JPS6229557A - Dilower alkylphenol derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is phenyl having 1-3 substituent groups selected from halogen, carboxyl, OH, amino, lower alkylthio and phenylthio, etc.; R<2> and R<3> are lower alkyl). EXAMPLE:4-(4-Fluorophenylamno)-2,6-di-tert-butylphenol. USE:Useful as an anti-inflammatory agent antirheumatic agent, antiallergic agent, analgesic agent, diuretic agent, antithrombotic agent, hypotensive agent, antihyperlipemic agent, etc., and exhibiting blocking action and regulating action on biosynthesis of prostaglandin and hypolipemic action, etc. PREPARATION:A benzoquinone derivative expressed by formula II is condensed with an aniline derivative expressed by the formula R<1>NH2 in the presence of a catalyst, e.g. BF3.Et2O, at 30-200 deg.C to give a compound expressed by formula III, which is then reduced with an aqueous solution of a hydrosulfite added thereto to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel di-lower alkylphenol derivatives and salts thereof.

Background of the Invention The di-lower alkylphenol derivative of the present invention is a novel compound that has not been described in any literature.

SUMMARY OF THE INVENTION The present invention aims to provide compounds useful as pharmaceuticals, as described below.

Means for Solving Problem 1 According to the present invention, a compound represented by the following general formula (1) is provided.

In formula C, R1 is a halogen atom, a carboxyl group, a hydroxyl group,
Amino group, cyanogen group, lower alkyl group, lower alkoxy group, hydroxy lower alkyl group, lower alkoxycarbonyl lower alkyl group, carboxy lower alkyl group, halogeno-substituted lower alkyl group, lower alkyl carbonyl group,
It represents a phenyl group having 1 to 3 substituents selected from a lower alkylthio group and a phenylthio group.

R2 and R3 are the same or different and each represents a lower alkyl group. ] In this specification, the term lower alkyl group has 1 carbon number
-6 straight or branched alkyl groups, specific examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, t-butyl, pentyl, and hexyl groups. etc. can be exemplified.

The term lower alkoxy group has 1 to 6 carbon atoms as above.
refers to a straight-chain or branched alkoxy group, examples of which include methoxy, ethoxy, propoxy, isopropoxy, 5eC-butoxy, t-butoxy, pentyloxy, hexyloxy, and the like.

Halogen atoms include fluorine, chlorine, bromine and iodine atoms.

As mentioned above, the term hydroxy lower alkyl group refers to a linear or branched hydroxyalkyl group having 1 to 6 carbon atoms, examples of which include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl. , 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-methylethyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl,
1-hydroxyhexyl, 2-hydroxyhexyl, 6
-Hydroxyhexyl group, etc. can be exemplified.

Examples of lower alkoxycarbonyl lower alkyl groups include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethylbonylmethyl, hexyloxycarbonylmethyl, 1-
Methoxycarbonylethylcarbonylethyl, 3-methoxycarbonylpropyl, 2
-methoxycarbonylbutylsicarbonylbutyl, 3-methoxycarbonylpentyl, 5-methoxycarbonylpentyl, 4-methoxycarbonylhexylbonylhexyl, 4-ethoxycarbonylbutyl, 3-
Examples include (1-butoxy)carbonylpropyl and 6-(1-propoxy)carbonylhexyl groups.

Examples of the term carboxy lower alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 2-carboxybutyl, 4-carboxybutyl, 3-carboxypentyl, Examples include 5-carboxypentyl and 3-carboxyhexylxyl groups.

Specific examples of the term halogeno-substituted lower alkyl group include:
For example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, iodomethyl, shortmethyl, triiodomethyl, 1-fluoroethyl, 2-fluoroethyl, 1, 2
-difluoroethyl, 2,2-difluoroethyl, 1,
2-dichloroethyl, 2.2-dichloroethyl, 2-chloro-2-fluoroethyl, 2-bromoethyl, 2.2
-dibromoethyl, 2.2.2-trifluoroethyl,
1,3-difluoropropyl, 3,3,3-trifluoroethyl, 3,3-dichloropropyl, 2,4-dibromobutyl, 4.

4,4-tribromobutyl, 4,4-difluorobutyl, 3.5-dichloropentyl, 5,5-difluoropentyl, 5.5.5-trifluoropentyl, 6.6-dibromohexyl, 6,6. Examples include a rottrifluorohexyl group.

Specific examples of the lower alkylcarbonyl group include acetyl, ethylcarbonyl, 1-propylcarbonyl, 2-propylcarbonyl 1-butylcarbonyl,
Examples include 2-butylcarbonyl, t-butylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, and 3-hexylcarbonyl.

Specific examples of the term lower alkylthio include methylthio, ethylthio, 1-propylthio, 2-propylthio, 1-butylthio, 2-butylthio, [-butylthio, 1-pentylthio, 2-pentylthio, 3-pentylthio, 1- hexylthio, 2-hexylthio, 3-
Examples include hexylthio group.

Furthermore, as specific examples of the phenyl group having 1 to 3 of the above groups as substituents, the following groups can be exemplified.

2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-
Bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2.
4-difluorophenyl, 2,4-dichlorophenyl,
2.4.

Lotrifluorophenyl, 2.4.6-Trichlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2.

4-dihydroxyphenyl, 2.4.6-trihydroxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-nitrifluoromethylphenyl, 3.5-di(trifluoromethylphenylcarboxymethylphenyl) Dimethylphenyl, 2-ethoxycarbonylmethylphenyl, 3-ethoxycarbonylmethylphenyl, 4-ethoxycarbonylmethylphenyl, 2,4-jethoxycarbonylmethylphenyl, 2,4.6-driethoxycarbonylmethylphenyl, 4 -methoxyphenyl, 2.4-dimethoxyphenyl, 2.4.6-trimethoxyphenyl, 3, 4.5
-trimethoxyphenyl, 2-ethoxyphenyl, 4-
Ethoxyphenyl, 2,4-jethoxyphenyl, 2,
4.6-)-jethoxyphenyl, 2-carboxymethylphenylruboxymethylphenyl, 4-carboxymethylphenyl, 2,4-dicarboxymethylphenyl,
2, 4.6-t-dicarboxymethylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2.4-diacetylphenyl, 2- (1-
Carboxyethyl)phenyl, 3-(1-carboxyethyl)phenyl, 4-(1-carboxyethyl)phenyl, 2.4-di(1-carboxyethyl)phenyl, 2
-(2-carboxyethyl)phenyl, 3-(2-carboxyethyl)phenyl, 4-(2-carboxyethyl)phenyl, 2,4-di(2-carboxyethyl)phenyl, 2-methylthiophenyl, 3-methylthio Phenyl, 4-methylthiophenyl, 2.4-dimethylthiophenyl, 2,4.6-trimethylthiophenyl, 3.
4.5-trimethylthiophenyl, 2-7minophenyl, 3-aminophenyl, 4-aminophenyl, 2.4-
Diaminophenyl, 2,4,6-triaminophenyl,
2-phenylthiophenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 2-(1-pentylthio)phenyl, 3-(1-pentylthio)phenyl,
4-(1-pentylthio)phenyl, 2.

4-di(1-pentylthio)phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2
．． 4-dimethylphenyl, 2.4.

6-trimethylphenyl, 2-(1-butyl)phenyl, 3-(1-butyl)phenyl, 4-(1-butyl)
Phenyl, 2.4-di(1-butyl)phenyl, 2.4
．． 6-tri(1-butyl)phenyl, 3-chloro-2
-Hydroxyphenyl, 4-chloro-2-hydroxyphenyl, 5-chloro-2-hydroxyphenyl, 6-chloro-2-hydroxyphenyl, 4-chloro-3-hydroxyphenyl, 5-chloro-3-hydroxyphenyl, 2- (3-carboxypropyl)phenyl, 3-(3
-carboxypropyl)phenyl, 4-(3-carboxypropyldi(3-carboxypropyl)phenyl, 2-humanOxy4-carboxymethylphenylhydroxy-5-carboxymethylphenyl-hydroxy-6-carboxymethylphenyl, 3- Hydroxy-5-carboxymethylphenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3.5-dicarboxyphenyl, 2-chloro-6-carboxyphenyl,
4-chloro-6-carboxyphenyl, 2-chloro-o-4
-carboxyphenyl, 3-chloro-5-carboxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4
-cyanophenyl, 3.

5-dicyanophenyl, 2,4.6-tricyanophenyl, 4-methyl-2-carboxyphenyl, 6-methyl-2-carboxyphenyl, 2-methyl-4-carboxyphenylcarpoxyphenyl, 4-hydroxy-3 -carboxyphenyl, 4-hydroxy-2-carboxyphenyl,
6-hydroxy-2-carboxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl,
4-hydroxymethylphenyl, 2.6-di(hydroxymethyl)phenyl, 2,4.6-tri(hydroxymethyl)phenyl, 2-(2-hydroxyethyl)phenyl, 3-(2-hydroxyethyl)phenyl, 4 −(2
-hydroxyethyl)phenyl, 3.5-di(2-hydroxyethyl)phenyl, 2-(1-hydroxyethyl)phenyl, 3-(1-hydroxyethyl)phenyl,
4-(1-hydroxyethyl)phenyl, 2,4-di(
1-hydroxyethyl)phenyl, 2.4.6-t-li(1-hydroxyethyl)phenyl, 2-(3-hydroxypropyl)phenyl, 3-(3-hydroxypropyl)phenyl, 4-(3-hydroxy propyl)phenyl, 3,5-di(3-hydroxypropyl)phenyl, 2,4-di(3-hydroxypropyl)phenyl,
2-(4-hydroxybutyl)phenyl, 3-(4-
hydroxybutyl)phenyl, 4-(4-hydroxybutyl)phenyl, 2,4-di(4-hydroxybutyl)
Phenyl, 2-(1-hydroxyisopropyl)phenyl, 3-(1-hydroxyisopropyl)phenyl, 4
- (1-HydoOxyisopropyl)phenyl, 2.6
-di(1-hydroxyisopropyl)phenyl, 2-chloro-6-hydroxymethylphenyl, 3-chloro-6
-Hydroxymethylphenyl, 4-chloro-6- and droxymethylphenyl, 2-chloro-4-hydroxymethylphenyl, 2-chloro-5-hydroxymethylphenyl, 2-hydroxy-4-(2-hydroxyethyl)phenyl , 2-hydroxy-5-(2-hydroxyethyl)phenyl, 2-hydroxy-6-(2-hydroxyethyl)phenyl, 3-hydroxy-5-(2-hydroxyethyl)phenyl, 6-methyl-2-( hydroxymethyl)phenyl, 5-methyl-2-(hydroxymethyl)phenyl, 4-methyl-2-(hydroxymethyl)phenyl, 2-methyl-4-(hydroxymethyl)phenyl, and the like.

The compound represented by the above general formula (1) of the present invention and its salt have an effect of blocking or regulating prostaglandin biosynthesis and a hypolipidemic effect, and have anti-inflammatory and anti-inflammatory effects on animals, especially mammals. Shows rheumatism, antiallergy, analgesia, diuresis, platelet aggregation inhibition, blood pressure lowering, and antihyperlipidemic effects. Therefore, it is useful as a medicine such as an anti-inflammatory agent, an anti-rheumatic agent, an anti-allergy agent, an analgesic, a diuretic, an antithrombotic agent, an antihypertensive agent, and an antihyperlipidemic agent.

The compounds of the present invention can be produced, for example, by the methods shown in the following reaction schemes.

<Reaction scheme-1> (In the formula, R1, R2, and R3 are the same as above.) According to reaction process-1, the condensation reaction between the benzoquinone derivative (2) and the aniline derivative (3) and the subsequent Compound (1) of the present invention can be obtained by reduction operation.

The above condensation reaction can be carried out using known methods such as Riker et al.
Tetrahedron by Reker et al., Volume 23, 3723
(1967) and Fuiguelas et al.
, F igueras et al) in the Journal of Organic Chemistry (J, Org.
.

Chew, ), 36.3497 (1971). More specifically, the above condensation reaction is carried out using acetic acid, BF3 ・Et20, etc. as a catalyst to form a compound (
Compound (3) is used in an amount of 1 to 5 times the molar amount of 2), and either no solvent or an appropriate solvent such as tetrahydrofuran (THF), ether, dioxane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, etc. It is carried out in a temperature range of about 30 to 200°C.

Compound (4) obtained as described above can be subjected to the subsequent reduction reaction without being isolated from the reaction system, but may of course be isolated.

The reduction reaction can be carried out according to a conventional method, for example, by transferring the above reaction product into water and adding an aqueous solution of hydrosulfide (Na 2320t ) in a 2 to 50-fold molar amount. Depending on the type of substituent of the R1 group of compound (4), the above reduction reaction can be carried out, for example, by using zinc powder in acetic acid, or by using palladium-carbon film in a solvent such as ethyl acetate, alcohol, THF, or water. It can also be carried out by a method of catalytic hydrogenation using P t O2 as a catalyst.

Furthermore, in the compound (1) of the present invention, R1 is a phenyl group having a hydroxy lower alkyl group, and R1 obtained according to the above method is a phenyl group having a carboxy lower alkyl group or a phenyl group having a lower alkoxycarbonyl lower alkyl group. A certain compound (1) is reduced with about 1 to 7 times the molar amount of LiAIHz in a suitable solvent such as ether or THF, or a compound (1) in which R1 is a phenyl group having a lower alkylcarbonyl group is reduced.
) in a suitable solvent such as a mixed solvent of methanol, ethanol, isopropanol, etc. with THF, dioxane, etc., with about 1.5 to 5 times the molar amount of NaBHz. be able to.

The compound (1) of the present invention obtained by each of the above reactions can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc.

Furthermore, the compound (1) of the present invention can be made into a pharmaceutically acceptable acid addition salt by subjecting it to an addition reaction with a suitable dispersible compound, and the present invention also includes such acid addition salts. . Examples of acidic compounds that can form the above-mentioned acid addition salts include salting, sulfuric acid, phosphoric acid, anhydrous and oxalic acids such as hydrogen bromide, maleic acid, fumaric acid, malic acid, tartaric acid, and citric acid. , and isoacids such as benzoic acid. Furthermore, among the compounds of the present invention, those having a free carboxyl group may be treated with alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and other copper salts. These also have the same pharmacological activity as the free form of the compound of the present invention and are included within the scope of the present invention.

EXAMPLES Examples will be given below to explain the present invention in more detail.

Example 1 4-(4-fluorophenylamino)-2°6-di℃
-Production of butylphenol 2.6-di[-butyl-1,4-benzoquinone 2.2
3.3 g of g and p-fluoroaniline were added to THF60-
0.3 mQ of BF3.Et20 was added thereto and the mixture was rapidly flowed for 6 hours. After 6 hours, add 5° of water, then add Na
2820420g17) A 150ml solution of water was added at room temperature, and stirring was continued for about 15 minutes until the red color of the reaction mixture disappeared. Thereafter, it was transferred to water, extracted with ethyl ether, and the organic layer was washed with saturated brine, dried with fVNlsOt, and concentrated. After purification, 2 g of the target compound was obtained.

The physical properties of the obtained compound are shown in Table 1 as N051.

Examples 2-23 Compounds N002- shown in Table 1 were prepared in the same manner as in Example 1.
11 were manufactured.

In addition, the free bases of Compounds No. 12 to 23 were prepared in the same manner, and 4N hydrochloric acid/ethyl acetate was added to each of them to obtain each of the target compounds in the form of hydrochloride.

Table 1 shows the physical properties of each compound obtained.

Example 24 Preparation of 4-(3-carboxyphenylamino 6-di-t-butylphenol) 2,6-di-t-butyl-1,4-benzoquinone 6,6
g, 1-7 Minobenzo Shun 4.2g and Vinegar I! 6 drops, 2
After heating and stirring for an hour, the reaction mixture was allowed to cool, and then 50 whales were added to the reaction mixture, followed by 200 m of THF, and further Na
2 S2 0h Add 300 ml of 50 CI in water at room temperature and stir for about 15 minutes until the red color fades, then
Transferred to water, extracted with ethyl acetate, treated the organic layer as in run VA1, column chromatography <CH2C
Q2:THF-5:1) to obtain the target compound 6.70.

The physical properties of the obtained compounds are shown in Table 1. Compound No.

24.

Examples 25-30 Compound No. 1 is shown in Table 1 in the same manner as in Example 24.

Compounds designated as 25 to 29 were obtained.

Similarly, compound No. The free base of 30 was prepared and 4N hydrochloric acid/ethyl acetate was added to it to obtain the desired compound in the form of the hydrochloride salt.

Example 31 4-(3-hydroxymethylphenylamino)-2.6
-Production of di-t-butylphenol hydrochloride 1.8 g of 4-(3-carboxyphenylamino)-2.6-di-t-butylphenol obtained in Example 24 was dissolved in 30-THF, and the solution was Li AQHt
It was added dropwise into a 1.7Q suspension of ethyl ether 150 at room temperature under stirring, and the reaction mixture was then refluxed for 3.5 hours. After 6, excess LiAQH↓ was carefully decomposed using aqueous ethyl ether and then water, and the organic layer was separated.
The crude product obtained by drying with MQSOh and S condensation was dissolved again in 100 mA of ethyl ether, and to this was added 1 m of 4N salt/ethyl acetate solution, and the precipitated crystals were separated and washed with ethyl ether. , air-dried, target compound 1
．． 5g was obtained.

The physical properties of the compound were determined using Compound No. 31 in Table 1.

Examples 32-40 Compound N shown in Table 1 was prepared by the same operation as in Example 31.
o. 32-40 were obtained.

Example 41 Production of 4-(3-α-methylhydroxymethylphenylamino)-2.6-di-t-butylphenol hydrochloride 4-(3-acetylphenylamino)-2.6 obtained in Example 10 -di-t-butylphenol (compound N0
．． 10) 1 was dissolved in ethanol 17 and TI-IF12, and Na BH4 20011 was added to this while stirring with water cooling.
;1 was added slowly and the reaction mixture was stirred for 1 hour. The reaction mixture was transferred to water, extracted with ethyl ether,
The organic layer was diluted with 10% Na2 until the yellow-red color of the layer faded.
Wash with S20 & aqueous solution, then wash with saturated saline, M
After drying with gsot and concentrating to about 100 tl, 4
6 mg of N-hydrochloric acid/ethyl acetate solution was added, and the precipitated crystals were separated, washed with ethyl ether, and air-dried to obtain 1 g of the target compound.

The physical properties of the compounds are shown in Table 1 below. 41.

No. 1 Table t-3u (above) Procedural amendment (ffl system September 1985! 1, 1985 Patent Application No. 168175 2, Invention (D name: di-lower alkylphenol derivative 3, amendment) Relationship with the patent applicant case
,,,,,/ 4. Agent: 10 Sawa no Tsuru Building, 2 Hirano-cho, Higashi-ku, Osaka Phone: 06-203
-0941 (Representative) 7, M. (7) v. I, ``Invention. Details, details, subsections. Section 8, Contents of amendment (1) Item 1 stated on page 32 of the specification. Compound M360 in the table
The description in section R1 is corrected as follows.

[ (CI2)2 H Cjl1m#1”) Yo (that's all) A1n-

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is a halogen atom, carboxyl group, hydroxyl group, amino group, cyano group, lower alkyl group, lower alkoxy group, hydroxy lower alkyl group, A phenyl group having 1 to 3 substituents selected from an alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, a halogeno-substituted lower alkyl group, a lower alkylcarbonyl group, a lower alkylthio group, and a phenylthio group. R^2 and R^3 are each the same or different and represent a lower alkyl group. ] A di-lower alkylphenol derivative represented by these and its salt.