JP2005298402A - Novel benzoxazolone compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug which is effective as a remedy, a prophylactic, and an ameliorating drug for Parkinson's disease or the like and exhibits an agonist action to both dopamine D<SB>2</SB>recipient and serotonin 5-HT<SB>1A</SB>recipient. <P>SOLUTION: There are provided a compound represented by formula (1), its prodrug, and their pharmaceutically allowable salts. In formula (1), ring A is a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocycle; R<SP>0</SP>, R<SP>2</SP>, R<SP>3</SP>, R<SP>4</SP>, and X are each a hydrogen atom or the like; p and q are each an integer of 0-3, and R<SP>1</SP>is a group represented by formula (2) (wherein R<SP>10</SP>and R<SP>11</SP>are each a hydrogen atom or the like; E<SP>1</SP>and E<SP>2</SP>are each a single bond, -O-, or the like; W is a substituted or unsubstituted 5- to 12-membered aromatic heterocycle or the like; Q is a substituted or unsubstituted 6- to 16-membered aromatic hydrocarbon cycle or the like; and n is an integer of 0-10). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel benzoxazolone derivative. These novel benzoxazolone derivatives are useful as therapeutic agents for Parkinson's disease.

Parkinson's disease is a movement disorder caused by a deficiency of the neurotransmitter dopamine in the brain. So far, Parkinson's disease has been mainly treated with dopamine precursor L-DOPA. However, long-term use of L-DOPA shortens the action time (wearing-off phenomenon) and destabilizes (On-off phenomenon). Involuntary movement disorders such as dyskinesia and the development of psychiatric symptoms such as hallucinations and delusions have become major problems. These problems with L-DOPA are thought to depend on the dose of L-DOPA and the length of the administration period. Therefore, by using a dopamine agonist (dopamine D ₂ agonist) from the early onset, -Delaying the start of DOPA and reducing the dose is considered important in the treatment of Parkinson's disease. However, existing dopamine agonists have problems such as vomiting / nausea at the initial stage of administration and insufficient efficacy after the middle period.
Serotonin 5-HT _1A agonists not only have an effect on depression and anxiety, but also may have an improvement effect on movement disorders such as Parkinson's disease in recent years, and an improvement action on involuntary movement disorders such as dyskinesia by taking L-DOPA The possibility of showing is found. In fact, the selective serotonin 5-HT _1A agonist tandospirone citrate has been reported to ameliorate movement disorders in Parkinson's disease. In addition, serotonin 5-HT _1A agonists reduce side effects such as suppression of vomiting by dopamine stimulation, shortened action time during long-term treatment with L-DOPA, and involuntary movements such as dyskinesia by taking L-DOPA. Improvement effects on disability have been reported. Therefore, drugs that show agonistic effects on both dopamine D ₂ receptor and serotonin 5-HT _1A receptor ameliorate the problems of conventional dopamine agonists, in addition to prolonged L-DOPA action and associated dyskinesia It may be a new treatment for Parkinson's disease that has both involuntary movement disorders such as depression, and depression / anxiety symptoms.
For example, Patent Document 1 discloses pyrido [1,2 that exhibits agonistic action on both dopamine D ₂ receptor and serotonin 5-HT _1A receptor as therapeutic agents for Parkinson's disease, attention deficit hyperactivity disorder (ADHD), and the like. Patent Document 2 discloses a tricyclic nitrogen atom-containing compound having a -a] -pyrazine derivative. Patent Document 3 discloses piperazine and piperidine derivatives that exhibit a partial agonistic action on both dopamine D ₂ receptor and serotonin 5-HT _1A receptor. Patent Document 4 discloses a benzoxazolone derivative exhibiting an agonistic action on both a dopamine D ₂ receptor and a serotonin 5-HT _1A receptor.
International Publication No. 00/16777 pamphlet International Publication No. 90/15058 Pamphlet International Publication No. 00/29397 Pamphlet International Publication No. 04/000837 Pamphlet

As mentioned above, drugs that show agonistic action on both dopamine D ₂ receptor and serotonin 5-HT _1A receptor improve the problems of conventional dopamine agonists, and in addition, prolong the action time of L-DOPA. It may be a new treatment for Parkinson's disease, which has both involuntary movement disorders, such as dyskinesia, and depression / anxiety symptoms. That is, an object of the present invention is to provide a drug having an agonistic action on both dopamine D ₂ receptor and serotonin 5-HT _1A receptor, which is effective as a therapeutic, preventive or ameliorating agent for Parkinson's disease and the like.

As a result of intensive studies, the present inventors have found that the compounds shown below have a high binding affinity and a strong agonistic action on both the dopamine D ₂ receptor and the serotonin 5-HT _1A receptor, The present invention has been completed.

That is, the present invention
[1] Formula (1)

［式中、Ａ環は４〜10員の飽和または不飽和の含窒素複素環を表す。
Ｙは炭素原子を表す。
Ｒ⁰は、複数ある場合にはそれぞれ独立して、水素原子、置換または無置換のアルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、置換または無置換のシクロアルキル基、または水酸基を表す。
ｐおよびｑはそれぞれ独立して０から３の整数を表す。
Ｒ¹は式（２）

[In the formula, A ring represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring.
Y represents a carbon atom.
R ⁰ is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, Or represents a hydroxyl group.
p and q each independently represents an integer of 0 to 3.
R ¹ is the formula (2)

（式中、Ｒ¹⁰およびＲ¹¹は同一または異なって、また複数ある場合にはそれぞれ独立して、水素原子、ハロゲン原子、水酸基、置換または無置換のアルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、置換または無置換のシクロアルキル基、置換または無置換のアリール基、または置換または無置換のヘテロアリール基を表す。
Ｅ¹およびＥ²は同一または異なって、単結合、−Ｏ−、−ＮＲ⁵−、−ＣＯ−、−ＣＯ−Ｏ−、−Ｓ（Ｏ）_m−、−ＮＲ⁵−ＣＯ−ＮＲ⁶−、−ＮＲ⁵−ＣＳ−ＮＲ⁶−、−Ｏ−ＣＯ−ＮＲ⁵−、−ＮＲ⁵−ＣＯ−Ｏ−、−ＮＲ⁵−ＳＯ₂−、−ＳＯ₂−ＮＲ⁵−、−ＣＳ−、−ＣＳ−Ｏ−、−ＮＲ⁵−ＣＯ−、−ＣＯ−ＮＲ⁵−、−Ｏ−ＣＯ−、または−Ｏ−ＣＳ−（式中、Ｒ⁵およびＲ⁶は、それぞれ独立して水素原子、置換または無置換のアルキル基、置換または無置換のアリール基、または置換または無置換のヘテロアリール基を表す。ｍは０から２の整数を表す。）を表す。
Ｗは置換または無置換の６から１６員の芳香族炭化水素環、置換または無置換の３から８員の脂肪族炭化水素環、置換または無置換の３から１２員の脂肪族複素環、または置換または無置換の５から１２員の芳香族複素環を表す。
Ｑは置換または無置換の６から１６員の芳香族炭化水素環、置換または無置換の３から８員の脂肪族炭化水素環、置換または無置換の３から１２員の脂肪族複素環、置換または無置換の５から１２員の芳香族複素環、ホルミル基、スルホン酸基、置換または無置換のアルキルチオウレイド基、置換または無置換のアルキルウレイド基、置換または無置換のアルキルカルバモイルオキシ基、置換または無置換のアルキルオキシカルボニルアミノ基、置換または無置換のアルキルスルホニルアミノ基、置換または無置換のアルキルスルファモイル基、または置換または無置換のアルキルスルフィニル基を表す。
ただし、Ｅ²が−ＣＯ−である場合、Ｑは置換または無置換のアリール基ではない。−Ｅ²−Ｑで表される基はそれぞれ独立して２個以上存在してもよい。
ｎは０から１０の整数を表す。）を表す。
Ｒ²およびＲ³はそれぞれ独立して水素原子、置換または無置換のアルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、または置換または無置換のシクロアルキル基を表す。
Ｒ⁴は水素原子、置換または無置換のアルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、または置換または無置換のシクロアルキル基を表す。
Ｘは、複数ある場合にはそれぞれ独立して、水素原子、ハロゲン原子、置換または無置換のアルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、置換または無置換のシクロアルキル基、水酸基、ニトロ基、置換または無置換のアルコキシ基、置換または無置換のアルキルチオ基、シアノ基、置換または無置換のカルバモイル基、カルボキシ基、置換または無置換のアルキルオキシカルボニル基、または置換または無置換のアミノ基を表す。］
で表される化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、

(Wherein R ¹⁰ and R ¹¹ are the same or different, and when there are a plurality of them, each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, It represents a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
E ¹ and E ² are the same or different and are a single bond, —O—, —NR ⁵ —, —CO—, —CO—O—, —S (O) _m —, —NR ⁵ —CO—NR ⁶ —. , —NR ⁵ —CS—NR ⁶ —, —O—CO—NR ⁵ —, —NR ⁵ —CO—O—, —NR ⁵ —SO ₂ —, —SO ₂ —NR ⁵ —, —CS—, — CS—O—, —NR ⁵ —CO—, —CO—NR ⁵ —, —O—CO—, or —O—CS— (wherein R ⁵ and R ⁶ are each independently a hydrogen atom, substituted Or an unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, wherein m represents an integer of 0 to 2.
W is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, a substituted or unsubstituted 3 to 8 membered aliphatic hydrocarbon ring, a substituted or unsubstituted 3 to 12 membered aliphatic heterocyclic ring, or Represents a substituted or unsubstituted 5- to 12-membered aromatic heterocycle.
Q is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, a substituted or unsubstituted 3 to 8 membered aliphatic hydrocarbon ring, a substituted or unsubstituted 3 to 12 membered aliphatic heterocycle, substituted Or an unsubstituted 5- to 12-membered aromatic heterocycle, formyl group, sulfonic acid group, substituted or unsubstituted alkylthioureido group, substituted or unsubstituted alkylureido group, substituted or unsubstituted alkylcarbamoyloxy group, substituted Or an unsubstituted alkyloxycarbonylamino group, a substituted or unsubstituted alkylsulfonylamino group, a substituted or unsubstituted alkylsulfamoyl group, or a substituted or unsubstituted alkylsulfinyl group;
However, when E ² is —CO—, Q is not a substituted or unsubstituted aryl group. Two or more groups represented by -E ² -Q may be present independently.
n represents an integer of 0 to 10. ).
R ² and R ³ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted cycloalkyl group.
R ⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted cycloalkyl group.
X is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl, Group, hydroxyl group, nitro group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylthio group, cyano group, substituted or unsubstituted carbamoyl group, carboxy group, substituted or unsubstituted alkyloxycarbonyl group, or substituted or Represents an unsubstituted amino group. ]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[2] Q is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, a substituted or unsubstituted 3 to 8 membered aliphatic hydrocarbon ring, a substituted or unsubstituted 3 to 12 membered aliphatic heterocycle The compound according to [1] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is a ring, a substituted or unsubstituted 5- to 12-membered aromatic heterocyclic ring,
[3] The compound according to [1] or [2], wherein Q is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, or a substituted or unsubstituted 5 to 12 membered aromatic heterocyclic ring Or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[4] The compound according to any one of [1] to [3], wherein the A ring is a 5- to 7-membered saturated or unsaturated nitrogen-containing heterocyclic ring, or a prodrug thereof, or a pharmaceutically acceptable salt thereof salt,
[5] The compound according to any one of [1] to [4], wherein E ² is a single bond, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[6] The formula (1) is converted into the following formula (1x) or (1y):

である、[１]〜[５]のいずれかに記載の化合物もしくはそのプロドラッグ、またはそれらの薬学上許容される塩、

The compound according to any one of [1] to [5] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[7] A medicament comprising the compound according to any one of [1] to [6] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[8] A therapeutic agent for Parkinson's disease containing the compound according to any one of [1] to [6] or a prodrug thereof, or a pharmaceutically acceptable salt thereof,
[9] A therapeutic agent for dyskinesia containing the compound according to any one of [1] to [6] or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and
[10] A therapeutic agent for dyskinesia associated with Parkinson's disease comprising the compound according to any one of [1] to [6] or a prodrug thereof, or a pharmaceutically acceptable salt thereof.
Hereinafter, the compound represented by the formula (1) or a prodrug thereof, or a pharmaceutically acceptable salt thereof is collectively referred to as “the compound of the present invention” as necessary.

It has been found that the compound of the present invention has a high binding affinity and a strong agonistic action on both the dopamine D ₂ receptor and the serotonin 5-HT _1A receptor. Therefore, the present invention can provide a new therapeutic agent for Parkinson's disease.

Hereinafter, the present invention will be described more specifically.
The description of each group in the present invention also applies to the case where the group is a part of another group, unless otherwise specified.
The number of substituents in this specification is not particularly limited as long as substitution is possible, and is one or more.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, hexyl, heptyl, octyl. , A linear or branched alkyl group having 1 to 10 carbon atoms, such as nonyl or decyl. Preferred alkyl groups are linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl. Can be mentioned.
Examples of the alkenyl group include at least one alkenyl group such as vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl or 1-methyl-1-butenyl. Examples thereof include a straight-chain or branched alkenyl group having 2 to 6 carbon atoms having a heavy bond. Preferred alkenyl groups are straight-chain or branched alkenyl groups having 3 to 6 carbon atoms such as 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3 -Butenyl or 1-methyl-1-butenyl and the like.
Alkynyl groups include, for example, at least one triple such as ethynyl, 1-propynyl, 2-propynyl, 1-methyl-1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl or 1-methyl-1-butynyl. Examples thereof include a linear or branched alkynyl group having 2 to 6 carbon atoms having a bond. Preferred alkynyl groups are linear or branched alkynyl groups having 3 to 6 carbon atoms such as 1-propynyl, 2-propynyl, 1-methyl-1-propynyl, 1-butynyl, 2-butynyl, 3 -Butynyl or 1-methyl-1-butynyl and the like.
Examples of the cycloalkyl group include saturated or unsaturated cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Preferred cycloalkyl groups include saturated or unsaturated cycloalkyl groups having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Examples of the alkoxy group include straight chain having 1 to 10 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonyloxy or decyloxy. And a branched alkoxy group. Preferred alkoxy groups are linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy Is mentioned.
Examples of the alkylthio group include alkylthio having 1 to 10 carbon atoms such as methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio, or decylthio. Groups. Preferred alkylthio groups include alkylthio groups having a linear or branched alkyl group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio. , Pentylthio or hexylthio.

  Examples of the substituent in the substituted alkyl group, the substituted alkenyl group, the substituted alkynyl group, the substituted cycloalkyl group, the substituted alkoxy group, and the substituted alkylthio group include, for example, the above-described halogen atoms (one to three substituted on the same carbon atom). Hydroxyl groups, nitro groups, cyano groups, alkoxy groups such as methoxy, ethoxy, or propoxy, amino groups such as alkylamino groups such as methylamino, ethylamino, or propylamino, such as dimethylamino, diethylamino, methyl Dialkylamino groups such as ethylamino or dipropylamino, for example acylamino groups such as acetylamino, propionylamino, benzoylamino, or naphthoylamino, such as methoxycarbonylamino, ethoxycarbonylamino, or t rt- butoxycarbonyl alkoxycarbonylamino group such as amino, such as an arylsulfonyl group such as an alkylsulfonyl group or for example benzenesulfonyl or toluenesulfonyl, such as methylsulfonyl or ethylsulfonyl, and the like.

In addition to the above, the substituted alkyl group may be substituted with an aryl group (for example, a halogen atom, a hydroxyl group, an alkyl group, an alkyl group substituted with a halogen atom, an alkoxy group, or an alkoxy group substituted with a halogen atom). And a heteroaryl group (for example, an alkyl group or an alkyl group substituted with a halogen atom).
In addition to the above, examples of the substituent of the substituted cycloalkyl group include an alkyl group.

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 5- or 6-membered aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. Examples include pyridyl (nitrogen atom may be oxidized), thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazyl, pyrimidyl, pyridazyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl. The bonding position may be any position as long as it is on an atom capable of bonding.

  Examples of the substituent for the substituted aryl group and the substituted heteroaryl group include a halogen atom, a hydroxyl group, a nitro group, a cyano group, a sulfate group, a formyl group, for example, an alkyl group such as methyl, ethyl, or propyl, such as difluoromethyl or trifluoromethyl. Alkyl groups substituted with halogen atoms such as alkoxy groups such as methoxy, ethoxy or propoxy, alkoxy groups substituted with halogen atoms such as difluoromethoxy or trifluoromethoxy, amino groups such as methylamino, ethylamino Or alkylamino groups such as propylamino, for example dimethylamino, diethylamino, methylethylamino, or dialkylamino groups such as dipropylamino, such as acetylamino, propionylamino, benzo Or an acylamino group such as naphthoylamino, an alkoxycarbonylamino group such as methoxycarbonylamino, ethoxycarbonylamino, or tert-butoxycarbonylamino, an alkylsulfonyl group such as methylsulfonyl or ethylsulfonyl, or a benzenesulfonyl or the like Examples include arylsulfonyl groups such as p-toluenesulfonyl.

Further, these adjacent substituents may be combined with each other to form a ring. As a specific example of such a substituted aryl group or substituted heteroaryl group, a substituted phenyl group can be represented by the following formula:

（上式中Ｒ⁷は水素原子、アルキル基、アルケニル基、アルキニル基、ベンジル基または窒素原子の保護基を表す。）
で表されるような環の炭素原子上または窒素原子上の水素原子が結合手に変わった基なども挙げられる。なお、置換基が２個以上存在する場合は、各々独立して、前記の基の中から選ぶことができる。

(In the above formula, R ⁷ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a benzyl group or a protecting group for a nitrogen atom.)
And a group in which a hydrogen atom on a ring carbon atom or nitrogen atom is changed to a bond. In addition, when two or more substituents are present, each can be independently selected from the above groups.

Examples of the 6 to 16-membered aromatic hydrocarbon ring include, for example, those in which two or more hydrogen atoms are changed to bonds in W on the ring of a benzene ring, naphthalene ring or anthracene ring. May be one in which one hydrogen atom is changed to a bond. A preferred aromatic hydrocarbon ring includes a benzene ring.
Examples of 3- to 8-membered aliphatic hydrocarbon rings include saturated or unsaturated, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, or cyclooctene. On the ring of the aliphatic hydrocarbon ring, in W, two or more hydrogen atoms are changed to bonds, and in Q, one hydrogen atom is changed to a bond. Preferred aliphatic hydrocarbon rings include those having 5 to 6 members.

Examples of the 3- to 12-membered aliphatic heterocyclic ring include a saturated or unsaturated aliphatic heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. In W, two or more hydrogen atoms are changed to bonds, and in Q, one hydrogen atom is changed to a bond. Examples include aziridine, azetidine, pyrrolidine, piperidine, azepine, and azepane. Imidazolidine, piperazine, diazepine, tetrahydrofuran, or tetrahydrothiophene.
The aliphatic heterocyclic ring may have an amide bond or an imide bond in the ring, such as a 5- to 6-membered cyclic imide group such as a succinimide group or a glutaric imide group, or a cyclic amide group. Is mentioned. More specifically, for example, the following formula is exemplified.

好ましい脂肪族複素環としては５から６員のものが挙げられる。

Preferred aliphatic heterocycles include those having 5 to 6 members.

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

（上記式中、実線と点線とで示される結合は単結合または二重結合であることを表し、Ｅ’は＝ＣＨ−、−ＣＨ₂−、−Ｏ−、−Ｓ−、−ＳＯ−または−ＳＯ₂−を表す。Ｒ⁸は水素原子、アルキル基、ベンジル基、窒素原子の保護基または上記で例示した置換アルキル基を表わす。）

(In the above formula, a bond represented by a solid line and a dotted line represents a single bond or a double bond, and E ′ represents ═CH—, —CH ₂ —, —O—, —S—, —SO— or —SO ₂ — R ⁸ represents a hydrogen atom, an alkyl group, a benzyl group, a protecting group for a nitrogen atom or a substituted alkyl group exemplified above.

Examples of the 5- to 12-membered aromatic heterocycle include aromatic heterocycles containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom. 2 on W on the ring of pyridine (nitrogen atom may be oxidized), thiophene, furan, pyrrole, pyrazole, imidazole, pyrazine, pyrimidine, pyridazine, oxazoline, thiazoline, oxadiazoline, triazole or tetrazole. Examples of Q include one in which one or more hydrogen atoms have changed to bonds, and Q includes one in which one hydrogen atom has changed to bonds.
The above aromatic heterocyclic group may form a condensed ring with another ring, and examples of such other ring include the same “other rings” as described in the above aliphatic heterocyclic ring. . Specific examples of such a condensed heterocyclic ring include quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, quinazoline, indole, isoindole, benzofuran, and benzothiophene. Preferably 9 to 10 members are used.
Preferred aromatic heterocycles include 5- to 6-membered ones. More preferred is pyridine.
Substituted 6-16 membered aromatic hydrocarbon ring, substituted 3-8 membered aliphatic hydrocarbon ring, substituted 3-12 membered aliphatic heterocycle, and substituted 5-12 membered Examples of the substituent in the aromatic heterocyclic ring include the same groups as the substituents in the above substituted aryl group and substituted heteroaryl group.

Examples of the substituent of the substituted amino group include the above-mentioned substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted cycloalkyl group such as acetyl, propionyl, Or an alkanoyl group having 7 or less carbon atoms such as butyryl, an aroyl group having 11 or less carbon atoms such as benzoyl or naphthoyl, or an alkoxycarbonyl group having 7 or less carbon atoms such as methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl Etc. Specific examples of the substituted amino group include, for example, methylamino group, ethylamino group, cyclopropylamino group, dimethylamino group, acetylamino group, propionylamino group, benzoylamino group, naphthoylamino group, methoxycarbonylamino group, ethoxy Examples thereof include a carbonylamino group and a tert-butoxycarbonylamino group.
Examples of the substituent in the substituted carbamoyl group include the same groups as those in the substituted amino group.
Substitution in substituted alkylthioureido groups, substituted alkylureido groups, substituted alkylcarbamoyloxy groups, substituted alkyloxycarbonyl groups, substituted alkyloxycarbonylamino groups, substituted alkylsulfonylamino groups, substituted alkylsulfamoyl groups, and substituted alkylsulfyl groups Examples of the group include the same groups as the substituents in the aforementioned substituted alkyl group, substituted alkoxy group, and substituted alkylthio group.

n represents an integer of 0 to 10, preferably 0 to 6. More preferably, 1 is mentioned.
Examples of the protecting group for the nitrogen atom include substituted or unsubstituted alkyloxycarbonyl such as tert-butoxycarbonyl or benzyloxycarbonyl, acyl such as acetyl, or arylsulfonyl such as p-toluenesulfonyl.

  Examples of the 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring represented by ring A include 4 to 10 containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Represents a saturated or unsaturated nitrogen-containing heterocycle having the following formula:

で表される基などを挙げることができる。好ましいＡ環としては、５から７員の飽和または不飽和の含窒素複素環が挙げられる。さらに好ましくは、５から６員の飽和または不飽和の含窒素複素環が挙げられる。なお、上記Ａ環は適宜Ｒ⁰で表わされる置換基を有していてもよい。

The group etc. which are represented by these can be mentioned. Preferred A ring includes a 5- to 7-membered saturated or unsaturated nitrogen-containing heterocycle. More preferably, a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic ring is used. In addition, the A ring may have a substituent represented by R ^{0 as} appropriate.

  Next, although this invention compound is illustrated, this invention compound is not limited to these.

The compound (1) of the present invention or a pharmaceutically acceptable salt thereof can be produced by the method shown in the following formula.
Production method 1 (amino group alkylation, acylation, etc.)

（式中、Ａ、Ｒ⁰、Ｒ¹、 Ｒ²、Ｒ³、Ｒ⁴、ｐ，ｑ，ＸおよびＹは前記のとおりであり、ＬＧは脱離基を表す。）
脱離基ＬＧとしては、例えば塩素原子、臭素原子またはヨウ素原子などのハロゲン原子や、例えばアセトキシ、トシルオキシまたはメシルオキシなどのアシルオキシ基、またはスルホニルオキシ基などが挙げられる。
一般式（1⁰）で表される原料化合物は、文献記載の方法（例えば、国際公開第０４／０００８３７号パンフレット）もしくはそれに準じた方法で合成することができる。
本発明化合物（１）またはその塩は、化合物（1⁰）またはその塩を化合物（３）またはその塩と反応させることにより得ることができる。反応は、必要により塩基の存在下、また、場合により相間移動触媒の存在下、適当な不活性溶媒中で約−２０℃〜用いた溶媒の沸点までの範囲の温度で、１０分間〜４８時間反応させることにより行うことができる。
塩基としては、例えばトリエチルアミンまたはピリジン等の有機塩基、炭酸カリウム、水酸化ナトリウムまたは水素化ナトリウム等の無機塩基、またはナトリウムメトキシドまたはカリウムtert-ブトキシド等の金属アルコキシド等が挙げられる。
相間移動触媒としては、例えば硫酸水素テトラブチルアンモニウムなどが挙げられる。
不活性溶媒としては、例えばアセトニトリルや、クロロホルムまたはジクロロメタン等のハロゲン化炭化水素系溶媒、ベンゼンまたはトルエン等の芳香族炭化水素系溶媒、ジエチルエーテル、テトラヒドロフランまたは１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノールまたは２−プロパノール等のアルコール系溶媒、またはＮ，Ｎ−ジメチルホルムアミド、Ｎ−メチルピロリドンまたはジメチルスルホキシド等の非プロトン性極性溶媒、もしくはこれらの混合溶媒が挙げられる。

(In the formula, A, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , p, q, X and Y are as defined above, and LG represents a leaving group.)
Examples of the leaving group LG include a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, an acyloxy group such as acetoxy, tosyloxy or mesyloxy, or a sulfonyloxy group.
The raw material compound represented by the general formula (1 ⁰ ) can be synthesized by a method described in the literature (for example, International Publication No. 04/000837 pamphlet) or a method analogous thereto.
The compound (1) of the present invention or a salt thereof can be obtained by reacting the compound (1 ⁰ ) or a salt thereof with the compound (3) or a salt thereof. The reaction is carried out at a temperature ranging from about −20 ° C. to the boiling point of the solvent used in a suitable inert solvent, optionally in the presence of a base and optionally in the presence of a phase transfer catalyst, for 10 minutes to 48 hours. It can be performed by reacting.
Examples of the base include an organic base such as triethylamine or pyridine, an inorganic base such as potassium carbonate, sodium hydroxide or sodium hydride, or a metal alkoxide such as sodium methoxide or potassium tert-butoxide.
Examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate.
Examples of the inert solvent include acetonitrile, halogenated hydrocarbon solvents such as chloroform and dichloromethane, aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, Examples thereof include alcohol solvents such as methanol, ethanol and 2-propanol, aprotic polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide, and mixed solvents thereof.

Among the compounds (1) of the present invention, the compound represented by the formula (1a) or a salt thereof can also be produced by the following method.
Production method 2 (Reduction of amide)

（式中、Ａ、Ｒ⁰、Ｒ²、Ｒ³、Ｒ⁴、ｐ、ｑ、Ｘ、Ｙ、Ｒ¹⁰、Ｒ¹¹、Ｅ²、ＷおよびＱは前記と同じ意味を、ｎ’は１から１０の整数を、およびＥ⁰は単結合または−ＮＲ⁵（式中、Ｒ⁵は前記と同じ。）を表わす。）
化合物（１⁰）またはその塩を化合物（４）またはその塩と反応させてアミド結合を形成させることにより、中間体（５）を製造することができる。このアミド結合形成反応は、塩化チオニルまたはオキサリルクロライド等を用いる酸クロライド法、対応する酸無水物を用いる酸無水物法、クロロ炭酸エステル等を用いる混合酸無水物法、またはジシクロヘキシルカルボジイミドやカルボニルジイミダゾール等の縮合剤を用いる方法などの通常の方法を用いて行うことができる。
中間体（５）を適当な還元剤（例えば水素化リチウムアルミニウムまたはジボランなど）を用いて、適当な不活性溶媒（例えばジエチルエーテル、テトラヒドロフランまたは１，４−ジオキサン等のエーテル系溶媒など）中で、−２０℃から用いた溶媒の沸点までの間の温度で、１０分間〜４８時間反応させることにより、化合物（１a）を得ることができる。より具体的には、テトラヒドロフラン中、氷冷下もしくは室温にてジボランを用いて２０分間〜１時間、還元反応を行うことにより化合物（１a）を得ることができる。

(In the formula, A, R ⁰ , R ² , R ³ , R ⁴ , p, q, X, Y, R ¹⁰ , R ¹¹ , E ² , W and Q have the same meanings as described above; An integer of 10, and E ⁰ represents a single bond or —NR ⁵ (wherein R ⁵ is the same as defined above).
Intermediate (5) can be produced by reacting compound (1 ⁰ ) or a salt thereof with compound (4) or a salt thereof to form an amide bond. This amide bond forming reaction may be carried out by using an acid chloride method using thionyl chloride or oxalyl chloride, an acid anhydride method using a corresponding acid anhydride, a mixed acid anhydride method using chlorocarbonate, etc., or dicyclohexylcarbodiimide or carbonyldiimidazole. It can carry out using normal methods, such as the method of using condensing agents, such as.
Intermediate (5) is used in a suitable inert solvent (eg, ether solvents such as diethyl ether, tetrahydrofuran or 1,4-dioxane) using a suitable reducing agent (eg, lithium aluminum hydride or diborane). The compound (1a) 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 (1a) can be obtained by performing a reduction reaction in tetrahydrofuran for 20 minutes to 1 hour using diborane under ice cooling or at room temperature.

Production Method 3 (Reductive Amination)

（式中、Ａ、Ｒ⁰、Ｒ²、Ｒ³、Ｒ⁴、ｐ、ｑ、Ｘ、Ｙ、Ｒ¹⁰、Ｒ¹¹、ｎ’、Ｅ⁰、Ｅ²、ＷおよびＱは前記と同じ意味を表わす。）
目的化合物（1a）またはその塩は、化合物（1⁰）またはその塩を化合物（６）またはその塩と、還元的アミノ化条件で反応させることにより得られる。還元剤としては例えばトリアセトキシ水素化ほう素ナトリウム、シアノ水素化ほう素ナトリウムまたは水素化ほう素ナトリウムなどを用いることができ、化合物（1⁰）と化合物（６）はそのまま混合しても、またはあらかじめエナミンを形成させておいてから反応させてもよい。反応は適当な不活性溶媒、例えばアセトニトリルや、クロロホルムまたはジクロロメタン等のハロゲン化炭化水素系溶媒、ベンゼンまたはトルエン等の芳香族炭化水素系溶媒、ジエチルエーテル、テトラヒドロフランまたは１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、２−プロパノールまたは酢酸等のプロトン性極性溶媒、ジメチルホルムアミド、Ｎ−メチルピロリドンまたはジメチルスルホキシド等の非プロトン性極性溶媒、もしくはこれらの混合溶媒中、−２０℃から用いた溶媒の沸点までの間の温度で、１０分間〜４８時間反応させることにより行うことができる。

(In the formula, A, R ⁰ , R ² , R ³ , R ⁴ , p, q, X, Y, R ¹⁰ , R ¹¹ , n ′, E ⁰ , E ² , W and Q have the same meaning as described above. Represents.)
The target compound (1a) or a salt thereof can be obtained by reacting the compound (1 ⁰ ) or a salt thereof with the compound (6) or a salt thereof under reductive amination conditions. As the reducing agent, for example, sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride can be used, and the compound (1 ⁰ ) and the compound (6) may be mixed as they are, or You may make it react after forming enamine beforehand. The reaction is carried out in a suitable inert solvent such as acetonitrile, halogenated hydrocarbon solvent such as chloroform or dichloromethane, aromatic hydrocarbon solvent such as benzene or toluene, ether system such as diethyl ether, tetrahydrofuran or 1,4-dioxane. Solvent, protic polar solvent such as methanol, ethanol, 2-propanol or acetic acid, aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, or a solvent used from −20 ° C. in a mixed solvent thereof It can carry out by making it react for 10 minutes-48 hours at the temperature between the boiling point of.

Further, in the compound of the formula (1), another compound of the formula (1) may be obtained by appropriately converting a functional group. The transformation of the functional group is carried out by a commonly used general method [for example, Comprehensive Organic Transformations, R.I. C. By Larock (1989) etc.].
The compounds represented by formula (3), formula (4) and formula (6) are known compounds or can be synthesized from known compounds by known methods.

Throughout this specification, protecting groups, condensing agents and the like may be represented by abbreviations by IUPAC-IUB (Biochemical Nomenclature Board) commonly used in this technical field.
Suitable and pharmaceutically acceptable salts of the starting and target compounds are the conventional non-toxic salts, including organic acid salts (eg acetate, trifluoroacetate, maleate, fumarate) Citrate, tartrate, methanesulfonate, benzenesulfonate, formate or toluenesulfonate) and inorganic acid salts (eg hydrochloride, hydrobromide, hydroiodide, sulfate) Acid addition salts such as nitrates or phosphates, etc., salts with amino acids such as arginine, aspartic acid or glutamic acid, alkali metal salts such as sodium or potassium salts and alkaline earth metal salts such as calcium Metal salts such as salts or magnesium salts), ammonium salts, or organic base salts such as trimethylamine salts, triethyl Min salt, pyridine salt, picoline salt, dicyclohexylamine salt, or N, N'-dibenzylethylenediamine salt, etc.) Other such, a person skilled in the art can be selected appropriately.
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 reaction other than the reaction point is protected and reacted. Then, the desired compound can be obtained by deprotection. Protecting groups include, for example, Protective Groups in Organic Synthesis, TW Greene, John Wiley and Sons Incorporated (John Wiley & Sons Inc.) (1981) can be used. More specifically, amine protecting groups include ethoxycarbonyl, tert-butoxycarbonyl, acetyl or the like. Examples of the protecting group for the hydroxyl group include benzyl and the like, and trialkylsilyl, acetyl, benzyl and the like.
The introduction and removal of protecting groups should be carried out by methods commonly used in organic synthetic chemistry [see, for example, Protective Groups in Organic Synthesis above] or methods based thereon. Can do.
The intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in synthetic organic chemistry such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. In addition, the intermediate can be subjected to the next reaction without any particular purification.

Some of the compounds of the present invention contain asymmetric carbon atoms and stereoisomers exist, but the compounds of the present invention include mixtures and isolated isomers.
The compound of the present invention may be any of a free form, salt, hydrate, solvate such as ethanol.

Furthermore, the scope of the present invention includes prodrugs of the compounds of the present invention. In the present invention, the prodrug means a derivative that is obtained by acid hydrolysis or enzymatic degradation in vivo to give the compound of the formula (1). For example, when the compound of the formula (1) has a hydroxyl group, an amino group, or a carboxy group, these groups can be modified according to a conventional method to produce a prodrug.
For example, in the case of a compound having a carboxy group, a compound in which the carboxy group has become an alkoxycarbonyl group, a compound in which the alkylthiocarbonyl group has been formed, or a compound in which an alkylaminocarbonyl group has been mentioned.
Further, for example, in the case of a compound having an amino group, a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, an acyloxymethylamino group, Or a compound that has become hydroxylamine.
In addition, for example, in the case of a compound having a hydroxyl group, a compound in which the hydroxyl group is substituted with the acyl group to become an acyloxy group, a compound in which a phosphoric acid ester is formed, or a compound in which an acyloxymethyloxy group is formed may be mentioned.
Examples of the alkyl portion of the group used for forming a prodrug include the alkyl group, and the alkyl group may be substituted with, for example, an alkoxy group having 1 to 6 carbon atoms. Preferred examples include the following.
For example, examples of the compound in which the carboxy group is an alkoxycarbonyl group include C1-C6 alkoxycarbonyl groups such as methoxycarbonyl or ethoxycarbonyl, or methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2- And C1-C6 alkoxycarbonyl groups substituted by alkoxy groups such as methoxyethoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl.

  The compound of the present invention has a pharmacological action such as a dopamine agonist action. Therefore, it is useful for the treatment or prevention of diseases mediated by dopamine nerve, such as Parkinson's disease, anxiety, depression, hypertension, concomitant hypertension, and schizophrenia. Furthermore, since the compound of the present invention also has a pharmacological action such as a serotonin agonistic action, movement disorder, anxiety disorder, depressive symptom, dementia symptom, dyskinesia symptom in Parkinson's disease; Stabilization, involuntary movement disorders such as dyskinesia symptoms, psychiatric symptoms, autonomic dysfunction; mood disorders; anxiety disorders including obsessive-compulsive disorder and panic disorder; memory disorders including dementia, amnesia and age-related memory disorders; Disorders of eating behavior including anorexia nervosa and nervous starvation; obesity; sleep disorders; drug addiction such as alcohol, cigarettes and nicotine; cluster headache; migraine; pain; Alzheimer's disease; chronic seizure migraine; Headaches related to vascular disorders; neuroleptic-induced Parkinsonism, Parkinsonism syndrome including late-onset dyskinesia, striatal nigra degeneration Line supranuclear palsy, also useful for the treatment or prevention of movement disorders such as cerebellar degeneration diseases. In addition, endocrine abnormalities such as hyperprolactinemia; vasospasm (especially of the cerebral vasculature); disorders of the gastrointestinal tract involving changes in motility and secretion; sexual dysfunction including premature ejaculation; and drugs Useful for the treatment or prevention of addiction.

  For medical purposes, the compounds of the invention may be administered orally, parenterally, including topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intrathecal, tracheal or ocular administration, It can be used in the form of pharmaceutical preparations as a mixture with pharmaceutically acceptable carriers such as solid or liquid organic or inorganic excipients suitable for external use. The pharmaceutical preparations include capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops , Solids such as liquids, syrups, aerosols, suspensions, emulsions, semi-solids or liquids. These preparations can be produced by a usual method. If desired, auxiliaries, stabilizers, wetting or emulsifying agents, buffering agents and other conventional additives can be added to these preparations.

  The dose of the compound of the present invention varies depending on the age and condition of the patient. The average single dose of compound (1) is about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1,000 mg, for example For diseases such as Parkinson's disease, dyskinesia associated with Parkinson's disease, schizophrenia, depression, mood disorders including seasonal affective disorder and mood modulation; anxiety including general anxiety disorder and panic disorder, and other movement disorders including dyskinesia It is valid. Generally, when administered to a human, an amount of 0.1 mg / individual to about 1,000 mg / individual per day, preferably 1 mg / individual to about 100 mg / individual per day can be administered.

  The present invention will be described in detail below using examples and test examples, but the present invention is not limited to these examples.

Example 1
(+)-7-Piperidin-3-yl-1,3-benzoxazol-2 (3H) -one is represented as shown below. Furthermore, a compound produced from (+)-7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one is represented by adding an “*” to the asymmetric carbon.

7-ピペリジン-3-イル-1,3-ベンズオキサゾール-2(3H)-オン(15.0 g, 68.5 mmol)の２−プロパノール溶液(300 mL)と(2S)-(アセチルアミノ)(フェニル)酢酸(13.2 g, 68.5 mmol) の２−プロパノール溶液(800 mL)を混合し、室温にて16時間静置した。析出物をろ取した。得られた析出物(10.1 g)に２−プロパノール(750 mL)を加え、30分間加熱還流後、室温まで徐々に冷却し7時間静置した。ついで、析出物をろ取し、さらに得られた析出物(8.57 g)に２−プロパノール(200 mL)を加え、1時間加熱還流後、室温まで徐々に冷却し4時間静置した。析出物をろ取し、得られた析出物(8.25 g)に10% 炭酸カリウム水溶液(100 mL)を加え、さらに塩析し、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムにより乾燥後、ろ過、溶媒を減圧留去し、(+)-7-ピペリジン-3-イル-1,3-ベンズオキサゾール-2(3H)-オン(5.07 g, 99 % ee)を得た。
[α]²⁵ _D +14°(c=1.0, メタノール)
保持時間 26.5 分

7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one (15.0 g, 68.5 mmol) in 2-propanol (300 mL) and (2S)-(acetylamino) (phenyl) acetic acid A 2-propanol solution (800 mL) of (13.2 g, 68.5 mmol) was mixed and allowed to stand at room temperature for 16 hours. The precipitate was collected by filtration. 2-Propanol (750 mL) was added to the resulting precipitate (10.1 g), heated under reflux for 30 minutes, gradually cooled to room temperature, and allowed to stand for 7 hours. Next, the precipitate was collected by filtration, and 2-propanol (200 mL) was added to the resulting precipitate (8.57 g). The mixture was heated under reflux for 1 hour, then gradually cooled to room temperature, and allowed to stand for 4 hours. The precipitate was collected by filtration, and 10% aqueous potassium carbonate solution (100 mL) was added to the resulting precipitate (8.25 g), and further salted out and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give (+)-7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one (5.07 g, 99% ee).
[α] ²⁵ _D + 14 ° (c = 1.0, methanol)
Retention time 26.5 minutes

  The compound of Example 2 was produced in the same manner as in Example 1, using (2R)-(acetylamino) (phenyl) acetic acid as a resolving agent.

Example 2
(-)-7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one is represented as shown in the figure below. Furthermore, compounds produced from (-)-7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one shall be indicated by adding "**" to the asymmetric carbon. .

保持時間 28.5 分

Retention time 28.5 minutes

Example 3
7- (1-{[5- (4-Fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl) -1,3-benzoxazol-2 (3H) -one

7-ピペリジン-3-イル-1,3-ベンズオキサゾール-2(3H)-オン(267 mg, 1.22 mmol)、５−(４−フルオロフェニル)ニコチンアルデヒド(270 mg, 1.34 mmol)と酢酸(2 mL)のジクロロメタン溶液(40 mL)に室温でトリアセトキシ水素化ホウ素ナトリウム(1.03 g, 4.88 mmol)を加え、反応混合物を室温にて4時間攪拌した。反応終了確認後、反応系中に10 % 炭酸カリウム水溶液を加え、クロロホルムにて抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過、溶媒を減圧留去し、濃縮残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=50:1)にて粗精製した。得られた残渣を分取用薄層シリカゲルクロマトグラフィーにて精製し、７−(１−｛［５−（４−フルオロフェニル）ピリジン−３−イル］メチル｝ピペリジン−３−イル)−１，３−ベンズオキサゾール−2（3Ｈ）−オン(155 mg)を得た。
保持時間 22.5 分 23.3 分

7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one (267 mg, 1.22 mmol), 5- (4-fluorophenyl) nicotinaldehyde (270 mg, 1.34 mmol) and acetic acid (2 mL) in dichloromethane (40 mL) at room temperature was added sodium triacetoxyborohydride (1.03 g, 4.88 mmol) and the reaction mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, 10% aqueous potassium carbonate solution was added to the reaction system, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the concentrated residue was roughly purified by silica gel column chromatography (chloroform: methanol = 50: 1). The obtained residue was purified by preparative thin layer silica gel chromatography to obtain 7- (1-{[5- (4-fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl) -1, 3-Benzoxazol-2 (3H) -one (155 mg) was obtained.
Retention time 22.5 minutes 23.3 minutes

Example 4
7- (1-{[5- (4-Fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl) -1,3-benzoxazol-2 (3H) -one dihydrochloride

７−(１−｛［５−（４−フルオロフェニル）ピリジン−３−イル］メチル｝ピペリジン−３−イル)−１，３−ベンズオキサゾール−2（3Ｈ）−オン(138 mg, 0.342 mmol)のメタノール溶液(5.0 mL)に1N 塩酸−ジエチルエーテル溶液(1.03 mL)を加え、室温にて0.5時間攪拌した。溶媒を減圧留去し、過剰のn−ヘキサンを加えた。析出物をろ取して７−(１−｛［５−（４−フルオロフェニル）ピリジン−３−イル］メチル｝ピペリジン−３−イル)−１，３−ベンズオキサゾール−2（3Ｈ）−オン 二塩酸塩(142 mg)を得た。
保持時間 22.5 分 23.3 分

7- (1-{[5- (4-Fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl) -1,3-benzoxazol-2 (3H) -one (138 mg, 0.342 mmol) To a methanol solution (5.0 mL) was added 1N hydrochloric acid-diethyl ether solution (1.03 mL), and the mixture was stirred at room temperature for 0.5 hour. The solvent was distilled off under reduced pressure, and excess n-hexane was added. The precipitate was collected by filtration to 7- (1-{[5- (4-fluorophenyl) pyridin-3-yl] methyl} piperidin-3-yl) -1,3-benzoxazol-2 (3H) -one Dihydrochloride (142 mg) was obtained.
Retention time 22.5 minutes 23.3 minutes

  Using the same method as in Example 3, the compounds of Example 5 and Example 6 were produced from the compounds of Example 1 and Example 2, respectively.

Example 5

保持時間 22.5 分

Retention time 22.5 minutes

Example 6

保持時間 23.3 分

Retention time 23.3 minutes

The conditions for the liquid chromatography analysis in which the retention times are described in Example 1, Example 2, Example 3, Example 4, Example 5, and Example 6 are as follows.
LC measurement condition column: SUMICHIRAL OA-4000 (particle size 5 μm, inner diameter 4.6 mm, total length 25 cm, Sumika Chemical Analysis Center)
Flow rate: 1.0 mL / min
Measurement wavelength: 254 nm
Mobile phase: n-hexane: isopropanol: methanol: trifluoroacetic acid = 80: 15: 5: 0.1

Test Example 1: Screening test using [ ³ H] quinpirole binding 1-1 Preparation of striatal membrane preparation The membrane preparation was prepared by the method of Levant et al. (J. Pharmacol. Exp. Ther., 262, 929). -935 (1992)). That is, male rats were decapitated, the whole brain was quickly removed, and the striatum was fractionated under ice cooling. Add 20 times the buffer (50 mM Tris-HCl, 5 mM KCl, 2 mM MgCl ₂ , 2 mM CaCl ₂ , pH 7.4) to the wet weight, and add Teflon (registered trademark) glass in ice-cooling. Homogenization was performed using a homogenizer (Teflon-glass homogenizer). This was centrifuged at 48,000 xg for 15 minutes at 4 ° C, and the resulting sediment was placed in ice-cold buffer (50 mM Tris-HCl, 5 mM KCl, 2 mM MgCl ₂ , 2 mM CaCl ₂ , pH 7.4). The mixture was dispersed using Hiscotron (registered trademark), and centrifuged again at 48,000 xg for 15 minutes at 4 ° C. The membrane preparation thus obtained was suspended in the above buffer solution and stored frozen at -80 ° C.
1-2 receptor binding experiment
[ ³ H] quinpirole binding was measured according to the method of Levant et al. That is, 50 μL of [ ³ H] quinpirole (final concentration 2 nM) diluted with 50 mM Tris-HCl (pH 7.4) buffer containing 5 mM KCl, 2 mM MgCl ₂ and 2 mM CaCl ₂ 447.5 μL of the product 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 by suction onto a glass fiber filter paper. The glass fiber filter paper was washed 3 times with 5 mL of the same buffer solution, then transferred to a glass vial containing 4 mL 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 10 μM (+)-butaclamol.
The binding inhibition rate was calculated by the following formula:
Binding inhibition rate (%) = 100−100 × {[[ ³ H] quinpirole binding amount in the presence of test substance] − [[ ³ H] quinpirole binding amount in the presence of 10 μM (+)-butaclamol]} / {[[ ³ H] quinpriole binding in the absence of test substance] − [[ ³ H] quinpriole binding in the presence of 10 μM (+)-butaclamol]}

Test Example 2: [ ³ H] 8-Hydroxy-2- (dipropylamino) tetralin (8-OH-DPAT) binding test 2-1 test method Method by MD Hall et al. (J. Neurochem ., 44 , 1685-1696 (1985)). Male rats were decapitated, the whole brain was quickly removed, and the hippocampus was fractionated under ice cooling. Add 40 mM of 50 mM Tris-HCl (pH 7.4) to wet weight and homogenize (3 min, 1 stroke / min using Teflon-glass homogenizer in an ice bath) And then centrifuged (4 ° C.) at 40,000 × g for 10 minutes. The obtained precipitate was dispersed in ice-cold buffer (50 mM Tris-HCl (pH 7.4)) using Hiscotron (registered trademark), and centrifuged (4 ° C.) at 40,000 × g for 10 minutes. Further, the suspension was resuspended and the washing operation was repeated once. The obtained precipitate was dispersed in ice-cold buffer (50 mM Tris-HCl (pH 7.4)) using Hiscotron (registered trademark), incubated at 37 ° C. for 1 hour, and then centrifuged at 40,000 × g for 10 minutes ( 4 ° C.). Further, the suspension was resuspended and the washing operation was repeated once. The obtained membrane preparation was suspended in the above buffer and stored frozen at -80 ° C.
[ ³ H] 8-hydroxy-2- (dipropylamino) tetralin (hereinafter abbreviated as 8-OH-DPAT) in a buffer containing 50 mM Tris-HCl (pH 7.4) and 4 mM CaCl ₂ (final concentration) 0.2 nM) 50 μL, test drug solution 2.5 μL, and hippocampal membrane preparation 447.5 μL were added, and the total amount was measured using a 500 μL reaction solution. The reaction solution was reacted at room temperature for 20 minutes, and then quickly filtered under low pressure with suction onto a glass fiber filter paper. The glass fiber filter paper was washed 3 times with 5 mL of buffer solution, added to a glass vial containing 4 mL of ACS-II (Amersham), and the receptor-bound radioactivity remaining on the filter paper was measured with a liquid scintillation counter. Nonspecific binding was defined as the amount of binding in the presence of 1 μM 8-OH-DPAT.
The binding inhibition rate was calculated by the following formula:
Binding inhibition rate (%) = 100-100 × {[[ ³ H] 8-OH-DPAT binding amount in the presence of test substance]-[ ³ H] 8-OH in the presence of 1 μM 8-OH-DPAT -DPAT binding amount]} / {[[ ³ H] 8-OH-DPAT binding amount in the absence of test substance]-[[ ³ H] 8-OH-DPAT binding in the presence of 1 μM 8-OH-DPAT amount]}

Test Example 3: Serotonin 5-HT _1A Receptor and Dopamine D ₂ Receptor Operation Test 3-1 Preparation of Cells and Membrane Samples Chinese hamster ovary (CHO) cells expressing human serotonin 5-HT _1A receptor (Human 5-HT _1A / CHO) or Chinese hamster ovary (CHO) cells (human D _2L / CHO) expressing human dopamine D _2L receptor were used. Cells are cultured in F12 (all Gibco) containing 10% FCS, 500 μg / mL Geneticin and 100 U / mL penicillin-100 μg / mL streptmoycin in a 5% CO ₂ incubator. (A. Newman) et al. (Eur. J. Pharmacol., 307 , 107-111 (1996)). That is, the cells detached and collected with buffer A (20 mM HEPES, 5 mM MgSO ₄ ) were homogenized with Teflon-glass homogenizer, and then centrifuged (50,000 × g, 30 min, 4 min. ° C). The sediment was resuspended in an appropriate amount of buffer A and stored at −80 ° 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 [ ³⁵ S] GTPγS binding to human serotonin 5-HT _1A receptor and human dopamine D ₂ receptor was measured by the method of A. Newman et al. (Eur. J. Pharmacol., 307 , 107-111 (1996)). That is, 0.05 nM [ ³⁵ S] GTPγS (DuPont NEN) in buffer B (20 mM HEPES, 100 mM NaCl, 10 mM MgSO ₄ , 1 μM GDP, 0.1 mM DTT) containing 10 ⁻⁵ M of each test substance. ) And a fixed amount (about 50 μg / tube) of a membrane preparation were added, and a total volume of 1 mL 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-cooled buffer B, and the reaction was terminated by rapid suction filtration using glass fiber filter paper (Whatman, GF / B). Glass fiber filter paper washed twice with the same buffer was placed in a vial and 4 mL of ACS-II was added. The radioactivity of [ ³⁵ S] GTPγS on the filter paper was measured with a liquid scintillation counter. Specific binding of [ ³⁵ S] GTPγS was determined from nonspecific binding obtained in the presence of 10 μM GTPγS (Sigma). Serotonin 5-HT _1A receptor and dopamine D ₂ receptor agonistic activity of each test substance was increased when the increase in [ ³⁵ S] GTPγS binding by 10 μM serotonin (5-HT) and dopamine was taken as 100%, respectively. It was expressed as

  The compound obtained in Example 4 was tested in Test Example 1, Test Example 2, and Test Example 3 described above. The results are shown in Table 1.

Test Example 4: L-DOPA-induced dyskinesia behavior evaluation using unilateral dopamine disrupted rats 4-1. Creation of rats with L-DOPA-induced dyskinesia symptoms
SD male rats were held on a fixation device under pentobarbital anesthesia, then the medial forebrain bundle on the right (anterior -4.0mm from Bregma, 0.75mm to the right, and 8.0mm from brain surface, anterior -4.4mm from Bregma) 6-hydroxydopamine (6.0 μg / 2.0 μL and 7.5 μg / 2.5 μL, respectively) was injected into 1.2 mm to the right and 7.8 mm from the brain surface. Two weeks after the injection of 6-hydroxydopamine, apomorphine (0.1 mg / kg, sc) was administered to the rat and placed in a ball (radius approximately 40 cm). Was measured. Animals immediately exceeding 30 rotations for 30 minutes immediately after administration of Apomorphine were subjected to subsequent experiments on the assumption that unilateral dopamine destruction was completed.
For animals with complete unilateral dopamine disruption, L-DOPA (L-DOPA, 6 mg / kg, ip) and benserazide (benserazide, 15 mg / kg, ip) were introduced after 2 weeks of the apomorphine test. ) Once a day for 4 weeks. Dyskinesia symptoms were evaluated 4 weeks after the start of L-DOPA administration, and only animals exhibiting stable symptoms were used for evaluation of drug efficacy. Even after symptom confirmation, L-DOPA was administered twice or more per week.
4-2. Evaluation of dyskinesia symptoms induced by L-DOPA (M. Lundblad et al, Eur. J. Neurosci. 15, 120-132, 2002) ). That is, observe for 1 minute every 20 minutes until 360 minutes after administration of L-DOPA and benserazide and score abnormal involantary movements (AIMs) according to the following method. did.
・ Limb AIMs ・ ・ Involuntary bending and stretching of the forelimbs on the opposite side of the dopamine nerve destruction side and movement of the palm and wrist. A chore of chorea and dystonia.
・ Axial AIMs ・ ・ Upper body to the opposite side of the destruction ・ Neck twisting, falling out of balance or maintaining its unstable posture ・ Orolingual AIMs ・ ・ Jaw movement of the jaw, protruding tongue violently forward.
・ Locomotive AIMs ・ ・ Rotating behavior to the opposite side from the destruction side The score is 0: no observation, 1; less than 30 seconds, 2; more than 30 seconds, 3; Stopped by sound stimulation, 4; expressed constantly, and continued by sound stimulation.
Furthermore, these scores were totaled for each item, and Locomotive AIMs were used as dopamine stimulation scores, and the sum of Limb AIMs, Axial AIMs, and Orolingual AIMs was used as dyskinesia scores. The evaluation of L-DOPA (L-DOPA) -induced dyskinesia inhibitory effect of the test compound was performed 30 minutes after administration of the test compound. L-DOPA (L-DOPA, 3 mg / kg, ip) and benserazide (benserazide, 15 mg / kg) , ip) was administered, and the scores from 20 minutes to 180 minutes later were counted.

  With respect to the compound obtained in Example 4, the test of Test Example 4 was performed. The results are shown in Table 2. Example compound 4 increased the dopamine stimulation score with little increase in dyskinesia score.

Claims (10)

Formula (1)

[In the formula, A ring represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring.
Y represents a carbon atom.
R ⁰ is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, Or represents a hydroxyl group.
p and q each independently represents an integer of 0 to 3.
R ¹ is the formula (2)

(Wherein R ¹⁰ and R ¹¹ are the same or different, and when there are a plurality of them, each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, It represents a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
E ¹ and E ² are the same or different and are a single bond, —O—, —NR ⁵ —, —CO—, —CO—O—, —S (O) _m —, —NR ⁵ —CO—NR ⁶ —. , —NR ⁵ —CS—NR ⁶ —, —O—CO—NR ⁵ —, —NR ⁵ —CO—O—, —NR ⁵ —SO ₂ —, —SO ₂ —NR ⁵ —, —CS—, — CS—O—, —NR ⁵ —CO—, —CO—NR ⁵ —, —O—CO—, or —O—CS— (wherein R ⁵ and R ⁶ are each independently a hydrogen atom, substituted Or an unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, wherein m represents an integer of 0 to 2.
W is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, a substituted or unsubstituted 3 to 8 membered aliphatic hydrocarbon ring, a substituted or unsubstituted 3 to 12 membered aliphatic heterocyclic ring, or Represents a substituted or unsubstituted 5- to 12-membered aromatic heterocycle.
Q is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, a substituted or unsubstituted 3 to 8 membered aliphatic hydrocarbon ring, a substituted or unsubstituted 3 to 12 membered aliphatic heterocycle, substituted Or an unsubstituted 5- to 12-membered aromatic heterocycle, formyl group, sulfonic acid group, substituted or unsubstituted alkylthioureido group, substituted or unsubstituted alkylureido group, substituted or unsubstituted alkylcarbamoyloxy group, substituted Or an unsubstituted alkyloxycarbonylamino group, a substituted or unsubstituted alkylsulfonylamino group, a substituted or unsubstituted alkylsulfamoyl group, or a substituted or unsubstituted alkylsulfinyl group;
However, when E ² is —CO—, Q is not a substituted or unsubstituted aryl group. Two or more groups represented by -E ² -Q may be present independently.
n represents an integer of 0 to 10. ).
R ² and R ³ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted cycloalkyl group.
R ⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted cycloalkyl group.
X is independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl, Group, hydroxyl group, nitro group, substituted or unsubstituted alkoxy group, substituted or unsubstituted alkylthio group, cyano group, substituted or unsubstituted carbamoyl group, carboxy group, substituted or unsubstituted alkyloxycarbonyl group, or substituted or Represents an unsubstituted amino group. ]
Or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Q is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, a substituted or unsubstituted 3 to 8 membered aliphatic hydrocarbon ring, a substituted or unsubstituted 3 to 12 membered aliphatic heterocycle, substituted Or the compound according to claim 1, which is an unsubstituted 5- to 12-membered aromatic heterocycle, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, or a prodrug thereof, wherein Q is a substituted or unsubstituted 6 to 16 membered aromatic hydrocarbon ring, or a substituted or unsubstituted 5 to 12 membered aromatic heterocyclic ring, or Their pharmaceutically acceptable salts. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the A ring is a 5- to 7-membered saturated or unsaturated nitrogen-containing heterocyclic ring. The compound according to any one of claims 1 to 4, wherein E ² is a single bond, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Formula (1) is the following formula (1x) or (1y):

The compound according to any one of claims 1 to 5, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. The pharmaceutical containing the compound as described in any one of Claims 1-6, its prodrug, or those pharmacologically acceptable salts. A therapeutic agent for Parkinson's disease comprising the compound according to any one of claims 1 to 6 or a prodrug thereof, or a pharmaceutically acceptable salt thereof. A therapeutic agent for dyskinesia containing the compound according to any one of claims 1 to 6, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. A therapeutic agent for dyskinesia associated with Parkinson's disease, comprising the compound according to any one of claims 1 to 6 or a prodrug thereof, or a pharmaceutically acceptable salt thereof.