JPS6340426B2 - - Google Patents
Info
- Publication number
- JPS6340426B2 JPS6340426B2 JP14707480A JP14707480A JPS6340426B2 JP S6340426 B2 JPS6340426 B2 JP S6340426B2 JP 14707480 A JP14707480 A JP 14707480A JP 14707480 A JP14707480 A JP 14707480A JP S6340426 B2 JPS6340426 B2 JP S6340426B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- same manner
- pyrrolidone
- formula
- reaction
- 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
Links
- 150000003953 γ-lactams Chemical class 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 7
- WDQFELCEOPFLCZ-UHFFFAOYSA-N 1-(2-hydroxyethyl)pyrrolidin-2-one Chemical compound OCCN1CCCC1=O WDQFELCEOPFLCZ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- -1 terpene carboxylic acids Chemical class 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 235000007586 terpenes Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- GLZPCOQZEFWAFX-YFHOEESVSA-N Geraniol Natural products CC(C)=CCC\C(C)=C/CO GLZPCOQZEFWAFX-YFHOEESVSA-N 0.000 description 1
- 239000005792 Geraniol Substances 0.000 description 1
- GLZPCOQZEFWAFX-UHFFFAOYSA-N KU0063794 Natural products CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HIGQPQRQIQDZMP-UHFFFAOYSA-N geranil acetate Natural products CC(C)=CCCC(C)=CCOC(C)=O HIGQPQRQIQDZMP-UHFFFAOYSA-N 0.000 description 1
- 229940113087 geraniol Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- NQEKGMWPZUWNSN-FNFKDMCFSA-N methyl (2e,6e,10e)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenoate Chemical compound COC(=O)\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C NQEKGMWPZUWNSN-FNFKDMCFSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は新規な２―ピロリドン誘導体に関する
ものであり、さらに詳しくは一般式(1)
（式中ｍは２または３、ｎは０または１である）
で示される２―ピロリドン誘導体に関する。
従来テルペンカルボン酸のエステル類は種々知
られており、それらの薬理作用についても多くの
研究がなされている。たとえばフアルネシル酢酸
のゲラニオールエステルは抗潰瘍剤として商品化
されており、またアルコール部分にアミン性窒素
原子を有するフアルネシル酢酸エステルも抗潰瘍
作用を示すことが公知である。
本発明者らは種々のテルペン類を有するカルボ
ン酸の種々の誘導体を合成しそれらの薬理作用を
検討した結果、前記の一般式(1)で示される２―ピ
ロリドン誘導体が抗腫瘍作用を有することを見出
し、本発明を完成するに至つた。
本発明の化合物のうちの例えばｍ＝２、ｎ＝１
の化合物〔化合物(1)とする〕およびｍ＝３、ｎ＝
１の化合物〔化合物(2)とする〕についてそれらの
薬理データを示せば次のとおりである。
抗腫瘍作用
ddY―マウス（雄、５週令）の腹腔内にエーリ
ツヒ腹水腫瘍細胞2.5×106個を移植し、腫瘍移植
後24時間経過後より表１に示す投与スケジユール
で化合物(1)または(2)を腹腔内に投与した。各マウ
スの生存日数を観察し、中央値によつて延命率を
算出した。
The present invention relates to a novel 2-pyrrolidone derivative, and more specifically, to a novel 2-pyrrolidone derivative represented by the general formula (1). (In the formula, m is 2 or 3, and n is 0 or 1)
The present invention relates to a 2-pyrrolidone derivative represented by Various esters of terpene carboxylic acids have been known, and many studies have been conducted on their pharmacological effects. For example, geraniol ester of phalnesylacetic acid is commercially available as an anti-ulcer agent, and it is also known that phalnesyl acetate having an amine nitrogen atom in the alcohol moiety also exhibits anti-ulcer effects. The present inventors synthesized various derivatives of carboxylic acids having various terpenes and investigated their pharmacological effects. As a result, the 2-pyrrolidone derivative represented by the above general formula (1) has an antitumor effect. They discovered this and completed the present invention. Among the compounds of the present invention, for example, m=2, n=1
[referred to as compound (1)] and m=3, n=
The pharmacological data for Compound 1 [referred to as Compound (2)] are as follows. Antitumor effect ddY-mice (male, 5 weeks old) were intraperitoneally transplanted with 2.5 × 10 Ehritzch ascites tumor cells, and 24 hours after tumor transplantation, compound (1) or compound (1) was administered according to the administration schedule shown in Table 1. (2) was administered intraperitoneally. The number of days each mouse survived was observed, and the survival rate was calculated based on the median value.
【表】
本発明の化合物は、対応する出発物質を用いる
以外は公知のカルボン酸エステルの製法として知
られている各種の方法により製造することができ
る。最も一般的な方法は下記の一般式（）
（式中ｍおよびｎは一般式（）中のそれらと同
じ意味を有し、Ｘはアルコール性水酸基と反応し
てエステルを生成しうるかまたは有機ハライドと
反応してエステルを生成しうる基たとえば水酸
基、アルコキシ基、ハロゲン原子、―Ｏ―アルカ
リ金属などを表わす）で示される化合物と下記の
一般式（）
（式中Ｙは水酸基またはハロゲン原子を表わす）
で示される化合物とを必要に望じエステル生成用
触媒の存在下に反応させる方法である。
本発明により提供される一般式（）で示され
る２―ピロリドン誘導体は前記のように抗腫瘍作
用を有し、したがつて抗腫瘍剤などの医薬品とし
て有用である。
以下、本発明を実施例により説明するが、本発
明はこれらの実施例によつて制限を受けるもので
はない。
実施例 １
温度計、滴下ロートおよびビグリユーカラムを
備えた三つ口フラスコにフアルネシル酢酸メチル
27.8g、Ｎ―β―ヒドロキシエチル―２―ピロリ
ドン19.4g、水酸化ナトリウム0.4gおよびトルエ
ン200mlを入れ、内温110〜116℃に加熱し、トル
エンおよび反応の結果生成するメタノールを留去
しながら３時間反応させた。反応中、滴下ロート
からトルエンをその留去速度に応じて滴下補給し
た。反応後、反応混合物に水200mlおよびジエチ
ルエーテル200mlを加え、水層とエーテル層とに
分液し、エーテル層を水200mlで２回洗浄したの
ち無水硫酸マグネシウムで乾燥した。該エーテル
層からエーテルおよびトルエンを留去し、残留物
を分取用液体クロマトグラフ（ウオータース社、
システム500）によりｎ―ヘキサン：イソプロパ
ノール＝85：15（体積比）の混合溶媒を用いて精
製し、淡黄色の液体31gを得た。このものはプロ
トンNMRおよび質量分析により下記構造式で示
される化合物であることが確認された。
NMRのデータを次に示す。（90MHz；CDCl3
溶液として測定）[Table] The compounds of the present invention can be produced by various methods known as methods for producing carboxylic acid esters, except for using the corresponding starting materials. The most common method is the following general formula () (In the formula, m and n have the same meanings as those in the general formula (), and X is a group that can react with an alcoholic hydroxyl group to produce an ester or react with an organic halide to produce an ester, such as a hydroxyl group. , alkoxy group, halogen atom, -O-alkali metal, etc.) and the following general formula () (In the formula, Y represents a hydroxyl group or a halogen atom)
This is a method in which a compound represented by the following formula is reacted in the presence of a desired ester-forming catalyst. The 2-pyrrolidone derivative represented by the general formula () provided by the present invention has an antitumor effect as described above, and is therefore useful as a pharmaceutical agent such as an antitumor agent. EXAMPLES The present invention will be explained below using Examples, but the present invention is not limited by these Examples. Example 1 Methyl phalnesyl acetate was added to a three-necked flask equipped with a thermometer, addition funnel, and Vigrieux column.
27.8 g, N-β-hydroxyethyl-2-pyrrolidone 19.4 g, sodium hydroxide 0.4 g and toluene 200 ml were added and heated to an internal temperature of 110 to 116°C, while distilling off toluene and methanol produced as a result of the reaction. The reaction was allowed to proceed for 3 hours. During the reaction, toluene was replenished dropwise from the dropping funnel according to its distillation rate. After the reaction, 200 ml of water and 200 ml of diethyl ether were added to the reaction mixture to separate it into an aqueous layer and an ether layer, and the ether layer was washed twice with 200 ml of water and then dried over anhydrous magnesium sulfate. Ether and toluene were distilled off from the ether layer, and the residue was collected using a preparative liquid chromatograph (Waters Co., Ltd.,
System 500) using a mixed solvent of n-hexane:isopropanol=85:15 (volume ratio) to obtain 31 g of a pale yellow liquid. This product was confirmed to be a compound represented by the following structural formula by proton NMR and mass spectrometry. The NMR data is shown below. (90MHz; CDCl 3
(measured as a solution)
【表】
実施例 ２
ゲラニルゲラニル酢酸メチル17.3gとＮ―ヒド
ロキシエチル―２―ピロリドン12.5gを実施例１
と同様にしてエステル交換反応させ、反応生成物
を実施例１と同様にして分離精製することによ
り、淡黄色液体として下記構造式で示される化合
物18.2gを得た。
上記化合物のNMRデータ（90MHz、CDCl3溶
液で測定）：[Table] Example 2 17.3 g of methyl geranylgeranyl acetate and 12.5 g of N-hydroxyethyl-2-pyrrolidone were added in Example 1.
A transesterification reaction was carried out in the same manner as in Example 1, and the reaction product was separated and purified in the same manner as in Example 1 to obtain 18.2 g of a compound represented by the following structural formula as a pale yellow liquid. NMR data of the above compound (90MHz, measured in CDCl 3 solution):
【表】【table】
【表】
実施例 ３
フアルネシル酸メチル25.0gとＮ―ヒドロキシ
エチル―２―ピロリドン19.4gを実施例１と同様
にしてエステル交換反応させ、反応生成物を実施
例１と同様にして分離精製することにより、淡黄
色液体として下記構造式で示される化合物29.5g
を得た。
上記化合物のNMRデータ（90MHz；CDCl3溶
液で測定）：[Table] Example 3 25.0 g of methyl pharnesylate and 19.4 g of N-hydroxyethyl-2-pyrrolidone were transesterified in the same manner as in Example 1, and the reaction product was separated and purified in the same manner as in Example 1. 29.5g of the compound shown by the following structural formula as a pale yellow liquid
I got it. NMR data of the above compound (90MHz; measured in CDCl 3 solution):
【表】【table】
【表】
実施例 ４
ゲラニルゲラン酸メチル15.9gとＮ―ヒドロキ
シエチル―２―ピロリドン12.5gを実施例１と同
様にしてエステル交換反応させ、反応生成物を実
施例１と同様にして分離精製することにより、淡
黄色液体として下記構造式で示される化合物
17.1gを得た。
上記化合物のNMRデータ（90MHz；CDCl3溶
液で測定）：[Table] Example 4 15.9 g of methyl geranylgeranate and 12.5 g of N-hydroxyethyl-2-pyrrolidone were transesterified in the same manner as in Example 1, and the reaction product was separated and purified in the same manner as in Example 1. By this, the compound shown by the following structural formula as a pale yellow liquid
Obtained 17.1g. NMR data of the above compound (90MHz; measured in CDCl 3 solution):
【表】【table】
【表】
実施例 ５
ゲラニル酢酸エチル11.2gとＮ―ヒドロキシエ
チル―２―ピロリドン12.5gを実施例１と同様に
してエステル交換反応させ、反応生成物を実施例
１と同様にして分離精製することにより、淡黄色
液体として下記構造式で示される化合物14.0gを
得た。
上記化合物のNMRデータ（90MHz；CDCl3溶
液で測定）：[Table] Example 5 11.2 g of ethyl geranylacetate and 12.5 g of N-hydroxyethyl-2-pyrrolidone were transesterified in the same manner as in Example 1, and the reaction product was separated and purified in the same manner as in Example 1. As a result, 14.0 g of a compound represented by the following structural formula was obtained as a pale yellow liquid. NMR data of the above compound (90MHz; measured in CDCl 3 solution):
【表】【table】
【表】
実施例 ６
ゲラン酸エチル14.7gとＮ―ヒドロキシエチル
―２―ピロリドン12.5gを実施例１と同様にして
エステル交換反応させ、反応生成物を実施例１と
同様にして分離精製することにより、淡黄色液体
として下記構造式で示される化合物16.3gを得た。
上記化合物のNMRデータ（90MHz；CDCl3溶
液で測定）：[Table] Example 6 14.7 g of ethyl gellanate and 12.5 g of N-hydroxyethyl-2-pyrrolidone were transesterified in the same manner as in Example 1, and the reaction product was separated and purified in the same manner as in Example 1. As a result, 16.3 g of a compound represented by the following structural formula was obtained as a pale yellow liquid. NMR data of the above compound (90MHz; measured in CDCl 3 solution):
【表】【table】
Claims (1)
で示される２―ピロリドン誘導体。[Claims] 1. General formula (In the formula, m is 2 or 3, n is 0 or 1)
A 2-pyrrolidone derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14707480A JPS5770862A (en) | 1980-10-20 | 1980-10-20 | 2-pyrrolidone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14707480A JPS5770862A (en) | 1980-10-20 | 1980-10-20 | 2-pyrrolidone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5770862A JPS5770862A (en) | 1982-05-01 |
| JPS6340426B2 true JPS6340426B2 (en) | 1988-08-11 |
Family
ID=15421875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14707480A Granted JPS5770862A (en) | 1980-10-20 | 1980-10-20 | 2-pyrrolidone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5770862A (en) |
-
1980
- 1980-10-20 JP JP14707480A patent/JPS5770862A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5770862A (en) | 1982-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CH626337A5 (en) | ||
| Fiandanese et al. | Synthesis of naturally occurring polyacetylenes via a bis-silylated diyne | |
| JPS6340426B2 (en) | ||
| US4591651A (en) | Process for directly converting an aldehyde into an ethylene ester | |
| Berens et al. | The First Stereoselective Synthesis of Racemic. beta.-Multistriatin: A Pheromone Component of the European Elm Bark Beetle Scolytus multistriatus (Marsh.) | |
| Lim et al. | Rhodium-catalyzed coupling reaction of 2-vinylpyridines with allyl ethers | |
| JP4399885B2 (en) | Method for producing 4-methyltetrafluorobenzyl alcohol derivative | |
| JPS5826330B2 (en) | Method for producing stereo-regulated farnesyl acetate | |
| US4060691A (en) | 7-{3-Hydroxy-2-[4-hydroxy-4-(lower alkyl)-trans-1-octen-1-yl]-5-oxocyclopent-1-yl}heptanoic acids and esters | |
| JPS6123178B2 (en) | ||
| Bellina et al. | Synthesis of 2-tributylstannyl-1-alkenes from 2-tributylstannyl-2-propen-1-yl acetate | |
| JPH0749435B2 (en) | Method for producing 1α, 3β, 24-trihydroxy-Δupper-5-steroids | |
| Hernández et al. | One-pot synthesis of benzyltriphenylphosphonium acetates from the corresponding activated benzyl alcohols | |
| JPS6257181B2 (en) | ||
| JP2770357B2 (en) | Method for producing nucleoside derivative | |
| JPS6212770B2 (en) | ||
| JPH0358335B2 (en) | ||
| JPS61118348A (en) | Manufacture of hydroxymethylenealkoxyacetic acid ester | |
| JP2938225B2 (en) | Production method of allyl alcohol | |
| Meese et al. | Dimethyl 3, 3, 4, 4,. 5,. 5, 6, 6‐(2H8)‐6‐methoxycarbonyl‐2‐oxo‐hexanephosphonate, a versatile reagent for the synthesis of deuterated ω‐carboxy prostanoids | |
| Reetz et al. | α-Alkylation of carbonyl compounds using 1-acetoxy-1-ferrocenylethane | |
| CN117024499A (en) | Preparation method of steroid compound with methylene hydroxyl introduced at 2-position | |
| JPS63170335A (en) | Synthesis of dl-cis-chrysanthemumic acid | |
| JP2791572B2 (en) | Macrocyclic compound and method for producing the same | |
| US4100343A (en) | 11-Deoxyprostaglandin derivatives |