JPS6176433A - Novel chalcone derivative - Google Patents

Abstract

NEW MATERIAL:The chalcone derivative of formula I [one of R<1> and R<2> is H and the other is methoxy; R<3> and R<4> are same or different H, hydroxy, methoxy, nitro, amino, or RCONH (R is aryl); R<5> is H or RCO] or its salt. EXAMPLE:3-(4-Hydroxyphenyl)-1-(2,3,4-trimethoxyphenyl)-2-prope-n-1-one. USE:It has anti-allergic activity and is useful as an antiallergic agent. Useful for the prevention and remedy of various allergic diseases caused by chemical mediator, e.g. histamine, SRS-A (slow reacting substance of anaphylaxis), etc. PREPARATION:The compound of formula I can be prepared by the condensation reaction of the acetophenone derivative of formula II with the compound of formula III in the presence of a catalyst according to the reaction formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel chalcone derivative that has excellent antiallergic activity and is useful as an antiallergic agent.

BACKGROUND OF THE INVENTION Research and development of preventive and therapeutic agents for various allergic symptoms has been carried out, and various drugs are already on the market. Among these allergic symptoms, bronchial asthma,
Urticaria, allergic rhinitis, etc. are immediate allergies classified as type ■.

This type (1) allergy is generally classified into three stages based on the mechanism of the allergic reaction and the point of action of the antiallergic agent. First, IgE antibodies are produced by interactions between macrophages, T cells, and B cells in response to foreign antigens that invade the body, and these TgE antibodies adhere to IgE receptors on mast cells and basophils in tissues. This process is called the first stage. Next, when a foreign antigen enters the body again, the foreign antigen binds to the IgE fixed to the cell's IgE receptor, triggering an antigen-antibody reaction that activates cell membrane enzymes and releases calcila into the cell. The influx of 11 ions occurs, which causes biochemical changes such as enzyme reactions and histological changes such as degranulation. As a result, histamine and SRS-A (slow r
acting 5ubstance ofana
chemical mediators such as phylaxis) are released outside the cell. This process is called the second stage.

Chemical mediators liberated outside the cells in the second step cause smooth muscle spasms, capillary permeability light channels, and secretion promoting effects, causing various allergic symptoms. This process is called the third stage.

Among the conventionally known antiallergic agents, antibody production inhibitors are drugs that act in the first step, and antihistamines are drugs that act in the third step.

In addition, as an antiallergic agent that acts in the second stage, S
CG and Toranirasuto are known.

The inventors of the present invention have conducted extensive research to obtain a drug that exhibits excellent anti-allergic effects against the second stage of allergic symptoms. It was discovered that the present invention has excellent activity in inhibiting the release of chemical mediators such as 5R9-A, and the present invention was completed. That is, the present invention provides novel chalcone derivatives useful for the prevention and treatment of various allergic diseases caused by chemical mediators.

Constituent Structure of the Invention The compound of the present invention has the formula: [In the formula, one of R1 and R2 is a hydrogen atom and the other is a methoxy group, and R3 and R4 are the same or different and each is a hydrogen atom, a hydroxy group, a methoxy group, or a nitro group. , amino group or RCON H- (R is phenyl, tolyl,
aryl=3- group such as naphthyl, R5 is a hydrogen atom or RC0-(R
means a group represented by (same as above)] These are chalcone derivatives shown in Table 4.

” - Among the compounds represented by formula (1), R3 and /
Alternatively, compounds where R4 is an amino group may form acid addition salts with pharmaceutically acceptable acids, and compounds where R5 is a hydrogen atom may form salts with pharmaceutically acceptable bases. The present invention also includes salts thereof.

Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, and acetate, lactate, tartrate, citrate, methane. Examples include organic acid salts such as sulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and isethionate. Examples of salts with bases include sodium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts.

Although the chalcone derivative of the present invention can be produced by various methods, it is basically produced, for example, by the method shown in the following reaction formula.

(Engineering I) (EEE) [In the formula, R1 and R2 are the same as above, R3° and R4 are the same or different and each means a hydrogen atom, a hydroxy group, a methoxy group or a nitro group] That is, the formula (11 ) and the acetophenone derivative of formula (I
It is produced by subjecting the benzaldehyde derivative of II) to a condensation reaction in the presence of an acid or alkali catalyst at room temperature or under heating for several tens of minutes to several hours.

Examples of the acid or alkali catalyst used include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The above reaction is preferably carried out using an alcohol such as methanol or ethanol, or a suitable organic solvent such as water.

Among the chalcone derivatives (1) of the present invention, compounds in which R3 and/or R4 are amino groups can be obtained by reducing the corresponding compounds in which R3 and/or R' are nitro groups to primary amines by a conventional method. Manufactured by. This reduction can be carried out, for example, by catalytic reduction to hydrogen gas in the presence of a catalytic reduction catalyst such as platinum, palladium on carbon, or in the presence of iron, zinc, tin, or stannous chloride with hydrochloric acid or benzene. A reduction method using titanium trichloride, sulfur sulfide, ammonium sulfide, aqueous ammonia and hydrozulfite in water or hydrous alcohol is employed.

In addition, in the chalcone derivative (I), R3 and/or R'
is a group represented by RCON tr-, a compound in which the corresponding R3 and/or R4 are an amino group is reacted with the formula RCOOH (wherein R is the same as above) in the presence of a base such as pyridine or triethylamine. They are produced by reacting with the indicated carboxylic acids or reactive derivatives thereof, such as acid chlorides, acid anhydrides or mixed acid anhydrides.

Furthermore, in the chalcone derivative (1), the compound in which R5 is a group represented by RC-- is obtained by converting the corresponding phenol compound in which R5 is a hydrogen atom in the presence of a base such as pyridine or triethylamine as described in "1. It is produced by reaction with a carboxylic acid of the similar formula RCOOH or a reactive derivative thereof.

In addition, the salts of the chalcone derivatives of the present invention can be easily obtained from the corresponding free compounds by conventional methods, for example, R3
The corresponding acid addition salt can be obtained by reacting a compound in which is an amino group with a theoretical amount of the desired acid in a suitable solvent, and a compound in which R5 is a hydrogen atom can be reacted with a theoretical amount of the desired acid in a suitable solvent. The corresponding base salt is obtained by reacting with a theoretical amount of base.

The compounds of the present invention have excellent chemical mediator release inhibiting activity, as shown in the following test examples.

Test Example I T-Tartley guinea pigs (one male weighs approximately 400 g)
) were passively sensitized by intravenously administering anti-ovalbumin guinea pig serum, and 48 hours later, the lungs were removed and cut into small pieces to prepare a lung suspension. The test compound and ovalbumin were added to this and incubated at 37°C. After the reaction was completed,
The lung sections were filtered to remove histamine and 5r(S-
Afi was measured. The amount of histamine was determined by the method of May et al. [J
, Allerg, Vol. 40, p. 12 (1970)]. ST' (S-A amount was measured by bioassay using guinea pig ileum. In other words, antihistamines, antiacetylcholine agents, and test solution were added to the guinea pig ileum suspended in a Magnus bath, and Sl' ( The amount of S'-A was calculated.

Table 1 shows the inhibition rates of the compounds of the present invention on the release of histamine and 5R9-A.

=8- Table 1 *) The test compounds are as follows.

1:3-(4-hydroxyphenyl)-1-(2,3,
4-trimethoxyphenyl)-2-propen-1-one 2:3-(4-hydroxyphenyl)-1-(3,4,
5-Trimethoxyphenyl)-2-propene-■-one 3.1-(3,4-dihydroxyphenyl)-1-(
2,3,4-trimethoxyphenyl)-2-propen-1-one 4:3-(4-hydroxy-3-methoxyphenyl)-
1(2,3,4-)rimethoginophenyl)-2-propen-1-one 5: 3-(3,5-nomethoxo-4-hydroxyphenyl)l-(2,3,4-1,rimetquin phenyl)−
2-propen-1-one 6:3-(4-hydroxy-3
-nitrophenyl)-1-(3,4,5-trimethogynphenyl)-2-propen-1-one 7: 3-(3-amino-4-hydroginphenyl)-
1-(3,4,5-1,rimetogynophenyl)-2-[Jpen-1-one] The compounds of the present invention may be administered orally or parenterally; Or preferable. For use, they are prepared into various formulations by conventional methods using conventional pharmaceutical carriers.

For example, tablets, capsules, granules,
Examples include fine granules, powders, and powders.

Example 1 3-(4-hydroxyphenyl)-1-(2,3°4-
Preparation of trimethogyne phenyl)-2-propen-1-one.

2°, 3°, 4° -trimethoxyacetophenone 1.
0g and 06g of 4-hydroquine-benzaldehyde in 4
J in ethanol, 7 m, l of a 70% aqueous potassium hydroxide solution was added dropwise thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was made acidic with hydrochloric acid, and then extracted three times with ethyl acetate. The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound 670m having the following physical properties.
get g.

Melting point: 130~13+'C IR (KBr): ν=3360.1645°15
90.1550. +520.1440°14.10. +
345.1290,1275°+245. +225.1
170.1+00°1005.830cm' NMR (acetone-d6): δ-8,82 (IH.

s), 7. 71-6.75 (81-1, m),
3.871l- (6LI, s), 3. 78 (31-Ls
) Elemental analysis calculated value: C, 68,78, I-1,5,77 (%) Actual value: C, 68,65; H, 5,70 (%) Example 2 3-(4-hydrogine phenyl)-1-(3,4゜5-
Production of (trimethoquinophenyl)-2-propen-1-one; In the same manner as in Example 1, from 3°, 4°, 5″-trimethoxyacetophenone and 4-hydrogine benzaldehyde, a notation having the following physical properties 420 mg of compound is obtained.

Melting point: 196-198°C IR (KBr): v-3450, 3170°164
0.1555. +505. '1440°1350.13
10.1280. +235°1170, I 130cm
'NMR (DMSO-d6): δ-10,1(I)
■, s), 7.78 (211, d), 7.73 (2
H,S).

7, 43(21-1,s), 6. 87 (21
(,d), 3゜93(6H,s), 3.78(
3H,s) Elemental analysis value Calculated value: C, 68,78; I-I, 5.77 (%) Actual value: C, 68,63, H, 5,73 (%) Example 3 3-(3 ,4-dihydroxyphenyl)-1-(2,3
,4-1rimethoxyphenyl)-2-propen-I-one: 2°,3',4'-trimethoxyacetophenone 4
．． 2g and 3,4-dihydroxybenzaldehyde 2.8
g was suspended in 80n+4 ethanol, and hydrogen chloride gas was introduced at 0° C. for 3 hours. 600 m4 of water was added to this reaction solution, and the mixture was allowed to stand overnight at 4°C to precipitate crystals. This was collected to obtain 5.2 g of crude crystals, which was further recrystallized from a mixed solvent of ethanol/water to obtain 4.3 g of the title compound.

Melting point: 170-172°C (decomposition) IR (KBr): v = 3460.1640°159
0.1550, 1530, 1,450°1410, +2
80.1250.1200゜1100.1010.98
0,810cm'NMR (acetone-d8) δ-8
,33(21+.

s), 7.50-6.80 (7 (1, m), 3.92 (
611,s), 3. 83 (311, s) Elemental analysis value calculation value: C, 65, 45, II, 5. /19 (%) Actual value C, 65,27; 11,5.56 (%) Example 4 3-(4-hydroxy-3-methogynphenyl)-1-
Preparation of (2,3,4-)rimetogynephenyl)-2-propen-1-one.

Dissolve 3.0 g of 2°, 3', 4°-trimethoxoacetophenone and 2.1 g of vanillin in 15 m4 of ethanol, and add 25 mj of 70% potassium hydroxide solution at 0°C.
Drop u. After the addition is complete, stir at room temperature for 48 hours. The reaction solution is cooled to 0° C., and hydrochloric acid is gradually added thereto to make it acidic. The precipitated crystals were collected and recrystallized from a mixed solvent of n-hexane/ethyl acetate to obtain 1.2 g of the title compound.

Melting point: 99~1006C IR (KBr): v-3600~3100°164
0.1600, 1510, 1460°14'30. +3
90.1370.1200゜1020.800cm-' NMR (CDC!.): δ-7,7~6.2 (7H, m
), 3.90 (+ 20.s) Elemental analysis calculated value: C, 66,27; Example 5 3-(3,5-dime)gin-4-hydroxyphenyl)-1-(2,3,4-1-rimethogynphenyl)-2
-Production of propen-1-one.

2°, 3°, 4° -1-rimetogine acetophenone 4
．． 2 g and 3.6 g of syringaldehyde to obtain 3.5 g of the title compound in the same manner as in Example 3.

Melting point 134-136°C IR (KBr): v-3430, 1590°1515
．． 1465,1430.14+5゜+305.1270
．． 1210. 1110°1105, 1005,81
5c111'NMR (acetone-d8): δ-7,
72 (III.

s), 7.45-6.78 (6J(,m), 3.8
8 (15LT, br, s) Elemental analysis value calculation value: C, 64, 16; II, 5.92 (%) Actual value C, 64, 34, H, 5, 88 (%) Example 6 3-( 4-hydroxy-3-nitrophenyl)-1-(
3,4,5-trimethogynephenyl)-2-propene-
Preparation of 1-one: 3', 4', 5'-trimethogine acetophenone 42
g and 4-hydroquine-3-nitrohenzaldehyde 33
Dissolve g in 80ml of ethanol, and introduce hydrogen chloride gas at 0°C for 3 hours. Add 500 J of water to this reaction solution,
-Crystals precipitate when left at 4°C overnight. This was collected and recrystallized from ethanol/ethyl acetate to obtain 5.2 g of the title compound.

Melting point: 205-207°C (decomposition) IR (KBr): v-3450, 1660°160
0.1575, 1535.14+5゜1350.133
0. +310.1285°1245.1185.115
5.1145゜l 125.1005,985,935
,835°820.770cm' NMR (DMSO-do): δ-8,4,3(I
I-T.

d), 8.15(11(, d(1), 7.82
(2H, (1).

7.45 (2H,s), 7.23 (IH,d),
3°92 (6H9s), 3.78 (3H,s) Elemental analysis calculated value: C,60,I 6. I(, /1.7?, N.

3.90(%) Actual measurement value C, 60, 15', I (, 4, 70, N.

3.96 (%) Example 7 3-(3-amino-4-hydroxophenyl)-+-(
3,4,5-trimethogynophenyl)-2-propene-
Production of 1-one: 3-(4-hydroxy-3-di[1 phenyl)-1
-(3,4,5-trimethquinphenyl)-2-propen-1-one 3.6g and 80ml of water! , TE), add and dissolve 100+J of lahydrofuran and 26.5 J of concentrated aqueous ammonia. Add to this sodium didionite 18.
5g in 80m of water! Add the solution dissolved in water under water cooling and add 40
Stir for a minute.

The reaction solution is extracted with ethyl acetate, the extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. The obtained crude crystals were recrystallized from ethyl acetate to obtain 1.3 g of the title compound.

Melting point: 182-184°C (decomposition) IR (KBr): v-3470, 3400°1640
, +610.1585,1545°+505.1445
．． 1415', +385°1355.1320,130
5. +285°+270; 12/10. +220.
．． 1160°1140.1125.1080,1000
゜985, 835. 805cm-' NMR (DMS Odo/Acetone-d6)
: δ-7,71~6.80 (7H,m), 3.95
(6LI.

s), 3. 80 (31-I, s) Elemental analysis calculated: C, 65, 64; II, 5.82; N.

425 (%) Actual value: C, 65,78, r"L 5.91; N.

4.12 (%) Example 8 3-(3-benzoylamino-4-benzoyloxyphenyl)-1-(3,4,5-)rimethoxyphenyl)
-Production of 2-propen-1-one 3-(3-amino-4
-Hydroxyphenyl)-1-(3,4,5-1-rimethquinphenyl)-2=0.9 g of propen-1-one and 15 m of anhydrous pyridine! 0.35 J of benzoyl chloride was added dropwise while cooling with water. After stirring this at room temperature for 2 hours, water was added and the mixture was left at -4°C overnight. The precipitated crystals? and recrystallized from ethanol to obtain the title compound 0.4
get g.

Melting point 178~+81'C TR (K13r): ν -1740,I
660. i 580.1345, 1330.1245
,116(1°1130.710cm' NMR(1)MSO-d, ): δ-10,20(I
N, s), 8.10-7.46 (1711, m),
390 (6Ir,s), 3. 79(3H,s
) Calculated elemental analysis value: C, 71,50, IJ, 5.06; N.

2.61 (%) Actual measurement value: C, 71,72, H, 5,00; N.

2.79 (%)

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, one of R^1 and R^2 is a hydrogen atom, the other is a methoxy group, and R^3 and R^4 are the same or different. each a hydrogen atom, hydroxy group, methoxy group, nitro group, amino group or RCONH- (R is an aryl group)
A chalcone derivative or a pharmaceutically acceptable salt thereof, represented by the group represented by the following formula, R^5 means a hydrogen atom or a group represented by RCO- (R is the same as above).