JPS5989656A - Aletheine derivative - Google Patents
Aletheine derivativeInfo
- Publication number
- JPS5989656A JPS5989656A JP57200934A JP20093482A JPS5989656A JP S5989656 A JPS5989656 A JP S5989656A JP 57200934 A JP57200934 A JP 57200934A JP 20093482 A JP20093482 A JP 20093482A JP S5989656 A JPS5989656 A JP S5989656A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- group
- benzyloxycarbonylamino
- acid anhydride
- 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.)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】 本発明は式ＣＩ、ｌで表わされる化合物に関する。[Detailed description of the invention] The present invention relates to compounds of formula CI, l.
ＲＩＱ−（ＣＨ２０）ｎ−ＣＯＮＨＣＨ，、ｃＨ２ＣＯ
ＮＨＣＬ、Ｇリ−Ｒ２ＣＩＩ）〔式中 Ｒ１は水素原子
、低級アルキル基または低級アルコキシ基を示す。RIQ-(CH20)n-CONHCH,,cH2CO
NHCL, G-R2CII) [wherein R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group.
Ｒ２は低級アルカノイル基または低級アルキルアミノチ
オカルボニル基を示す。R2 represents a lower alkanoyl group or a lower alkylaminothiocarbonyl group.
ｎ ＦｉＯまたに′ｉｌを示す。以下同じ。〕・本発明
化合物ＣＩ）の主骨格であるβ−アレティンは補酵素Ａ
（以下ＣｏＡと略す）の末端部分の構成成分であり、チ
オール基を有する物質である。nFiO also indicates 'il. same as below. ]・β-aretin, which is the main skeleton of the compound CI) of the present invention, is coenzyme A
(hereinafter abbreviated as CoA), and is a substance having a thiol group.
ＣｏＡｔ；を生体内に広く分布するが特に肝臓に多く存
在しており、炭水化物、脂肪および蛋白質の代謝におい
て中心的な役割を果している。代謝経路においてＣｏＡ
が関与するものの内で最吃重要なものはアセチルＣｏＡ
であるといわれており、アセチルＣｏＡが種々の物質を
アセチル化すること（アセチル基の転位）により代謝が
進行するとされている。このアセチル基の転位の媒介を
なしているのがチオール基であり、又ＣｏＡのチオール
末端の構成成分がβ−アレティンである事に着目し、β
−アレティン誘導体の研究を行った。その結果本発明化
合物〔Ｉ〕が脂質代謝改善作用を有し、肝臓疾患治療剤
として有用である事を見い出した。Although CoAt; is widely distributed in living organisms, it is particularly present in large quantities in the liver, and plays a central role in the metabolism of carbohydrates, fats, and proteins. CoA in metabolic pathways
The most important one involved is acetyl-CoA.
Metabolism is said to proceed as acetyl-CoA acetylates various substances (transfer of acetyl groups). Noting that it is the thiol group that mediates this rearrangement of the acetyl group, and that the constituent component of the thiol terminal of CoA is β-aretin,
- Conducted research on aretin derivatives. As a result, it was found that the compound [I] of the present invention has a lipid metabolism improving effect and is useful as a therapeutic agent for liver diseases.
本発明化合物〔■〕は例えば下記Ａ）、Ｂ）のような方
法により合成することができる。The compound of the present invention [■] can be synthesized, for example, by the following methods A) and B).
Ａ）式［１１）で表わされる化合物と式［１１）で表わ
される化合物またはその反応性誘導体（例えば、酸無水
物、混合酸無水物等）を反応させることにより本発明化
合物ＣＩ）を得る。A) Compound CI) of the present invention is obtained by reacting the compound represented by formula [11) with the compound represented by formula [11] or a reactive derivative thereof (e.g., acid anhydride, mixed acid anhydride, etc.).
Ｒ１−Ｑ−（ＣＨρ）ｎ−ＣＯＮＨｃＨ２ＣＨ２ＣＯＮ
ＩＨＣＨ２ＣＩ（２ＳＨ＋Ｒ２−Ｘ→〔工〕叩
■
〔式中、Ｘはハロゲン原子または水酸基を示す。〕Ｂ）
式［ＩＤで表わされる化合物と式〔ｖ〕で表わされる化
合物を反応させることにより本発明化合物ＣＩ）を得る
。R1-Q-(CHρ)n-CONHcH2CH2CON
IHCH2CI (2SH+R2-X → [engineering]
(2) [In the formula, X represents a halogen atom or a hydroxyl group. ]B)
Compound CI) of the present invention is obtained by reacting a compound represented by formula [ID] with a compound represented by formula [v].
［′ｌＶ）〔ｖ〕
〔式中、Ｙはハロゲン原子を示し９Ｍはアルカリ金属を
示す。〕
以下に実施例を示して具体的に説明する。['lV) [v] [In the formula, Y represents a halogen atom and 9M represents an alkali metal. ] Examples will be specifically described below.
実施例１゜
Ｎ−（２−アセチルチオエチル）−３−（ベンジルオキ
シカルボニルアミノ）プロピオンアミドの製造
３−（ベンジルオキシカルボニルアミノ） −Ｎ−（２
−メルカプトエチル）プロピオニル（ド（２ｙ）とトリ
エチルアミン（０，８ｆ／ ）の無水ＴＨＦ溶液（１５
ｄ）に氷冷撹拌下アセチルクロリド（０，６Ｐ ）を滴
下する。滴下終了後水冷下３０分間。Example 1 Preparation of N-(2-acetylthioethyl)-3-(benzyloxycarbonylamino)propionamide 3-(benzyloxycarbonylamino)-N-(2
Anhydrous THF solution of -mercaptoethyl)propionyl (do(2y) and triethylamine (0,8f/
Acetyl chloride (0,6P) is added dropwise to d) while stirring on ice. After dropping, cool with water for 30 minutes.
さらに室温で３０分間撹拌した後沢過する。ｐ液を減圧
濃縮し、残渣に酢酸エチル（３０ｍ／）を加えて溶解後
、飽和重曹水、ＮＨＣｌ、飽和食塩水の順に洗浄する。After further stirring at room temperature for 30 minutes, the mixture is filtered. The p solution is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate (30 m/m), followed by washing in this order with saturated aqueous sodium bicarbonate, NHCl, and saturated brine.
この酢酸エチル溶液を硫酸マグネシウムで乾燥後減圧濃
縮して標記化合物１．６！Ｐ（収率７０％）を得る。This ethyl acetate solution was dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound 1.6! P (yield 70%) is obtained.
融点８３−１０８℃（ベンゼン−シクロヘキサン）ＩＲ
（ＫＢｒ、閑 ）
３３２８．３２９２，１６７８，１６３８，１５３５゜
１４３７．１３３６，１２７２．１２３７．１２２１゜
１１３７．１０３０，７３０，６９５，６２５ＮＭＲ（
ＣＤＣｌ２．δ）
２．２８（３Ｈ、ｓ 、−８ＣＯＣＨ３）２．３４−２
．６８ （２Ｈ、ｍ 、 −ＮＨＣＨ２ＣＨ，ＣＯ−）
２．８０−３．１１ （２Ｈ、ｍ 、 −ＮＨＣＨ２Ｃ
ｐｓ−）３．１８−３．６８ （４Ｈ，ｍ 。Melting point 83-108℃ (benzene-cyclohexane) IR
(KBr, blank) 3328.3292,1678,1638,1535°1437.1336,1272.1237.1221°1137.1030,730,695,625NMR(
CDCl2. δ) 2.28 (3H, s, -8COCH3) 2.34-2
．． 68 (2H, m, -NHCH2CH,CO-)
2.80-3.11 (2H, m, -NHCH2C
ps-) 3.18-3.68 (4H, m.
−ＮＨＣ豆２ＣＨ２ＣＯＮＨＣ馬Ｃ）Ｉ２Ｓ−＞５．０
４ （２Ｈ、ｓ 、−０ＣＨ２Ｃ６Ｈ１，）５．２８−
５．８４ （ＩＨ，ｂｒ、−ＣＯＮＨ−）６．０９−６
．５１ （ＩＨ，ｂｒ 、−ＣＯＮＨ−）７．２４（５
Ｈ，ｓ、−０６巧）
ＴＬＣＲｆ値（ａ）： ０．２７
（ａ） ニジリカゲル；ベンゼン−酢酸エチル−酢酸（
２５：２５：１）
実施例２゜
３−（ベンジルオキシカルボニルアミノ） −Ｎ−（２
−プロピオニルチオエチル）プロピオンアミドの製造
実施例１におけるアセチルクロリドの代りにプロピオニ
ルクロリド（０，７２ｙ）を用い、実施例１と同様に操
作して標記化合物１．９ ｆ （収率７９％）を得る。-NHC beans 2CH2CONHC horses C) I2S->5.0
4 (2H, s, -0CH2C6H1,)5.28-
5.84 (IH, br, -CONH-)6.09-6
．． 51 (IH,br, -CONH-)7.24(5
TLCRf value (a): 0.27 (a) Nijilica gel; benzene-ethyl acetate-acetic acid (
25:25:1) Example 2゜3-(benzyloxycarbonylamino)-N-(2
-Production of propionyl thioethyl) propionamide Propionyl chloride (0,72y) was used in place of acetyl chloride in Example 1, and the title compound 1.9 f (yield 79%) was prepared in the same manner as in Example 1. obtain.
融点７７−１０４℃（ベンゼン−シクロヘキサン）ＩＲ
（ＫＢｒ、σ ）
３３２’８，３２８８．１６７８，１６３８，１５３６
゜１４３７．１３３７，１２７３．１２３７．１０３３
゜９４４．７３０．６９３
ＮＭＲ（ＣＤＣｌ２．δ）
１．１２（３Ｈ、ｔ 、Ｊ＝７．０Ｈｚ、−８ＣＯＣＨ
２ＣＨ３） ５−
２．３４ （２Ｈ、ｔ 、 Ｊ＝６．０Ｈｚ 、 −Ｎ
ＨＣＨ２Ｃ隻Ｃｏ−）２−５３ （２Ｈ、ｑ 、 Ｊ
＝７．０ Ｈｚ 、 ５ＣＯＣＨ２Ｃ）Ｒ３）２．７
７−３．１４ （２Ｈ、ｍ 、 −ＮＨＣＨ，、ＣＨ，
，５−）３．１４−３．６７ （４Ｈ、ｍ 。Melting point 77-104℃ (benzene-cyclohexane) IR
(KBr, σ) 332'8,3288.1678,1638,1536
゜1437.1337, 1273.1237.1033
゜944.730.693 NMR (CDCl2.δ) 1.12 (3H, t, J=7.0Hz, -8COCH
2CH3) 5-2.34 (2H, t, J=6.0Hz, -N
HCH2C ship Co-)2-53 (2H, q, J
=7.0 Hz, 5COCH2C)R3)2.7
7-3.14 (2H, m, -NHCH,,CH,
,5-)3.14-3.67 (4H, m.
−ＮＨＣ県０Ｈ２ＣＯＮＨＣ見、ＣＨ２５−）５．０３
（２Ｈ、ｓ 、−０ＣＨ２Ｃ６Ｈ５）５．３４−５．
８１ （ＩＨ、ｂｒ、−ＣＯＮＨ−）６．１４−６．６
４ （ＩＨ、ｂｒ 、−ＣＯＮＨ−）７．２６ （５Ｈ
、ｓ 、−Ｃ６ＨＪ））ＴＬＣＲｆ値（” ： ０．３
４
実施例３゜
３−（ベンジルオキシカルボニルアミノ） −Ｎ−（２
−ピバロイルチオエチル）プロピオンアミドの製造
実施例ＩＫおけるアセチルクロリドの代りにピバロイル
クロリド（０，９４ｙ）を用い、実施例１と同様に操作
して標記化合物１．８ｐ（収率６９％）を得る。-NHC prefecture 0H2CONHC viewing, CH25-) 5.03
(2H, s, -0CH2C6H5)5.34-5.
81 (IH, br, -CONH-)6.14-6.6
4 (IH, br, -CONH-)7.26 (5H
, s, -C6HJ)) TLCRf value ('': 0.3
4 Example 3゜3-(benzyloxycarbonylamino)-N-(2
-Production of pivaloylthioethyl)propionamide Using pivaloyl chloride (0,94y) in place of acetyl chloride in Example IK, the procedure was repeated in the same manner as in Example 1 to produce 1.8p of the title compound (yield 69%). ).
融点８７−８８℃・（エーテル−イソプロピルエーテル
）ＩＲ（ＫＢｒ、ｃ＋＋＋−”）
６−
３３２８．３２９２，１６８５．１６３８，１５４２゜
１４５２，１４３７．１３６１．１３３７，１２６３゜
１２４２．１００４，９４７，７５０．６９７ＮＭＲ（
ＣＤＣｌ２．δ）
１．２２（９Ｈ、ａ 、−８ＣＯＣ（ＣＨ３）３）２．
３３（２Ｈ、ｔ、Ｊ＝６．０Ｈｚ、−ＮＨＣＨ２０Ｈ２
Ｃｏ−）２．８２−３．１３ （２Ｈ、ｍ 、 −ＮＨ
ＣＨ２ＣＨ２Ｓ−）３．２０−３．６７ （４Ｈ、ｍ
。Melting point 87-88℃・(ether-isopropyl ether) IR (KBr, c+++-”) 6- 3328.3292, 1685.1638, 1542° 1452, 1437.1361.1337, 1263° 1242.1004, 947, 750. 697NMR(
CDCl2. δ) 1.22 (9H, a, -8COC(CH3)3)2.
33 (2H, t, J=6.0Hz, -NHCH20H2
Co-)2.82-3.13 (2H, m, -NH
CH2CH2S-)3.20-3.67 (4H, m
.
−ＮＨＣ馬ＣＨ２Ｃ０ＮＨＣ￥２ＣＨ２Ｓ−）５．０４
（２Ｈ、ｓ 、 −〇〇馬Ｃ６１（、、）５．３０−
５．７８ （ＩＨ、ｂｒ、−ＣＯＮＨ−）５．９５−６
．４３（ＩＨ，ｂｒ、−ＣＯＮ）ｉ−）７．２６ （５
Ｈ、ｓ 、 −Ｃ６Ｈ５）ＴＬＣＲｆ値（ａ）： ０
．３９
実施例４゜
３−（ベンジルオキシカルボニルアミノ） −Ｎ−Ｃ２
−〔ジエチルアミノ（チオカルボニル）チオ〕エチル〕
プロピオンアミドの製造
３−（ベンジルオキシカルボニルアミノ） −Ｎ−（２
−ブロモエチル）プロピオンアミド（ＩＯｙ）のアセト
ン溶液（２５０ｍｅ ） Ｋ 、ジエチルジチオカルバ
ミン酸ナトリウム・三水和物（６，８ｙ）のアセトン溶
液（１５０ｍｅ ）を加え、室温で４０分間撹拌後ｐ遇
する。Ｐ液を減圧濃縮し、残渣に酢酸エチル（１５０慴
ｅ）を加えて溶解後、ＮＨＣｌ。-NHC horse CH2C0NHC￥2CH2S-)5.04
(2H, s, -〇〇horse C61(,,)5.30-
5.78 (IH, br, -CONH-)5.95-6
．． 43(IH,br,-CON)i-)7.26 (5
H, s, -C6H5) TLCRf value (a): 0
．． 39 Example 4゜3-(benzyloxycarbonylamino) -N-C2
−[diethylamino(thiocarbonyl)thio]ethyl]
Preparation of propionamide 3-(benzyloxycarbonylamino)-N-(2
An acetone solution (250 me) of propionamide (IOy) and an acetone solution (150 me) of sodium diethyldithiocarbamate trihydrate (6,8y) are added, stirred at room temperature for 40 minutes, and then treated. The P solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (150 ml), followed by dilution with NHCl.
水、 ＮＮａＯＨ、水、飽和食塩水の順に洗浄する。Wash with water, NNaOH, water, and saturated saline in this order.
この酢酸エチル溶液を硫酸マグネシウムで乾燥後減圧濃
縮【−て標記化合物１０．７９ （収率８９％）を得る
。This ethyl acetate solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound 10.79 (yield 89%).
融点９０−９３℃（ベンゼン−ヘキサン）ＩＲ（ＫＢｒ
、側 ）
３３２５．３２９６，１６８５，１６３５，１５３７゜
１４８８．１４１３．１２６７．１２４０．１２０１゜
１１４３．６９６
ＮＭＲ（ＣＤＣｌ２．δ）
１．２４ （６Ｈ、ｔ 、 Ｊ＝７．０Ｈｚ 、−Ｎ（
ＣＬ、ＣＨ３）２）２．３６ （２）Ｉ、ｔ 、Ｊ＝６
．０）Ｉη、 −ＮＨＣｆ（２Ｃ県Ｃ０−）３．１７−
４．２０ （ｌ ＯＨ、ｍ 。Melting point 90-93℃ (benzene-hexane) IR (KBr
, side) 3325.3296,1685,1635,1537゜1488.1413.1267.1240.1201゜1143.696 NMR (CDCl2.δ) 1.24 (6H, t, J=7.0Hz, -N(
CL, CH3) 2) 2.36 (2) I, t, J=6
．． 0) Iη, -NHCf (2C prefecture C0-) 3.17-
4.20 (l OH, m.
−ＮＨＣＨ２ＣＨ２ＣＯＮＨＣ馬Ｃ見２ＳＣ８Ｎ（Ｃ馬
Ｃ鵬）２）５．０４ （２Ｈ、ｓ 、−０ＣＨ２Ｃ６Ｈ
５）５．３０−５．７５ （ＩＨ，ｂｒ、 −ＣＯＮＨ
−）６．２０−６．８０ （ＩＨ、ｂｒ 、−ＣＯＮＨ
−）７．２８（５Ｈ，ｓ、−Ｃ６挑）
ＴＬＣＲｆ値（ＪＬ） ： ０，４０出願人 参天製
薬株式会社
代理人 滝 川 敏 雄
９−-NHCH2CH2CONHC Ma C Mi 2 SC8N (C Ma C Peng) 2) 5.04 (2H, s, -0CH2C6H
5) 5.30-5.75 (IH, br, -CONH
-) 6.20-6.80 (IH, br, -CONH
-) 7.28 (5H, s, -C6 challenge) TLCRf value (JL): 0.40 Applicant Santen Pharmaceutical Co., Ltd. Agent Toshio Takigawa 9-
Claims (1)
ＮＨｃＨ２ｃ４Ｓ−Ｒ２〔Ｉ〕〔式中 Ｒ１は水素原子
、低級アルキル基または低級アルコキシ基を示す。 Ｒ２１ｒｉ低級アルカノイル基または低級アルキルアミ
ノチオカルボニル基を示す。 ｎ ＃′１０または１を示す。〕[Claims] A compound represented by the formula [■]. R1-Q-(CH20)n-CONHCH2cH2cO
NHcH2c4S-R2[I] [In the formula, R1 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group. R21ri represents a lower alkanoyl group or a lower alkylaminothiocarbonyl group. n Indicates #'10 or 1. ]
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57200934A JPS5989656A (en) | 1982-11-15 | 1982-11-15 | Aletheine derivative |
| US06/488,100 US4552765A (en) | 1982-05-14 | 1983-04-25 | Aletheine derivatives |
| IT21040/83A IT1164218B (en) | 1982-05-14 | 1983-05-11 | ALETEIN DERIVATIVES |
| GB08313145A GB2123815B (en) | 1982-05-14 | 1983-05-12 | Aletheine derivatives |
| DE3317529A DE3317529C2 (en) | 1982-05-14 | 1983-05-13 | ß-Aletheinderivate, processes for their preparation and pharmaceutical compositions containing them |
| FR8308048A FR2526792B1 (en) | 1982-05-14 | 1983-05-16 | ALETHEIN DERIVATIVES USEFUL FOR THE TREATMENT OF HEPATIC LESIONS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57200934A JPS5989656A (en) | 1982-11-15 | 1982-11-15 | Aletheine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5989656A true JPS5989656A (en) | 1984-05-23 |
| JPH0261940B2 JPH0261940B2 (en) | 1990-12-21 |
Family
ID=16432717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57200934A Granted JPS5989656A (en) | 1982-05-14 | 1982-11-15 | Aletheine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5989656A (en) |
-
1982
- 1982-11-15 JP JP57200934A patent/JPS5989656A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0261940B2 (en) | 1990-12-21 |
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