JPS61180752A - Cinnamamidobenzoic ester - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is phenyl which is replaced with one or more lower alkoxy groups; R<2> is hydrocarbon residue which is interrupted or replaced with ester bond). EXAMPLE:N-(3, 4-Dimethoxycinnamoyl)anthranilic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester. USE:An antiallergic. PREPARATION:A compound shown by the formula II or a reactive derivative (acid halide, acid anhydride, etc.) at its caraboxyl group is reacted with a compound shown by the formula R<2>-OH or a reactive derivative at its hydroxyl group, to give a compound shown by the formula I. The compound shown by the formula I is considered to be converted into a compound of a parent substance shown by the formula II in body, and has more improved solubility, stability, absorption properties, etc., than the compound of parent substance.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel cinnamamide benzoic acid ester, a method for producing the same, and a medicine made from the same.

[Summary 1] The novel cinnamamide benzoate ester provided by this invention is represented by the following general formula.

(In the formula, R1 represents a phenyl group substituted with one or more lower alkoxy groups, and R2 represents a hydrocarbon residue interrupted or substituted with an ester bond.)' [Prior Art] Japanese Patent Publication No. 57-36905 claims a method for producing hydrocarbon esters, substituted hydrocarbon esters, and cyclic ether esters of cinnamamide benzoic acid substituted with lower alkoxy. However, chloroethyl ester and hydroxyethyl ester are exemplified as substituted hydrocarbon esters, and tetrahydropyranyl ester is exemplified as cyclic ether esters. There is no suggestion or mention of this.

[Description of the Invention] As mentioned above, the present invention provides a cinnamamide benzoic acid ester represented by the general formula (I). The above compound (1) is a compound represented by the formula (wherein R1 is the above-mentioned meaning) or a reactive derivative thereof at the carboxyl group, with the formula % formula % ([) (wherein R2 is the above-mentioned meaning) They can be prepared by reacting the indicated compounds or their reactive derivatives at the hydroxy group.

A more detailed explanation of each of the above compounds and the terms used in their definitions is as follows.

The compound represented by the formula (D) may have trans and cis forms as geometric isomers based on 10H=CH-, but both of these are included in the present invention. If not, it indicates trans isomer.

The lower alkoxy in R1's "phenyl group substituted with one or more lower alkoxy" has 1 to 6 carbon atoms, such as methoxy, ethoxy, isopropoxy, butoxy, tertiary butoxy, pentoxy, hexyloxy, etc. alkoxy groups, of which methoxy and ethoxy are preferred. Lower alkoxy can be bonded to any position of the phenyl group, and 1 to 5 lower alkoxy groups can be present, but 1 to 3 lower alkoxy groups are preferable. Group R'-CH=CH
C0NH- can be bonded at any position ortho, meta and para to the group -GOOR'.

r? 2 r -r-2-r rb story A-z Yamatai 10), I
-)gm7 to)6$hydrogen residue" means a group in which a carbon chain in a hydrocarbon residue is interrupted or substituted with an ester bond. The ester bond referred to here includes a carboxylic acid ester bond (i.e. -
C(=O)-0-) and carbonate bonds (i.e., -0-C(=O)-0-). Hydrocarbon residues also include aliphatic, aromatic, and aromatic-aliphatic groups, and aliphatic groups or moieties may be unsaturated. In these groups, the ester bond is directly attached to the alpha carbon atom, or the group contains π electrons (e.g.
Preferably, they are bonded via a double bond or a military bond. More specifically, for example, a group represented by the following formula R30 R' 0 (wherein R3 and R4 represent the remainder of the hydrocarbon residue), for example, (5-methyl-2-oxo-1°3-dioxo -4-ylmethyl, pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 3
-Includes phthalidyl, etc. These are groups that form esters that can be hydrolyzed in vivo under physiological conditions.

The method for producing the compound of formula (I) above will be explained in more detail as follows.

As mentioned above, the compound of formula (I) is a compound of formula (II) or a reactive derivative thereof at the carboxy group which has the formula (
It is produced by reacting the compound of II) or its reactive derivative at the hydroxyl group.

Reactive derivatives at the carboxy group of compounds of formula (n) include acid halides, acid anhydrides, active esters and active amides. Among them, as acid halide,
Acid chlorides are frequently used.

Acid anhydrides include symmetrical anhydrides, intramolecular cyclic anhydrides resulting from imidization of the amide moiety (i.e., the following formula 0), and mixed acid anhydrides; the latter include, for example, dialkyl phosphoric acid mixed anhydrides, dialkyl phosphoric acid mixed anhydrides, Included are phosphorous acid mixed anhydrides, alkyl carbonic acid mixed anhydrides, aliphatic carboxylic acid (eg, pivalic acid, trichloroacetic acid) mixed anhydrides, and the like. As the active ester, cyanomethyl ester, p-nitrophenyl ester, ester with N-hydroxysuccinimide, trimedelsilyl ester, etc. are used.

As the active amide, amides with imidazole, dimethylimidazole, and triazole are used.

Reactive derivatives at the hydroxy group of the compound of formula (III) include halides, inorganic acid esters such as sulfuric acid esters, organic acid esters such as methanesulfonic acid esters and toluenesulfonic acid esters, alkaline metal salts, diazotides, etc. It will be done. These are represented by the following general formula % formula %) (wherein, R5 is a residue from R2 excluding one H bonded to the α-carbon, and X and Y are one of H and the other a reactive group. or jointly represents a group "Nt". Note that the term "reactive group" means a group that is easily separated by reaction, and includes a group that forms a reactive ester in the above-mentioned hydroxy group. do.

When using the compound of formula (n) as a carboxylic acid,
It is advantageous to carry out the reaction in the presence of a condensing agent. As a condensing agent, N,N'-dicyclohexylcarbodiimide,
N-cyclohexyl-No-morpholinoethylcarbodiimide, N,N'-diisopropylcarbodiimide, N
-Ethylbenzisoxazolium salt, 2-chloro-I-
Methylpyridinium salt, N,N'-carbonyldiimidazole, phosphorus trichloride, phosphorus oxychloride, etc. are used.

It may also be advantageous to carry out this reaction in the presence of a base.

This reaction is usually carried out in a solvent. As a solvent, dioxane, methylene chloride, tetrahydrofuran,
Dimethylformamide, pyridine, benzene, toluene, xylene, etc. are used.

The reactive derivative at the carboxy group of compound (II), the reactive derivative at the hydroxo group of compound (TII), the condensing agent, the base, the solvent, etc.
) is appropriately selected depending on the group R2. For example, when the group R2 is pivaloyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl, etc., the compound (n
) and the compound R"-X'(X' is In some cases, iodides (e.g. NaI)
Preferably, the reaction is carried out in the presence of. Also, the compound (, I
A compound of formula (I[a) is used as a reactive derivative of I), and a compound R2-0X'(X'' is an alkaline metal,
Preferably, it is also possible to react with Ll, Na or K).

The manufacturing method for some of the compounds of formula (II) is disclosed in Japanese Patent Publication No. 1983.
-, No. 36905, and other products can be produced in the same manner. The compound of formula (III) can be easily produced from known compounds.

[effect〕 The compound of formula (1) has anti-allergic action.

These compounds are thought to convert into the parent compound (n) in the body, but they are more soluble and less soluble than the parent compound (I[).
It has excellent stability, absorbency, etc., and as a result shows excellent effects.

In the above applications, the dosage will, of course, vary depending on the compound used, the method of administration and the treatment desired.

However, generally 1 to 6 mg/kg, preferably 1
Satisfactory results are obtained when administered in divided doses two to four times a day or in the form of a sustained release formulation.

When administered for prophylactic and/or therapeutic purposes,
In the form of conventional pharmaceutical preparations containing the compounds of this invention as active ingredients, mixed with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. can be administered. Such formulations can be solid, such as capsules, tablets, dragees, ointments, suppositories, or liquid, such as solutions, suspensions, emulsions. If necessary, auxiliaries, stabilizers, wetting agents, emulsifiers, buffers and other conventional additives can also be added to the above formulations.

[Examples] This invention will be explained in more detail by Examples below, and the effects of the invention will be clarified by Test Examples.

Example 1 Preparation of N-(3,4-dimethoxycinnamoyl)anthranilic acid (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl ester.

N-(3,4-dimethoxycinnamoyl)anthranilic acid (327 m 9.1 mmol) and triethylamine (0,211112S 1.4 mmol) are stirred in dry acetone (loff(2)) for 30 min at room temperature. , 4-bromomethyl-5-methyl = 1.3 under water cooling
A solution of -dioxol-2-one (386 mg, 1.4 mmol) in dry acetone (2 liters) is added and heated under reflux for 1.5 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in chloroform, washed with a warm solution of saturated sodium bicarbonate and an aqueous solution of 11 um, and dried. The solvent was distilled off, and the residue was washed with silica gel.
Purification by column chromatography (eluent: benzene:ether = 9+1) gave the title compound (2) as pale yellow crystals.
9819, yield 68%). mp161-163℃
(methanol/tetrahydrofuran).

I R (KBr, cm'): 3300.1830.17
30.1680 (shoulder), 167O NMR (CD Cl s , δ): 2.23 (s,
3H), 3.91 (d, 6H), 5.08 (s, 2H)
, 6.25-8゜12 (m, 8.8), 8.83 (
d, IH), 11.11 (brs, IH) Example 2 Preparation of N-(3,4-dimethoxycinnamoyl)anthranilic acid pivaloyloxymethyl ester.

N-(3,4-dimethoxycinnamoyl)anthranilic acid (327y, 1 mmol) and triethylamine (
0.17xQ, 1.2 mmol) in dry acetone (1
This solution was stirred for 30 minutes at room temperature in 0j+12).
Add chloromethyl pivalate (0.18m+2.1°2 mmol) and sodium iodide (180 mg, 1.2 mmol) and heat to reflux for 3 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in chloroform, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried. Distill the solvent,
The residue is recrystallized from methanol to obtain the title compound (1 g at 320° C., yield 73%) as white crystals. mp122-
123℃.

I R (KBr, cm'): 3310. 1750.1
700, NMR (CD C13, δ): 1.23
(s, 9H), 389(s, 3H), 3.93(s,
3H), 6.00 (s, 2H), 5.28-8.16 (
m, 8H), 8.83 (d, IH), l 1 , I 0
(brs, IH) Example 3 Preparation of N-(3,4-dimethoxycinnamoyl)anthranilic acid 1(ethoxycarbonyloxy)ethyl ester.

N-(3,4-dimethoxycinnamoyl)anthranilic acid (327R9,1 mmol) and triethylamine (0,2xL 1.4 mmol) were dissolved in dry acetone (
Stir in 1-Oz (2) for 30 minutes at room temperature. Add ethyl 1-chloroethyl acid (214R9) to this solution under water cooling.
, 1,4 mmol) and sodium iodide (210x
g, 1.4 mmol) and heated under reflux for 23 hours.

The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in chloroform, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried.

The solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: benzene:ether = 9:1), and the obtained oil was cooled with isopropyl ether/hexane in a dry ice and acetone bath. The title compound (322ag, yield 73%) is obtained as white crystals.

mp104-106°C (benzene:hexane).

I R (KBr, Cx'): 3300.1750.17
10,68O NMR (CD Cls, δ): 1.32 (t, 3H),
■, 67 (d, 3H), 3.92 (d, 6H), 4.2
2 (Q, 2H), 6.25-8.12 (m, 9H), 8
．． 82 (d.

IH), 11.15 (brs, IH) Example 4 Preparation of N-(3,4-dimethoxycinnamoyl)anthranilic acid 3-thucridyl ester.

N-(3,4-dimethoxycinnamoyl)anthranilic acid (500y9.1.53 mmol) and triethylamine (0.26 mmol, 1.84 mmol) are stirred in dry acetone (10me) for 30 minutes at room temperature. Add 3-bromophthalide (393J!9,!,
A solution of 84 mmol) in dry acetone (211Q) is added and stirred at room temperature for 8 hours. The precipitated solid is collected by filtration, distilled water is added to the solid, and insoluble matter is extracted with chloroform. The residue is recrystallized from chloroform/hexane to obtain the title compound (381j!9, yield 54%) as white crystals. m
p219-221°C.

I R (KBr, c, w'): 3350. 178 Q
, 171G.

67O NMR (CD C1, δ): 3.92 (d, 6H),
6.27-8.10 (m, 13H), 8.83 (d, I
H), ratio 10 (brs, IH) Example 5 (1) Active ingredient 25. OOmg(
2) Lactose 49.00mg Crystalline Cellulose 36.00mg Cornstarch 5.00111g (3) Hydroxypropyl Cellulose 1.00mg (4) E CG
505 (carboxymethylcellulose calcium)
2. OOmg (5) Magnesium stearate 1.00mg (6) Talc
1.00mg total 120mg (1) + (2) are kneaded with a 5% aqueous solution of (3), dried, sized, (4), (5), (6) are added and mixed, 120 mg
Compress into tablets (φ7 mm) in mg.

Example 6 (active ingredient 50.OOmg (2
) Lactose 124.50n+g (3
) Cornstarch 20. OOmg(4
) Hydroxypropyl cellulose 2. OOmg(5)
Light anhydrous silicic acid 1.50mg (6) Magnesium stearate 2.00mg total 200m
g (1) + (2) + (3) are kneaded with a 5% aqueous solution of (4), dried and sized, then (5) and (6) are added and mixed, and 200 mg is placed in a No. 3 hard capsule. Fill.

(In Example 7.8 above, the active ingredient indicates any one of the compounds of general formula (I).) Test Example 1 Anti-passive cutaneous anaphylaxis (PCA) in rats
Action.

(Test method) Wistar rats were sensitized in advance with ovalbumin using aluminum hydroxide gel and pertussis vaccine as adjuvants, and diluted antiserum (12 and 24 times ) was intradermally administered at 0.1 x 12 doses per site into the back skin of syngeneic rats and kept for 48 hours. One hour after the oral administration of the sample solution, a mixture of the antigen ovalbumin and the dye Evans blue was administered into the tail vein according to a conventional method, and 30 minutes later, the animals were exsanguinated to death. The area (longer axis x shorter axis) was determined, and the inhibition rate was determined based on the average shown by the control group animals.

(Results) Compound Dose Administration (N) Inhibition rate (%) R9
/to9 Route (antiserum dilution rate)xtex
32 Control -PO500 Example 1 too PO510,819,4 Example 3 100 PO59,523,3 As is clear from the above table, anti-PCA activity was observed in the compound of this invention.

Test Example 2 Acute Toxicity (Test Method) As for the animals, mice (male) were used. According to the usual method,
The suspension of the compound obtained in Example 1 was orally administered to animals. As a result, no deaths were observed even at 300 ra9/ktt.

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a phenyl group substituted with one or more lower alkoxy groups, and R^2 is a hydrocarbon residue interrupted or substituted with an ester bond. A compound represented by (meaning a group). (2) A compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 means a phenyl group substituted with one or more lower alkoxy) or its reactive derivative in the carboxy group by reacting a compound of the formula (wherein R^2 means a hydrocarbon residue interrupted or substituted with an ester bond) or a reactive derivative thereof at the hydroxy group, There are chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 have the meanings above.) Manufacturing method for the compound shown. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^2 is a phenyl group substituted with one or more lower alkoxy, R^2 is a hydrocarbon residue interrupted or substituted with an ester bond. An anti-allergic agent containing a compound represented by (meaning a group) as an active ingredient.