[go: up one dir, main page]

WO2002074762A1 - Procede relatif a l'elaboration de derive sulfone - Google Patents

Procede relatif a l'elaboration de derive sulfone Download PDF

Info

Publication number
WO2002074762A1
WO2002074762A1 PCT/JP2002/002323 JP0202323W WO02074762A1 WO 2002074762 A1 WO2002074762 A1 WO 2002074762A1 JP 0202323 W JP0202323 W JP 0202323W WO 02074762 A1 WO02074762 A1 WO 02074762A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
optionally substituted
substituted
hydrocarbon group
formula
Prior art date
Application number
PCT/JP2002/002323
Other languages
English (en)
Japanese (ja)
Inventor
Hideya Mizufune
Hiroaki Yamamoto
Shokyo Miki
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Publication of WO2002074762A1 publication Critical patent/WO2002074762A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides

Definitions

  • the present invention inhibits activated blood coagulation factor X (FXa) and has an anticoagulant effect as well as an antithrombotic effect.
  • the present invention relates to a method for producing a therapeutically useful sulfone derivative or a salt thereof. Background technology,
  • Japanese Patent Application No. 2000-0221065 (WO 02/0623) describes an FXa inhibitor that is an anticoagulant effective for the prevention and treatment of myocardial infarction, cerebral thrombosis, etc.
  • various new sulfone derivatives and methods for producing the same are disclosed.
  • (1) aryl sulfide is used as a starting material, which is reduced with lithium aluminum hydride to produce aryl thiols.
  • alkenyl carboxylic acid ester derivative or halogenoalkyl (2) alkenyl carboxylic acid ester derivative or halogenoalkyl.
  • the reaction is carried out by reacting a sulfonic acid ester derivative to produce an arylthioalkyl carboxylic acid ester derivative, and 3 an oxidation reaction using peracetic acid is carried out to produce an arylsulfonylalkyl carboxylic acid derivative.
  • the number of steps is large because the reduction and oxidation reactions of sulfur atoms are each performed once.
  • the oxidation reaction process is carried out on an industrial scale, it is necessary to take safety measures.
  • a method for synthesizing a sulfone derivative for example, there is the following report.
  • J. Org. Chem., Vol. 61, pp. 3849, 1996 and US Pat. No. 5,625,055 include ketones and hydrogenated triacyroxy. Hydrogen sodium or sodium borohydride and aliphatic power A method that describes the method of reductive amination with amines in the presence of rubonic acid 1_ (pyridine-4-yl) pyridine-4- No reductive amination of ketones having a substituent useful as an intermediate of an FXa inhibitor represented by an on derivative is described.
  • the following report describes a method for producing 4-amino-1- (4-pyridyl) piperidine, which is useful as an intermediate of an Fxa inhibitor.
  • EP 1 707 714 and USP 575 369 59 disclose 4-amino (4-pyridyl) piperidine. a lot. Disclosure of the invention
  • an industrially advantageous method for producing an aryl sulfolalkyl carboxylic acid derivative useful as an FXa inhibitor and an intermediate thereof which requires a small number of steps and avoids oxidation reaction Is required.
  • a method for producing amines useful as intermediates for Fxa inhibitors there is a demand for a safe and simple, industrially advantageous production method that does not use highly toxic reducing agents.
  • arylsulfonyl chlorides are converted to arylsulfinic acids or salts thereof with a reducing agent such as sodium borohydride, and then alkenyl carboxylic acid esters or halogenates. It has been found that a sulfone derivative useful as an FXa inhibitor can be obtained by reacting with an alkyl carboxylic acid derivative.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • L 1 represents a leaving group
  • X represents a divalent chain hydrocarbon group which may be substituted
  • R ′ represents a carboxyl group or a carboxyl group which may be esterified or amidated. Represents a cyano group.
  • Z ' is — N (R 5b ) _, -CO- -S (O)-, — S (0) 2 —, — CH 2 —, — N (R 5b )-CO-,- CO-CH 2 -or a bond
  • ring A represents a nitrogen-containing heterocyclic ring which may be substituted
  • R 5b and R 6b each independently represent a hydrogen atom or a hydrocarbon group which may be substituted
  • Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R 1 R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R 1 and R 2 , R 1 and R 3, or R 2 and R 3 3 may be mutually bonded to form an optionally substituted ring, and R, represents a carboxyl group or a cyano group which may be esterified or amidated.
  • R represents a carboxyl group or a cyano group which may be esterified or amidated.
  • ring A represents an optionally substituted nitrogen-containing heterocyclic ring
  • R 5b and R 6b are each independently a hydrogen atom or a substituted R 6b represents a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group.
  • Z ′ may be an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.
  • R represents a substituted or unsubstituted, cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or an optionally substituted divalent chain hydrocarbon group
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R 4 represents a hydrogen atom or a hydrocarbon group which may be substituted
  • R ′ represents a carboxyl group or a cyano group which may be esterified or amidated.
  • Z ' is —N (R 5b )-, —CO-, one S (O) —, — S (0) 2 —, _CH 2 —, _N (R 5b ) _CO-, -CO- CH 2 -or a bond
  • ring A, R 5b and R 6b each independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or R 6b may be bonded to a substituent of ring A ′ to form a ring
  • Z ′ may be an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group. Shows a ring group.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a heterocyclic group which may be substituted;
  • R and are cyclic hydrocarbon groups substituted with a halogen atom or an alkenyl group. Or an optionally substituted heterocyclic group; W represents a bond or an optionally substituted divalent chain hydrocarbon group; and M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R 1 a sulfinic acid derivative represented by the general formula (R 1 ) (R 2 ) CC (R 3 ) (Y'-L 2 ) (lib)
  • RR 2 and R 3 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R 1 and R 2 , R 1 and R 3, or R 2 and R 3 may form a even better ring is bonded to a substituted each other, Y, is - C_ ⁇ _, - S (O) - or _S (0) 2 - a, L 2 represents a hydrogen atom, a hydroxyl group or a substituted Represents an optionally substituted alkoxy group.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R 4 represents a hydrogen atom or a hydrocarbon group which may be substituted
  • Y ′ represents -CO-
  • L 2 represents hydrogen.
  • R is a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group or a heterocyclic group which may be substituted;
  • R and represent a cyclic hydrocarbon group or a heterocyclic group which may be substituted with a halogen atom or an alkenyl group
  • W represents a bond or a divalent chain which may be substituted.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • I 1 , R 2 and R 3 each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R 1 and R 2 , R 1 and R 3 or R 2 R 3 may be bonded to each other to form an optionally substituted ring, Y ′′ represents —CO—, and L 2a represents an optionally substituted alkoxy group. Reacting with a salt thereof, a general formula
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R la , R 2a , R 3a and R 4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R la and R 2a , R la and R 3a or R 2a and R 3a may combine with each other to form an optionally substituted ring
  • Y represents —CO—, — S (O) — or _S (O) 2
  • Z represents _N (R 5a ) —, —CO —, — S (0) _, one S (0) 2 —, —CH 2 — or a bond
  • ring A represents an optionally substituted nitrogen-containing heterocyclic ring
  • R 5a and R 6a each independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group, or R 6a substituent or R la ring a, R 2a, combined with R 3a
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or an optionally substituted divalent chain hydrocarbon group. Is shown.
  • L 1 represents a leaving group
  • X represents a divalent chain hydrocarbon group which may be substituted
  • R represents a carboxyl group or a carboxyl group which may be esterified or amidated.
  • Re represents a cyano group.
  • ring A represents an optionally substituted nitrogen-containing heterocyclic ring
  • R 5b and R 6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group
  • R 6b may be bonded to a substituent of ring A ′ to form a ring
  • R 1 R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R 1 and R 2 , R 1 and R 3, or R 2 and R 3 3 may combine with each other to form an optionally substituted ring, and R 'represents a carboxyl group or a cyano group which may be esterified or amidated. And a salt thereof, in the presence of a base,
  • Z ′ is —N (R 5b )-, -CO- -S (O)-, -S (0) 2- , _CH 2 —, — N (R 5b )-CO-, -CO -CH 2 -or a bond
  • ring A represents an optionally substituted nitrogen-containing heterocyclic ring
  • R 5b and R 6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, Represents an alkoxy group which may be substituted, a carboxyl group or an acyl group which may be esterified or amidated, and R 6b may be bonded to a substituent of ring A ′ to form a ring
  • R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • R 4 represents a hydrogen atom or a hydrocarbon group which may be substituted
  • R ′ represents a carboxyl group or a cyano group which may be esterified or amidated.
  • a salt thereof or a salt thereof in the presence of a base
  • ring A represents an optionally substituted nitrogen-containing heterocyclic ring
  • R 5b and R 6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, Represents an optionally substituted alkoxy group, a carboxyl group or an acyl group which may be esterified or amidated, and 161 ) may form a ring by bonding to the substituents of the rings and.
  • R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • L 1 represents a leaving group
  • X represents an optionally substituted divalent chain hydrocarbon group
  • Y represents -N (R 5 )-, -CO-, -S (O )-, _S (0) 2 _, -CH 2 -or a bond
  • L 2 represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group
  • R 5 represents a hydrogen atom or a substituted A hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group or an acyl group which may be esterified or amidated.
  • Formula R to a compound or wherein the to reaction a salt thereof in the presence of a base represented by] - W- S (0) 2 - X- Y- L 2 (I lia)
  • R ′ ′ represents a cyclic hydrocarbon group or a heterocyclic group which may be substituted with a halogen atom or an alkenyl group
  • W represents a bond or a divalent chain which may be substituted. Shows a hydrocarbon group.
  • a sulfinic acid derivative represented by the general formula (R 1 ) (R 2 ) C C (R 3 ) (Y′-L 2 ) (lib)
  • RR 2 and R 3 are each independently a hydrogen atom or a substituted Or R 1 and R 2 , R 1 and R 3 or R 2 and R 3 may be bonded to each other to form an optionally substituted ring; - CO-, -S (O) - , - the S (0) 2 _, L 2 represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group.
  • the compound represented by the general formula (1) or a salt thereof is reacted in the presence of a base.
  • R 4 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • Y ′ represents a hydrogen atom or an optionally substituted hydrocarbon group
  • L 2 represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group.
  • R ′ ′ represents a cyclic hydrocarbon group or a heterocyclic group which may be substituted with a halogen atom or an alkoxy group
  • W represents a bond or a divalent chain which may be substituted.
  • a salt thereof represented by the general formula (R 1 ) (R 2 ) C C (R 3 ) (Y ′′ to L 2a ) (lib ′ ′)
  • R 1 R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R 1 and R 2 , R 1 and R 3, or R 2 and R 3 3 is They may combine with each other to form an optionally substituted ring, Y ′′ represents —CO—, and L 2a represents an optionally substituted alkoxy group.
  • the compound represented by the formula (I) or a salt thereof is reacted in the presence of a base:
  • R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • R la , R 2a , R 3a and R 4a each independently represent a hydrogen atom or a hydrocarbon group which may be substituted, or R la and R 2a , R la and R 3a or R 2a and R 3a may be bonded to each other to form an optionally substituted ring
  • Y ′ represents —CO—, — S (O) — or — S (O) 2 —
  • Z represents — N (R 5a ) —, -CO- 1 S (O)-, 1 S (0) 2 --CH 2 -or a bond
  • ring A represents an optionally substituted nitrogen-containing heterocyclic ring
  • R 5a and R 6a each independently represent a hydrogen atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group which may be esterified or amidated, or an acyl group.
  • R 6a substituent or R la ring a, R 2a may form a ring which may be substituted in conjunction with R 3a or R 4a, Z 'is Shows the conversion which may be imidoyl group or an optionally substituted nitrogen-containing heterocyclic radical, n is 0 or 1. ] Represented by Reacting the compound or a salt thereof in the presence of a base, a general formula
  • ring “′′ represents an optionally substituted nitrogen-containing aliphatic heterocycle
  • Z ′ represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.
  • R 6 represents a hydrogen atom or a hydrocarbon group which may be substituted. Wherein the compound represented by the formula or a salt thereof is reacted in the presence of a triacyloxyborohydride complex compound;
  • ring ⁇ represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring, and ⁇ , represents an optionally substituted imidoyl group or an optionally substituted nitrogen-containing heterocyclic group.
  • R 6 represents a hydrogen atom or a hydrocarbon group which may be substituted.
  • a compound represented by the formula (I) or a salt thereof is reacted with formic acid or a salt thereof or hydrogen gas in the presence of a palladium catalyst;
  • R 6 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • ring A represents an optionally substituted nitrogen-containing aliphatic heterocyclic ring
  • Z ′ represents an optionally substituted Represents an imidoyl group or a nitrogen-containing heterocyclic group which may be substituted. Or a salt thereof,
  • L 3 represents a leaving group
  • R 1 R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R 1 and R 2 , R 1 and R 3 or R 2 and R 3 may combine with each other to form an optionally substituted ring
  • R 4 represents a hydrogen atom or an optionally substituted hydrocarbon group
  • 'Indicates -CO-, -S (O)-or -S (O) 2- A compound represented by the formula: or a salt thereof,
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted compound group
  • W represents a bond or an optionally substituted divalent chain hydrocarbon group.
  • X is a substituted by 2 may be divalent chain hydrocarbon group
  • Y is - N (R 5) -, - CO-, -S (O) -, - S (0) 2 -, —CH 2 — or a bond
  • Y ′ represents —CO—, —S (O) — or —S ( ⁇ ) 2 —
  • L 2 represents a hydrogen atom, a hydroxyl group, or an optionally substituted alkoxy.
  • R 4 represents a hydrogen atom or an optionally substituted hydrocarbon
  • R 5 represents a hydrogen atom, a hydrocarbon group which may be substituted, an alkoxy group which may be substituted, a carboxyl group or an acyl group which may be esterified or amidated. Show.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal, and R and W have the same meanings as described above.
  • R and W have the same meanings as described above.
  • R and ' represent a cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group, or an optionally substituted heterocyclic group, and W is a bond or a divalent group which may be substituted.
  • a chain hydrocarbon group; I 1 , R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R 1 and R 2 , R 1 and R 3 Or R 2 and R 3 may combine with each other to form a ring that may be substituted, and Y ′ represents —CO—, —S ( ⁇ ) — or —S ( ⁇ ) 2 —, L 2 Represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group.
  • a general formula for producing the sulfone derivative or a salt thereof represented by the formula:
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal, and R ′′ ′ W has the same meaning as described above.
  • R ′′ ′ W has the same meaning as described above.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • R la , R 2 R 3a and R 4a each independently represent a hydrogen atom or an optionally substituted hydrocarbon group, or R la and R 2a , R la and R 3a or R 2a and R 2a 3a may combine with each other to form an optionally substituted ring
  • Z represents -N ( R5a ) -, -C O- -S (O ) -, one S (0) 2 -, -CH 2 - or denotes a valence bond
  • ring a represents a nitrogen-containing heterocyclic ring which may be substituted
  • R 5a and R 6a are each independently a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted
  • RW-S (0) 2 -M (I) (in the formula, M represents a hydrogen atom, an alkali metal or an alkaline earth metal, R and W are as defined above.
  • M represents a hydrogen atom, an alkali metal or an alkaline earth metal
  • R and W are as defined above.
  • R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group.
  • Examples of the cyclic hydrocarbon group of the “optionally substituted cyclic hydrocarbon group” represented by R include, for example, an alicyclic hydrocarbon group, an aryl group and the like, and among them, an aryl group and the like are preferable.
  • Examples of the “alicyclic hydrocarbon group” as an example of the cyclic hydrocarbon group include a saturated or almost unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group.
  • the "consequent opening alkyl group” for example consequent opening propyl, consequent opening Petit Honoré, cyclopentyl Honoré, Kishinore cyclohexane, Puchinore cyclohexane, sik clever speech Kuchinore, C of the consequent opening nonyl 3 - 9 cycloalkyl such as Is mentioned.
  • cycloalkenyl group examples include 2-cyclopentene-11-yl, 3-cyclopentene-11-inole, 2-cyclohexene-1-inole, 3-cyclohexene-1-inole, and 1-cyclobutene-1 1-I le, 1 Shiku port pentene one 1 Inore, 1-- hexene one 1-I le to link port, c 3, such as 1-Sik port heptene one 1 Iru - like 9 consequent Roarukeniru group.
  • C 4 _ 6 such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadien-1-ynole, and 2,5-cyclohexadien-1-yl A cycloalkadienyl group;
  • cyclic hydrocarbon groups monocyclic or fused polycyclic aromatic hydrocarbon group, for example phenyl, naphthyl, anthryl, Fuena Ntoriru, C 6 _ 1 4 such Asenafuchireniru Aryl groups and the like, among which phenyl, 11-naphthinole, 2-naphthyl and the like are particularly preferred.
  • cyclic hydrocarbon group examples include the above-mentioned alicyclic hydrocarbons such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthinole, indur, dihydrobenzocycloheptenyl, and fluorenyl.
  • alicyclic hydrocarbons such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthinole, indur, dihydrobenzocycloheptenyl, and fluorenyl.
  • examples thereof include a bi- or tricyclic hydrocarbon group derived from the condensation of 2 to 3 identical or different groups (preferably 2 or more groups) selected from a hydrogen group and an aromatic hydrocarbon group.
  • heterocyclic group of the “optionally substituted heterocyclic group” represented by R examples include, for example, a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom as an atom (ring atom) constituting a ring system.
  • aromatic heterocyclic group examples include, for example, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isotizazolyl, imidazolyl, pyrazolyl, 1,2,3 oxaziazolyl, 1,2,4 oxaziazolyl, 1,3,3 , Four - Oxaziazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolinole, 1,2,4-triazolyl, tetrazolyl, pyridyl, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyridazyl, pyrimidinyl, pyrazinyl, and triazinyl; and, for example, benzofuranole, isobenzofuranole, benzo [] cheninore,
  • a heterocycle in which 2 to 3 (preferably 2) heterocycles are condensed more preferably a heterocycle in which the 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, particularly preferably benzofuranyl Benzoviral, benzo [] chenyl, etc.).
  • non-aromatic heterocyclic group examples include 3- to 8-membered (preferably 5- to 8-membered, such as oxilael, azetidul, oxetanyl, cetanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydrobilanyl, morpholinyl, thiomorpholinyl, piperazinyl and the like).
  • the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R may have an oxo group, for example, R is benzopyranyl. In this case, R may form benzo-a-pyronyl, benzo- ⁇ -pyronyl and the like.
  • alkyl in the “optionally substituted alkyl” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R include, for example, Methyl, ethyl, n-propyl, isopropyl, n-butynole, isobutyl, sec-butynole, tert-butynole, n-pentyl, isopench , Neopentynole, 1-methynolepropyl, n-hexyl, isohexynole, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and alkyl such as 3,3-dimethylpropyl.
  • examples of the alkyl substituent include a lower alkoxy group (eg, 6 alkoxy such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl (e.g., methyl, Echiru, alkyl of propyl, etc.), lower alkenyl (e.g., vinyl, C 2 6 alkenyl such as Ariru), lower alkynyl (eg, Echini Le, c 2 _ 6 alkynyl, etc.
  • a lower alkoxy group eg, 6 alkoxy such as methoxy, ethoxy, propoxy, etc.
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • lower alkyl e.g., methyl, Echiru, alkyl of propyl, etc.
  • lower alkenyl e
  • Hajime Tamaki e.g., pyridinyl, etc.
  • C i-6 alkyl or Ashiru e.g, formyl, C 2 _ 6 Arukanoiru, Ben Zoiru, halogenated C 6 alkoxycarbonyl, optionally halogenated — 6- alkylsulfonyl, benzenesulfonyl, etc.
  • rubamoyl group 1-azetidylcarbonyl, 1-pyrrolidinylcarbonyl , Piperidinocanolepol, monorefolino-potenol, thiomorpholinocarbonyl (sulfur atom may be oxidized), 1-piperazylcarbonyl, etc., and these optional substituents can be substituted.
  • One to three positions may be substituted.
  • alkenyl in the “optionally substituted alkenyl” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” for R include, for example, Bull, Aryl, Isopropenyl, 2-Methyl Arinole, 1-Propenyl, 2-Methinole 1-Pininole, 1-buteninole, 2-butul, 3-butenyl, 2-ethyl- 1-butenyl, 2-methyl-1 2-butyr, 3-methylinole 2-Petul, 1-penthenore, 2-penthenore, 3-penthenore, 4-penthenore, 4-methinolle 3-penthenore, 1-hexeninole, 2-hexeninole, 3 cyclohexenyl one, 4 one hexenyl, C 2 of cyclohexenyl, etc., to 5 one - 6 Aruke - le, and the like.
  • alkynyl in the “optionally substituted alkynyl” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” for R include, for example, Ethur, 1-Propiel, 2-Probul, 1-Butininole, 2-Putinyl, 3-Petinole, 1-Pentinyl, 2-Pentunole, 3-Pentinole, 4-Pentinole, 1-Hexchel, 2 - to Kisheru, key shell to 3, Kishuru to 4 include C 2 _ 6 alkynyl hexynyl, etc., to 5 scratch.
  • substituent of alkynyl include the same number and similar substituents as those of the above-mentioned “optionally substituted alkyl”.
  • aryl in the “optionally substituted aryl” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R include, for example, phenyl, naphthyl, anthryl, Fuenantoriru, 0 6 such Asenafuchireniru - 1 4 Ariru the like.
  • examples of the aryl substituent include the same number and similar substituents as those in the aforementioned “optionally substituted alkyl”.
  • Examples of the aralkyl in the “optionally substituted aralkyl” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R include, for example, And aralkyl such as benzyl, phenethyl and naphthylmethyl.
  • examples of the substituent of aralkyl include the same number and similar substituents as those in the above-mentioned “optionally substituted alkyl”.
  • Optionally substituted cycloalkyl as a substituent of the “optionally substituted ⁇ -hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R
  • R for example Shikuropuropinore, Shikuropuchiru, consequent opening Penchinore, cyclohexyl, C 3 7 cycloalkyl
  • Anore keno les such as Puchinore are exemplified up to consequent opening.
  • substituent of the cycloalkyl include the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl”.
  • cycloalkenyl in the ⁇ optionally substituted cycloalkenyl '' as a substituent of the ⁇ optionally substituted cyclic hydrocarbon group '' and the ⁇ optionally substituted heterocyclic group '' represented by R for example, Shikuropuro Bae cycloalkenyl, cyclobutenyl, consequent opening Penteyuru, Ru c 3 _ 6 cycloalkenyl, etc. cyclohexenyl, etc., to a consequent opening can be mentioned.
  • substituent of the cycloalkyl which may be substituted include the same number of the same substituents as those in the above-mentioned “alkyl which may be substituted”.
  • heterocyclic group in the “optionally substituted heterocyclic group” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” for R examples thereof include the same as the above-mentioned “optionally substituted heterocyclic group” for R.
  • substituents which the “optionally substituted heterocyclic group” as the substituent may have include lower alkyl (eg, C 6 alkyl such as methyl, ethyl, propyl and the like), lower alkenyl (eg, Bulle, C 2 6 alkenyl such as Ariru), lower Arukini Le (eg, Echuru, c 2 _ 6 alkynyl, etc.
  • lower alkyl eg, C 6 alkyl such as methyl, ethyl, propyl and the like
  • lower alkenyl eg, Bulle, C 2 6 alkenyl such as Ariru
  • Arukini Le eg, Echuru, c 2 _ 6 alkynyl, etc.
  • the doyl and the optionally substituted amidino include the optionally substituted cyclic hydrocarbon group and the optionally substituted heterocyclic group represented by R described below.
  • Optionally substituted amino “optionally substituted hydroxyl group”, “optionally substituted imido” And the same as the above-mentioned "optionally substituted amidino”.
  • Optionally substituted cyclic hydrocarbon group represented by R and “optionally substituted amino” as a substituent which the optionally substituted heterocyclic group may have, “ Examples of the substituent in the “optionally substituted imidoyl”, the “optionally substituted amidino”, the “optionally substituted hydroxyl group”, and the “optionally substituted thiol group” include, for example, halogen Atoms (eg, fluorine, chlorine, bromine, iodine, etc.) and optionally halogenated — 6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trimethoxy, Lower alkyl (eg, methyl, ethyl, propyl, isopropyl) which may be substituted with a substituent selected from 2,2,2-trichloromouth ethoxy, etc.
  • halogen Atoms eg, fluorine, chlorine, bromine, iodine
  • amino in the “optionally substituted amino” as a substituent means an optionally substituted imidoyl (for example, C- 6 alkylimidoyl (eg, holmylimidoyl, acetylimidoyl, etc.) ), Ci- 6 alkoxyimidoyl, Ci- 6 alkylthioimidoyl, amidino, etc.), and amino or the like which may be substituted with one or two C- 6 alkyls. Also, two substituents may form a cyclic amino together with a nitrogen atom.
  • examples of the cyclic amino include 1-azetidur, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1
  • One piperazinyl and lower alkyl at the 4-position eg, Methyl, Echinore, propyl, isopropyl, butyl, t-butyl, pentyl, C _ 6 alkyl or the like hexyl, etc.
  • Ararukiru e.g., benzyl, C 7 such Fuwenechiru - 1 0 Ararukiru etc.
  • Ariru e.g., Hue - 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, etc., which may have 1-naphthyl, 2-naphthyl, 2-naphthyl, etc. 3- to 8-membered (preferably 5- to 6-membered) rings And amino.
  • Optionally substituted alkyls / refinyl J as a substituent which the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R may have Examples of the alkyl sulfiel in the above are methyl sulfinyl, ethinolesulfenyl, propyl sulfinole, isopropyl sulfenyl, butyl sulfinole, isobutyl sulfinole, sec-butylsulfinyl, tert-butylsulfinyl, And C alkylsulfiel such as pentylsulfininole, hexylsulfininole, etc.
  • the substituent of the alkylsulfinole is the same as the substituent in the aforementioned “alkyl which may be substituted”. Similar numbers are included.
  • substituents which the "optionally substituted cyclic hydrocarbon group” and “optionally substituted heterocyclic group” represented by R may have, the term “esterified or amidated”
  • the "good carboxyl group” include a carboxyl group, an alkoxycarbonyl, aryloxycarbo-nore, aranolequinoleoxycarbonyl, carbamoyl, N-monosubstituted carbamoyl, and N, N-disubstituted rubamoyl. Is received.
  • Alkoxycarbonyl The ⁇ example main butoxycarbonyl, Etokishika Noreboninore, propoxy Kano repo - Honoré, isopropoxide Shikano repo two Honoré, Butokishikanorepo two Honoré, isobutoxide Shikano repo two Honoré, sec- butoxycarbonyl, tert- Butokishikanore Boenore , pliers Norre O carboxymethyl carbonylation Honoré, isopentyl Honoré O carboxymethyl Kano repo sulfonyl, such as C _ 6 alkoxycarbonyl such as neopentyl O alkoxycarbonyl, and among them main Tokishikaruboeru, ethoxycarbonyl - le, propoxy force Lupo - Alkoxy carbole such as phenyl is preferred.
  • the “lower alkoxycarbonyl” may have a substituent, and the substituent may be a hydroxyl group or an optionally substituted amino
  • the Amino is, for example, lower alkyl optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methyl, ethyl, propyl, isopropyl / iso, butynole, isoptinole, C-alkyl such as tert-butyl / pentinole, hexyl, etc., preferably methyl, ethyl, etc.), acyl (eg, C 6 alkanol such as formyl, acetyl, propionyl, bivaloyl, benzoyl, etc.) , C i _ 6 - one or two such alkoxycarbonyl may be useful as a substituent.
  • halogen atoms eg
  • a halogen atom eg, fluorine, chlorine, bromine, iodine, etc.
  • a nitro group e.g., a cyano group, and a lower alkoxy
  • 1 to 5 halogen atoms eg, fluorine, chlorine, bromine, iodine, etc.
  • these substituents are preferably the same or different and are substituted with 1 or 2 to 3 (preferably 1 or 2).
  • aryloxycarbol may have a substituent, and examples of the substituent include the same number of the same substituents as in the above “alkoxycarbol”.
  • aralkyloxycarbonyl examples include C 7 —i such as benzyloxycarbonyl and phenethyloxycarbonyl. ⁇ Lal Kill O butoxycarbonyl, etc. (rather preferably is, C 6 - 1 0 Ariru such as single alkoxy one carbonyl) is preferable.
  • the “aralkyloxycarbo-norre” may have a substituent, and examples of the substituent include the same number of the same substituents as in the above “alkoxycarbonyl”.
  • N-monosubstituted lubamoyl j is, for example, lower alkyl
  • ⁇ reel alkenyl e.g., C 8- i Ari Ruaruke alkenyl of cinnamyl etc., preferably Fuweniru C 2 -. Represented by Le, etc.
  • Hajime Tamaki e.g., the above-described R - 4 Aruke The same as the “heterocyclic group” in the “optionally substituted heterocyclic group”
  • amino optionally substituted with 1 to 2 alkyl groups and the like.
  • the lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic group may have a substituent, and the substituent is the same as the substituent in the above-mentioned “alkoxycarbonyl”. Similar numbers are included. ,
  • N, N-disubstituted carpamoyl means a rubamoyl group having two substituents on a nitrogen atom, and one example of the substituent is “N-monosubstituted rubamoyl” described above. And the other examples are lower alkyl (eg, C ⁇ 6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.). ), C 3 - 6 cycloalkyl (e.g., cyclohexyl, etc. Shikuropuropinore, cyclobutyl, consequent opening pentyl, consequent opening), c 7 _ 1
  • aralkyl eg, benzyl, phenethyl, etc., preferably, fuel-C alkyl, etc.
  • two substituents may be combined with a nitrogen atom to form a cyclic amino.
  • examples of the cyclic aminocarbamoyl include 1-azetidyl carbonyl and 1-pyrrolidinyl.
  • Lecarbole piperidinocarbonyl, morpholinocarbonyl, thiomorpholinol-based alcohol (sulfur atom may be oxidized), 1-piperazinylcarbonyl and lower alkyl at 4-position (eg, methinole, Echinore, propyl, isopropyl Honoré, Buchinore, tert- butyl, C of hexyl etc.
  • Ararukiru e.g., benzyl, C 7 such Fuwenechiru - 1 0 Ararukiru etc.
  • Ariru e.g., phenyl, 1 to 6-membered such as 1-naphthyl, 2-naphthyl or the like C 6 ⁇ .aryl, etc. 1-piperazylcarbonyl or the like (preferably And cyclic aminocarbonyl of 5-6 membered) can be mentioned.
  • Optionally substituted cyclic hydrocarbon group and "substituted
  • the substituents of ⁇ optionally substituted thiocarpamoinole '' and ⁇ optionally substituted sulfamoyl '' as the substituents which the ⁇ optionally substituted heterocyclic group '' may have are as described above.
  • substituents which the ⁇ optionally substituted cyclic hydrocarbon group '' and the ⁇ optionally substituted heterocyclic group '' represented by R may have, ⁇ esterified or amidated '' Examples include the same substituents as the “N-mono-substituted carpamoyl” and “N, N-disubstituted rubamoyl” in the “good carboxyl group”.
  • ⁇ acyl derived from sulfonic acid '' as a substituent which the ⁇ optionally substituted cyclic hydrocarbon group '' and the ⁇ optionally substituted heterocyclic group '' represented by R may have,
  • the above-mentioned “N-monosubstituent rubamoyl” is obtained by bonding a substituent having one on the nitrogen atom to a sulfonyl, and the like.
  • Ashinore such Bok 6 alkylsulfonyl.
  • Examples of the ⁇ carboxylic acid-derived acyl '' as a substituent include those in which a hydrogen atom or the above-mentioned ⁇ N-monosubstituent rubamoyl '' has one substituent on a nitrogen atom and carbonyl bonded thereto, and the like.
  • formyl, Asechiru, propionitrile alkenyl, C _ 6 Arukanoiru such PIPA port I le include Ashiru such Benzoiru.
  • -A heterocyclic group which may be substituted with a substituent selected from toro, cyano, amidino which may be substituted, and carboxyl block which may be esterified or amidated is preferable.
  • aryl optionally substituted with a halogen atom or C 2 _ 4 alkenyl, and heterocyclic group optionally substituted with a halogen atom are preferred, and even more preferred are those substituted with a nitrogen atom.
  • Preferred are naphthyl or benzopyrazole, such as 6-halo-substituted naphthalene-12-yl.
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted.
  • the “optionally substituted divalent chain hydrocarbon group” represented by W includes, for example, C— 6 anolexylene such as methylene, ethylene, trimethylene, and tetramethylene, for example, biylene, propylene, 1- or 2 - C 2 6 of Aruke such butenylene - les down, Arukajie two lens etc. of C 2 6 such Butajeniren like. .
  • Examples of the substituent which the divalent chain hydrocarbon group of the ⁇ optionally substituted divalent chain hydrocarbon group '' represented by W may have, for example, the above-mentioned R
  • the same substituents as those which the “cyclic hydrocarbon group” of the “optionally substituted cyclic hydrocarbon group” may have are mentioned.
  • a bond or C 6 alkylene is preferable, and among them, a bond is preferably used.
  • X represents a divalent chain hydrocarbon group which may be substituted.
  • the “optionally substituted divalent chain hydrocarbon group” represented by X is, for example, —8 alkylene such as methylene, ethylene, trimethylene, tetramethylene, etc., for example, vinylene, propylene, 1- or 2- Aruke etc.
  • an optionally substituted C ⁇ e lower alkylene is preferable.
  • the optionally substituted divalent hydrocarbon group represented by X may be substituted by the aforementioned optionally substituted cyclic hydrocarbon group represented by R
  • R ′ represents a carboxyl group or a cyano group which may be esterified or amidated.
  • the “optionally esterified or amidated lipoxyl group” represented by R ′ is the “optionally substituted cyclic hydrocarbon group” represented by the aforementioned R.
  • Ring A ′ represents an optionally substituted nitrogen-containing complex ring
  • R 5b and R 6b each independently represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted alkoxy group.
  • an optionally esterified or ami de I spoon is unprotected carboxyl group or Ashiru group, 1 615 may form a ring with the ring, the substituent, Z 'is substituted A good imidoyl group or a nitrogen-containing heterocyclic group which may be substituted;
  • the ⁇ optionally substituted hydrocarbon group '' represented by R 5b and R 6b is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, Optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, and the like.
  • Optionally substituted alkynyl ",” optionally substituted aryl “,” optionally substituted aralkyl ",” optionally substituted cycloalkyl Include those similar to the "good substituted I cycloalkenyl".
  • alkoxy group of the “optionally substituted alkoxy group” represented by R 5b and R 6b examples include d- 6 alkoxy such as methoxy, ethoxy, propoxy and tert-butoxy, and Ce— such as benzyloxy and phenethyloxy. . And aryloxy.
  • substituent of the "optionally substituted alkoxy group” The same number of substituents as “optionally substituted alkyl” as a substituent of the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” for R Similar ones can be mentioned.
  • the “optionally esterified or amidated lipoxyl group” represented by R 5b and R 6b , and the “acyl” include the “optionally substituted cyclic hydrocarbon group” represented by R and “substituted An optionally esterified or amidated carboxy group as a substituent which the heterocyclic group which may be optionally substituted, and an ⁇ acyl derived from a sulfonic acid ''; Similar to “Asil”.
  • the above-mentioned “optionally substituted heterocyclic group” represented by R is constituted Among those exemplified as "heterocycle", those containing at least one nitrogen atom, such as those containing at least one nitrogen atom as an atom (ring atom) constituting a ring system, and further containing an oxygen atom
  • Nitrogen-containing aromatic heterocyclic ring which may contain 1 to 3 (preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms selected from, a sulfur atom and a nitrogen atom Group, saturated or unsaturated nitrogen-containing non-aromatic heterocyclic group (nitrogen-containing aliphatic heterocyclic group), etc., and nitrogen-containing aliphatic heterocyclic group (nitrogen-containing non-aromatic heterocyclic group), etc. Is preferably used.
  • ⁇ nitrogen-containing heterocycle '' in the ⁇ nitrogen-containing heterocycle optionally substituted '' represented by ring A ′ a ⁇ monocyclic or bicyclic 5- to 12-membered nitrogen-containing heterocycle '' is preferable.
  • “monocyclic or bicyclic 5- to 12-membered nitrogen-containing aliphatic heterocycle” is preferable.
  • nitrogen-containing aliphatic heterocycle examples include 3 to 8 membered (preferably 5 to 6 membered) saturated or unsaturated (preferably saturated) such as azetidine, pyrrolidine, piberidine, morpholine, thiomorpholine, and piperazine.
  • Monocyclic nitrogen-containing aliphatic heterocyclic groups or 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrothiazolo [5,4 — C] Pyridine, 4,5,6,7-tetrahydropyrazo mouth [4,3-c] pyridine, 4,5,6,7-tetrahydroimidazolo [4,5-c] pyridine, etc. (Preferably 10-12 members) saturated or unsaturated bicyclic 1 "raw nitrogen-containing aliphatic heterocyclic group, etc.
  • the substituent which may be possessed by the ⁇ nitrogen-containing heterocyclic ring '' includes the above-mentioned ⁇ optionally substituted
  • Examples of the substituent which may be possessed by the “heterocyclic group” in the “good heterocyclic group” include an oxo group and a thioxo group.
  • rings A,, Z,,, and Z have the same meanings as described above, and R 7 and R 8 are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted Kenyl, alkynyl which may be substituted, hydroxyl group which may be substituted, thiol group which may be substituted, alkylsulfinyl which may be substituted, amino which may be substituted, esterification or amidification are unprotected Cal Bokishiru group, a halogen atom, a Ashiru from Shiano group or a sulfonic acid, in may be R 7 and R 8 or R 7 and R 6 b forms a connexion ring such together] Those represented are preferably used.
  • R 7 and R 8 "alkyl which may be substituted", "Yoi Arukeniru be substituted", “alkynyl which may be substituted”, “hydroxy group which may be substituted”, ""Optionally substituted thiol group”, “optionally substituted alkylsulfyl”, “optionally substituted amino”, “optionally esterified or amidated carboxyl group” and " Examples of the sulfonic acid-derived acyl group include an optionally substituted heterocyclic group represented by R.
  • R 7 and R 8 may be a hydrogen atom, an optionally substituted amino, or an esterified or amidated amino acid. Preferred are carboxyl groups and the like.
  • ring A ′ When is bonded to a substituent of ring 8 ′ (preferably, R 7 as a substituent of ring A, in the above formula) to form a ring, ring A ′ is represented by one NZ, ( ⁇ ', is a carbon atom or a nitrogen atom bonded to the ring A') together with one may form an “optionally substituted spiro ring” or an “optionally substituted nitrogen-containing fused heterocyclic ring” Guess.
  • an atom (ring atom) constituting a ring other than one nitrogen atom contained in the ring may be an oxygen atom, a sulfur atom, a nitrogen atom, or the like.
  • a saturated or unsaturated nitrogen-containing aliphatic heterocycle which may contain 1 to 4 (preferably 1 to 2) 1 to 3 (preferably 1 to 2) heteroatoms selected from And spiro rings formed by bonding of individual rings.
  • the same or different 2 selected from a 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) nitrogen-containing aliphatic heterocycle such as morpholine, thiomorpholine, and piperazine; And spiro rings formed by bonding individual rings.
  • the heterocyclic ring of the “optionally substituted heterocyclic group” represented by R preferably a monocyclic heterocyclic ring
  • a ring formed by condensing the same with ring A ′ preferably a monocyclic heterocyclic ring
  • R 1 ° represents a hydrogen atom;
  • R 9 represents a thiol group or a hydroxyl group and R 1 C) represents a hydrogen atom
  • optionally substituted hydrocarbon group represented by R 9 and R 1 Q may include those similar to the “optionally substituted hydrocarbon group” represented by R 5b and R 6b described above Can be
  • R 9 and R "optionally substituted hydroxy group" represented by 1 Q, as “carboxylic SanYukari come in Ashiru” is aforementioned “optionally substituted cyclic hydrocarbon group” represented by R and " Examples of the same as the “optionally substituted hydroxyl group” and the “carboxylic acid-derived acyl” as the substituent which the “optionally substituted heterocyclic group” may have include.
  • the ⁇ optionally substituted cyclic hydrocarbon group '' for R described above may be ⁇ The same as the ⁇ optionally substituted amino group '' or the amino group optionally having one or two ⁇ optionally substituted hydrocarbon group '' represented by R 6b described above. .
  • R 1 an “esterified carboxyl group” represented by 5 is an esterified carbohydrate group that may be possessed by the “optionally substituted cyclic hydrocarbon group” represented by R; And the same as the “lower alkoxy group luponyl”, “aryloxycarbinole” and “aralkyloxycarbonyl” of the "carboxyl group which may be optionally converted”.
  • Compound R 1 ° is Ashiru group derived from the force Rupon acids are useful as prodrugs of compounds R 1 ° is a hydrogen atom.
  • R 9 represents an optionally substituted amino group (preferably, amino, methylamino, ethynoleamino, propylamino, dimethylamino, getylamino, hydrazino, piperidino, piperazino, morpholino, thiomorpholino, etc.)
  • Z ′ The “optionally substituted imidoyl group” represented by represents an optionally substituted amidino group. Specific examples of such an amidino group which may be substituted include one or two lower (C ⁇ 6 ) alkyl groups, lower (C- 6 ) alkenyl groups, and a benzoyl group.
  • Amidino groups eg, amidino, N-methylamidino, N-ethylamidino, N-propylamidino, N, N'-dimethylamidino, N, N'-getylamidino, N-methyl-N'-methylamidino, N —Formylamidino, N-acetylamidino and the like).
  • R 9 include a hydrogen atom, a lower alkyl group (for example, a -6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl), an optionally substituted amino group (for example, ⁇ 2 identical or different lower alkyl groups (e.g., 6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or acyl groups (e.g., alkanols such as formyl, acetyl, propionyl, bivaloyl, benzoyl, etc.) ) May be substituted with an amino group, a hydrazino group, a 5- to 6-membered cyclic amino group (eg, piperidino, thiomorpholino, morpholino, piperazino, etc.), and an optionally substituted hydroxyl group (eg,
  • R 1 D include hydrogen, a lower alkyl group (eg, a C 6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl), a hydroxyl group, and an esterified carboxyl group (eg, methoxycarbol).
  • a lower alkyl group eg, a C 6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl
  • a hydroxyl group eg, methoxycarbol
  • Etokishikarupo two Honoré propoxy Kano levo Nino Le, I source propoxy Kano repo sulfonyl, Putokishikanorepo two Honoré, isopropoxy butoxycarbonyl C i-8 alkoxycarbonyl, such as such as Benjiruokishika Ruponiru, Hue phenethyl Ruo carboxymethyl c 7 _ l t3 such carbonyl ⁇ Lal kill O alkoxycarbonyl, etc.), Ashiru derived from a carboxylic acid (e.g. formyl, Asechiru, propionyl, d_ 6 Arukanoiru such pin Baroiru; Benzoiru) and the like, among which hydrogen is preferable.
  • a carboxylic acid e.g. formyl, Asechiru, propionyl, d_ 6 Arukanoiru such pin Baroiru; Benzoiru
  • nitrogen-containing heterocyclic group in the “optionally substituted nitrogen-containing heterocyclic group” represented by Z ′, at least a nitrogen atom other than a carbon atom as an atom (ring atom) constituting a ring system is used. 1 (preferably 1 to 4, more preferably 1 to 3)), and may further contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom. And heterocyclic groups and saturated or unsaturated non-aromatic nitrogen-containing heterocyclic groups (aliphatic nitrogen-containing heterocyclic groups).
  • aromatic nitrogen-containing heterocyclic group examples include, for example, pyrrolyl, oxazolyl, isoxoazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazole-1-1yl, 1H-imidazole-14-yl, etc.), pyrazolyl, 1,2 , 3-Oxaziazolyl, 1,2,4-oxaziazolyl, 1,3,4-oxaziazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2 , 3-triazolinole, 1,2,4-triazolyl (1,2,4-triazolyl — 1-yl, 1,2,4-triazolyl-1-yl, etc.), tetrazolyl, pyridyl (2,1,3 or 4 _Pyridyl), pyridazinyl, pyrimidazinyl
  • indolyl isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolinole, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzo Triazolyl, quinolinole, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazi'nyl, naphthyridyl, purinyl, buteridinyl, carbazolyl, ⁇ -carbolinyl, ⁇ -carbolinyl, ⁇ -carbolinyl, atenozinyl, phenoxalinyl , Phenazinyl, phenatrizinyl, phenatrolinyl, indolidinyl, pyro-mouth [1, 2-b] pyridazinyl,
  • a 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is preferable, and imidazolyl and pyridyl are particularly preferable.
  • pyridyl 4-pyridyl which may have a substituent at the 2-position (eg, an optionally substituted lower alkyl group, etc.) is preferable.
  • non-aromatic nitrogen-containing heterocyclic group examples include partially reduced forms of the above-mentioned “aromatic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidyl, etc.), for example, azetidur, pyrrolidinyl, piperidyl (2_, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinole (e.g., 1-piperazinyl), homopiperazul, and the like. Among them, a 5- to 6-membered non-aromatic monocyclic nitrogen-containing complex is preferred. Ring groups are preferred.
  • the substituent of the “nitrogen-containing heterocyclic group” represented by Z ′ is represented by R described above. The same substituents as the "heterocyclic group" are used. Further, the nitrogen atom constituting the nitrogen-containing heterocyclic group may be oxidized. Further, the substituents of the “nitrogen-containing heterocyclic group” represented by Z and may be combined with each other to form a ring (eg, a benzene ring or the like).
  • Z ′ is preferably an optionally substituted nitrogen-containing heterocyclic group or the like, and among them, may be substituted with a substituent selected from an optionally substituted alkyl and an optionally substituted amino. Nitrogen-containing heterocyclic groups are preferred.
  • an optionally substituted aromatic nitrogen-containing heterocyclic group or the like is preferable, and among them, an optionally substituted pyridyl group is preferable, and in particular, an optionally substituted 4-pyridyl group Is preferred.
  • Preferred embodiments of the optionally substituted nitrogen-containing heterocyclic group as Z ′ include, for example,
  • R 12 and R 13 are each independently a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted amino, esterification which may be a carboxyl group, an optionally substituted force Rubamoiru, halogen atom, a Shiano group or a Toro group, R 1 2 and R 1 3 is may be taken together to form a ring] And the groups represented.
  • R 1 2 and R 1 3 "alkyl which may be substituted", "alkenyl which may be substituted", “alkynyl which may be substituted”, “optionally substituted Amino"
  • R “optionally esterified carboxyl group” and “optionally substituted carbamoyl” “optionally substituted cyclic hydrocarbon” represented by R “optionally substituted heterocyclic ring” ⁇ Optionally substituted alkyl '', ⁇ optionally substituted alkenyl '', ⁇ optionally substituted alkynyl '', ⁇ optionally substituted And carbamoyl groups which may be esterified, and carbamoyl which may be substituted.
  • C which may be substituted A 4- alkyl or an optionally substituted amino is preferred, and one of R 12 and R 13 is more preferably a hydrogen atom.
  • Examples of the ⁇ optionally substituted hydrocarbon group '' represented by R ⁇ R 2 and R 3 include the same as the ⁇ optionally substituted hydrocarbon group '' represented by R 5b and R 6b described above. Is included. R 1 and R 2 , R 1 and R 3 , R 2 and R 3 are bonded to each other, for example, the formula
  • Ring B is preferably, for example, a homocyclic ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and more preferably cyclopentane, cyclohexane, cycloheptane and the like.
  • Ring C is preferably a homocyclic ring such as cyclobutene, cyclopentene, cyclohexene or cycloheptene, and more preferably cyclopentene, cyclohexene or cycloheptene.
  • the ring D is preferably, for example, cycloheptene, cyclootaten or the like, and particularly preferably cyclooctene or the like.
  • These rings B, C and D may have a substituent, and such a substituent may be a cyclic hydrocarbon group of the “optionally substituted cyclic hydrocarbon group” represented by R And the same as the substituents which may be mentioned.
  • R 4 the same as the “optionally substituted hydrocarbon group” for R 5b and R 6b described above can be mentioned.
  • Optionally substituted hydrocarbon group represented by R 5, "but it may also be substituted alkoxy group", “optionally esterified or Ami de of which may be carboxyl group”, “Ashiru group” May be a “optionally substituted hydrocarbon group”, an “optionally substituted alkoxy group”, or an “esterified or amide” represented by R 5b. Carboxyl group which may be converted “and those similar to” acyl group ".
  • Examples of the alkoxy group of the “optionally substituted alkoxy group” represented by L 2 include the same as the “optionally substituted alkoxy group” represented by R 5b and R 6b .
  • the “cyclic hydrocarbon group” represented by “a cyclic hydrocarbon group substituted by a halogen atom or an alkenyl group” represented by R ′ or includes a “cyclic hydrocarbon group” represented by R And the same as the cyclic hydrocarbon group represented by "hydrocarbon group”.
  • the “halogen atom” represented by the “cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group” represented by R or ′ includes chlorine, bromine, fluorine, iodine and the like.
  • alkenyl represented by the “cyclic hydrocarbon group substituted with a halogen atom or an alkenyl group” includes, for example, butyl, aryl, isopropyl, 2-methylinole, 1-propenyl, 2-methyl-1-alkyl 1-Propenyl, 1-buteninole, 2-buteninole, 3-butenyl, 2-ethyiyl 1-butur, 2-methinole 1-butenyl, 3-methinole_2-butur, 1_penthenol, 2- C 2 — such as pentyl, 3-pentyl, 4-pentynole, 4-methinole 3-pentul, 1-hexenyl, 2-hexeninole, 3-hexenyl, 4-hexeninole, 5-hexenyl, etc. 6- anolequenyl and the like.
  • heterocyclic group represented by “optionally substituted heterocyclic group” represented by R ′ ′ is a heterocyclic group represented by “optionally substituted heterocyclic group” represented by R Examples are the same as the groups.
  • alkoxy group of the “optionally substituted alkoxy group” for L 2a the same as the “optionally substituted alkoxy group” for L 2 can be mentioned.
  • the ⁇ optionally substituted hydrocarbon group '' represented by R la , R 2a and R 3a is the same as the ⁇ optionally substituted hydrocarbon group '' represented by RR 2 and R 3 above Is mentioned.
  • R la and R 2a , R la and R 3a , R 2a and R 3a may combine with each other to form a ring, and these rings are composed of R 1 and R 2 , R 1 and R 3 , R 2 And R 3 are the same as the ring formed by bonding to each other.
  • R 4a examples include the aforementioned R 4 The same as the “optionally substituted hydrocarbon group” shown can be mentioned.
  • “optionally substituted hydrocarbon group” represented by R 5 a and R 6 a substitution which may be an alkoxy group", “optionally esterified or amidated carboxyl group which may be”
  • “acyl group” include the “optionally substituted hydrocarbon group”, the “optionally substituted alkoxy group”, the “esterified or amidated” represented by R 5b and R 6b described above. Carboxyl group "and” acyl group ".
  • R 6 a for example by binding R la, R 2 a, R 3 a, and R 4 a,
  • Ring ⁇ represents a 5- to 10-membered nitrogen-containing heterocyclic ring
  • F represents a 5- to 10-membered nitrogen-containing heterocyclic ring
  • G represents a 4- to 8-membered nitrogen-containing heterocyclic ring
  • ⁇ represents a 5 to 10-membered heterocyclic ring.
  • rings E, F, G, and H may have a substituent, and such a substituent is represented by R
  • R The same as the substituent which the cyclic hydrocarbon group of "may be substituted! / Cyclic hydrocarbon group” may have.
  • Y is - CO-, - S (0) -, -S (0) 2 - a, Z is - N (R 5a), - CO -, - S (0) -, - S (0) 2 - , _CH 2 -or a bond.
  • Specific examples of the combination of Y and Z include when Y is -CO- and Z is -N ( R5a )-;
  • Y is -CO- and Z is s (o) 2 _;
  • Y is - CO - and is, Z mosquito CH 2 - if it;
  • Y is _S (0) - a and, Z is - - N (R 5 a);
  • Y is -S (0) _ and Z is -C0-;
  • Y is -S (0)-and Z is -S (0) 2- ;
  • Y is - S (0) is _, Z mosquito CH 2 - if it;
  • Y is - S (0) 2 - a and, Z is - - CH 2;
  • Y is -S (0) 2- and Z is a bond
  • n may be either 0 or 1.
  • Y and Z are —N (R 5a ) —, b preferably represents 0.
  • Y is - C0- or - S (0) is 2 _
  • Z is - preferably be a C0- or a bond, especially, Y is - C0- or - S (0) 2 - a is And Z is a bond; Further, a case where Z is not -C0- is also a preferable example.
  • the compound (Villa) includes 3-[(6-chloro-2--2-naphthyl) sulfonyl] -N-meth Tyl-N- [l- (4-pyridyl) -4-piperidyl] propanamide, 2- [N- [3-[(6-chloro-2-2-naphthyl) sulfonyl] propanoyl] -N- [1_ (4 -Pyridyl)-4-piperidyl] amino] ethyl acetate, 3-[N- [3-[(6-ku Mouth-2-naphthyl) sulfonyl] propanoyl]-N-[1-(4-pyridyl)- 4-Piperidyl] amino] ethyl ethyl propionate, 3-[(6-Mouth-2-naphthyl) sulfonyl] -N-methyl-N
  • halogen atom e.g., fluorine, chlorine, bromine, iodine
  • 1 may be substituted with three halogen atoms (6 ⁇ alkylsulfonyl Oxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), and optionally substituted arylinosulfonyloxy group (eg, benzenesulfonyloxy, ⁇ -Toluenesulfonyloxy, ⁇ -bromobenzenesulfonyloxy, etc.) or hydroxyl group, free carboxylic acid, its salt (inorganic salt, organic salt, etc.) or its reactive derivative (eg, acid halide, ester, acid azide, Acid anhydride, mixed acid anhydride, active amide, active ester, active thioester,
  • alkali metal or alkaline earth metal represented by the formula include alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium, with sodium being preferred.
  • the “optionally substituted nitrogen-containing aliphatic heterocycle” represented by the ring ⁇ ” includes a part of the“ optionally substituted nitrogen-containing heterocyclic ring ”represented by the aforementioned ring A ′.
  • examples thereof include those excluding a nitrogen-aromatic heterocyclic ring.
  • piperidine and piperazine are preferable, and piperidine is particularly preferable.
  • the hydrocarbon of the "optionally substituted hydrocarbon” represented by wherein R 6, wherein include those similar to the "optionally substituted hydrocarbon group" represented by R 5b and R 6b Can be
  • the raw material reagent used in each production method will be described below.
  • the compound represented by the formula (I) or a salt thereof may be referred to as “compound I”
  • the compound represented by (II) or a salt thereof, and the compound represented by the formula (IV) or a salt thereof may be referred to as “compounds II and IV”.
  • the cyclic ketone derivative (compound IX) is reacted with compound VII using a triacyloxyborohydride complex or a combination of a palladium catalyst and a hydrogen source (hydrogen gas or formic acid or a salt thereof) as a reducing agent.
  • the triacyloxyborohydride complex conjugate used is a product obtained by reacting a borohydride complex compound with 3 equivalents of carboxylic acid. Sodium triformyloxyborohydride, sodium triacetoxyborohydride, sodium tribenzoyloxyborohydride and the like are preferable, and sodium triacetoxyborohydride and the like are preferable.
  • borohydride complex compound examples include metal borohydride, alkali metal borohydride, alkaline earth metal borohydride, quaternary ammonium borohydride, and the like.
  • metal borohydride alkali metal borohydride, alkaline earth metal borohydride, quaternary ammonium borohydride, and the like.
  • lithium borohydride potassium borohydride, calcium borohydride, borohydride balm, etc.
  • a combination of sodium borohydride and an alkali (earth) metal salt for example, lithium salt lithium, calcium chloride
  • carboxylic acid e.g. formic acid, etc. acetate
  • aromatic carboxylic acids e.g. benzoic acid
  • six fat aliphatic carboxylic acids are preferably used .
  • the palladium catalyst examples include heterogeneous catalysts such as palladium black, palladium carbon, palladium-silica gel, and palladium monosulfate, palladium (II) acetate, palladium trifluoroacetate (11), palladium chloride (11), and palladium bromide (11). ), Yoka palladium (11), divalent palladium salts such as bis (triphenylphosphine) palladium (II) chloride and its complexes, A zero-valent palladium metal such as bon, tetrakis triphenylphosphine palladium (0), bis (dibenzalacetone) dipalladium (0), or a complex thereof is used.
  • palladium carbon, palladium acetate (11) and palladium chloride (II) are preferred, and palladium carbon is particularly preferred.
  • a ligand for forming a palladium complex in the reaction system may be used.
  • a ligand include triphenylphosphine and tri (0-trinolene).
  • Phosphine, tri (3-methoxyphenyl) phosphine, tri (4-chlorophenyl) phosphine, tri (2-furyl) phosphine, tri (2-phenyl) phosphine, 1,2-bis (diphenylphosphino) ethane are used.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • aliphatic hydrocarbons such as hexane, pentane and heptane
  • esters such as ethyl acetate and butyl acetate, getyl ether, disopropyl ether, ethers such as t-butyl methyl ether and tetrahydrofuran
  • aliphatic halogen hydrocarbons such as methylene chloride, chloroform and dichloroethane
  • methanol, ethanol, 1-propanol, and 2-propanol such as benzene, toluene and xylene
  • aliphatic hydrocarbons such as hexane, pentane and heptane
  • esters such as ethyl acetate and butyl acetate, getyl ether, disopropyl ether, ethers such as t-butyl methyl ether
  • Alcohols such as ethanol, 1-butanol, 2-ptanol ⁇ ⁇ , 2-methyl-propanol, and amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, ⁇ -methylbiperidone , Dimethylsulfoxide, hexamethylphosphoramide, dimethylimidazolidinone, water, etc., among which the above-mentioned alcohols, esters, ethers, and aromatic hydrocarbons are preferable, and particularly, methanol, ethanol, and 2_propanol , Ethyl acetate, tetrahydrofuran and toluene are preferred.
  • the amount of the solvent used in this reaction is 5 to 50 times, preferably 5 to 30 times, particularly preferably 5 to 20 times, the weight of the sulfinic acid derivative (I) or (1 ′).
  • the amount of the compound (IIa,)-(IIc,), (Ila)-(llc), (VIIa) or (VIIb) used is determined based on the sulfinic acid derivative (I) or (Ib).
  • ') Is 1 to 10 moles, preferably 1 to 5 moles, particularly preferably 1 to 3 moles relative to 1).
  • This reaction may be carried out in the presence of a base.
  • a base examples include alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxide, lithium tert-butoxide, sodium methoxide, and the like.
  • C1-C6 metal alkoxides such as sodium ethoxide, carboxyl-tert-butoxide, etc .
  • inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.
  • Triethylamine tri (n-propyl) amine, tri (n-butyl) amine, disopropylethylamine, cyclohexyldimethylamine, pyridine, noretidine, ⁇ -collidine,
  • Tertiary amines such as ⁇ , ⁇ -dimethylaniline, ⁇ -methylbiperidine, ⁇ -methylpyrrolidine and ⁇ _methylmorpholine are used. Among them, tertiary amine is preferably used.
  • the amount of the base to be used is 1 to 30 moles, preferably 1 to 10 moles, particularly preferably 1 to 5 moles, per mole of the sulfinic acid derivative (I) or (1 ').
  • the reaction temperature is usually 0 to 200 ° C, preferably 10 to 100 ° C, and the reaction time is usually 1 to 100 hours, preferably 1 to 50 hours, particularly preferably 1 to 20 hours.
  • the cyclic ketone derivative (compound IX) is reacted with alkylamines (compound X) using sodium triacyloxyborohydride or a combination of palladium catalyst and hydrogen gas or formic acid or a salt thereof as a reducing agent to give an amine derivative (compound X).
  • the solvent used may affect the reaction. There is no particular limitation as long as it is not changed, and in addition to the same as in the above-mentioned production method 1, carboxylic acids such as acetic acid are used.
  • the amount of the solvent used in this reaction is 5 to 50 times by weight, preferably 5 to 30 times by weight, particularly preferably 5 to 20 times by weight, relative to the cyclic ketone derivative (I-conjugated product IX).
  • the amount of the alkylamine (compound X)) to be used is 1 to 100-fold mol, preferably 1 to 50-fold mol, particularly preferably 1 to 50 mol, per mol of the cyclic ketone derivative (compound VI). 30 times mol.
  • the amount of the triacyloxyborohydride complex used is 1 to 30 times, preferably 1 to 10 times the amount of the cyclic ketone derivative (compound IX). Mole, particularly preferably 1 to 5 moles.
  • the amount of the palladium catalyst to be used is about 0.0001 to about 2 mol, preferably about 0.001 to about 2 mol, based on the cyclic ketone derivative (compound VI). It is about 0.001 to about 1 mol.
  • the hydrogen pressure is 1 to 100 atm, preferably 1 to 3 atm.
  • the amount of formic acid used is 1 to 30 moles, preferably 1 to 10 moles, and particularly preferably 1 to 5 moles relative to the cyclic ketone derivative (compound VI).
  • the reaction temperature is generally 0 to 150 ° C, preferably 10 to: 100 ° C, particularly preferably 10 to 50 ° C, and the reaction time is usually 1 to 20 hours, preferably 1 to 10 hours, particularly preferably 1 to 10 hours. ⁇ 5 hours.
  • Starting compounds (I), (I '), (IIa')-(lIc ') (Ila) — (IIc), (VIIa) (VI (lb), (IX) or (X) can be produced by a method known per se or a method analogous thereto. .
  • R represents a cyclic hydrocarbon group or a heterocyclic group which may be substituted
  • W represents a bond or a divalent chain hydrocarbon group which may be substituted
  • Ha 1 represents a halogen atom.
  • the above-mentioned borohydride complex compound aluminum hydride compounds (eg, dihydrobis (2-methoxyethoxy) sodium aluminate, diisobutylaluminum hydride, trimethoxylithium lithium anolemmium, tri-tert-butoxylithium aluminum hydride, hydrogen Anoremi sodium hydroxide, sodium triethoxyaluminum hydride, and sulfites (eg, sodium sulfite) are used.
  • borohydride complex conjugates particularly sodium borohydride
  • the compound When the compound is obtained in a free state by each reaction of the present invention, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. It can also be converted. '
  • the compounds (IIIa ') thus obtained — (II.Ic';), (Ilia), (IIIc), (Villa) and (VIIIb) can be isolated from the reaction mixture by themselves. Isolation and purification can be performed by using known means, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin-layer chromatography, and the like. Further, if desired, the reaction mixture may be used for the next reaction without isolation and purification.
  • Compounds (I lia ') — (III c), (I lia)-(III c), (VI lia) and (VIII b) salts can be prepared by known methods, for example using the compound (IIIa) ') _ (IIIc, :), (Illa)-(IIIc), (VIIIa) and (VIIIb) by adding an inorganic or organic acid.
  • compounds (I lia ') — (III c'), (III a) — (III c), (VIII a) and (VIII b) may have stereoisomers, these individual isomers and mixtures thereof All of these are naturally included in the scope of the present invention, and if desired, these isomers can be produced individually. Further, the compound (I lia ') — (III c'), (III a) _ (III c), (Villa) and (VIII b) or a salt thereof may be a hydrate, And non-hydrates are included within the scope of the present invention.
  • the compound (I lia ') — (III c') is hydrolyzed under acidic or basic conditions and condensed with an amine derivative represented by the general formula (V) to obtain FX.
  • aIt is also possible to produce a compound represented by the general formula (VI a ′) — (VI c ′) or a salt thereof having an inhibitory action.
  • the starting compound used in each of the above-mentioned production methods and the target compound obtained in each of the above-mentioned production methods may form a salt.
  • a salt examples include trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, and the like.
  • Examples of the formic acid salt used in each of the above production methods include metal salts such as sodium, potassium, magnesium, and calcium, such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N- Examples thereof include organic salts such as methylbiberidine and N-methylmorpholine, and ammonium formate. Any one may be used as long as it does not inhibit the reaction.
  • the compounds (VIa ′) — (VIc,), (VIIIa) and (VIIIb) obtained by the production method of the present invention are low-toxic and safe, inhibit FXa, and have an anticoagulant effect.
  • mammals eg, humans, monkeys, cats, pigs, pests, pests, mice, rats, guinea pigs, dogs, puppies, etc.
  • mammals eg, humans, monkeys, cats, pigs, pests, pests, mice, rats, guinea pigs, dogs, puppies, etc.
  • it is preferably used for the prevention or treatment of cerebral infarction due to atrial fibrillation, deep vein thrombosis, and the like.
  • Brain cerebral embolism, cerebral infarction due to atrial fibrillation, acute ischemic stroke, acute cerebral thrombosis, cerebral vasospasm after hemorrhage of arachnoid Bye, a Ruzheimer's disease, transient ischemic attack (TIA), mixed dementia, cerebral vascular Z multiple infarction dementia, heart: acute coronary artery disease, acute myocardial infarction, sequela of myocardial infarction, improved prognosis of myocardial infarction Unstable angina, angina pectoris, stent placement or PTC A (percutaneous coronary artery angioplasty) and revascularization and stenosis after coronary intervention such as atherectomy, peripheral: deep vein thrombosis, Prevention of deep venous thrombosisPrevention of secondary onset, chronic arterial occlusion, peripheral vascular disease, pulmonary thromboembolism, economy class syndrome, adult respiratory distress syndrome, chronic kidney disease (eg, diabetic nephropathy
  • the compound (I lia ') — (III c'), is optionally converted to the carboxylic acid form (IV a ') — (IV c'), and the compound (V ) Is condensed with the compound (Via ')-(Vic'), which is useful as an intermediate for FXa inhibitors.
  • compounds (Ilia) — (IIIc) are also useful as intermediates for FXa inhibitors.
  • This condensation reaction is generally carried out in a solvent, and if necessary, a base or a condensing agent (for example, phenolic imides (DCC (dicyclohexyl carbodiimide)), WSC (1-ethyl-3- (3-dimethylaminohydrochloride) Propyl) carbodiimide), DIC (2-dimethylaminoisoprovir chloride hydrochloride), etc.), phosphoric acid derivatives (eg, ethyl cyanophosphate, DPPA (diphenylphosphoryl azide), BOP-C1 (bis (2 —Oxo-1 3-—oxazolidinyl) phosphinic chloride) etc.).
  • a base or a condensing agent for example, phenolic imides (DCC (dicyclohexyl carbodiimide)), WSC (1-ethyl-3- (3-dimethylaminohydrochloride) Propyl) carbodiimide), DIC
  • the solvents and bases described in the above-mentioned Production method 1 can be used as they are.
  • the compound (V) is used in an amount of 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents, based on the compound (I Va)-(IV c).
  • the reaction temperature is from 150 to 150 ° C, preferably from 120 to 100 ° C.
  • the reaction time varies depending on the type of the compound (I Va ')-(I Vc') or (V), the type of the solvent and the base, the reaction temperature, etc., but is usually about 1 minute to about 100 hours. About 15 minutes to about 48 hours.
  • Tetrahydrofuran (1 L) was charged to a 3L4 type colben, and sodium borohydride (37.8 g, 1.0 mol) was added thereto while stirring at room temperature in a nitrogen stream. Subsequently, a suspension of 6-chloronaphthalene-2-sulfol chloride (131 g, 0.5 mmol) in tetrahydrofuran (1 L) was added. After stirring at around 40 for 2.5 hours, cool to room temperature, pour the reaction solution into a separately prepared ice water (2.3 L) and ethyl acetate (200 ml) in a 5-beaker in a nitrogen stream, and continue. Then concentrated hydrochloric acid (350 ml) was added dropwise.
  • the concentrated slurry was charged into a 2L4 neck corvene, methyl acrylate (43.0 g, 0.5 mol) and triethylamine (76.7 g, 0.5 mol) were added, and the mixture was reacted at 75 to 85 ° C for 7 hours. . After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol was added to the residue, and the mixture was concentrated under reduced pressure. After heating and dissolving with ethanol (1.21), foreign substances were removed by filtration while hot and washed with ethanol.
  • reaction solution was slowly poured in a nitrogen stream into ice water (300 ml) ethyl in a separately prepared 5 L beaker, followed by dropwise addition of 6N-hydrochloric acid (200 ml).
  • the mixture was extracted with ethyl acetate (600 ml + 300 ml), and the organic layers were combined, washed with saturated saline and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the crystals are collected by filtration, sprinkled and washed with methanol-denatured ethanol (40 ml), dried under reduced pressure at 40 ° C, and dried at 3-[(6-chloro-2--2-naphthyl) sulfonyl] -N-methyl-N-[[ (2-Methyl-4-pyridyl) -4-piperidinyl] propanamide (7.34 g) was obtained.
  • the production method of the present invention is useful for the prevention and treatment of arterial and venous thromboembolic diseases, inflammation, cancer, etc., which have an anticoagulant effect and an antithrombotic effect by inhibiting activated blood coagulation factor X (FXa). It is advantageously used for producing useful sulfone derivatives or salts thereof.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé relatif à l'élaboration d'un dérivé sulfone, y compris un sel correspondant, représenté par la formule générale R-W-S (O)2-X-Y-L2 (IIIa). Dans ladite formule, R est un groupe hydrocarbure cyclique éventuellement substitué, etc.; W est une liaison ou un groupe hydrocarbure à chaîne bivalente éventuellement substitué; X est un groupe hydrocarbure à chaîne bivalente éventuellement substitué; Y est -N(R5)-, -CO-, -S(O)-, -S(O)¿2?-, -CH2-, ou une liaison; et L?2¿ est hydrogène, hydroxy, ou alcoxy éventuellement substitué. Selon ce procédé, on fait réagir un dérivé acide sulfinique, y compris un sel correspondant, représenté par la formule générale R-W-S(O)¿2?-M (I), dans laquelle R et W sont tels que définis ci-dessus, et M est hydrogène, un métal alcalin, ou un métal alcalinoterreux, avec un composé, y compris un sel correspondant, représenté par la formule générale L?1-X-Y-L2¿ (IIa), dans laquelle X, Y et L2 sont tels que définis ci-dessus, L1 est un groupe partant, et R5 est hydrogène, etc.
PCT/JP2002/002323 2001-03-15 2002-03-13 Procede relatif a l'elaboration de derive sulfone WO2002074762A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001074010 2001-03-15
JP2001-74010 2001-03-15

Publications (1)

Publication Number Publication Date
WO2002074762A1 true WO2002074762A1 (fr) 2002-09-26

Family

ID=18931354

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2002/002323 WO2002074762A1 (fr) 2001-03-15 2002-03-13 Procede relatif a l'elaboration de derive sulfone

Country Status (1)

Country Link
WO (1) WO2002074762A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035579A1 (fr) * 2002-10-15 2004-04-29 Takeda Pharmaceutical Company Limited Derive imidazopyridine, procede de production de ce dernier et utilisation correspondante
CN112067746A (zh) * 2020-08-20 2020-12-11 广西特色作物研究院 一种活体测定桃需冷量的方法

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1381570A (en) * 1972-09-02 1975-01-22 Bayer Ag Perfluoroalkylsulphones
EP0008014A1 (fr) * 1978-07-18 1980-02-20 Hoechst Aktiengesellschaft Dérivés de la 1-(4-aminopipéridino)-3.4-dihydroisoquinoléine, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation
JPS5942359A (ja) * 1982-09-01 1984-03-08 Nippon Tokushu Kagaku Kogyo Kk スルホン類の製造法
JPH0525119A (ja) * 1991-07-18 1993-02-02 Mitsui Toatsu Chem Inc ｐ−トルエンスルホニル酢酸の製造方法
EP0619303A1 (fr) * 1993-04-03 1994-10-12 Hoechst Aktiengesellschaft Acides 4-alkyl-3-chloro-benzène sulfiniques, acides 4-alkyl-3-chloro-benzène sulfoniques, 4-alkyl-3-chloro-alkylsulfonylbenzènes et procédé pour leur préparation
WO1994022826A1 (fr) * 1993-04-07 1994-10-13 Otsuka Pharmaceutical Co., Ltd. Agents vasodilatateurs peripheriques comportant comme principe actif des derives de la piperidine 4-amino n-acylee
JPH0748341A (ja) * 1993-07-30 1995-02-21 Toyo Kasei Kogyo Co Ltd ２−クロル−４−メチルスルホニル安息香酸の製造法
WO1995028420A1 (fr) * 1994-04-18 1995-10-26 Corvas International, Inc. Derives du type methionine-sulfone et du type cysteine-sulfone substituee en s utilises comme inhibiteurs d'enzymes
WO1996010022A1 (fr) * 1994-09-26 1996-04-04 Zeneca Limited Derives aminoheterocycliques en tant qu'agents antithrombotiques ou anticoagulants
WO1997036899A1 (fr) * 1996-03-30 1997-10-09 Boehringer Mannheim Gmbh Nouveaux derives de l'oxazolidine, leur procede de production et medicaments les contenant
JP2000178247A (ja) * 1998-12-15 2000-06-27 Ishihara Sangyo Kaisha Ltd ビニルスルホン誘導体またはその塩、それらの製造方法、それらの中間体およびそれらを有効成分として含有する有害生物防除剤
WO2001066541A1 (fr) * 2000-03-08 2001-09-13 Takeda Chemical Industries, Ltd. Procede de preparation de derives d'hydrazine
WO2002006234A1 (fr) * 2000-07-17 2002-01-24 Takeda Chemical Industries, Ltd. Derives de sulfonate, procede de production et utilisation de ces derives

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1381570A (en) * 1972-09-02 1975-01-22 Bayer Ag Perfluoroalkylsulphones
EP0008014A1 (fr) * 1978-07-18 1980-02-20 Hoechst Aktiengesellschaft Dérivés de la 1-(4-aminopipéridino)-3.4-dihydroisoquinoléine, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation
JPS5942359A (ja) * 1982-09-01 1984-03-08 Nippon Tokushu Kagaku Kogyo Kk スルホン類の製造法
JPH0525119A (ja) * 1991-07-18 1993-02-02 Mitsui Toatsu Chem Inc ｐ−トルエンスルホニル酢酸の製造方法
EP0619303A1 (fr) * 1993-04-03 1994-10-12 Hoechst Aktiengesellschaft Acides 4-alkyl-3-chloro-benzène sulfiniques, acides 4-alkyl-3-chloro-benzène sulfoniques, 4-alkyl-3-chloro-alkylsulfonylbenzènes et procédé pour leur préparation
WO1994022826A1 (fr) * 1993-04-07 1994-10-13 Otsuka Pharmaceutical Co., Ltd. Agents vasodilatateurs peripheriques comportant comme principe actif des derives de la piperidine 4-amino n-acylee
JPH0748341A (ja) * 1993-07-30 1995-02-21 Toyo Kasei Kogyo Co Ltd ２−クロル−４−メチルスルホニル安息香酸の製造法
WO1995028420A1 (fr) * 1994-04-18 1995-10-26 Corvas International, Inc. Derives du type methionine-sulfone et du type cysteine-sulfone substituee en s utilises comme inhibiteurs d'enzymes
WO1996010022A1 (fr) * 1994-09-26 1996-04-04 Zeneca Limited Derives aminoheterocycliques en tant qu'agents antithrombotiques ou anticoagulants
WO1997036899A1 (fr) * 1996-03-30 1997-10-09 Boehringer Mannheim Gmbh Nouveaux derives de l'oxazolidine, leur procede de production et medicaments les contenant
JP2000178247A (ja) * 1998-12-15 2000-06-27 Ishihara Sangyo Kaisha Ltd ビニルスルホン誘導体またはその塩、それらの製造方法、それらの中間体およびそれらを有効成分として含有する有害生物防除剤
WO2001066541A1 (fr) * 2000-03-08 2001-09-13 Takeda Chemical Industries, Ltd. Procede de preparation de derives d'hydrazine
WO2002006234A1 (fr) * 2000-07-17 2002-01-24 Takeda Chemical Industries, Ltd. Derives de sulfonate, procede de production et utilisation de ces derives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004035579A1 (fr) * 2002-10-15 2004-04-29 Takeda Pharmaceutical Company Limited Derive imidazopyridine, procede de production de ce dernier et utilisation correspondante
CN112067746A (zh) * 2020-08-20 2020-12-11 广西特色作物研究院 一种活体测定桃需冷量的方法
CN112067746B (zh) * 2020-08-20 2022-11-08 广西特色作物研究院 一种活体测定桃需冷量的方法

Similar Documents

Publication Publication Date Title
JP6884801B2 (ja) 血漿カリクレインインヒビターとしてのピラゾール誘導体
TWI313264B (en) Triamide-substituted heterobicyclic compounds
TWI344955B (en) Heterocyclic rinf having nitrogen atom derivatives and medicament containing the derivatives as active ingredient
TWI258473B (en) Dipeptide nitrile cathepsin K inhibitors
JP2021169499A (ja) ヒト血漿カリクレイン阻害剤
JP2004501913A (ja) ヘテロアリール−フェニル置換Ｘａ因子阻害剤
JP2001526268A (ja) Ｘａ因子阻害剤としての、オルト−置換Ｐ１を有する、窒素含有複素環式芳香族化合物
CZ510889A3 (en) Cycloalkyl substituted glutaramide derivatives,pharmaceutical composition containing such compounds and the use thereof
JP2017524026A (ja) 強力なｒｏｃｋ阻害剤としてのタイドバックのベンズアミド誘導体
JP2004503547A (ja) セリンプロテアーゼインヒビター
JPH11508242A (ja) アリールスルホニルアミノベンゼン誘導体およびＸａ因子阻害物質としてのその使用
JP2016510033A (ja) 強力なｒｏｃｋ１およびｒｏｃｋ２阻害剤としてのフェニルピラゾール誘導体
WO2004013100A2 (fr) Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
TW201114744A (en) New HSL inhibitors useful in the treatment of diabetes
JPH06509076A (ja) ２−［３−（４−アミジノ−フェニル）］−プロピオン酸誘導体、その製造および使用
WO2007079003A2 (fr) Amides inhibiteurs de la leucotriene a4 hydrolase
CA2104456C (fr) Agents derives de pyridines et d'imidazoles utilises pour le traitement des maladies cardiovasculaires
JPWO2005030773A1 (ja) 新規ピラゾロピリミジン誘導体
SK33099A3 (en) Novel tricyclic piperidinyl compounds useful as inhibitors of farnesyl-protein transferase
WO2008156208A1 (fr) Dérivé de 5-phényl-3-pyridazinone
AU2001275857A1 (en) Thrombin or factor xa inhibitors
TWI295290B (en) Novel pyrrolidine-3,4-dicarboxamide derivatives
CN116813691B (zh) 新的二肽类化合物及其用途
WO1998046569A1 (fr) Derives de benzene
WO2002074762A1 (fr) Procede relatif a l'elaboration de derive sulfone

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP