JP3394280B2 - Hydrophilic β-carboric acid derivative - Google Patents
Hydrophilic β-carboric acid derivativeInfo
- Publication number
- JP3394280B2 JP3394280B2 JP01030193A JP1030193A JP3394280B2 JP 3394280 B2 JP3394280 B2 JP 3394280B2 JP 01030193 A JP01030193 A JP 01030193A JP 1030193 A JP1030193 A JP 1030193A JP 3394280 B2 JP3394280 B2 JP 3394280B2
- Authority
- JP
- Japan
- Prior art keywords
- hydrophilic
- acid derivative
- compound
- reduced pressure
- under reduced
- 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
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
【０００１】
【産業上の利用分野】本発明は、向精神作用剤として有
用な親水性β−カルボリン酸誘導体に関する。
【０００２】
【従来の技術】テトラヒドロ−β−カルボリン酸を含め
たカルボリン類は、向精神作用をはじめ多種多様な薬理
作用を有することが知られている［Eur. J. Pharmaco
l., 195,261(1991); Biochem. Pharmacol., 42, 459(19
91); Chem. Pharm. Bull., 37,1808(1989); Neuropharm
acology, 28, 539(1989); Neuroscience Lett., 81, 32
5(1987); Biochem. Biophys. Res. Commun., 141, 1(19
86); Medical Biology,59, 190(1981); Medical Biolog
y, 59, 21(1981); Proc. Natl. Acad. Sci., 77, 2288
(1980)］。また、近年、トリプトファン製剤中に含まれ
ていた３−カルボキシ−１−メチル−１，２，３，４−
テトラヒドロ−β−カルボリン（ＭＴＨＣＡ）が好酸球
筋痛症候群（ＥＭＳ）の原因物質であるとの可能性が指
摘された［MMWR, 39, 589(1990); N. Engl. J. Med., 3
23, 357(1990); N. Engl. J. Med., 323, 992(1990); Ar
thritis ＆ Rheumatism, 33, 913(1990)］。しかし、カ
ルボリン類のほとんどは水に難溶であり、各種動物実験
を行う際、大量投与が困難である。
【０００３】
【発明が解決しようとする課題】カルボリン類の薬理
学、病理学的研究あるいは新規医薬品の開発の観点か
ら、親水性β−カルボリン酸誘導体が期待され望まれて
いる。
【０００４】
【課題を解決するための手段】本発明は、式（Ｉ）
【０００５】
【化２】
【０００６】（式中、ｎは、２から５の整数を表す）で
表されるβ−カルボリン酸誘導体に関する。以下、式
（Ｉ）で表される化合物を化合物（Ｉ）という。次に、
化合物（Ｉ）の製造法について説明する。化合物（Ｉ）
は、トリプトファンと式
【０００７】
【化３】
【０００８】（式中、ｎは、前記と同義である）で表さ
れるアルデヒド類とから、J. Chem. Soc., 153(1941)に
記載の方法に準じて製造することができる。また、化合
物（Ｉ）は、人尿中から、抽出、濃縮、各種クロマトグ
ラフィー処理等の単離、精製操作をくり返すことにより
得ることもできる。化合物（Ｉ）は、水あるいは各種溶
媒との付加物の形で存在することもあるが、これら付加
物も本発明に包含される。
【０００９】上記製造法によって得られる化合物（Ｉ）
の具体例を第１表に示す。
【００１０】
【表１】
【００１１】以下に、本発明の実施例を示す。
【００１２】
【実施例】各目的化合物の検出は、下記条件下の高速液
体クロマトグラフィー（ＨＰＬＣ）によって行った。
カラム： Radial-Pak C18カラム(８mm×１０cm, ウ
ォーターズ社)
展開溶媒： アセトニトリル−０．１３ｍｏｌ／Ｌクエ
ン酸−０．１３ｍｏｌ ／Ｌリン酸２ナトリウム＝１：
５：４（ｐＨ ３．５）
流速： ２ml/min
測定波長： ３５０nm
励起波長： ３０２nm
【００１３】実施例１
３−カルボキシ−１−（１，２−ジヒドロキシエチル）
−１，２，３，４−テトラヒドロ−β−カルボリン
（ＤＨＥ−ＴＨＣＡ）
褐色試験管中、トリプトファン０．１ｇ（０．５mmol）
を０．１ｍｏｌ／Ｌ水酸化ナトリウム水溶液５mlに溶解
し、これに、アルゴン雰囲気下Ｄ−グリセルアルデヒド
０．１ｇ（０．７mmol）を加え、室温で５時間反応させ
た。生成物を、ＨＰＬＣ（アセトニトリル−蒸留水＝
１：６）で精製し、目的物約１０mgを得た。1
H NMR：δ, ppm （400MHz, D2O ） 3.25(dd, J=12.1,
16.5Hz, 1H), 3.67(dd,J=5.0, 16.5Hz, 1H), 3.94(dd,
J=2.7, 12.1Hz, 1H), 4.11(dd, J=4.5, 12.1Hz,1H), 4.
20(dd, J=5.0, 12.1Hz, 1H), 4.60(ddd, J=2.7, 3.6,
4.5Hz, 1H), 5.16(d, J=3.6Hz, 1H), 7.42(dd, J=7.2,
7.2Hz, 1H), 7.51(dd, J=6.6, 7.2Hz, 1H), 7.72(d, J=
6.6Hz, 1H), 7.87(d, J=7.2Hz, 1H)13
C NMR ：δ, ppm （400MHz, D2O ） 28.2, 57.0, 60.
7, 65.6, 74.8, 112.1,113.8, 120.3, 121.6, 124.1, 1
29.2, 135.1, 138.9, 182.8
UV：λmax （０．１ｍｏｌ／Ｌリン酸緩衝液） 281nm
蛍光極大：λmax （０．１ｍｏｌ／Ｌリン酸緩衝液、励
起波長:295nm） 354nm
【００１４】実施例２
３−カルボキシ−１−（１，２，３−トリヒドロキシプ
ロピル）−１，２，３，４−テトラヒドロ−β−カルボ
リン （ＴＨＰ−ＴＨＣＡ）
Ｄ−グリセルアルデヒドに代えてＤ−エリトロースを用
いる以外は、実施例１の方法に準じて、目的物を得た。
実施例３
３−カルボキシ−１−（１，２，３，４−テトラヒドロ
キシブチル）−１，２，３，４−テトラヒドロ−β−カ
ルボリン （ＴＨＢ−ＴＨＣＡ）
Ｄ−グリセルアルデヒドに代えてＤ−リボースを用いる
以外は、実施例１の方法に準じて、目的物を得た。
実施例４
３−カルボキシ−１−（１，２，３，４，５−ペンタヒ
ドロキシペンチル）−１，２，３，４−テトラヒドロ−
β−カルボリン （ＰＨＰ−ＴＨＣＡ）
Ｄ−グリセルアルデヒドに代えてガラクトースを用いる
以外は、実施例１の方法に準じて、目的物を得た。
【００１５】実施例５２−アミノ−３−［２−（α−マンノピラノシル）イン
ドール−３−イル］プロピオン酸
健常人尿１０Ｌを１Ｌまで減圧濃縮し、１．２Ｌのブタ
ノール−氷酢酸（５：１）溶液で３回抽出した。ブタノ
ール層に四ほう酸ナトリウム２００ｇを加え、１晩放置
後、生じた水層を回収した。水層を約５０mlまで減圧濃
縮し、フェニルセファロース−ＣＬ−４Ｂカラム（４．
２×５０cm；５．０ｍｏｌ／Ｌ塩化アンモニウム）で精
製した。目的物を含む画分を１０分の１に減圧濃縮し、
セファデックスＧ−２５スーパーファインカラム（４．
２×１２０cm；蒸留水）で精製し、目的物を含む画分で
電気伝導度が５ミリモー以下の画分のみを回収すること
によって脱塩を行った。目的物を含む画分で電気伝導度
が５ミリモー以上の画分は、回収後再び減圧濃縮し、同
様の操作を繰り返した。次いで、電気伝導度が５ミリモ
ー以下の画分を、２００mlずつ陽イオン交換樹脂ＣＭ−
セファロース ファスト フロウカラム（４．２×５０
cm；蒸留水）で精製し、目的物を含む画分を５０mlまで
減圧濃縮した。さらに、この濃縮液を陰イオン交換樹脂
ＤＥＡＥ−セファセルカラム（２．６×４５cm；蒸留
水）で精製し、目的物を含む画分を２mlまで減圧濃縮し
た。この濃縮液をＨＰＬＣ（アセトニトリル−蒸留水＝
１：９）で精製し、目的物を含む画分を１mlまで減圧濃
縮し、最後に、この濃縮液をさらにＨＰＬＣ（アセトニ
トリル−蒸留水＝１：４５）で精製し、目的物約０．１
mgを得た。なお、各精製段階での減圧濃縮操作の際、生
じた塩は、ガラスフィルター（２５Ｇ１）を用いて除去
した。
【００１６】FAB-MS：m/z 365(M - -1),367(M + +1)1
H NMR：δ, ppm （400MHz, D2O ） 3.47(dd, J=9.2, 1
5.2Hz, 1H), 3.67(dd, J=5.2, 15.2Hz, 1H), 3.85(dd,
J=3.3, 12.5Hz, 1H), 4.01(ddd, J=3.3, 3.4, 8.9Hz, 1
H), 4.07(dd, J=3.4, 4.6Hz, 1H), 4.14(dd, J=5.2, 9.
2Hz, 1H), 4.24(dd, J=3.4, 4.6Hz, 1H), 4.36(dd, J=
8.9, 12.5Hz, 1H), 4.54(dd, J=3.4, 8.3Hz, 1H), 5.23
(d, J=8.3Hz, 1H), 7.32(dd, J=7.3, 7.8Hz, 1H), 7.42
(dd, J=7.3,8.1Hz, 1H), 7.64(d, J=8.1Hz, 1H), 7.85
(d, J=7.8Hz, 1H)13
C NMR ：δ, ppm （400MHz, D2O ） 29.9, 58.6, 61.
9, 69.1, 70.6, 71.7, 73.3, 81.8, 112.1, 114.7, 12
1.6, 122.5, 125.6, 130.0, 135.9, 138.8, 174.0UV：
λmax （εmax ）（水） 281nm（5550）
蛍光極大：λmax （水、励起波長:301nm） 357nm
【００１７】
【発明の効果】本発明により、向精神作用剤として有用
な新規親水性β−カルボリン酸誘導体が提供される。Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hydrophilic β-carbolinic acid derivative useful as a psychotropic agent. BACKGROUND OF THE INVENTION Carbolines, including tetrahydro-β-carbolinic acid, are known to have a wide variety of pharmacological effects including psychotropic effects [Eur. J. Pharmaco.
l., 195 , 261 (1991); Biochem. Pharmacol., 42 , 459 (19
91); Chem. Pharm. Bull., 37 , 1808 (1989); Neuropharm.
acology, 28 , 539 (1989); Neuroscience Lett., 81 , 32
5 (1987); Biochem.Biophys.Res.Commun., 141 , 1 (19
86); Medical Biology, 59 , 190 (1981); Medical Biolog
y, 59 , 21 (1981); Proc. Natl. Acad. Sci., 77 , 2288
(1980)]. In recent years, 3-carboxy-1-methyl-1,2,3,4-
It has been pointed out that tetrahydro-β-carboline (MTHCA) may be a causative agent of eosinophil myalgia syndrome (EMS) [MMWR, 39 , 589 (1990); N. Engl. J. Med., 3] .
23 , 357 (1990); N. Engl. J. Med., 323 , 992 (1990); Ar
thritis & Rheumatism, 33 , 913 (1990)]. However, most of carbolines are hardly soluble in water, and it is difficult to administer a large amount of them when conducting various animal experiments. [0003] From the viewpoint of the pharmacology and pathological study of carbolines or the development of new pharmaceuticals, hydrophilic β-carbolinic acid derivatives are expected and desired. [0004] The present invention provides a compound of the formula (I) (Wherein, n represents an integer of 2 to 5). Hereinafter, the compound represented by the formula (I) is referred to as compound (I). next,
The production method of compound (I) will be described. Compound (I)
Is represented by tryptophan and the formula The compound can be produced from an aldehyde represented by the formula (wherein n is as defined above) according to the method described in J. Chem. Soc., 153 (1941). Compound (I) can also be obtained from human urine by repeating isolation and purification procedures such as extraction, concentration, and various chromatographic treatments. Compound (I) may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Compound (I) obtained by the above production method
Table 1 shows specific examples. [Table 1] An embodiment of the present invention will be described below. EXAMPLES Detection of each target compound was carried out by high performance liquid chromatography (HPLC) under the following conditions. Column: Radial-Pak C18 column (8 mm × 10 cm, Waters) Developing solvent: acetonitrile-0.13 mol / L citric acid-0.13 mol / L disodium phosphate = 1:
5: 4 (pH 3.5) Flow rate: 2 ml / min Measurement wavelength: 350 nm Excitation wavelength: 302 nm Example 1 3-carboxy-1- (1,2-dihydroxyethyl)
-1,2,3,4-tetrahydro-β-carboline
(DHE-THCA) 0.1 g (0.5 mmol) of tryptophan in a brown test tube
Was dissolved in 5 ml of a 0.1 mol / L aqueous sodium hydroxide solution, to which 0.1 g (0.7 mmol) of D-glyceraldehyde was added under an argon atmosphere, and reacted at room temperature for 5 hours. The product was analyzed by HPLC (acetonitrile-distilled water =
1: 6) to give about 10 mg of the desired product. 1 H NMR: δ, ppm (400 MHz, D 2 O) 3.25 (dd, J = 12.1,
16.5Hz, 1H), 3.67 (dd, J = 5.0, 16.5Hz, 1H), 3.94 (dd,
J = 2.7, 12.1Hz, 1H), 4.11 (dd, J = 4.5, 12.1Hz, 1H), 4.
20 (dd, J = 5.0, 12.1Hz, 1H), 4.60 (ddd, J = 2.7, 3.6,
4.5Hz, 1H), 5.16 (d, J = 3.6Hz, 1H), 7.42 (dd, J = 7.2,
7.2Hz, 1H), 7.51 (dd, J = 6.6, 7.2Hz, 1H), 7.72 (d, J =
6.6 Hz, 1H), 7.87 (d, J = 7.2 Hz, 1H) 13 C NMR: δ, ppm (400 MHz, D 2 O) 28.2, 57.0, 60.
7, 65.6, 74.8, 112.1,113.8, 120.3, 121.6, 124.1, 1
29.2, 135.1, 138.9, 182.8 UV: λ max (0.1 mol / L phosphate buffer) 281 nm Fluorescence maximum: λ max (0.1 mol / L phosphate buffer, excitation wavelength: 295 nm) 354 nm Example 2 3-carboxy-1- (1,2,3-trihydroxypropyl) -1,2,3,4-tetrahydro-β-carboline (THP-THCA) D-erythrose in place of D-glyceraldehyde A target product was obtained according to the method of Example 1 except for using. Example 3 3-carboxy-1- (1,2,3,4-tetrahydroxybutyl) -1,2,3,4-tetrahydro-β-carboline (THB-THCA) D in place of D-glyceraldehyde -The desired product was obtained according to the method of Example 1 except for using ribose. Example 4 3-carboxy-1- (1,2,3,4,5-pentahydroxypentyl) -1,2,3,4-tetrahydro-
β-carboline (PHP-THCA) The desired product was obtained according to the method of Example 1, except that galactose was used instead of D-glyceraldehyde. Example 5 2-amino-3- [2- (α-mannopyranosyl) in
Dole-3-yl] propionic acid 10 L of urine from a healthy subject was concentrated under reduced pressure to 1 L, and extracted three times with a 1.2 L butanol-glacial acetic acid (5: 1) solution. 200 g of sodium tetraborate was added to the butanol layer, and after standing overnight, the resulting aqueous layer was collected. The aqueous layer was concentrated under reduced pressure to about 50 ml, and a phenyl sepharose-CL-4B column (4.
2 × 50 cm; 5.0 mol / L ammonium chloride). The fraction containing the target substance was concentrated under reduced pressure to 1/10,
Sephadex G-25 super fine column (4.
2 × 120 cm; distilled water), and desalting was performed by collecting only the fraction containing the target substance and having an electric conductivity of 5 mmho or less. The fraction containing the target substance and having a conductivity of 5 millimho or more was collected, concentrated again under reduced pressure, and the same operation was repeated. Then, the fraction having an electric conductivity of 5 millimho or less was added to the cation exchange resin CM-200 in 200 ml portions.
Sepharose Fast Flow Column (4.2 × 50
cm; distilled water), and the fraction containing the desired product was concentrated under reduced pressure to 50 ml. Further, this concentrated liquid was purified by an anion exchange resin DEAE-Sephacel column (2.6 × 45 cm; distilled water), and the fraction containing the target substance was concentrated under reduced pressure to 2 ml. This concentrated solution was subjected to HPLC (acetonitrile-distilled water =
1: 9), and the fraction containing the desired product was concentrated under reduced pressure to 1 ml. Finally, the concentrated solution was further purified by HPLC (acetonitrile-distilled water = 1: 45) to give about 0.1
mg was obtained. In addition, at the time of the vacuum concentration operation in each purification step, the generated salt was removed using a glass filter (25G1). FAB-MS: m / z 365 (M -- 1), 367 (M + +1) 1 H NMR: δ, ppm (400 MHz, D 2 O) 3.47 (dd, J = 9.2, 1
5.2Hz, 1H), 3.67 (dd, J = 5.2, 15.2Hz, 1H), 3.85 (dd,
J = 3.3, 12.5Hz, 1H), 4.01 (ddd, J = 3.3, 3.4, 8.9Hz, 1
H), 4.07 (dd, J = 3.4, 4.6Hz, 1H), 4.14 (dd, J = 5.2, 9.
2Hz, 1H), 4.24 (dd, J = 3.4, 4.6Hz, 1H), 4.36 (dd, J =
8.9, 12.5Hz, 1H), 4.54 (dd, J = 3.4, 8.3Hz, 1H), 5.23
(d, J = 8.3Hz, 1H), 7.32 (dd, J = 7.3, 7.8Hz, 1H), 7.42
(dd, J = 7.3,8.1Hz, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.85
(d, J = 7.8Hz, 1H) 13 C NMR: δ, ppm (400 MHz, D 2 O) 29.9, 58.6, 61.
9, 69.1, 70.6, 71.7, 73.3, 81.8, 112.1, 114.7, 12
1.6, 122.5, 125.6, 130.0, 135.9, 138.8, 174.0UV:
λ max (ε max ) (water) 281 nm (5550) Fluorescence maximum: λ max (water, excitation wavelength: 301 nm) 357 nm According to the present invention, a novel hydrophilic β useful as a psychotropic agent -A carboric acid derivative is provided.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 405/04 A61K 31/405 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. 7 , DB name) C07D 405/04 A61K 31/405 CA (STN) REGISTRY (STN)
Claims (1)
ラノシル）インドール−３−イル］プロピオン酸。 (57) [Claims 1] 2-Amino-3- [2- (α-mannopi)
Lanosyl) indol-3-yl] propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP01030193A JP3394280B2 (en) | 1993-01-25 | 1993-01-25 | Hydrophilic β-carboric acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP01030193A JP3394280B2 (en) | 1993-01-25 | 1993-01-25 | Hydrophilic β-carboric acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06220056A JPH06220056A (en) | 1994-08-09 |
| JP3394280B2 true JP3394280B2 (en) | 2003-04-07 |
Family
ID=11746441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP01030193A Expired - Lifetime JP3394280B2 (en) | 1993-01-25 | 1993-01-25 | Hydrophilic β-carboric acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3394280B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004105753A1 (en) * | 2003-05-29 | 2004-12-09 | Kyowa Medex Co., Ltd. | Antidepressant or food or beverage for antidepression |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69836279T2 (en) | 1997-08-20 | 2007-05-31 | Kyowa Medex Co. Ltd. | Novel compound, 2-amino-3- [2- (α-mannopyranosyl) indole-3-YL] propionic acid, method of preparation and methods for in vivo assay with the novel compound |
-
1993
- 1993-01-25 JP JP01030193A patent/JP3394280B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| Ｚ．Ｌｅｂｅｎｓｍ．−Ｕｎｔｅｒｓ．Ｆｏｒｓｃｈ．，１３２（２），６５−６９ |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004105753A1 (en) * | 2003-05-29 | 2004-12-09 | Kyowa Medex Co., Ltd. | Antidepressant or food or beverage for antidepression |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06220056A (en) | 1994-08-09 |
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