JPH01102057A - Cysteamine derivative and 5-lipoxygenase inhibitor containing same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 is H or methyl; n is number of double bonds having trans configuration and is 1 or 2; X is group of formula II, formula III, etc.). EXAMPLE:2-[5-(4-Hydroxy-3-methoxyphenyl)-2,4-pentadienoylamino]thiazol ine. USE:A 5-lipoxygenase inhibitor. Effective against allergic asthma, rhinitis, nephritis, hepatitis, rheumatism and gastric ulcer. PREPARATION:The compound of formula I can be produced by the condensation reaction and deprotection reaction of a carboxylic acid derivative of formula IV (Rm is 3,4-dimethoxymethyloxy, etc.) with an amine derivative of formula V, VI, VII or VIII (R2 is H or 1-10C alkyl).

Description

DETAILED DESCRIPTION OF THE INVENTION 10 Background of the Invention The present invention relates to a novel cysteamine derivative and a 5-lipoxygenase action inhibitor containing the same. The cysteamine derivative provided by the present invention has an activity of inhibiting the action of the enzyme 5-lipoxygenase.

Leukotriene C4 (LT), a factor that causes allergies
Leukotrienes such as C4) and leukotriene D4 (LTD4) are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase.

Recently, it has been revealed that leukotrienes are involved in the development of pathological conditions such as nephritis, hepatitis, rheumatism, and gastric ulcers, as well as allergies.

Therefore, the cysteamine derivative of the present invention, which has 5-lipoxygenase action inhibiting activity, inhibits leukotriene biosynthesis and is useful for treating allergic diseases such as asthma and rhinitis, as well as nephritis, hepatitis, rheumatism, and gastric ulcer.

The present inventors synthesized various cysteamine derivatives and conducted extensive research on their 5-lipoxygenase action inhibitory activity. As a result, the cysteamine derivatives of the present invention have a strong 5-
It was discovered that this compound has an activity of inhibiting the action of lipoxygenase, and the present invention was completed.

(1) Purpose of the Invention The object of the present invention is to provide a novel cysteamine derivative and a 5-lipoxygenase action inhibitor containing the same.

The present invention in accordance with the above object is based on the general formula (1) (where R1 represents a hydrogen atom or a methyl group, and U represents the number of double bonds in trans configuration, which is 1 or 2. 10 or the following formula (III) or the following formula (IV) or the following formula (V) -8 to 5-R2(y) [wherein R2 is a hydrogen atom or a straight chain or branched chain having 1 to 10 carbon atoms] This is a cysteamine derivative represented by a group selected from a group containing a cysteamine moiety (NAVS) in the molecule represented by [representing an alkyl group].

Further, the present invention relates to the general formula (I) (wherein R4 represents a hydrogen atom or a methyl group, and n represents 1t'ft of a double bond in trans configuration, which is 1 or 2) or the following formula (m or The following formula (III) or the following formula C■) or the following formula (V) -N8 to-R2(V) ■ [In the formula, R2 is a hydrogen atom or a straight or branched alkyl having 1 to xot carbon atoms] 5- containing a cysteamine derivative represented by (indicates a group selected from groups containing a cysteamine moiety (N%S) in the molecule shown in [indicates a group])
It is a lipoxygenase action inhibitor.

In the present invention, a 5-lipoxygenase action inhibitor means a preparation that suppresses the action of 5-lipoxygenase.

■1 Detailed description of the invention The cysteamine derivative represented by the above formula fI) of the present invention is a carboxylic acid derivative represented by the following formula (V 4
-methoxymethyloxy group, 3,4-dihydroxy group,
or 3-methoxy-4-hydroxy group, n represents the number of double bonds in trans configuration, and is 1 or 2. ) and the following formula (■) or the following formula (■) or the following formula (■) or the following formula (X) H2N~8-R2(X) It can be obtained by carrying out a condensation reaction with an amine derivative represented by [representing a chain or branched alkyl group] and a deprotection reaction.

The cysteamine derivative of the present invention is used as a 5-lipoxygenase action inhibitor, and the dosage varies depending on the symptoms, but in general, the daily dose for adults is 10 to 2000 μl, preferably 20 to 2000 μl per day.
600 ml, and should be administered in 1 to 3 divided doses depending on the symptoms. The administration method can be any form of administration, and oral administration is particularly desirable, but intravenous injection is also possible.

The compound of the present invention can be used as an active ingredient or one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner, and can be used as a tablet, sugar-coated tablet, powder, capsule, granule, suspension, emulsion, or injection. It can be applied in various forms such as liquid formulations.

Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate, and the like.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 5-(4-hydroxy-3-methoxyphenyl)-2
, 3.0Of of 4-pentadienoic acid is suspended in 5 Qrnl of 1,1-dichloroethane and cooled to 0<0>C. N, N-
Add 7.10 ft of diisopropylethylamine and 4.11 ft of chloromethyl methyl ether and stir for 16 hours. The reaction mixture is poured into water and extracted with chloroform.

The organic layer is washed with saturated brine and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 4.0 Off of 5-(4-methoxymethoxy-3-methoxyphenyl)-2,4-pentadienoic acid methoxymethyl ester from the chloroform eluted fraction.

5-(4-methoxymethoxy-3-methoxyphenyl)
-2,4-pentadienoic acid methoxymethyl ester 4
．． 0Of is dissolved in 25 g of methanol, and a solution of 2.6 Of sodium hydroxide dissolved in 15 g of water is added. 1
After stirring for 0 hours, methanol was distilled off under reduced pressure, the residue was poured into water, and 2N hydrochloric acid was added to make it weakly acidic. Extract with chloroform, wash the organic layer with saturated brine, and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.359 of 5-(4-methoxymethoxy-3-methoxyphenyl)-2,4-pentadienoic acid.

5-(4-methoxymethoxy-3-methoxyphenyl)
-2,4- to entadiene e 3.35t@1.1-dichloroethane 80g dissolved in 2-mercaptothiazoline 1.63 flN, N'-dicyclohexylcal diimyl rz, sxr, 4-dimethylaminopyridine 0.
17ft-add. After stirring for 16 hours, the reaction mixture was filtered and the precipitate was washed with benzene. Combine the filtrate and washing liquid,
2N-Hydroxide) Washed in this order with IJum aqueous solution, water, and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and N-(5-(4-
methoxymethoxy-3-methoxyphenyl) -2,4
-Pentanoenoyl]tazolidine-2-thione 3.
I got 85f.

N-[5-(4-methoxymethoxy-3-methoxyphenyl)-2,4-pentagenoylctiazolidine-
2-thione 2.00t and 2-aminothiazoline 1.
Dissolve 11P in 101 grams of tetrahydrofuran and stir for 5 hours. The precipitated crystals were filtered, washed with tetrahydrofuran, and dried under reduced pressure to obtain 2-[5-(4-methoxymethoxy-3-methoxyphenyl)-2,4-pentagenoylaminocthiazoline 1.10f.

2-(5-(4-methoxymethoxy-3-methoxyphenyl)-2,4-pentagenoylaminoctiazoline 1.0Of was added with 20nL of hydrochloric acid-methanol,
Heat to reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to give 2-C3-(4-hydroxy-3
-Methoxyphenyl)-2,4-pentagenoylaminocthiazoline (XI) 0.49 f was obtained.

Spectroscopic data of this product support the structure of formula (XI) below.

NMR (DMso-a6) δ: 6.10 (IH, d, J = -15Hz) 4.10 (2H
, t, J==7Hz) 3.83 (3H, s) 3.55 (2B, t, J=7Hz) Example 2 N-(5-(4-methoxymethoxy-3-methoxyphenyl) -2, 4-Pentagenoyl]deacylidine-
2-thione 1.93f and thiomorpholine 0.54f
was dissolved in tetrahydrofuran 401MK and stirred for 16 hours.

Pour the reaction solution into water and extract with chloroform.

The organic layer is washed successively with a 2N aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using methanol/loloform (3:97
) Elution i1 minute, 1N-(5-(4-methoxymethoxy-3-methoxyphenyl)-2,4-pentagenoylkothiomorpholine 1.48f was obtained.

N-["5-(4-Methoxymethoxy-3-methoxyphenyl)-2,4-pentagenoylcothiomorpholine Dissolved in 1.48 fe methanol and 30 g L, p-) Added 0.08 f of luenesulfonic acid. , t, and stirred for 18 hours. The reaction mixture was poured with water (G) and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the entire residue was transferred to a silica gel column. Chromatography was applied to the chloroform elution fraction to obtain N-(5-(4-hydroxy-3-methoxyphenyl)-2,4-pentagenoyl)thiomorphoyl(
Xll) o, set@get.

Spectroscopic data of this product support the structure of the following formula (X[[).

NMR (CDC2,) δ: 6.11 (IE, d, J=15Hz) 3.87 (7H, s) ″ 3.7 (m, 4H) 2.6 (m, 4H) Example 3 Under argon atmosphere , 5-(4-hydroxy-3-methoxyphenyl)-2,4-pentadienoic acid 1.02F
was suspended in 20 g of methylene chloride and cooled to -15'IC. Triethylamine 1.03P, ethyl chlorocarbonate
Add 1.079. After stirring for 30 minutes, a methylene chloride solution (51 nl) of 2-thiophenemethylamine 0.639 was added.
Add to '. Stir at -15°C to 0°C for 5 hours. IN-hydrochloric acid is added to the reaction solution, extracted with methylene chloride, and then the organic layer is washed once with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and the fraction eluted with methylene chloride was extracted with 2-(5-(4-ethoxycarbonyloxy-3-methoxyphenyl)-2,4-pentagenoylamino). Methylcothiophene 1.505
got '.

2-[5-(3-methoxy-4-ethoxycarbonyloxyphenyl)-2,4-ntadienoylaminomethyl]thiophene 1.21ft) Inor 20F16
Add IN-sodium hydroxide aqueous solution and stir at room temperature for 30 minutes. After making it acidic by adding IN-hydrochloric acid, it was concentrated under reduced pressure, the methanol was distilled off, and the mixture was extracted with chloroform.
Dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography, and 2-(5-(4-hydroxy-3-
xyphenyl) -2,4-pentagenoylaminomethylcothiophene (XI[[) 0.98 F was obtained.

Spectroscopic data of this product support the structure of the following formula (XII[).゛NMR (CDCl2) δ: 5.95 (d, J = 14.0 Hz, IH) 4.55 (d
, J = 6.0 Tlz, 2H) 3.75 (s, 3H) Example 4 Under an argon atmosphere, sodium hydride 0.90F is suspended in dry tetrahydrofuran 60M and cooled to 0°C.

A solution of 3,002 g of n-octyl mercaptan dissolved in 5 g of dry tetrahydrofuran is gradually added dropwise. After stirring for 1 hour, a solution of 2-promoethyl phthalimirs, 21t, in 5 ml of dry tetrahydrofuran is added. After stirring for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and 2-phthaloylethyl n-octyl sulfy ys2 was extracted from the eluted fraction of ethyl acetate-hexane (1:19).
Obtain ゜t.

Phthaloylethyl n-octyl sulfide 2.0Of
was dissolved in 40 mJ of ethanol, and 0.0 mJ of hydrazine hydrate was added.
Add 4.7t. Heat to reflux for 3 hours. The solvent was distilled off under reduced pressure to obtain a mixture of 2-aminoethyl-n-octyl sulfide and hydrazide.

On the other hand, under an argon atmosphere, 5-(4-hydroxyproxy3-
methoxyphenyl)-2,4-pentadienoic acid 1.
379 with methylene chloride 30mA! and cooled to -10°C. Add 1.75 d1 of triethylamine and 1.20 d1 of ethyl chlorocarbonate. After stirring for 30 minutes, a solution of a mixture of 2-aminoethyl-n-octyl sulfide and hydrazide suspended in methylene chloride is added. -10℃～O
Stir at ℃ for 4 hours. The reaction mixture is filtered and the precipitate is washed with methylene chloride. The filtrate and washing solution are combined, washed with water, then with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and 2-(5
2.169 ft of -(4-ethoxycarbonyloxy-3-methoxyphenyl)-2,4-=ntadienoylamino]-ethyl n-octyl sulfide was obtained.

2-[5-(4-Ethoxycar?nyloxy-3-methoxyphenyl)-2,4-pentanenoylaminocoethyl n-octyl sulfide 2.1611 Dissolved in 30 g of methanol, added 30 ml of 28% aqueous ammonia, and stirred for 6 hours. do. The reaction mixture was made acidic by adding 2N hydrochloric acid and extracted with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was subjected to silica gel column chromatography, and the chloroform eluted fraction was collected. )2-(5-(4-hydroxy-3-methoxyphenyl)-2,4-e entadienoylamino]ethyl n-octyl sulfide (X
IV) Obtain 1.19 t.

The spectroscopic data of this product support the structure shown below.

NMR (CDCl2) δ: 5.93 (IB, d, J ± 15EZ) 3.87 (31!, a) 3.53 (2H, dt, J = 6Hz, 6Hz) 2.70
(2E, t, J=6Hz)2.53(2H
, t, J=6Hz) Example 5 Under an argon atmosphere, 2.0Of of 5-(4-hydroxy-3-methoxyphenyl)-2,4-pentadienoic acid was dissolved in 40rnl of methylene chloride and cooled to -10°C. do. Triethylamine 92.53ml1. ethyl chlorocarbonate
Add 1.74m. After stirring for 30 minutes, cysteamine 1
．． A solution of 40fi dissolved in 20 tnl of methylene chloride is added and stirred at -10 to 0°C for 3 hours. The reaction mixture is poured into water and extracted with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From the chloroform elution fraction, N(5-(4-ethoxycalyloxy-3-methoxyphenyl)-2
,4-Hentadienoyl]cysteamine 1.3Of was obtained.

N-(5-(4-ethoxy-3-methoxyphenyl)-2,4-'e-ntadienoyl)cysteamine Dissolved in 1.30ml methanol,
Add 30 mj'l of 28% aqueous ammonia and stir for 4 hours. 2N-hydrochloric acid is added to the reaction mixture to make it slightly acidic, and the mixture is extracted with chloroform. The organic layer was washed with water and saturated saline,
Dry with anhydrous sulfuric acid (IJum). The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform was extracted with N-(5-(4-hydroxy-3-methoxyphenyl)-2,4-pentagenoylfucysteamine (XV)). 0.46 f was obtained.

Spectroscopic data of this product supports the structure of formula (5) below.

NMR (CD, OD) δ: 6.00 (IH, d, J = 1511z) 3.90 (3B
, s) 3.47 (2B, t, J = 6Hz) 2.67 (2H, t, J = 6Hz) Test Example 5 - Lipoxygenase action inhibition activity ゛Rat-derived basophilic leukemia cell line RBL-1t Eagle (g
agle) basal medium [Gibcolago Latries (Gib
co Laboratories)] with 10% FC
After suspending the cells in a culture solution containing 8 and culturing them at 37°C in a 5% CO2 incubator, the culture solution was centrifuged at 4°C to collect the cells. The cells were resuspended in -7.4 phosphate buffer to a cell density of i, o ~ 3.0 x 10' cells/rn.
Let it be l. After the suspension is treated with an ultrasonic cell disrupter, it is centrifuged for 30 minutes at 15.00 Orpm and 4°C, and the supernatant is used as a 5-lipoxygenase enzyme solution. Radioactively labeled arachidonic acid (10μJ-/m#) 12oμt1 and the cysteamine derivative according to the present invention to be tested were placed in test tubes, and 0.4μt of phosphate buffer (JIL1) was added to the test tubes.
1 0.10g of the above enzyme layer, 100mM Ca1l,
Add 5μtf of (calcium chloride) solution and heat at 37℃ for 15 minutes.
Let it react for a minute. After water cooling IN-) 1 ct (hydrochloric acid) 1
Add a drop and extract with 2 ml of ethyl acetate. Concentrate the extract and transfer the resulting concentrate to a silica gel thin layer plate (
Mark 60F254) and develop. The inhibitory activity was measured using a radio thin layer chromatography scanner [Di
innjchicht-8canner11LB272
3. Manufactured by Bar thold]
The 5-lipoxygenase product detected in 5-
HETE (5-(s)-hydroxyproxy6,8,11.
14-eicosatetraenoic acid) is collected,
This is done by measuring radioactivity with a liquid scintillation counter. The inhibition activity of 5-IJ/xygenase is confirmed by the decrease in the production amount of the 5-lysoxygenase product. As a result of the test, remarkable 5-lipoxygenase action inhibitory activity was found as shown in Table I below. Furthermore, it was confirmed that cysteamine derivatives according to the present invention not shown in Table I also have similar 5-lipoxygenase action inhibiting activity.

Table I 5-riboxidanase inhibitory effect The 50% inhibitory concentration in the table refers to the amount of 5-HETH produced when the cysteamine derivative according to the present invention is not introduced.
When it is defined as 0%, it means the cysteamine derivative concentration required to suppress the production amount of the 5-lipoxygenase product to 50% by introducing the cysteamine derivative.

Acute Toxicity An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). The LD5o values of the compounds of the present invention were all 100 ray/kq or more, confirming high safety compared to the effective dose.

(1) Effects of the Invention According to the present invention, a novel cysteamine derivative and a 5-lipoxygenase action inhibitor containing the same are provided.

It has been revealed that the above-mentioned compound of the present invention has an activity of inhibiting the action of 5-lipoxygenase. That is, the above compound inhibits the action of 5-lipoxygenase, thereby inhibiting the LT produced by the action of 5-lipoxygenase.
It is possible to suppress the production of leukotrienes such as C4 and LTD4. Therefore, the cysteamine derivative has 5
- It can be effectively used as a lipoxygenase action inhibitor against allergic diseases such as asthma and rhinitis, as well as nephritis, hepatitis 1, rheumatism, and gastric ulcer.

Claims (2)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom or a methyl group, n represents the number of double bonds in trans configuration, 1 or 2 . , chemical formulas, tables, etc. ▼ (IV) or the following formula (V) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (V) Indicates a branched alkyl group] Indicates a group selected from groups containing a cysteamine moiety (▲numerical formula, chemical formula, table, etc.▼) in the molecule)
A cysteamine derivative represented by (2) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents a hydrogen atom or a methyl group, n represents the number of double bonds in trans configuration, and 1 or 2. There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) or the following formula (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) [In the formula, R_2 is a hydrogen atom or a linear or Indicates a branched chain alkyl group] Indicates a group selected from the groups containing a cysteamine moiety (▲numerical formula, chemical formula, table, etc.) in the molecule)
A 5-lipoxygenase action inhibitor containing a cysteamine derivative represented by: