JPS60116657A - Aniline derivative, its production, and remedy containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 2-15C alkyl, alkynyloxy, benzyl or phenyl; R<2> is H or methyl; R<3> is carboxy, carboxymethyl, 2-6C alkoxycarbonyl, etc.; n is 0-2; the combination of the solid line and the dotted line is double bond or single bond). EXAMPLE:N-[p-(2-octinyloxy)cinnamoyl]anthranylic acid methyl ester. USE:A leucotriene antagonistic agent. A phospholipase inhibitor. A 5alpha-reductase inhibitor. Useful for the remedy of various allergic diseases, prostamegaly, alopecia, thrombosis, inflammation, etc. PREPARATION:The compound of formula I can be produced by reacting the acid chloride of formula II with the amine of formula III in an inert organic solvent in the presence of a tertiary amine at -20-+40 deg.C, and if necessary, saponifying or esterifying the product.

Description

[Detailed description of the invention] The present invention relates to novel aniline derivatives.

More specifically, the present invention relates to novel aniline derivatives having leukotriene antagonistic activity, phospholipase inhibitory activity, and 5α-reductase inhibitory activity, methods for producing the same, and pharmaceuticals containing these as active ingredients.

Prostaglandin (Prostaglandin,
Hereinafter, it will be abbreviated as PG. ) Several important discoveries have been made one after another in the last few years in the field of research. Therefore, there have been major changes in the flow of PC research and development in recent years. Newly discovered or newly determined PC
Among the family members, PGzyp peroxide (PG e
ncloperoxides (i.e. PGG2 and PGI2), Thromboxane A2 (Thromboxa
ne A2, hereinafter abbreviated as TXA2. ), Prostacyclin (PG)
I2) and leukotrienes C, D and E (hereinafter abbreviated as LTC, LTD and I, TE, respectively).
etc. In addition to these compounds, the PC family, which includes various PGs, which have already been well known, are biosynthesized in living organisms using arachidonic acid as a common parent, and therefore the metabolism starts from arachidonic acid. The entire pathway consists of the arachidonic acid cascade t' (Arachidonic acid
onate cascade). For detailed explanations of each route and the pharmacological properties of each product, see Medical History, 114°378 (1980), 114.
, 462 (1980), ibid.

114.866 (1980), R114,929 (19
80), Modern Medicine, 12,909 (1980), 1
2,1029 (1980), 12.1065 (19
80) and 12°1105 (1980).

In the arachidonic acid cascade, cyclooxygenase acts on arachidonic acid to pass through PGG2 and then PC)12 to various PGs, such as prostaglandin F2a (hereinafter referred to as P
It is abbreviated as GF2a. ), prostaglandin E2 (
Hereinafter, it will be abbreviated as PGE2. ), PGI2. Lipoxygenase acts on the pathway leading to TXA2 etc. and arachito9anoic acid to produce hydroperoxy-eicosate.
traenoic acid (hereinafter) IPg'l'E
It is abbreviated as @) and then hydroxyeicosat' (hydroxyeicosat).
etraenoic 8cid.

Hereinafter, it will be abbreviated as HETE. ) or the route leading to leukotrienes.

Since the former route is already well known, we will not discuss it in detail here. For details, see Nobu Katori et al., eds., Prostaglandins (1978).

Please refer to the publication by Kodansha.

Regarding the latter route, it is known that various compounds are produced by the route shown in Scheme I.

Arachidonic acid is metabolized by a known pathway, i.e. via PC enzyme oxide.
It is metabolized by lipoxygenase through a completely different route. That is, lipoxygenase such as 5-lipoxygenase, 12-lipoxygenase or 15-lipoxygenase acts on arachidonic acid to produce 5-lipoxygenase, respectively.
-HPETE, 12-HPETE or 15-HPE
TE is generated.

These 1-[PETEs are converted into 5-HETEs, 12-[PETEs] by converting hydrogen peroxide groups into hydroxyl groups by peroxidase
-HETE or 15-HETH.

Further, among these HPETEs, 5-HPETE is converted to LTA4 by being dehydrated.

Furthermore, LTA 4 is enzymatically converted into leukotriene B4 (hereinafter abbreviated as LTB4) and glutathione-8.
- Converted to LTC4 by a transferase.

LTC4 is then converted to LTD4 by γ-glutamyl transpeptidase. LTD4 is further L
Recently, it has become profitable to be metabolized to TE4 (B
'iochem-Biophys-Re5- Comm
un, ,dan.

1266 (1979) and Prostaglandin
s, 19(5) 645 (1980)).

On the other hand, speaking about SR8, what is SR8?
It is an abbreviation for Reacting 5 ubstance, and this name was used by Feldberg et al. for the substance liberated when cobra venom is perfused into the lungs or when cobra venom is incubated with egg yolk, and this substance slowly contracts the isolated guinea pig ileum. , its action is reported to be long-lasting [J, Phys io.

94.187 (1938)].

Furthermore, KellaWay et al. sensitized 5R8-A (Slow Rea
ctingSubstance of Anaplyl
5R8-A axis), and demonstrated for the first time a relationship between 5R8-A and allergic reactions (Quant, J.
, Exp, Physiol,, 30.121 (
1940)]. In addition, BrocklehurQt produces histamine and 8R8 when the antigen is applied to surgically removed lung sections of bronchial asthma patients for whom the specific antigen is known.
-A is released and strongly contracts the bronchial muscles, and this contraction is not relieved by antihistamines, so 5FtS-A is an important bronchial constrictor during asthma attacks.
oconst, rictor) [Progr, Allergy, 6.539 (
(1962)].

Subsequently, 5R8-A obtained from human lung tissue fragments caused bronchial ring contraction in normal humans [: Int, Arch
.

Allergy Appl, Immunol, 3
8.217 (1970)], rat 5R8-A
When administered intravenously to guinea pigs, an increase in pulmonary airway resistance was observed [J, C11n-Invest, 53*167
9 (1974)]; intravenous injection of 5R8-A in guinea pigs, rats, and monkeys restores vascular permeability (Advances in Immunology,
10.105 (1969), J. Allergy C.
11n.

Immunol, 621.371 (197B), P
rostaglandins.

19 (5), 779 (1980), etc.].

As mentioned above, SR8 uses 5R8-A, calcium ionophore (calci), which is released due to the involvement of immune reactions.
There are two types of SR8 that are released without immune reactions such as treatment (e.g. um 1onophore), but there are many similarities between the two, and it is thought that there is a strong possibility that they are the same substance. ing.

Furthermore, it has become clear that LTC and LTD 4 are the same substances as 5FtS or 5R8-A, and therefore the pharmacological properties of these leukotrienes are similar to those of SR8,
Alternatively, it can be considered in place of the pharmacological properties of 5R3-A [Proc, Natl, Acad,
Sci.

USA, 76.4275 (1979), Biochem
, Biophys.

Res-Gommun, 91.1'266 (197
9), Proc-Na, tl.

Acad-Sci, USA, YuL2014 (1980
), Nature.

285.104 (1980)].

Based on the results of many such studies, various leukotrienes (LTC4, LTD4, LTE4, and leukotrienes whose structures may be determined in the future) are currently biosynthesized from arachidonic acid via LTA4.
are allergic tracheal and bronchial or pulmonary diseases;
It is considered to be an important factor involved in the development of allergic shock or various types of allergic inflammation.

Therefore, by suppressing these leukotrienes, it is possible to prevent and/or treat allergic tracheal and bronchial diseases such as asthma, allergic shock, and various allergic diseases in mammals including humans, especially humans. It is valid.

In addition, arachidonic acid is a phospholipase (phospholipase).
It is released from phospholipids by the action of
That is, (11 phosphatidyl choline (phosph
atidyl chlorine) and phospholipase A
(2) Phospholipase C acts on phosphatidyl inositol and 1,2-diglyceride (1,2-diglyceride)
1,2-digly-ceride) is produced, and this is further followed by trap diglyceride, e-ze (diglyceride).
It is generally thought that the release route is through the action of monoglyceride lipase) and then monoglyceride lipase (see Chemistry and Biology 154 (1983)).

The liberated arachidonic acid can be further processed through two routes namely (11 cyclooxygen-4).
ase: Prostaglandin (PG) by metabolic pathway
or (2) lipoxygenase (LI).
poxygenase) metabolic pathway, 5R8-A
(SlowReact, ing 5 ubstances
of anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotrixyB4
(Leukotriene B4) [Chemistry and Biology 21.1]
54 (1983)].

These metabolites include, for example, TxA2, which is a substance with strong blood thinning & aggregation and vasoconstriction effects; 5) (S-
A is a chemical mediator of asthma.
LTB4 is a chemical mediator of inflammation such as gout, and PC is a chemical mediator that has vasodilation, pain-causing, fever, and leukocyte migration effects in inflammation. is known [Metabolism 20, 317 (1983
), The Lancet 1122 (1982), Prostaglandins (1978) edited by Shin Katori et al., Kodansha].

In this way, arachidonic acid is converted and metabolized in vivo into chemical mediators that play physiologically important roles, but an imbalance in these mediators causes a number of diseases.

The present inventors conducted extensive research to find compounds that antagonize leukotrienes or inhibit phospholipases (phospholipase A2 and/or phospholipase C), and as a result, the aniline derivative represented by the general formula (1) below was found. The inventors have discovered that the object can be achieved and have completed the present invention.

The compound of the present invention strongly inhibits phospholipase and suppresses the release of arachidonic acid from phospholipids, so it can prevent diseases caused by arachidonic acid metabolites such as TXA2, PG, and leukotrienes in mammals including humans, especially humans. Effective for prevention and/or treatment.

Examples of target diseases include the aforementioned various allergic diseases caused by leukotrienes and thrombosis, such as thrombosis caused by damage to the endothelium and intima of the brain and coronary arteries, and inflammation, such as arthritis and rheumatism. [See Circulation Science 3,484 (1983) ν and Pharmacy 34,167 (1983)].

Furthermore, in addition to the above-mentioned uses of the compound of the present invention as a leukotriene antagonist and phospholipase inhibitor, the following 5α-reductase inhibitory action has also been found.

5α-reductase exists in the endoplasmic reticulum and nucleic acids, and has the effect of converting testosterone ingested into target tissues into the active form of 5α-dihydrotestosterone. It is said that binding with the drug causes cell proliferation, and when this action progresses, it causes the onset of benign prostatic hyperplasia, alopecia, or sitting ulcers.

For example, in the case of benign prostatic hyperplasia, conventionally, as drug therapy, estrogen agents, which are female hormones, and gestagen agents, which have anti-androgen effects, have been used. However, in both cases, the original hormonal effects remained as side effects, so it was difficult to say that the treatments were adequate.

Of course, the compound of the present invention has hormone-specific effects, and moreover, it strongly inhibits 5α-reductase, suppresses the increase in 5α-dihydrotestosterone, and suppresses cell proliferation. It can effectively prevent and/or treat benign prostatic hyperplasia, alopecia, and sitting ulcers.

The present invention is based on the general formula [wherein R represents (1) a linear or branched alkynyl group or an alkynyloxy group having 2 to 15 carbon atoms;
(1) Represents a benzyl group or phenyl group, R represents a hydrogen atom or a methyl group, R represents a carboxy group, a carboxymethyl group, a carboxymethoxy group, carbon number 2-6
straight or branched alkoxycarbonyl group, R element J
[-7 represents a straight-chain or branched alkoxycarbonylmethyl group, or a straight-chain or branched alkoxycarbonylmethoxy group having 3-7 carbon atoms, ru represents O5l or 2, and the symbol == Double bond (E.

1 or EZ mixture) or a single bond. The present invention relates to aniline derivatives represented by the above, non-toxic salts thereof, or non-toxic acid addition salts thereof, methods for producing them, and pharmaceuticals containing them as active ingredients.

In the general formula (1), the alkynyl group in the linear or branched alkynyl group having 2 to 15 carbon atoms or the alkynyloxy group represented by R is an ethynyl group, a propynyl group, a futhynyl group, a hancynyl group, a hexynyl group. , hexynyl group, octenyl group, phenyl group, decynyl group, randecynyl group, rdecynyl group, tridecynyl group, tetradecynyl group, ntadecynyl group, and isomers thereof, and preferable groups include propynyl group, hantynyl group, Mention may be made of hexynyl, octenyl and corresponding alkynyloxy groups.

In general formula (1), an alkoxy group in a straight chain or branched chain alkoxycarbonyl group having 2 to 6 carbon atoms and a straight chain or branched chain alkoxycarbonylmethyl group having 3 to 7 carbon atoms or alkoxy Examples of the alkoxy group in the carbonylmethoxy group include methoxy group, ethoxy group, propyloxy group, butoxy group, pentyloxy group and isomers thereof, and preferred are methoxy group and ethoxy group. Preferred groups as R include a carboxy group, a carboxymethyl group, a carboxymethoxy group, a methoxycarbonyl group, a methoxycarbonylmethyl group, a methoxycarbonylmethoxy group, an ethoxycarbonyl group, an ethoxycarbonylmethyl group, and an ethoxycarbonylmethoxy group.

The compound of the present invention represented by the general formula (1) is considered to have isomers, and when the symbol = in % represents a double bond, the symbol = may be a simple When R represents a bond and R represents a methyl group, the carbon atom to which the methyl group is bonded is an asymmetric carbon and isomers exist.

Further, when a branched chain exists in the alkyl or alkylene moiety in each substituent in general formula (1), further isomers may occur. The present invention also provides gold coloring of all these isomers and mixtures thereof.

Several patent applications containing compounds with structures similar to the compounds of the present invention have been filed, such as JP-A-49-93335, JP-A-50-135047, and JP-A-57-106651.
The number is mentioned.

However, in these applications, the substituent corresponding to R in the general formula (]) of the compound of the present invention is an alkyl group or an alkoxy group, and these applications relate to a chemically different group of compounds.

Furthermore, the above specification does not mention any use as a phospholipase inhibitor or a 5α-reductase inhibitor, and the present application is completely new in these fields.

According to the present invention, the aniline derivative represented by the general formula (1) is obtained by the general formula (wherein all symbols have the same meanings as above). It can be produced by reacting and distorting the acid chloride r represented by the following formula with an amine represented by the general formula [wherein all symbols have the same meanings as above].

This reaction is a well-known reaction, for example, an inert organic solvent (
For example, the reaction is carried out in methylene chloride, chloroform, tetrahydrofuran) in the presence of a tertiary amine (eg triethylamine, pyridine) at a temperature of -20°C to 40°C. It is preferably carried out in methylene chloride in the presence of triethylamine at 0°C to room temperature.

The compound represented by the general formula (III) is a known compound, and for example, a compound in which R is a 2-carboxy group is commercially available as anthranilic acid.

The compound represented by the general formula (n) is represented by the general formula 1 [wherein all symbols have the same meanings as above]. ] It is produced by converting the carboxylic acid represented by the formula into an acid chloride.

The reaction of converting a carboxylic acid to an acid chloride is well known and involves converting chlorides such as thionyl chloride, oxalyl chloride, and ethyl chloroformate in an inert organic solvent (e.g., methylene chloride, tetrahydrofuran) or without a solvent. It is carried out at a temperature of -40°C to 30°C.

Preferably, oxalyl chloride is used without solvent, or
The reaction is carried out using ethyl chloroformate in methylene chloride at θ°C to room temperature.

The conversion of the compound represented by the general formula (IV) to the compound represented by the general formula (11) and the reaction of the compound represented by the general formula (■) and the compound represented by the general formula (II) must be carried out at the same time. You can also do it.

The compound represented by general formula (IV) is known per se or can be produced by a known method,
Examples of this are shown in the following diagrams (■) and (■).

The meanings of the symbols in Scheme 1... and ■ are as follows, and the other symbols have the same meanings as above.

R - Straight chain or branched alkynyloxy group having 2 to 15 carbon atoms.

Rlb-hensyl group or phenyl group.

R - Straight chain or branched alkynyl group having 2 to 15 carbon atoms.

R4-single bond or straight or branched alkylene group having 1-13 carbon atoms;

THP-tetrahydropyran-2-yl group.

m −1 or 2° The reactions in the schemes The reaction is carried out using the corresponding Wit and Tig reagents in a solvent (ethyl ether, tetrahydrofuran, chloroform, benzene, etc.) at -78°C to room temperature.

Using this reaction, products of m w l or 2 are obtained.

Steps (h), (A) and (W) are reduction reactions, such as catalytic reduction reactions. This reaction is carried out, for example, under a hydrogen atmosphere in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) in the presence of a catalyst (palladium-carbon, palladium, platinum black, nickel, etc.).
It is carried out at a temperature of 0°C.

Step (C1, (-1 and (yl+t), is an alkynylation reaction, for example, in an inert organic solvent (tetrahydrofuran, ethyl ether) using sodium hydride as a base, optionally in the presence of dimethylformamyl, anhydrous 03-8 using the corresponding alkynyl halide under the conditions
The reaction is carried out at a temperature of 0°C.

Process (dl, (a), (Al, 0°), (ll, (vl)
,(A):M,1:Hi(G)k'! , is a saponification reaction in which an alkaline substance (
It is carried out using an aqueous solution of potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.) at a temperature of 0°C to 80°C.

The steps (rIL) and () are oxidation reactions, which are carried out at a temperature of -20°C to 40°C by, for example, Jones oxidation, Collins oxidation, and Swann oxidation, although some are known.

Steps (rL), (0) and times are Perkin reactions or Depner reactions, which are carried out, for example, in the presence of piperidine, using pyridine as a solvent, using malonic acid or an ester of malonic acid, at 100° C. to reflux temperature.

When this reaction is used, the products are m, l, and R2 is a hydrogen atom.

Step (P) is a THP reaction, for example, an inert organic solvent < methylene chloride, chloroform, ethyl ether,
(tetrahydrofuran, etc.), condensing agent (p-toluenesulfonic acid, its salt, (ilE acid, )!J fluoroacetic acid, etc.)
-30 using 2.3-:) hydropyran in the presence of
It is carried out at between °C and room temperature.

Step (q) is an oxidation reaction, for example, using an inert organic solvent (
The reaction is carried out using oxalyl chloride in the presence of a tertiary amine (triethylamine, pyridine, etc.) in methylene chloride, dimethoxysulfoxide, etc. at a temperature of 0° C. to 40° C.

Steps <s), (-) and (Di are THP removal reactions, for example, organic acids (acetic acid, P-toluenesulfone) in water-miscible organic solvents (methanol, ethanol, tetrahydrofuran, dioxane, etc.) acids, trifluoroacetic acid, oxalic acid, etc.) or inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, etc.)
The process is carried out at temperatures between 0'C and 90C.

Steps (t), (y) and @) are metalation, tosylation or halogenation reactions, for example in an inert organic solvent (
The reaction was carried out using mesyl chloride, p-toluenesulfonyl chloride 9, thionyl chloride 9, etc. at a temperature of -40°C to 50°C in the presence of a tertiary amine (triethylamine, pyridine, etc.) in methylene chloride, tetrahydrofuran, etc. It will be done.

Step (tL), (4 and 0 is a reaction for introducing an alkynyl group, for example, in an inert organic solvent (ethyl ether, tetrahydrofuran, etc.), in the presence of a promoter (hexamethylphosphatamine, etc.), rubyl lithium and the corresponding alkynes at 8°C to room temperature.

Process s<a> is an esterification reaction, for example, meta/-
The reaction is carried out in the presence of an acid (hydrochloric acid, p-)luenesulfonic acid, etc. at a temperature of 0°C to 40°C. Of course, in addition to the above-mentioned methanol, an organic solvent that does not participate in the reaction (tetrahydrofuran, dichloromethane, tyrene, etc.) may be added. Further, hydrogen chloride gas may be used as the acid.

Each of the starting materials in formulas ■ and ■ and the compound represented by formula (Vl) are commercially available products or known compounds. It represents a carboxy group, a carboxymethyl group, or a carboxymethoxy group, and other symbols have the same meanings as above. ] The compound represented by the general formula [wherein R is a straight-chain or branched alkoxycarbonyl group having a carbon number of 2 to 6, or a straight-chain or branched alkoxycarbonylmethyl group having a carbon number of 3 to 7] group, or an alkoxycarbonylmethoxy group, and other symbols have the same meanings as above. ] It can also be obtained by subjecting it to a saponification reaction.

The saponification reaction is carried out, for example, using an aqueous solution of an alkaline substance (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in a water-miscible solvent (ethanol, methanol, tetrahydrofuran, etc.) at a temperature of 0 to 80°C. , preferably at room temperature.

Of course, the compound represented by the general formula (1α') can also be obtained by esterifying the compound represented by the general formula (Iα).

The esterification reaction is carried out, for example, in a corresponding alkanol in the presence of an acid (P-toluenesulfonic acid, hydrochloric acid, hydrogen chloride gas, etc.) at a temperature of θ°C to 80°C, preferably at room temperature. Of course, it is also possible to use a solvent such as dihydrofuran or methylene chloride, which does not participate in the reaction.

Furthermore, among the compounds shown in the general formula (formula), R represents a straight chain or branched alkoxycarbonylmethoxy group or carboxymethoxy group having 3 to 7 carbon atoms, and other symbols are as above. ] The compound represented by the general formula [In the formula, all symbols have the same meanings as above] is reacted with the corresponding alkoxycarbonyl bromide, and if necessary, the compound represented by It can be manufactured by

This reaction is a well-known reaction, and is carried out under anhydrous conditions in an organic solvent (
ethyl ether, tetrahydro7ran, methyl ethyl ketone, acetone, etc.) in the presence of a base (sodium hydride, potassium carbonate, etc.), and if necessary in the presence of sodium iodide or dimethylformamyl, at 40°C to reflux temperature. be called.

The reaction product can be purified by conventional purification means, such as distillation under normal or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization, etc. It can be further refined. Purification may be performed after each reaction or after the completion of several reactions.

As mentioned above, the compound of the present invention has leuco)liene antagonistic activity, phospholipase inhibitory activity, and 5α-reductase inhibitory activity, and for example, in laboratory experiments, it exhibited the following effects.

The antagonistic effect of the compound of the present invention on LTD4 was determined by the following experimental method.

The ileum (3 cm) removed from a male guinea pig weighing 300 to 400 I was heated at 37°C, Tyrode's solution, and oxygen (95%
%)-carbon dioxide (5%) mixed gas in a Magnus tube, and after stabilizing for about 30 minutes, LTD4 was
The concentration of the compound of the present invention was added at a concentration of El/ml, and the concentration of the compound of the present invention was varied in response to the shrinkage at this time, the shrinkage height was measured, and the engineering C5o value was calculated from this.

The inhibitory effect of the compounds of the present invention on phospholipase A2 was determined using a modified 5hakir method using L-β-[1 as a substrate.
-C]-Araki F Niru α-stearoyl-phos-7 atidylcholine was measured using phospholipase A2 obtained from guinea pig lung as the enzyme [: Anal, Bj, o
chem, 114.67 (1981)].

The inhibitory effect of the compounds of the present invention on 5α-reductase was determined using 5α-reductase obtained from rat prostate nuclear fraction, with reference to the method of J. Shimazaki et al. 5α-reductase activity was measured using 0.09 MHepes (pH 7,4), 0.22
M sucrose, 5 X 10 M NADPH 15 μM [4
-C] A reaction was carried out at 37° C. for 60 minutes using a mixture of testosterone, 5α-reductase and the compound of the present invention. Reaction stop beam/roloform-methanol (1/
2), and after centrifugation, spot the upper ↑ on a silica gel thin layer plate and add chloropform-methanol/I'
-Radioactive T of dihydrotestosterone produced by separation using acetic acid (99,2:0.6:0.2)
Measurement was performed using an LC scanner, and enzyme activity inhibition was calculated [Endocrinol.

Japan, 18, 179 (1971)].

Preferably, the salts and acid addition salts are non-toxic. Here, non-toxic salts and acid addition salts are relatively harmless to animal tissues, and when used in the amount necessary for treatment, the compound represented by general formula (1) has effective pharmacological properties. means a salt consisting of an anion or cation such that the anion or cation is not impaired by side effects caused by the anion or cation.

It is also preferred that the salts and acid addition salts are water-soluble.

Suitable salts include, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include, for example, amines that could theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups. The groups may be the same or different when one or more hydrogen atoms are substituted, but for example have 1 to 6 carbon atoms.
alkyl groups, and hydroxyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclomethylamine salts, benzylamine salts, phenethylamine salts, pyridine salts, monoethanolamine salts. Examples include organic amine salts such as salts, jetanolamine salts, lysine salts, and arginine salts.

Suitable acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoic acid. salt,
Examples include organic acid salts such as citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and isethionate.

The salt of the aniline derivative represented by the general formula (11) can be prepared by adding the acid represented by the general formula (1) to a suitable base, such as an alkali metal or alkaline earth metal hydroxide, in a suitable solvent using a known method. (. is obtained by reacting with carbonate or organic amine.

The acid addition salt of the aniline derivative represented by the general formula (1) is
The compound represented by the general formula (11) is prepared by a known method, for example, in a suitable solvent, with a suitable acid, such as an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, or It is obtained by reaction with organic acids such as acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid.

In mammals including humans, especially humans, suppressing leukotrienes can prevent allergic tracheal and bronchial diseases such as asthma, allergy a lung disease, allergic shock, and various allergic diseases. and/or therapeutically effective and may also contain phospholipases (phospholipase A2 and/or phospholipase C).
) can be used to prevent diseases caused by arachidone metabolites, including the above-mentioned leukotrienes, such as thrombosis due to damage to the endothelium and intima of the brain and coronary arteries, and various inflammations such as arthritis and rheumatism. /or therapeutically effective. Furthermore, inhibiting 5α-reductase is effective in preventing and/or treating benign prostatic hyperplasia, alopecia, and acne scars.

The aniline derivatives represented by the general formula (11) or their non-toxic salts or acid additions are used for the above purposes (as leukotriene antagonists, phospholipase inhibitors or 5α-reductase inhibitors). It is usually administered systemically or locally, orally or non-applied.The dosage is determined based on age, body weight, symptoms, therapeutic effect, method of administration,
It varies depending on the processing time, etc., but usually per adult, 1"& ~1g at a time, preferably 20 + 111
i'~200! ng, administered orally once to several times a day, or once to several times a day, per adult, in the range of 100 μg to ioom9, preferably 1 to 10 da, each at a time. Administered parenterally. Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases where it is sufficient to use an amount smaller than the above-mentioned dosage range, and there are also cases where it is necessary to administer the dosage beyond the range.

Solid compositions for oral administration according to the invention include tablets, powders, granules, etc. In such solid compositions, one or more active substances are present in at least one inert diluents such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate, in accordance with conventional methods. Tablets or pills may be coated with a film of enteric substances such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, etc., or may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , including ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline.

Examples of non-aqueous solutions and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysoleat 80, Arabia! and sodium alginate. Such compositions may further contain preservatives, humectants,
Auxiliary agents such as emulsifiers and dispersants may also be included. These can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation with disinfectants or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Other compositions for parenteral administration include topical solutions, liniments such as ointments, containing one or more active substances and formulated in a manner known per se, for rectal administration. Includes suppositories and 4-touch saris for intracavitary administration.

Among the compounds of the present invention represented by the general formula DJ, preferred compounds include N-(7)-(2-7'lopynyl)cinnamoyl]anthranilic acid, N-(p-phenylcinnamoyl)anthranilic acid, N-(p-phenylcinnamoyl)anthranilic acid,
-(p-indylincinnamoyl)anthranilic acid,
and the corresponding methyl esters, ethyl esters, non-toxic salts, and non-toxic acid addition salts of these acids.

Hereinafter, the present invention will be explained in detail with reference to reference examples and examples.
The present invention is not limited to these examples. Note that rbp], “TLOJ”, “rbp” in Reference Examples and Examples
The symbols IRJ, NM FtJ and 1 MSJ stand for boiling point, thin layer chromatography, infrared absorption, nuclear magnetic resonance, and mass spectrometry, respectively. The proportions of solvents listed in the separation section indicate volume ratios, and are referred to as "TLO
The solvent in parentheses of "J" indicates the developing solvent, and "IRJ is measured by the KBr tablet method unless otherwise specified."
J is deuterated chloroform CGDC4 unless otherwise specified.
3) Measure the ffl liquid chamber.

Reference example 1 ■-(2-tetrahydropyranyloxy)off)-2-
InTHPO△MeC5H□1 600 dah of liquid ammonia cooled with dry ice and 100 dah of ferric chloride nonahydrate were added, and then 1419 dah of metallic sodium was added over 1 hour. This solution Fc2-tetrahydropyranyl propargyl ether 70.9 was added to tetrahydrofuran at 100 mA! 20% of the solution dissolved in
To the reaction mixture, 751 l-bromopentane was added over 10 min and stirred for 20 min.
0m solution was added over 15 minutes. After dripping 4
The mixture was refluxed for an hour and then heated overnight to remove ammonia. Ether and water were added to the residue, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure,
Purification by vacuum distillation gave the title compound 671/ having the following physical properties.

hP: 120-123℃/2 mt HR; O
NMR: δ-4,60 (71!, IH), 3.98 (
t, 2H), 3.9-3.1 Cm, 2H), 2.
10 (m, 2H), 0.90 (m, 3H).

Reference example 1 (α) l-(2-tetrahyF-ranyloxy) bent-2-
In addition to l-bromopentane, 1-bromoethane 5Qm
A! Using the same procedure as in Reference Example 1, the title compound 45.9 having the following physical properties was obtained.

NMR: δ-4,58 (m, IH), 3.98 (t,
2H), 3.9-3.1 (7, , 2H), 2.1
1 (at 7, 2H), 0.88 (t, 3H).

Reference Example 2 Oct-2-yn-1-ol HO/″
F-) luenesulfonic acid 3.6 dissolved in WLl at room temperature
Ii was added and stirred for 7 hours. After adding 4.5 ml of triethylamine to this, the mixture was concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to obtain the title compound 411I having the following physical properties.

bp near 7-79°G/2 wing tHg.

TLC: Rf=0.21 (methylene chloride) ONMR:
δ-4,58 (dt, 2H), 2.16 (7+1.2H
), 1.77Ct, IH), 0.90(yx, 3H
).

Reference Example 2 (α) Venter 2-yn-1-ol HO″Sulfur′ Reference Example 1
Using 45 g of the compound produced in (α), the title compound 271 was obtained by the same procedure as in Reference-2! I got it.

Reference example 3 1-bromo-2-octyne Br~ size, H□1 triphenyl phosphite 54.219 and ethyl ether 2
A mixture of 001ffJ was cooled to 0°C, and 28g of bromine was added to 5
The compound 20II prepared in Reference Example 2 was added dropwise over a period of 1 minute, and then allowed to stand for another 10 minutes.
Add the solution dissolved in Ogo over 30 minutes, and leave for 1 hour 3
It was stirred for 0 minutes. After the reaction, roohexane, ethyl ether and water were added, and the organic layer was washed successively with water and saturated brine, and then dried with anhydrous sulfuric acid.) It was dried over IJum, concentrated under reduced pressure, and purified by vacuum distillation to give the following physical properties. The title compound 22.5# was obtained.

HP Tomi 8g-89℃/12hof (g.

NMR (0014): δ-3,75Ct, 2H), 2
．． 33 (m.

2H), 0.90 (711,3H).

Reference Example 3 (α) 1-zolomo-2-pentyne Br'\/ゝReference Example 2 (α
) Using Compound 27I prepared in Example 3, the title compound 311 having the following physical properties was obtained by the same procedure as in Reference Example 3.
I got a 9. -NMR (GGJ4): J-3,73(m
, 2H), 2.31 (71!, 2H), 0.88 (t,
3H).

Reference Example 4 Methyl P-hydroxycinnamate Main ster P-hydroxycinnamic acid 8.2.9 was dissolved in methanol 150, hydrogen chloride gas was passed through it for 5 minutes at room temperature, and then 0.
It was cooled to 0.degree. C. and stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, thoroughly washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and connected under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:cyclohexane 7==1:3) to obtain the title compound '1.64ji having the following physical properties.

TLC: Rf=0.58 (ethyl acetate:cyclohexane 2:1).

MS:yn/Z=178(M), 160,147,1
19.91°5O NMR (GDGlj +DMSO-46Cδ-8,98
(-?, rf(), 7.62(d,tH), 7.37(
d,, 2H), 6.85 (d, 2H), 6.24 (cL
, LH), 3.76C8,3H).

Reference Example 5 p-(2-octenyloxy)cinnamic acid methyl ester sodium hydride (64%) 36m9 was dissolved in anhydrous tetrahedron 1
A solution of Compound 178 prepared in Reference Example 4 dissolved in anhydrous tetrahydrone 1- was added thereto at 0°C, and the mixture was stirred at room temperature for 5 minutes. Add 0.1 ml of dimethylformamide to the reaction solution,
After stirring for 15 minutes, a solution of 227 my of l-bromo-2-octyne (produced in Reference Example 3) and 0.3 ml of anhydrous tetrahydroalane was added at room temperature.
The mixture was stirred at 0°C for 1 hour and at 60°C for 30 minutes. Water and ethyl acetate were added thereto, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: cyclohexane - 1:1) to obtain the title compound 26511I9 having the following physical properties: 0TLC:R
f-0,52 (ethyl acetate:cyclohexane-1:3)
.

MS: m/Z=286CM), 255.215.19
8.187.178.147.119.67°NMR:
δ = 7.64 (d, IH), 7.46 (ct, 2)
().

6.95 (d, 2) 1), 6.28 (d, IH), 4
．． 67 (t, 2H), 3.76 (#, 3H), 2.
05-2.35 (71L, 2H), 1.05-1.70
(yx, 6H), 0.84 (t, 3Ho) Reference Example 5 (
α) p-(2-7'rovinyloxy)cinnamic acid methyl ester 1-Bromo-2-octyne was replaced with propargyl bromide 245In9, and the title compound having the following physical property values was obtained by the same operation as in Reference Example 5. 201~ was obtained.

MS: m/Z=216(M”'), 201.184,1
77°156.149°NMR: δ = 1.24Cdd, 4H), 6.99(q
, 2H), 4.71 (d, 2H), 3.78 (J', 3
H), 2.54Ct, LH).

Reference Example 5(b) P-(2-pentynyloxy)cinnamic acid methyl ester 1
The title compound 211Da having the following physical property values was obtained by the same procedure as in Reference Example 5, except that Compound 250* produced in Reference Example 3(a) was used in place of -7' lomo-2-octyne.

MS Near 7! /Z=244CM), 213.187.
178.147°NMft: δ = 7.23 (dd, 4
H), 6.98 (q, 2H), 4. '68 (t, 2H
), 3.78(y, 3H), 2.22(7)l, 2
H), “1.11(t, 3H).

Example 6 p-(2-octenyloxy)cinnamic acid Compound 2 (:y5m9) prepared in Reference Example 5 was dissolved in a mixture of tetrahydrofuran (31 nl) - methanol <4 ml', and 2N hydroxide was added. Aqueous solution 1.4
ml and stirred at 50°C for 1 hour and 30 minutes.

After cooling to room temperature, neutralizing with 1N hydrochloric acid, and extracting with ethyl acetate, the extract was washed successively with water and saturated brine.
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 240m9 of the title compound having the following physical properties.

TLc: Rf=o, 3o (ethyl acetate:cyclohexane-1:1).

MS: m1Z=272 (M+), 255,215
,201°198.173.164.147.67°N
MR: δ-10,30 (J', IH), 7.74 (d,
1) l), 7.49 (d, 2H), 6.97 (d
,,2H), 6.30(ili!, LH), 4.6s
(t, 2H), 2.00-4.00 (m, 2H)
, 1.05-x,i.

(door, 6H), 0.84 (t, 3H).

Reference Example 6 (α) P-(2-propynyloxy)cinnamic acid The title compound 210Da having the following physical property values was obtained by the same operation as in Reference Example 6 using the compound 260In9 produced in Reference Example 5 (α). Obtained.

MS near X/Z=202(M”), 184,163,1
56°135.128°NMR: δ-7,26 (dd, 4H), 6.99 (
qt 2H), 4.73(d, 2H), 2.63Ct
, 18).

Reference example 6 (h)
) Using Compound 270 prepared in Example 6), the title compound 250~ having the following physical property values was obtained by the same operation as in Reference Example 6.

MS: m/Z-230CM'), 215.213.2
01.184.173.164.147°NMR: δ-7,26 (cLd, 4H), 6.99 (
q, 2) 1), 4.71 (t, 2H), 2.23 (m
, 2H), 1.12(t, 3H).

Reference Example 7 P-penzylbenzaldehyr 21g of hexamethylenetetramine was mixed with 2g of trifluoroacetic acid.
0'07dK was dissolved, Penzil Hanzey122I was added, and the mixture was stirred at 90°C overnight. The reaction solution was concentrated under reduced pressure, 50°C of ice water was added, and after stirring for 30 minutes, sodium bicarbonate was added to make it alkaline, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by vacuum distillation to obtain the title compound 69. having the following physical properties. 0MS near 1 that got P! /Z-196(M), 167.165
．． 152°NMR: δ=9L94(J', tH), 7.
77 (d, 2H), 7.32 (d, 2H), 7.2
2 (m, 5H), 4.01 (θ, 2H).

Reference Example 8 P-benzyl cinnamic acid 4.8 g of the compound produced in Reference Example 7 was added to 25 mJ of pyridine.
111 tl of piperidine and 3 g of malonic acid were added thereto, and the mixture was reacted at 120°C for 4 hours. The reaction solution was allowed to cool to room temperature, water and concentrated hydrochloric acid were added, and the mixture was filtered. The filtrate was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by recrystallization using a benzene-hexane mixture to obtain 3.5 g of the title compound having the following physical properties.

MS: m/Z=238 (M”), 220.192.17
8.165°NMR: δ-7,77 (d, IH), 7
．． 48Cd, 2H), 7.20-7.30 (771,7
)1), 6.40 (d, IH), 3.98 (#, 2H
).

Reference Example 9 P-phenylbenzaldehye F 4-hydroxymethylpiphenyl 2.19tt Dissolved in 5odK of dimethyl sulfoxide, dissolved in triethylamine 9.
2d was added and cooled on ice. A solution of 5.25 g of sulfur trioxide-pyridine complex dissolved in 20 m# of dimethylsulfoxy was added dropwise to this, and the mixture was allowed to stand at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and concentrated under reduced pressure.The residue was purified by recrystallization using benzene to obtain the title compound 1.09 having the following physical properties.

MS: m/Z=182(M), 181,152.12
7.79°NMR: δ-9,98 (m, LH), 7.0
-9.0Cm, 9B).

Reference Example 1O P-phenylcinnamic acid Using 1.6 g of the compound produced in Reference Example 9, Reference Example 8
By the same operation as y, the title compound 1.019 having the following physical properties was obtained.

MS: m/Z=224 (M), 207.178.16
7.165.152°NMR (CD0I 3+ (3D30D): δ-7,4
-7,6 (9H), 7.72Cd,tH), 6.48
(d, IH).

Example 1 N-[p-(2-octenyloxy)cinnamoyl]anthranilic acid methyl ester p-octenyloxycinnamic acid 240 under argon atmosphere
QJ (produced in Reference Example 6) was dissolved in 5 m/m of methylene chloride, 0.18 m of triethylamine and 92 μl of ethyl chloroformate were added at 0°C, and the mixture was stirred at the same temperature for 20 minutes. To this, a solution of anthranilic acid methyl ester 2001119 dissolved in 2 m of methylene chloride was slowly added at 0°C, and after stirring at room temperature for 1 hour,
It was poured into water and extracted with 80 d of ethyl acetate. Add the extract to water,
The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (Lover column, ethyl acetate:cyclohexane-1:10) to obtain the title compound 78■ having the following physical properties.

TLC: Rf-0,70 (ethyl acetate:cyclohexane-1:3).

MS: m/Z-405 (M''), 390.374.3
46.296.264.255.208.151゜14
7.119°NMR (CDGA3): δ-11,28 (s, IH)
, 8.86 (dd.

lB), s, ol(dcL, IH), 7.70CtL
.

IH), 7.40-7.70 (m, IH), 7.
50 (d, IH), 6.80-7.20 (FW, t)
l), 6.96 (d, IH), 6.46Cd, IH),
4.68 (t, 2H), 3.91 (J, 3H), 2
．． 05-2.35 (m, 2.H), 1.05-1.
70 (m, 6H), 0.85 (t, 3H).

Example 1 (g) N-Cp-C2-pentynyloxy)cinnamoyl]anthranilic acid methyl ester p-, (2--?cytinyloxy)cinnamic acid 2341n
9 (produced in Reference Example 6(b)) and anthranilic acid methyl ester 153 Da, the title compound 150 Da having the following physical property values was obtained by the same operation as in Example 1.

TLC: Rf=0.72 (ethyl acetate #: n-hexane-
1:4).

MS: fi/Z=363(M').

Example 2 N-[7)-(2-octenyloxy)cinnamoyl]
Anthranilic acid and its sodium salt.

Methyl ester 781n9 produced in Example 1 was dissolved in a mixed solution of methanol (2d)-tetrahydrofuran (2d), and 0.58+1L of 1N hydroxide/hylithium aqueous solution was added.
7. Add / and stir at room temperature for 2 days. After neutralization with -01N hydrochloric acid, the mixture was extracted with 7 otnl of ethyl acetate, and the extract was washed with water until it became neutral, then washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-cyclohexane) to obtain the title compound [acid] 641n9 having the following physical properties. Furthermore, acid 621n9 was dissolved in ethanol 3-, and 1N sodium hydroxide aqueous solution 9.15mj! Add [concentrate under reduced pressure,
Ethanol (5 ml -) and toluene (5-) were added to the residue, dried by azeotropy, and further dried in a desiccator (P2O
3) to obtain the title compound [salt] 66■ having the following physical properties.

TLC (acid): Rf 0.25 (ethyl acetate:cyclohexane 2:l).

IR [acid] (KBr) Niji (rx)-2700-3
600, 2960, 2940, 2860, 1690, 1
625, 1600, 1585, 1510, 1450, 1
400, 1340, 1310, 1290, 1220, 1
175,1140,1000,820,755,650
, 520°MS [acid]: m/Z-391 (M), 37
3.264.255.147.119°NMR (salt') (CD30D): δ-8,60 (dd
, 1)l), 8.07(dd, 1)I), 7.60
(d, IH), 7.59 (d, 2H), '1.38 (d
t, IH), 7.06 (dt, IH), 7.01 (IL
, 2H), 6.62 (d, IH), 4.74Ct, 2B
), 2.15-2.30 (m, 2H), 1.20-1.
60 (m, 6H), 0.88 (t:3H). − Shape [Vehicle: Pale yellow solid.

Example 2 (α) N-[F-(2-pentynyloxy)cinnamoyl]anthranilic acid and its sodium salt By using the compound 150W9 produced in Example 1 (α), the following was obtained by the same operation as in Example 2. The title compound [acid] 13 having physical property values of
I got 0 da. Further, 125 µm of the acid was dissolved in 3-methanol and 140 µm of the title compound [salt] having the following physical properties was obtained using an equivalent amount of an aqueous solution of 1N hydroxide.

TLC (acid): Rf-0,40 (ethyl acetate).

IR [Salt] Rainbow 1660.1600.1580.15
00.1435.1400cm.

MS [acid]nia 7L/Z-349 (M), 331,2
13.147°NMR [salt] (CDC13+CD30D
): δ-8,65 (d, IH), 8.05 (d, IH)
, 7.64 (d, IH), 7.45-7.60 (m,
2 H), 7.40 (t, LH), 7.04 (t, I
H), 6.90-7.00 (m, 2H), 6.52
Cd, IH), 4.68 (m, 2H).

Form [Salt]: Pale yellow solid.

Example 3 N-CP-(2-propynyloxy)cinnamoyl]anthranilic acid and its sodium salt p-(2--10
vinyloxy) cinnamic acid (produced in Reference Example 6 (α))
41 ml of oxalyl chloride was added to 210TR9, stirred at room temperature for 1 hour, and concentrated under reduced pressure. A solution of the residue in methylene chloride ld was added with 156 g of anthranilic acid and 230 g of triethylamine in methylene chloride ld.
d, added to the ice-cooled solution, and stirred at room temperature for 2 hours and 30 minutes. After stirring, 3 d of 1N hydrochloric acid was added, extracted with ethyl acetate, washed successively with 1N hydrochloric acid and water, and concentrated under reduced pressure. The residue was washed with methanol and purified by recrystallization (methanol) to obtain the title compound [acid] 1511n9 having the following physical properties. Further, 149 μm of this acid was dissolved in 3-methanol, 05 m7 of an ice-free aqueous sodium hydroxide solution was added, and the mixture was concentrated under reduced pressure to give the title compound [salt,
1150 mg of yellow solid was obtained.゛TLC (acid): Rf-o, 4or ethyl acetate).

1 1R [acid] (KBr) Rainbow (cm) 71670
．． 1600.1500.1440°MS [acid 1 nia FL/Z=321.303.264.2
08.185°NMR [acid] (CDC13+CD30D
): δ-8,79 (LL, LH), 8.11 (d, I
H), 7.67 (dt IH), -7,45-7,65
(Full, 2H), 7.10 (t, IH), 6.95-
7.15 (m, 2I('l, 7.50(d, 1)
1), 4.74 (77m, 2H), 2.60 (71L,
IH).

Example 3 (→ N-CP-benzylcinnamoyl) anthranilic acid and its sodium salt p-benzyl cinnamon @ (produced in Reference Example 8) 250■
Using 144 mg of anthranilic acid and 144 mg of anthranilic acid, the title compound [acid 82 and salt] having the following physical properties was obtained by the same procedure as in Example 3. Purification was carried out by recrystallization (a-hexane-ethyl acetate) on 0 TLC [acid']: Rf-o, sot ethyl acetate; lu-hexane = 2:1).

IR [acid 1 (KBr) ca-” 2 1670.
1600.1580.1520.1505°MS [acid]: m/Z-357,339,221,191
, 178°165° NMR [acid] (CDC13+ CD30D): δ-
8,79(cL, 1B), 8.13(dd, 1i()
, 7.68(d, 1B), 7.5Hdt, IH), 7
．． 05-7.60 (m.

10H), 6.60 (d, IH/).

Form [Salt]: White solid.

Example 3(b) Do(p-phenylcinnamoyl)anthranilic acid and its sodium salt p-phenylcinnamic acid (produced in Reference Example 1O) 240
Using ~・[, the title compound [acid] 64■ having the following physical property values was obtained by the same operation as in Example 3. Acid 621!
0 TLC [acid]: Rf-0,25 (ethyl acetate:cyclohexane-2:l).

IRE acid) (!IIL)-2700-3600
,2960,2940,2860,1690,1625
,1600,1585,1510,1450,1400
,1340,1310,1290,1220,1175
,1175,1140,1000,820,755,6
50,520°MS [acid] near 1! /Z-391(M”
), 373.264.255.147.119°NMR [salt] ((3D30D): δ-8,79(d
d, IH), 8.07 (deL, 1B), 7.60 (d
, IH), 7.59 (d, 2H), 7.38 (dt, 1
B), 7.06<cat, tH), 7.01(d, 2H
), 6.62 (ti,,tH), 4.74 (t, 2
H), 2・15-2.30 (m, 2H), 1.2
0-1.60 (m, 6H), 0.88Ct, a)
l).

Example 7 N-[7)-(2-octenyloxy)cinnamoyl]
Anthranilic acid 5I, ``Fillin calcium gluconate (
Disintegrant) 2007V, magnesium stearate (lubricant) Looby, and microcrystalline cellulose 4,7y were mixed and pressed in a conventional manner to obtain IOO tablets containing 50 to 50 active ingredients in one tablet.

Claims (1)

[Scope of Claims] 1) General formula [wherein R represents (1) a straight chain or branched alkyl group or alkynyloxy group having 2 to 15 carbon atoms;
ll) represents a Hensyl group or a phenyl group, R represents a hydrogen atom or a methyl group, R represents a carboxy group, a carboxymethyl group, a carboxymethoxy group, carbon number 2-6
represents a straight chain or branched chain alkoxycarbonyl group, a straight chain or branched chain alkoxycarbonylmethyl group having 3 to 7 carbon atoms, or a straight chain or branched chain alkoxycarbonylmethoxy group having 3 to 7 carbon atoms. 1σ represents 0.1 or 2, and the symbol == represents a double bond←4, mixed or mixed) or a single bond. ] Aniline derivatives thereof, non-toxic salts thereof, or non-toxic acid addition salts thereof. 2) R is a propynyloxy group, a kantynyloxy group,
The compound according to claim 1, which is a heptynyloxy group or an octenyloxy group. 1. 3) The compound according to claim 1, wherein R is a phenyl group or a benzyl group. 4) The compound according to claim 1, item 2 or 3, wherein R is a hydrogen atom, the symbol π= represents a double bond, and L is 1. 5) Claim 1 in which R is a carboxy group, a carboxymethyl group, a carboxymethoxy group, a methoxycarbonyl group, a methoxycarbonylmethyl group, a methoxycarbonylmethoxy group, an ethoxycarbonyl group, an ethoxycarbonylmethyl group, or an ethoxycarbonylmethoxy group
A compound according to item 1, item 2, item 3, or item 4. 6) The compound according to claim 1, which is N-[:F-(2-octenyloxy)cinnamoyl]anthranilic acid methyl ester. 7) The compound according to claim 1, which is N-CF-(2-pentynyloxy)cinnamoyl]anthranilic acid methyl ester. 8) The compound according to claim 1, which is N-[p-(2-octenyloxy)cinnamoyl]anthranilic acid or its sodium salt. 9) The compound according to claim 1, which is N-[:p-(2-pentynyloxy)cinnamoyl]anthranilic acid or its sodium salt. 10) The compound according to claim 1, which is N-Cp-[-propynyloxy)cinnamoyl]anthranilic acid or its sodium salt. 11) The compound p according to claim 1, which is N-(p,-hensylcinnamoyl)anthranilic acid or its sodium salt. 12) The compound according to claim 1, which is N-(7)-phenylcinnamoyl)anthranilic acid or its sodium salt. 13) General formula [wherein R represents (1) a linear or branched alkynyl group or an alkynyloxy group having 2 to 15 carbon atoms;
(1) Represents a benzyl group or a phenyl group, R represents a hydrogen atom or a methyl group, and R represents 0.1. or 2, and the symbol = represents a double bond (Mu, -4- or E-B mixture) or a single bond. ] Acid chloride 9 represented by the general formula [wherein R is a carboxy group, a carboxymethyl group, a carboxymethoxy group, a straight-chain or branched alkoxycarbonyl group having 2-6 carbon atoms, Straight chain or branched alkoxycarbonylmethyl group, or 3 carbon atoms
-7 represents a linear or branched alkoxycarbonylmethoxy group. [In the formula, all symbols have the same meanings as above. ] A method for producing an aniline derivative. 14) General formula [wherein R represents (1) a straight or branched alkynyl group or alkynyloxy group having 2 to 15 carbon atoms;
(1)-? R represents a hydrogen atom or a methyl group, R3 represents a carboxy group,
Carboxymethyl group, carboxymethoxy group, carbon number 2
26 straight-chain or branched alkoxycarbonyl group, straight-chain or branched alkoxycarbonylmethyl group having 3-7 carbon atoms, or straight-chain or branched alkoxycarbonylmethoxy group having 3-7 carbon atoms represents Oll,
or 2, and the symbol =: represents a double bond (E, Z or EZ mixture) or a single bond. ] A leukotriene antagonist containing an aniline derivative represented by the following, a non-toxic salt thereof, or a non-toxic acid addition salt thereof as an active ingredient. 15) General formula [In the formula, all symbols have the same meanings as in claim 14. ] A phospholipase inhibitor characterized by containing an aniline derivative represented by the above, a non-ditoxic salt thereof, or an acid addition salt thereof as an active ingredient. 16) General formula [In the formula, all symbols have the same meanings as in claim 14. ] 5 characterized by containing the aniline derivative represented by, its non-toxic salt or its acid addition salt as an active ingredient.
α-reductase inhibitor.