JPH0615529B2 - Novel piperidine derivative - Google Patents
Novel piperidine derivativeInfo
- Publication number
- JPH0615529B2 JPH0615529B2 JP60068650A JP6865085A JPH0615529B2 JP H0615529 B2 JPH0615529 B2 JP H0615529B2 JP 60068650 A JP60068650 A JP 60068650A JP 6865085 A JP6865085 A JP 6865085A JP H0615529 B2 JPH0615529 B2 JP H0615529B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- piperidine
- piperidine derivative
- oxazine
- benzo
- 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.)
- Expired - Lifetime
Links
Landscapes
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 本発明は新規なピペリジン誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel piperidine derivatives.
即ち本発明は、一般式(1) 〔式中、Ｒはイミダゾール、ピペリジン、モルフォリ
ン、ウラシル、ジヒドロウラシル、テオブロミン、ベン
ツイミダゾール、置換基として低級アルキル基又はフェ
ニル基を有してもよいベンツイミダゾロン、置換基とし
てハロゲン原子又は低級アルキル基を有してもよいベン
ツトリアゾール、ベンツオキサゾロン、フタールイミ
ド、テトラハイドロイソキノリン、ベンゾ−1,3−オキ
サジン−2,4−ジオン、ベンゾ−2,4−オキサジン−1,3
−ジオンから選ばれるものから誘導される１価の基、A1
kは低級アルキレン基、-COCH2-，-CH2CO-， -CH2CH＝CHCH2-，又は であり、Ｘは 又は であり、Arはベンゼン又は置換されたベンゼンから誘導
される１価の基である。That is, the present invention is represented by the general formula (1) [In the formula, R is imidazole, piperidine, morpholine, uracil, dihydrouracil, theobromine, benzimidazole, benzimidazolone which may have a lower alkyl group or a phenyl group as a substituent, a halogen atom or a lower alkyl group as a substituent. Benztriazole which may have a group, benzoxazolone, phthalimide, tetrahydroisoquinoline, benzo-1,3-oxazine-2,4-dione, benzo-2,4-oxazine-1,3
A monovalent radical derived from a dione selected from: A1
k is a lower alkylene group, -COCH 2- , -CH 2 CO-, -CH 2 CH = CHCH 2- , or And X is Or And Ar is a monovalent group derived from benzene or substituted benzene.
のＲ′はアルキル、アラルキル又はアシル基である。〕 で表わされる新規なピペリジン誘導体及びその製薬学的
に許容しうる酸付加塩に関する。 R'of is an alkyl, aralkyl or acyl group. ] The novel piperidine derivative represented by these and its pharmaceutically acceptable acid addition salt.
これらの化合物は抗セロトニン作用を有することから、
セロトニンの遊離が重要である種々の病気の治療に使用
することができる。Since these compounds have anti-serotonin action,
It can be used in the treatment of various diseases in which the release of serotonin is important.
上記式（１）で表わされる新規ピペリジン誘導体は、例
えば以下に述べる方法により合成することができる。The novel piperidine derivative represented by the above formula (1) can be synthesized, for example, by the method described below.
合成法 １） ブロモアルキル体とベンゾイルピペリジンをメタノー
ル、エタノール、プロパノール、ブタノール、ベンゼ
ン、トルエン等の有機溶媒の存在下、NaHCO3，K2CO3等
の塩基と加熱、還流することにより製することができ
る。Synthesis method 1) The bromoalkyl derivative and benzoylpiperidine can be produced by heating and refluxing with a base such as NaHCO 3 or K 2 CO 3 in the presence of an organic solvent such as methanol, ethanol, propanol, butanol, benzene or toluene.
２） ベンゾイルピペリジン体はメタノール溶媒中、NaBH4に
より容易に還元されアルコール体を得ることが出来る。2) The benzoylpiperidine derivative can be easily reduced with NaBH 4 in a methanol solvent to obtain an alcohol derivative.
３） アルコール体は、テトラヒドロフラン、DMF等の溶媒中N
aHの存在下アルキルハライド、アラルキルハライド、ア
シルハライド等と室温もしくは加熱下に反応することに
より得られる。（R′＝アルキル、アラルキル、アシ
ル、Y=C1，Br） 以下実施例により本発明を更に詳細に説明する。3) The alcohol compound is N in a solvent such as tetrahydrofuran or DMF.
It can be obtained by reacting with an alkyl halide, aralkyl halide, acyl halide or the like in the presence of aH at room temperature or under heating. (R '= alkyl, aralkyl, acyl, Y = C1, Br) The present invention will be described in more detail with reference to the following examples.
実施例１ １−（２−ピペリジニル−１）エチル−４−（ｐ−フル
オロベンゾイル）ピペリジン２塩酸塩の合成 １−（２−クロロエチル）ピペリジン3.7g、４−（ｐ−
フルオロベンゾイル）ピペリジン塩酸塩5.0g、NaHCO34.
2gをブタノール中３時間還流、攪拌する。Example 1 Synthesis of 1- (2-piperidinyl-1) ethyl-4- (p-fluorobenzoyl) piperidine dihydrochloride 1- (2-chloroethyl) piperidine 3.7 g, 4- (p-
(Fluorobenzoyl) piperidine hydrochloride 5.0 g, NaHCO 3 .
2 g is refluxed and stirred in butanol for 3 hours.
反応液を水にあけ、クロロホルムで抽出する。The reaction solution is poured into water and extracted with chloroform.
粗成物をシリカゲルカラムで精製した後、塩酸塩とす
る。The crude product is purified with a silica gel column and then converted into the hydrochloride.
収量 1.5g m.p. ＞290℃ 元素分析 C19H27N2OF・2HCl 実施例２ ３−〔２−（４−ｐ−フルオロベンゾイルピペリジニル
−１）エチル〕ウラシル塩酸塩の合成 ３−（２−ブロモエチル）ウラシル1.6g、４−（ｐ−フ
ルオロベンゾイル）ピペリジン塩酸塩1.8g、NaHCO32.5g
をトルエン中、３時間還流、攪拌する。反応液を水にあ
けクロロホルムで抽出する。Yield 1.5g mp ＞ 290 ℃ Elemental analysis C 19 H 27 N 2 OF ・ 2HCl Example 2 Synthesis of 3- [2- (4-p-fluorobenzoylpiperidinyl-1) ethyl] uracil hydrochloride 3- (2-Bromoethyl) uracil 1.6 g, 4- (p-fluorobenzoyl) piperidine hydrochloride 1.8g, NaHCO 3 2.5g
Is refluxed and stirred in toluene for 3 hours. The reaction solution is poured into water and extracted with chloroform.
粗生物をシルカゲルカラムで精製した後、塩酸塩とす
る。The crude product is purified on a silica gel column and then converted to the hydrochloride.
収量 1.1g m.p. 291〜293℃（分解） 元素分析 C18H20N3O3F・HCl・1/4H2O 実施例３ ３−〔４−（４−ｐ−フルオロベンゾイルピペリジニル
−１）ｎ−ブチル〕−5,6−ジヒドロウラシル酒石酸塩
の合成 ３−（４−ブロモブチル）−5,6−ジヒドロウラシル1.5
g、４−（ｐ−フルオロベンゾイル）ピペリジン塩酸塩
1.5g、K2CO32.8gをブタノール中、７時間還流、攪拌す
る。Yield 1.1g mp 291-293 ℃ (decomposition) Elemental analysis C 18 H 20 N 3 O 3 F ・ HCl ・ 1 / 4H 2 O Example 3 Synthesis of 3- [4- (4-p-fluorobenzoylpiperidinyl-1) n-butyl] -5,6-dihydrouracil tartrate 3- (4-Bromobutyl) -5,6-dihydrouracil 1.5
g, 4- (p-fluorobenzoyl) piperidine hydrochloride
1.5 g and K 2 CO 3 2.8 g are refluxed and stirred in butanol for 7 hours.
反応液を水にあけクロロホルムで抽出する。粗成物をシ
リカゲルカラムで精製した後、酒石酸塩とする。The reaction solution is poured into water and extracted with chloroform. The crude product is purified with a silica gel column and then converted to the tartrate salt.
収量 1.2g m.p. 176〜179℃（分解） 元素分析 C24H32N3O9F 実施例４ １−エチル−２−オキソ−３−〔２（４−ｐ−フルオロ
ベンゾイルピペリジニル−１）−エチル〕ベンツイミダ
ゾール塩酸塩の合成 １−エチル−２−オキソ−３−（２−ブロモエチル）ベ
ンツイミダゾール5.4g、４−（ｐ−フルオロベンゾイ
ル）ピペリジン塩酸塩4.9g、NaHCO33.4gをエタノール30
mlに懸濁し、還流下５時間攪拌する。Yield 1.2g mp 176-179 ℃ (decomposition) Elemental analysis C 24 H 32 N 3 O 9 F Example 4 Synthesis of 1-ethyl-2-oxo-3- [2 (4-p-fluorobenzoylpiperidinyl-1) -ethyl] benzimidazole hydrochloride 1-ethyl-2-oxo-3- (2- Bromoethyl) benzimidazole 5.4 g, 4- (p-fluorobenzoyl) piperidine hydrochloride 4.9 g, NaHCO 3 3.4 g, ethanol 30
Suspend in ml and stir under reflux for 5 hours.
反応液を水にあけクロロホルムで抽出する。The reaction solution is poured into water and extracted with chloroform.
K2CO3で乾燥し、溶媒を減圧で留去した後、残渣をシリ
カゲルカラム(CHCl3:MeOH＝10:1)で精製する。これをエ
タノールに溶解し10％塩酸−酢酸エチル10mlを加え塩酸
塩とする。エタノールから再結晶する。After drying over K 2 CO 3 and evaporating the solvent under reduced pressure, the residue is purified on a silica gel column (CHCl 3 : MeOH = 10: 1). This is dissolved in ethanol and 10% hydrochloric acid-ethyl acetate (10 ml) is added to give a hydrochloride. Recrystallize from ethanol.
収量 4.4g m.p. 233〜236℃（分解） 元素分析 C23H26N3O2F・HCl 実施例５ 実施例１〜４と同様にして合成した化合物を表１に示
す。Yield 4.4g mp 233-236 ℃ (decomposition) Elemental analysis C 23 H 26 N 3 O 2 F ・ HCl Example 5 Table 1 shows compounds synthesized in the same manner as in Examples 1 to 4.
尚、表１に示す化合物は式 で表わされるものである。The compounds shown in Table 1 have the formula Is represented by.
本発明の化合物の抗セロトニン作用についての実験は以
下の方法に従って行った。 The experiment on the antiserotonin action of the compound of the present invention was carried out according to the following method.
実験方法 体重300g前後のSD系雄性ラットを撲殺後、開腹して胸部
大動脈血管を摘出する。Experimental method After sterilizing SD male rats weighing about 300 g, the laparotomy is performed and the thoracic aortic blood vessels are removed.
結合組織を剥離した後、血管を螺旋状に切断する。これ
を約２cmの長さに切り、37℃のkrebs溶液を満たした10m
lのマグヌス管中につるし、95%O2＋５％CO2の混合ガス
を通気する。標本の一端を糸で等張性トランスジューサ
ーに接続し、１ｇ負荷のもとで標本の状態が一定になる
まで放置する。Agonistであるセロトニンの濃度は１×1
0-7M〜１×10-4Mを用い、マイクロシリンジにより累積
的にマグヌス管中に添加する。コントロールの用量反
応曲線を描いた後、標本をよく洗浄し、被験化合物１×
10-6M〜１×10-8Mのいずれかの濃度を含む栄養液で30分
間インキュベーションする。After detaching the connective tissue, the blood vessel is cut into a spiral shape. Cut this to a length of about 2 cm and fill it with 10 m of the 37 ° C krebs solution.
Suspend in a lmagnus tube and ventilate a mixture of 95% O 2 + 5% CO 2 . One end of the sample is connected with a thread to an isotonic transducer and left under a 1 g load until the condition of the sample is constant. The concentration of serotonin, an Agonist, is 1 x 1
With 0 -7 M~1 × 10 -4 M, cumulatively added into the Magnus tube by microsyringe. After drawing a dose-response curve for the control, the sample was washed thoroughly and the test compound 1 ×
Incubate for 30 minutes with a nutrient solution containing a concentration of 10 −6 M to 1 × 10 −8 M.
被験化合物存在下、再びセロトニンの用量反応曲線を
描き、Van Rossumらの方法によりPA2値を算出する。A dose-response curve of serotonin is drawn again in the presence of the test compound, and the PA 2 value is calculated by the method of Van Rossum et al.
被験化合物は精製水に溶かし、難溶の場合には希塩酸を
少量加えて可溶化し使用した。The test compound was dissolved in purified water, and when it was sparingly soluble, a small amount of dilute hydrochloric acid was added to solubilize it for use.
本発明により得られた化合物の主なもののPA2を表２に
示す。Table 2 shows PA 2 's of major compounds obtained by the present invention.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｄ 401/06 ２３３ 8829−4Ｃ ２３９ 8829−4Ｃ ２４９ 8829−4Ｃ 413/06 ２１１ 8829−4Ｃ 473/10 // Ａ６１Ｋ 31/445 ＡＥＮ 9360−4Ｃ 31/505 9360−4Ｃ 31/535 9360−4Ｃ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical indication location C07D 401/06 233 8829-4C 239 8829-4C 249 8829-4C 413/06 211 8829-4C 473 / 10 // A61K 31/445 AEN 9360-4C 31/505 9360-4C 31/535 9360-4C
Claims (2)
ン、ウラシル、ジヒドロウラシル、テオブロミン、ベン
ツイミダゾール、置換基として低級アルキル基又はフェ
ニル基を有してもよいベンツイミダゾロン、置換基とし
てハロゲン原子又は低級アルキル基を有してもよいベン
ツトリアゾール、ベンツオキサゾロン、フタールイミ
ド、テトラハイドロイソキノリン、ベンゾ−1,3−オキ
サジン−2,4−ジオン、ベンゾ−2,4−オキサジン−1,3
−ジオンから選ばれるものから誘導される１価の基、A1
kは低級アルキレン基、-COCH2-，-CH2CO-， -CH2CH＝CHCH2-，又は であり、Ｘは であり、Arはベンゼン又は置換されたベンゼンから誘導
される１価の基である。 のＲ′はアルキル、アラルキル又はアシル基である。〕 で表わされる新規ピペリジン誘導体又はその製薬学的に
許容しうる酸付加塩。1. A general formula (1) [In the formula, R is imidazole, piperidine, morpholine, uracil, dihydrouracil, theobromine, benzimidazole, a lower alkyl group or a benzimidazolone which may have a phenyl group as a substituent, a halogen atom or a lower alkyl as a substituent. Benztriazole which may have a group, benzoxazolone, phthalimide, tetrahydroisoquinoline, benzo-1,3-oxazine-2,4-dione, benzo-2,4-oxazine-1,3
A monovalent radical derived from a dione selected from: A1
k is a lower alkylene group, -COCH 2- , -CH 2 CO-, -CH 2 CH = CHCH 2- , or And X is And Ar is a monovalent group derived from benzene or substituted benzene. R'of is an alkyl, aralkyl or acyl group. ] The novel piperidine derivative represented by these, or its pharmaceutically acceptable acid addition salt.
ジン誘導体の群から選択される一つである特許請求の範
囲第１項記載の新規ピペリジン誘導体又はその製薬学的
に許容しうる酸付加塩。 2. The novel piperidine derivative according to claim 1, wherein the compound is one selected from the group of piperidine derivatives represented by the following chemical structural formulas, or a pharmaceutically acceptable acid addition thereof. salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60068650A JPH0615529B2 (en) | 1985-04-01 | 1985-04-01 | Novel piperidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60068650A JPH0615529B2 (en) | 1985-04-01 | 1985-04-01 | Novel piperidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61227565A JPS61227565A (en) | 1986-10-09 |
| JPH0615529B2 true JPH0615529B2 (en) | 1994-03-02 |
Family
ID=13379786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60068650A Expired - Lifetime JPH0615529B2 (en) | 1985-04-01 | 1985-04-01 | Novel piperidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0615529B2 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR910006138B1 (en) * | 1986-09-30 | 1991-08-16 | 에자이 가부시끼가이샤 | Cyclic amine derivatives |
| JP2643168B2 (en) * | 1987-08-24 | 1997-08-20 | エーザイ株式会社 | Arrhythmia treatment / prevention agent |
| ATE133942T1 (en) * | 1987-11-27 | 1996-02-15 | Eisai Co Ltd | CYCLIC AMINE AND PHARMACOLOGICAL COMPOUNDS |
| US5196439A (en) * | 1987-11-27 | 1993-03-23 | Eisai Co., Ltd. | Piperidine compounds useful to treat cerebrovascular diseases |
| US5523307A (en) * | 1987-11-27 | 1996-06-04 | Eisai Co., Ltd. | Cyclic amine and pharmacological composition |
| WO1994021627A1 (en) * | 1993-03-18 | 1994-09-29 | Merck Sharp & Dohme Limited | Indole derivatives as dopamine d4 antagonists |
| FR2735129B1 (en) * | 1995-06-07 | 1997-07-11 | Adir | NOVEL INDOLE, INDAZOLE AND BENZISOXAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| ZA9610745B (en) * | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
| ZA9610738B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | Subtype selective nmda receptor ligands and the use thereof |
| ZA9610736B (en) * | 1995-12-22 | 1997-06-27 | Warner Lambert Co | 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists |
| ZA9610741B (en) | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
| GB9613423D0 (en) * | 1996-06-26 | 1996-08-28 | Lilly Industries Ltd | Pharmaceutical compounds |
| ES2157148B1 (en) * | 1998-11-18 | 2002-03-01 | Faes Fabrica Espanola De Produ | NEW 4-SUBSTITUTED PIPERIDINS. |
| KR20060061393A (en) * | 2003-10-24 | 2006-06-07 | 에프. 호프만-라 로슈 아게 | Ccr3 receptor antagonists |
| US7790726B2 (en) * | 2005-08-16 | 2010-09-07 | Chemocentryx, Inc. | Monocyclic and bicyclic compounds and methods of use |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5022033A (en) * | 1973-06-27 | 1975-03-08 | ||
| JPS53112882A (en) * | 1977-03-14 | 1978-10-02 | Hoechst Ag | Benzoylpiperidylalkylindoles and and related compounds |
| JPS55105679A (en) * | 1979-01-08 | 1980-08-13 | Janssen Pharmaceutica Nv | Novel *piperidinylalkyl*quinazoline derivative |
| JPS56150091A (en) * | 1980-03-28 | 1981-11-20 | Janssen Pharmaceutica Nv | 3-(1-piperidinylalkyl)-4h-pyrido(1,2-a)pyrimidine- 4-one derivative and its manufacture |
| JPS5824585A (en) * | 1981-07-20 | 1983-02-14 | ジ−クフリ−ト・アクチエンゲゼルシヤフト | Novel theophylline derivative and manufacture |
-
1985
- 1985-04-01 JP JP60068650A patent/JPH0615529B2/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5022033A (en) * | 1973-06-27 | 1975-03-08 | ||
| JPS53112882A (en) * | 1977-03-14 | 1978-10-02 | Hoechst Ag | Benzoylpiperidylalkylindoles and and related compounds |
| JPS55105679A (en) * | 1979-01-08 | 1980-08-13 | Janssen Pharmaceutica Nv | Novel *piperidinylalkyl*quinazoline derivative |
| JPS56150091A (en) * | 1980-03-28 | 1981-11-20 | Janssen Pharmaceutica Nv | 3-(1-piperidinylalkyl)-4h-pyrido(1,2-a)pyrimidine- 4-one derivative and its manufacture |
| JPS5824585A (en) * | 1981-07-20 | 1983-02-14 | ジ−クフリ−ト・アクチエンゲゼルシヤフト | Novel theophylline derivative and manufacture |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61227565A (en) | 1986-10-09 |
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