JP2001261679A - Pyrrolidinone derivative, method for producing the same and medicament containing the same compound - Google Patents
Pyrrolidinone derivative, method for producing the same and medicament containing the same compoundInfo
- Publication number
- JP2001261679A JP2001261679A JP2000079045A JP2000079045A JP2001261679A JP 2001261679 A JP2001261679 A JP 2001261679A JP 2000079045 A JP2000079045 A JP 2000079045A JP 2000079045 A JP2000079045 A JP 2000079045A JP 2001261679 A JP2001261679 A JP 2001261679A
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- diazaspiro
- general formula
- chlorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 150000004040 pyrrolidinones Chemical class 0.000 title claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title abstract description 12
- 208000008589 Obesity Diseases 0.000 claims abstract description 16
- 235000020824 obesity Nutrition 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 208000030814 Eating disease Diseases 0.000 claims abstract description 8
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 8
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 8
- -1 allyl halide Chemical class 0.000 claims description 190
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 239000004480 active ingredient Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 108010085082 sigma receptors Proteins 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000001887 anti-feedant effect Effects 0.000 abstract description 3
- 229940043274 prophylactic drug Drugs 0.000 abstract 3
- 229940126585 therapeutic drug Drugs 0.000 abstract 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- QMCMFUXRGPXJPD-UHFFFAOYSA-N 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN1CCCC1=O QMCMFUXRGPXJPD-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
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- 238000001914 filtration Methods 0.000 description 8
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- 239000000969 carrier Substances 0.000 description 5
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- 150000008064 anhydrides Chemical class 0.000 description 3
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- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
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- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
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- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 2
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- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
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- 231100000419 toxicity Toxicity 0.000 description 2
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は新規なピロリジノン
誘導体またはその薬理学的に許容される塩に関する。さ
らに詳しくは、該化合物を含有し、特にシグマ受容体に
対する親和性を有する薬剤として、肥満症、摂食障害、
肥満が原因となる生活習慣病の治療または予防に有効な
薬剤に関するものである。TECHNICAL FIELD The present invention relates to a novel pyrrolidinone derivative or a pharmaceutically acceptable salt thereof. More specifically, as a drug containing the compound, particularly having affinity for sigma receptor, obesity, eating disorders,
The present invention relates to a drug effective for treating or preventing a lifestyle-related disease caused by obesity.
【０００２】[0002]
【従来の技術】肥満は先進工業国において深刻な問題化
しつつあり、糖尿病、高脂血症、高血圧などの生活習慣
病、虚血性心疾患や動脈硬化症の基盤になっている。肥
満治療の原則は食事・運動療法であるが、高度肥満者や
骨・関節疾患のために運動療法が困難な肥満者の治療に
は、薬物治療が必要である。肥満の薬物治療として、食
欲抑制薬であるマジンドールが唯一現在国内で上市され
ているが、依存性、耐性など副作用の問題から使用が厳
しく制限されており、臨床のニーズを十分満足するには
至っていない。2. Description of the Related Art Obesity is becoming a serious problem in industrialized countries, and is the basis for lifestyle-related diseases such as diabetes, hyperlipidemia and hypertension, ischemic heart disease and arteriosclerosis. The principle of obesity treatment is diet / exercise therapy, but drug treatment is necessary for the treatment of highly obese people and those who have difficulty in exercise therapy due to bone and joint diseases. As a drug treatment for obesity, the only appetite suppressant, mazindol, is currently on the market in Japan, but its use is severely restricted due to problems with side effects such as dependence and resistance, and it has not been possible to fully satisfy clinical needs. Not in.
【０００３】近年シグマ受容体の薬理学的研究が活発に
行われ、例えば、Ｊｏｕｒｎａｌｏｆ Ｍｅｄｉｃｉｎ
ａｌ Ｃｈｅｍｉｓｔｒｙ，３８，１９９８−２０１７
（１９９５）に総説が記載されている。またシグマ受容
体に親和性を有するピロリジノン誘導体が、抗精神作用
を有することが、例えば特開平１０−１８２６０２に報
告されている。しかしながらシグマ受容体については不
明な点が多く、現在シグマ受容体と摂食との関係を示す
報告は、Ｂｌａｋｅ，Ａ．Ｇ：Ｐｈａｒｍａｃｏｌ．Ｂ
ｉｏｃｈｅｍ．＆ Ｂｅｈａｖｏｉｒ，１９，７３７
（１９８３）に記載されているＳＫＦ−１０，０４７に
よる摂食亢進作用のみであり、摂食抑制作用の報告はな
い。[0003] In recent years, pharmacological studies on sigma receptors have been actively conducted, and for example, Journalof Medicin.
al Chemistry, 38 , 1998-2017.
(1995) provides a review. Further, it has been reported, for example, in JP-A-10-182602 that a pyrrolidinone derivative having an affinity for a sigma receptor has an antipsychotic effect. However, there are many unknowns about sigma receptors, and a report showing the relationship between sigma receptors and feeding at present has been reported by Blake, A .; G: Pharmacol. B
iochem. & Behavoir, 19 , 737
(1983), only SKF-10,047 has the effect of enhancing food intake, and there is no report of the effect of suppressing food intake.
【０００４】[0004]
【発明が解決しようとする課題】シグマ受容体に親和性
を有し、肥満症、摂食障害、肥満が原因となる生活習慣
病の治療または予防薬として有用な化合物および該化合
物を含有する医薬用組成物を提供すること。A compound having affinity for a sigma receptor and useful as an agent for treating or preventing obesity, eating disorders and lifestyle-related diseases caused by obesity, and a medicament containing the compound Providing a composition for use.
【０００５】[0005]
【課題を解決するための手段】本発明者らは前記課題解
決のため、シグマ受容体に親和性を有する化合物を鋭意
検討する中で、ピロリジノン誘導体がシグマ受容体に強
い親和性を有し、摂食抑制作用を有することを見いだ
し、本発明を完成した。すなわち、本発明は、〔１〕式
（１）[化６]Means for Solving the Problems In order to solve the above problems, the present inventors have intensively studied a compound having an affinity for a sigma receptor, and found that a pyrrolidinone derivative has a strong affinity for a sigma receptor. The present inventors have found that they have an antifeeding effect, and have completed the present invention. That is, the present invention relates to [1] Formula (1)
【０００６】[0006]
【化６】 Embedded image
【０００７】（式中、X1およびX2は同一または異なって
もよい水素原子、炭素数１〜６のアルキル基、ハロゲン
原子、炭素数１〜６のアルキルオキシ基を表わす。Ｒは
炭素数２〜６のアルキル基、末端にフェニル基が置換し
た炭素数２〜６のアルキル基、末端に炭素数１〜４のア
ルキルオキシ基が置換した炭素数１〜６のアルキル基、
もしくは末端に炭素数１〜４のアルキルチオ基が置換し
た炭素数１〜６のアルキル基を表わす。）で表わされる
ピロリジノン誘導体またはその薬理学的に許容される塩
であり、また、〔２〕Rが炭素数１〜６のアルキル基で
ある〔１〕記載のピロリジノン誘導体またはその薬理学
的に許容される塩であり、また、〔３〕X1およびX2が水
素原子もしくはハロゲン原子である〔２〕記載のピロリ
ジノン誘導体またはその薬理学的に許容される塩であ
り、また、〔４〕式（２）[化７](Wherein X 1 and X 2 represent a hydrogen atom which may be the same or different, an alkyl group having 1 to 6 carbon atoms, a halogen atom, an alkyloxy group having 1 to 6 carbon atoms. An alkyl group having 2 to 6 carbon atoms, an alkyl group having 2 to 6 carbon atoms substituted by a phenyl group at a terminal, an alkyl group having 1 to 6 carbon atoms substituted by an alkyloxy group having 1 to 4 carbon atoms at a terminal,
Alternatively, it represents an alkyl group having 1 to 6 carbon atoms in which a terminal is substituted by an alkylthio group having 1 to 4 carbon atoms. Or a pharmacologically acceptable salt thereof, and [2] the pyrrolidinone derivative according to [1], wherein R is an alkyl group having 1 to 6 carbon atoms, or a pharmacologically acceptable salt thereof. [3] The pyrrolidinone derivative according to [2], wherein X 1 and X 2 are a hydrogen atom or a halogen atom, or a pharmacologically acceptable salt thereof; (2) [Formula 7]
【０００８】[0008]
【化７】 Embedded image
【０００９】（式中、X1、X2、Rは〔１〕の場合と同
義。）で表わされるピロリジノン誘導体とハロゲン化ア
リルを反応させ、式（３）[化８](Wherein X 1 , X 2 and R have the same meanings as in [1]), and a pyrrolidinone derivative represented by the formula (3) is reacted with an allyl halide.
【００１０】[0010]
【化８】 Embedded image
【００１１】（式中、X1、X2は〔１〕の場合と同義。）
で表わされる３，３−ジアリルピロリジノン誘導体と
し、炭素−炭素２重結合を酸化的分解により式（４）
[化９](Wherein, X 1 and X 2 have the same meanings as in [1].)
3,4-diallylpyrrolidinone derivative represented by the formula (4) by oxidative decomposition of carbon-carbon double bond
[Formula 9]
【００１２】[0012]
【化９】 Embedded image
【００１３】（式中、X1、X2は〔１〕の場合と同義。）
で表わされる３，３−ジヒドロキシエチルピロリジノン
誘導体とし、さらに式（５）[化１０](Wherein, X 1 and X 2 have the same meanings as in [1].)
3,3-dihydroxyethylpyrrolidinone derivative represented by the following formula (5):
【００１４】[0014]
【化１０】 Embedded image
【００１５】（式中、X1、X2は〔１〕の場合と同義。Q
はハロゲン原子、炭素数１〜４のアルキルスルホニルオ
キシ基もしくはアリールスルホニルオキシ基を表わ
す。）で表わされるピロリジノン誘導体をR−NH2（Rは
〔１〕の場合と同義。）と反応させることによる〔１〕
記載のピロリジノン誘導体の製造方法であり、また、
〔５〕〔１〕、〔２〕、〔３〕記載のピロリジノン誘導
体またはその薬理学的に許容される塩を有効成分とする
医薬用組成物であり、また、〔６〕〔１〕、〔２〕、
〔３〕記載のピロリジノン誘導体またはその薬理学的に
許容される塩を有効成分とする肥満症、摂食障害、肥満
が原因となる生活習慣病の治療または予防剤。(Where X 1 and X 2 have the same meanings as in [1].
Represents a halogen atom, an alkylsulfonyloxy group having 1 to 4 carbon atoms or an arylsulfonyloxy group. Pyrrolidinone derivative represented by) the R-NH 2 (R by reacting synonymous.) In the case of [1] [1]
A method for producing a pyrrolidinone derivative according to the above,
[5] A pharmaceutical composition comprising, as an active ingredient, the pyrrolidinone derivative or a pharmaceutically acceptable salt thereof according to [1], [2], or [3], and [6] [1], [ 2],
[3] An agent for treating or preventing obesity, eating disorders, and lifestyle-related diseases caused by obesity, comprising the pyrrolidinone derivative or a pharmaceutically acceptable salt thereof according to [3] as an active ingredient.
【００１６】[0016]
【発明の実施の形態】以下、本発明を詳細に説明する。
一般式（１）[化１１]において、BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
In the general formula (1),
【００１７】[0017]
【化１１】 Embedded image
【００１８】炭素数１〜６のアルキル基とは、炭素数１
〜６の直鎖状、分岐状または環状のアルキル基を表わ
し、メチル基、エチル基、、ｎ−プロピル基、ｎ−ブチ
ル基、ｎ−ペンチル基、ｎ−ヘキシル基、イソプロピル
基、シクロプロピル基、２−メチルプロピル基、１−メ
チルプロピル基、ｔ−ブチル基、シクロブチル基、シク
ロペンチル基、３-メチルブチル基、２−メチルブチル
基、１-メチルブチル基、１，１−ジメチルプロピル
基、１，２−ジメチルプロピル基、２，２−ジメチルプ
ロピル基、シクロヘキシル基、４-メチルペンチル基、
３−メチルペンチル基、２−メチルペンチル基、１−メ
チルペンチル基、１，２，２−トリメチルプロピル基、
１，１，２−トリメチルプロピル基、１，１−ジメチル
ブチル基、２，２−ジメチルブチル基、１，３−ジメチ
ルブチル基、２，３−ジメチルブチル基等の基が例示で
きる。An alkyl group having 1 to 6 carbon atoms means 1 carbon atom.
Represents a linear, branched or cyclic alkyl group of from 1 to 6, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, cyclopropyl , 2-methylpropyl, 1-methylpropyl, t-butyl, cyclobutyl, cyclopentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1,1-dimethylpropyl, 1,2 -Dimethylpropyl group, 2,2-dimethylpropyl group, cyclohexyl group, 4-methylpentyl group,
3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 1,2,2-trimethylpropyl group,
Examples thereof include 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, and 2,3-dimethylbutyl group.
【００１９】ハロゲン原子とはヨウ素原子、臭素原子、
塩素原子、フッ素原子が例示できる。A halogen atom is an iodine atom, a bromine atom,
Examples thereof include a chlorine atom and a fluorine atom.
【００２０】炭素数１〜６のアルキルオキシ基とは、炭
素数１〜６の直鎖状、分岐状または環状のアルキルオキ
シ基を表し、メトキシ基、エトキシ基、ｎ−プロピルオ
キシ基、ｎ−ブチルオキシ基、ｎ−ペンチルオキシ基、
ｎ−ヘキシルオキシ基、イソプロピルオキシ基、ｔ−ブ
チルオキシ基、シクロプロピルオキシ基、シクロブチル
オキシ基、シクロペンチルオキシ基、シクロヘキシルオ
キシ基等の基が例示できる。The alkyloxy group having 1 to 6 carbon atoms means a linear, branched or cyclic alkyloxy group having 1 to 6 carbon atoms, and includes a methoxy group, an ethoxy group, an n-propyloxy group and an n- Butyloxy group, n-pentyloxy group,
Examples include n-hexyloxy group, isopropyloxy group, t-butyloxy group, cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, and cyclohexyloxy group.
【００２１】炭素数２〜６のアルキル基とは、炭素数２
〜６の直鎖状、分岐状または環状のアルキル基を表わ
し、例えばエチル基、、ｎ−プロピル基、ｎ−ブチル
基、ｎ−ペンチル基、ｎ−ヘキシル基、イソプロピル
基、シクロプロピル基、２−メチルプロピル基、１−メ
チルプロピル基、ｔ−ブチル基、シクロブチル基、シク
ロペンチル基、３-メチルブチル、２−メチルブチル
基、１-メチルブチル、１，１−ジメチルプロピル基、
１，２−ジメチルプロピル基、２，２−ジメチルプロピ
ル基、シクロヘキシル基、４-メチルペンチル基、３−
メチルペンチル基、２−メチルペンチル基、１−メチル
ペンチル基、１，２，２−トリメチルプロピル基、１，
１，２−トリメチルプロピル基、１，１−ジメチルブチ
ル基、２，２−ジメチルブチル基、１，３−ジメチルブ
チル基、２，３−ジメチルブチル基等の基が例示でき
る。An alkyl group having 2 to 6 carbon atoms refers to an alkyl group having 2 carbon atoms.
To 6, a linear, branched or cyclic alkyl group, for example, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, cyclopropyl group, -Methylpropyl group, 1-methylpropyl group, t-butyl group, cyclobutyl group, cyclopentyl group, 3-methylbutyl, 2-methylbutyl group, 1-methylbutyl, 1,1-dimethylpropyl group,
1,2-dimethylpropyl group, 2,2-dimethylpropyl group, cyclohexyl group, 4-methylpentyl group, 3-
Methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 1,2,2-trimethylpropyl group, 1,
Examples thereof include a 1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, and a 2,3-dimethylbutyl group.
【００２２】末端にフェニル基が置換した炭素数２〜６
のアルキル基とは、例えば２−フェニルエチル基、３−
フェニルプロピル基、４−フェニルブチル基、５−フェ
ニルペンチル基、６−フェニルヘキシル基等の基が例示
できる。C2-C6 substituted by a phenyl group at the terminal
And the like are, for example, a 2-phenylethyl group,
Examples thereof include a phenylpropyl group, a 4-phenylbutyl group, a 5-phenylpentyl group, and a 6-phenylhexyl group.
【００２３】末端に炭素数１〜４のアルキルオキシ基が
置換した炭素数１〜６のアルキル基とは、メトキシメチ
ル基、、メトキシエチル基、、メトキシプロピル基、エ
トキシプロピル基、ｎ−プロピルオキシブチル基、ｎ−
ブチルオキシメチル基、、ｎ−ペンチルオキシエチル
基、、ｎ−ヘキシルオキシプロピル基、イソプロピルオ
キシペンチル基、ｔ−ブチルオキシヘキシル基等の基が
例示できる。A C1-C6 alkyl group having a C1-C4 alkyloxy group at the terminal is a methoxymethyl group, a methoxyethyl group, a methoxypropyl group, an ethoxypropyl group, an n-propyloxy group. Butyl group, n-
Examples include a butyloxymethyl group, an n-pentyloxyethyl group, an n-hexyloxypropyl group, an isopropyloxypentyl group, and a t-butyloxyhexyl group.
【００２４】末端に炭素数１〜４のアルキルチオ基が置
換した炭素数１〜６のアルキル基とは、メチルチオエチ
ル基、、メチルチオプロピル基、エチルチオプロピル
基、ｎ−プロピルチオブチル基、ｎ−ブチルチオメチル
基、、メチルチオヘキシル基、シクロプロピルチオプロ
ピル基、イソプロピルチオペンチル基、イソブチルチオ
ヘキシル基等の基が例示できる。一般式（５）[化１２]
においてThe alkyl group having 1 to 6 carbon atoms in which the alkylthio group having 1 to 4 carbon atoms is substituted at the terminal includes methylthioethyl group, methylthiopropyl group, ethylthiopropyl group, n-propylthiobutyl group and n-propylthio group. Examples thereof include a butylthiomethyl group, a methylthiohexyl group, a cyclopropylthiopropyl group, an isopropylthiopentyl group, and an isobutylthiohexyl group. General formula (5)
At
【００２５】[0025]
【化１２】 Embedded image
【００２６】Qのハロゲン原子とは、ヨウ素原子、臭素
原子、塩素原子が例示できる。炭素数１〜４のアルキル
スルホニルオキシ基とは、メタンスルホニルオキシ基、
エタンスルホニルオキシ基、ｎ−プロパンスルホニルオ
キシ基、ｎ−ブタンスルホニルオキシ基、イソプロパン
スルホニルオキシ基、ｔ−ブタンスルホニルオキシ基、
シクロプロパンスルホニルオキシ基、シクロブタンスル
ホニルオキシ基等の基が例示できる。アリールスルホニ
ルオキシ基とは、ベンゼンスルホニルオキシ基、トルエ
ンスルホニルオキシ基等の基が例示できるExamples of the halogen atom for Q include an iodine atom, a bromine atom and a chlorine atom. The alkylsulfonyloxy group having 1 to 4 carbon atoms means a methanesulfonyloxy group,
Ethanesulfonyloxy group, n-propanesulfonyloxy group, n-butanesulfonyloxy group, isopropanesulfonyloxy group, t-butanesulfonyloxy group,
Examples thereof include a cyclopropanesulfonyloxy group and a cyclobutanesulfonyloxy group. Examples of the arylsulfonyloxy group include groups such as a benzenesulfonyloxy group and a toluenesulfonyloxy group.
【００２７】本発明の一般式（１）で表される化合物に
おいて、分子内に不斉炭素を有する場合には、これらの
不斉炭素に関してＲ配置、Ｓ配置のいずれの光学異性体
も本発明に包含される。When the compound represented by the general formula (1) of the present invention has an asymmetric carbon in the molecule, any of the optical isomers of the R configuration and the S configuration with respect to these asymmetric carbons can be used in the present invention. Is included.
【００２８】一般式（１）の化合物は、必要に応じて薬
理学的に許容される塩とすることができ、例えば塩酸、
臭化水素酸、リン酸、硫酸などの無機酸またはギ酸、酢
酸、フマル酸、クエン酸、マレイン酸、シユウ酸、リン
ゴ酸、酒石酸、メタンスルホン酸、ベンゼンスルホン
酸、ｐ−トルエンスルホン酸などの有機酸との塩が挙げ
られる。The compound of the general formula (1) can be converted into a pharmacologically acceptable salt, if necessary.
Inorganic acids such as hydrobromic acid, phosphoric acid and sulfuric acid or formic acid, acetic acid, fumaric acid, citric acid, maleic acid, oxalic acid, malic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. And salts with organic acids.
【００２９】次に本発明化合物の製造方法について詳細
に説明する。式（１）の化合物は、例えば下記のような
方法により製造できる。 ［工程１］一般式（２）［化１３］Next, the method for producing the compound of the present invention will be described in detail. The compound of the formula (1) can be produced, for example, by the following method. [Step 1] General formula (2)
【００３０】[0030]
【化１３】 Embedded image
【００３１】（式中、X1、X2は前記の定義と同義。）で
表わされるピロリジノン誘導体とハロゲン化アリルを適
当な塩基の存在下、適当な溶媒中もしくは無溶媒で反応
させることにより、一般式（３）［化１４］(Wherein X 1 and X 2 have the same meanings as defined above) by reacting the pyrrolidinone derivative represented by the formula with an allyl halide in a suitable solvent or without a solvent in the presence of a suitable base. General formula (3)
【００３２】[0032]
【化１４】 Embedded image
【００３３】（式中、X1、X2は前記の定義と同義。）で
表わされる３，３−ジアリルピロリジノン誘導体を合成
できる。反応温度は−９０℃〜２００℃、好ましくは−
７５℃〜１００℃であり、反応時間は１〜２０時間、好
ましくは１〜１０時間である。(Wherein X 1 and X 2 have the same meanings as defined above), and a 3,3-diallylpyrrolidinone derivative represented by the following formula can be synthesized. The reaction temperature is -90 ° C to 200 ° C, preferably-
75 ° C to 100 ° C, and the reaction time is 1 to 20 hours, preferably 1 to 10 hours.
【００３４】塩基としては、例えばｎ−ブチルリチウ
ム、ｓｅｃ−ブチルリチウム、ｔ−ブチルリチウム、フ
ェニルリチウムなどの有機リチウム試薬、リチウム ジ
イソプロピルアミド（LDA）、リチウム ヘキサメチルジ
シラザン（ＬＨＭＤＳ）などのリチウムアミド類、水素
化ナトリウム、水素化リチウム、水素化カリウムなどの
水素化金属試薬が挙げられる。Examples of the base include organic lithium reagents such as n-butyllithium, sec-butyllithium, t-butyllithium, and phenyllithium; and lithium amides such as lithium diisopropylamide (LDA) and lithium hexamethyldisilazane (LHMDS). And metal hydride reagents such as sodium hydride, lithium hydride and potassium hydride.
【００３５】用いられる溶媒としては例えば、ジエチル
エーテル、テトラヒドロフラン、１，４−ジオキサン、
１，２−ジメトキシエタン等のエーテル類、ジクロロメ
タン、クロロホルム、１，２−ジクロロエタン等のハロ
ゲン化炭化水素、ベンゼン、トルエン、ヘキサン等の炭
化水素類が挙げられる。As the solvent to be used, for example, diethyl ether, tetrahydrofuran, 1,4-dioxane,
Examples thereof include ethers such as 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane, and hydrocarbons such as benzene, toluene, and hexane.
【００３６】一般式（２）とハロゲン化アリルの使用割
合に特に制限はないが、通常はモル比で前者：後者が
１：１〜１：３０、好ましくは１：２〜１：１０であ
る。There are no particular restrictions on the proportions of the general formula (2) and the allyl halide, but the molar ratio of the former to the latter is usually from 1: 1 to 1:30, preferably from 1: 2 to 1:10. .
【００３７】［工程２］工程１で得た一般式（３）で表
わされる化合物の炭素−炭素２重結合を不活性溶媒中、
オゾンと反応させ、さらに酸化生成物を還元剤で分解す
ることにより、一般式（４）［化１５］[Step 2] The carbon-carbon double bond of the compound represented by the general formula (3) obtained in Step 1 is converted into an inert solvent
By reacting with ozone and further decomposing the oxidation product with a reducing agent, the compound represented by the general formula (4)
【００３８】[0038]
【化１５】 Embedded image
【００３９】（式中、X1、X2は前記の定義と同義。）で
表わされる３，３−ジヒドロキシエチルピロリジノン誘
導体を得ることができる。反応温度は−９０℃〜２００
℃、好ましくは−７５℃〜室温℃で、反応時間は１〜２
０時間、好ましくは１〜１０時間である。(Wherein, X 1 and X 2 have the same meanings as defined above), whereby a 3,3-dihydroxyethylpyrrolidinone derivative represented by the following formula can be obtained. Reaction temperature is -90 ° C to 200
° C, preferably -75 ° C to room temperature, and the reaction time is 1-2.
0 hours, preferably 1 to 10 hours.
【００４０】用いる溶媒としては例えば、メタノール、
エタノール、プロパノール等のアルコール類、ジクロロ
メタン、クロロホルム、１，２−ジクロロエタン等のハ
ロゲン化炭化水素類、ベンゼン、トルエン、ヘキサン等
の炭化水素類、酢酸エチル等のエステル類が挙げられ、
特に好ましいのはアルコール類である。酸化生成物を分
解する際には、水素化ホウ素ナトウム、水素化リチウム
アルミニウム等の還元試薬を用いることができる。As the solvent to be used, for example, methanol,
Ethanol, alcohols such as propanol, dichloromethane, chloroform, halogenated hydrocarbons such as 1,2-dichloroethane, benzene, toluene, hydrocarbons such as hexane, esters such as ethyl acetate, and the like.
Particularly preferred are alcohols. When decomposing the oxidation product, a reducing reagent such as sodium borohydride and lithium aluminum hydride can be used.
【００４１】［工程３］工程２で得た一般式（４）を塩
基の存在下、チオニルハライドまたはリンハライドと反
応させ相当するハロプロピル基、あるいはアルキルまた
はアリールスルホン酸ハライド、アルキルまたはアリー
ルスルホン酸無水物と反応させることにより、一般式
（５）［化１６］[Step 3] The general formula (4) obtained in the step 2 is reacted with a thionyl halide or a phosphorus halide in the presence of a base to react with a corresponding halopropyl group, or an alkyl or arylsulfonic acid halide, an alkyl or arylsulfonic anhydride. By reacting with a product, the compound represented by the general formula (5)
【００４２】[0042]
【化１６】 Embedded image
【００４３】（式中、X1、X2、Qは前記の定義と同
義。）で表わされるピロリジノン誘導体を得ることがで
きる。(Wherein X 1 , X 2 and Q have the same meanings as defined above).
【００４４】反応温度は０℃〜２００℃、好ましくは０
℃〜１５０℃で、反応時間は１〜４８時間、好ましくは
１〜１０時間である。The reaction temperature is 0 ° C. to 200 ° C., preferably 0 ° C.
C. to 150.degree. C., the reaction time is 1 to 48 hours, preferably 1 to 10 hours.
【００４５】用いる溶媒としては例えば、ジエチルエー
テル、テトラヒドロフラン、１，４−ジオキサン等のエ
ーテル類、ベンゼン、トルエン、ヘキサン等の炭化水素
類が挙げられる。Examples of the solvent to be used include ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane, and hydrocarbons such as benzene, toluene and hexane.
【００４６】チオニルハライドとしては、塩化チオニ
ル、臭化チオニル、リンハライドとしては、３塩化リ
ン、３臭化リン等が挙げられる。The thionyl halide includes thionyl chloride and thionyl bromide, and the phosphorus halide includes phosphorus trichloride and phosphorus bromide.
【００４７】アルキルまたはアリールスルホン酸ハライ
ドとしては、メタンスルホニルクロリド、エタンスルホ
ニルクロリド、ベンゼンスルホニルクロリド、トルエン
スルホニルクロリド等が挙げられる。Examples of the alkyl or aryl sulfonic acid halide include methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride.
【００４８】アルキルまたはアリールスルホン酸無水物
としては、メタンスルホン酸無水物、エタンスルホン酸
無水物、ベンゼンスルホン酸無水物、トルエンスルスル
ホン酸無水物等が挙げられる。Examples of the alkyl or aryl sulfonic anhydride include methanesulfonic anhydride, ethanesulfonic anhydride, benzenesulfonic anhydride, and toluenesulfonic anhydride.
【００４９】原料の一般式（４）とチオニルハライド、
リンハライド、アルキルまたはアリールスルホン酸ハラ
イド、アルキルまたはアリールスルホン酸無水物の使用
割合に特に制限はないが、通常はモル比で前者：後者が
１：１〜１：２０、好ましくは１：２〜１：１０であ
る。The raw material represented by the general formula (4) and thionyl halide,
The proportion of the phosphorus halide, alkyl or aryl sulfonic acid halide, alkyl or aryl sulfonic anhydride used is not particularly limited, but usually the former: the latter is 1: 1 to 1:20, preferably 1: 2 to 1 in a molar ratio. : 10.
【００５０】［工程４］工程３で得た一般式（５）の化
合物とＲ−ＮＨ２（Rは前記の定義と同義。）で表わさ
れるアミンを適当な塩基の存在下、不活性溶媒または無
溶媒で反応させることにより、一般式（１）の化合物を
得ることができる。反応温度は０℃〜２００℃、好まし
くは０℃〜１５０℃であり、反応時間は１〜４８時間、
好ましくは１〜１０時間である。反応を促進させるた
め、オートクレーブを用いることもできる。[Step 4] The compound of the general formula (5) obtained in Step 3 and an amine represented by R-NH2 (R is as defined above) are reacted with an inert solvent or a non-solvent in the presence of a suitable base. By reacting with a solvent, a compound of the general formula (1) can be obtained. The reaction temperature is 0 ° C to 200 ° C, preferably 0 ° C to 150 ° C, and the reaction time is 1 to 48 hours.
Preferably, it is 1 to 10 hours. An autoclave may be used to promote the reaction.
【００５１】反応に用いられる塩基としては、例えばト
リエチルアミン、ピリジンなどの有機塩基、水酸化ナト
リウム、水素化カリウムなどの無機塩基を挙げることが
できる。Examples of the base used in the reaction include organic bases such as triethylamine and pyridine, and inorganic bases such as sodium hydroxide and potassium hydride.
【００５２】用いられる溶媒としては例えば、ジエチル
エーテル、テトラヒドロフラン、１，４−ジオキサン、
１，２−ジメトキシエタン等のエーテル類、ジクロロメ
タン、クロロホルム、１，２−ジクロロエタン等のハロ
ゲン化炭化水素、ベンゼン、トルエン、ヘキサン等の炭
化水素類、アセトニトリルなどが挙げられる。Examples of the solvent used include diethyl ether, tetrahydrofuran, 1,4-dioxane,
Examples thereof include ethers such as 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, hydrocarbons such as benzene, toluene and hexane, and acetonitrile.
【００５３】一般式（５）とＲ−ＮＨ２の使用割合に特
に制限はないが、通常はモル比で前者：後者が１：１〜
１：３０、好ましくは１：１〜１：１０である。本反応
により得た化合物はさらに再結晶、シリカゲルカラムク
ロマトグラフィーなど通常の方法で精製することができ
る。Although there are no particular restrictions on the proportions of the general formula (5) and R-NH2, the former: the latter is usually 1: 1 to 1: 1 in molar ratio.
The ratio is 1:30, preferably 1: 1 to 1:10. The compound obtained by this reaction can be further purified by a usual method such as recrystallization and silica gel column chromatography.
【００５４】本発明の一般式（１）に含まれる化合物と
して、例えば下記に具体的化合物名が挙げられるが、本
発明はこれらのものに限定されることはない。 （１） ２−フェニル−８−エチル−２，８−ジアザス
ピロ［４，５］デカン−１−オン （２） ２−フェニル−８−（ｎ−プロピル）−２，８
−ジアザスピロ［４，５］デカン−１−オン （３） ２−フェニル−８−（ｎ−ブチル）−２，８−
ジアザスピロ［４，５］デカン−１−オン （４） ２−フェニル−８−（ｎ−ペンチル）−２，８
−ジアザスピロ［４，５］デカン−１−オン （５） ２−フェニル−８−（ｎ−ヘキシル）−２，８
−ジアザスピロ［４，５］デカン−１−オン （６） ２−（４−クロロフェニル）−８−エチル−
２，８−ジアザスピロ［４，５］デカン−１−オン （７） ２−（３−ヨードフェニル）−８−（ｎ−プロ
ピル）−２，８−ジアザスピロ［４，５］デカン−１−
オン （８） ２−（４−クロロフェニル）−８−（ｎ−ブチ
ル）−２，８−ジアザスピロ［４，５］デカン−１−オ
ン （９） ２−（４−クロロフェニル）−８−シクロプロ
ピルメチル−２，８−ジアザスピロ［４，５］デカン−
１−オン （１０） ２−（２−ブロモフェニル）−８−（ｎ−ペ
ンチル）−２，８−ジアザスピロ［４，５］デカン−１
−オン （１１） ２−（４−クロロフェニル）−８−（ｎ−ペ
ンチル）−２，８−ジアザスピロ［４，５］デカン−１
−オン （１２） ２−（４−クロロフェニル）−８−シクロペ
ンチル−２，８−ジアザスピロ［４，５］デカン−１−
オン （１３） ２−（４−クロロフェニル）−８−ネオペン
チル−２，８−ジアザスピロ［４，５］デカン−１−オ
ン （１４） ２−（４−クロロフェニル）−８−（ｎ−ヘ
キシル）−２，８−ジアザスピロ［４，５］デカン−１
−オン （１５） ２−（４−フルオロフェニル）−８−（ｎ−
ヘキシル）−２，８−ジアザスピロ［４，５］デカン−
１−オン （１６） ２−（３，４−ジクロロフェニル）−８−
（ｎ−ヘキシル）−２，８−ジアザスピロ［４，５］デ
カン−１−オン （１７） ２−（４−メチルフェニル）−８−エチル−
２，８−ジアザスピロ［４，５］デカン−１−オン （１８） ２−（４−エチルフェニル）−８−イソプロ
ピル−２，８−ジアザスピロ［４，５］デカン−１−オ
ン （１９） ２−（３−ｎ−プロピルフェニル）−８−シ
クロブチル−２，８−ジアザスピロ［４，５］デカン−
１−オン （２０） ２−（３−ｎ−ブチルフェニル）−８−（ｎ
−ペンチル）−２，８−ジアザスピロ［４，５］デカン
−１−オン （２１） ２−（４−ｎ−ペンチルフェニル）−８−エ
チル−２，８−ジアザスピロ［４，５］デカン−１−オ
ン （２２） ２−（４−ｎ−ヘキシルフェニル）−８−イ
ソプロピル−２，８−ジアザスピロ［４，５］デカン−
１−オン （２３） ２−フェニル−８−（ｎ−ヘキシル）−２，
８−ジアザスピロ［４，５］デカン−１−オン （２４） ２−（４−メトキシフェニル）−８−（ｎ−
ブチル）−２，８−ジアザスピロ［４，５］デカン−１
−オン （２５） ２−（４−エトキシフェニル）−８−（ｎ−
ペンチル）−２，８−ジアザスピロ［４，５］デカン−
１−オン （２６） ２−（３−ｎ−プロピルオキシフェニル）−
８−（ｎ−ヘキシル）−２，８−ジアザスピロ［４，
５］デカン−１−オン （２７） ２−（４−ｎ−ブチルオキシフェニル）−８
−イソブチル−２，８−ジアザスピロ［４，５］デカン
−１−オン （２８） ２−（４−ｎ−ペンチルオキシフェニル）−
８−ｔ−ブチル−２，８−ジアザスピロ［４，５］デカ
ン−１−オン （２９） ２−（４−ｎ−ヘキシルオキシフェニル）−
８−ｎ−ペンチル−２，８−ジアザスピロ［４，５］デ
カン−１−オン （３０） ２−フェニル−８−フェニルエチル−２，８
−ジアザスピロ［４，５］デカン−１−オン （３１） ２−（４−クロロフェニル）−８−フェニル
エチル−２，８−ジアザスピロ［４，５］デカン−１−
オン （３２） ２−（３−クロロフェニル）−８−フェニル
エチル−２，８−ジアザスピロ［４，５］デカン−１−
オン （３３） ２−（４−クロロフェニル）−８−フェニル
プロピル−２，８−ジアザスピロ［４，５］デカン−１
−オン （３４） ２−（４−クロロフェニル）−８−フェニル
ブチル−２，８−ジアザスピロ［４，５］デカン−１−
オン （３５） ２−（４−クロロフェニル）−８−フェニル
ペンチル−２，８−ジアザスピロ［４，５］デカン−１
−オン （３６） ２−（４−クロロフェニル）−８−フェニル
ヘキシル−２，８−ジアザスピロ［４，５］デカン−１
−オン （３７） ２−フェニル−８−（２−メトキシエチル）
−２，８−ジアザスピロ［４，５］デカン−１−オン （３８） ２−（４−クロロフェニル）−８−（２−メ
トキシエチル）−２，８−ジアザスピロ［４，５］デカ
ン−１−オン （３９） ２−（３−クロロフェニル）−８−（２−メ
トキシプロピル）−２，８−ジアザスピロ［４，５］デ
カン−１−オン （４０） ２−（２−クロロフェニル）−８−（２−エ
トキシブチル）−２，８−ジアザスピロ［４，５］デカ
ン−１−オン （４１） ２−フェニル−８−（２−プロピルオキシペ
ンチル）−２，８−ジアザスピロ［４，５］デカン−１
−オン （４２） ２−（４−ブロモフェニル）−８−（２−ブ
トキシヘキシル）−２，８−ジアザスピロ［４，５］デ
カン−１−オン （４３） ２−クロロフェニル−８−（２−メチルチオ
エチル）−２，８−ジアザスピロ［４，５］デカン−１
−オン （４４） ２−（４−クロロフェニル）−８−（２−メ
チルチオエチル）−２，８−ジアザスピロ［４，５］デ
カン−１−オン （４５） ２−（４−クロロフェニル）−８−（２−エ
チルチオプロピル）−２，８−ジアザスピロ［４，５］
デカン−１−オン （４６） ２−（３−クロロフェニル）−８−（２−プ
ロピルチオブチル）−２，８−ジアザスピロ［４，５］
デカン−１−オン （４７） ２−（２−クロロフェニル）−８−（２−メ
チルチオペンチル）−２，８−ジアザスピロ［４，５］
デカン−１−オン （４８） ２−（４−ブロモフェニル）−８−（２−メ
チルチオヘキシル）−２，８−ジアザスピロ［４，５］
デカン−１−オン （４９） ２−（４−メチルフェニル）−８−（２−メ
チルチオエチル）−２，８−ジアザスピロ［４，５］デ
カン−１−オン （５０） ２−（４−メトキシフェニル）−８−（２−
メチルチオエチル）−２，８−ジアザスピロ［４，５］
デカン−１−オンThe compounds included in the general formula (1) of the present invention include, for example, the following specific compound names, but the present invention is not limited to these. (1) 2-phenyl-8-ethyl-2,8-diazaspiro [4,5] decane-1-one (2) 2-phenyl-8- (n-propyl) -2,8
-Diazaspiro [4,5] decane-1-one (3) 2-phenyl-8- (n-butyl) -2,8-
Diazaspiro [4,5] decane-1-one (4) 2-phenyl-8- (n-pentyl) -2,8
-Diazaspiro [4,5] decane-1-one (5) 2-phenyl-8- (n-hexyl) -2,8
-Diazaspiro [4,5] decan-1-one (6) 2- (4-chlorophenyl) -8-ethyl-
2,8-diazaspiro [4,5] decane-1-one (7) 2- (3-iodophenyl) -8- (n-propyl) -2,8-diazaspiro [4,5] decane-1-
ON (8) 2- (4-chlorophenyl) -8- (n-butyl) -2,8-diazaspiro [4,5] decane-1-one (9) 2- (4-chlorophenyl) -8-cyclopropyl Methyl-2,8-diazaspiro [4,5] decane-
1-one (10) 2- (2-bromophenyl) -8- (n-pentyl) -2,8-diazaspiro [4,5] decane-1
-One (11) 2- (4-chlorophenyl) -8- (n-pentyl) -2,8-diazaspiro [4,5] decane-1
-One (12) 2- (4-chlorophenyl) -8-cyclopentyl-2,8-diazaspiro [4,5] decane-1-
On (13) 2- (4-chlorophenyl) -8-neopentyl-2,8-diazaspiro [4,5] decane-1-one (14) 2- (4-chlorophenyl) -8- (n-hexyl)- 2,8-diazaspiro [4,5] decane-1
-One (15) 2- (4-fluorophenyl) -8- (n-
Hexyl) -2,8-diazaspiro [4,5] decane-
1-one (16) 2- (3,4-dichlorophenyl) -8-
(N-hexyl) -2,8-diazaspiro [4,5] decan-1-one (17) 2- (4-methylphenyl) -8-ethyl-
2,8-diazaspiro [4,5] decane-1-one (18) 2- (4-ethylphenyl) -8-isopropyl-2,8-diazaspiro [4,5] decane-1-one (19) 2 -(3-n-propylphenyl) -8-cyclobutyl-2,8-diazaspiro [4,5] decane-
1-one (20) 2- (3-n-butylphenyl) -8- (n
-Pentyl) -2,8-diazaspiro [4,5] decane-1-one (21) 2- (4-n-pentylphenyl) -8-ethyl-2,8-diazaspiro [4,5] decane-1 -One (22) 2- (4-n-hexylphenyl) -8-isopropyl-2,8-diazaspiro [4,5] decane-
1-one (23) 2-phenyl-8- (n-hexyl) -2,
8-diazaspiro [4,5] decan-1-one (24) 2- (4-methoxyphenyl) -8- (n-
Butyl) -2,8-diazaspiro [4,5] decane-1
-One (25) 2- (4-ethoxyphenyl) -8- (n-
Pentyl) -2,8-diazaspiro [4,5] decane-
1-one (26) 2- (3-n-propyloxyphenyl)-
8- (n-hexyl) -2,8-diazaspiro [4,
5] Decan-1-one (27) 2- (4-n-butyloxyphenyl) -8
-Isobutyl-2,8-diazaspiro [4,5] decane-1-one (28) 2- (4-n-pentyloxyphenyl)-
8-t-butyl-2,8-diazaspiro [4,5] decan-1-one (29) 2- (4-n-hexyloxyphenyl)-
8-n-pentyl-2,8-diazaspiro [4,5] decane-1-one (30) 2-phenyl-8-phenylethyl-2,8
-Diazaspiro [4,5] decane-1-one (31) 2- (4-chlorophenyl) -8-phenylethyl-2,8-diazaspiro [4,5] decane-1-
ON (32) 2- (3-chlorophenyl) -8-phenylethyl-2,8-diazaspiro [4,5] decane-1-
ON (33) 2- (4-chlorophenyl) -8-phenylpropyl-2,8-diazaspiro [4,5] decane-1
-One (34) 2- (4-chlorophenyl) -8-phenylbutyl-2,8-diazaspiro [4,5] decane-1-
ON (35) 2- (4-chlorophenyl) -8-phenylpentyl-2,8-diazaspiro [4,5] decane-1
-One (36) 2- (4-chlorophenyl) -8-phenylhexyl-2,8-diazaspiro [4,5] decane-1
-One (37) 2-phenyl-8- (2-methoxyethyl)
-2,8-Diazaspiro [4,5] decane-1-one (38) 2- (4-chlorophenyl) -8- (2-methoxyethyl) -2,8-diazaspiro [4,5] decane-1- ON (39) 2- (3-chlorophenyl) -8- (2-methoxypropyl) -2,8-diazaspiro [4,5] decane-1-one (40) 2- (2-chlorophenyl) -8- ( 2-ethoxybutyl) -2,8-diazaspiro [4,5] decane-1-one (41) 2-phenyl-8- (2-propyloxypentyl) -2,8-diazaspiro [4,5] decane- 1
-One (42) 2- (4-bromophenyl) -8- (2-butoxyhexyl) -2,8-diazaspiro [4,5] decane-1-one (43) 2-chlorophenyl-8- (2- Methylthioethyl) -2,8-diazaspiro [4,5] decane-1
-One (44) 2- (4-chlorophenyl) -8- (2-methylthioethyl) -2,8-diazaspiro [4,5] decane-1-one (45) 2- (4-chlorophenyl) -8- (2-ethylthiopropyl) -2,8-diazaspiro [4,5]
Decane-1-one (46) 2- (3-chlorophenyl) -8- (2-propylthiobutyl) -2,8-diazaspiro [4,5]
Decane-1-one (47) 2- (2-chlorophenyl) -8- (2-methylthiopentyl) -2,8-diazaspiro [4,5]
Decane-1-one (48) 2- (4-bromophenyl) -8- (2-methylthiohexyl) -2,8-diazaspiro [4,5]
Decane-1-one (49) 2- (4-methylphenyl) -8- (2-methylthioethyl) -2,8-diazaspiro [4,5] decane-1-one (50) 2- (4-methoxy) Phenyl) -8- (2-
Methylthioethyl) -2,8-diazaspiro [4,5]
Decane-1-one
【００５５】製剤化は公知の方法によって可能である。
剤形としては、各種の形態が治療目的に応じて選択で
き、その代表的なものとして固形製剤、液剤、その他坐
剤等が挙げられる。より詳しくは、次のような各種製剤
である。すなわち、固形製剤としては、錠剤、丸剤、散
剤、顆粒剤、カプセル剤等、液剤としては、溶液として
の注射剤の他、懸濁剤、シロップ剤、乳剤等、その他の
製剤としては、坐剤等である。Formulation can be performed by a known method.
As the dosage form, various forms can be selected according to the purpose of treatment, and typical examples thereof include solid preparations, liquid preparations, and other suppositories. More specifically, there are the following various preparations. That is, as solid preparations, tablets, pills, powders, granules, capsules, etc., as liquid preparations, in addition to injections as solutions, suspensions, syrups, emulsions, etc. Agent and the like.
【００５６】錠剤の形態に成形するに際しては、担体と
してこの分野で従来よりよく知られている各種のものを
広く使用することができる。その例としては、乳糖、白
糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸
カルシウム、カオリン、結晶セルロース、ケイ酸等の賦
形剤、水、エタノール、プロパノール、単シロップ、ブ
ドウ糖液、デンプン液、ゼラチン溶液、セラック溶液、
メチルセルロース溶液、ヒドロキシプロピルセルロース
溶液、ポリビニルピロリドン溶液、カルボキシメチルセ
ルロース溶液等の結合剤、乾燥デンプン、アルギン酸ナ
トリウム、カンテン末、炭酸水素ナトリウム、炭酸カル
シウム、ポリオキシエチレンソルビタン脂肪酸エステル
類、ラウリル硫酸ナトリウム、ステアリン酸グリセリ
ド、デンプン、乳糖等の崩壊剤、白糖、ステアリン酸、
カカオバター、水素添加油等の崩壊抑制剤、第４級アン
モニウム塩基、ラウリル硫酸ナトリウム等の吸収促進
剤、グリセリン、デンプン等の保湿剤、デンプン、乳
糖、カオリン、ベントナイト、コロイド状ケイ酸、結晶
性セルロース、軽質無水ケイ酸等の吸着剤、タルク、ス
テアリン酸塩、ホウ酸末、ポリエチレングリコール等の
滑沢剤等である。In molding into tablets, various carriers well known in the art can be widely used as carriers. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin. Solution, shellac solution,
Binders such as methylcellulose solution, hydroxypropylcellulose solution, polyvinylpyrrolidone solution, carboxymethylcellulose solution, dried starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid Disintegrants such as glyceride, starch, lactose, sucrose, stearic acid,
Disintegration inhibitors such as cocoa butter and hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, crystalline Adsorbents such as cellulose and light silicic anhydride; and lubricants such as talc, stearates, boric acid powder, and polyethylene glycol.
【００５７】さらに錠剤の場合、必要に応じ通常の剤皮
を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被
錠、フィルムコーティング錠あるいは二層錠、多層錠と
することができる。Further, in the case of tablets, tablets which have been coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets or two-layer tablets or multi-layer tablets can be prepared.
【００５８】丸剤の形態に成形するに際しては、担体と
して従来この分野で公知のものを広く使用できる。その
例としては、例えばブドウ糖、乳糖、デンプン、カカオ
脂、硬化植物油、カオリン、タルク等の賦形剤、アラビ
アゴム末、トラガント末、ゼラチン等の結合剤、カルメ
ロースカルシウム、カンテン等の崩壊剤等を挙げること
ができる。In molding into a pill form, a wide variety of carriers conventionally known in this field can be used. Examples thereof include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, binders such as gum arabic, powder tragacanth, gelatin, disintegrants such as carmellose calcium, agar and the like. Can be mentioned.
【００５９】カプセル剤は、常法に従い通常有効成分化
合物を上記で例示した各種の担体と混合して硬質ゼラチ
ンカプセル、軟質カプセル等に充填して調製される。Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture in a hard gelatin capsule, soft capsule or the like according to a conventional method.
【００６０】注射剤として調製する場合、液剤、乳剤お
よび懸濁剤の形態に成形するに際しては、希釈剤として
この分野において汎用されているもの、例えば水、エタ
ノール、マクロゴール、プロピレングリコール、エトキ
シ化イソステアリルアルコール、ポリオキシ化イソステ
アリルアルコール、ポリオキシエチレンソルビタン脂肪
酸エステル類、綿実油、トウモロコシ油、ラッカセイ
油、オリーブ油等が使用できる。さらに本発明の化合物
に水を加え、適切な界面活性剤の存在下に懸濁性水溶
液、さらにはポリオキシエチレン硬化ヒマシ油（HCO-6
0）、ポリソルベート80、ポリエチレングリコール等の
界面活性剤を用いた乳濁液として調製することができ
る。なお、食塩、ブドウ糖あるいはグリセリンを医薬製
剤中に含有させてもよく、また通常の溶解補助剤、緩衝
剤、無痛化剤等を添加してもよい。When prepared as an injection, when it is formed into liquids, emulsions and suspensions, diluents generally used in this field, for example, water, ethanol, macrogol, propylene glycol, ethoxylated Isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, cottonseed oil, corn oil, peanut oil, olive oil and the like can be used. Further, water is added to the compound of the present invention, and a suspension aqueous solution in the presence of a suitable surfactant, and further a polyoxyethylene hydrogenated castor oil (HCO-6
0), it can be prepared as an emulsion using a surfactant such as polysorbate 80 or polyethylene glycol. In addition, salt, glucose or glycerin may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent and the like may be added.
【００６１】坐剤の形態に成形するに際しては、担体と
して従来公知のものを広く使用することができる。その
例としては、ポリエチレングリコール、カカオ脂、高級
アルコール、高級アルコールのエステル類、ゼラチン、
半合成グリセライド等を挙げることができる。For shaping in the form of suppositories, conventionally known carriers can be widely used. Examples include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin,
Semi-synthetic glycerides and the like can be mentioned.
【００６２】さらに必要に応じて着色剤、保存剤、香
料、風味剤、甘味剤等や他の医薬品を医薬製剤中に含有
させることもできる。Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained in the pharmaceutical preparation as required.
【００６３】本発明のこれら医薬製剤の投与方法は特に
制限はなく、各種製剤形態、患者の年齢、性別その他の
条件、疾患の程度に応じた方法で投与される。例えば、
錠剤、丸剤、液剤、懸濁剤、乳剤、散剤、顆粒剤、シロ
ップ剤およびカプセル剤の場合には経口投与される。注
射剤の場合には、単独でまたはブドウ糖、アミノ酸等の
通常の補液と混合して静脈内投与され、さらに必要に応
じて筋肉内、皮下もしくは腹腔内投与される。坐剤の場
合は直腸内投与される。The method of administration of the pharmaceutical preparations of the present invention is not particularly limited, and the pharmaceutical preparations are administered according to various preparation forms, the age, sex and other conditions of the patient, and the degree of the disease. For example,
In the case of tablets, pills, solutions, suspensions, emulsions, powders, granules, syrups and capsules, they are orally administered. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, subcutaneously or intraperitoneally. Suppositories are administered rectally.
【００６４】本発明のこれら医薬製剤の投与量は、用
法、患者の年齢、性別その他の条件、疾患の程度により
適宜選択されるが、通常有効成分化合物の量が１日当た
り成人１日当たり、0.001〜1,000mg程度とするのがよ
い。また投与単位形態の製剤中には有効成分化合物が約
0.001〜1,000mgの範囲で含有されることが望ましい。以
下に、本発明の製造実施例、製剤例および試験例を記載
するが、本発明はこれらに限定されるものではない。The dosage of these pharmaceutical preparations of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, and the degree of the disease. Usually, the amount of the active ingredient compound is 0.001 to 0.001 per day per adult per day. It is better to be about 1,000mg. In addition, the active ingredient compound may be contained in a dosage unit form of the preparation.
Desirably, it is contained in the range of 0.001 to 1,000 mg. Hereinafter, Production Examples, Preparation Examples, and Test Examples of the present invention will be described, but the present invention is not limited thereto.
【００６５】[0065]
【実施例】［実施例１］ ３，３−ジアリル−１−（４−クロロフェニル）−２−
ピロリジノンの合成 窒素雰囲気下、１，１，１，３，３，３，−ヘキサメチ
ルジシラザン（３２．４ｍｌ）を無水テトラヒドロフラ
ン（以下ＴＨＦと表記）（３００ｍｌ）に溶解し、内温
−６５℃まで冷却した。それに、n−ブチルリチウムの
ヘキサン溶液（１．５３Ｍ，１００．２ｍｌ）を滴下
し、１５分攪拌した。続いて、１−（４−クロロフェニ
ル）−２−ピロリジノン（１０ｇ）の無水ＴＨＦ（５０
ｍｌ）溶液を、１５分間かけて滴下した。１時間攪拌
後、臭化アリル（２４．７ｇ）の無水ＴＨＦ溶液（１２
０ｍｌ）を１５分かけて滴下し、さらに３０分攪拌し
た。反応終了後、２Ｎの塩酸を加え、酢酸エチルで抽出
した後、有機層を硫酸マグネシウムで乾燥後、減圧下で
濃縮し、残渣をシリカゲルカラムクロマトグラフィーで
精製して、表題化合物１４．２ｇを無色の油状物として
得た。 1H-NMR(CDCl3)δ2.27(2H,dd,J=8.3,13.9Hz)、2.67(2H,t,
J=7.1Hz)、2.49(2H,m)、3.68(2H,t,J=7.1Hz)、5.1-5.2(4H,
m)、5.7-5.9(2H,m)、7.31(2H,m)、7.61(2H,m)EXAMPLES Example 1 3,3-Diallyl-1- (4-chlorophenyl) -2-
Synthesis of pyrrolidinone Under a nitrogen atmosphere, 1,1,1,3,3,3-hexamethyldisilazane (32.4 ml) was dissolved in anhydrous tetrahydrofuran (hereinafter referred to as THF) (300 ml), and the internal temperature was -65 ° C. Cooled down. A hexane solution of n-butyllithium (1.53 M, 100.2 ml) was added dropwise thereto, and the mixture was stirred for 15 minutes. Subsequently, anhydrous THF (50 g) of 1- (4-chlorophenyl) -2-pyrrolidinone (10 g) was used.
ml) solution was added dropwise over 15 minutes. After stirring for 1 hour, a solution of allyl bromide (24.7 g) in anhydrous THF (12
0 ml) was added dropwise over 15 minutes, and the mixture was further stirred for 30 minutes. After completion of the reaction, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 14.2 g of the title compound as colorless. As an oil. 1H-NMR (CDCl3) δ 2.27 (2H, dd, J = 8.3, 13.9 Hz), 2.67 (2H, t,
J = 7.1Hz), 2.49 (2H, m), 3.68 (2H, t, J = 7.1Hz), 5.1-5.2 (4H, m
m), 5.7-5.9 (2H, m), 7.31 (2H, m), 7.61 (2H, m)
【００６６】［実施例２］ １−（４−クロロフェニル）−３，３―ビス（２−ヒド
ロキシエチル）−２−ピロリジノンの合成 実施例１で合成した３，３−ジアリル−１−（４−クロ
ロフェニル）−２−ピロリジノン（８．０ｇ）のメタノ
ール溶液（２００ｍｌ）を、ドライアイス−メタノール
浴で冷却後、オゾンガスを反応溶液が青色になるまで吹
き込んだ。次に水素化ホウ素ナトリウム（８．０ｇ）を
加えた後、氷浴下で反応を行った。反応終了後、反応混
合物を塩酸で処理し、減圧下でメタノールを除去した
後、酢酸エチルで抽出し、硫酸マグネシウムで乾燥し
た。硫酸マグネシウムを濾過し、減圧下で濃縮した後、
残渣をシリカゲルカラムクロマトグラフィーにて精製
し、表題化合物５．６ｇを淡桃色固体として得た。 1H-NMR(DMSO-d6)δ1.70(4H,t,J=7.4Hz)、2.09(2H,t,J=7.
2Hz)、3.4-3.6(4H,m)、3.73(2H,t,7.2Hz)、4.45(2H,t,J=5.
1Hz)、7.42(2H,m)、7.70(2H,m)Example 2 Synthesis of 1- (4-chlorophenyl) -3,3-bis (2-hydroxyethyl) -2-pyrrolidinone 3,3-diallyl-1- (4-) synthesized in Example 1 After cooling a methanol solution (200 ml) of (chlorophenyl) -2-pyrrolidinone (8.0 g) in a dry ice-methanol bath, ozone gas was blown in until the reaction solution turned blue. Next, after adding sodium borohydride (8.0 g), the reaction was performed in an ice bath. After completion of the reaction, the reaction mixture was treated with hydrochloric acid, methanol was removed under reduced pressure, extracted with ethyl acetate, and dried over magnesium sulfate. After filtering magnesium sulfate and concentrating under reduced pressure,
The residue was purified by silica gel column chromatography to obtain 5.6 g of the title compound as a pale pink solid. 1H-NMR (DMSO-d6) δ 1.70 (4H, t, J = 7.4 Hz), 2.09 (2H, t, J = 7.
2Hz), 3.4-3.6 (4H, m), 3.73 (2H, t, 7.2Hz), 4.45 (2H, t, J = 5.
1Hz), 7.42 (2H, m), 7.70 (2H, m)
【００６７】［実施例３］ １−（４−クロロフェニル）−３，３―ビス（２−メタ
ンスルホニルオキシエチル）−２−ピロリジノンの合成 実施例２で合成した１−（４−クロロフェニル）−３，
３―ビス（２−ヒドロキシエチル）−２−ピロリジノン
（２．０ｇ）の塩化メチレン（３０ｍｌ）溶液に、トリ
エチルアミン（２．４ｍｌ）、メタンスルホニル クロ
リド（１．３ｍｌ）の順に加え、室温にて３０分間反応
した。次に、２Ｎの塩酸を加え、クロロホルムで抽出
後、さらに有機層を飽和重曹水、水の順で洗浄し、硫酸
マグネシウムで乾燥した。硫酸マグネシウムを濾過し、
減圧下で濃縮した後、残渣をシリカゲルカラムクロマト
グラフィーにて精製し、表題化合物２．８１ｇを白色固
体として得た。 1H-NMR(CDCl3)δ2.14(4H,m)、2.24(2H,t,J=7.1Hz)、2.97
(6H、s)、3.83(2H,t,J=7.1Hz)、4.41(4H,m)、7.35(2H,dd,J=
2.3,6.9Hz)、7.60(2H,dt,J=2.6,8.9Hz)Example 3 Synthesis of 1- (4-chlorophenyl) -3,3-bis (2-methanesulfonyloxyethyl) -2-pyrrolidinone 1- (4-chlorophenyl) -3 synthesized in Example 2 ,
To a solution of 3-bis (2-hydroxyethyl) -2-pyrrolidinone (2.0 g) in methylene chloride (30 ml) were added triethylamine (2.4 ml) and methanesulfonyl chloride (1.3 ml) in this order, and the mixture was added at room temperature for 30 minutes. Reacted for minutes. Next, 2N hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was further washed with saturated aqueous sodium hydrogen carbonate and water in that order, and dried over magnesium sulfate. Filter magnesium sulfate,
After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (2.81 g) as a white solid. 1H-NMR (CDCl3) δ 2.14 (4H, m), 2.24 (2H, t, J = 7.1Hz), 2.97
(6H, s), 3.83 (2H, t, J = 7.1 Hz), 4.41 (4H, m), 7.35 (2H, dd, J =
2.3,6.9Hz), 7.60 (2H, dt, J = 2.6,8.9Hz)
【００６８】［実施例４］ ８−（ｎ−ブチル）−２−（４−クロロフェニル）−
２，８−ジアザスピロ［４，５］デカン−１−オン・１
塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（０．２ｇ）、ｎ−ブチルアミン（０．０
５ｍｌ）、トリエチルアミン（０．１５ｍｌ）をアセト
ニトリル（５ｍｌ）に溶解して、７時間加熱還流した。
放冷後、減圧下で濃縮し、残渣をシリカゲルカラムクロ
マトグラフィーにて精製し、８−（ｎ−ブチル）−２−
（４−クロロフェニル）−２，８−ジアザスピロ［４，
５］デカン−１−オンを得た。さらにこれを１Ｎの塩酸
エタノール溶液（２ｍｌ）に加えた後、濃縮し、残渣に
ジエチルエーテルを加え析出した固体を濾取することに
より、表題化合物４０ｍｇを白色固体として得た。 融点：２５０℃以上 1H-NMR(DMSO-d6)δ0.92(3H,t、J=7.3Hz)、1.32(2H,sext,J
=7.4Hz)、1.68(2H,m)、1.77(2H,m)、2.06(2H,m)、2.16(2H,
t,J=6.9Hz)、2.9-3.1(4H,m)、3.48(2H,brd,J=12.2Hz)、3.8
3(2H,t,J=6.9Hz)、7.46(2H,d,J=9.2Hz)、7.72(2H,dt,J=3.
5,10.23Hz)Example 4 8- (n-butyl) -2- (4-chlorophenyl)-
2,8-diazaspiro [4,5] decan-1-one / 1
Synthesis of hydrochloride 1- (4-chlorophenyl) -3, synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (0.2 g), n-butylamine (0.0
5 ml) and triethylamine (0.15 ml) were dissolved in acetonitrile (5 ml) and heated under reflux for 7 hours.
After allowing to cool, the mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give 8- (n-butyl) -2-
(4-chlorophenyl) -2,8-diazaspiro [4,
5] Decan-1-one was obtained. This was further added to a 1N ethanol solution of hydrochloric acid (2 ml), and then concentrated. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to obtain 40 mg of the title compound as a white solid. Melting point: 250 ° C or higher 1H-NMR (DMSO-d6) δ 0.92 (3H, t, J = 7.3Hz), 1.32 (2H, sext, J
= 7.4Hz), 1.68 (2H, m), 1.77 (2H, m), 2.06 (2H, m), 2.16 (2H, m
t, J = 6.9Hz), 2.9-3.1 (4H, m), 3.48 (2H, brd, J = 12.2Hz), 3.8
3 (2H, t, J = 6.9Hz), 7.46 (2H, d, J = 9.2Hz), 7.72 (2H, dt, J = 3.
(5,10.23Hz)
【００６９】［実施例５］ ２−（４−クロロフェニル）−８−（ｎ−ペンチル）−
２，８−ジアザスピロ［４，５］デカン−１−オン・１
塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（１．０ｇ）、n−ペンチルアミン（０．
７９ｍｌ）、アセトニトリル（１５ｍｌ）をオートクレ
ーブに装入し、１００℃にて６時間反応した。冷却後、
減圧濃縮し、残渣に飽和重曹水を加え、クロロホルムで
抽出した後、硫酸マグネシウムで乾燥した。硫酸マグネ
シウムを濾過後、減圧下で濃縮すると固体が析出し、エ
タノールで洗浄した。得られた固体をエタノールとジエ
チルエーテルの混合溶液に完全に溶解し、１Ｎの塩酸エ
タノール溶液を加えることにより、結晶が析出した。こ
れを濾取し、表題化合物（３０４ｍｇ）を白色固体とし
て得た。 融点：２５０℃以上 1H-NMR(DMSO-d6)δ0.90(3H,t,J=6.7Hz)、1.25-1.35(4H,
m)、1.66(2H,m)、1.79(2H,brd,J=8.4)、2.01(2H,m)、2.15(3
H,t,J=6.9Hz)、2.98(4H,m)、3.50(2H,brd,J=12.9Hz)、3.83
(2H,t,J=6.9Hz)、7.45(2H,d,J=8.9Hz)、7.73(2H,d,J=8.9H
z)Example 5 2- (4-chlorophenyl) -8- (n-pentyl)-
2,8-diazaspiro [4,5] decan-1-one / 1
Synthesis of hydrochloride 1- (4-chlorophenyl) -3, synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (1.0 g), n-pentylamine (0.
79 ml) and acetonitrile (15 ml) were charged into an autoclave and reacted at 100 ° C. for 6 hours. After cooling,
The mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and dried over magnesium sulfate. After the magnesium sulfate was filtered, it was concentrated under reduced pressure to precipitate a solid, which was washed with ethanol. The obtained solid was completely dissolved in a mixed solution of ethanol and diethyl ether, and a 1N hydrochloric acid-ethanol solution was added to precipitate crystals. This was collected by filtration to give the title compound (304 mg) as a white solid. Melting point: 250 ° C. or more 1H-NMR (DMSO-d6) δ 0.90 (3H, t, J = 6.7 Hz), 1.25-1.35 (4H,
m), 1.66 (2H, m), 1.79 (2H, brd, J = 8.4), 2.01 (2H, m), 2.15 (3
H, t, J = 6.9Hz), 2.98 (4H, m), 3.50 (2H, brd, J = 12.9Hz), 3.83
(2H, t, J = 6.9Hz), 7.45 (2H, d, J = 8.9Hz), 7.73 (2H, d, J = 8.9H)
z)
【００７０】［実施例６］ ２−（４−クロロフェニル）−８−（ｎ−ヘキシル）−
２，８−ジアザスピロ［４，５］デカン−１−オン・１
塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（１．０ｇ）、ｎ−ヘキシルアミン（０．
９ｍｌ）、アセトニトリル（１５ｍｌ）を用いて、実施
例５と同様に操作することにより、表題化合物０．２９
ｇを白色固体として得た。 融点：２５０℃以上 1H-NMR(DMSO-d6)δ0.88(3H,t,J=6.5Hz)、1.29(6H,m)、1.6
9(2H,m)、1.78(2H,d,J=7.1Hz)、2.02(2H,m)、2.15(2H,t,J=
6.9Hz)、2.9-3.2(4H,m)、3.49(2H,brd,J=12.2Hz)、3.83(3
H,t,J=6.9Hz)、7.45(2H,d,J=8.9Hz)、7.72(2H,d,J=8.9Hz)Example 6 2- (4-chlorophenyl) -8- (n-hexyl)-
2,8-diazaspiro [4,5] decan-1-one / 1
Synthesis of hydrochloride 1- (4-chlorophenyl) -3, synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (1.0 g), n-hexylamine (0.
9 ml) and acetonitrile (15 ml) in the same manner as in Example 5 to give the title compound 0.29.
g was obtained as a white solid. Melting point: 250 ° C. or higher 1H-NMR (DMSO-d6) δ 0.88 (3H, t, J = 6.5 Hz), 1.29 (6H, m), 1.6
9 (2H, m), 1.78 (2H, d, J = 7.1Hz), 2.02 (2H, m), 2.15 (2H, t, J =
6.9Hz), 2.9-3.2 (4H, m), 3.49 (2H, brd, J = 12.2Hz), 3.83 (3H
H, t, J = 6.9Hz), 7.45 (2H, d, J = 8.9Hz), 7.72 (2H, d, J = 8.9Hz)
【００７１】［実施例７］ ２−（４−クロロフェニル）−８−ネオペンチル−２，
８−ジアザスピロ［４，５］デカン−１−オン・１塩酸
塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（１．０ｇ）、ネオペンチルアミン（０．
８ｍｌ）、アセトニトリル（１５ｍｌ）を用いて、実施
例５と同様に操作することにより、表題化合物０．３５
ｇを白色固体として得た。 融点：２６０℃以上 1H-NMR(DMSO-d6)δ1.07(9H,s)、1.76(2H,brd,J=6.8Hz)、
2.05(2H,m)、2.16(2H,t,J=6.9Hz)、3.0-3.3(4H,m)、3.54(2
H,m)、3.83(2H,t,J=6.8Hz)、7.46(2H,d,J=8.9Hz)、7.74(2
H,m)Example 7 2- (4-chlorophenyl) -8-neopentyl-2,
Synthesis of 8-diazaspiro [4,5] decan-1-one monohydrochloride 1- (4-chlorophenyl) -3, synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (1.0 g), neopentylamine (0.
8 ml) and acetonitrile (15 ml) in the same manner as in Example 5 to give the title compound 0.35
g was obtained as a white solid. Melting point: 260 ° C. or higher 1H-NMR (DMSO-d6) δ1.07 (9H, s), 1.76 (2H, brd, J = 6.8Hz),
2.05 (2H, m), 2.16 (2H, t, J = 6.9Hz), 3.0-3.3 (4H, m), 3.54 (2
H, m), 3.83 (2H, t, J = 6.8Hz), 7.46 (2H, d, J = 8.9Hz), 7.74 (2
H, m)
【００７２】［実施例８］ ２−（４−クロロフェニル）−８−（シクロプロピルメ
チル）−２，８−ジアザスピロ［４，５］デカン−１−
オン・１塩酸塩の合成 （アミノメチル）シクロプロパン塩酸塩（１．０ｇ）
を、冷却した３３％水酸化カリウム水溶液に溶解し、ベ
ンゼン（１５ｍｌ）で抽出した。ベンゼン層を硫酸マグ
ネシウムで乾燥後、硫酸マグネシウムを濾過し、この濾
液と、実施例３で合成した１−（４−クロロフェニル）
−３，３―ビス（２−メタンスルホニルオキシエチル）
−２−ピロリジノン（１．０ｇ）、アセトニトリル（１
５ｍｌ）を、オートクレーブに装入した。これを１００
℃にて６時間反応した。放冷後、反応の処理を実施例５
と同様に行い、表題化合物０．３４ｇを白色固体として
得た。 融点：２６０℃以上 1H-NMR(DMSO-d6)δ0.39(2H,d,J=4.0Hz)、0.64(2H,d,J=6.
9Hz)、1.35(1H,m)、1.79(2H,d,J=13.5Hz)、2.0-2.2(4H,m)、
2.98(4H,m)、3.4-3.6(2H,m)、3.83(2H,t,J=6.9Hz)、7.45(2
H,d,J=8.9Hz)、7.77(2H,d,J=8.9Hz)Example 8 2- (4-chlorophenyl) -8- (cyclopropylmethyl) -2,8-diazaspiro [4,5] decane-1-
Synthesis of on monohydrochloride (aminomethyl) cyclopropane hydrochloride (1.0 g)
Was dissolved in a cooled 33% aqueous potassium hydroxide solution and extracted with benzene (15 ml). After drying the benzene layer with magnesium sulfate, the magnesium sulfate was filtered, and the filtrate was combined with 1- (4-chlorophenyl) synthesized in Example 3.
-3,3-bis (2-methanesulfonyloxyethyl)
-2-pyrrolidinone (1.0 g), acetonitrile (1
5 ml) was charged to the autoclave. This is 100
Reaction was carried out at 6 ° C. for 6 hours. After allowing to cool, the reaction was processed in Example 5.
In the same manner as described above, 0.34 g of the title compound was obtained as a white solid. Melting point: 260 ° C. or higher 1H-NMR (DMSO-d6) δ 0.39 (2H, d, J = 4.0 Hz), 0.64 (2H, d, J = 6.
9Hz), 1.35 (1H, m), 1.79 (2H, d, J = 13.5Hz), 2.0-2.2 (4H, m),
2.98 (4H, m), 3.4-3.6 (2H, m), 3.83 (2H, t, J = 6.9Hz), 7.45 (2
(H, d, J = 8.9Hz), 7.77 (2H, d, J = 8.9Hz)
【００７３】［実施例９］ ２−（４−クロロフェニル）−８−シクロペンチル−
２，８−ジアザスピロ［４，５］デカン−１−オン・１
塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（０．８８ｇ）、アセトニトリル（１０ｍ
ｌ）、シクロペンチルアミン（０．５９ｍｌ）をオート
クレーブに装入し、１００℃で５時間反応した。冷却後
減圧下で濃縮し、飽和重曹水を加えクロロホルムで抽出
した。硫酸マグネシウムで乾燥後、濾過し減圧下で濃縮
した後に、残渣をシリカゲルカラムクロマトグラフィー
にて精製した。これに、１Ｎの塩酸エタノールを加え
て、析出した固体を濾取し、表題化合物０．３３ｇを白
色固体として得た。 融点：２５０℃以上 1H-NMR(DMSO-d6)δ1.53-1.98(8H,m)、2.05(4H,m)、2.17(2
H,t,J=6.9Hz)、3.01(2H,dd,J=10.2,22.8Hz)、3.38(1H,m)、
3.51(2H,m)、3.83(2H,t,J=6.9Hz)、7.45(2H,d,J=8.9Hz)、
7.73(2H,m)Example 9 2- (4-chlorophenyl) -8-cyclopentyl-
2,8-diazaspiro [4,5] decan-1-one / 1
Synthesis of hydrochloride 1- (4-chlorophenyl) -3, synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (0.88 g), acetonitrile (10 m
l) and cyclopentylamine (0.59 ml) were charged into an autoclave and reacted at 100 ° C for 5 hours. After cooling, the mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography. To this, 1N hydrochloric acid ethanol was added, and the precipitated solid was collected by filtration to obtain 0.33 g of the title compound as a white solid. Melting point: 250 ° C. or higher 1H-NMR (DMSO-d6) δ1.53-1.98 (8H, m), 2.05 (4H, m), 2.17 (2
H, t, J = 6.9Hz), 3.01 (2H, dd, J = 10.2,22.8Hz), 3.38 (1H, m),
3.51 (2H, m), 3.83 (2H, t, J = 6.9Hz), 7.45 (2H, d, J = 8.9Hz),
7.73 (2H, m)
【００７４】［実施例１０］ ２−（４−クロロフェニル）−８−（２−フェニルエチ
ル）−２，８−ジアザスピロ［４，５］デカン−１−オ
ン・１塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（０．５４ｇ）、２−フェニルエチルアミ
ン（０．２２ｇ）、トリエチルアミン（０．５２ｍｌ）
を順次、アセトニトリル（１０ｍｌ）に加え、１０時間
還流した。放冷後、実施例４と同様に操作を行うことに
より、表題化合物０．１５ｇを白色固体として得た。 融点：２５０℃以上 1H-NMR(DMSO-d6)δ1.82(2H,m)、2.05(2H,m)、2.17(2H,t、J
=6.9Hz)、3.07(4H,m)、3.31(2H,m)、3.60(2H,m)、3.84(2H,
t,J=6.8Hz)、7.2-7.4(5H,m)7.46(2H,d,J=8.9Hz)、7.73(2
H,m)Example 10 Synthesis of 2- (4-chlorophenyl) -8- (2-phenylethyl) -2,8-diazaspiro [4,5] decan-1-one monohydrochloride Example 3 1- (4-chlorophenyl) -3 synthesized,
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (0.54 g), 2-phenylethylamine (0.22 g), triethylamine (0.52 ml)
Was successively added to acetonitrile (10 ml) and refluxed for 10 hours. After allowing to cool, the same operation as in Example 4 was performed to obtain 0.15 g of the title compound as a white solid. Melting point: 250 ° C. or higher 1H-NMR (DMSO-d6) δ1.82 (2H, m), 2.05 (2H, m), 2.17 (2H, t, J
= 6.9Hz), 3.07 (4H, m), 3.31 (2H, m), 3.60 (2H, m), 3.84 (2H, m
t, J = 6.8Hz), 7.2-7.4 (5H, m) 7.46 (2H, d, J = 8.9Hz), 7.73 (2
H, m)
【００７５】［実施例１１］ ２−（４−クロロフェニル）−８−（３−フェニルプロ
ピル）−２，８−ジアザスピロ［４，５］デカン−１−
オン・１塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（１．０ｇ）、３−フェニルプロピルアミ
ン（０．９７ｍｌ）、アセトニトリル（１５ｍｌ）を用
いて、実施例９と同様に操作を行うことにより、白色固
体として表題化合物０．３５ｇを得た。 融点：２６０℃以上 1H-NMR(DMSO-d6)δ1.77(2H,m)、1.9-2.1(4H,m)、2.14(2H,
t,J=6.9Hz)、2.64(2H,t,7.4Hz)、3.04(2H,m)、3.33-3.53(4
H,m)、3.82(2H,t,J=6.9Hz)、7.2-7.4(5H,m)、7.45(2H,d,J=
8.9Hz)、7.75(2H,d,J=8.9Hz)Example 11 2- (4-chlorophenyl) -8- (3-phenylpropyl) -2,8-diazaspiro [4,5] decane-1-
Synthesis of on monohydrochloride 1- (4-chlorophenyl) -3 synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
The same operation as in Example 9 was performed using pyrrolidinone (1.0 g), 3-phenylpropylamine (0.97 ml), and acetonitrile (15 ml) to obtain 0.35 g of the title compound as a white solid. Melting point: 260 ° C. or higher 1H-NMR (DMSO-d6) δ1.77 (2H, m), 1.9-2.1 (4H, m), 2.14 (2H, m)
t, J = 6.9Hz), 2.64 (2H, t, 7.4Hz), 3.04 (2H, m), 3.33-3.53 (4
H, m), 3.82 (2H, t, J = 6.9Hz), 7.2-7.4 (5H, m), 7.45 (2H, d, J =
8.9Hz), 7.75 (2H, d, J = 8.9Hz)
【００７６】［実施例１２］ ２−（４−クロロフェニル）−８−（２−メトキシエチ
ル）−２，８−ジアザスピロ［４，５］デカン−１−オ
ン・１塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（１．０ｇ）、２−メトキシメチルアミン
（０．５９ｍｌ）を順次、アセトニトリル（２０ｍｌ）
に加え、実施例４と同様に操作することにより、表題化
合物０．２７ｇを白色固体として得た。 融点：２２４−２２６℃ 1H-NMR(DMSO-d6)δ1.77(2H,d,J=15.2Hz)、1.75-2.2(4H,
m)、3.03(1H,d,J=10.0Hz)、3.11(1H,d,J=9.6Hz)、3.31(3H,
m)、3.4-3.55(4H,m)、3.71(2H,t,J=4.5Hz)、3.83(2H,t,J=
6.9Hz)、7.45(2H,d,J=8.9Hz)、7.72(2H,m)Example 12 Synthesis of 2- (4-chlorophenyl) -8- (2-methoxyethyl) -2,8-diazaspiro [4,5] decan-1-one monohydrochloride Example 3 1- (4-chlorophenyl) -3 synthesized,
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (1.0 g) and 2-methoxymethylamine (0.59 ml) were sequentially added to acetonitrile (20 ml).
And the same operation as in Example 4 to give 0.27 g of the title compound as a white solid. Melting point: 224-226 ° C 1H-NMR (DMSO-d6) δ 1.77 (2H, d, J = 15.2 Hz), 1.75-2.2 (4H,
m), 3.03 (1H, d, J = 10.0 Hz), 3.11 (1H, d, J = 9.6 Hz), 3.31 (3H,
m), 3.4-3.55 (4H, m), 3.71 (2H, t, J = 4.5Hz), 3.83 (2H, t, J =
6.9Hz), 7.45 (2H, d, J = 8.9Hz), 7.72 (2H, m)
【００７７】［実施例１３］ ２−（４−クロロフェニル）−８−（２−メチルチオエ
チル）−２，８−ジアザスピロ［４，５］デカン−１−
オン・１塩酸塩の合成 実施例３で合成した１−（４−クロロフェニル）−３，
３―ビス（２−メタンスルホニルオキシエチル）−２−
ピロリジノン（１．５ｇ）、２−（メチルチオ）エチル
アミン（０．９８ｇ）、アセトニトリル（２０ｍｌ）
を、オートクレーブに装入し、１００℃で６時間反応し
た。反応終了後、冷却し、減圧下で濃縮した後に、飽和
重曹水を加えクロロホルムで抽出した。硫酸マグネシウ
ムで乾燥後、濾過し減圧下で濃縮した後に、残渣をシリ
カゲルカラムクロマトグラフィーにて精製して、２−
（４−クロロフェニル）−８−（２−メチルチオエチル
エチル）−２，８−ジアザスピロ［４，５］デカン−１
−オン０．４７ｇを得た。続いて、これを（１５０ｍ
ｇ）をエタノールに溶解し、１Ｎの塩酸エタノール溶液
を加え、析出物を濾取し、表題化合物０．１８ｇを白色
固体として得た。 融点：２５０℃以上 1H-NMR(DMSO-d6)δ1.08(2H,brd,J=13.5Hz)、2.03(2H,m)、
2.1-2.2(4H,m)、2.13(3H,s)、2.87(2H,m)、3.05(1H,m)、3.3
0(1H,m)、3.55(2H,m)、3.83(2H,t,J=6.9Hz)、7.45(2H,d,J=
8.9Hz)、7.73(2H,d,J=8.9Hz)Example 13 2- (4-chlorophenyl) -8- (2-methylthioethyl) -2,8-diazaspiro [4,5] decane-1-
Synthesis of on monohydrochloride 1- (4-chlorophenyl) -3 synthesized in Example 3
3-bis (2-methanesulfonyloxyethyl) -2-
Pyrrolidinone (1.5 g), 2- (methylthio) ethylamine (0.98 g), acetonitrile (20 ml)
Was charged into an autoclave and reacted at 100 ° C. for 6 hours. After completion of the reaction, the mixture was cooled, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. After drying over magnesium sulfate, filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 2-
(4-Chlorophenyl) -8- (2-methylthioethylethyl) -2,8-diazaspiro [4,5] decane-1
0.47 g of -on was obtained. Then, this is (150m
g) was dissolved in ethanol, a 1N ethanol solution of hydrochloric acid was added, and the precipitate was collected by filtration to obtain 0.18 g of the title compound as a white solid. Melting point: 250 ° C. or higher 1H-NMR (DMSO-d6) δ1.08 (2H, brd, J = 13.5Hz), 2.03 (2H, m),
2.1-2.2 (4H, m), 2.13 (3H, s), 2.87 (2H, m), 3.05 (1H, m), 3.3
0 (1H, m), 3.55 (2H, m), 3.83 (2H, t, J = 6.9Hz), 7.45 (2H, d, J =
8.9Hz), 7.73 (2H, d, J = 8.9Hz)
【００７８】［製剤例１］ ２−（４−クロロフェニル）−８−（ｎ−ヘキシル）−
２，８−ジアザスピロ［４，５］デカン−１−オン・１
塩酸塩（実施例６）を有効成分とする経口剤 本発明化合物４５ｇ、乳糖４０ｇ、トウモロコシデンプ
ン５０ｇおよび結晶セルロース３０ｇをよく混合した。
これにヒドロキシプロピルセルロース５ｇを水に溶解し
た液で練合造粒し、５０℃で４時間乾燥した。これにス
テアリン酸マグネシウム３ｇを加えて良く混合し、打錠
機を用いて１錠当たり２００ｍｇの重量を打錠し、錠剤
を得た。[Formulation Example 1] 2- (4-chlorophenyl) -8- (n-hexyl)-
2,8-diazaspiro [4,5] decan-1-one / 1
Oral preparation containing hydrochloride (Example 6) as an active ingredient 45 g of the compound of the present invention, 40 g of lactose, 50 g of corn starch and 30 g of crystalline cellulose were well mixed.
This was kneaded and granulated with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in water, and dried at 50 ° C. for 4 hours. 3 g of magnesium stearate was added thereto and mixed well, and the mixture was tableted with a tableting machine to a weight of 200 mg per tablet to obtain tablets.
【００７９】［製剤例２］ ２−（４−クロロフェニル）−８−（ｎ−ブチル）−
２，８−ジアザスピロ［４，５］デカン−１−オン・１
塩酸塩（実施例４）を有効成分とする注射剤 本発明化合物０．５ｇを取り、０．９％生理食塩水１０
ｍｌに溶かし、ろ過除菌し、１０ｍｌアンプルに封入し
て注射剤とした。[Formulation Example 2] 2- (4-chlorophenyl) -8- (n-butyl)-
2,8-diazaspiro [4,5] decan-1-one / 1
Injection containing hydrochloride (Example 4) as an active ingredient Take 0.5 g of the compound of the present invention, and add 0.9% physiological saline 10
The solution was dissolved in a 10 ml solution, sterilized by filtration, sealed in a 10 ml ampule, and used as an injection.
【００８０】［試験例１］受容体結合試験 σ１受容体結合性試験は、Bowen,W.D.等の方法（J．Pha
rmacol． Exp． Ther．262,32(1992)）に従い実施し
た。5週齢の雄性モルモット（Std:Hartley）の全脳P2フ
ラクションと［３H］-(+)-pentazocineを用いて行っ
た。測定結果を表１［表１］に示す。Test Example 1 Receptor Binding Test The σ1 receptor binding test was carried out by the method of Bowen, WD and others (J. Pha
rmacol. Exp. Ther. 262, 32 (1992)). The test was performed using whole brain P2 fraction of 5-week-old male guinea pig (Std: Hartley) and [3H]-(+)-pentazocine. The measurement results are shown in Table 1 [Table 1].
【００８１】[0081]
【表１】 [Table 1]
【００８２】［試験例２］摂食抑制作用 （１）24時間絶食ラットで摂餌におよぼす作用 摂食抑制作用は、Grignaschi,G.等の方法（Int． J． O
bes． 21(Suppl.2):Abst167(1997)）に従い実施した。8
週齢のWistar系雄性ラット(Std:Wistar/ST)を24時間絶
食させ、投薬後30分後より給餌し、３０、６０、１２０
分後に摂餌量の測定を行った（例数１０）。表２［表
２］に生理食塩水投与群に対する試験化合物投与群の摂
餌量の割合率を示した。[Test Example 2] Feeding Inhibition (1) Effect on Feeding in 24-Hour Fasted Rats The feeding inhibition was determined by the method of Grignaschi, G. et al. (Int. J. O.
bes. 21 (Suppl.2): Abst167 (1997)). 8
Week-old male Wistar rats (Std: Wistar / ST) were fasted for 24 hours and fed 30 minutes after dosing.
One minute later, the amount of food consumed was measured (the number of cases was 10). Table 2 [Table 2] shows the ratio of the food consumption of the test compound administration group to the physiological saline administration group.
【００８３】[0083]
【表２】 [Table 2]
【００８４】［試験例３］ラット簡易急性毒性試験 試験化合物を7週齢のWistar系雄性ラット３匹(Std:Wist
ar/ST)に投与し、毒性を検討した。試験化合物につき３
００ｍｇ／ｋｇを経口投与し、ラットの死亡率から毒性
を評価した。その結果を表３［表３］に示す。Test Example 3 Simple Acute Toxicity Test in Rats The test compound was administered to three 7-week-old Wistar male rats (Std: Wist).
ar / ST) and examined for toxicity. 3 per test compound
The toxicity was evaluated from the mortality of rats by orally administering 00 mg / kg. The results are shown in Table 3 [Table 3].
【００８５】[0085]
【表３】 [Table 3]
【００８６】[0086]
【発明の効果】以上のように本発明の化合物は、シグマ
受容体に親和性を有する薬剤として摂食抑制作用を有
し、肥満症、摂食障害、肥満が原因となる生活習慣病の
治療または治療薬として有用である。As described above, the compound of the present invention has an antifeeding effect as a drug having an affinity for a sigma receptor, and is useful for treating obesity, eating disorders, and lifestyle-related diseases caused by obesity. Or it is useful as a therapeutic.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 森実 邦彦 千葉県茂原市東郷1144番地 三井化学株式 会社内 (72)発明者 逆井 一也 千葉県茂原市東郷1144番地 三井化学株式 会社内 (72)発明者 曽根原 和彦 千葉県茂原市東郷1900番地の１ 三井製薬 工業株式会社内 (72)発明者 堀込 和利 千葉県茂原市東郷1900番地の１ 三井製薬 工業株式会社内 Ｆターム(参考） 4C065 AA16 BB04 CC01 DD02 EE02 HH09 JJ01 KK09 LL04 QQ01 4C086 AA01 AA02 AA03 AA04 CB05 MA01 MA04 ZA18 ZA70 ──────────────────────────────────────────────────の Continuing on the front page (72) Inventor Kunihiko Morimi 1144 Togo, Mogo-shi, Chiba Mitsui Chemicals Co., Ltd. (72) Inventor Kazuya Sakai 1144 Togo, Togo, Mobara-shi, Chiba Mitsui Chemicals Co., Ltd. (72) Invention Person Kazuhiko Sonehara 1900 Togo, Togo, Mobara City, Chiba Prefecture Inside of Mitsui Pharmaceutical Industry Co., Ltd. (72) Inventor Kazutori Horimoto 1900, Togo, Togo, Mobara City, Chiba Prefecture F-term in Mitsui Pharmaceutical Industry Co., Ltd. 4C065 AA16 BB04 CC01 DD02 EE02 HH09 JJ01 KK09 LL04 QQ01 4C086 AA01 AA02 AA03 AA04 CB05 MA01 MA04 ZA18 ZA70
Claims (6)
子、炭素数１〜６のアルキル基、ハロゲン原子、炭素数
１〜６のアルキルオキシ基を表わす。Ｒは炭素数２〜６
のアルキル基、末端にフェニル基が置換した炭素数２〜
６のアルキル基、末端に炭素数１〜４のアルキルオキシ
基が置換した炭素数１〜６のアルキル基、もしくは末端
に炭素数１〜４のアルキルチオ基が置換した炭素数１〜
６のアルキル基を表わす。）で表わされるピロリジノン
誘導体またはその薬理学的に許容される塩。1. A compound represented by the following general formula (1): (Wherein X 1 and X 2 represent a hydrogen atom which may be the same or different, an alkyl group having 1 to 6 carbon atoms, a halogen atom, an alkyloxy group having 1 to 6 carbon atoms. R represents 2 to 6 carbon atoms)
Alkyl group having 2 to 2 carbon atoms substituted with a phenyl group at the terminal
6 alkyl groups, 1 to 6 carbon atoms substituted with an alkyloxy group having 1 to 4 carbon atoms at the terminal, or 1 to 1 carbon atoms substituted with an alkylthio group having 1 to 4 carbon atoms at the terminal
6 represents an alkyl group. Or a pharmacologically acceptable salt thereof.
項１記載のピロリジノン誘導体またはその薬理学的に許
容される塩。2. The pyrrolidinone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is an alkyl group having 1 to 6 carbon atoms.
子である請求項２記載のピロリジノン誘導体またはその
薬理学的に許容される塩。3. The pyrrolidinone derivative or the pharmaceutically acceptable salt thereof according to claim 2 , wherein X 1 and X 2 are a hydrogen atom or a halogen atom.
されるピロリジノン誘導体とハロゲン化アリルを反応さ
せ、一般式（３）[化３] 【化３】 （式中、X1、X2は請求項１の場合と同義。）で表わされ
る３，３−ジアリルピロリジノン誘導体とし、炭素−炭
素２重結合を酸化的分解により一般式（４）[化４] 【化４】 （式中、X1、X2は請求項１の場合と同義。）で表わされ
る３，３−ジヒドロキシエチルピロリジノン誘導体と
し、さらに一般式（５）[化５] 【化５】 （式中、X1、X2は請求項１の場合と同義。Qはハロゲン
原子、炭素数１〜４のアルキルスルホニルオキシ基もし
くはアリールスルホニルオキシ基を表わす。）で表わさ
れるピロリジノン誘導体をR−NH2（Rは請求項１の場合
と同義。）と反応させることによる請求項１記載のピロ
リジノン誘導体の製造方法。4. A compound of the general formula (2) (Wherein X 1 , X 2 and R have the same meanings as in claim 1), and a pyrrolidinone derivative represented by the general formula (3) is reacted with an allyl halide. (Wherein X 1 and X 2 have the same meanings as in claim 1), and a carbon-carbon double bond is oxidatively decomposed to give a general formula (4) ] (Wherein X 1 and X 2 have the same meanings as in claim 1), and a 3,3-dihydroxyethylpyrrolidinone derivative represented by the following general formula (5): (Wherein X 1 and X 2 have the same meanings as in claim 1. Q represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group having 1 to 4 carbon atoms.) A pyrrolidinone derivative represented by R- The method for producing a pyrrolidinone derivative according to claim 1, wherein the method is reacted with NH 2 (R is as defined in claim 1).
たはその薬理学的に許容される塩を有効成分とする医薬
用組成物。5. A pharmaceutical composition comprising the pyrrolidinone derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
たはその薬理学的に許容される塩を有効成分とする肥満
症、摂食障害、肥満が原因となる生活習慣病の治療また
は予防剤。6. An agent for treating or preventing obesity, eating disorders and lifestyle-related diseases caused by obesity, comprising the pyrrolidinone derivative or the pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
Priority Applications (1)
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|---|---|---|---|
| JP2000079045A JP2001261679A (en) | 2000-03-21 | 2000-03-21 | Pyrrolidinone derivative, method for producing the same and medicament containing the same compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000079045A JP2001261679A (en) | 2000-03-21 | 2000-03-21 | Pyrrolidinone derivative, method for producing the same and medicament containing the same compound |
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Family
ID=18596361
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|---|---|---|---|
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