JPH06220056A - Hydrophilic beta-carbolic acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new hydrophilic compound useful as a medicine having psychotropic action. CONSTITUTION:A compound of formula I ((n) is 2-5) such as 3-carboxy-1-(1,2- dihydroxyethyl)-1,2,3,4-tetrahydro-beta-carboline. The compound of formula I is obtained by reacting tryptophan with an aldehyde of formula II. The compound is also obtained by extracting human urine, concentrating, repeating isolation and purification such as treatment with various chromatographies.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hydrophilic β-carbophosphoric acid derivative useful as a psychotropic agent.

[0002]

2. Description of the Related Art Carbolines including tetrahydro-β-carboline are known to have various pharmacological actions including psychotropic action [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)]. Moreover, in recent years, 3-carboxy-1-methyl-1,2,3,4- which was contained in tryptophan preparations was used.
It was 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); Art
hritis & Rheumatism, 33, 913 (1990)]. However, most of carbolines are poorly soluble in water, and it is difficult to administer them in large amounts in various animal experiments.

[0003]

[Problems to be Solved by the Invention] From the viewpoint of pharmacological and pathological studies of carbolines and development of new pharmaceuticals, hydrophilic β-carbophosphate derivatives are expected and desired.

[0004]

The present invention provides a compound of formula (I)

[0005]

[Chemical 2]

[0006] The present invention relates to a β-carbophosphoric acid derivative represented by the formula (n represents an integer of 2 to 5). Hereinafter, the compound represented by formula (I) is referred to as compound (I). next,
The production method of compound (I) is explained. Compound (I)
Tryptophan and formula

[0007]

[Chemical 3]

It can be produced from an aldehyde represented by the formula (wherein n has the same meaning 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 extraction, concentration, isolation and purification operations such as various chromatographic treatments. The compound (I) may exist in the form of an adduct 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 of the above.

[0010]

[Table 1]

Examples of the present invention will be shown below.

[0012]

Example 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 x 10 cm, Waters) Developing solvent: Acetonitrile-0.13 M citric acid-
0.13M 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) Tryptophan 0.1 g (0.5 mmol) in a brown test tube.
Was dissolved in 5 ml of 0.1 M aqueous sodium hydroxide solution, and 0.1 g of D-glyceraldehyde was added to the solution.
(0.7 mmol) was added, and the mixture was reacted at room temperature for 5 hours. The product was purified by HPLC (acetonitrile-distilled water = 1: 6) to obtain the desired product (about 10 mg). ¹ H NMR: δ, ppm (400MHz, 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 =
6.6Hz, 1H), 7.87 (d, J = 7.2Hz, 1H) ¹³ C NMR: δ, ppm (400MHz, 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 (0.1M phosphate buffer) 281nm Fluorescence maximum: λ _max (0.1M phosphate buffer, excitation wavelength: 2
95nm) 354nm

Example 2 3-Carboxy-1- (1,2,3-trihydroxypropyl) -1,2,3,4-tetrahydro-β-carboline (THP-THCA) Instead of D-glyceraldehyde The target product was obtained according to the method of Example 1 except that D-erythrose was used. Example 3 3-Carboxy-1- (1,2,3,4-tetrahydroxybutyl) -1,2,3,4-tetrahydro-β-carboline (THB-THCA) D-instead of D-glyceraldehyde The target product was obtained according to the method of Example 1 except that ribose was used. Example 4 3-Carboxy-1- (1,2,3,4,5-pentahydroxypentyl) -1,2,3,4-tetrahydro-
β-Carboline (PHP-THCA) The target product was obtained according to the method of Example 1 except that galactose was used instead of D-glyceraldehyde.

Example 5 3-carboxy-1- (1,2,3,4,5-pentahydroxypentyl) -1,2,3,4-tetrahydro-
β-Carboline (PHP-THCA) 10 L of healthy human urine was concentrated under reduced pressure to 1 L, and extracted with 1.2 L of butanol-glacial acetic acid (5: 1) solution three times. Sodium tetraborate (200 g) was added to the butanol layer, and the mixture was left standing overnight, and 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 M ammonium chloride).
The fraction containing the target substance was concentrated under reduced pressure to 1/10, and separated on a Sephadex G-25 Superfine column (4.2 × 12).
(0 cm; distilled water), and desalting was carried out by collecting only a fraction containing the target compound and having an electric conductivity of 5 mm or less. A fraction containing the target substance and having an electric conductivity of 5 mm or more was collected, concentrated again under reduced pressure, and the same operation was repeated. Then, the fractions with an electric conductivity of 5 mm or less were purified by 200 ml each with a cation exchange resin CM-Sepharose Fast Flow column (4.2 × 50 cm; distilled water), and the fractions containing the target substance were concentrated under reduced pressure to 50 ml. did. Furthermore, this concentrated solution is used as an anion exchange resin DEAE.
-Purified on a Sephacel column (2.6 x 45 cm; distilled water), and the fraction containing the desired product was concentrated under reduced pressure to 2 ml. The concentrate was purified by HPLC (acetonitrile-distilled water = 1: 9), and the fraction containing the target substance was concentrated under reduced pressure to 1 ml. Finally, the concentrate was further subjected to HPLC (acetonitrile-distilled water = 1: 45). ) And obtained about 0.1 mg of the desired product.
During the vacuum concentration operation at each purification stage, the salt produced was
It was removed using a glass filter (25G1).

[0016] FAB-MS: m / z 365 (M - -1), 367 (M + +1) 1 H NMR: δ, ppm (400MHz, 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 (400MHz, 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

[0017]

INDUSTRIAL APPLICABILITY The present invention provides a novel hydrophilic β-carbophosphate derivative useful as a psychotropic agent.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, n represents an integer of 2 to 5) β-
Carbophosphate derivative.