JPS59176268A - Spiroisoxazoline compound - Google Patents

Abstract

NEW MATERIAL:A spiroisoxazoline of formula I (R<1>, R<2> are H, lower alkoxy; R<3>, R<4> are lower alkyl, aralkyl, aryl, which may be substituted and R<3> and R<4> may form a hyterocyclic ring together with an adjacent nitrogen atom). EXAMPLE:8-Oxo-1-oxa-2-azaspiro[4,5]-deca-2,6,9-triene-3-carboxylic acid N,N- dimethylamide. USE:It is useful as a drug, because of its carcinostatic activity. It features in low toxicity and high stability. PREPARATION:A carboxylic acid or its reactive derivative of formula II is allowed to react with an amine of formula III or its reactive derivative in a solvent such as benzene at room or lower temperature to give the compound of formula I . In an alternate way, an amidoxim derivative of formula IV is subjected to ring closure under acidic conditions to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to general formula 1 in which xl and R2 represent a hydrogen atom or a lower alkoxy group, and R3 and R' represent a hydrogen atom or a lower alkyl group or aralkyl group which may have a substituent. or an aryl group, of which R3 and R' may form a heterocyclic ring together with adjacent nitrogen atoms] and a method for producing the same.

To further explain the compound represented by the above general formula (13), the term "lower" in formula 1 refers to a straight or branched carbon chain having 1 to 5 carbon atoms.

Therefore, the lower alkoxy group means a methoxy group, an ethoxy group, an isopropoxy group, a butoxy group, etc. In addition, a lower alkyl group which may have a substituent,
Examples of the aralkyl group and aryl group include substituents such as) rogene, hydroxyl group, amine group, and lower alkoxy group.

A methyl group, an ethyl group, a butyl group, a benzyl group, which may have a lower alkoxycarbonyl group, etc.

Examples include phenyl group, naphthyl group, etc., and examples of heterocyclic rings formed with adjacent nitrogen atoms include pyrrolidine ring, piperidine ring 1 morpholine term, etc.

The present inventors first synthesized spiisoxazoline carboxylic acid derivatives represented by the general formula [wherein R5 and R6 represent hydrogen atoms or...rogen], and demonstrated that the two compounds have strong anticancer effects. (Japanese Patent Application No. 73408/1982). Now the inventors have further discovered a carboxylic acid (formerly a closely related derivative of formula (
The amide compound of I) similarly has strong anticancer activity,
Moreover, they discovered that it has excellent properties in terms of toxicity and stability, and completed the present invention.

According to the present invention, compound (1) can be produced by the following synthetic route.

Route (al (1) Route (b) (V) r in the formula R1, R2, R3 and R' have the meanings given above] Route (a) is a method in which the carboxylic acid of formula (1) or an activated derivative thereof is substituted with the formula This is a production method in which (IY) is reacted with an amine or an activated derivative thereof.Formula (1) used in this reaction example
) is a compound that has not been described in any literature, but it can be obtained by the production method described in the reference examples below.
Examples of the activated derivatives at the carboxyl group of this carboxylic acid compound include acid halides and mixed acid anhydrides, and these derivatives usually react easily with the amine of formula (IV) to form the formula (1). Gives an amide compound. Examples of activated derivatives of the amine of formula (■) include, for example, phosazo derivatives obtained by reaction with phosphorus trichloride.

For K to carry out this reaction, the carboxylic acid of the above formula (formula) or its activated derivative is used for the reaction with the formula (■) of 1.
or an activated derivative thereof, usually in a solvent. The solvent is not particularly limited as long as it does not participate in the two reactions, such as benzene, acetone, tetrahydrofuran, dioxane, ethyl acetate, and chloroform.

Acetonitrile or dimethylformamide and the like are preferred. The reaction temperature is generally room temperature or lower, taking into account the stability of the starting compound (I[+).

Next, route (b) is a production method in which the amidoxime derivative of formula (V) is ring-closed under oxidative conditions.

The amidoxime derivative of formula (V) used in this reaction is a new compound, and the present inventors synthesized it by the method described in Reference Example.

In carrying out this reaction, the above-mentioned amidoxime derivative ffl is oxidized usually in a solvent, in the presence of an oxidizing agent, or under conditions such as electrolytic oxidation.

General This oxidation reaction is preferably carried out under mild conditions, and therefore the oxidizing agent used is also a halogen such as salt, bromine, iodine, or an organic halogen compound such as N-bromosuccinimide.

Silver oxide, manganese dioxide or manganecetris acetylacetonate are suitable.

The solvent is not particularly limited as long as it does not participate in the reaction.
For example, benzene, acetone, ethanol, tetrahydrofuran, dioxane, ethyl acetate, chloroform, acetonitrile or dimethylformamide are suitable.

Although the reaction temperature is not particularly limited, the reaction may be carried out with heating or cooling depending on the type of oxidizing agent used.

The target compound (1) obtained by the reaction according to route (a) or route (b) above is separated according to a conventional method, for example, by collecting crystals from the reaction solution or by solvent extraction. The objective compound of the present invention obtained here (1
) is a common law if necessary.

For example, it can be further purified by recrystallization or column chromatography.

The present invention will be specifically explained below with reference to button examples and reference examples, but these examples do not limit the present invention.

Reference example 1 a) 4-hydroxyphenylpyruvin fli6.98f
was dissolved in 35 parts of pyridine, and 11 parts of acetic anhydride was added with water cooling and stirring.
0rn1. After adding, leave it at room temperature for 15 hours. The reaction solution was poured into ice water, and 35X hydrochloric acid was added to make it strongly acidic to pH 1. The product was separated, washed with water, and then recrystallized from aqueous methanol to yield α,4-diacetoxycinnamic acid 5.9
5f' is obtained.

Melting point: 158-16 o r (decomposition point).

b) 2.50f of α,4-diacetoxycinnamic acid and 1-hydroxybenzotriazole L34f' are dissolved in 25- of anhydrous tetrahydrofuran, and 2.0! of N,N'-dicyclohexylcarbodiimide is dissolved. Add IM and stir at room temperature for 2 hours.

The reaction solution was cooled with water, 1.2-40X (w/w) dimethylamine tetrahydrofuran solution was added thereto, stirred for 2 hours, and then left in an ice chamber for 15 hours.

After condensing the reaction solution under reduced pressure, the residue was diluted with 50fnI of ethyl acetate! 7. Then, after dissolving the insoluble matter, wash the F solution with water.
The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate-hexane to give α.

4-diacetoxycinnamic acid N,N-dimethylamide 1.8
2 f is obtained.

Melting point 135-13'7 U 0 C) α,4-diacetoxycinnamic acid N,N-dimer fat
, Ami)' 1.30 f, 1.8e51 F of hydroxylamine hydrochloride and 1.42 f' of sodium carbonate are added to 30rnt of methanol and stirred at room temperature for 15 hours.

After removing insoluble matter, the Oki liquid was dried under reduced pressure and the residue was recrystallized from aqueous methanol to obtain 2-hydroxyimino-3-(4-
0.68f of hydroxyphenyl)propionic acid N,N-dimethylamide is obtained.

Melting point: 17o-172c (decomposition point).

Engineering R spectrum νInaXCm 3310, 3200.3060.1600.1585° 1510, 1440.1405.1265.1220° Reference Example 2 Select 4-hydroxy-3-methoxyphenylpyruvic acid as the starting material and carry out the same reaction as in Reference Example 1. This gives 4-hydroxy-3-methoxyphenylpyruvate N,N-dimethylamide'oxime.

Melting point ko, 5'i' -159U0 Engineering R spectrum νmax "" 3375, 1620.1595.1510.1270° 1240, 1200.1115.965° Reference example 3 a) 2-hydroxyimino-3-(4-hydroxyphenyl ) Propionic acid 5.0Of ethyl acetate 500
After dissolving in 1 nl and adding 5.47 Y of diphenyldiazomethane, the mixture was stirred at room temperature for 7 hours.

After washing the reaction solution with 5X aqueous sodium bicarbonate solution, the solvent was distilled off and the residue was recrystallized from aqueous methanol to give 2-hydroxyimino-3-(4-hydroxyphenyl)propionate benzhydryl ester 'i', 7HM'. is obtained.

Melting point: 139-14oc (decomposition point).

b) Esteroxy as above! Add 3.5 or of A and 8.529 of manganecetris acetylacetonate to 105 of acetonitrile and heat under reflux and stirring for 4 hours.
After removing insoluble matter, liquid E was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from chloroform-hexane to give 8-oxo-1-oxa-2-
AzaspiroC4,5) deca-2,6,9-triene-3
-Carboxylic acid benzhydryl ester 1. '761F is obtained.

Melting point 187-189 [1"0 C) The ester obtained above 0.902
．． Suspend 6ml of 1K and add trifluoroacetic acid 3.
Add 5- and stir for 2 hours.

When the product is constant, washed with benzene and dried, 8-oxo-1-oxa-2-azaspiro(4,5]]decar2
6.9-) Diene-3-carboxylic acid 0332 is obtained.

Melting point: 154C (decomposition point).

Engineering R spectrum νmax Cm 2900, 2'i'50.2640.2550.1'7
15.1660°1610, 1595.12'70.1
255.1125゜Example 1 2-Hydroquinimino-3-(4-
Hydroxyphenyl)propionic acid N,N-dimethylamide 0.50F was dissolved in acetonitrile 20-
Add 1.9 sr of manganesetrisacetylacetonate and heat under reflux and stirring for 5 hours. After P separation of insoluble matter.

The flow liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 8-oxo-1-oxa-2-azaspiro r4,5)deca-2,6,9-triene-3-
Carboxylic acid N.

0.40 f of N-dimethylamide is obtained as a colorless oil.

KBr -1 Engineering R spectrum νmax Cm 3040, 2930.1660.1630.1600.
1500°1410, 1400.1255.1080° NMR spectrum (0DO131 δ: 6.91 (2H, d, J=9Hz), 6.2
4 (2H, d, J=9H2), 3.44 (2H, e)
, 3.29 (3H,S).

3.05 (3H, S).

Example 2 2- obtained in Reference Example 2 in place of the raw material compound in Example U
Hydroxyimino-3-(4-hydroxy-3-methoxyphenyl)propionic acid N,N-dimethylamide was used, otherwise the treatment was the same as in Example 1, and the product was recrystallized from benzene to give 7-medoxy-8- Oxo-1
-oxa-2-azaspiro[4,5]deca-2,6,9
-triene-3-carboxylic acid N,N-dimethylamide is obtained.

Melting point 128-12900 KBr -1 1R spectrum νIIIaX Cm 2925, 1670.1630.159i5.1255
゜1220, 1210.1180.1100.900.
850° NMR spectrum (ODO: L31 δ: 3.02 (3H, S), 3.27 (3H, e
), 3.44(2H, +91°3.65(3H, Fs
), 5.74 (IH, d, J = 3Hz).

a, 1s (xn, a, , T=9H2), 6.82
(IH, +1.C1°J =9H2,3Hz).

Example 3 8-oxo-nioxa-2-azaspiro r' + 5) deca-2,6,9-triene- obtained in Reference Example 3
0.385' of 3-carboxylic acid and 0.3C1 of 1-hydroxybenzotriazole are dissolved in 40-40% of tetrahydrofuran, 0.44F of N,N-dicyclohexylcarbodiimide is added, and the mixture is stirred at room temperature for 2 hours. Cool the reaction mixture on ice.

2.8N methylamine tetrahydrofuran solution 0.84
- and stirred at room temperature for 3 hours.
- Pour into. Count the precipitation.

After purification by silica gel column chromatography, recrystallization from methanol yields 8-okine-J-oxer-2-azaspiro r'+')deca-2,6,9-)diene-3-carboxylic acid N-methylamide 0.26f'. can get.

Melting point 1'76-1781; 0 KBr -1 Engineering R spectrum νmaXCm 3315, 1660.1615.1605.1560.
1270°1000.905° NMR spectrum (DMSOd6) δ: 2.69 (3H, a,, T-7Hz), 3.
40 (2H, S).

6, Technique 8 (2H, d, , T=9Hz l, 'i'
, 08 (2H, a, J=9H2), 8.40 (IH,
br, d).

Example 4 A reaction similar to that in Example 3 was carried out to obtain the following compound.

4-1) 8-oxo-1-oxa-2-azaspiro [4
,53deca-2,6,9-triene-3-carboxylic acid N
-Benzylamide.

Melting point 1B2-1s4c (decomposition point) IR spectrum νmaXCm 3:l15.1650.1625.1600.1435
゜1320, 1265.1250.1005. 865
゜'735. 695° NMR spectrum # (DMSO-delδ: 3.
43 (2H, S), 4.34 (2H, d, J=7)
.

6.15 (2H, d, , T mi 9 base), '7.06
(2H, d.

J=9H21,'2.24(5H,Sl,8.98(L
H.

br, ).

4-2) 8-oxo-1-oxa-2-azaspiro C'+5) deca-2,6,9-)diene-3-carboxylic acid anilide.

Melting point: 177-178 r: (decomposition point).

KBr -1 Engineering R spectrum νmax ”” 3330, 1680.1645.1610.1545°1455, Yu265. 930. 885. '77
0°705° NMR spectrum (DMEIO-d6) δ: 3.5
0(2H,S), 6.18(2H,d, J=9H2
).

7.19 (2H, d, J = 9Hz), 6.
50~'7.49 (3H, m 1. '7.71 (2
H, a, J = 8H21.

10.20 (4H, s).

Patent applicant: Man Yukiyaku Co., Ltd.

Claims (1)

[Claims] (2) In the general formula r, R1 and R2 represent a hydrogen atom or a lower alkoxy group, and R3 and R' represent a hydrogen atom or a lower alkyl group, an aralkyl group which may have a substituent, or A spiroisoxazoline compound represented by the following formula: R3 and R' may form a heterocyclic ring together with adjacent nitrogen atoms. (2) A carboxylic acid represented by the general formula (R1 and R2 represent a hydrogen atom or a lower alkoxy group) or its reactive derivative; represents a lower alkyl group, aralkyl group or aryl group which may have a group, and R3 and R' may form a heterocyclic ring together with the adjacent nitrogen atom, or an activated derivative thereof. A method for producing a spiroisoxazoline compound represented by the general formula r, wherein u1, R2, u3 and R' have the above-mentioned meanings. (3) General formula r In the formula, R1 and R2 represent a hydrogen atom or a lower alkoxy group, R3 and R' represent a hydrogen atom or a lower alkyl group, an aralkyl group, or an aryl group which may have a substituent, and In the general formula r, R'L, R2 is characterized by ring-closing an amidoxime derivative represented by R3 and R' may form a heterocyclic ring together with the adjacent nitrogen atom under oxidative conditions. , R3 and R4 have the above-mentioned meanings].