • the “C 1-4 alkylene group” means a divalent hydrocarbon group having 1 to 4 carbon atoms.
  • a methylene group, an ethylene group, and a propylene group are mentioned.
  • “Pharmaceutically acceptable salt” is a salt with an alkali metal, alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt or potassium salt.
  • Calcium salt ammonium salt, aluminum salt, triethylammonium salt, formate, acetate, propionate, butyrate, hexanoate, octanoate, trifluoroacetate, maleate, tartrate, citric acid Salt, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucuronate, glucoheptonate, glutarate, pimelate, suberate, azelate, sebacate, 1,9-nonanedicarboxylate, dodecanedioate, tridecanedioate, tetradecanedioate, pentadecanedioate, Xadecane diacid salt, heptadecane diacid salt, benzoate, 2-hydroxybenzoate, methanesulfonate, ethanesulfonate, ethanedisulfonate, 2-hydroxyethanesul
  • the compound of the present invention or a salt thereof includes pharmaceutically acceptable hydrates thereof.
  • the compound of the present invention or a salt thereof may be exposed to the atmosphere, or may absorb moisture during the production process to form adsorbed water or become a hydrate.
  • the hydrate in the present invention includes such a hydrate.
  • Postprandial hyperglycemia-improving drug refers to a drug that suppresses postprandial hyperglycemia, thereby suppressing the onset of postprandial hyperglycemia, such as diabetes or metabolic syndrome, or treating these diseases .
  • postprandial hyperglycemia refers to a state in which the blood glucose level is abnormally high after the meal, specifically, a state in which the blood glucose level for 2 hours after the meal exceeds 140 mg / dL.
  • the compound of the present invention has strong SGLT1 inhibitory activity. Therefore, it is considered that the compound of the present invention has a property that is excellent in practicality as a pharmaceutical having an excellent blood glucose lowering action.
  • the compound of the present invention does not tend to remain in the body, and is considered to have a property that is excellent in practicality as a pharmaceutical with few side effects and toxicity due to continuous administration. Even after 7 days after oral administration of 1 mg / kg of the compound disclosed in WO2007 / 136116, the compound tended to remain in the kidney without being excreted, whereas the compound of the present invention had a tendency to remain in the body. It is considered that it is excellent in that it is not.
  • the compound of the present invention is provided as a pharmaceutical
  • various forms of preparations such as solid preparations and liquid preparations can be appropriately adopted.
  • such carriers include common excipients, bulking agents, binders, disintegrants, coating agents, dragees, pH adjusters, solubilizers or aqueous or non-aqueous solvents. Tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions and the like can be prepared from the compound of the present invention and these carriers.
  • the compound of the present invention and general excipients used for the production of solid preparations and the like can be mixed and then tableted to provide tablets for oral administration.
  • solubility of the compound of the present invention can also be improved by inclusion in ⁇ , ⁇ or ⁇ -cyclodextrin or methylated cyclodextrin.
  • the dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is 0.1 to 1000 mg / kg body weight per day for an adult, kg body weight is preferable, and 0.1 to 10 mg / kg body weight is more preferable. This can be administered once to several times a day.
  • the compound of the present invention can be synthesized by the following method.
  • the following production method is an example of a general production method and does not limit the production method.
  • X represents an acetyl group, an acetyloxy group or a C 1-4 alkyl group which may be substituted with a halogen atom
  • R 2A and R 3A are the same or different and represent a hydrogen atom, a methyl group or an ethyl group
  • R 2A and R 3A together with the adjacent carbon atom form a C 3-6 cycloalkane ring or a 2,2-dimethyldioxane ring.
  • R 6A represents a R 6 wherein R 6 or an amino group is protected with tert- butylcarbonyl (Boc) group
  • m represents an integer of 1 to 4, and other symbols are as defined above.
  • Step 1 acetylation or alkylation
  • the intermediate (1B) can be produced by protecting the hydroxyl group of the compound (1A) with an acetyl group or performing alkylation such as methylation.
  • Compound (1A) can be reacted with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base to obtain intermediate (1B).
  • Solvents used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
  • Preferable examples of the base include triethylamine, collidine, pyridine and the like.
  • the intermediate (1B) can be obtained by reacting the compound (1A) with methyl iodide, ethyl iodide or the like in a solvent in the presence of an appropriate base.
  • Solvents used for the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetone and the like.
  • Examples of the base include potassium carbonate and cesium carbonate.
  • Step 2 Compound (1C) can be obtained by subjecting compound (1B) and olefin carboxylic acid (4A) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and an appropriate base.
  • a palladium catalyst used at this time include palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone palladium, bis (triphenylphosphine) palladium chloride, bis (tricyclohexylphosphine) palladium chloride, and palladium activated carbon.
  • Examples of the phosphine ligand include triphenylphosphine and tri-o-tolylphosphine.
  • As the base triethylamine, N, N-diisopropylethylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used.
  • Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran and the like.
  • the reaction temperature is 0 ° C. to reflux temperature. A microwave can also be used.
  • Step 3 Conversion to amide group
  • Compound (1C) can be condensed with amine (4B) to give compound (1D).
  • Examples of the solvent used in this reaction include chloroform, dichloromethane, N, N-dimethylformamide and the like, and examples of the condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), N-ethyl-N′-3-dimethyl.
  • the reaction temperature here is 0 ° C. to 60 ° C.
  • Step 4 The compound (1E) can be obtained by oxidizing the primary alcohol of the compound (1D).
  • the solvent used in this reaction chloroform, dichloromethane, dimethyl sulfoxide and the like are preferable, and as the oxidizing agent, Dess-Martin periodinane, IBX and the like are preferable.
  • the reaction temperature here is 0 ° C. to room temperature.
  • Step 5 Reductive amination
  • Compound (1F) can be obtained by reductive amination reaction using compound (1E) and an amine (R 6A R 7 NH (4C)). Examples of the solvent used in this reaction include N, N-dimethylformamide, chloroform, dichloromethane, methanol and the like.
  • Step 6 Compound (I) can be obtained by removing the Boc group in compound (1F) under acidic conditions and removing the acetyl (Ac) group under basic conditions. In removing the Boc group, hydrochloric acid or trifluoroacetic acid is allowed to act in a solvent such as dichloromethane, chloroform, dioxane or the like or without a solvent.
  • a base such as sodium methoxide, sodium ethoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used.
  • the solvent include methanol, ethanol, hydrous methanol and the like.
  • the reaction temperature here is 0 ° C. to 60 ° C.
  • Examples of the solvent used in this reaction include tetrahydrofuran, dioxane, ethyl acetate, and examples of the acid include hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.
  • the compound (Ia) of the present invention in which W is a single bond or methylene group and Y is a carbonyl group can be synthesized by the following method.
  • L shows a bromo group or a mesyl group
  • r shows 0 or 1
  • other symbols are as defined above.
  • Step 7 (Heck reaction)
  • Compound (2C) can be obtained by performing Heck reaction described in Step 2 of Production Method 1 from Compound (1B) and acrylic acid or butenoic acid (4D).
  • Step 8 (reduction)
  • Compound (2D) can be obtained by reducing the carboxy group of compound (2C).
  • the solvent used in this reaction include tetrahydrofuran and diethyl ether.
  • An example of the reducing agent is borane-tetrahydrofuran complex.
  • the reaction temperature is 0 ° C. to 60 ° C., preferably room temperature.
  • Step 9 (bromination or mesylation)
  • the compound (2E) can be obtained by brominating or mesylating the primary alcohol of the compound (2D).
  • chloroform chloroform, dichloromethane, tetrahydrofuran and the like are preferable.
  • the bromination reagent include triphenylphosphine (PPh 3 ) -DEAD-lithium bromide, PPh 3 -carbon tetrabromide, N-bromosuccinimide (NBS), and the like.
  • PPh 3 triphenylphosphine
  • NBS N-bromosuccinimide
  • methanesulfonyl chloride is used in the presence of triethylamine. The reaction temperature is 0 ° C. to room temperature.
  • Step 10 (amination)
  • Compound (2F) can be obtained by reacting compound (2E) with amine (4E).
  • the solvent used in this reaction include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and the reaction temperature is from room temperature to 150 ° C.
  • Step 11 (deprotection) Compound (2F) obtained above can be led to compound (Ia) by the deprotection reaction described in Step 6 of Production Method 1.
  • Step 12 Heck reaction
  • Compound (3A) can be obtained by performing the Heck reaction described in Step 2 of Production Method 1 using Compound (1B) and Compound (4F).
  • Step 13 Conversion to amide group
  • Compound (3B) can be obtained by performing the dehydration condensation reaction described in Step 3 of Production Method 1 using Compound (3A) and amine (4C).
  • Step 14 deprotection
  • Compound (3B) obtained above can be led to compound (Ib) by the deprotection reaction described in Step 6 of Production Method 1.
  • Production method of intermediate (1A) Intermediate (1A) can be synthesized by the method shown below. However, the symbols are as defined above.
  • Step 15 (coupling)
  • An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium for the compound (5A).
  • Compound (5C) can be obtained by adding gluconolactone (5B) to this.
  • the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like.
  • the reaction temperature is ⁇ 80 ° C. to room temperature, preferably ⁇ 78 ° C. to ⁇ 25 ° C.
  • Step 16 silation
  • the 1-position hydroxyl group of the compound (5C) can be protected with a silyl group such as a trimethylsilyl group.
  • the reaction liquid in Step 15 can be reacted with trimethylsilyl chloride to obtain compound (5D).
  • the solvent and reaction temperature used for the reaction are the same as in Step 15.
  • Step 17 coupling
  • an aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium or the like to the compound (5D) produced.
  • Compound (5F) can be obtained by adding aldehyde (5E) to this.
  • Step 18 (acid hydrolysis and methyl etherification)
  • the MOM group and silyl group in the compound (5F) can be simultaneously removed in methanol under acidic conditions, and the 1-position of the sugar can be methyletherified to obtain the compound (5G).
  • the acid used at this time include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonic acid, and the like.
  • the reaction temperature varies depending on the acid used, it is 0 ° C. to 100 ° C., preferably 25 ° C.
  • a compound (5H) can be obtained by protecting the hydroxyl group in the compound (5G) with an acetyl group.
  • Compound (5H) can be obtained by reacting compound (5G) with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base.
  • Solvents used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like.
  • the base include triethylamine, collidine, pyridine and the like. 4-Dimethylaminopyridine can also be used as a catalyst for the reaction.
  • Step 20 Compound (1A) can be obtained by reacting compound (5H) with Et 3 SiH, i-Pr 3 SiH, t-BuMe 2 SiH or Ph 2 SiHCl in the presence of an acid.
  • the acid used in this reaction include BF 3 ⁇ OEt 2 , CF 3 COOH, InCl 3 , TiCl 4 , TMSOTf, p-toluenesulfonic acid monohydrate, methanesulfonic acid, and the like, and the solvent includes chloroform.
  • a preferable solvent is a mixed solvent of acetonitrile and other solvents such as acetonitrile / chloroform, acetonitrile / dichloromethane, acetonitrile / tetrahydrofuran and acetonitrile / tetrahydrofuran / toluene.
  • N, N-diisopropylethylamine (364 mL, 2.09 mol) was added to a solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol) in chloroform (1.74 L), and the mixture was ice-cooled.
  • Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was ice-cooled, and 1M aqueous sodium hydroxide solution (1.5 L) was added dropwise to separate the organic layer.
  • the obtained residue (546 g) was dissolved in methanol (3.0 L), methanesulfonic acid (3.84 mL, 0.0592 mol) was added, and the mixture was heated to reflux for 1.5 hours.
  • the reaction mixture was cooled to room temperature, neutralized with triethylamine (25 mL, 0.179 mol), and the reaction mixture was concentrated.
  • the concentrate was dissolved in toluene (1.0 L) and washed with water (0.5 L, 1.0 L).
  • a 1 M aqueous sodium hydroxide solution (0.6 L) and toluene (1.0 L) were added to the organic layer to perform a liquid separation operation, and the aqueous layer was separated.
  • the aqueous layer was washed with toluene (1.0 L, 0.5 L). To the aqueous layer, 10% hydrochloric acid (0.7 L) was added and extracted with toluene (1.0 L), and the organic layer was separated. The organic layer was washed with 10% brine (1.0 L) and water (0.5 L), and the solvent was evaporated under reduced pressure.
  • Acetic anhydride (385 mL) was added dropwise to a solution of intermediate (1A) (600 g, 0.592 mol) in pyridine (770 mL) over 10 minutes under ice cooling.
  • the reaction solution was raised to room temperature, stirred at the same temperature for 18 hours, and ice-cooled again, and then the reaction was stopped with ice (1.0 L).
  • the reaction solution was diluted with toluene (1.0 L) and then stirred for 1.5 hours.
  • the organic layer was separated, washed twice with 2M hydrochloric acid (1.25L), washed with 5% aqueous sodium hydrogen carbonate solution (1.0L), 10% brine (1.0L), water (0.5L) and reduced pressure. The bottom was concentrated.
  • Potassium hydroxide (19.8 g, 35.2 mmol) was slightly added to an acetonitrile-water mixed solution (1: 1, 235 mL) of intermediate (1A) (15.3 g, 23.5 mmol) at an internal temperature of ⁇ 8.9 ° C. Added in portions and stirred for 7 minutes. Next, diethyl (bromodifluoromethyl) phosphonate (9.40 g, 35.2 mmol) was added dropwise at an internal temperature of ⁇ 1.3 ° C., and the mixture was stirred for 7 minutes.
  • Step 1 and Step 2 The method described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.0 g, 1.4 mmol) and 3-aminopropanol (0.14 mL, 1.8 mmol) as starting materials. To obtain intermediate (1E-2) (0.77 g, 72% for 2 steps).
  • Step 1 and Step 2 Intermediate (1C-1) (1.0 g, 1.4 mmol) and 3-amino-3-methylbutanol (0.19 g, 1.8 mmol, Journal of Labeled Compounds & Radiopharmaceuticals (2001), 44 (4), 265 -275.)
  • intermediate (1E-3) (0.77 g, 2 steps 55%) was obtained according to the method described in steps 1 and 2 of Reference Example 12.
  • Step 4 and Step 5 Using the intermediate (1C-1) (500 mg, 0.69 mmol) and the intermediate (4B-5c) (72 mg, 0.83 mmol) as starting materials, the method described in steps 1 and 2 of Reference Example 12 was used. Based on the above, Intermediate (1E-5) (305 mg, 98% for 2 steps) was obtained as colorless amorphous.
  • Step 1 and Step 2 Described in Step 1 and Step 2 of Reference Example 12 using intermediate (1C-1) (1.00 g, 1.38 mmol) and (1-aminocyclobutyl) methanol (210 mg, 2.07 mmol) as starting materials
  • the intermediate (1E-6) (355 mg, 2 steps: 32%) was obtained as a pale yellow amorphous product in accordance with the method described above.
  • Step 1 and Step 2 Starting from intermediate (1C-1) (1.00 g, 1.38 mmol) and 1-amino-1-cyclopentanemethanol (207 mg, 1.79 mmol) as starting materials, described in Step 1 and Step 2 of Reference Example 12
  • the intermediate (1E-7) (850 mg, 71% for 2 steps) was obtained as a colorless amorphous product.
  • Step 6 Using the intermediate (1C-1) (500 mg, 0.690 mmol) and the intermediate (4B-8e) (107 mg, 0.830 mmol) as starting materials, the method described in steps 1 and 2 of Reference Example 12 was used. Based on the above, Intermediate (1E-8) (89 mg, 16% for 2 steps) was obtained as colorless amorphous.
  • Step 1 and Step 2 Intermediate (1C-1) (1.00 g, 1.38 mmol) and (1-aminocyclohexyl) methanol (267 mg, 2.07 mmol) are used as starting materials and described in Step 1 and Step 2 of Reference Example 12. According to the method, intermediate (1E-9) was obtained.
  • MS ESI / APCI Dual nega 868 [M + Cl] - .
  • Step 4 and Step 5 Using the intermediate (1C-1) (815 mg, 1.12 mmol) and the intermediate (4B-10c) (174 mg, 1.69 mmol) as starting materials, the method described in steps 1 and 2 of Reference Example 12 was used. Based on the above, Intermediate (1E-10) (483 mg, 69% for 2 steps) was obtained as colorless amorphous.
  • Step 3 and Step 4 The intermediate (1C-1) (7.0 g, 9.7 mmol) and the intermediate (4B-11b) (1.5 g, 9.3 mmol) are used as starting materials, and are described in Step 1 and Step 2 of Reference Example 12.
  • Intermediate (1E-11) (2.0 g, 25% over 2 steps) was obtained according to the method described above.
  • Step 1 and Step 2 Intermediate (1E-12) (1.00 g, 1.44 mmol) as a starting material and intermediate (1E-12) as a yellow amorphous substance according to the method described in Step 1 and Step 2 of Reference Example 12 ) (815 mg, 73% over 2 steps).
  • Step 1 and Step 2 Steps 1 and 2 of Reference Example 12 using Intermediate (1C-2) (3.00 g, 4.31 mmol) and 3-amino-3-methylbutanol (567 mg, 5.60 mmol, Reference Example 14) as starting materials
  • the intermediate (1E-13) (2.58 g, 74% for 2 steps) was obtained as a pale yellow amorphous product in accordance with the method described in 1).
  • Step 1 and Step 2 The intermediate (1C-2) (3.00 g, 4.31 mmol) and 1-amino-1-cyclopentanemethanol (645 mg, 5.60 mmol) were used as starting materials and described in Step 1 and Step 2 of Reference Example 12.
  • Step 1 Step 2
  • Step 3 Starting from intermediate (1B-1) (1.00 g, 1.45 mmol) and 2,2-diethylbut-3-enoic acid (493 mg, 3.47 mmol, Journal of Heterocyclic Chemistry (2005), 42, 327) According to the methods described in Reference Example 8 and Reference Example 12, Step 1 and Step 2, Intermediate (1E-15) (709 mg, 3 steps 60%) was obtained as a colorless amorphous substance.
  • Step 1 Step 2
  • Step 3 Intermediate Example (1B-1) (146 mg, 0.21 mmol) and 1-vinylcyclobutanecarboxylic acid (40 mg, 0.32 mmol, Journal of Heterocyclic Chemistry (2005), 42,327) were used as starting materials, and Reference Example 8, Reference According to the method described in Step 1 and Step 2 of Example 12, intermediate (1E-16) (709 mg, 3 steps 60%) was obtained as a colorless amorphous substance.
  • Step 1 Step 2
  • Step 3 Intermediate (1B-1) (683 mg, 0.990 mmol) and 2,2-dimethyl-5-vinyl-1,3-dioxane-5-carboxylic acid (276 mg, 1.48 mmol, Journal of Heterocyclic Chemistry (2005), 42,327) as a starting material, intermediate (1E-17) (709 mg, 3 steps 66% as a colorless amorphous) according to the method described in steps 1 and 2 of Reference Example 8 and Reference Example 12.
  • Step 1 and Step 2 Intermediate (1C-3) (9.00 g, 0.0129 mol) was used as a starting material and the intermediate (1E-18) was converted into a yellow amorphous substance according to the method described in Step 1 and Step 2 of Reference Example 12. ) (7.60 g, 77% over 2 steps).
  • Step 1 and Step 2 In accordance with the method described in Step 1 and Step 2 of Reference Example 12, using Intermediate (1C-4) (6.05 g, 9.04 mmol) as a starting material, Intermediate (1E-19 ) (3.44 g, 2 steps 52%).
  • Step 1 and Step 2 Described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-3) (668 mg, 0.959 mmol) and 3-amino-3-methylbutanol (129 mg, 1.25 mmol, Reference Example 14) as starting materials
  • the intermediate (1E-20) (329 mg, 44% for 2 steps) was obtained as a yellow amorphous substance in accordance with the described method.
  • Step 1 Step 2
  • Step 3 Intermediate (1B-3) (1.00 g, 1.48 mmol) was used as a starting material in accordance with the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12 as a colorless amorphous intermediate.
  • (1E-21) (175 mg, 3 steps 15%) was obtained.
  • Step 1 Step 2
  • Step 3 The intermediate (1E-6) (480 mg, 0.653 mmol) was used as a starting material in the form of a colorless amorphous substance according to the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12. -22) (250 mg, 46% over 3 steps).
  • Step 1 Step 2
  • Step 3 The intermediate (1E-4) (200 mg, 0.29 mmol) was used as a starting material in the form of a colorless amorphous substance according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. -23) (185 mg, 57% over 3 steps).
  • Step 1 Step 2
  • Step 3 Intermediate (1B-5) (10.6 g, 15.2 mmol) was used as a starting material, and the intermediate was obtained as a colorless amorphous according to the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12.
  • (1E-24) (6.62 g, 56% over 3 steps) was obtained.
  • intermediate (1B-1) (5.00 g, 7.23 mmol), intermediate (4F-2) (2.59 g, 13.0 mmol), palladium (II) acetate (328 mg, 1.45 mmol)
  • Tri-o-tolylphosphine (880 mg, 2.89 mmol
  • triethylamine (3.0 mL, 9.00 mmol) in acetonitrile (24 mL) was stirred at 120 ° C. for 20 minutes under microwave irradiation.
  • the reaction solution was filtered through Celite (registered trademark) and washed with ethyl acetate.
  • N-carbobenzoxy-1,2-diaminoethane hydrochloride (1.0 g, 4.33 mmol), 2- (tert-butoxycarbonylamino) isobutyric acid (1.15 g, 5.64 mmol), EDC-HCl (762 mg) , 5.64 mmol), HOBt ⁇ H 2 O (1.08 g, 5.64 mmol), triethylamine (1.8 mL, 13 mmol) in N, N-dimethylformamide (22 mL) was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, washed with water, and dried over sodium sulfate.
  • Step 1 and Step 2 The intermediate (4C-3b) (1.0 g, 3.86 mmol) was used as a starting material in accordance with the method described in Steps 1 and 2 of Reference Example A-4, and the amine intermediate ( 4C-5) (490 mg) was obtained.
  • 1 H NMR 300 MHz, CHLOROFORM-d
  • ppm 1.26 (s, 6 H) 1.43 (s, 9 H) 1.52 (s, 6 H) 3.34 (d, J 5.8 Hz, 2 H).
  • Step 1 and Step 2 Starting from 1-carbobenzoxypiperazine (1.00 g, 4.54 mmol) as a starting material, according to the method described in Step 1 and Step 2 of Reference Example A-4, the amine intermediate ( 4C-6) (1.05 g) was obtained.
  • 1 H NMR 300 MHz, CHLOROFORM-d
  • Step 1 and Step 2 Starting from Cbz-Aib-OH (1.0 g, 4.21 mmol) and 2-amino-2-methylpropanamide (516 mg, 5.05 mmol) as described in the steps 1 and 2 of Reference Example A-4 According to the above method, amine intermediate (4C-9) (668 mg) was obtained as a colorless oil.
  • 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ ppm 1.22 (s, 6 H) 1.39 (s, 6 H).
  • MS ESI / APCI Dual nega 186 [MH] - , 222 [M + Cl] - .
  • Step 1 and Step 2 Starting from Cbz-Aib-OH (3.00 g, 12.6 mmol) and tris (hydroxymethyl) aminomethane (1.60 g, 13.3 mmol) as starting materials, described in Step 1 and Step 2 of Reference Example A-8
  • the amine intermediate (4C-11) (634 mg) was obtained as a colorless solid.
  • 1 H NMR 300 MHz, CHLOROFORM-d) ⁇ ppm 1.39 (s, 6 H) 3.69 (s, 6 H).
  • Step 1 and Step 2 The method described in Step 1 and Step 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and glycine methyl ester / hydrochloride (1.6 g, 13 mmol) as starting materials To obtain an amine intermediate (4C-12) (1.3 g, 87% for 2 steps).
  • 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ ppm 1.21 (s, 6 H) 3.64 (s, 3 H) 3.81-3.89 (m, 2 H) 8.31 (br. S, 1 H).
  • Step 1 and Step 2 Conforms to the methods described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 3-aminopropanol (0.96 mL, 13 mmol) as starting materials.
  • amine intermediate (4C-13) (0.31 g, 46% for 2 steps) was obtained as a colorless liquid.
  • MS ESI / APCI Dual nega: 159 [MH] - .
  • Step 1 and Step 2 Conforms to the methods described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 4-aminobutanol (1.2 mL, 13 mmol) as starting materials.
  • an amine intermediate (4C-14) (0.52 g, 71% for 2 steps) was obtained as a colorless liquid.
  • MS ESI / APCI Dual nega: 173 [MH] - .
  • Step 1 and Step 2 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.80 g, 3.2 mmol, WO2004018491) and glycinamide hydrochloride (0.35 g, 3.2 mmol)) as starting materials, According to the method described in Step 1 and Step 2 of Reference Example A-4, amine intermediate (4C-16) (0.49 g, 2 steps 89%) was obtained.
  • 1 H NMR 600 MHz, METHANOL-d 4 ) ⁇ ppm 1.25 (s, 6 H) 2.88 (s, 2 H) 3.86 (s, 2 H).
  • Step 1 and Step 2 Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (1.0 g, 4.0 mmol, WO2004018491) and glycine methyl ester hydrochloride (0.79 g, 6.3 mmol) as starting materials, According to the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-17) (0.58 g, 2 steps 77%) was obtained.
  • Step 1 and Step 2 Reference example using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 3-aminopropanol (0.46 mL, 6.0 mmol) as starting materials According to the method described in Step 1 and Step 2 of A-8, amine intermediate (4C-18) (0.30 g, 87% for 2 steps) was obtained as a colorless solid.
  • 1 H NMR 300 MHz, CHLOROFORM-d
  • Step 1 and Step 2 Reference examples using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 4-aminobutanol (0.56 mL, 6.0 mmol) as starting materials According to the method described in Step 1 and Step 2 of A-8, amine intermediate (4C-19) (0.23 g, 2 steps 61%) was obtained as a colorless liquid.
  • Step 1 and Step 2 Reference was made using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 5-aminopentanol (0.6 mg, 6.0 mmol) as starting materials. According to the method described in Step 1 and Step 2 of Example A-8, amine intermediate (4C-20) (0.36 g, 87% for 2 steps) was obtained as a colorless liquid.
  • Step 1 and Step 2 Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and N, N-dimethylethylenediamine (0.66 mL, 6.0 mmol) as starting materials, According to the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-21) (0.34 g, 2 steps 91%) was obtained as a colorless liquid.
  • Step 1 and Step 2 Starting from 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and N, N-dimethylpropylenediamine (0.76 mL, 6.0 mmol) According to the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-22) (0.23 g, 2 steps 59%) was obtained as a colorless liquid.
  • Step 1 and Step 2 3- (Benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.502 g, 2.00 mmol, WO2004018491) and 4- (dimethylamino) butylamine dihydrochloride (1.13 g, 6.00 mmol) was used as a starting material, and an amine intermediate (4C-23) (0.375 g, 87% for 2 steps) was obtained as a colorless liquid in accordance with the method described in Step 1 and Step 2 of Reference Example A-8. It was. 1 H NMR (300 MHz, CHLOROFORM-d) ⁇ ppm 1.13 (s, 6 H) 1.49-1.57 (m, 4 H) 2.00 (br.
  • Step 1 and Step 2 Starting materials: 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.502 g, 2.00 mmol, WO2004018491) and 5- (dimethylamino) pentylamine (0.78 g, 6.00 mmol) As a result, the amine intermediate (4C-24) (0.505 g, 2 steps 100%) was obtained as a colorless liquid according to the method described in Step 1 and Step 2 of Reference Example A-8.
  • Examples 1-4 to 1-25 and 1-27 to 1-40 were also prepared using the intermediate (1E-1) and the corresponding amine in Examples 1-1, 1-2, or 1-3. Synthesis was performed according to any method described in the process. The structures, NMR data, and MS data of these compounds are shown in Table 1-1 to Table 1-10.
  • Examples 1-42 to 1-57 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using intermediate (1E-1) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 1-11 to 1-14.
  • Step 1 and Step 2 Using Intermediate (1E-2) (0.384 g, 0.492 mmol) and glycinamide hydrochloride (81.6 mg, 0.739 mmol) as starting materials, Step 1 and Example 1-3 of Example 1-2 In accordance with the method described in Step 2, a colorless amorphous compound (2-1) (133 mg, 43% for 2 steps) was obtained.
  • Examples 2-2 to 2-12 were also prepared according to Examples 1-1, 1-2, or 1-3 using the intermediate (1E-2) to intermediate (1E-10) and the corresponding amine. Synthesis was performed according to any method described in the process. The structures, NMR data, and MS data of these compounds are shown in Tables 2-1 to 2-3.
  • Examples 3-2 to 3-12 below are also described in the steps of Examples 1-1, 1-2, 1-3, or 3-1, using the intermediate (1E-11) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 to 3-3.
  • Step 1 and Step 2 Using Intermediate (1E-12) (300 mg, 0.392 mmol) and N, N-dimethylethylenediamine (51.8 mg, 0.588 mmol) as starting materials, Step 1 of Example 1-2 and Example 1-3 In accordance with the method described in Step 2, colorless amorphous compound (4-1) (26.8 mg, 2 steps 11%) was obtained.
  • Examples 4-2 to 4-16 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-12) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 4-1 to 4-5.
  • Step 1 and Step 2 Step 1 of Example 1-2 and Step of Example 1-3 using intermediate (1E-13) (135 mg, 0.174 mmol) and glycinamide hydrochloride (29.0 mg, 0.261 mmol) as starting materials
  • glycinamide hydrochloride 29.0 mg, 0.261 mmol
  • Examples 5-2 to 5-4 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-13) and the corresponding amine. It was synthesized in accordance with the method. The structure, NMR data and MS data of these compounds are shown in Table 5-1.
  • Intermediate (1E-14) 300 mg, 0.379 mmol
  • glycinamide hydrochloride 62.8 mg, 0.568 mmol
  • colorless amorphous compound (6-1) 81.4 mg, 34% for 2 steps) was obtained.
  • Examples 6-2 to 6-4 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-14) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Table 6-1.
  • Step 1 and Step 2 Using the intermediate (1E-15) (200 mg, 0.24 mmol) and glycinamide hydrochloride (35 mg, 0.32 mmol) as starting materials, the method described in steps 1 and 2 of Example 1-1 was used. Based on the above, colorless amorphous compound (7-1) (67 mg, 42% for 2 steps) was obtained.
  • Example 7-2 uses intermediate (1E-16) and glycinamide / hydrochloride
  • Example 7-3 uses intermediate (1E-17) and glycinamide / hydrochloride
  • Synthesis was performed according to the method described in Example 1-1.
  • Table 7-1 shows the structures, NMR data, and MS data of these compounds.
  • Step 1 and Step 2 Using Intermediate (1E-18) (150 mg, 0.196 mmol) and N, N-dimethylethylenediamine (26.0 mg, 0.294 mmol) as starting materials, Step 1 of Example 1-1 and Example 1-3 In accordance with the method described in Step 2, colorless amorphous compound (8-1) (77.1 mg, 2 steps 61%) was obtained.
  • Examples 8-2 to 8-31 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using intermediate (1E-18) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 8-1 to 8-9.
  • Step 1 and Step 2 Using Intermediate (1E-19) (100 mg, 0.136 mmol) and N, N-dimethylethylenediamine (0.044 mL, 0.407 mmol) as starting materials, Step 1-2 of Example 1-2 and Example 1-3 In accordance with the method described in Step 2, colorless amorphous compound (9-1) (5.0 mg, 7% for 2 steps) was obtained.
  • Examples 9-2 to 9-15 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using intermediate (1E-19) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 9-1 to 9-5.
  • Step 1 and Step 2 Using Intermediate (1E-20) (0.329 g, 0.422 mmol) and glycinamide hydrochloride (60.6 mg, 0.548 mmol) as starting materials, Step 1 and Example 1-3 of Example 1-1 In accordance with the method described in Step 2, a colorless amorphous compound (10-1) (21.6 mg, 12% for 2 steps) was obtained.
  • Examples 10-2 to 10-5 below are also any of those described in the steps of Examples 1-1, 1-2, or 1-3 using the intermediate (1E-20) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Table 10-1 to Table 10-2.
  • Step 1 and Step 2 Using the intermediate (1E-21) (175 mg, 0.22 mmol) and glycinamide hydrochloride (32 mg, 0.29 mmol) as starting materials, the method described in steps 1 and 2 of Example 1-1 was used. Based on the above, colorless amorphous compound (11-1) (80 mg, 56% over 2 steps) was obtained.
  • Examples 11-2 and 11-3 were also prepared according to the method described in Example 1-1 using Intermediate (1E-22), Intermediate (1E-23) and glycinamide / hydrochloride. Synthesized in compliance. The structures, NMR data, and MS data of these compounds are shown in Table 11-1.
  • Step 1 and Step 2 Using Intermediate (1E-24) (150 mg, 0.187 mmol) and N, N-dimethylethylenediamine (22 mg, 0.243 mmol) as starting materials, Step 1 of Example 1-1 and Step 2 of Example 1-3 The colorless amorphous compound (12-1) (22 mg, 17% for 2 steps) was obtained according to the method described in 1).
  • Examples 12-2 to 12-20 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-24) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 12-1 to 12-6.
  • Examples 13-2 to 13-4 were also synthesized using the intermediate (2C-1) and the corresponding amine according to the method described in the step of Example 13-1.
  • the structures, NMR data, and MS data of these compounds are shown in Table 13-1.
  • Examples 14-2 to 14-16 were also synthesized using the intermediate (2E-1) and the corresponding amine according to the method described in the step of Example 14-1.
  • the structures, NMR data, and MS data of these compounds are shown in Tables 14-1 to 14-5.
  • Example 15-2 The following Example 15-2, Example 15-3, Reference Example 39 and Example 15-5 are also described in the process of Example 15-1 using the intermediate (3A-1) and the corresponding amine. Synthesized according to the method. The structures, NMR data and MS data of these compounds are shown in Table 15-1.
  • Test example 1 Preparation of CHO-K1 cells stably expressing human SGLT1 A plasmid vector expressing human SGLT1 protein was transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT1-expressing cells were cultured in the presence of geneticin at a concentration of 500 ⁇ g / mL, resistant strains were selected, and sugar uptake ability was obtained as an index by the system shown below. (2) Sodium-dependent glucose uptake inhibition test in stably expressing cells The stably expressed cells were used in a sodium-dependent glucose uptake activity inhibition test.
  • Pretreatment buffer 140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4 was added to the stably expressing cells and incubated for 20 minutes.
  • the pretreatment buffer is removed, and the uptake buffer containing the test compound ([ 14 C] methyl ⁇ -D-glucopyranoside containing methyl ⁇ -D-glucopyranoside (1 mM), 145 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) was added, and an uptake reaction was performed at 37 ° C. for 30 minutes (SGLT1) or 60 minutes (SGLT2).
  • the cells were washed twice with a washing buffer (10 mM methyl ⁇ -D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) and 0.25 M. Dissolved in NaOH solution. After adding a liquid scintillator (Perkin Elmer) and mixing well, the radioactivity was measured using a ⁇ ray measuring apparatus. As a control group, an uptake buffer containing no test compound was prepared. For basal uptake, an uptake buffer containing choline chloride instead of NaCl was prepared.
  • a washing buffer 10 mM methyl ⁇ -D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris
  • test compound concentration (IC 50 value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. .
  • the test results are shown in Tables 17-1 to 17-3.
  • the inhibitory activity of the compound of the present invention against human SGLT2 can be confirmed according to the method of Test Example 2 below.
  • Test example 2 (1) Preparation of CHO-K1 cells that stably express human SGLT2 and sodium-dependent sugar uptake inhibition test in stably expressing cells
  • a plasmid vector that expresses human SGLT2 protein was CHO using Lipofectamine LTX (Invitrogen).
  • SGLT2-expressing cells can be obtained by culturing in the presence of geneticin at a concentration of 1000 ⁇ g / mL, selecting a resistant strain, and using the system shown in (2) of Test Example 1 as an index, the sugar uptake ability.
  • the compound of the present invention has no tendency to remain in the body by measuring the drug concentration in the kidney according to the method of Test Example 3 below.
  • Test example 3 (1) Renal concentration after repeated oral administration of the compound of the present invention for 3 days A 7-week-old SD / IGS rat (Nippon Charles River Co., Ltd., male, non-fasted) was prepared in 0.5% CMC aqueous solution. The compound of the present invention (3 mg / kg) is orally administered once a day for 3 consecutive days. At 48 hours after drug administration on the final day, whole blood is collected from the posterior vena cava under anesthesia with isoflurane, and the kidney is removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, weigh it, add 4 times the amount of purified water, and homogenize under ice cooling.
  • a postprandial hyperglycemia-improving drug having strong SGLT1 inhibitory activity can be provided, and by inhibiting SGLT1 activity, contributing to effective treatment / prevention for diseases derived from postprandial hyperglycemia, It contributes to the promotion of health and the development of a healthy pharmaceutical industry.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne un composé pour l'inhibition de l'intolérance anormale au glucose et de l'hyperglycémie postprandiale chez les patients diabétiques par inhibition de l'activité du transporteur sodium-glucose 1 (SGLT 1) et de l'absorption de glucose. De façon spécifique, sont proposés un composé 4-isopropylphényl glucitol représenté par la formule (I) et un sel pharmaceutiquement acceptable dudit composé. Dans la formule, R1 représente un atome d'hydrogène ou un groupe alkyle en C1-4 facultativement substitué; R2 et R3 représentent un atome d'hydrogène, un groupe méthyle, un groupe éthyle ou un groupe hydroxyméthyle; R4 and R5 représentent un atome d'hydrogène, un groupe méthyle ou un groupe hydroxyméthyle; n est 0 ou 1; R6 représente un atome d'hydrogène, un groupe pipéridyle facultativement substitué ou un groupe alkyle en C1-6 facultativement substitué; R7 représente un atome d'hydrogène ou un groupe alkyle en C1-4; W représente une liaison simple, un groupe méthylène ou un groupe carbonyle; et Y représente un groupe alkylène en C1-4 ou un groupe carbonyle.
PCT/JP2011/068674 2010-08-19 2011-08-18 Composé 4-isopropylphényl glucitol WO2012023582A1 (fr)

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JP2010184462A JP2013224263A (ja) 2010-08-19 2010-08-19 ４−イソプロピルフェニルグルシトール化合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012062308A (ja) * 2010-08-20 2012-03-29 Taisho Pharmaceutical Co Ltd ４−イソプロピルフェニルグルシトール化合物を有効成分として含有することを特徴とする糖尿病の予防又は治療剤
JP2014505709A (ja) * 2011-02-18 2014-03-06 シャンハイ インリ サイエンス アンド テクノロジー カンパニー，リミティド アリールグルコシド化合物、その調製方法及び使用
WO2014119787A1 (fr) 2013-02-04 2014-08-07 大正製薬株式会社 Médicament à visée prophylactique ou thérapeutique pour la constipation
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
CN108137457A (zh) * 2016-03-15 2018-06-08 盐野义制药株式会社 苯氧乙醇衍生物的制造方法
WO2019144864A1 (fr) 2018-01-23 2019-08-01 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle et utilisation associée
EP3747892A4 (fr) * 2018-01-31 2021-11-03 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle et utilisation associée

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WO2004014932A1 (fr) * 2002-08-08 2004-02-19 Kissei Pharmaceutical Co., Ltd. Derive de pyrazole, composition medicinale contenant ce derive, utilisation therapeutique de ceux-ci et intermediaire pour la production de cette composition
JP2008524162A (ja) * 2004-12-16 2008-07-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング グルコピラノシル置換ベンゼン誘導体、該化合物を含む薬物、その使用及びその製造方法
JP2009537509A (ja) * 2006-05-19 2009-10-29 大正製薬株式会社 Ｃ−フェニルグリシト−ル化合物

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WO2004014932A1 (fr) * 2002-08-08 2004-02-19 Kissei Pharmaceutical Co., Ltd. Derive de pyrazole, composition medicinale contenant ce derive, utilisation therapeutique de ceux-ci et intermediaire pour la production de cette composition
JP2008524162A (ja) * 2004-12-16 2008-07-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング グルコピラノシル置換ベンゼン誘導体、該化合物を含む薬物、その使用及びその製造方法
JP2009537509A (ja) * 2006-05-19 2009-10-29 大正製薬株式会社 Ｃ−フェニルグリシト−ル化合物

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012062308A (ja) * 2010-08-20 2012-03-29 Taisho Pharmaceutical Co Ltd ４−イソプロピルフェニルグルシトール化合物を有効成分として含有することを特徴とする糖尿病の予防又は治療剤
JP2014505709A (ja) * 2011-02-18 2014-03-06 シャンハイ インリ サイエンス アンド テクノロジー カンパニー，リミティド アリールグルコシド化合物、その調製方法及び使用
WO2014119787A1 (fr) 2013-02-04 2014-08-07 大正製薬株式会社 Médicament à visée prophylactique ou thérapeutique pour la constipation
US9394329B2 (en) 2013-09-27 2016-07-19 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivatives and their uses in medicine
US10472312B2 (en) 2016-03-15 2019-11-12 Shionogi & Co., Ltd. Method for producing phenoxyethanol derivative
CN108137457A (zh) * 2016-03-15 2018-06-08 盐野义制药株式会社 苯氧乙醇衍生物的制造方法
CN108137457B (zh) * 2016-03-15 2022-09-06 盐野义制药株式会社 苯氧乙醇衍生物的制造方法
WO2019144864A1 (fr) 2018-01-23 2019-08-01 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle et utilisation associée
US11084842B2 (en) 2018-01-23 2021-08-10 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof
EP3743412A4 (fr) * 2018-01-23 2021-11-03 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle et utilisation associée
AU2019211664B2 (en) * 2018-01-23 2022-08-11 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof
EP3747892A4 (fr) * 2018-01-31 2021-11-03 Sunshine Lake Pharma Co., Ltd. Dérivé de glucopyranosyle et utilisation associée
US11186602B2 (en) 2018-01-31 2021-11-30 Sunshine Lake Pharma Co., Ltd. Glucopyranosyl derivative and use thereof

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