WO2004000837A1 - Novel benzoxazolinone derivative - Google Patents

Abstract

A novel benzoxazolinone derivative represented by the formula (1). [1] Also provided is a novel therapeutic agent for Parkinson's diseases which has a high bonding affinity for and high agonistic activity against both a dopamine D2 receptor and a serotonin 5-HT1A receptor.

Description

 Specification

 New Benzoxazolinone Derivatives '' Technical Field

 The present invention relates to novel benzoxazolinone derivatives. These novel benzoxazolinone derivatives are useful as therapeutic agents for Parkinson's disease. Background art

Parkinson's disease is a movement disorder caused by a deficiency of the neurotransmitter dopamine in the brain. Until now, treatment of Parkinson's disease has mainly been replacement therapy with dopamine precursor L-D0PA, but long-term administration of L-D0PA shortens the action time (we aring_o phenomenon) and destabilizes (on-off phenomenon) Involuntary movement disorders such as dyskinesia and mental symptoms such as hallucinations and delusions have become major problems. Since these L-D0PA problems are considered to depend on the dose of L-D0PA and the length of the administration period, the use of dopamine agonists (dopamine D ₂ agonist) from the onset of the disease Delaying the onset of L-D0PA and reducing the dose is considered important in the treatment of Parkinson's disease. However, there are problems with existing dopamine agonists, such as vomiting and nausea in the early stage of taking the drug, and insufficient efficacy in the middle and later stages.

Serotonin 5-HT A agonists have been found to have an effect on improving not only depression and anxiety, but also movement disorders such as Parkinson's disease in recent years. In fact, it has been reported that the selective 5_HT _1A agonist tandospirone quenate improves motor impairment in Parkinson's disease. Calorie, 5-ffl _A agonists have been reported to reduce side effects such as suppression of vomiting by dopamine stimulation and shortening of the duration of action during long-term L-D0PA therapy. Therefore, a drug that exhibits an agonistic action on both dopamine D ₂ receptor and serotonin 5-HT _{1 A} receptor improves the problems of conventional dopamine agonists and also increases the action time of L-D0PA. Concomitant depression · It may be a new treatment for Parkinson's disease that has an effect of improving anxiety symptoms.

For example, TO00 / 1677 ⁷ contains dopamine as a treatment for Parkinson's disease, ADHD, etc. _A pyrido [1,2-a] -pyrazine derivative showing agonist action on both D ₂ receptor and serotonin 5-ΗΊA receptor, W090 / 15058 contains tricyclic nitrogen atom with central nervous system activity Compounds are disclosed. Further, W000 / 29397 discloses piperazine and piperidine derivatives which show partial agonism at both dopamine D ₂ receptor and serotonin 5- -A receptor. Disclosure of the invention

The present inventors have conducted intensive studies and found that the following compounds have high binding affinity and strong agonist action for both dopamine D 2 receptor and seotonin 5-HT _1A receptor. And completed the present invention.

 That is, the present invention

 [1] Equation (1)

 [In the formula, ring A represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring.

R ^e represents a hydrogen atom, a substituted or unsubstituted alkyl group or a hydroxyl group, and two or more R ^e may be independently present.

R ¹ is the formula (2)

(In the formula, R ^lfl and R ¹¹ independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Represents a hydroxyl group. E is a single bond, one O—, one NR ⁵ —, one CO_, one CS—, one S (O) _m —, -C OOs — CS—O—, one NR ⁵ CO—, one CONR ⁵ —, one O—CO— or one O—CS— (wherein, R ⁵ represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. M represents an integer of 0 to 2) ).

 B represents a single bond, a 6- to 16-membered aromatic hydrocarbon ring, a 3- to 8-membered aliphatic hydrocarbon ring, a 3- to 12-membered aliphatic heterocycle, or a 5- to 12-membered aromatic heterocycle .

 Q represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkyl group, an alkoxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted amino group, Or unsubstituted rubamoyl, carboxy, nitro, cyano, hydroxyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, Or a substituted or unsubstituted alkylsulfonyl group. When B represents a group other than a single bond, each of the groups represented by Q may be independently two or more. N represents an integer of 0 to 10. ).

R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkylthio group.

R ⁴ represents a hydrogen atom or a substituted or unsubstituted alkyl group.

 X is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a hydroxyl group, a nitro group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a cyano group, a substituted or unsubstituted rubamoyl group, Represents a carboxy group, a substituted or unsubstituted alkyloxycarbel group, or a substituted or unsubstituted amino group. ]

Or a pharmaceutically acceptable salt thereof,

 [2] The compound of the above-mentioned 1, wherein the A ring is a 5- to 7-membered saturated or unsaturated nitrogen-containing heterocyclic ring, or a pharmaceutically acceptable salt thereof,

[3] The compound of the above-mentioned 1 or 2, wherein the A ring is piperidine-13-yl or 1,2,5,6-tetrahydropyridine-13-yl, or a pharmaceutically acceptable salt thereof. [4] The compound described in the above 1 to 3, wherein E is a single bond, or a pharmaceutically acceptable salt thereof,

 [5] The compound according to any one of the above 1 to 4, wherein B is a 3- to 8-membered aliphatic heterocycle, or a pharmaceutically acceptable salt thereof,

 [6] The compound according to any one of the above 1 to 5, wherein B is a pyrrolidine ring or a piperidine ring, or a pharmaceutically acceptable salt thereof,

 [7] The compound according to any one of the above 1 to 5, wherein B is a pyrrolidine ring, or a pharmaceutically acceptable salt thereof,

 [8] Q is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted arylylcarbonyl group, or a substituted or unsubstituted 1 to 7 above, which is a substituted alkylsulfonyl group, the compound according to any one of the above or a pharmaceutically acceptable salt thereof,

 [9] The compound according to the above 1-7V, wherein Q is an alkyloxy group or an alkylcarbonyl group, or a pharmaceutically acceptable salt thereof,

 [10] The compound according to any one of the above 1 to 7, wherein Q is a methyl / reoxycarbonyl group, or a pharmaceutically acceptable salt thereof,

 [11] The compound according to any one of the above 1 to 10, wherein n is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof,

[12] The compound according to any one of the above items 1 to 11, wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof;

 [13] The compound of the above-mentioned 1, which is any compound selected from the group consisting of the following (1) to (23), or a pharmaceutically acceptable salt thereof,

 (1) Methyl 3- {3-[3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1 / le 7-inole) piperidine-1 1-inole] propyl} pyrrolidine-11-carboxylate

(2) Methynole 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidin-1-yl] propyl} piperidine One-one-strength noreboxylate

 (3) Methyl 3- {2_ [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-1-ynole] ethyl} pyrrolidine-1 1-force norreboxylate

 (4) Methyl 3- {2_ [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidin-1 1-yl] ethyl} piperidine-1 (1) One strength olepoxylate

 (5) Methyl 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-7-inole) piperidine-1-1-inole] methinolepyrrolidine-1-one-forceboxylate

 (6) Methyl 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-7-inole) piperidine-1-1-inole] methinoleviperidin-1

 (7) Methyl 2- {3- (3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-yl) piperidine-11-yl] propyl} pyrrolidine-1 1—force norboxylate

 ('8) Methyl 2- {3- (3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1 / le 7-yl) piperidine-1-11] propyl} piperidine One 1—Canolepoxylate

 (9) Methynole 2- {3- [2- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-yl) piperidine-1-1-yl] ethyl} pyrrolidine-1 / Repoxylate

 (10) Methyl 2_ {2- [3 -— (2-oxo-1,2,3-dihydro-1,3-benzoxazono-1-yl) piperidine-1-11-yl] ethyl} piperidine-1 1-cano Reoxylate

(1 1) Methyl 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-11-yl] methylpyrrolidine-1-force ropoxylate (12) Methyl 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1 / le7-yl) piperidine-1-1-inole] methylpiperidine-1

 (13) Methyl 4- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-yl] propyl} piberidine-1 One strength / Repoxylate

 (14) Methinole 4- {2- [3- (2-oxo-1,2,3-dihydro-1,3-onebenzoxazole-7-inole) piperidine-1-1-inole] ethyl} piperidine-11

 (1 5) Methyl 4- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-1-yl] methylbiperidine-11-norreboxylate

 (16) Methyl (3 S) —3— {3-[(3 S) -3- (2-oxo-1

3-dihydro-1,3-benzoxazo-1-one 7-inole) piperidine-1 1-inole] propyl} pyrrolidine-1 1-canolepoxylate

 (1 7) Methyl (3 S) —3— {3- [(3 R) -3— (2-oxo-1,2

3-dihydro 1,3-benzoxazono 1 7-inole) piperidine 1-isle] propyl} pyrrolidine-1 1-carboxylate

 (18) Methyl (3 R)-3-{3-[(3 S) 13-(2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1 -inole

] Propyl} pyrrolidine-1-force / repoxylate

 (19) Mail (3R) -3- {3-[(3 R) —3— (2-oxo-1 2,

3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl] propyl} pyrrolidine-11-carboxylate

 (20) Methyl (3 S) —3— [(3 S) —3— (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-1-inole] Rupyrrolidine-one-strength noreboxylate

(21) Methyl (3 S) — 3— [(3 R) 1 3— (2—oxo 1,2,3-di Hydro-1,3-benzoxazole-7-yl) piperidine-1] -methylphenolyl-1-yl oxy-loxylate

 (22) Methyl (3 R)-3-[(3 S) -3- (2-oxo-1,2,3-dihydro-1,3-benzoxazono 1-7-inole) Piperidine 1 1-inole] Methi Norepyrrolidine 1-carboxylate

 (23) Methinole (3 R) —3— [(3 R) _3_ (2-oxo-1,2,3-dihydro-1,3-benzoxazozo / le 7 f) piperidine-1 1-inole] methinolepyrrolidine 1-11 carboxylate

 [14] A medicament comprising the compound according to any one of the above 1 to 13 or a pharmaceutically acceptable salt thereof,

 [15] The present invention relates to a therapeutic agent for Parkinson's disease, comprising the compound described in any one of the above items 1 to 13, or a pharmaceutically acceptable salt thereof.

[16] The compound of the above-mentioned 1, wherein R ¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof,

 [17] Any of the above-mentioned compounds selected from the group consisting of the following compounds (1) to (5) or a pharmaceutically acceptable salt thereof,

 (1) 7-piperidine-1 3-yl 1,3-benzoxazonole _2 (3H) one year old

 (2) (+) 1 7-piperidine-1 3-yl _1,3-benzoxazole-2 (3H) -one

 (3) (1) 1 7-Pyridine-1 3-yl _ 1, 3—Benzoxazole-2 (3 H) —one

 (4) 7-Pyrrolidine-3-yl-1,3-benzoxazole-2 (3H)

 (5) 7-azepan-1-yl-1, 3-benzoxazo-one-2 (3H) -one Best mode for carrying out the invention

Hereinafter, the present invention will be described more specifically. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentinole, 1-methylinobutynole, 2-methylinobutynole, 3-methylbutyl, 1-ethylpropynole, hexyl, Examples thereof include a linear or branched alkyl group having 1 to 10 carbon atoms, such as heptyl, octyl, nor or decyl. Preferred alkyl groups include linear or branched alkyl groups having 1 to 6 carbon atoms. More preferably, methyl or ethyl is used.

 Examples of the alkenyl group include straight-chain or branched alkenyl groups having 2 to 5 carbon atoms having at least one double bond, such as vinylol, propyl, methylpropyl, butenyl or methylputur. -Alkyl group. Preferred alkenyl groups include linear or branched alkenyl groups having 3 to 4 carbon atoms.

 Examples of the alkynyl group include a linear or branched alkynyl group having 2 to 5 carbon atoms and having at least one triple bond, such as ethur, propiel, methylpropynyl, butynyl or methylbutynyl. Preferred alkyl groups include linear or branched alkynyl groups having 3 to 4 carbon atoms.

 Examples of the alkoxy group include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, otoxy, nonyloxy, and decyloxy. And 0 linear or branched alkoxy groups. Preferred alkoxy groups include linear or branched alkoxy groups having 1 to 6 carbon atoms. More preferably, methoxy or ethoxy is used.

Examples of the alkylthio group include, for example, methylthio, ethylthio, propylthio, petitnorethio, isopropinorethio, isoptinorethio, sec-puchinorethio, tert-butylthio, pentinorecio, hexinorethio, heptinorethio, octinorethio, And an alkylthio group having 1 to 10 carbon atoms such as o, decylthio and the like. Preferable alkylthio groups include alkylthio groups having a linear or branched alkyl group having 1 to 6 carbon atoms.

 Examples of the substituent in the substituted alkyl group, the substituted alkoxy group, and the substituted alkylthio group include the above-mentioned halogen atom (the same carbon atom may be substituted by 1 to 3), hydroxyl group, methoxy, ethoxy, propoxy and the like. Alkoxy, amino, methinoleamino, ethynoleamino, alkylamino such as propylamino, dimethylamino, dimethylamino, methylethylamino, dialkylamino such as dipropylamino, acetylamino, propionylamino, benzoylamino, naphthoamino, naphthoamino, etc. Alkoxycarbamino groups such as methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, etc., such as methinolesulfenole and etinolesulfonyl Examples include olequinorenolehonyl group, benzensorenohonore, and honoreensorehonenole group.

. More preferred are an alkoxy group such as a hydroxyl group, methoxy, ethoxy, and propoxy.

 Examples of the aryl group include aryl groups having 10 or less carbon atoms, such as phenyl and naphthyl.

 Examples of the heteroaryl group include a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. Pyridyl (the nitrogen atom may be oxidized), thienyl, furyl, pyrrolyl, virazolyl, imidazolyl, virazyl, pyrimidyl, pyridazyl, oxazolyl, thiazolyl, lyxadiazolyl, triazolyl, tetrazolyl and the like.

Examples of the substituent of the substituted aryl group and the substituted heteroaryl group include a halogen atom, a hydroxyl group, an alkyl group such as methyl, ethyl and propyl, and an alkoxy group such as methoxy, ethoxy, and propoxy. In addition, these substituents may be bonded to two adjacent ones to form a ring. 0

(In the above formula, R ⁶ represents a hydrogen atom, a lower alkyl group, an benzyl group or a protecting group for a nitrogen atom.)

And the like represented by

 When two or more substituents are present, they can be independently selected from the above groups.

 Examples of the 6- to 16-membered aromatic hydrocarbon ring include a benzene ring, a naphthalene ring, and an anthracene ring.

 Examples of the 3- to 8-membered aliphatic hydrocarbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclootaten And a saturated or unsaturated aliphatic hydrocarbon ring. Preferred aliphatic hydrocarbon rings include those having 5 to 6 members.

 Examples of the 3- to 12-membered aliphatic heterocycle include a saturated or unsaturated aliphatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Examples include aziridine, azetidine, pyrrolidine, piperidine, azepine, azepan, imidazolidine, piperazine, diazepine, dihydrofuran, tetrahydrofuran, tetrahydrothiophene and the like. The above aliphatic heterocyclic ring may have an amide bond or an imido bond in the ring, for example, a 5- to 6-membered cyclic imido group such as an succinic imid group or a glutaric imid group. Or a cyclic amide group. For example, the following formula is given.

Preferred aliphatic heterocycles include those having 5 to 6 members. More preferably Pyrrolidine and piperidine.

 The above-mentioned aliphatic heterocyclic ring may be a condensed ring condensed with another ring, and such “other ring” includes a hydrocarbon ring and a heterocyclic ring. Examples of the hydrocarbon ring include a benzene ring and an aliphatic hydrocarbon ring (for example, the above-mentioned 5- to 6-membered saturated or unsaturated aliphatic hydrocarbon ring). The heterocyclic ring is, for example, a 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, and is a saturated or unsaturated aliphatic heterocyclic ring. And a ring or an aromatic heterocyclic ring. Examples of such a condensed ring include those represented by the following formula.

(In the above formula, the bond shown by the solid line and the dotted line represents a single bond or a double bond, and E ′ is = CH—, one CH ₂ —, _〇_, one S—, one SO— or a S 0 ₂ -. a represents R ⁷ represents a hydrogen atom, an alkyl group, a benzyl group, the protective group or a substituted alkyl group as defined above nitrogen atom).

Examples of the 5- to 12-membered aromatic heterocyclic ring include an aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Specifically, pyridine (nitrogen atom may be oxidized), thiophene, furan, pyrrole, pyrazole, imidazole, pyrazine, pyrimidine, pyrimidine Dazine, oxazoline, thiazoline, oxaziazoline, triazole, tetrazole and the like.

 The above aromatic heterocyclic group may form a condensed ring with another ring, and examples of such another ring include the same as the “other ring” described in the above aliphatic heterocyclic ring. . Specific examples of such a fused heterocyclic ring include, for example, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, quinazoline, indole, isoindole, benzofuran, benzothiophene and the like. Preferred are those having 9 to 10 members.

 Examples of the substituent of the substituted amino group include the above-mentioned substituted or unsubstituted alkyl group, alkenyl group having 7 or less carbon atoms such as acetyl, propionyl, and butyryl; and carbon atom having 11 or less such as benzoyl and naphthoyl. Examples thereof include alkoxycarbonyl groups having 7 or less carbon atoms, such as an arylone group, methoxycarbole, ethoxycanoleboninole, and tert-butoxycarbonyl. Specific examples of the substituted amino group include, for example, methylamino group, ethylamino group, dimethylamino group, acetylamino group, propionylamino group, benzoylamino group, naphthoylamino group, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycano. Leponinoleamino and the like.

 The substituent in the rubamoyl group includes, for example, the above-mentioned substituted or unsubstituted alkyl group, alkenyl group having 7 or less carbon atoms such as acetyl, propionyl, and butyryl, and arylo group having 11 or less carbon atoms such as benzoyl and naphthoyl. And so on. Specific examples of the substituent rubamoyl group include, for example, a monomethylcarbamoyl group, a dimethinolecanolebamoinole group, an ethylcarbamoinole group, an acetinolecanolebamoyl group, and a benzoylcarbamoyl group.

 The substituents in the substituted alkyloxycarbonyl group, the substituted alkylcarbonyl group, the substituted aryl group and the substituted alkylsulfonyl group are the same as the above-mentioned substituents in the substituted alkyl group, the substituted alkoxy group and the substituted alkylthio group. Groups.

n represents an integer of 0 to 10, preferably 0 to 6. The 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring represented by ring A includes, for example, 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring;

And the like. Preferred ring A includes a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic ring. In addition, the ring A may have a substituent represented by R ° as appropriate.

 The compound (1) of the present invention or a pharmaceutically acceptable salt thereof can be produced by a method represented by the following formula.

Production _Method 1 (Alkylation of amino group ^ _Sylation, etc.)

4

Four

 (1)

(Wherein,,! ^.,! ^ 1, R 2, R 3, R 4, and X are as defined above, LG represents a leaving group.)

 Examples of the leaving group LG include a halogen atom such as a chlorine atom, a bromine atom, and an iodine atom, and an acyloxy group such as acetoxy, tosyloxy, and mesiloxy.

The compound (1) of the present invention or a salt thereof can be obtained by reacting the compound ( ^1β ) or a salt thereof with the compound (3) or a salt thereof. The reaction is carried out in a suitable inert solvent at a temperature ranging from about 120 ° C to the boiling point of the solvent used for 10 minutes in the presence of a base, if necessary, and optionally a phase transfer catalyst. The reaction can be carried out for up to 48 hours.

 Examples of the base include organic bases such as triethylamine and pyridine; inorganic bases such as lithium carbonate, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

 Examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate and the like.

Examples of the inert solvent include, for example, halogenated hydrocarbons such as acetonitrile II, chloroform, dichloromethane and the like, aromatic hydrocarbons such as benzene and toluene, ether solvents such as getyl ether, tetrahydrofuran (THF), and 1,4-dioxane. And aprotic polar solvents such as lower alcohols such as methanol, ethanol, and isopropanol; dimethinolephonamide, N-methylpyrrolidone, and dimethyl sulfoxide; and mixed solvents thereof. Among the compounds (1) of the present invention, the compound represented by the formula (la) or a salt thereof can also be produced by the following method.

Production method 2 (Ami reduction)

(Wherein, A, R., R ² , R ³ , R ⁴ , X, R ¹⁰ , R ", B and Q have the same meanings as above, n 'is an integer from 1 to 10, and E. A single bond or one NR ⁵ (wherein R ⁵ is the same as defined above).

Intermediate (5) can be produced by reacting compound (1 °) or a salt thereof with compound (4) or a salt thereof to form an amide bond. The amide bond formation reaction may be performed by an acid chloride method using thiol chloride, oxalyl chloride, or the like; an acid anhydride method using a corresponding acid anhydride; It can be carried out by a usual method such as a method using a condensing agent such as oral hexylcarbodiimide ゃ carbodilidimidazole. The intermediate (5) is converted to a suitable inert solvent (eg, ether such as getyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.) using a suitable reducing agent (eg, lithium aluminum hydride or diborane). Compound (la) can be obtained by reacting at a temperature between −20 ° C. and the boiling point of the solvent used for 10 minutes to 48 hours. More specifically, the compound (la) can be obtained by performing a reduction reaction in tetrahydrofuran (THF) with diborane under ice cooling or at room temperature for 20 minutes to 1 hour.

Production Method 3 (Reducible Amino 1 Dani)

 (la)

(Wherein, A, R., R ² , R ³ , R ⁴ , X, R ¹ R ¹¹ n, E., B and Q have the same meanings as described above.)

The target compound (la) or a salt thereof can be obtained by reacting the compound (1) or a salt thereof with the compound (6) or a salt thereof under reductive amination conditions. As a reducing agent For example, sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride can be used.Compound (2) and compound (6) can be mixed as they are, or they can be formed in advance by forming enamine. The reaction may be performed afterwards. The reaction is carried out in a suitable inert solvent, for example, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as ethyl ether, tetrahydrofuran, and 1,4-dioxane. In a protic polar solvent such as a system solvent, methanol, ethanol, isopropanol, and acetic acid, an aprotic polar solvent such as dimethylformamide, N-methinolepyrrolidone, and dimethylsulfoxide, or in a mixed solvent thereof at 120 ° C. To a boiling point of the solvent used for 10 minutes to 48 hours.

Further, the compound of the formula (1) may be converted to another compound of the formula (1) by appropriately converting the functional group. Conversion of functional groups, generally methods [eg normally performed, the completion Nshibu ■ Organic Transformations's _{(Comprehen sive Organic Transformations) N R} . C. Rarokku (Larock) Author (1 9 8 9 years), etc. See ].

Preparation of intermediates

Although some of the intermediates used in the present invention are novel, they can be produced by the methods described in the Examples below, or by methods similar thereto, or according to general methods. For example, Compound ^{(1 β), (l 0} a) or salts thereof can be by connexion manufacturing to the method shown in the following equation.

8

(In the formula, R °, RRRX, A, and LG are as described above. PG represents a protecting group for a nitrogen atom.) The protecting group PG ² nitrogen atoms, include appropriate protecting groups for secondary Amin, e.g. downy Njiru group.

 Compound (9) can be obtained by converting compound (7) to compound (7 ') by a method described in the literature (eg, JOC, 1982, 47, 2804-2806, W000 / 29397) or a method analogous thereto. It can be obtained by reacting with (8).

 The compound (9) can be converted to the compound (10) by dehydration. More specifically, the reaction can be carried out in a 48% aqueous solution of hydrobromic acid at 80 to 100 ° C. for 1 to 5 hours.

 Compound (11) can be obtained by reacting compound (10) with compound (3 ′). This transformation is carried out in a suitable inert solvent at a temperature ranging from about 120 ° C. to the boiling point of the solvent used, in the presence of a base, if necessary, and optionally a phase transfer catalyst. The reaction can be carried out by reacting for a period of from 48 minutes to 48 minutes. Examples of the base include organic bases such as triethylamine and pyridine; inorganic bases such as carbonated lime, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

 Examples of the inert solvent include halogenated hydrocarbons such as acetonitrile II, chloroform, dichloromethane and the like, aromatic hydrocarbons such as benzene and toluene, ethers such as getyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Examples thereof include solvents, lower alcohols such as methanol, ethanol, and isopropanol; aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide; and mixed solvents thereof.

The desired compound (1 °) can be obtained by reducing and deprotecting the compound (11) by a conventional method. Similarly, compound (l ° ^a ) can be obtained from compound (10). More specifically, the compound (10) or compound (11) in which PG ^{2 is a} benzyl group is heated and refluxed in ethanol for 1 to 5 hours in the presence of 10% palladium carbon and ammonium formate. By doing so, compound ( ^1β ) or compound ( ^a ) can be obtained.

Throughout this specification, protecting groups, condensing agents, etc., are commonly used in the art. IUPAC — May be abbreviated by IUB (Biochemical Naming Commission). The starting compound or a suitable salt of the target compound or a pharmaceutically acceptable salt is a conventional non-toxic salt and includes organic acid salts (eg, acetate, trifluoroacetate, maleate). , Fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc., inorganic salts (eg hydrochloride, hydrobromide, hydroiodic acid) Acid addition salts, such as salts, sulfates, nitrates, phosphates, etc., salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), or alkali metal salts (eg, sodium, potassium salts, etc.) and Metal salts such as alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (eg, trimethylamine salts) , Triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N, dibenzylethylenediamine salt, etc.), and the like, and others can be appropriately selected by those skilled in the art.

 In the production method described above, if any functional group other than the reaction point changes under the reaction conditions described or is inappropriate for carrying out the method described, the protection is performed at a position other than the reaction point, After the reaction, the target compound can be obtained by deprotection. Protecting groups include, for example, Protective Groups in Organic Synthesis, Guton (T. Ha, John Wiley and Sons Incorporated). nc.) (1989), and the like. More specifically, as the protecting group for amine, ethoxycarbonyl, t-butoxycarbol, Examples of acetyl, benzyl and the like, and examples of the hydroxyl-protecting group include trialkylsilyl, acetyl and benzyl.

 The introduction and elimination of protecting groups should be carried out by a method commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis (see above, Protective Groups in Organic Synthesis)] or a method analogous thereto. There is a monkey.

Intermediates and target compounds in each of the above production methods are purified methods commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographs It can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without purification.

 Some of the compounds (1) of the present invention may have tautomers, and the present invention includes all possible isomers, including these, and mixtures thereof.

 When it is desired to obtain a pharmaceutically acceptable salt of the compound (1) of the present invention, if the compound (1) can be obtained in the form of a pharmaceutically acceptable salt, it can be purified as it is, When it is obtained in the form of a salt, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a usual method. The compound (1) and its pharmaceutically acceptable salt may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. The compound (1) of the present invention may include one or more stereoisomers based on an asymmetric carbon atom, and such heterogeneous to living organisms and mixtures thereof are all included in the scope of the present invention.

 Furthermore, the scope of the present invention also includes prodrugs of the compound (1) of the present invention. In the present invention, the term “prodrug” refers to a derivative which is decomposed in vivo by acid hydrolysis or enzymatically to give the compound of the above formula (1). For example, when the compound of the formula (1) has a hydroxyl group or a carboxy group, these groups can be modified according to a conventional method to produce a prodrug.

The compound (1) of the present invention and a pharmaceutically acceptable salt thereof have a pharmacological action such as dopamine agonist action. Therefore, it is useful for treating or preventing diseases mediated by dopaminergic neurons, such as Parkinson's disease, anxiety, depression, hypertension, associated hypertension, and schizophrenia. Furthermore, the compound (1) of the present invention and a pharmaceutically acceptable salt thereof also have a pharmacological action such as a seroto-agonist action. Mood disorders; anxiety disorders, including obsessive-compulsive disorders and panic disorders; memory disorders, including dementia, amnesia and age-related memory disorders; disorders of eating behavior, including anorexia nervosa and neural starvation; Obesity; sleep disorders; drug dependence such as a / recall, tobacco, and nicotine; cluster headache; migraine; pain; Alzheimer's disease; chronic seizures migraine; Parkinson's disease, including B-immobilized dyskinesia, striatum It is also useful for treating or preventing motor disorders such as substantia nigra, progressive supranuclear palsy, and cerebellar degenerative disorders.

 The compound (1) of the present invention and a pharmaceutically acceptable salt thereof further include endocrine disorders such as hyperprolactinemia; vasospasm (especially of the cerebrovascular system); gastrointestinal tract in which motility and secretory changes are involved. Sexual dysfunction, including premature ejaculation; and treatment or prevention of drug dependence.

 For medical purposes, compound (1) of the present invention and pharmaceutically acceptable salts thereof may be used topically, enterally, intravenously, intramuscularly, by inhalation, intranasally, intraarticularly, intrathecally, intratracheally or transocularly It can be used in the form of a pharmaceutical preparation as a mixture with a pharmaceutically acceptable carrier such as a solid or liquid organic or inorganic excipient suitable for oral and parenteral administration including external administration, and external application. The pharmaceutical preparations include capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops Solids, semi-solids or liquids such as solutions, solutions, syrups, aerosols, suspensions and emulsions. These preparations can be manufactured by a usual method. If desired, auxiliaries, stabilizers, wetting or emulsifying agents, buffers and other conventional additives can be added to these preparations.

 The dose of Compound (1) and its pharmaceutically acceptable salts may be reduced depending on the age and condition of the patient, but the average single dose of Compound (1) is about 0.1 mg, lmg, 1 Omg, 50mg, 100mg, 250mg, 500mg and 1000mg strength Mood disorders including Parkinson's disease, schizophrenia, depression, seasonal affective disorder and dysthymia; including general anxiety disorder and panic disorder It is effective for diseases such as anxiety and other movement disorders. Generally, when administered to humans, an amount of 0.1 mg / B to about 1,000 mg / individual / B, preferably 1 mg / Z to about 100 mg / Z / day can be administered. . Example

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited thereto. Example 1

 7- (1-benzyl-3-hydroxypyrrolidine-3-yl) -1,3-benzoxazole-2 (3H) one

t e r t一プチノレ 3—フノレオロフェニノレカノレバメート

tert-Putinole 3-funoleolopheninolecanolebamate

 A tetrahydrofuran (50 mL) solution of m-funoleoloaniline (5 g, 45 mmo 1) and di-tert-ptinoresin-potionate (10.8 g, 49.5 mmo 1) was heated under reflux for 7 hours, and then allowed to cool. After distilling off tetrahydrofuran under reduced pressure, the residue is suspended in hexane and getyl ether, and the precipitate is collected by filtration and washed with hexane to give tert-butynole 3-funoleo mouth fu-norrecanatebamate (8 g) was obtained as a white solid.

 1-2) '7- (1-Benzyl_3-hydroxypyrrolidine-l-yl) 1-1,3-Benzoxazolyl / leh 2 (3H) -one

tert-Ptinole 3-fluorophenylcanolebamate (1.20 g, 5.71 mmo 1) in tetrahydrofuran (50 mL) was added to N, N, Ν,, N, 1-tetramethynoleethylenediamine. The reaction system was cooled with a dry ice-acetone bath, and tert-butyllithium (1.56 M heptane solution, 8.55 mL, 12.6 mmo) was added. 1) was slowly added dropwise. After slowly raising the temperature of the reaction system to 120 ° C and stirring for 1 hour, the reaction system was cooled again in a dry ice-acetone bath, and N-benzyl-13-pyrrolidone (1.00 g, 5.71 mmol 1 ) In tetrahydrofuran (10 mL) The mixture was heated to room temperature and stirred for 1 hour. Thereafter, 1 N hydrochloric acid (80 mL) was added, and the mixture was stirred at room temperature for 0.5 hour. After the completion of the reaction, the mixture was poured into a 10% aqueous potassium carbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography _{(S i 0 2; 1 20} g, black hole Holm Z methano Ichiru = 1 00/1, 80/1, 60/1,

40/1, 20/1), and purified by 7- (1_benzyl_3-hydroxypyrrolidine-1-3-yl) 1-1,3-1-benzoxazonore-2 (3H) -one (8 10 mg) as light brown morphus.

^{1 H-NMR (30 OMH z} CDC 1 3); 2. 20- 2. 3 2 (1 H, m), 2. 5 7- 2. 70 (21-1, m), 2. 8 5 (1 H, d), 3.04 (1 H, d), 3.19-3.25 (1 H, m), 3.75 (l H, d), 3.80 (1 H, d) , 6.94 (1 H, dd), 7.13 (1 H, t), 7.26-7.40 (6 H, m)

 Using the same method as in Example 1, the following compounds of Examples 2 and 3 were produced. Example 2

 7 1 (1-benzyl-3-hydroxypiperidine-1-3-1) 1, 3-Benzoxazo-1-2 (3H)-on

 I R (cm-1); 922, 1 1 1 7, 1 146, 1 298, 1450

Example 3

 7-(1-Benzylou 3-Hydroxazepane 1-3-Innole)-1, 3-Benzoki Sazol-2 (3H) 1 on

Example 4

実施例 1の化合物 （500 mg, 1. 61 mm o 1 ) のエタノール溶液 （ 10 mL) に 10 % パラジウム炭素 （50 %ウエット， 200 mg) 、 ぎ酸アンモニゥム （500 mg) を加え、 1時間加熱還流した。 反応終了後、 セライトを用いてろ過し、 溶媒を減圧留去した。 得られた残渣に 10 % 炭酸力 リウム水溶液、 クロ口ホルムを加え、 分液した。 有機層を無水硫酸ナトリウムで乾 燥し、 溶媒を減圧留去し、 7— （3—ヒドロキシピロリジン一 3—ィル） 一1， 3 一ベンズォキサゾーノレ一 2 (3H) —オン (86 mg) を白色ァモルファスとして 得た。 7 One (3-hydroxypyrrolidine-1-inole)-1, 3-benzoxazole-2 (3H) -one

10% palladium on carbon (50% wet, 200 mg) and ammonium formate (500 mg) were added to an ethanol solution (10 mL) of the compound of Example 1 (500 mg, 1.61 mmo 1), and the mixture was heated for 1 hour. Refluxed. After completion of the reaction, the mixture was filtered using Celite, and the solvent was distilled off under reduced pressure. A 10% aqueous solution of potassium carbonate and chloroform were added to the obtained residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 7- (3-Hydroxypyrrolidine-3-yl) 1-1,3-benzoxazonolone-2 (3H) -one (86 mg) as white amorphous.

 Using the same method as that in Example 4, the following compound of Example 5 was produced.

Example 5

 7- (3-Hydroxypiperidine-1-3-yl) 1,3,1-benzoxazo-l / le 2 (3H) 1-on; lH_NMR (300MHz DMS0-d6); 1.60 (1H, d), 1.77 (1H , d), 1.89-2.06 (1H, m), 2.15 (1H, ddd), 2.75 (1H, ddd), 2.94 (1H, d), 3.09 (1H, d), 3.21 (1H, d), 7.00 ( 1H, dd), 7.13 (1H, t), 7.24 (1H, dd)

Example 6

 7-(1 Benzinole 1, 5-dihydro 1 H-pyrrole 1-3 -yl) 1 3 Benzoxazono 1 2 (3H)-ON

A 48% aqueous solution of hydrobromic acid (6.0 mL) of the compound of Example 1 (300 mg, 0.967 mmo 1) was stirred at 90 ° C. for 1 hour. After completion of the reaction, the mixture was poured into a 10% aqueous carbonated lime solution and extracted with a black hole form. Organic layer is sulfuric anhydride It was dried over sodium and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Si ₂ ; 20 g, n-hexane / ethyl acetate = 3/1,

2/1, 1/1) to give 7- (1-benzyl-2,5-dihydro-1H-pyrrole-13-yl) -1,3-benzoxazole_2 (3H) -one (181 mg). Obtained as a monorefass.

_{'H-NMR (300MHz CDC1 3} ); 3.74-3.79 (2H, ra), 3.92-3.98 (4H, m), 6.60 - 6.62 (1H, m), 6.86 - 6.93 (2H, m), 7.07 (1H, t), 7.28- 7.43 (5H, m)

 Using the same method as in Example 6, the compound of Example 7 was prepared from the compound of Example 2 and the compound of Example 8 from the compound of Example 3.

Example 7

 7- (1-Penzinole 1,2,5,6-tetrahydropyridine_3-yl) —1,3-Benzoxazono 1 2 (3H) 1-one

 I R (cm-1); 947, 1041, 11 19, 1 149, 1446

Example 8

 7— (1-Benzyl-1,2,5,6,7—Tetrahydro-1H-azepine_3-inole) 1-1,3-Benzoxazonole-1 (31-I) —one

Example 9

 7-pyrrolidine-1-3 / re 1, 3-benzoxazono 1-2 (3H) 1-on

10% palladium on carbon (50% wet, 100 mg) and ammonium formate (388 mg) were added to an ethanol solution (10 mL) of the compound of Example 6 (180 mg, 0.616 mmo 1), and heated for 1 hour. Refluxed. After completion of the reaction, the mixture was filtered using Celite, and the solvent was distilled off under reduced pressure. To the obtained residue was added a 10% aqueous solution of carbon dioxide and chloroform, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The aqueous layer at the time of the above liquid separation is concentrated, and the obtained residue is concentrated. A mixed solvent of chloroform / methanol (20/1) was added, the solid was filtered off, and the solvent was distilled off under reduced pressure. Again, a mixed solvent of chloroform / methanol (20/1) was added to the obtained residue, the solid was filtered off, and the solvent was distilled off under reduced pressure to give 7-pyrrolidine-1-yl-1,3-benzo. Xazol-2 (3H) -one (crude 61 mg (including inorganic substances)) was obtained as a white solid.

 Using the same method as in Example 9, the compound of Example 10 was produced from the compound of Example 7 and the compound of Example 11 was produced from the compound of Example 8.

Example 10

 7—Pyridine-1-3-yl-1,3-benzoxazole-2 (3H) —on IR (cm-1); 908, 1036, 1153, 1269, 1440

Example 1 1

 7-azepanone 3-inoleic 1,3_benzoxazole-2 (3H) -one Example 1 2

 7-(1-benzylpiperidine-1-3-yl)-1, 3-1-benzoxazozol-1 / le 2 (3 H)-on

To a dimethyl sulfoxide (1.5 mL) of the compound of Example 10 (80 mg, 0.37 mmo 1) was added benzyl (46 L, 0.39 mmo 1) to benzyl sulfoxide (1.5 mL). The reaction was performed at 85 ° C for 3 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (form / methanol = 100/1, 80/1, 50/1, 30/1) to give 7- (1-benzylpiperidine-3-yl). One 1,3-benzoxazole-2 (3H) one (light yellow oil, 44 mg) was obtained.

IR (cm-1); 904, 1 028, 1 142, 1 27 1, 145 6 Using the same method as in Example 12, the following compounds of Examples 13 to 18 were produced from the compound of Example 10.

Example 13

 7— [1— (2,3-Dihydro-1,4-benzodioxane-1-2-ylmethinole) piperidine-1-3-inole] —1,3-Benzoxazole-2 (3H) —one

 I R (cm-1) 912, 1036, 1259, 1458, 1493 Example 14

 7-[1-(2-phenylethyl) pyridin-1-yl] —1, 3-benzoki sazonore 1 (3H) —on

 I R (cm-1); 901, 1095, 1275, 1444, 1462 Example 15

 1 1 {2-[3-(2-oxo 1, 2,3 zhi draw 1, 3-1 benzoxazonole-71 yl) pyridin 1 1 _ yl] etinole} pyrrolidine 1, 5 dione IR (cm-1); 919, 1 117, 1 1 32, 1327, 1402

Example 16

 1- {3- [3 -— (2-oxo_2,3-dihydro_1,3-benzoxazonole-1-7-yl) piperidine-1-1-yl] propyl} pyrrolidine-1 2,5 —Zeon IR

(cm-1); 916, 1 138, 1 176, 1296, 1400

Example 1

1-1- {4- [3- (2-oxo-1,2,3-dihydro_1,3--1-benzoxazonole-71-yl) pyridin-1-11-yl] puchinole} Pyrrolidine-1 2,5 —Zion IR (cm-1); 914, 1134, 1402, 1457, 1689 Example 18

 2— {4- [3 -— (2-oxo-1,2,3-dihydro_1,3-benzoxazonole-7-yl) piperidine_1-yl] butynole} Hexahi draw 11-1 —4,7—Methanoisoindole-1,3-dione

IR (cm-1); 910, 1138, .1396, 1456, 1691 Example 19 7- {1-1- [3- (2-Methoxyphenyl) propyl] piperidin-3-yl} 1,3-benzoxazole-2 (3H) -one

 19-1)

7- {1- [3- (2-Methoxyphenyl) propanoyl] piperidine-3-inole} _1,3-benzoxazole-2 (3H) -one

To a solution of the compound of Example 10 (100 mg, 0.458 mmo 1) in dimethylformamide (3.0 ml) was added WSC-HC1 (105 mg, 0.550 mmo 1) and 1-hydroxybenzoic acid. Triazonole (74 mg, 0.550 mmol) and 3- (2-methoxyphenyl) propionic acid (99 mg, 0.550 mmo 1) were added, and the mixture was reacted at room temperature for 17 hours. After the completion of the reaction, the mixture was diluted with a black hole form and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Si ₂ ; 5 g, black form methanol = 100/1, 80/1, 50/1) to give 71 {1-[3- (2-Methoxyphenyl) propanoyl] piperidin-3-yl} -1,3-benzoxazole-2 (31-I) one (92 mg) was obtained as an amorphous substance.

19-2)

 7— {1- [3- (2-Methoxyphenyl) propyl] piperidine-3-yl} -1-3, benzoxazole-2 (3H) one

7- {1- [3- (2-Methoxyphenyl) propanoinole] piperidin-1-yl} 1-1,3-1-benzoxazo-1- / re 2 (3H) -one (92 mg, 0.242 mm o To a solution of 1) in tetrahydrofuran (3.0 ml) was added a borane tetrahydrofuran complex (1M, 0.97 mL, 0.970 mmo 1), and the mixture was added at room temperature. Reacted for 6 hours. After the reaction was completed, excess methanol was added, and after bubbling subsided, the solvent was distilled off under reduced pressure. Methanol (3.0 mL) and 6N-hydrochloric acid (3.0 mL) were added to the residue, and the mixture was stirred at 80 ° C for 3 hours. After the completion of the reaction, the mixture was poured into a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography _{(S i 0 2; 5 g} , Kurorohonoremu Z Metanonore = 100/1, 80/1, 30/1, 10/1) to give 7- {1 one [3 — (2-Methoxyethoxy) propyl] piperidin-1-yl} -1, 3-benzoxazole-2 (3H) one (77 mg) was obtained as amorphus.

 I R (cm-1); 910, 1028, 1240, 1456, 1492 Using the same method as in Example 19, the compound of Example 10 was used to prepare the following Examples 20 to 5

Compound 3 was prepared.

Examples 20 to 53

Table 1 Example number n IR (cm-l)

20 1 cyclopropyl 889, 1034, 1277, 1452, 1612

 21 1 cyclopentyl 910, 1032, 1140, 1271, 1456

 22 1 tetrahydrofuran-2-yl 899, 1032, 1065, 1136, 1458

23 2 cyclopentyl 908, 1095, 1138, 1271, 1456

 24 2 cyclohexyl 887, 897, 1138, 1275, 1446

 25 2 2-fluorophenyl 903, 1111, 1228, 1454, 1491

26 2 3-fluorophenyl 904, 1095, 1138, 1444, 1462 27 2 4-fluorophenyl 904 1090, 1219, 1462, 1510

 9 2-chlorophenyl 912, 1051 1097, 1138, 1456

 Q 9 3_chlorophenyl 906 1093, 1138, 1275, 1460

 9 4-chlorophenyl 912 1014, 1092, 1456, 1491

 4-(trifluoromethyl) phenyl 914, 1066, 1111 1161, 1323

9 2-raethylphenyl 901 1092 1140, 1275, 1460

 9 3-methylphenyl 910 1038 1140, 1265, 1458

 Q 9 4-raethylphenyl 901, 1034, 1093, 1275 1462

 9 pyridin-3-yl 922 1068, 1138, 1196 1464

 0 pyridin-4-yl 918, 1124, 1174, 1416, 1460

 eye 丄 opeirtyl 908 1140, 1263 1296 1458

 O Q cyclohexyl 910 1036, 1140, 1261 1458

QQ Q 2-fluorophenyl 910 1138 1227, 1456, 1491

 o 3-f luorophenyl 914, 1138, 1178, 1203, 1456

 4_: r 丄 uorophenyl 910, 1138 1219, 1458, 1508

 49 2-chlorophenyl 904, 1051, 1136, 1273 1458

 ¾ 4-chlorophenyl 910, 1014, 1090, 1263 1460

44 3-raethoxyphenyl 912, 1038, 1149, 1259, 1454

 4-raethoxyphenyl 910, 1034, 1176, 1242, 1456

46 3 2, 5-dihydrofuran-2-yl 903 1028, 1070 1277 1456

47 thien-2-yl 912, 1099 1140, 1271, 1456

48 3 pyridin-2-yl 933 1065, 1140, 1267, 1458

49 3 pyridin-3-yl 930, 1126 1169, 1200 1458

50 3 pyridin-4-yl 916 933, 1124, 1170 1466

 51 3 4-aminophenyl 916 1045, 1140, 1265, 1458

52 4 phenyl 910, 1097 1140, 1273, 1454 Example 5 3 7— (1-Propylpyrrolidine-1-3- ^ f1) 1-13 Nsoxa Zol-1 (3H) 1 ON

Acetic acid (0.5 mL), propionanoledehydride (12 uL, 0.172 mm o 1), methanol in a methanol solution (5.0 mL) of the compound of Example 9 (32 mg of crude product), and cyano hydrogen Sodium boride (40 mg, 0.628 mmo 1) was added, and the mixture was stirred for 1 hour. After completion of the reaction, the mixture was poured into 10% aqueous potassium carbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Si ₂ ; 10 g, black form / methanol) = 100/1, 50/1, 30/1, 10/1, 5/1. 7- (11-Propinolepyrrolidine-1-yl) -1,3,1-benzoxazol-2 (3H) -one (7.1 mg) was obtained.

 IR (cm-1); 956, 1028, 1105, 1142, 1458 Using the same method as in Example 53, starting from the compound of Example 4 and starting with the compound of Examples 54 and 55, starting with the compound of Example 5 From the compounds of Examples 56 to 58, the compounds of Example 9 and the compounds of Example 59, the compounds of Examples 60 to 68 were prepared from the compounds of Example 10. Example 54

 7- (3-Hydroxy-1-propynolepyrrolidine-1-3-inole) 1-, 3-Benz-aged Xazozo 1-one 2 (3H) 1-one.

 I R (cm-1); 910, 1049, 1151, 1277, 1437 Example 55

 7— [3-Hydroxy-1- (3-phenylpropyl) pyrrolidine-1--3-yl] —1,3-benzoxazole-2 (3H) —one

^{1 H-NMR (30 OMH z} CDC 1 3);. 1. 96 (2 H, quint), 2. 23-2 34 (1 H, m), 2. 60- 2. 80 (6 H, m) , 2.99 (1 H, d), 3.33 (1 H, d), 3.43-3.52 ( 1H, m), 6.95 (1H, dd), 7.11—7.32 (6H, m), 7.44 (1H, dd)

Example 5 6

 7- (3-Hydroxy-1-methylbiperidine_3-yl) 1-1,3-Benzoxazole-2 (3H) one

^{1 H-NMR (3 0 0MH} z CDC 1 3); 1. 6 5- 1. 7 8 (2H, m), 2. 04 - 2. 2 1 (3 H, m), 2. 3 4 and 2 3 3 (tota 1 31-I, s), 2.72 (2 H, d), 2.85-2.92 (1 H, m), 5.39 (1 H, s) , 6.96 and 7.09 (tota 1 1H, dd), 7.16 and 7.23 (total 1H, t), 7.49 and 7.52 (total 1H, dd)

Example 5 7

 7- (3-Hydroxy-1-propinolepiperidine _3-inole)-1,3,1-Benzoxazoluru 2 (3H) -one

Example 5 8

 7— [3-Hydroxy-1- (3-phenolic pill) piperidine-1 3-yl] 1-1,3-Benzoxazole _2 (31-I) -one

Example 5 9

 7-[1— (3-Fue-norepropyl) pyrrolidine-1-inole] — 1, 3-benzoxazone 1 2 (3H) one

Example 6 0

 7- (1-butylpiperidine-1-3-yl) 1-1,3-1-benzoxazo-1 / leh 2 (3H) 1-on

^{1 H-NMR (3 0 OMH} z CDC 1 3); 0. 9 0 (3 H, t), 1. 5 0 - 2. 1 0 (7 H, m), 2. 2 5 (l H, t ), 2.32-2.40 (21-1, m), 2.97-3/08 (2H, m), 3.12-3.20 (1H, m), 6.90 (1 H, dd), 6.99 (1 H, dd), 7.09 (1 H, t)

Table 2 Example number m R ¹ IR (cm-l)

61 2 CH ₂ CH ₂ C¾ C 906, 1093, 1136, 1271, 1456

62 2 CH ₂ CH ₂ tBu 897, 1101, 1138, 1277, 1456

63 2 CH. CH ₂ CH ₂ Ph 910, 1101, 1140, 1271, 1452

64 2 CH ₂ cyclohexyl 912, 1140, 1269, 1294, 1448

65 2 CH ₂ CH ₂ CH ₂ (2-C0NHMePh) 912, 1142, 1269, 1302, 1458 66 2 CH ₂ C¾ CH ₂ (4-CONHMePh) 914, 1099, 1142, 1302, 1456 67 3 C¾CH ₂ CH ₃ 916 , 1120, 1180, 1200, 1460

68 3 CH ₂ CH ₂ CH ₂ Ph 917, 1132, 1200, 1458

(In the table, t Bu represents a t er t—ptinole group.)

Example 69

 7- (1-Methynole 1'2,5,6-tetrahydropyridine-13-yl) 3-benzoxazole-2 (3H) one

A 48% aqueous solution of hydrobromic acid (2 mL) of the compound of Example 56 (14 mg, 0.056 mmol) was stirred at 90 ° C. for 1 hour. After the completion of the reaction, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. I left. The obtained residue was purified by silica gel column chromatography (Si ₂ ; 15 g, chloroform / methanol = 100/1, 20/1, 10/1, 4/1) to give 7_ (1_methyl-1, 2,5,6-Tetrahydropyridin-3-yl) -1, 3-benzoxazole-2 (3H) -one (colorless oil, 6.5 mg) was obtained.

^{1 H-NMR (300MHz CDC 1} 3); 2. 40- 2. 50 (2H, m), 2. 50 (3H, s), 2. 67 (2H, t), 3. 38- 3. 4 3 (2H, m), 6.43-6.47 (1H, m), 6.90 (1H, dd), 7.01 (1H, dd), 7.08 (1H, t)

 Using the same method as in Example 69, the compound of Example 70 was produced from the compound of Example 57, and the compound of Example 71 was produced from the compound of Example 58.

Example 70

 7- (1-Propyl-1,2,5,6-tetrahydropyridine-13-yl) 1-1,3-Benzoxazole-2 (3H) -one

^{1 H-NMR (30 OMH z} CDC 1 3);. 0. 95 (3 H, t), 1. 59-1 71 (2H, m), 2. 42- 2. 49 (2 H, m), twenty five

1-2.57 (2H, m), 2.70 (2H, t), 3.45 (2Η, d), 6.41-6.46 (1H, m), 6.91 (1Η, dd) ), 7.02 (1 H, dd), 7.09 (1 H, t)

Example 71

 7- [1- (3-Phenylpropyl) -1,2,5,6-tetrahydropyridin-3-yl] -1, 3-benzoxazomono-one 2 (3H) one

1 H-NMR (300MHz CDC 1 3);... 1. 89-2 00 (2H, m), 2. 57-2 63 (2H, m), 265-2 71 (4H, m), 3. 43 (2H, d), 6.42-6.46 (1Η, m), 689 (

1 H, d d), 7.00 (1 H, d d), 7.07 (1 H, t), 7.14-7.30 (5H, m)

Example 72 7 1 (1-Methinolepiperidine-1 3-yl) 1 1, 3 1 Benzoxazonone 1 2 (3H

To a solution of the compound of Example 69 (5.5 mg, 0.024 mmol) in ethanol (5 mL) was added 10% palladium on carbon (50% wet, 50 mg) and ammonium formate (200 mg) for 1 hour Heated to reflux. After completion of the reaction, the mixture was filtered using celite, and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 7- (1-Methylbiperidin-1-inole) -1, 3-benzoxazo-inole-1 (3H) -one (amonorefase, 4. 2 mg) was obtained.

^{1 H-NMR (300MHz CDC 1} 3); 1. 60- 1. 68 (1 H, m), 1. 77- 1. 84 (2 H, m), 1. 92- 1. 98 (1 H, m), 2.03-2.12 (1H, m), 2.28 (1H, t), 2.35 (3H, s), 2.94-3.06 (2H, m), 3 18 (1 H, dddd), 6.92 (1 H, dd), 6.98 (1 H, dd), 7.09 (1 H, t)

 The compound of Example 73 was produced in the same manner as in Example 72.

Example 73

 7- (1-Methynolepyrrolidine-1-3-inole) 1-1,3-Benzoxazole-2 (3H) -one

Example 74

実施例 51の化合物 （50 mg, 0. 142 mm o 1 ) のピリジン溶液 （ 3 . 0 mL) に塩化ァセチル （12 u 1 , 0. 171 mm o 1 ) を加え、 室温にて 1時間撹拌した。 ついで、 塩化ァセチル （24 u 1 , 0. 342 mmo 1 ) を追加し、 室温にて更に 1時間撹拌した。 反応終了後、 クロ口ホルムに て希釈し、 飽和重曹水にて洗浄した。 有機層を硫酸ナトリウムで乾燥し、 溶媒を減 圧留去した。 得られた残渣をシリカゲルカラムクロマトグラフィー （S i〇₂ ； 15 g， クロ口ホルム/メタノ一ル= 100/1， 80/1, 50/1 ) にて精製し、 白色アモルファスを得た。 この生成物をメタノール (2. 0 mL) に溶解し、 2N 水酸化カリウム溶液 （1. 0 mL) を加え、 50°Cにて 4時間 撹拌した。 反応終了後、 クロ口ホルムにて希釈し、 水洗した。 有機層を硫酸ナトリ ゥムで乾燥し、 溶媒を減圧留去し、 N— (4— {3- [3- (2—ォキソ一 2， 3 —ジヒドロ一 1， 3—ベンズォキサゾールー 7—ィル） ピペリジン— 1一ィル] プ 口ピル } フエニル) ァセトアミド (25 mg) を白色アモルファスとして得た。 I R (c m— 1) ; 916, 1099, 1 142, 1267, 131 5 実施例 74と同様の方法を用いて、 実施例 9の化合物から実施例 75の化合物、 実 施例 51の化合物から実施例 76の化合物を製造した。 N- (4- {3- [3- [2-oxo-1,2,3-dihydro-1,1,3-benzoxazol-17-yl) piperidine-11-yl] propyl} feninole) Acetamide

Acetyl chloride (12 u 1, 0.171 mm o 1) was added to a pyridine solution (3.0 mL) of the compound of Example 51 (50 mg, 0.142 mm o 1), and the mixture was stirred at room temperature for 1 hour. . Then, acetyl chloride (24 u 1, 0.342 mmo 1) was added, and the mixture was further stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Si ₂ ; 15 g, chloroform / methanol = 100/1, 80/1, 50/1) to obtain a white amorphous substance. This product was dissolved in methanol (2.0 mL), 2N potassium hydroxide solution (1.0 mL) was added, and the mixture was stirred at 50 ° C for 4 hours. After the completion of the reaction, the reaction mixture was diluted with a black hole form and washed with water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give N- (4- (3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7). —Yl) piperidine—11-yl] pyruvyl} phenyl) acetoamide (25 mg) was obtained as a white amorphous. IR (cm—1); 916, 1099, 1 142, 1267, 131 5 Using the same method as in Example 74, the compound of Example 9 to the compound of Example 75, and the compound of Example 51 to the compound of Example 51 76 compounds were prepared.

Example 75

Methinole 3- (2-oxo_2,3-dihydro-1,3-benzoxazole-7-yl) pyrrolidine-1-carboxylate

Example 76

Methyl 4- {3- [3- [2-oxo-1,2,3-dihydro-1,3-benzoxosazol-71-yl] piperidine-11-]] propyl} phenylcarbamate IR (cm-1) 912 , 1066, 1228, 1315, 1458 Example 77 7-[1-(3-piperidine-2-ylpropyl) piperidine-3-inole] 1 1 3-benzoxazole-2 (3H) 1-one

 77-1)

t e rt—Puchinore 2--(3- {[(4-methinorefenyl) snorefoninole] oxy} propyl) piperidine— 1-stroke lipoxylate

Under nitrogen atmosphere, 2-pyridinepropanol (3 g, 21.87 mmo 1) was dissolved in acetic acid (9 mL) at room temperature, platinum oxide (containing 33% water, 391 mg) was added, and hydrogenation was performed using an autoclave. (100 kg / cm ² ). After filtration through celite, the solvent was concentrated under reduced pressure to obtain 3-piperidine- ¹² -ylpropane-111-acetic acid salt (brown oil, 8.04 g).

Under a nitrogen atmosphere, dissolve 3-piperidine-1-ylpropane-1-orthoacetate (4.45 g, 21.87 mmo 1) in methanol (12 mL), cool on ice, and add 2 N hydroxide. An aqueous solution of sodium (55 mL) was added (pH> 10). Di-t-butyl dicarbonate (4.77 g, 21.87 mmo 1) was added, and after stirring at room temperature for 6.5 hours, the reaction solution was poured into water and extracted with getyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by elution with silica gel chromatography (ethyl acetate: hexane = 1: 1) to give tert-butyl 2- (3-hydroxypropyl) piberidine-1-carboxylate (colorless oil, 4%). 18 g) were obtained.

Under a nitrogen atmosphere, tert-butyl 2- (3-hydroxypropyl) piperidine-one-pot olepoxylate (2 g, 8.22 mmo 1) was dissolved in dichloromethane (20 mL) at room temperature, and triethylamine (2. 3 m 1, 1.66 g,

16.4 mmo 1), ρ _ _ Tosleens norehoninole chloride (1.57 g, 8.22 mmo 1) were added, and a small amount of dimethylaminopyridine was added under ice cooling, and the mixture was left at room temperature for 1 hour. After stirring, the mixture was left overnight. The reaction solution was added to water, extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained pale yellow oil was purified by elution with silica gel gel chromatography (ethyl acetate / hexane-1: 4) to obtain tert-butyl 2- (3-{[ (4-Meth / refeninole) snorefoninole] propyl) piperidine-one-strength lipoxylate (colorless oil, 2.74 g) was obtained.

 7 7- 2)

 tert-Ptinole 2- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl] propyl} piperidine-1 (1) One strength olepoxylate

The compound of Example 10 (200 mg, 0.92 mmo 1) was dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under a nitrogen atmosphere, and the solution was dissolved in tert-butyl 2- (

3-{[(4-Methylphenyl) sulfonyl] propyl} propyl) piperidine

(1) One-strength noreboxylate (3 64 mg, 0.92 mmo 1) was added, and the mixture was stirred at 70 to 80 ° C for 9 hours. The reaction solution was added to saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure, and the obtained residual oil was purified by elution with silica gel column chromatography (methanol Z chlorophonolem = 2: 98 → 3: 97) to give tert-butyl 2- {3- [ 3- (2-oxo2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1 1-yl] propyl} piperidine-1 1-stroke lipoxylate (light yellow powder, 200 mg).

 77-3)

 7- [1- (3-Piperidin-2-ylpropyl) piperidin-3-yl] 1-1,3_Benzoxazole-2 (3H) —one 2Trifluoroacetate

At room temperature under nitrogen atmosphere, tert-butyl 2- (3- [3- (2-oxo-2,3-dihydro-1,3-benzoxazole 7 _yl) pyridin-1 1-yl] propinole } Piperidine-1-1-potassoleboxylate (180 mg, 0.41 mmo 1) was dissolved in trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours. Decompress the solvent When concentrated, 7- [1— (3-piperidine_2-ylpropyl) piperidin-3-yl] ―1,3-benzoxazole-2 (3H) -one 2trifluoroacetate (yellow oil 280 mg).

 I R (cm-1); 922, 1032, 1128, 1174, 1460 The compound of Example 78 was produced in the same manner as in Example 77.

Example 78

 7- [1- (3-Piperidin-1--4-inolepropyl) piperidin-3-yl] —1,3-Benxoxazol-2 (3H) —one 2 Trifluoroacetate

 I R (cm-1); 923, 1063, 1134, 1174, 1464 Example 79

 7-[1-(2-piperidine 1 4 _ inolechitinole) piperidine 1 3-isle] — 1, 3 1 benzoxaxanolone 2 (3H) — on

 79-1)

 tert-Butyl 4- {2-oxo-1 2-[3- (2-oxo-1,2-dihydro-1,3-benzoxazo-1 / le7-yl) piperidine-1-11] ethyl} piperidine — 1-strength noreboxylate

The compound of Example 10 (400 mg, 1.8 mmo 1) and 1- (tert-butoxycarbol) piperidin-4-yl] acetic acid (445 mg, 1.83 mmo 1) and 1- To a solution of hydroxybenzotriazonole (247 mg, 1.8 mmo 1) in dimethylformamide (10 mL) at room temperature was added WSC hydrochloride (351 mg, 1.8 mmo 1), and the reaction mixture was allowed to stand at room temperature. Stirred for 22 hours. The mixture was diluted with ethyl acetate Z toluene (1: 1, 100 mL), washed with water, saturated aqueous sodium hydrogen carbonate, and saturated saline in that order, and concentrated. The concentrated residue is purified by silica gel column chromatography. Tert-Butyl 4- {2-oxo-1-2- [3- (2-oxo_2,3-dihydro-1,3-benzoxazole-17-yl)] Lysine-11-yl] piperidine-1-carboxylate (colorless foamy solid, 700 mg) was obtained.

79- 2)

 7- [1-(Piperidin-1-ylacetyl) piperidin-3-yl] 1-1,3-Benzoxazole_2 (3H) -one hydrochloride

 tert-butyl 4- {2-oxo_2— [3- (2-oxo-1,2,3-dihydro 1,3-benzoxazono 1-7-inole) piperidine 1-11] ethyl} pi To a solution of peridine- 1-canolepoxylate (700 mg, 1.6 mmo 1) in 1,4-dioxane (5 mL) and methanol (5 mL) at room temperature was added a 4N-dioxane hydrochloride solution (5 mL). ) Was added and the reaction mixture was stirred at room temperature for 1 hour. After distilling off the solvent, toluene was added to the concentrated residue and the mixture was evaporated under reduced pressure to give 7- [1- (piperidine-1-4-ylacetyl) piperidin-3-yl] -1,3-benzoxazono 1-2 ( 3 H) -on (crude, 600 mg) was obtained.

 79-3)

 7-1- [1-(2-Piperidine _ 4 ^^ rutyl) piperidin-3-yl] —1, 3 —Benzoxazole-2 (3H) —one dihydrochloride

7— [1— (Piperidin-4-ylacetyl) piperidin-3-yl] 1-1,3-1 Benzoxazole-2 (3H) 1-one was suspended in tetrahydrofuran (5 mL) without purification. Then, a borane tetrahydrofuran complex (1.0 M, 7.9 mL, 7.9 mmol) was added at room temperature, and the reaction mixture was heated to reflux for 7.5 hours. After cooling, methanol (5 mL) was added little by little, and when the foaming stopped, the solvent was distilled off. To the concentrated residue was added 6N-hydrochloric acid (5 mL) and methanol (5 mL), and the mixture was heated under reflux for 6.5 hours and allowed to cool. The solvent is distilled off and azeotroped with toluene to give 7- [1-1 (2-piperidine-14-ylethyl) piperidine-13-yl] -1, 3-benzoxazole-2 (3H) one Dihydrochloride (white foamy solid, 514 mg) was obtained. IR (cm-1); 916, 038, 1 140, 267, 1458 Example 80

 7-[1-(3-Pyridine-1-3-ylpropyl) piperidine-1 _yl]

3-Benzoxazole-2 (3H)-ON

 80-1)

 tert-Puchinore 3— {3- [3 -— (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1 7-inore) Piperidine-1 1 //] propinole} Piperidine-1 1 One strength noreboxylate

Acetic acid (1.0 mL) in a methanol solution (5.0 mL) of the compound of Example 10 (369 mg, 1.69 mmo 1), tert-butyl 3- (3-oxop pill) To the mixture were added 1-potassolevoxylate (490 mg, 2.03 mmo 1) and sodium cyanoborohydride (531 mg, 8.45 mmo 1), and the mixture was stirred at room temperature for 0.5 hour. After the completion of the reaction, the mixture was poured into a 10% aqueous potassium carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography _{(S i 0 2; 30 g} , black hole Holm methano Ichiru = 100/1, 80/1, 50 / \, 30/1, 15/1) to give tert-butyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-7-inole) piperidine-1-11] propyl} piperidine-1 1 One carboxylate (587 mg) was obtained as amorphus.

80-2)

 7- [1- (3-Piperidine_3-ylpropyl) piperidine-1-3-yl] 1-1,3-Benzoxazole-2 (3H) oneone dihydrochloride

tert-butyl 3— {3— [3— (2 oxo-1,2,3-dihydro-1,3- Benzoxazono 1-yl) piperidine 1-yl] propyl} piperidine 1-potassoleboxylate (58 3 mg, 1.32 mmo 1) in methanolic solution (4 (0.0 mL) was added IN dimethyl hydrochloride (4.0 mL), and the mixture was reacted at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and Ί- [1- (3-piperidine_3-inolepropyl) piperidin-1-3-yl] _1,3-benzoxazole-2 (3H) -1 On dihydrochloride (495 nig) was obtained as amorphous.

 IR (c m-1); 9 18, 1 13 0, 1 17 3, 1 4 6 0, 16 6 8 In the same manner as in Example 80, the following Examples 8 1 and 8 2 The compound was prepared.

Example 8 1

 7-[1-(piperidin-2-ylmethyl) piperidin-3-yl] — 1, 3—benzoxazo-1 / leh 2 (3H) one-on

 I R (cm-1); 9 14, 10 8 2, 11 9, 12 5 4, 4 5 6 Example 8 2

 7-[1-(piperidine-1-irmethinole) piperidin-1-3-inore]-3

 I R (cm-1); 9 18, 1 13 8, 1 2 6 7, 1 2 9 2, 450 Example 8 3

 7- {1-[2--(1-acetylbiperidine 1-41 / f) ethyl] piperidine-1-3}} 1, 1, 3-Benzoxazono 1-2 (3H)-ON

Example 7 To a solution of the compound of 9 (50 mg, 0.12 mmo 1) in 1 N sodium hydroxide (1 mL) and 1,4-dioxane (1 mL) was added acetic anhydride (1 mL) at room temperature. Add 0.19 mmo 1) and stir the reaction mixture at room temperature for 1.5 hours. Stirred. Subsequently, acetic anhydride (10 / iL, 0.1 mmo 1) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, ethyl acetate and water were added to separate the layers, and the aqueous layer was extracted again with ethyl acetate. The whole organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the concentrated residue was purified by silica gel column chromatography (clonal honolem: methanol = 100: 1 → 10: 1) to obtain 7- { 1- [2- (1-Acetylbiberidine-1 4-ethyl) ethyl] piperidine-3-inole} -1,3-benzoxazonolone 2 (3H) one (brown oil, 15 mg ).

 I R (cm-1); 910, 972, 1138, 1269, 1456 The following compounds of Examples 84 to 94 were produced in the same manner as in Example 83.

Examples 84 to 94

Table 3 Example number n IR (cm-l)

84 1 COMe 912, 1099, 1138, 1265, 1456

85 1 C0 ₂ Me 916, 1049, 1138, 1261, 1448

 86 3 COMe 908, 1034, 1136, 1265, 1456

 87 3 CO.Me 910, 1092, 1138, 1265, 1452

表 4 実施例番号 n R IR(cm-l)

Table 4 Example number n R IR (cm-l)

88 COMe 910, 1032, 1138, 1263, 1456

89 C0 ₂ Me 912, 1134, 1240, 1259, 1454 Example 90

 7- {1-[3- (1-Acetylbiperidine-1-3-yl) propyl] piperidine-1-3-yl} -1, 3-Benzoxazonole _2 (31-I) one

^{1 H-NMR (300MHz CDC 1} 3);. 1. 10-2 06 (14H, m), 2. 08 (3 H, s), 2. 18- 2. 30 (2H, m), 2.

32-2.4.42 (2H, b rm), 2.58-2.76 (1 I-I, m), 2

93—3.06 (2 H, b rm), 3.09—3.19 (1H, b rm), 3.65-3.75 (1 H, m), 4.42 (1 H, brt) ), 6.

90-6.94 (1 H, m), 6.98 (1 H, d), 7.08 (1 H, d d d)

Example 91

Methynole 3- {3- [3_ (2-oxo-1,2,3-dihydro-1,3-benzoxazole-17-yl) piperidine-1-yl] propyl} piperidine-11-carboxylate

^{1 H-NMR (300MHz CDC 1} 3); 1. 35- 1. 90 (7H, m), 1. 90- 2. 06 (2H, b rm), 2. 21 (1 H, t), 2. 30-2.48 (3H, brm), 2.75 (1H, ddd), 2.92-2-3.06 (2H, brm), 3.10-3.20 (11-1, b rm),

表 5 実施例番号 n IR(cra-l) 3.67 (3H, s), 3.90—4.08 (2 H, b rm), 6.90 (1 H, dd), 7.00 (1 H, dd), 7.09 (1 H , T)

Table 5 Example number n IR (cra-l)

92 2 C0 ₂ Me 912, 1093, 1248, 1275, 1448

 93 3 COMe 839, 1126, 1176, 1203, 1437

_{94 3 C0 2 Me 926, 1051} , 1146, 1323, 1458 Example 95

 7 1 {1 1 [3- (1-Methylbiperidin-1-yl) propyl] piperidin-1 3 —yl} — 1,3 Benzoxazole-2 (3H) 1-one

To a solution of the compound of Example 78 (44 mg, 0.08 mmo 1) in methanol (2.4 mL), acetic acid (0.6 mL), 36% formaldehyde solution (20 mg), sodium cyanoborohydride (19 mg, 0.3 mmo 1) was added and the mixture was stirred at room temperature. A 10% aqueous potassium carbonate solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, the solvent is distilled off, and the concentrated residue is purified by silica gel column chromatography (form: methanol: triethylamine = 95: 5: 2). 7 _ {1- [3- (1-Methylpiperidin-1-yl) propyl] piperidin-3-yl} —1,3-Benzoxazole-2 (3H) one (colorless oil, 27 mg). IR (cm-1); 908, 1095, 1140, 1275, 1456 Example 96

 7- {1-[3- (1-Glycoylbiperidin-1-yl) propyl] piberidin-3-yl} 3-benzoxazo-l-u 2 (3H) -on

Triethylamine (0.10 mL, 0.72 mL) was added to a solution of the compound of Example 80 (100 mg, 0.240 mmo 1) in dimethinolevenolemamide (3.0 m 1).

0 mmo 1), WSC- HC 1 (55 mg, 0. 288 mmo 1), 1- hydroxycarboxylic benzotriazole § zone Honoré _{(39 m g, 0. 288 mmo} 1), glycol acid (20 mg, 0 .264 mmo 1) was added, and the mixture was reacted at room temperature for 17 hours. After the completion of the reaction, the reaction mixture was diluted with chloroform and washed with a 10% aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue by silica genome Les column chromatography _{(S i 0 2; 10 g} , black hole Hol arm / methanol = 50/1, 30/1, 1 5/1, 10/1) to give 7 -{1- [3- (1-Glycoylbiperidin-1-yl) propyl] piberidin-1-3-yl}-1,3-Benzoxazole-2 (3H) one (76 mg ) Was obtained as amorphous. '

 1 R (cm-1); 908, 1047, 1082, 1259, 1458 The compound of Example 97 was produced in the same manner as in Example 96. .

Example 97

 7 1 (1-1 (3-[1-(Methoxyacetyl) piperidine 1-3-inole] propyl) piperidine-1-3-yl) 1 1, 3-1-Benzoxazono 1-2 (3H) 1 -one

 I R (cm-1); 906, 1034, 1 115, 1259, 1458 Example 98

(+)-7-Pyridin-3-yl-1,3-benzoxazole-2 (3H) -one is shown in the table below. It will be described. Furthermore, compounds prepared from (+)-7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one should be indicated by adding * to the asymmetric carbon. And

A solution of 7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one (15.0 g, 68.5 mmol) in isopropyl alcohol (300 m) and (2S) _ A solution of (acetylamino) (phenyl) acetate acid (13.2 g, 68.5 mmol) in isopropyl alcohol (800 mL) was mixed, and allowed to stand at room temperature for 16 hours. The precipitate was collected by filtration. Isopropyl alcohol (750 mL) was added to the obtained precipitate (10.1 g), and the mixture was heated under reflux for 30 minutes, gradually cooled to room temperature, and allowed to stand for 7 hours. Then, the precipitate was collected by filtration, isopropyl alcohol (200 mL) was added to the obtained precipitate (8.57 g), and the mixture was heated under reflux for 1 hour, gradually cooled to room temperature, and allowed to stand for 4 hours. . The precipitate was collected by filtration, and a 10% aqueous potassium carbonate solution (100 mL) was added to the obtained precipitate (8.25 g), and the mixture was further subjected to salting out and extracted with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and (+)-7-piperidin-3-yl-1,3-benzoxazole-2 (3H) -one (5.07 g, 99 % ee).

[a] ²⁵ _D + 14 ° (c = 1.0, methanol)

Retention time 26.5 minutes The compound of Example 99 was produced in the same manner as in Example 98.

Example 9 9

保持時間 28. 5分 (-)-7-Piperidin-3-yl-1,3-benzoxazole-2 (3H) -one is shown as below. Furthermore, compounds prepared from (-)-7-piperidin-3-yl-1,3-benzoxazolyl-2 (3H) -one should be indicated by adding ** to the asymmetric carbon. And

Retention time 28.5 minutes

Example 98 Liquid chromatography in which the retention time is described in Example 98 and Example 99 The conditions for carrying out one analysis are as follows.

LC measurement conditions

Column: SUMICHIRAL OA-4000 (5 um, 4.6 mm ■ ■ X 25 cm)

Flow rate: 1.0 inL / min

Measurement wavelength: 254 nm

Mobile phase: n-hexane: isopropanol: methanol: trifluoroacetic acid = 80: 15: 5: 0.1

Example 1 100

 1 0 0-1)

1.15 M in a solution of (3S) -5_oxo-[(IS)-1-phen-norethyl] pyrrolidine-3-carboxylic acid (4.90 g, 0.021 mmol) in tetrahydrofuran (250 mL) Of a borane-tetrahydrofuran complex in tetrahydrofuran (3 mL, 0.063 mol) was added, and the mixture was stirred under reflux for 4 hours. After the completion of the reaction, excess methanol was slowly added, and the solvent was distilled off under reduced pressure. Methanol (40 mL) and 6N aqueous hydrochloric acid (10 mL) were added to the residue, and the mixture was heated under reflux for 1 hour. Pour the reaction mixture into a 20% aqueous potassium carbonate solution, and use Extracted. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain {(3S) -1 _ [(1S) -1-phenylethyl] pyrrolidine-3-ylmethanol (4.31 g, quant.).

1 00-2)

 Η

 {(3S) -1-[(IS) -1-phenylethyl] pyrrolidine-3-yl} 10% palladium on carbon (50% wet, 3.8 mL) in methanol (3.8 mL, 18.5 mmol) in methanol (50 mL). After g) was added, the mixture was stirred at room temperature under a hydrogen atmosphere for 4.5 hours. After the reaction solution was filtered using celite, the filtrate was concentrated to obtain (3S) -pyrrolidine-3-ylmethanol (L85 g, y. 98%).

00-3)

 -OH

, N

 CO ヮ Me

To a solution of (3S) _pyrrolidine-3-ylmethanol (1.84 g, 18.2 mmol) in 1,4-dioxane (30 mL) was added a 2N aqueous solution of sodium hydroxide (50 m), and the mixture was heated at 0 ° C. Methyl formate (7.65 g, 81 mmol) was added dropwise over 20 minutes, and the mixture was stirred at the same temperature for 6 hours. After the completion of the reaction, the reaction solution was poured into a saturated saline solution, and extracted with a black hole form. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, methyl C3S) - ³ - to give 1-carboxylate (2.47 g, y 85%) - ( hydroxymethyl) pyromellitic lysine..

1 00-4)

C0 ₂ Me

Triethylamine (4.1 raL, 30 mmol) was added to a methylene chloride solution (70 mL) of methyl (3S) -3- (hydroxymethinole) pyrrolidine-1-carboxylate (1.7 g, 10.7 mmol), and chloride was added under ice cooling. Add P-toluenesulfonyl (3.8 g, 20 mmol) and stir at room temperature for 2 hours did. Triethylamine (4.0 m, 29 ramol) and p-toluenesulfonyl chloride (3.8 g, 2 O mmol) were added, and the mixture was further stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was poured into a saturated saline solution and extracted with a black hole form. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel gel chromatography (n-hexane / ethyl acetate = 5/1, 1/1) to give methyl (3S) -3 _ ({[(4-methylphenyl Ninole) sulfoninole] oxy} methyl) pyrrolidine-1-carboxylate (3.3 g, y. 98%) was obtained.

 1 00-5)

Methyl (3S) -3 _ ({[(4-methylphenyl) sulfonyl] oxy} methyl) pyrrolidine-1-carboxylate (1.29 g, 4.13 mmol), (+) _ 7-piperidin-3-yl-1,3- A dimethylsulfide solution (11 mL) of benzsaixazonole-2 (3H) -one (0.89 g, 4.13 mmol) was stirred at 80 ° C for 18 hours. The reaction solution was added to a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate / le. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel gel column chromatography (cloth form / methanol) = 50/1. The purified product obtained was dissolved in ethyl acetate (50 mL) and washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (436 mg, y. 30%). Retention time: 16.9 min. ~ 103 compounds were prepared.

保持時間： 14. 1分 Example 10 1

Retention time: 14.1 minutes

Example 102

Retention time: 14.4 minutes

Example 103

Retention time: 15.0 minutes

Example 104

04

t-Butyl (2S) -2- (2-hydroxyxetyl) piperium oleboxylate (3.00 g, 13 mmol) and triethynoleamine (5.5 itiL, 39 ramo hydroxide solution (35 m L) was added sulfur trioxide pyridine complex (6.25 g, 39 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour and poured into water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue is purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to obtain t_butyl (2S) -2- (2-oxoethyl). Piperidine-1-carboxylate (colorless oil, 2.47 g, 82%) was obtained.

 1 0 4-2)

 (+) _7-piperidin-3-yl-1,3-benzoxazole-2 (3H) -one (500 mg, 2.3 mmol), t-ptinole (2S) -2- (2-oxoethyl ) Pyridine-1-carboxylate (518 mg, 2.3 mmol) and acetic acid (1 mL) in methanol (5 mL) at room temperature in sodium cyanoborohydride (170 mg, 2.7 mmol) Was added and the reaction mixture was stirred at room temperature for 3.5 hours. Methanol was distilled off under reduced pressure, and the concentrated residue was added with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 30: 1) (brown oil, 597 mg). , 61%).

 1 0 4-3)

To a methanol solution (5 mL) of (590 mg, 1.4 mmol) was added 10% hydrochloric acid-methanol (10 mL) at room temperature, and the reaction mixture was stirred for 1.5 hours. A methanol (10 mL) solution was added, and the mixture was further stirred for 2.5 hours. The solvent is distilled off under reduced pressure, and the concentrated residue is The mixture was neutralized with an aqueous solution of sodium chloride, extracted with a 10% methanol form, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 10-3 (458 mg). This was used for the next step 10-4) without purification.

1 04-4)

 10-3 (458 mg) and triethylamine (375 μL, 2.7 mraol) in dichloromethane (10 mL) were added under ice-cooling to methyl chloroformate (100 μΐ ^, 1.3 mmol) in dichloromethane (3 mL). mL) was added dropwise over 5 minutes, and the reaction mixture was stirred for 40 minutes. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction system, extracted with chloroform, washed successively with water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the concentrated residue was purified by silica gel gel chromatography (Chrome form: methanol = 30: 1 → 10: 1) (light brown foamy solid, 187 mg, 35%). I got

Retention time: 9.3 minutes

The compounds of Examples 105 to 107 were produced in the same manner as in Example 104.

Example 10 5

Retention time: 8.7 minutes

Example 1 06

保持時間： 8 5分

Retention time: 85 minutes

Example 107

Retention time: 83 minutes

Example 108

Dissolve (3S) -5-oxo-[(IS) -1-phenylethyl) pyrrolidine-3-carboxylacid (5.0 g, 0.021 mmol) in tetrahydrofuran ί 1.15 M borane tetrahydrofuran complex in night (450 mL) A solution (25 mL, 0.029 mol) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, excess water was slowly added, and then saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. Purified by chromatography (chloroform / methanol = 100/1, 80/1, 60/1, 30/1, 20/1), and (4S) -4- (hydroxymethyl)-1-[(IS )-1-Phenylethyl] pyrrolidine-2-one

(4.26 g, y. 91%) was obtained.

 1 08- 2)

 Triethylamine (1.79 mL) was added to a methylene chloride solution (10 mL) of (4S) -4- (hydroxymethinole) -1-[(IS) -1-phenylethyl] pyrrolidin-2-one (937 mg, 4.27 mmol). , 12.8 mmo 1), p-toluenesulfol chloride (L 22 g, 6.41 ranol) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with chloroform and washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel gel chromatography (toluene / ethyl acetate = 2/1, 1/1) to give {(3S) -5-oxo-1-[(IS phenylethyl) pyrrolidine-3. -Yl} methyl 4-methylbenzenesulfonate (1.41 g, y. 89%) was obtained.

 1 08-3)

Dimethyl malonate (13.7 g, 103 mol) was added dropwise to a suspension of sodium hydride (2.47 g, 103 mmol) in dimethylformamide (150 mL) over 10 minutes under ice-cooling, and then the temperature was raised to room temperature. Heated and agitated for 1 hour. To the reaction mixture was added tetrabutylammonium iodide (8.8 g, 23.9 mmol), {(3S) -5-oxo-1-[(1S) _1_phenylethyl] pyrrolidine-3-yl} methyl 4- After a solution (80 raL) of methinolebenzenesnorefonate (29.8 g, 79.8 mmol) in dimethinolehonoremamide was added, the mixture was stirred at 80 ° C for 2 hours. After cooling, the reaction mixture is The mixture was poured into hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (toluene: ethyl acetate = 5: 1 to 1: 1).

2: Purify in 1). Dimethyl ({(3S) _5-oxo-1 _ [(1S) _1-phenylethyl] pyrrolidin-3-yl} methyl) malonate (13.2 g, y. 64%) was obtained.

 108-4)

A solution of dimethyl ({(3S) -5-oxo-1-[(IS) -1-phenyl / reethynole] pipalysin-3-yl} methyl) malonate (18.2 g, 55 ramol) in dimethyl sulfoxide (100 Water (25 mL sodium chloride (3.2 g, 55 mmol)) was added to the mixture, and the mixture was heated under reflux for 28 hours.After standing to cool, the reaction mixture was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give crude methyl 3 _ {(3S) -5-oxo-1 _ [(1S) -1 -Finnylethyl] pyrrolidine-3-inole} propanate (13.7 g) was obtained.

108-5)

Methyl 3-{(3S) -5-oxo-1-[(1S) -1-phenylethyl] pipalysin-3-yl} propanate (8.6 g) in methanol (60 mL) An aqueous solution (45 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, 1N aqueous hydrochloric acid was added to the reaction mixture to make the pH of the system weakly acidic, and the solvent was distilled off under reduced pressure. 1N aqueous hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure to obtain 3 _ {(3S) -5-oxo-1-[(IS) -1-phenylethyl] pyrrolidine-3-inole} propanoitic acid (8.1 g, quant.). Was.

 108-6)

 OH

 1.1B1 porane was added to a solution of 3-{(3S) -5-oxo_1 _ [(1S) _1-phenylethyl) pyrrolidine-3-yl} propanoitic acid (8.1 g, 31 ramol) in tetrahydrofuran (100 mL).

-Add tetrahydrofuran solution of tetrahydrofuran complex (δΐ mL, 93 mmol) and add ³ .

The mixture was refluxed for 5 hours. After cooling, slowly add methanol to the reaction system and stir for 1 hour.

The solvent was distilled off under reduced pressure. Methanol (50 mL) and 4N aqueous hydrochloric acid (20 mL) were added to the obtained residue, and the mixture was heated under reflux for 30 minutes. The reaction solution was concentrated, and the residue was added to a mixture of 2N aqueous sodium hydroxide solution (15 ml) and sodium chloride added thereto, followed by extraction with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 3-{(3S) -l-[(1S) _1-phenylethyl] pyrrolidine-3-ynole} propan-1-ol (7.25 g, quant.).

 108-7)

10 in a methanol solution (100 ml) of 3 _ {(3S) -1-[(1S) _1-phenylethyl] pyrrolidine-3-yl} pulppan-1-ol (6.1 g, 26.1 mmol). /. -Palladium carbon (50% wet, 6.1 g) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. Further, 10% _palladium carbon (50% wet, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. After completion of the reaction, the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure, 3 _ [(3S) - pyrrolidin - ³ - I le] propane - to give 1- ol ^{(3 4 g, quant..} ) The Was.

108-8)

 To a solution of 3-[(3S) -pyrrolidine-3-yl] propane-1_ol (3.39 g, 26.2 mmol) in 1,4-dioxane (33 mL) was added aqueous solution of 2N-titanium thiocyanate (33 mL). added. Methyl chloroformate (7.53 g, 79.7 mmol) was added to the reaction mixture at 0 ° C, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with chloroform. The obtained organic layer was washed successively with a saturated aqueous solution of ammonium chloride and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and methyl (3S) -3- (3-hydroxypropyl) pipa-lysine-1-canolepoxylate (3.6 g, y. 74%) I got

108-9)

Methyl (3S) -3- (3-hydroxypropyl) pyrrolidine-1-carboxylate (1.80 g, 10.4 mmol) in dimethyl sulfoxide solution (30 mL) was added to triethylamine (4.3 mL, 31.2 mmol), sulfur trioxide pyridine complex ( 4.96 g, 31.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction system was poured into water and extracted with ethyl acetate. The organic layer was washed with a 5% aqueous hydrogen sulfate aqueous solution and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1, 1/2) to give methyl (3S) -3- (3-oxoprop) pyrrolidine-1-carboxy. Rate (1.13 g, y. 63%) was obtained.

108- 10)

(+)-7-Piperidine-3-inole-1,3-benzoxazol-2 (3H) -one (1.30 g, 5.95 mmo 1) In a methanol solution (30 mL) of methyl (3S) -3- (3-oxopropyl) pyrrolidine-1-carboxylate (1.10 mg, 5.95 mraol), acetic acid (3 mL), sodium cyanoborohydride (630 rag, 10 mol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was added to a saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 30/1 to 10/1) to obtain Compound 100 (1.69 g, y. 73%). .

Retention time: 21.3 minutes

The compounds of Examples 109 to 111 were produced in the same manner as in Example 108.

Example 109

Retention time: 180 minutes

Example 110

Retention time 5.3 minutes

Liquid Chromatography with Retention Times Described from Examples 100 to 11 Are as follows.

LC measurement conditions

Column: CHIRALCE 0D-H (5 urn, 4.6 mm ·-X 25 cm)

 : 1.0 mL / min

Measurement wavelength: 230 nm Mobile phase: n-hexane: ethanol = 90:10

 The following compounds can be produced in the same manner as in the above Examples.

 7-[1-(3-pyrrolidine- 1-2-propyl) piperidine-1-3-] 1, 1-3-Benzoxazono 1-2 (3 H) -one

Methyl 2- {3- [3-(2-1,3-dihydro-1,3-dibenzo-1-azole-71-yl) piperidine-1-1-yl] propyl) pyrrolidine-1-1-hydroxypropyloxylate

 t er t-butyl 2_ {3— [3- (2-oxo_2,3-dihydro-1,3-benzoxazono-1-yl) piperidine-1-1-inole] propyl} pyrrolidine-1

 7-{1— [3- (1-Acetylpyrrolidine-1-2-yl) propyl] piperidine-1-3-y / re} 1-1,3-benzoxazonore-1 (3H) one.

 7-1- {1— [3- (1-Methylpyrrolidine-1-yl) propyl] piperidine-1-yl} -1, 3 _benzoxazonole-1 (3H) —one

 7— (11 {3— [1— (methylsulfonyl) pyrrolidine_2-yl] propyl} piperidine-1-3-inole) 1,3-benzoxazono-one 2 (3 H) one 7— [1— (3-pyrrolidine-1-3-inolepropinole) piperidine—3-—isle] 1,1,3-benzoxazono 1-2 (3H) one

 t er t-butyl 3- {3- (3- (2-oxo-1,2,3-dihydro-1,3_benzoxazole-1-7-yl) piperidine-1-1-ynole] propyl} pyrrolidine-1

7 1 {1 1 [3-(1-Acetylpyrrolidine 13 _yl) propyl] piperidine 1 -3-yl} 1, 1, 1-Benzoxazole 2 (3 H) -one 7- {1- (3- (1-Methylpyrrolidine-3-yl) propyl] piperidin-3-yl}-1,3-benzoxazole-1 (3H) -one

7— (1-{3- [1- (methylsulfonyl) pyrrolidine-1--3-yl] propyl} piperidin-3-yl) 1,1,1-benzoxazole-2 (3H) one 7- [1— (3-Piperazine-1-ylpropyl) piperidine-3-yl] 1-1,3-Benzoxazole-1 (3H) one

tert-butyl 4- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1-7yl) piperidine-1-11] propyl} piperazine-1 1— Power noreboxylate

Methyl 4- {3- [3-(2-oxo-1,2,3-dihydro_1,31-benzoxazole-17-yl) piperidine-11-yl] propyl} piperazine-11-canolepoxylate

 7-1- {1- [3- (4-Acetylbiperazine-1-11yl) propyl] piperidine-1-3-yl} —1,3—Benzoxazonole 2 (3H) — On

 7- (1-{3- [4- (methylsulfonyl) piperazine-1-yl] propyl} piperidin-3-inole) 1,1,3-benzoxazonole_2 (3H) —On 7- {1- [3- (4-Methinoleviperazine-1 f) propyl] piperidine-1 3 —yl} 1, 1—3-Benzoxazonole 2 (3 H) 1 on

 7-{1-1 [2-(1, 2, 3, 4-tetrahydroquinoline-1-5-yl) ethyl] piperidine-1-^ ^}-1, 3-benzoxazole-2 (3 H) 1-Methyl 5- {2- [3- (2-oxo-1,2,3-dihydro-1,3_benzoxazol-17-yl) piperidine-1-1-yl] ethyl} 1,3,4-dihydroquinolori 1 (2H) One-strength lipoxylate

 7- {1-[2- (1-Acetyl-l, 2,3,4-tetrahydroquinoline-l-yl) ethyl] piperidin-l- 3-yl} —1,3-Benzoxazonole One 2 (3H) — ON

7- (1- {1- [2- (methylsulfonyl)-1,2,3,4-tetrahydroquinoline-1-5-inole] ethyl} piperidine-3-yl) —1,3-one Lou 2 (3H) One On

 7- {1- [2- (1-Methyl-1,2,3,4-tetrahydroquinoline-1-yl) ethyl] piperidine-1-3-yl} _ 1,3 Benzoxazole-1 2 (3 H) One on '"

7- {1-[2- (1,2,3,4-tetrahydroquinoline-l- 7-yl) ethyl] piperidin-l- 3-yl} —1, 3-benzoxazonole-1 (3 H) —Onmethyl 7— {2- [3 -— (2-oxo-1,2,3-dihydro-1,3-benzoxazole-17.1-fur) piperidine-1-l] ethyl} -3,4 Droquinolin-1 (2H) —carboxylate

 7- {1-[2- (1_Acetyl_1,2,3,4-tetrahydroquinoline-1- 7-yl) ethyl] piperidine-1-3-yl} -1 1,3-benzoxazole 2 (3H) One ON

 tert-butyl 3- [3- (2-oxo-1,2,3-dihydro_1,3-benzoxazono 1-7-1) piperidine_1-yl] propyl

N— {3- [3- (2-oxo_2,3-dihydro-1,3-benzoxazole-7-yl) piperidin-11-yl] propyl} acetamide

Methyl 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-1 7-yl) piperidine-11-yl] propylcarbamate

N- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-7-yl) piperidine-1-1- / re] propyl} methanesulfonamide

 N— {3- [3- (2-oxo-1,2,3-dihydro_1,3-benzoxazole-7-yl) piperidin-1-yl] propyl} benzamide

Feninole 3— [3— (2 oxo-1,2,3-dihydro-1,3—benzoxazo 1-71-yl) piperidine-1-11-yl] propylcarpamate

N- {3- [3 -— (2-oxo-1,2,3-dihydro_1,3-benzoxazole-17-1-yl) piperidine-1-1-inole] propinole} cyclohexanole cyclohexanol 3 — [3-(2-oxo-1,2,3-dihydro-1,3-benzo-xazo-one-one-yl) piperidine-one-one] 7- [1- (3-Hydroxypropyl) piperidin-3-yl] —1,3-benzoxazole- ₂ (3H) one

 7- {1- [3- (cyclohexyloxy) propyl] piperidine-3-yl} 1-1,3-benzoxazono 1-2 (3H) -one

7-[1-(3-phenoxypropinole) piperidine-1-3-inole] —1,3-benzoxazole-2 (3 H) one

 7 1 {1— [3- (Hexahexylmethoxy) propyl] piperidine-3-yl} 1 1,3-Benzoxazono 1-2 (3H) —one

 7- {11- [3- (benzyloxy) propyl] piperidine-3-yl} 1-1,3-benzoxazono-le-2 (3H) one

 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-17-yl) piperidine-1-1-inole] propinoleethylcarbamate

 3- [3- (2-oxo-1,2,3-dihydro_1,3-benzoxazol-7-yl) piperidine-1-1-yl] propylcyclohexylcarbamate

 3— [3 -— (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-yl) piperidine-1-11-yl] propinole feninolecanolebamate

 tert-butynole 3- (3- [3- (2-oxo-1,2,3-dihydro_1,3-benzoxazonole-7-yl) piperidin-1 1-yl] propyl) piperidine-1

1 power / repoxylate

Isopropyl 3- {3- [3- (2-oxo-1,3-dihydro-1,3-benzoxazonole-1-7-yl) piperidine-1-11-yl] propyl} Piperidine-1 1-carboxylate

Propyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzo-xazo-one-one-7-inole) piperidine-1-1] propyl} Piperidine-one Poxilate

Isoptinole 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7- ^ f1) piperidine-1-yl] propyl} piperidine-1 1-force Pentyl 3_ {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole_7-inole) piperidine-1-1-inole] propinole}

 2-Methoxyxetil 3— {3_ [3 -— (2-oxo-1,3-dihydro-1,3-benzoxazonole-1-yl) piperidine-1-yl] propyl} piperidine-1 1— Carboxylate

 2- (benzyloxy) ethyl 3- (3- [3- (2-oxo-2,3-dihydro-1,3-benzoxazo-one-one-7-1-yl) piperidine-1-one-ino] propyl} piperidine-1-kano Reoxylate

2-hydroxyethyl 3— {3— [3— (2-oxo-1,2,3-dihydro-1,

3-Benzoxazole-1-yl) piperidine-11-yl] propyl} piperidin-1-carboxylate

 7-[1-(2-Pyridine-1-2-ylethyl) piperidine-3-yl] 1 1, 3 1 Benzoxazono 1-2 (3H)-ON

 7-[1-(2-Piperidine-1 3-Illechinole) Piperidine-1 3-Isle] — 1, 3 Benzoxazonole _2 (3H) 1one

 7- [1-(piperidine-1_4-methyl) piperidine-1 3 f] 1, 1, 3_ benzoxazo-one 2 (31-I) 1-one

 7— [1— (2-pyrrolidine-1-ylethyl) piperidine-1 3] —1,3 1-benzoxazole_2 (3H) 1-one

 7— [1— (2-pyrrolidine-1-3-ylethyl) piperidine-1-3-yl] — 1,3,1 benzoxazozoone 2 (3H) one

 7-[1-(Pyrrolidine-2-ylmethyl) piperidin-3-yl]-1, 3-Benzoxazoone 1 (3H) 1one

 7-[1-(Pyrrolidin-1-3-ylmethyl) piperidine-1 3-yl] 1, 1-3-Benzoxazol / le 2 (3H) -one

7— {1-[2 -— (1-acetinolebiperidine-1-2-inole) ethyl] piperidine-1-3-inole} 1-1,3-benzoxazole-2 (3H) -one 7-{1-1-[1-2-acetyl-piperidine-1-3-yl) ethyl] piperidine-1-3-yl} 1, 1-3-Benzoxazole 1-2 (3H) 1 -one

 7— [1— (1-Acetylbiperidine-1-4-ylmethyl) piperidine-1-3-yl] 1-1,3-Benzoxazonole-1 (3H) —one

7-{1-[2- (1-acetylpyrrolidine-1-yl) ethyl] piperidine-1 3 f} — 1,3-benzoxazo-1 / leh 2 (3H) —on

7― {1-[2 -— (1-acetylpyrrolidine-1-3-yl) ethyl] piperidine-1 3-one} —1,3-benzoxazolone 2 (31-I) one-on

 7— [1- (1-acetylpyrrolidine-2-ylmethyl) piperidin-3-yl] —1,3-benzoxazonole-1 (3H) one

 7- [1-(1-Acetinolepyrrolidine-1-3-inolemethyl) piperidine-1 3-yl]-1, 3-Benzoxazole-1 2 (3H) one

Methyl 3- {2- [3- (2-oxo-2,3-dihydro-1,3-1-benzoxazole-1 7-inole) piperidine-1 1-yl] ethyl] piperidine-1 1-carboxy Rate

Methyl 4- [4- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-inole) piperidine-1-ylmethyl] piperidine-1-1-carboxylate methyl 2 -— {2-— 3- (2-oxo-2,3-dihydro-1,3-benzoxazo-1-ru 7-inole) piperidine-1-1-yl] ethyl} pyrrolidine-1-carboxylate

Methyl 3- {2- [3_ (2-oxo-1,2,3-dihydro-1,3-benzoxazole-17-yl) piperidine-11-yl] ethyl] pyrrolidine-11-carboxylate

Methynole 2- [4- (2-oxo-1,3-dihydro-1,3-benzoxazonole-7-yl) piperidine-1-ylmethyl] piperidine-1-carboxylate

7- {1- [1- (1-Methinoleviperidin-1-2-/) propyl] piperidine-3-yl} 1-1,3-benzoxazole-2 (3H) 1-one

7- {1- (3-Methyl-biperidin-3-yl) propyl] piperidine-1 —Innole} —1,3—Benzoxazonole 1 (3H) 1 on

 7-{1-[2- (1-Methinoleviperidin-1-yl) ethyl] piperidin-3-yl} —1,3

 7-1- {1- [2- (1-Methylbiperidin-3-yl) ethyl] piperidine-1-3-yl} -1, 3-benzoxazole-2 (3H) one

 7― {1- [1—2- (1-Methylbiperidine-1 4-yl) ethynole] piperidin-1 3-yl} —1,3-Benzoxazole-2 (3H) —one

 7- [1- (1-Methylbiperidin-1-ylmethyl) piperidin-3-yl] 1-1,3-Benzoxazole-1 (3H) one

7— [1— (1-Methynolepiperidine-1-3-inoremethinole) piperidine-1-3-inole] -1,3—benzoxazonole-1 (3H) one

7-[1-(1-Methylbiperidin-1-41-methyl) piperidine-3-inole]-1,3 -Benzoxazosole _2 (3H) one

 7-{1— [2 -— (1-Methinolepyrrolidine-1-yl) ethyl] piperidine-1 3 _inole} —1,3-benzoxazole-2 (3H) one

 7- {1- (2- (1-Methynolepyrrolidine-1-3-inole) ethyl) piperidine-1-3-inole} -1,3-benzoxazole-2 (3H) —one

 7- [1- (1-Methylpyrrolidine-1-2-inolemethyl) piperidin-1-yl] 1-1,3-Benzoxazole-1 (3H) -one

 7— [1— (1-Methynolepyrrolidine-1-3-ylmethyl) piperidine-1—3-inole]-1,3-Benzoxazole-2 (3H) one

 7- {1- [3- (1-Glycoylbiperidin-1-yl) propyl] piperidin-1-3-inole} 1,3-benzoxazonole 2 (3H) -one

 7— {1-[3--(1-glycolylbiperidine-1-4-yl) propyl] piperidin-3_inole} 1 1,3-benzoxazono 1 2 (3H) 1one

 7- {1-1- [2 -— (1-glycoloylbiperidine-1-2-yl) ethyl] piperidine

-3-yl} 1-1, 3-Benzoxazole-2 (3H) — ON

7-1- {1- [2- (1-glycolylbiperidine-1-3-yl) ethyl] piperidine One 3-innole) One 1, 3-benzoxazono one two (3H) — on

7- {1-[2 -— (1-glycoloylbiperidine-4-yl) ethyl] piperidin-3-yl} —1,3-benzoxazole-2 (3H) —one

7— [1— (1—Glycoylbiperidine-1-2-f-methyl) piperidine-3-yl] — 1,3-Benzoxazole-1 (3H) one

 7- [1— (1-Glycoylbiperidine_3-ylmethyl) piperidin-3-yl] -1,3-benzoxazole-2 (3H) —one

 7— [1— (1—Glycoylbiperidine-1_4-methyl) piperidine-1—3-yl] 1-1,3—Benzoxazonore 2 (3H) —one

7- {1-[3- (1-Glycoylpyrrolidine-1-yl) propyl] piberidine-1 3-inole)-1,3 _Benzoxazonole 1 (3H) one

7— {1— [3 -— (1-Glycolylopyrrolidin-1-yl) propyl] piberidin-3-yl} 1-1,3 Benzoxazono 1-2 (3H) 1-one

7-{1-[2- (1-glycolonepyrrolidine-1-2-yl) ethyl] piperidine —3-inole} —1,3

 7-{1-[2- (1-Glycoleinorepyrrolidine-1-3-inole) eth / re] piperidine--3-yl} — 1, 3-benzoxazonolone 2 (3H) one

 7- [1-(1-Glycoylpyrrolidine_2-ylmethyl) piperidin-3-inole] 1,1,3-benzoxazonole 2 (31-I) -one

 7-[1-(1-Glycoroylpyrrolidine-1-3-inolemethyl) piperidine-1 3-inole] 1-1,3-Benzoxazomono 1 2 (3H) 1one

 7— (1— {3- (1- (Methoxyacetyl) piperidin-1-yl] propyl} piperidin-3-yl)-1,3,1-benzoxazole-2 (3H) — On

 7— (1-{3- [1- [Methoxyacetyl) piperidine-41-yl] propyl} piperidine-1-3-inole) 1,3-benzoxazonole 2 (3H) one

 7- (1— {2- [1— (Methoxyacetyl) piperidin-2-yl] ethyl} piperidin-1-3-yl) 1,1,1-benzoxazole-2 (3H) —one

7- (1-{2- [1- (Methoxyacetyl) piperidine-1-3-yl] ethyl} pi Peridine-1 3-inole) -1,3-Benzoxazonole 2 (3H)

7- (1— {2- [1— (Methoxyacetyl) piperidine-1-4-yl] ethyl} piperidine-1-3-inole) 1,1,3-benzoxazonole 2 (3H) —one

7- {1-[1- (Methoxyacetyl) piperidine-1_2_methyl] piperidine-1-3-inole) 1,1,3-benzoxazonole 2 (3H) -one

 7-{1-[1- (Methoxyacetyl) piperidine-1-3-ylmethyl] piperidine-1 3-inole} -1,3-benzoxazonole 2 (3H) one

 7— {1- [1- (Methoxyacetyl) piperidine-1-41methyl] piperidine—3} —1,3-Benzoxazole-1 (31-I) —one

 7- (1- {3- [1- (Methoxyacetyl) pyrrolidine-1-2-yl] propyl} piperidine-1-3-y / re) 1,3—benzoxazonore 2 (3H) 1 On

 7- (1— {3- [1-[(Methoxyacetyl) pyrrolidine-1-3- ^ fur] propyl] piperidine-1-3-inole) 1 1, 3-1-benzoxazo-1 / le 2 (3I-I) -one

 7— (1- {2- [1- (Methoxyacetyl) pyrrolidine-2-yl] ethyl} piperidine-1-3-inole) —1,3-benzoxazo-1- / le 2 (31-I) —one

 7- (1- {2- [1-(Methoxyacetyl) pyrrolidine-1-3-yl] ethyl} piperidine-1-3-inole) 1,3-benzoxazonole 2 (3H) one

 7— {1-[1— (Methoxyacetyl) pyrrolidine_2-ylmethyl] piperidine-1-3-inole} -1,3—benzoxazonole_2 (3H) —one

 7- {1- [1- (Methoxyacetyl) pyrrolidine-1-3-ylmethyl] pyridine-1-3-yl} -1 1,3_benzoxazonole-1 (3H) -one

 7- (1- {3- [1- (methylsulfonyl) piperidin-2-yl] propyl} piperidin-3-yl)-1,3,1-benzoxazole-2 (3H) -1 On

 7- (1— {3- [1- (methylsulfonyl) piperidin-1-yl] propyl} piperidine-3-inole) ―1,3-benzoxazole-2 (3H) one

 7- (1-{3-1- [1- (methylsulfonyl) piperidine-1-4-yl] propyl) piperidine-1-3 ^^) 1-1,3-benzoxazole-2 (3H) 1-one

7- (1— {2- [1- (methylsulfonyl) piperidin-1-yl] ethyl} pi Peridine-1-3-yl-1-1,3-benzoxazonore-1 (3H) one

7- (1- {2- [1- (methylsulfol-yl) piperidin-1-yl] ethyl} piperidin-1-3-yl)-1,3-benzoxazole-2 (3H) -1 On

7- (1- {2- [1- (methylsulfol-yl) piperidine-1-4-yl] ethyl} piperidine-1-3-yl)-1,3,1-benzoxazole-2 (3H) one

 7- {1- [1- (methylsulfonyl) piperidin-2-ylmethyl] piperidin-3-yl} —1,3-benzoxazole-2 (3H) one

 7― {1— [1— (methinoresnolehoninole) piperidin-3-inolemethyl] piperidine—3-inole) 1,1,3-benzoxazo-one-one 2 (31-I) one

 7-{1-[1-(methylsulfoel) piperidin-1-ylmethyl] piperidine — 3-inole} — 1,3-benzoxazonole 2 (3H) one

 7- (1- {1- [2- (methylsulfol-yl) pyrrolidine-1--2-yl] ethyl} piperidine-1-3- ^ f1) 1,3-benzoxazo-1 / le 2 (3H) -one

 7-1- (1- {2- [1- (Methylsulfur) pyrrolidine-1-3-yl] ethyl} piperidine-1-3-yl) 1,1,1-benzoxazole-2 (3H) one

 7 1 {1-[1— (meth / res / lephoninole) pyrrolidine 1 2 1 ^ f noremethyl] piperidine —3—inole} 1 1, 3—benzoxazo mono 1 2 (3H) 1one

 7-{1-[1- (methylsulfol) pyrrolidine-1-3-ylmethyl] piperidine-1 3-inole} 1, 1

Ethyl 3- {3- [3- (2-oxo-1,3-dihydro-1,3-benzoxysazol-7-yl) piperidine-1-1-yl] propyl} piperidine-11-carbo Xylate

2-Ethyl 2- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxysazol-7-yl) piperidine-1] -propyl] piperidine-11-canolepoxylate

Isopropyl 2_ {3- [3 -— (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1 7-inole) piperidine_1-yl] propinole) Propyl 2- {3- [3- (2-oxo-1,2,3-dihydro-1,3_benzoxazo-1-yl 7-yl) piperidine-1-1-yl] propyl} piperidine-11-carboxylate

 2-Methoxyxetil 2- {3- [3- (2-oxo-1,2,3-dihydro-1,1,3-benzoxazono-le-71-yl) piperidine-1-yl] propyl} piperidine-1 1 One carboxylate

 2- (benzyloxy) ethyl 2- {3- [3- (2-oxo-1,3-dihydrid _ 1,3-benzoxazole-1 71-yl) piperidine-1 1-yl] propyl) piperidine-1 One-strength ropoxylate

2-hydroxyethynole 2-{3-[3- (2-oxo-1,2,3-dihidro 1,

3-benzoxazole-7-yl) piperidine-1-one] propyl} piperidine-1-one-norreboxylate

Ethyl 4- {3- [3-(2-oxo-1,2,3-dihydro-1,3-benzoxysazole-71-yl) piperidine-1-1-yl] propyl} piperidine-11-carboxylate

Isopropyl 4- {3- [3-(2-oxo-1,3-dihydro_1,3-benzoxazole-7f) piperidine-1-yl] propyl} piperidine-1 1-carboxylate

Propyl 4- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-l-71-yl) piperidine-1-1-yl] propyl} piperidine-1-1-carboxylate

 2-methoxetinole 4- {3— [3- (2-oxo-1,2-dihydro-1,3-benzoxazolyl-7-yl) piperidine-1-1-yl] propyl} piperidine-1

 2- (benzyloxy) ethyl 4- {3- [3- (2-oxo_2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-yl] propyl} piぺ Lysine 1-carboxylate

2-hydroxyethyl 4--1- {3-(3- (2-oxo-1,2,3-dihydro-1,1) 3 Benzoxazono 1 7-inole) piperidine 1-yl] propyl} piberidine

Ethyl 2- {2_ [3 -— (2-oxo-1,3-dihydro-1,3-benzoxazole-1-7-yl) piperidine_1-inole] ethinole} piperidine-1-1-carboxylate

Isopropyl 2- {2- [3-[(2-oxo-1,2,3-dihydro-1,3-benzoxazono-le-71-yl) piperidine-1--1-inole] ethyl} piperidine-one

Propyl 2- {2- [3- (2-oxo-1,3-dihydro 1,3-benzoxazole-7-inole) piperidine-1-yl] ethyl} Piperidine-1 1-canolepo 'xylate

 2-Methoxyquinone 2— {2-—3— (2-oxo-1,2-dihydro_1,3-one-benzoxazo-one-one 7-inore) piperidine-1 1-inore] etinole} piperidine-one-one-force / Reoxylate

 2- (benzyloxy) ethynole 2- (2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole_7-yl) piperidine-1-yl] ethyl } 1 piperidine / reoxylate

 2-Hydroxyshetinole 2 -— {2- [3- (2-oxo-1,3-dihydro-1,3,3-benzoxazonole-1-7-inole) piperidine-1-1-inole] etizole} piperidine-1 1-carboxylate

Ethyl 3_ {2-[3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1 7-yl) piperidine-1 1-yl] ethyl} Piperidine-1

Isopropyl 3- {2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidin-1-yl] ethyl} Piperidine-1

Propyl 3- {2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-l-u 7-i ^^) piperidin-1 1-yl] ethyl} piperidin-1 1 ^^ Xylate

 2-Methoxyxetil 3- (2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1 7-inole) piperidine-1 1-yl] ethyl} piperidine-1 1 One carboxylate

2- (benzyloxy) ethyl 3- {2- [3- (2-oxo_2,3-dihydrid_1,3-benzoxazole-7_yl) piperidine-1-ethyl] ethyl} Piperidine 1

 2-Hydroxyethynole 3- {2_ [3--(2-oxo-1,2,3-dihydro 1,3,1-benzoxazo-1 / le 7-1 "^ I) piperidine 1 1 ^^] ethyl} piperidine _1_Canolepoxylate

Ethyl 4-1 {2- [3- (2-dioxo-1,3-dihydro-1,3-benzoxysazol-7-yl) piperidine-1-1-yl] ethyl} piperidine-1 .

Isopropyl 4- {2- [3 -— (2-oxo-1-2,3-dihydro-1,3-benzoxazole-7-1-fl) piperidine-1-1-fl] ethyl} Poxilate

Propynole 4- {2- [3-(2-oxo-1,3-dihydro-1,3-benzoxazo-1-one 7-yl) piperidine-1-11] ethyl} piperidine-11-carboxylate

 2 _METOXECHINORE 4— {21- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1 7-inole) Piperidine-1 1-inole] Etinole} piperidine-1

1—force norboxylate

 2- (benzylisoxy) ethyl 4- {2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1 7-inole) piperidine-1 1-inole] ethyl} piperidine-1 (1) One-stroke repo xylate

2-Hydroxyshetinole 4- {2- [3- (2-oxo-1,3-dihydro-1,3-benzoxazo-1 / le 7-yl) piperidine-1 1-yl] ethyl} piperidine-1 1 One strength olepoxylate Ethyl 2_ [3— (2-oxo_2,3-dihydro-1,3_benzoxazolyl 7-yl) piperidin-1-ylmethyl] piperidine-1 1-carboxylate isopropyl 2 -— [3 -— (2 —Oxo-1,2,3-dihydro-1,3—benzoxazole-1-7-yl) piperidine-1 _inolemethyl] piperidine-11-norreboxylate

Propinole 2- [3- (2-oxo_2,3-dihydro 1,3-benzoxazo-l-u 7-inole) piperidine-l-ylmethyl] piperidine-l-carboxylate

 2-Methoxyxeti / r 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazono 1-7-yl) piperidine-1 1-ylmethyl] piperidine-1 Boxylate

 2- (benzinoleoxy) ethyl 2- [3- (2-oxo_2,3-dihydro_1,3-benzoxazole-1 7-yl) piperidine-1-1-ylmethyl] piperidine-1-canoleboxylate

 2-Hydroxyshetinole 2- [3- (2-oxo-1,2,3-dihydro-1,3_benzoxazole-1 7-yl) piperidine-1_ylmethyl] piperidine-1 1-force ruboxylate

Ethyl 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-17-yl) piperidine-1-ylmethyl] piperidine-1-11-carboxylate isopropyl 3- [3- (2 —Oxo-1,2,3-Dihydro-1,3-Benzoki Sazonole 7-inole) Piperidine-1-1 ^ f-Lumetinole] Piperidine—One-pot oleboxylate

Propinole 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1 7-yl) piperidine-11-inolemethinole] piperidine-11-carboxylate

2-Methoxyxenino 3-—3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1-yl 7-yl) piperidine-1-ylmethyl] piperidine-1 2- (benzyloxy) ethyl 3- (3- (2-oxo-1,3-dihydro-1,3,1-benzoxazole-7-yl) piperidine-1-ylmethyl] piperidine-11

 2-Hydroxyethyl 3- [3- (2-oxo1-2,3-dihydro-1,3-benzoxazo-one-one-one-one- f-four) piperidine-one-one-inolemethyl] piperidine-one-one Ruboxile

Ethyl 4- [3-(2-oxo-1,2,3-dihydro-1,3-benzoxazolu 7-yl) piperidine-1 1-inoremethinole] piperidine-1 1-carboxylate isopropyl 4- [3-( 2-oxo-1,2,3-dihydro-1,3-benzoxazole-1 7-yl) piperidine-11-inolemethinole] piperidine-1 1-potanolboxylate

Propinole 4- [3- (2-oxo-1,2,3-dihydro-1,3, benzoxazo-one-one 7-inole) piperidine-1-1-ylmethyl] piperidine-1-1-carboxylate

2-Methoxyschinole 4- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazono-le-71-yl) piperidine-1-ylmethyl] piperidine-one 1-forceboxylate

 2- (benzyloxy) ethyl 4- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-inole) piperidine-1-1-inolemethyl] piperidine-1-1-force oleboxylate

 2-Hydroxitytil 4_ [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-l-u 7-yl) Piperidine-1-1-Inolemethinole] Piperidine-1-1

Echinole 2- {3- [3- (2-oxo-1,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-1-y] / propinole} Pyrrolidine-1

Isopropyl 2- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1-yl 7-yl) piperidine-1-1-yl} propyl} pyrrolidine-1-11 Canolepoxylate

Propyl 2- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1-yl 7-yl) piperidine-1-1-yl] propyl} pyrrolidine-1

2-Methoxyxetil 2- {3- (3- (2-oxo-l, 3-dihydro-l, l-l-benzoxazole-7-yl) piperidine-l-l-yl] propyl) pyrrolidine-l 1- Carboxylate

 2- (benzinoleoxy) ethynole 2 -— {3- [3- (2-oxo-1,2,3-dihydro 1,1,3-benzoxazol-7-inole) piperidine-11-yl] propyl} Pyrrolidine-1

 2-Hydroxyethyl 2- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-17-yl) piperidine-1_yl] propyl} pyrrolidin-11 Power noreboxylate

Ethyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidin-11-yl] propyl} pyrrolidine-1-carboxylate

Isopropyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidin-1-yl] propyl} pyrrolidine-one-boxylate

Propinole 3- (3- [3-(2-oxo-1,2,3-dihydro-1,3-benzoxazo-l-71-yl) piperidine-1-1-inole] propyl) pyrrolidine-1-1-carboxylate

 2-Methoxyxetil 3- {3- (3- (2-oxo-1,2-dihydro-1,3-benzoxazole-71-yl) piperidine-1-1-^-fl] propyl} pyrrolidine-1 1_ Power noreboxylate

2- (benzyloxy) ethyl 3- (3- [3- (2-oxo-1,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-yl] propyl } Pyrrolidine 2—Hydroxyshetinole 3— {3-[3— (2-oxo-1,2,3-dihydro-1,

3-benzoxazole-7-yl) piperidine_1-yl] propyl} pyrrolidin-1-one-force oleboxylate

Ethyl 2- {2- [3-(2-oxo-1,2,3-dihydro-1,3-benzoxy sazono 1-7-inole) piperidine 1 1 / re] ethinole} pyrrolidine 1-one-force oleboxylate

Isopropynole 2- {2- [3- (2-oxo-1,2,3-dihydro-1,3, -benzoxazole-7-inole) piperidine-1-1-inole] ethynole} Pyrrolidine-1 1-force norreboxylate

Propynole 2- {2- [3- (2-oxo-1,2,3-dihydro 1,3 _benzo-xazo-one-one 7-yl) piperidine-1-1-yl] etinole} pyrrolidine-one-force / repo Xylate

 2-Methoxyxetil 2- {2- (3- (2-oxo-1,2,3-dihydro_1,3-one-benzoxazo-1 / le 7-inole) Piperidine-1 1-isle] ethyl} Pyrrolidine-1

 2- (benzyloxy) ethyl 2- {3- [2- (2-oxo-1,2,3-dihydrochloride _ 1,3-benzoxazole-7-yl) piperidine-1-ethyl] ethyl } 1-carboxylate

 2-Hydroxyethyl 2- {3- [3- (2-oxo-l, 3-dihydro-l, 3-l-benzoxazole-7-yl) piperidin-l-l] ethyl] pyrrolidine One-one-strength noreboxylate

Ethyl 3- {2- [3 -— (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1-7-yl) piperidine-1-11] ethyl} pyrrolidine-1-carboxylate

Isopropyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl] ethyl} Pyrrolidine-1 1-force

Propyl 3— {2-[3— (2-oxo-1,2,3-dihydro-1,3-benzo 7-yl) piperidine-1-yl] ethyl} pyrrolidine-1-yloxypropylate

 2-Methoxyxetil 3- {2- (3- (2-oxo-1,2,3-dihydro_1,3—benzoxazo-1 / le7-yl) piperidine-1-yl] ethyl} pyrrolidine-1— Power / Repoxylate

 2- (benzyloxy) ethyl 3-{2- [3- (2-oxo-1,2,3-dihydro-1,3_benzoxazol-7_yl) piperidine-11-yl] ethyl Mouth lysine 1-1 carboxylate

 2-Hydroxyshetinole 3_ {2- [3- (2-oxo- 1,3-dihydro_1,3-one-benzoxazo-one / le 7-ile) Piperidine-1-yl] ethyl} Pyrrolidine-1-carboxylate

Ethyl 2- [3-(2-oxo-1,3-dihydro-1,3-benzoxazol-17-yl) piperidine-1-ylmethyl] pyrrolidine-1-1-carboxylate isopropyl 2 -— [3-- (2-oxo-1,2,3-dihydro_1,3-benzoxazole-7-inole) Piperidine-1 1-Lumetinole] Pyrrolidine-1 / power / repoxylate

Propyl 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1-7-yl) piperidine-1-ylmethyl] pyrrolidine-11-carboxylate

2-Methoxyxyl 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-l-ylmethyl] pyrrolidine-l-carboxylate

 2- (Benzi / reoxy) ethyl 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-1 7-yl) piperidine-1-ylmethyl] pyrrolidine-1-carboxylate

2-Hydroxyshetinole 2- [3- (2-oxo-1,2,3-dihydro-1,3-bensoxazolu-71-yl) piperidine-1-1-inolemethinole] pyrrolidine-one-force norreboxylate 3- (3- (2-oxo-1,2,3-dihydro-1,3-benzoxazolu 7-inole) piperidine-1 1-ylmethinole] pyrrolidine-11-carboxylate isopropynole 3- [3- (2— Oxo-1,2,3-dihydro-1,3_benzoxazol-17-yl) piperidine_1-ylmethyl] pyrrolidine-11-carboxylate

Propyl 3- [3- (2-oxo_2,3-dihydro-1,3-benzoxazo-l-u 7-inole) piperidine-l-l- ^ methy / re] pyrrolidine-l-l-carboxylate

 2-Methoxyethynole 3- [3- (2-oxo-1,2,3-dihydro_1,3-benzoxazonole-7-isle) piperidine-1-ylmethyl] pyrrolidine-11-carboxylate

 2- (benzyloxy) ethyl 3-[3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-1-fur) piperidine-1-ylmethyl] pyrrolidine-1 1-force norreboxylate

2-Hydroxyethyl 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzobenzoxazolone 7— ^ ί) V) piperidine-1-ylmethinole] pyrrolidine-1-potassium test example 1: screening test using ^"3 H] quinpirole binding

 1-1 Preparation of striatal membrane preparation

Membrane preparations were prepared according to the method of Levant et al. (J. Pharmacol. Exp. Ther., 262, 929-935 (1992)). That is, a male rat was decapitated, the whole brain was immediately removed, and the striatum was collected under ice cooling. To this was added 20 volumes of a buffer solution (50 mM Tris-HCl, 5 raM KCl, 2 mM MgCl ₂ , 2 raM CaCl ₂ , pH 7,4) based on the wet weight, and Teflon-glass homog Homogenized using an enizer. This was centrifuged 1δ min at 4 ^8, 000 X g at 4 ° C and the resulting precipitate with a water-cooled buffer (50 mM Tris-HCl, 5 raM KCl, 2 mM MgCl 2, 2 raM C aCl 2, (pH 7.4) using a Hiscotron, and centrifuged again at 4 ° C at 48,000 X g for 15 minutes. The membrane preparation thus obtained is suspended in the above buffer solution and then And stored frozen.

 1-1-2 Receptor binding experiment

[ ³ H] quinpirole binding was measured according to the method of Levant et al. That, 5 mM K Cl, 2 mM MgCl 2 and 2 mM containing _{CaCl 2 50 mM Tris-HCl (} pH 7. 4) was diluted in buffer ^[3 H] quinpirole (final concentration 2 nM) 50/1, line A striatal membrane sample of 447.51 and 2.5 μl of the test drug solution dissolved in dimethyl sulfoxide were added to make a total volume of 500 μl. This solution was reacted at 23 ° C. for 5 hours, and then quickly filtered under low pressure on glass fiber filter paper. The glass fiber filter paper was washed three times with 5 ml of the same buffer, transferred to a glass spiral containing 4ral of ACS-II (Amersham), and the radioactivity remaining on the filter paper was measured using a liquid scintillation counter.

Non-specific binding of [ ³ H] quinpirole was defined as the amount of binding in the presence of ΙΟμΜ (+)-butaclamol.

Binding inhibition rate = 1 0 0 _ 1 0 0 X {[ test substance present under ^[3 H] quinpirole binding amount] one [10 μΜ (+) (° /.) - butaclamol in the presence ^[3 H] quinpirole binding amount]} Z {[test substance in the absence ^[3 H] quinpriole binding amount] one. - quinpriole bond amount ^{[10 μΜ (+) [3} H in the presence Butaclamol]]}

Test example 2: [ ³ H] 8-0H-DPAT binding test

 2-1 Test method

This was performed according to the method of Hall D. et al. (J. Neurochem., 44, 1685-1696 (1985)). Male rats were decapitated, the whole brain was immediately removed, and the hippocampus was collected under ice cooling. Add 50 mM Tris-HCl (pH 7.4) 40 times the wet weight and homogenize (3 min, 1 stroke / min) using a Teflon-glass homogenizer in an ice bath, and then 40,000 Xg Centrifugation (4 ° C) for 10 minutes. The resulting precipitate was dispersed using Physcotron ^{tau M} in ice-cold buffer (50 mM Tris-HCl (pH 7.4)), 40, 000 Xg by centrifugation for 10 minutes (4 ° C) was. Furthermore, the cells were resuspended and the washing operation was repeated once. The resulting precipitate was dispersed using Physcotron ^{tau M} in ice-cold buffer (50 raM Tris-HCl (pH 7.4)), 1 hour Inki-menu collected by centrifugation then 10 minutes at 40,000Xg at 3 7 Separated (4 ° C). In addition, resuspension Then, the washing operation was repeated once. The obtained membrane preparation was suspended in the above buffer solution and stored frozen at 180 ° C.

[ ³ H] 8-0H-DPAT (final concentration 0.2 nM) 50 / il, test drug solution 2.5 μ1, hippocampus in buffer containing 50 mM Tris-HCl (pH 7.4), 4 raM CaCl ₂ 447.5 was added to the membrane standard, and the measurement was performed using a reaction solution having a total volume of 500 μΐ. After allowing the reaction solution to react at room temperature for 20 minutes, the solution was quickly filtered under reduced pressure on glass fiber filter paper. Glass fiber filter paper, washed 3 times with buffer 5 ml, ACS-II! ^ 113 1 11 companies) were添Ka卩41 ₁ 11 entering the Garasubaiaru, liquid receptor bound radioactivity remaining on the filter paper It was measured with a scintillation counter. Non-specific binding was defined as the amount of binding in the presence of 1 / zM 8-0H-DPAT.

 The binding inhibition rate was calculated by the following formula:

Binding inhibition rate (%) = 1 00- 1 0 0 X {[ test of a material presence ^[3 H] 8-0H-DPAT binding amount] one [1 μΜ 8-0Η- DPAT in the presence ^[3 H ] ⁸ -0H-DPAT binding amount]] Ζ {[[ ³ H] 8-OH-DPAT binding amount in the absence of test substance] 1 [1 μΜ 8--0H-DPAT in the presence of [ ³ H] ⁸ _0H-DPAT binding amount]}

Test Example 3: 5-HT, octareceptor and D2 receptor operation test

 3-1 Preparation of cells and membrane preparation

Using _{- (HT 1A / CH0 human 5} ) or human dopam ine D _2L receptor-expressing CH0 cells _{(human D 2L / CH0) HT} 1A receptor expressing CH0 cells - human 5 in the experiment. Cells at 5% C0 ₂ incubator base one coater in, and cultured in F12 (all Gibco) containing 10% FCS, 500 ig / ral Geneticin and 100 U / ml penicillin-100 μ g / ml streptmoycin, membrane preparation Was prepared according to the method ³ ) of A. Newman et al. That is, buffer _{A (20mM HEPES, 5mM MgS0 4} ) Cells manual removal 'taken, Teflon-after homogenization with Glass homogenizer, was performed centrifugation (50,000Xg, 30min, 4 ° C ). The precipitate was resuspended in an appropriate amount of buffer A and stored at 180 ° C until use. The amount of protein in the membrane preparation was quantified by Dye Reagent Concentrate (BIO-RAD) using Albumin Bovine (SIGMA) as a standard substance.

 3-2 Experimental method

Human 5 -.. ΗΊ measurement of ^[35 S] GTPyS binding to the receptor Oyobihi preparative D ₂ receptor, using the above membrane preparation, A. Ne positions an et al. Method (Eur J. Pharmacol, 307 , 107-111 (1996) ). That is, 1 0 ⁵ Buffer B containing each test substance ^{M (2 0mM HEPES, 100 raM} NaCl, 10 mM MgS0 4, 1 μΜ GDP, 0.1 mM DTT) in, the 0.05 nM ^[35 S] GTP yS (DuPont NEN) and a fixed amount (approximately 50 μg / tube) of the membrane preparation were added, and a total of 1 ra 1 of the reaction solution was incubated at 22 to 30 ° C for 20 minutes. After completion of the reaction, the reaction solution was diluted with 5 ml of ice-cold buffer B, and the reaction was terminated by promptly performing suction filtration using glass fiber filter paper (Whatman, GF / B). The glass fiber filter paper washed twice with the same buffer was placed in a vial, and 4 ml of ACS-II was added thereto. The radioactivity of [ ³⁵ S] GTPγS on the filter paper was measured with a liquid scintillation counter. 10 // M GTPyS (Sigma) from non-specific binding obtained under existence ^[3 5 _S] was determined specific binding of GTP 7 S. 5- ΗΊ _A receptor Oyohi receptor agonist activity of each test substance was expressed in the rate of increase when respectively the ^[35 S] GTPyS binding increased by 10 Myumyu of 5-HT and dopamine and 1 0 0% .

The tests of Test Example 1, Test Example 2 and Test Example 3 described above were performed on the compounds obtained in the Examples. The results are shown in Table 6. Table 6: Test results Compound [ ³ H] quinpirole D ₂ receptor [ ³ H] 8-0H-DPAT 5-HT _1A receptor

(Example number) Binding inhibition rate (%) Agonist activity (%) Binding inhibition rate (%) Agonist activity (%)

13 95 67 73 76

 14 99 81 81 77 Industrial availability

As shown in the above test results, the compound of the present invention was found to have high binding affinity and strong agonist action for both dopamine D2 receptor and serotonin 5- _HT1A receptor did. Therefore, the present invention has made it possible to provide a new therapeutic agent for Parkinson's disease.

Claims

 The scope of the claims  Equation (1)

 [In the formula, ring A represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring. R ^D represents a hydrogen atom, a substituted or unsubstituted alkyl group or a hydroxyl group, and may each independently be present in two or more. R ¹ is the formula (2)

(In the formula, R ^ie and R ¹¹ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Represents E is a single bond, one O—, one NR ⁵ —, one CO—, _CS—, -S (O) _m —, -CO—O—, one CS—O—, one NR ⁵ CO—, one CONR ⁵ —, —O—CO—, or —0-CS— (wherein, R ⁵ represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. M represents 0 to 2 Represents an integer.  B is a single bond, 6- to 16-membered aromatic hydrocarbon ring, 3- to 8-membered aliphatic hydrocarbon ring, 3- to 5-membered aliphatic heterocycle, 5- to 12-membered aromatic ring Represents a heterocyclic ring. Q represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted amino group, a substituted or unsubstituted Substitution force Lubamoyl, carboxy, nitro, cyano, hydroxyl, substituted or unsubstituted alkyloxycarbo Represents a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted arylaryl group, or a substituted or unsubstituted alkylsulfonyl group. When B represents a group other than a single bond, the group represented by Q may be independently present in two or more groups. N represents an integer of 0 to 10. ). R ² and R ³ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkylthio group. R ⁴ represents a hydrogen atom or a substituted or unsubstituted alkyl group.  X is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a hydroxyl group, a nitro group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a cyano group, a substituted or unsubstituted rubamoyl group, Represents a carboxy group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted amino group. ] Or a pharmaceutically acceptable salt thereof.  2. The compound according to claim 1, wherein the A ring is a 5- to 7-membered saturated or unsaturated nitrogen-containing heterocycle, or a pharmaceutically acceptable salt thereof.  3. The compound according to claim 1 or 2, wherein the A ring is piperidine-3-yl or 1,2,5,6-tetrahydropyridine-13-yl, or a pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein E is a single bond.  5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein B is a 3- to 8-membered aliphatic heterocycle.  6. The compound according to any one of claims 1 to 5, wherein B is a pyrrolidine ring or a piperidine ring, or a pharmaceutically acceptable salt thereof.  7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein B is a pyrrolidine ring. 8. Q is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group The compound according to any one of the above 1 to 7, which is a carbonyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted arylcarbonyl group, or a substituted or unsubstituted alkylsulfonyl group, or a compound thereof Pharmaceutically acceptable salts, 9. The compound according to any one of claims 1 to 7, wherein Q is an alkyloxycarbonyl group, or an alkylcarbonyl group, or a pharmaceutically acceptable salt thereof,  10. The compound according to any one of claims 1 to 7, wherein Q is a methyloxycarbonyl group, or a pharmaceutically acceptable salt thereof,  11.The compound according to claim 1, wherein n is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof, 12. R ⁴ is a compound or a pharmaceutically acceptable salt thereof according to claim 1 to 1 1 any force, wherein a hydrogen atom,  13. The compound according to claim 1, which is any compound selected from the group consisting of the following (1) to (23), or a pharmaceutically acceptable salt thereof.  (1) Methyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazo-1 / le 7-y / re) piperidine-1 1-isole] propi / le} 1 _ force noreboxylate  (2) Methyl 3- {3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-7-yl) piperidine-1 1-yl] propyl} piperidine-1 1 One strength noreboxylate  (3) Methyl 3- {2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl] ethyl} pyrrolidine-1 —Canolepoxylate  (4) Methyl 3- {2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-7-yl) piperidin-1 1-yl] ethyl} piperidine-1 1- Canolepoxylate (5) Methyl 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-11-yl] methylpyrrolidine-11-carboxylate (6) Methinole 3- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-1-yl] methylbiperidine-1-1-yl propyloxylate  (7) Methyl 2- {3— [3 -— (2-oxo-1,2-dihydro-1,3-benzoxazole-7-yl) piperidine-1-1-yl] propyl} pyrrolidine Noreoxylate  (8) Methinole 2- (3- [3- (2-oxo-1,2,3-dihydro-1,3_benzoxazono-1-71-yl) piperidine-1-yl]ぺ lysine one-one strength / repoxylate  (9) Methyl 2- {2- [3-(2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-7-inole) piperidine-1-1-inole] ethinole}  (10) Methyl 2- {2- (3- (2-oxo-1,2,3-dihydro-1,3-benzoxazosole 7-yl) piperidine-1 1-yl] ethyl} piperidine-1 1 _Canolepoxylate  (1 1) Methyl 2- [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazonole-1-7-yl) piperidine-1-1-inole] Methylpyrrolidine-one-force  (12) Methyl 2_ [3- (2-oxo-1,2,3-dihydro-1,3-benzoxazono-1-yl) piperidine-1-11] methylpiperidine-1  (13) Methyl 4- {3— [3 -— (2-oxo-1,2,3-dihydro 1,3-1-benzoxazole-7-yl) piperidine-1-1-yl] propyl} piberidine (1) One-stroke olepoxylate  (14) Methyl 4- {3- (3- (2-oxo-1,3-dihydro-1,3-benzoxazole-7-1-^) piperidine-1--1-yl] ethyl} Lysine 1 1 force / Repoxylate (15) Methyl 4- [3- (2-oxo-1,2,3-dihydro-1,3-ben Zoxazozo-1 / le 7-inole) piperidine-1 1-yl] methinorebiperidine-1  (16) Methyl (3 S) — 3— {3_ [(3 S) 1 3— (2—oxo 1 2, 3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl] propyl} pyrrolidine-1-carboxylate  (17) Methyl (3 S) —3— {3_ [(3 R) 1 3— (2—oxo 1 2, 3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl] propinole}  (18) Methyl (3R) -3- {3-[(3S) -1-3- (2-oxo-1,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1ィ ] Propyl} pyrrolidine-1-carboxylate  (19) Methyl (3 R) -3- {3- [(3 R) 1 3— (2—oxo 1 2, 3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-yl Propyl} pyrrolidine  (20) Methyl (3S) -3-[(3S) -3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1 Yl] methynolepyrrolidine-1-carboxylate  (21) Methyl (3 S) — 3— [(3 R) —3— (2-oxo-1,2,3-dihydro-1,3-benzoxazol-7-yl) piperidine-1-yl ] Methinolepyrrolidine-1-carboxylate  (22) Methyl (3R) -1 3— [(3S) -3- (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1 1— Yl] methynolepyrrolidine-1-carboxylate  (23) Methyl (3R) -3-[(3R) —3— (2-oxo-1,2,3-dihydro-1,3-benzoxazole-7-yl) piperidine-1-1-inole] Norepyrrolidine 14. A medicament comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 15. A therapeutic agent for Parkinson's disease, comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. 16. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 17. The compound according to claim 1, which is selected from the group consisting of the following compounds (1) to (5), or a pharmaceutically acceptable salt thereof.  (1) 7-Pyridine-1 3-yl 1, 3 Benzoxazole-2 (3H) 1 ON  (2) (+) — 7—piperidine 3-irru 1,3 _benzoxazole-2 (3H) one  (3) (_) _7-piperidine-1-yl-1,3-benzoxazole-2 (3H) one  (4) 7-pyrrolidine-1 3-inole-1,3-benzoxazo '1-ru 2 (3H) -on  (5) 7-azepan-1-yl-1,3-benzoxazole-2 (3H) -one