WO2010117040A1 - Composé hétérocyclique à cinq chaînons - Google Patents

Composé hétérocyclique à cinq chaînons Download PDF

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WO2010117040A1
WO2010117040A1 PCT/JP2010/056379 JP2010056379W WO2010117040A1 WO 2010117040 A1 WO2010117040 A1 WO 2010117040A1 JP 2010056379 W JP2010056379 W JP 2010056379W WO 2010117040 A1 WO2010117040 A1 WO 2010117040A1
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carbon atoms
compound
added
mixture
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稔 田口
剛 毒島
亮 鈴木
陽平 小橋
匡宏 坊野
哲也 薮内
優子 橋本
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富士フイルム株式会社
大正製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a hetero 5-membered ring compound. More specifically, since it inhibits fatty acid-specific transporter FATP4 (Fatty acid transport protein 4) in small intestinal epithelial cells, it has an action to inhibit fatty acid absorption in the intestinal tract.
  • FATP4 Fatty acid transport protein 4
  • the present invention relates to a novel hetero 5-membered ring compound useful as a therapeutic agent.
  • a dihydropyrimidine derivative has been reported as a substance that inhibits FATP4 (see Non-Patent Document 1). However, it cannot be said that the FATP4 inhibitory action of these known compounds is sufficient, and they themselves do not show the fatty acid absorption inhibitory action in vivo. All have different chemical structures from the compounds of the present invention.
  • An object of the present invention is to provide a compound having an excellent FATP4 inhibitory action.
  • a hetero 5-membered ring compound inhibits FATP4 and completed the present invention.
  • One embodiment of the present invention is as follows: A hetero 5-membered ring compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • A represents —CO— or —CH 2 —
  • X represents —CH 2 —, —O— or —NH—
  • Y and W are the same or different
  • Or Indicate Z represents —CH 2 —, —O— or —NH—
  • Ar is
  • R 2 , R 3 and R 4 are the same or different and are a hydrogen atom, an alkyl group having 1 to 12 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom.
  • R 5 represents a halogen atom, a nitro group or a cyano group
  • R 1 is —CO—NR 6 R 7 , —CO 2 —R 8 , —NHCO—R 9
  • R 6 represents — (CH 2 ) n—R 14 , a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 18 carbon atoms
  • Indicate R 7 represents a hydrogen atom, — (CH 2 ) n—R 19 or an allyl group
  • R 8 is Or Indicate R 9 is Or Indicate R 10
  • R 15 , R 16 and R 17 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, R 18 is a phenyl group, an ethoxycarbonyl group, a phenethyl group, Or Indicate R 19 represents a hydrogen atom, a hydroxyl group, a carbamoyl group, a methylaminocarbonyl group, a cyano group, a carboxyl group, a methoxycarbonyl group or an allyl group, R 20 , R 21, and R 22 are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 12 carbon atoms that may be substituted with a halogen atom, or 1 to 10 carbon atoms that
  • R 23 represents a halogen atom, an alkyl group having 1 to 12 carbon atoms or an alkylthio group having 1 to 6 carbon atoms
  • R 24 , R 25 and R 26 are the same or different and each represents a halogen atom, an alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a nitro group
  • R 27 , R 28 and R 29 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms or a cyano group
  • n represents an integer of 1 to 20.
  • Another embodiment of the present invention is a hetero 5-membered ring compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.
  • R 18 has the same meaning as R 18 described above.
  • Ar is Or Indicates.
  • R 2 , R 3 and R 4 have the same meanings as R 2 , R 3 and R 4 , respectively.
  • another embodiment of the present invention is a hetero 5-membered ring compound represented by the following formula (III) or a pharmaceutically acceptable salt thereof.
  • R 13 and Ar have the same meanings as R 13 and Ar, respectively.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the alkyl group having 1 to 12 carbon atoms means a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a t-butyl group, Examples include a cyclopentyl group, a cyclohexyl group, and a cyclopentylmethyl group.
  • the alkyl group having 1 to 12 carbon atoms that may be substituted with a halogen atom refers to an alkyl group having 1 to 12 carbon atoms that is substituted with a linear, branched, or cyclic halogen atom.
  • Examples include a fluoromethyl group and a pentafluoroethyl group.
  • the alkoxy group having 1 to 10 carbon atoms refers to a linear, branched or cyclic alkoxy group having 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, a t-butoxy group, Examples include a cyclopentyloxy group, a cyclohexyloxy group, and a cyclopentylmethyloxy group.
  • the alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom refers to an alkoxy group having 1 to 10 carbon atoms substituted with a linear, branched or cyclic halogen atom.
  • alkylthio group having 1 to 6 carbon atoms refers to a linear, branched or cyclic alkylthio group having 1 to 6 carbon atoms, such as a methylthio group, an ethylthio group, a propylthio group, a t-butylthio group, Examples include a cyclopentylthio group, a cyclohexylthio group, and a cyclopentylmethylthio group.
  • Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • the alkenyl group having 2 to 18 carbon atoms is a linear, branched or cyclic alkenyl group having 2 to 18 carbon atoms, and examples thereof include a vinyl group, a pentenyl group, and a cyclohexenyl group.
  • Examples of the C 4-8 cycloalkenyl group include a cyclopentenyl group and a cyclohexenyl group.
  • Examples of pharmaceutically acceptable salts in the present invention include acid or alkali addition salts.
  • Examples of the acid include salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid and benzenesulfonic acid.
  • Examples of the alkali include metal ions such as sodium and potassium, and ammonium ions such as alkylammonium.
  • the compound of the present invention may be a single compound, a mixture of stereoisomers, or a hydrate or solvate thereof. Further, it may be a dimer of the compound represented by the formula (I) like the compound of Example 124 or 125 described later.
  • WSC ⁇ HCl is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • DCC is dicyclohexylcarbodiimide
  • HOBt is 1-hydroxybenzotriazole
  • CAN is cerium (IV) ammonium nitrate
  • TBAB is tetrabutylammonium Bromide and TMS represent a trimethylsilyl group.
  • A represents —CO—
  • X represents an oxygen atom
  • Y and W represent Z represents —CH 2 —
  • R 1 represents Wherein Ar, R 10 , R 11 and R 12 are as defined above, can be synthesized by the method shown in Reaction Scheme 1. That is, after protecting the hydroxyl group of compound (1) with tetrahydropyranyl, compound (2) is obtained by Horner-Emmons reaction, and after deprotection, the double bond is reduced and cyclized in the presence of acid to form cis of compound (3). A mixture of body and trans body can be obtained. By separating and purifying this mixture by silica gel chromatography, it is possible to obtain the cis form or the trans form of Compound (3) as a single compound.
  • Ar, R 10 , R 11 and R 12 are as defined above.
  • the compound (3) can also be synthesized by the method shown in Reaction Scheme 2. That is, compound (4) was subjected to wine levamidation, arylated to obtain compound (5), and then acetic acid was introduced, followed by reduction of ketone and hydrolysis of ester in the presence of hydrochloric acid.
  • the mixture of the cis form and the trans form of Compound (3) can be obtained by ring-closing at room temperature.
  • Ar, R 10 , R 11 and R 12 are as defined above, and R 30 represents a chlorine atom, a bromine atom or an iodine atom.
  • the mixture of the cis form and the trans form of compound (3) obtained here is isomerized by heating in the presence of acetic acid to obtain the trans form of compound (3) as a single compound.
  • A represents —CO—
  • X and Z represent oxygen atoms
  • Y and W represent R 1 is
  • Ar, R 10 , R 11 and R 12 are as defined above
  • a compound group (9) is obtained by reacting compound (7) with triphosgene after reduction of compound (7) as shown in Reaction Scheme 3.
  • Ar, R 10 , R 11 and R 12 are as defined above.
  • A represents —CO—
  • X and Z represent —NH—
  • Y and W represent R 1 is
  • Ar, R 10 , R 11 and R 12 are as defined above
  • the compound (8) obtained in Reaction Scheme 3 was azidated after mesylation as shown in Reaction Scheme 4.
  • the compound (10) can be obtained as a mixture of the cis form and the trans form by reacting the diamine compound obtained by reducing the azide with triphosgene. By separating and purifying the mixture by silica gel chromatography, the cis form or the trans form of compound (10) can be obtained as a single compound.
  • Ar, R 10 , R 11 and R 12 are as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —NH—
  • Y and W represent R 1 is
  • a compound group in which Ar, R 10 , R 11 and R 12 are as defined above is a compound obtained by reducing oxime after oximation of compound (1) as shown in Reaction Scheme 5. Is reacted with triphosgene to give compound (11) as a mixture of cis and trans isomers. By separating and purifying the mixture by silica gel chromatography, it is possible to obtain the cis form or the trans form of the compound (11) as a single compound.
  • Ar, R 10 , R 11 and R 12 are as defined above.
  • A represents —CO—
  • X and Z represent —NH—
  • Y represents W
  • R 1 is
  • Ar, R 10 , R 11, and R 12 are as defined above
  • the compound (13) is obtained by reacting compound (12) with substituted benzaldehyde as shown in Reaction Scheme 6.
  • A represents —CO—
  • X represents —NH—
  • Y and W represent Z represents —CH 2 —
  • R 1 represents —CO—NR 6 R 7
  • Ar, R 6 and R 7 are as defined above.
  • Ar, R 6 and R 7 are as defined above.
  • A represents —CO—
  • X represents —CH 2 —
  • Y represents Z represents —NH—
  • W represents Wherein R 1 represents —CO—NHR 6 and Ar and R 6 are as defined above, the compound group is obtained by reacting compound (17) with hydrazine as shown in Reaction Scheme 8, To obtain a compound (18).
  • Ar and R 6 are as defined above.
  • A represents —CO—
  • X represents —NH—
  • Y represents Z represents —CH 2 —
  • W represents Wherein R 1 represents —CO—NR 6 R 7 and Ar, R 6 and R 7 are as defined above, the compound group is represented by the following formula:
  • the compound (20) can be obtained by reacting with an acid, and the ester can be hydrolyzed and then amidated to obtain the compound (21).
  • Ar, R 6 and R 7 are as defined above.
  • A represents —CH 2 —
  • X represents an oxygen atom
  • Y and W represent Z represents —CH 2 —
  • R 1 represents —CO—NR 6 R 7
  • Ar, R 6, and R 7 are as defined above.
  • compound (14) is reacted with ethyl 4-bromobutyrate to obtain compound (22), and the ester is hydrolyzed and then amidated to obtain compound (23).
  • Ar, R 6 and R 7 are as defined above.
  • A represents —CO—
  • X and Z represent —CH 2 —
  • Y represents W
  • R 1 represents —NHCO—R 9 and R 9 represents R 1 is
  • compound (24) is amidated to obtain compound (25) as shown in Reaction Scheme 11, and after deprotection, arylation is performed to oxidize the hydroxyl group.
  • compound (26) is obtained in the formula, Ar and R 30 are as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —CH 2 —
  • Y and W represent R 1 represents —CO—NR 6 R 7 , —CO 2 —R 8 , —NHCO—R 9 , Or Ar, R 6 , R 7 , R 8 , R 9 and R 13 are the same as defined above.
  • the raw materials for synthesizing the compound group are as shown in Reaction Scheme 12 and compound (14) By reacting succinic anhydride, the compound (27) can be obtained as a mixture of the cis form and the trans form.
  • Trans isomer (29) can be obtained as a single compound.
  • an optically active compound (29) can be obtained by preparing a salt of the compound (29) with an optically active 1-phenethylamine or the like and optically resolving it.
  • Ar is as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —CH 2 —
  • Y and W represent R 1 represents —NHCO—R 9 and R 9 represents Or
  • the compound (27) obtained in the reaction scheme 12 was deprotected after Curtius rearrangement to obtain the compound (31), as shown in the reaction scheme 13. Subsequently, it can be obtained as a compound (32) or a compound (33) by reacting with an amine in the presence of triphosgene.
  • Ar is as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —CH 2 —
  • Y and W represent R 1 represents —NHCO—R 9 and R 9 represents
  • Ar is as defined above, as shown in Reaction Scheme 14, the compound (31) obtained in Reaction Scheme 13 is amidated, deprotected, and then reductively converted to an amine.
  • the compound (35) can be obtained by benzylation.
  • Ar is as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —CH 2 —
  • Y and W represent R 1 is
  • Ar is as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —CH 2 —
  • Y and W represent Wherein R 1 represents —CO 2 —R 8
  • Ar and R 8 are as defined above
  • the compound group represented by Reaction Scheme 12 as shown in Reaction Scheme 16 (27) Can be obtained as a mixture of cis and trans isomers.
  • the cis form or the trans form of the compound (37) can be obtained as a single compound.
  • Ar and R 8 are as defined above.
  • A represents —CO—
  • X represents an oxygen atom
  • Z represents —CH 2 —
  • Y and W represent Wherein R 1 represents —CO—NR 6 R 7
  • Ar, R 6 and R 7 have the same meanings as described above.
  • Compound (38) can be obtained as a mixture of a cis form and a trans form by amidating compound (27). By separating and purifying the mixture by silica gel chromatography, the cis form or the trans form of the compound (37) can be obtained as a single compound.
  • the optically active compound (38) can be obtained by using the optically active compound (29) obtained in reaction scheme 12 as a reaction starting material.
  • Reaction scheme 17 In the formula, Ar, R 6 and R 7 are as defined above.
  • Example 1 trans-4,5-di (4-methoxyphenyl) dihydrofuran-2 (3H) -one and (Example 2) cis-4,5-di (4-methoxyphenyl) dihydrofuran-2 Synthesis of (3H) -one
  • dihydropyran 4.4 mL
  • pyridinium p-tosylic acid 0.46 g
  • Example 2 The obtained residue was purified by silica gel column chromatography, and trans-4,5-di (4-methoxyphenyl) dihydrofuran-2 (3H) -one of Example 1 was eluted from the eluate of 18% ethyl acetate-hexane ( 0.75 g) as a colorless oily substance, and cis-4,5-di (4-methoxyphenyl) dihydrofuran-2 (3H) -one (0.43 g) of Example 2 from a fraction eluted with 20% ethyl acetate-hexane. ) was obtained as a colorless oil.
  • Example 3 trans-4,5-di (4-methylphenyl) dihydrofuran-2 (3H) -one and (Example 4) cis-4,5-di (4-methylphenyl) dihydrofuran-2 Synthesis of (3H) -one According to the method shown in Examples 1 and 2, starting from 4,4′-dimethylbenzoin, the trans-4,5-di (4-methylphenyl) dihydrofuran-2 of Example 3 was used. (3H) -one and cis-4,5-di (4-methylphenyl) dihydrofuran-2 (3H) -one of Example 4 were obtained.
  • a 1M p-tolylmagnesium bromide-tetrahydrofuran solution (28 mL) was added dropwise to a tetrahydrofuran (30 mL) solution of the obtained compound (2.00 g) under ice cooling, and the mixture was stirred at the same temperature for 5 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 7 Synthesis of trans-4- (4-chlorophenyl) -5-p-tolyl-1,3-dioxolan-2-one 1- (4-chlorophenyl) -5-p-tolylethane-1,2-dione (10.0 g ) In methanol (100 mL) was added sodium borohydride (1.46 g), and the mixture was stirred for 2 hours under ice cooling. A saturated aqueous ammonium chloride solution 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.
  • Example 8 Synthesis of trans-4- (4-chlorophenyl) -5-p-tolyrimidazolidin-2-one
  • methanol 14 mL
  • water 1.5 mL
  • Potassium carbonate 1.46 g
  • Water was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water to obtain trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diol (2.37 g) as a colorless powder. It was.
  • Triethylamine (2.8 mL) was added to a chloroform (24 mL) solution of the obtained compound (2.37 g), and then methanesulfonyl chloride (1.5 mL) was added dropwise under ice cooling, followed by stirring at the same temperature for 1 hour. did.
  • Water was added to the reaction solution, extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diyl dimethanesulfonate (3.87 g) as a colorless amorphous.
  • trans-1- (4-chlorophenyl) -2-p-tolylethane-1,2-diamine (0.88 g) as a yellow powder.
  • Triethylamine (0.8 ml) was added to a chloroform (10 mL) solution of the compound obtained here (0.60 g), and then triphosgene (0.27 g) was added under ice cooling, followed by stirring at the same temperature for 2 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, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with chloroform to give the title compound cis-4- (4-chlorophenyl) -5-p-tolyrimidazolidin-2-one (0.22 g) as a colorless powder.
  • Example 10 Synthesis of cis-4,5-di (p-tolyl) imidazolidin-2-one The method shown in Example 9 using 1- (4-chlorophenyl) -2-p-tolylethane-1,2-dione as a raw material Gave the title compound cis-4,5-di (p-tolyl) imidazolidin-2-one.
  • Example 13 Synthesis of 5-methylphenyl-1-phenyl-1,2,4-triazolidin-3-one The title compound 5-methylphenyl-1-phenyl- was synthesized by the method shown in Example 12 using p-tolylaldehyde as a starting material. 1,2,4-triazolidin-3-one was obtained.
  • Example 14 Synthesis of 5-methoxyphenyl-1-phenyl-1,2,4-triazolidin-3-one
  • the title compound 5-methoxyphenyl-1-phenyl- was synthesized by the method shown in Example 12 using p-methoxybenzaldehyde as a starting material. 1,2,4-triazolidin-3-one was obtained.
  • Example 17 Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2-phenyl-5-oxopyrrolidine-3-carboxamide Using the benzaldehyde as a starting material, the title compound trans-N- ( 1-Benzylpiperidin-4-yl) -2-phenyl-5-oxopyrrolidine-3-carboxamide was obtained.
  • Example 18 Synthesis of trans-N- [2- (4-chlorophenyl) ethyl] -2-phenyl-5-oxopyrrolidine-3-carboxamide
  • Trans-2- (4-chlorophenyl) -1 shown as a synthetic intermediate in Example 15 -(4-Methoxybenzyl) -5-oxopyrrolidine-3-carboxylic acid and 2- (4-chlorophenyl) ethylamine were condensed and deprotected by the method shown in Example 15 to give the title compound trans-N- [2 -(4-Chlorophenyl) ethyl] -2-phenyl-5-oxopyrrolidine-3-carboxamide was obtained.
  • Example 21 Synthesis of N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate
  • Example 20 After condensing 2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxylic acid shown as a synthetic intermediate with the compound obtained in Reference Example 4 by the method shown in Example 15, maleic acid
  • the title compound N- [1- (2,3,5-trifluorobenzyl) piperidin-4-yl] -2- (4-chlorophenyl) -5-oxopyrazolidine-3-carboxamide maleate was obtained as a salt. It was.
  • Example 23 Synthesis of trans-N- ⁇ [1- (4-chlorobenzyl) piperazin] -4-yl ⁇ -2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride
  • 2- (4-Chlorophenyl) tetrahydrofuran-3-carboxylic acid and 1- (4-chlorobenzyl) piperazine are condensed by the method shown in Example 22 to give the hydrochloride as the title compound trans-N- ⁇ [1- ( 4-Chlorobenzyl) piperazin] -4-yl ⁇ -2- (4-chlorophenyl) tetrahydrofuran-3-carboxamide hydrochloride was obtained.
  • Example 24 Synthesis of trans-N- (1-benzylpiperidin-4-yl) -2- (4-chlorophenyl) -N-methyl-tetrahydrofuran-3-carboxamide Trans-2- (4 shown as a synthetic intermediate in Example 22 -Chlorophenyl) tetrahydrofuran-3-carboxylic acid and 4-methylamino-1-benzylpiperidine were condensed by the method shown in Example 22 to give the title compound trans-N- (1-benzylpiperidin-4-yl) -2. -(4-Chlorophenyl) -N-methyl-tetrahydrofuran-3-carboxamide was obtained.
  • Example 29 Synthesis of 1-benzyl-N- [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide maleate (1) 4- ⁇ [trans-2- (4- Synthesis of chlorophenyl) -5-oxotetrahydrofuran-3-yl] carbamoyl ⁇ piperidine-1-carboxylate t-butyl To a suspension of the compound obtained in Example 26 (2) (1.00 g) in chloroform (10 mL) N-Boc-isonipecotic acid (1.10 g), triethylamine (0.74 mL), 1-hydroxybenzotriazole (0.70 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.00 g ) And stirred at room temperature for 24 hours.
  • Example 30 Synthesis of 1-benzyl-N- [trans-2- (4-trifluorophenyl) -5-oxotetrahydrofuran-3-yl] piperidine-4-carboxamide maleate
  • Reference Example 1 using 4-trifluorobenzaldehyde as a raw material Following the method shown in (1), the title compound 1-benzyl-N- [trans-2- (4-trifluorophenyl) -5-oxotetrahydrofuran-3-yl was synthesized by the method shown in Example 29. ] Piperidine-4-carboxamide maleate was obtained.
  • reaction solution was concentrated under reduced pressure, dissolved in tetrahydrofuran (8 mL), added with 4.3 mL of trimethylsilyldiazomethane under ice cooling, and stirred at the same temperature for 2 hours.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate-hexane), and trans-5- (4-chlorophenyl) -4- (2-diazoacetyl) dihydrofuran-2 (3H ) -One (0.88 g) was obtained as a yellow oil.
  • the aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain [trans-2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-yl] acetic acid (0.70 g) as a colorless powder.
  • Example 32 Synthesis of trans-1-benzylpiperidin-4-yl 2- (4-chlorophenyl) -tetrahydro-5-furanone-3-carboxylate To a solution of the compound (0.29 g) obtained in Reference Example 1 (3) in chloroform (15 mL), 1-benzylpiperidin-4-ol (0.19 g), 1-hydroxybenzotriazole monohydrate (0. 23 g) was added at room temperature and N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (0.29 g) was added.
  • the compounds of Examples 33 and 34 were synthesized by condensing the compound obtained in Reference Example 1 (4) with the corresponding alcohol compound by the method shown in Example 32.
  • Example 35 Synthesis of trans-1-benzylpiperidin-4-yl 2- (4-cyanophenyl) -tetrahydro-5-furanone-3-carboxylate Using 4-cyanobenzaldehyde as a raw material, Reference Example 1 (1) to Reference Example 1 Following the method shown in 4), the title compound trans-1-benzylpiperidin-4-yl 2- (4-cyanophenyl) -tetrahydro-5-furanone-3-carboxyl was synthesized by the method shown in Example 32. Got the rate.
  • the compounds of Examples 37 to 46 could be condensed with the corresponding amine compound by the method shown in Example 36 using the compound obtained in Reference Example 1 (5) as a raw material.
  • the compounds of Examples 47 to 53 could be condensed with the corresponding amine compound by the method shown in Example 36 using the compound obtained in Reference Example 2 as a raw material.
  • the compounds of Examples 54 to 61 could be condensed with the corresponding amine compound by the method shown in Example 36 using the compound obtained in Reference Example 3 as a raw material.
  • Example 62 Trans-N- (1-Benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxamide, and (Example 63) cis-N- (1- Synthesis of benzylpiperidin-4-yl) -2- (4-chlorophenyl) -5-oxotetrahydrofuran-3-carboxamide N, N-dimethylformamide of the compound (1.50 g) obtained in Reference Example 1 (1) ( 15 mL) in solution 4-amino-1-benzylpiperidine (1.20 g), 1-hydroxybenzotriazole (2.00 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.50 g) And stirred at room temperature for 18 hours.
  • the compounds of Examples 64 to 399 were obtained by the method shown in Reference Example 1 (1) using the compound obtained in Reference Example 1 (1) or the corresponding substituted benzaldehyde in Reference Example 1 (1) as a raw material.
  • the compound was synthesized from the compound by the method shown in Example 62 and Example 63.
  • the structures and NMR data of the compounds of Examples 64-327 are also shown in Table 1 below.
  • APCI atmospheric pressure chemical ionization
  • APCI atmospheric pressure chemical ionization
  • Table 2 The structures of the compounds of Examples 328 to 392 and the measured values of APCI are shown in Table 2 below.
  • electrospray ionization (ESI) was measured using the same mass spectrometer.
  • the structures of Examples 393 to 399 and the measured ESI values are shown in Table 3 below.
  • Test Example 1 Fatty acid absorption function inhibitory action (antagonist action) on human FATP4
  • the FATP4 fatty acid absorption inhibition test of the test compound was carried out by partially modifying the method of Andrew Stahl et al. (Molecular cell 1999 Sep; 4: 299-308).
  • HEK293 cell line stably expressing human-derived FATP4 was used for determination of fatty acid absorption function regulating action (antagonist action) on human-derived FATP4. Unless otherwise stated, these HEK293 cells were cultured in MEM medium (Gibco) containing 10% FBS, 1% non-essential amino acids (NEAA; Dainippon Pharmaceutical).
  • the test was conducted using a flat-bottomed 96-well Poly-D-Lycine Coated Microplates (Corning). Two days before the assay, the cells cultured until they became almost confluent were rinsed with PBS, then detached with trypsin (Gibco), and collected by centrifugation. The number of the obtained cells was measured, and the cells were seeded in each well of the plate so as to be 3 ⁇ 10 4 cells / well. After culturing in a CO 2 incubator for 2 days, a dimethyl sulfoxide (DMSO) solution of a cell test compound and DMSO as a control were added to a final DMSO concentration of 0.5%.
  • DMSO dimethyl sulfoxide
  • BODIPY 4,4-difluoro-5-methyl-4-bora-3a, 4a-diaza-s-indacene-3-dodecanoic acid; Funakoshi
  • BSA Sigma
  • 0.5N NaOH containing 0.1% SDS was added to each well and shaken for 1 hour to lyse the cells.
  • the antagonistic activity of each compound was determined based on the compound concentration (IC 50 value) at which 50% uptake was inhibited by the presence of the cell test compound when the fatty acid uptake in the well (control group) to which only DMSO was added was 100%. ).
  • the IC 50 value of the compound of the present invention is 100 ⁇ M to 10 nM, and typical examples are shown in Table 4 below.
  • mice Male C57 / BL 6N mice (8 weeks old, Charles River, Japan) containing 20 mM sodium glycochenodeoxycholate containing compound (15 mg / kg) and 14 C-labeled fatty acid (stearic acid: Muromachi Yakuhin) to a final concentration of 60 ⁇ M GCDC) solution was continuously administered by oral gavage (5 ml / kg).
  • Male C57 / BL 6N mice (8 weeks old, Charles River, Japan) containing 20 mM sodium glycochenodeoxycholate containing compound (15 mg / kg) and 14 C-labeled fatty acid (stearic acid: Muromachi Yakuhin) to a final concentration of 60 ⁇ M GCDC) solution was continuously administered by oral gavage (5 ml / kg).
  • the thigh was cut under anesthesia with isopropanol, and 300 ⁇ L of blood was collected, followed by centrifugation using Ceraquik (Alfresa Pharma), and serum was collected. Serum fatty acid concentration was measured with a liquid scintillation counter. The fatty acid concentration decrease rate relative to the 20 mM GCDC solution administration group (control group) was calculated and used as the fatty acid absorption inhibitory activity.
  • the compound of Example 36 showed 37.4% fat absorption inhibitory activity.
  • the compound of the present invention has an excellent FATP4 inhibitory action, and obesity, obesity, hyperlipidemia, anti-TGemia, dyslipidemia, diabetes, arteriosclerosis, or hyperlipidemia caused by obesity It is useful as a therapeutic or prophylactic agent for symptom, anti-TG disease, dyslipidemia, diabetes, arteriosclerosis, or hypertension.

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Abstract

L'invention porte sur un composé ayant une excellente activité inhibitrice de FATP4. De façon spécifique, l'invention porte sur un composé hétérocyclique à cinq chaînons représenté par la formule (I) ou sur un sel pharmaceutiquement acceptable de ce composé. Dans la formule (I), A représente -CO- or -CH2-; X représente -CH2-, -O- ou -NH-; Y et W peuvent être identiques ou différents et représentent chacun la formule (II) ou la formule (III); Ar représente la formule (IV) ou similaire; et R1 représente -CO-NR6R7, -CO2-R8, -NHCO-R9 ou similaire.
PCT/JP2010/056379 2009-04-10 2010-04-08 Composé hétérocyclique à cinq chaînons WO2010117040A1 (fr)

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WO2019201835A1 (fr) * 2018-04-17 2019-10-24 Bayer Aktiengesellschaft Composés hétéroaryle-triazole et hétéroaryle-tétrazole utilisés en tant que pesticides
CN112189011A (zh) * 2018-04-17 2021-01-05 拜耳公司 作为农药的杂芳基三唑和杂芳基四唑化合物
EP4039682A1 (fr) * 2018-04-17 2022-08-10 Bayer Aktiengesellschaft Nouveaux composés d'hétéroaryl-triazole et d'hétéroaryl-tétrazole utilisés comme pesticides

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