JPS60146855A - Aniline derivative, its preparation, and drug containing same as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is 1-15C alkyl, alkoxy, 2-15C alkenyl, phenyl, benzyl, etc.; R<2> and R<2>' are H, or 1-20C alkyl; R<3> is carboxy, 2-6C alkoxycarbonyl, mercapto, etc.; R<4> and R<5> are H, halogen, 1- 4C alkyl, alkoxy, etc.; n is 0-2; dotted line part is double bond or single bond). EXAMPLE:N-(P-Amylcinnamoyl)-3-chloroanthranilic acid. USE:A leukotriene antagonist. A phospholipase inhibitor. A 5alpha-reductase inhibitor. Useful for remedying allergic diseases, prostatic hypertrophy, alopecia, thrombosis, etc. PREPARATION:An acid chloride shown by the formula II is reacted with an amine shown by the formula III in an inert organic solvent in the presence of a tertiary amine (e.g., triethylamine or pyridine) at -20-40 deg.C preferably at 0 deg.C- room temperature to give a compound shown by the formula I .

Description

[Detailed description of the invention] The present invention relates to a novel aniline visiting conductor.

More specifically, the present invention relates to novel aniline derivatives having leukotriene antagonism, phospholipase inhibition, and 5α-reductase inhibition, 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 P
Among the 0 family, PG endoperoxide (PG endoperoxide) has particularly strong and unique biological activity.
endoperoxides, namely PGG 2 and ptai2), thromboxane A2 ('rhrombo
-Xane A2, hereinafter abbreviated as TXA2. ), prostacyclin (PGI2), and leukotrienes C, D, and E (hereinafter abbreviated as LTC, LTD, and LTE, respectively).

) etc. In addition to these compounds, all of the PGy amylides, including various PGs that have already been well known, are biosynthesized in vivo using a common parent substance, arachito/acid, and thus the entire metabolic pathway starting from arachidonic acid is is the arachidonic acid cascade (Arachidona
It is called te cascade). For detailed explanations of each route and the pharmacological properties of each product, see Igaku no Ayumi, Monthly 4, 378 (1980), 114462 (1980), 114462 (1980).
980), 114, 866 (1980), same.

Yu1929 (1980), Modern Medicine, 12.909 (
1980), 12, 1029 (1980), 1
2.1065 (1980) and LJ1105 (1980)
80) etc.

In the arachidonic acid cascade, cyclooxygenase acts on arachidonic acid to generate PGG2, and then PGH2 to various PGs, such as prostaglandyl F2a (
Hereinafter, it will be abbreviated as PGF2a. Uh, prostagrange/
k z (hereinafter abbreviated as PCrE2), RH2, T
Lipoxygenase acts on the pathway leading to XA2 etc. and arachito/acid to produce hydroperoxyeicosatetraenoic acid.
traenoicacid, hereinafter abbreviated as HPkTE. Hydroxyeicosatetraenoic acid (hydroxyeicosatetraenoic acid)
oic acid, hereinafter abbreviated as HETh; ) (・ is roughly divided into routes leading to leukotrienes.

Since the former route is already well known, we will not discuss it in detail here. For details, please refer to Shin Katori et al., ed., Prostaglandin (1978), published by Kodansha.

Regarding the latter route, it is known that various compounds are produced by the route shown in Scheme 1.

Arachito/acid is a well-known route, i.e. PG
In addition to being metabolized by the endoperoxide pathway, it is also metabolized by a completely different pathway by lipoxygenase. 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-HPET
E is generated.

In these HPETEs, hydrogen peroxide groups are converted to hydroxyl groups by peroxidase, resulting in 5-t-tg'rg, 1
2-H1! :Converted to TE or 15-HE'l'E. In addition, among these HPETWs, 5-HPETE
is converted to LTA by dehydration.

Furthermore, LTA4 is oxygenated by Leukotrie/B4 (hereinafter referred to as
It is abbreviated as LTB4. ) and converted to ta'c4 by glutathione-8-transferase.

Then, L'f'C4 is converted to LTD4 by γ-glutamyl transbutidase. It has recently been revealed that LTD4 is further metabolized to LTg4 [
Biochem, Bioahys, t(es-c
O ■ Concave -, LLl 266 (1979) and Prost
aglandinl:, 1 helmet 5) 645 (198
0) see].

On the other hand, when talking about sR8, 5L (S means Slow).
It is an abbreviation of Reacting 5 substances, and this name was used by Feldberg et al. for the substance liberated when copra toxin is perfused into the lungs or when copra toxin is incubated with egg yolk.This substance slowly contracts the isolated guinea pig ileum. However, it has been reported that the effect lasts for a long time [J, Physiol.

94.187 (1938)].

Furthermore, Kellaway et al. sensitized 383-A (Slow Re
agtingSubstance of Analyze
showed that 8R8-A was released and showed for the first time a relationship between 8R8-A and allergic reactions [Quant,
J, kxp, Physiol, 30r 121 (1
940)] 0 Also, Brockle
(S-A is released and strongly contracts the bronchial muscles, and this contraction is not relieved by antihistamines, so 5R8-A
is an important bronchoconstrictor during asthma attacks.
[Progr, Allergy, 6.539 (196
See 2)]. Subsequently, 5R8 obtained from a piece of human lung tissue
-A constricts the bronchial rings in normal people [Int-
Arch, AllergyAppl-Immunol,
, 217 (1970)], rat 5R8-A
Enhancement of pulmonary airway resistance is observed when K is injected intravenously [J, C11n, Invest, 5L1679 (19
74)], 8l-18-A for guinea pigs, rats,
When injected into monkeys, it restores blood vessel permeability [A
Advances in Immunology, 10
*105 (1969), J, Allergy C1
1n, Immunol, 621.371 (1978)
, Prostaglandins, 19(5), 779
(1980), etc.].

As described in Section 1, 5l-1s is released as a result of the immune reaction, and is converted into 5as-A and calcium ionophore (ca).
There are two types of SH8, which are released without immune reactions such as treatment with lcium 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. It is being

Furthermore, it has become clear that K LTC4 and LTD4 are the same substances as SR8 or 5R8-A.
Therefore, the pharmacological properties of these leukotrienes can be considered in place of those of SR8 or 5R8-A [Proc, Natl, Acad, Sci, USA
, ldan.

4275 (1979), Biochem + Bioph
yξf(es −Commun +.

91.1266 (1979), Proc, Natl.
, Acad-8ci, USA.

77.2014 (1980), Nature, 285
．． 104 (1980)).

Based on the results of many studies such as these, it is now known that each 1m leu:F biosynthesized from arachito/acid via LTA4.
) +Jzy (LTC4, L'rD4, LTE4, leuco, whose structure may be further determined in the future) IJen) is a compound that is associated with allergic tracheal and bronchial or pulmonary diseases, allergic shock, or various types of allergic inflammation. It is considered to be an important factor involved in expression.

Therefore, by suppressing these leukotrienes, it is possible to prevent allergic tracheal and bronchial diseases such as asthma, allergic shock, and various allergic diseases in mammalian animals including humans, especially humans. or effective for treatment.

In addition, arachito/acid is phospholipase (phospholipase).
Phosphatidyl choline (phosph-a
tidyl ch] orine) to phospholipase A2.
(2) Phospholipase C acts on phosphatidyl inositol (phosphatidyl inositol) and 1.2-diglyceride (1
, 2-diglyce-ride) is produced, which is further treated with diglyceride lipase (diglyceride lipase).
It is generally thought that a pathway in which the lipase is released by the action of monoglyceride 9 lipase and monoglyceride 9 lipase (see Chemistry and Biology, Dan, 154 (1983)).

The liberated arachidonic acid is further processed by two routes namely (11 cyclooxygenase).
Ase ) metabolic pathway leads to Prostagra/Schiff (PC
) and thromboxane A2 (TxA2), or (2) lipoxygenase (
lipox-ygenase) metabolic pathway, 8R8
-A (Slow Heating Substance
es of Anaphylaxlg), hydroxyeicosatetraenoic acid (HETE) and leukotriene/H
It is known that it is metabolized into physiologically active substances such as Leukotriene H4 (Chemistry and Biology 2).
1, 154 (1983)].

These metabolites include, for example, TxA2, which is a substance with strong platelet aggregation and vasoconstriction effects; 5) (S-
A is a chemical mediator of asthma.
LTB 4 is a chemical mediator of inflammation such as gout, and PC is a chemical mediator that has vasodilatory, carcinogenic, thermogenic, and leukocyte migration effects in inflammation. Known [Metabolism 20, 317 (19
83), 'rhe Lancet 1122 (198
2) See Prostada Ranjin (1978) Kodansha, edited by Makoto Katori et al.].

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 have conducted extensive research to develop compounds that antagonize leukotrienes or inhibit phospholipases (phospholipase A2 and/or phospholipase C). The present invention was completed based on the discovery that an IJ derivative achieves the objective.

The compound of the present invention strongly inhibits phosphoI)A-ase and inhibits the release of 7-rachidonic acid from phospholipids. It is effective in the prevention and/or treatment of diseases caused by.

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. [Circulation Science-3484 (1983) and Pharmacy, 167 (19
83)].

Furthermore, in addition to the aforementioned uses as leukotriene antagonists and phospholipase inhibitors, the compound of the present invention has also been found to have the following 5α-reductase inhibitory action.

5α-reductase exists in the endoplasmic reticulum and nucleic acids, and has the function of converting ingested testosterone into target tissues into active form of 5α-dihydrotestosterone. It is said that binding to intracellular receptors causes cell proliferation, and when this effect is reversed, 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 effect remains as a side effect, so it was difficult to say that the treatment was sufficient.

The compounds of the present invention naturally have hormone-specific effects,
Moreover, it strongly inhibits 5α-reductase, suppresses the increase in 5α-dihydrotestosterone, and suppresses cell proliferation, so it is effective for treating benign prostatic hyperplasia, alopecia, and acne in mammals including humans, especially humans. It is used for prevention and/or treatment.

The present invention is based on the general formula [wherein R is (1) a straight-chain or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, a straight-chain or branched alkenyl group having 2 to 15 carbon atoms, or alkenyl represents an oxy group, (Ml unsubstituted phenyl group or benzyl group, or hydrogen atom, or (IN) represents a cycloalkyl group 2' having 4 to 7 carbon atoms, and R and R are each independently , represents a hydrogen atom or a straight chain or branched alkyl group having 1 to 2 carbon atoms, and R represents (1) a carboxy group, a carboxymethyl group, or a carboxymethoxy group, or a straight chain or branched chain having 2 to 6 carbon atoms. It represents a branched alkoxycarbonyl group, a linear or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms, an alkoxycarbonylmethoxy group, or a hydroxyl group, or a (-) mercapto group, sulfo group, jetoxyphosphomyl group. group, or an acetyl group, and R4 and R5 each independently represent a hydrogen atom,
Baldness/Atom, linear or branched alkyl group or alkoxy group with 1 to 4 carbon atoms, carboxy group, 2 to 4 carbon atoms
6 represents a straight-chain or branched alkoxycarbonyl group, hydroxyl group, or nitro group, L represents 0.1 or 2, and the symbol == is a double bond (↓, ↓, or a mixture of 1 and 1).
Or represents a single bond. However, when R falls under (1) above, R4 and R5 are not hydrogen atoms at the same time. ] The present invention relates to aniline derivatives and non-toxic salts thereof, methods for producing them, and pharmaceuticals containing them as active ingredients.

In the general formula (1), as a linear or branched alkyl group having 1 to 15 carbon atoms or an alkyl group in an alkoxy group, R represents a methyl group, an ethyl group, a propyl group, a butyl group, and a methyl group. group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, tridecyl group, dodecyl group,
Examples include tridecyl group, tetradecyl group, (/tadecyl group) and isomers thereof. Preferred groups for H include isostyl group, n-1 ethyl group (amyl group), W-heptyl group, roudecyl group and rouoctyl group. An example is an oxy group.

In the general formula (1), the linear or branched alkenyl group having 2 to 15 carbon atoms or the realkenyl group in the alkenyloxy group represented by R includes an ethynyl group, a propynyl group,
Butenyl s,-! 7f = group, hexenyl group, heptenyl group, octenyl group, nonenyl group, thecenyl group, tri/thecenyl group, dodecenyl group, tridecyl group, tetradecenyl group, hantadecenyl group, and isomers thereof. However, ethynyloxy group is excluded.

In the compound represented by the general formula (11), when R represents an alkenyloxy group, there is a double bond between carbon atoms other than the carbon atom adjacent to the oxygen atom.

In the general formula (1), the cycloalkyl group having 4 to 7 carbon atoms represented by R includes a cyclobutyl group, a cycloothyl group,
cyclohexyl and cycloheptyl groups,
A preferred group is a cyclohexyl group.

In general formula (1), it is also preferable that R represents a hydrogen atom.

In general formula (1), R and R2/ represent 1 to 2 carbon atoms
0 linear or branched alkyl groups, or alkyl groups in alkoxy groups, include methyl group, ethyl group, propyl group, methyl group, pentyl group, hexyl group, hezotyl group, octyl group, nonyl group, decyl group. group, undecyl group,
Examples include dodecyl group, tridecyl group, tetradecyl group, 4-ntadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, and isomers thereof, and preferred groups for R2 and R2' include methyl group, Included are ethyl islands and pentadecyl groups. It is also preferable that R and R2/ are hydrogen atoms.

In general formula (1), the number of carbon atoms in R3, R4 and R5 is 2 to
Examples of the linear or branched alkoxycarbonyl group in 6 include methyl group, ethyl group, propyl group, butyl group, and isomer groups thereof, and preferred groups for R and R include methoxycarbonyl group, respectively. and ethoxycarbonyl group.

In general formula (1), as a straight chain or branched chain alkoxycarbonylmethyl group having 3 to 7 carbon atoms in R and a straight chain or branched chain alkyl group having 1 to 4 carbon atoms in the alkoxycarbonylmethoxy group Examples include methyl group, ethyl group, propyl group, butyl group and their isomer groups, and H
Preferred groups include methoxycarbonylmethoxy group and ethoxycarbonylmethoxy group.

In general formula (1), R4 and R5 represent 1 to 4 carbon atoms
Examples of the straight-chain or branched alkyl group or the alkyl group in the alkoxy group include methyl group, ethyl group, propyl group, butyl group and isomers thereof, and R4
Preferred groups for R5 include methyl, ethyl, methoxy and ethoxy groups.

In the general formula (1), examples of the atom represented by R and R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferred atoms for R and H include a fluorine atom and a chlorine atom. It will be done.

The present compound represented by the general formula (11) may have isomers. In particular, when the symbol = represents a double bond, the symbol 2 = may represent a single bond due to the ! or s of this double bond. When R and/or 2' represent an alkyl group, the carbon to which these alkyl groups are bonded is an asymmetric carbon atom and isomers exist.

Further, in each substituent in the general formula (1), realkyl,
Branching of the alkylene, alkenyl and/or alkenylene moieties and double bonds of the alkenyl and/or alkenylene moieties give rise to isomers in the same manner as described above. The present invention also includes all these isomers and mixtures thereof.

Several patent applications have been filed containing compounds whose structures are close to the compounds of the present invention, but the present invention cannot be easily derived from these patent applications.

A specific example is a compound represented by the formula, which is described as Example 2 in JP-A-50-135047. However, there is no example in the above specification that suggests that it is antagonizing Leukotriae, which is one of the objects of the present invention. Furthermore, the above formula (At
The compound represented by LTD as described herein
When subjected to a system for measuring 4 antagonistic effect and phospholipase A2 inhibitory effect, the respective ■D5o values were 30 μM and 100 μM.

However, the compound of the present invention, as represented by the formula and, has very strong LTD 4 antagonism and phospholipase inhibitory activity as described below. It was also revealed that by substituting the carboxy group with a specific substituent, the above-mentioned activity becomes more persistent than can be easily inferred.

In addition, the present inventors disclosed a compound similar to the compound of the present invention in Japanese Patent Application Publication No. 57-106651,
Although the purpose is to inhibit a-icotriene biosynthesis,
This goal is achieved by selectively inhibiting 5-lipoxygenase as a mechanism of action. On the other hand, the gist of the present invention is an action that antagonizes leukotriene itself, and these actions are essentially different.

Further, these two applications do not describe the use of the present invention as a phospholipase inhibitor or 5α-reductase inhibitor, but do not describe the use of the present invention as an antithrombotic agent, benign prostatic hyperplasia,
The use as prevention or treatment for alopecia and cancer healing was discovered for the first time in the present invention, and the present invention cannot be easily inferred from these prior art techniques.

According to the present invention, the aniline derivative represented by the general formula (1) is represented by the +11 general formula (wherein all symbols have the same meanings as above). ) The acid chloride represented by the general formula [wherein all symbols have the same meanings as above]. ] or by reacting with an amine of (
In formula 11, R has the same meaning as R, 5' R has the same taste as R, but may also be a hydrogen atom, and other symbols have the same meanings as above. [In the formula, R represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, and xJ and X2 each represent a halogen atom. ] It can be produced by reacting with a halide represented by the following.

The reaction of acid chloride and amine (1) is well known. For example, tertiary amine (
For example, in the presence of triethylamine, pyridine, -2
It is carried out at a temperature of 0°C to 40'C. Preferably in methylene chloride in the presence of triethylamine or pyridine,
It is carried out at θ°C to room temperature.

The reaction (1) between a phenol compound and a halide is also a well-known reaction, for example, in an inert organic solvent (methylene chloride, chloroform, methyl ethyl ketone, tetrahydrofuran, ethyl ether, etc.), a base (triethylamine, sodium hydride, The reaction is carried out under anhydrous conditions at 0° C. to reflux temperature in the presence of potassium carbonate, etc.), optionally in the presence of IJium iodide).

The compound represented by the general formula (III) is a known compound. For example, a compound in which R is a 2-carboxy group, R is a 5-chloro group, and R is a hydrogen atom is 4-chloroanthranyl, and R A compound in which is a 2-sulfo group and R and R are both hydrogen atoms is ortanilic acid, and both are commercially available.

The compound represented by the general formula +Ill is represented by the general formula [wherein all symbols have the same meanings as above]. ] is produced by converting the carboxylic acid represented by K into an acid chloride.

Reactions to convert carboxylic acid to acid chloride are well known and include thionyl chloride, thionyl chloride, etc. in an inert organic solvent (e.g. methylene chloride, tetrahydrofuran) or without solvent.
It is carried out using a chloride such as oxalyl chloride or ethyl chloroformate at a temperature of -40°C to 30°C. Preferably, it is carried out using oxalyl chloride without solvent or using ethyl chloroformate in methylene chloride at 0°C to room temperature.

The carboxylic acid represented by the general formula (■) is known per se or can be produced by a known method, and an example of the production method is shown in the scheme (■) below.

In the diagram (2), each symbol represents the following meaning, and the other symbols represent the same meanings as above. 15 linear or branched alkenyl groups, unsubstituted phenyl groups or benzyl groups, or hydrogen atoms or cycloalkyl groups having 4 to 7 carbon atoms.

b R-C1-C15 straight-chain or branched alkyloxy group or C2-C15 straight-chain or branched alkenyloxy group.

R7, R8 - each independently a straight or branched alkyl group having 1 to 4 carbon atoms.

m -1 or 2° Each step in the diagram (■) is all a known reaction, but to briefly explain, step (12) is a reaction for introducing a formyl group, for example, using hexamethylenetetramine in trifluoroacetic acid. It is carried out at a temperature of 50°C to reflux.

Step (bl is an oxidation reaction, e.g. Jones oxidation,
-20℃~4 by Collins oxidation, SW/oxidation method
It is carried out at a temperature of 0°C.

Steps (01 and (di) are Wittig reactions, for example in an inert organic solvent (ethyl ether, tetrahydrofuran, chloroform, benzene, etc.)
t, ig reagent (e.g., general formula φ3P R-UtJOH
, ) in the formula, R represents a single bond or an ethenylene group, and the other symbols have the same meanings as above. ) using −
The reaction is carried out at 78°C to room temperature.

Steps (11, σ) and (1) are saponification reactions, such as alkali (potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.) in a water-miscible organic solvent (tetrahydrofuran, methanol, ethanol, etc.). ) at a temperature of 0°C to 40°C.

Steps (71 and ti+ are reduction reactions, for example, in a hydrogen atmosphere, in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.), in the presence of a catalyst ()ξradium-carbon, palladium, platinum black, nickel, etc.) at 0°C to 40℃
It is carried out at a temperature of

Step C) is an esterification reaction, for example, an acid (
p-Toluenesulfonic acid, hydrochloric acid, Hanaka water.

It is carried out at 1M degrees at 0°C to 40°C in the presence of gas (such as elementary gas). Of course, in addition to the alkanol mentioned above, an organic solvent that does not participate in the reaction (tetrahydrofuran, methylene chloride, etc.) may also be used.

Steps (Al and (A) are reactions that convert hydroxyl groups into alkoxy groups or alkenyloxy groups, such as inert organic solvents (ethyl ether, tetrahydrofuran, etc.)
The corresponding alkyl halide or alkenyl halide (general formula R10 In the formula, R represents a linear or branched alkyl group or alkenyl group having 1 to 15 carbon atoms, and X represents a halogen atom) at a temperature of 40°C to reflux temperature.

The process is a Perke/Debner reaction and is carried out, for example, using malonic acid or its ester in pyridine as a solvent in the presence of piperidine at 100° C. to reflux temperature.

Step (0) is a Friedel-Crach reaction, for example, in an inert organic solvent (carbon disulfide, nitrobenzene, chloroform, methylene chloride/, carbon tetrachloride, tetrahydrofuran, etc.) with a catalyst (aluminum chloride, aluminum bromide, chloride, etc.). In the presence of ferric iron, etc.), the corresponding acid nolide ()
t"COX', in which X4 represents a halogen atom and R represents the same meaning as above), -20°C to 50°C
It is carried out at a temperature of °C.

1 [In the formula, R represents a carboxy group, a carboxymethyl group, or a carboxymethoxy group, and R and R each independently represent a hydrogen atom, a halogen atom, or a straight or branched chain alkyl group having 1 to 4 carbon atoms. Alternatively, it represents an alkoxy group, a carboxy group, a hydroxyl group, or a nitro group, and other symbols have the same meanings as above. ] The compound represented by the corresponding ester compound has the general formula [wherein R3A, R4A and 1 (5h is each R
, 1 (and represents a group corresponding to H, at least one of which represents an alkoxycarbonyl group, an alkoxycarbonylmethyl group, or an alkoxycarbonylmethoxy group, and the other symbols have the same meanings as above.) It can be produced by subjecting it to a saponification reaction.

Of course, a compound represented by the general formula (1h) can also be produced by subjecting the compound represented by the general formula (1h) to an esterification reaction.

In the saponification reaction and esterification reaction referred to herein, for example, the methods shown in steps (ma), (katana and (1)), and step (q) in the above-mentioned scheme (1) can be used.

Furthermore, among the compounds represented by general formula (1), compounds that do not have a double bond (alkenyl, alkenylene group),
That is, the general formula [wherein R is a linear or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, a phenyl group, a benzyl group,
It represents a hydrogen atom or a cycloalkyl group having 4 to 7 carbon atoms, and other symbols have the same meanings as above. ] The compound represented by the general formula [wherein, R represents a double bond when the symbol == represents a double bond, R1
However, when the symbol == represents a single bond, it represents a straight or branched alkenyl group or alkenyloxy group having 2 to 15 carbon atoms. ] It can be manufactured by subjecting the compound represented by these to a reduction reaction.

In the reduction reaction mentioned here, for example, the method used in the steps (fl and +L+) in the above-mentioned scheme (1) can be used.

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

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

The compounds of the present invention showed antagonistic effects against LTD 4 as shown in the table below.

The compounds of the present invention exhibited inhibitory effects on phospholipase A2 as shown in the table below.

The compound of the present invention exhibited an inhibitory effect on 5α-reductase as shown in the table below. The inhibition rate shows the value at a concentration of the compound of the present invention at 2 mM.1 The antagonistic effect of the compound of the present invention on LTD4 was determined by the following experimental method. It was measured by

Weight 300-400I! The ileum (3 volumes) removed from a male guinea pig was incubated at 37°C, Tyrode's solution, and oxygen (95°C).
%)-carbon dioxide (5%) mixed gas vented Magnus tube and stabilized for about 30 minutes.
The compound of the present invention was added at a concentration of 0 g/ml, and the concentration of the compound of the present invention was varied in relation 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 can be determined using a modified method of the 5h=qRir method using L- as a substrate.
β-[1-C]-2chitonyl-α'-stearoyl-
Phosphatidylcholine was measured using phospholipase A2 obtained from guinea pig lung as the enzyme [Ana
See I Biochem, 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 measurement is 0
．． 09 M Hepes (pH 7,4), 0.22 M sucrose, s x 10-3 M NADPI, 5 μM [4-
The reaction was carried out at 37°C for 60 minutes using a mixture of Cl testostero/, 5α-reductase and the compound of the present invention.The reaction was stopped using chloroform-methanol (1/2
), and after centrifugation, the supernatant was spotted on a silica gel thin layer plate and separated using chloroform-methanol-acetic acid (99,2: 0.6: 0.2) to separate the produced dihydrotestosterone/ TLC radioactivity
It was measured using a scanner and the enzyme activity inhibition rate was calculated [Endocrinol+ Jap6n.

See 18.179 (1971). ,].

Preferably, the salts according to the invention are non-toxic. The non-toxic salts mentioned here are relatively harmless to animal tissues, and when used in the amount necessary for treatment, the general formula (
It means a salt consisting of a cation such that the effective pharmacological properties of the compound represented by 1) are not impaired by the side effects caused by the cation. Moreover, it is preferable that the salt is 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 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 human 90xyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclotamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, Examples include organic amine salts such as tanolamine salt, lysine salt, and arginine salt.

The salt of the aniline-conductor represented by the general formula (1) can be prepared by adding the acid represented by the general formula (1) to a suitable base in a suitable solvent, for example, by hydration of an alkali metal or alkaline earth metal. It can be obtained by reacting with organic compounds, carbonates, or organic amines.

In mammals including humans, especially humans, by suppressing leukotrienes, we can prevent allergic tracheal and bronchial diseases, such as asthma, allergic lung diseases, allergic schizophrenia, and various allergic diseases. and/or therapeutically effective and also phospholipase (
Phospholipase A2 and/or Phospholipase C)
By inhibiting leukotriates, diseases caused by arachidonic acid metabolites, including leukotriates, 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. It is effective in the prevention and/or treatment of. In addition, inhibiting 5α-reductase can help prevent benign prostatic hyperplasia, alopecia, and/or
or a therapeutically effective anilJ/M conductor of general formula +11 or a salt thereof for the aforementioned purpose (as a leukotriene antagonist, phospholipase inhibitor or 5α-reductase inhibitor).
Each is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually 1 In9 per adult per dose.
-li preferably in the range of 20 to 200 Iny, administered orally once to several times a day, or in the range of 100 μg to 100 Da, preferably 9 to 10 mg per adult, at each time. It is administered parenterally once to several times a day. 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 present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, !
Crystalline cellulose, Denzo/, polyvinylpyrrolidone, me! Mixed with aluminum silicate y@magnesium. The compositions may contain additives other than inert diluents in conventional manner, such as lubricants such as magnesium stearate and disintegrants such as fibrin gluco/calcium acid. Tablets or pills may be coated with a film of a gastric or enteric substance such as white tL gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or may be coated with two or more layers, if necessary. 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, polyvine 80, gum arabic, and sodium alginate. Such compositions may further contain adjuvants such as preservatives, lidding agents, emulsifiers, and dispersants. These can be neutralized, for example, by filtration through a bacteria-retaining filter, by addition of 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. Included are suppositories and tsalaries for intracavitary administration.

Among the compounds of the present invention represented by the general formula (1), preferred compounds include N-CP-7milcinnamoyl)-3-hydroxyanthranilic acid, methoxyphenylranilic acid, methoxyphenylranilic acid, methoxyphenylranilic acid, 6-acetyl-N-(7)-isonitylcinnamoyl)anthranilic acid, N-(7)-hebutylcinnamoyl)-5-chloroanthranilic acid, N-(7)-hebutylcinnamoyl)- 4-Fluoroanthranilic acid, tophnyl crab, nilic acid, xyantho2nylic acid, 1,000 cyanthotunil, N-(7-fuamylcinnamoyl)orthanyl acid, N-
(p-isobutylcinnamoyl)orthanilic acid, N-(
7)-iso-antylcinnamoyl)orthanylic acid, N-
Cp-hebutylcinnamoyl)orthanylic acid, N-<p
-decylcinnamoyl)orthanilic acid, N-(p-octyloxycinnamoyl)orthanilic acid, N-(7)-
cyclohexylcinnamoyl)orthanilic acid, and
Corresponding methyl esters, ethyl esters and non-toxic salts of the above acids, as well as chlorothiophenol, 2-[N-(7)-cyclohexylcinnamoyl)amino]-4-ri-tetralothiophenol, 2-rN-( ρ-amylcinnamoyl)amine]pencitrifluoride, 2-[N-(p-isobutylcinnamoyl)aminocopencitrifluoride, 2-[N-(7)-isope/tyrsinnamoyl famino] Trifluoride, 2-(N-(F-hebutylcinnamoyl)aminecoincitrifluoride, 2-CN-<p-octyloxycinnamoyl)aminocoincitrifluoride, 2-[N-(P-cyclohexylcinnamoyl) Moyl) amino]be/citrifluoride.

2-CP-isointyrsinnamoyl)aminophenyldiethyl phosphate, 2-(p-octyloxycinnamoyl)aminophenyldiethyl phosphate.

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. In addition, rbpJ, "TLcJ, j" in Reference Examples and "Examples"
The symbols H(J, NMRJ and MsJ stand for boiling point, thin layer chromatography, infrared absorption spectrometry, nuclear magnetic resonance spectrometry, and mass spectrometry, respectively). The proportion of solvent described in the separation section indicates the volume ratio, and jl'I, C
The solvent in parentheses of J indicates the developing solvent; [IRJ is measured by the KBr tablet method unless otherwise specified; l'-NM
Unless otherwise specified, RJ is deuterated chloroform (CDC
J 3) Measured using a solution.

Reference Example 1 2-Human 90x-3-nitroacetophenone 10-hydroxyacetophenone 13.6II was dissolved in methylene chloride 30
Dissolve in 0R1 and wood vinegar #130#L/ and bring the internal temperature to 35
While maintaining the temperature at °C, concentrated nitric acid 4.1- was added dropwise over 15 minutes, and then heated under reflux for 1 hour.

After the reaction, the mixture was allowed to cool to room temperature and poured into ice water to separate the layers.

The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and vacuum I! I shrunk. The residue was purified by silica gel column chromatography (methylene chloride: rL-hexane = 2:1) to obtain the title compound 6.29II having the following physical properties.

TLC: Rf=0.13 (chloroform=n-hex/
-2:1).

MS two doors/Z=181(M), 166.164.12
0゜NM)t: δ-13,16(J', IH), 8.1
8 ((Ld, IH), 8.10 (ddttH), 7.0
6 (t, IH), 2.73 (♂.

3H).

Reference Example 2 H2 1 [/ Compound 6.29.9 produced in Reference Example 1 was dissolved in ethanol (
The mixture was dissolved in a mixture of oophor A (14ml) at a rate of 300ml, 600q of 5% palladium-carbon was added, and the mixture was vigorously stirred at room temperature for 1 hour and 30 minutes under a hydrogen gas atmosphere. After the reaction, it was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 hl of methanol, 5 d of concentrated hydrochloric acid was slowly added, and the resulting crystals were collected by filtration, washed with ethyl ether, and dried using a desiccator to obtain the title compound 6.0619 having the following physical properties. Ta.

MS: m/Z-151 (M), 136.133.10
8.104°NMR (CD30D+DMSO-d,):
δ-8,05 (md, IH), 7.52 (ctd, I
H), 7.12(t, lH,,2,71(#, 3H)
.

Reference Example 3 P-amylba/dualdehyde 9 Hexamethylenenat 2/21g and trifluoroacetic acid 2
00g, add 150d of amylbenzene, 90g
Stir overnight at ℃. The reaction solution was concentrated under reduced pressure and diluted with ice water for 50 mL.
Add 1 It, stir for 30 minutes, and add hydrogen carbonate) I
An aqueous solution of Jum and ethyl acetate were added to separate the layers. The organic layer was washed with water and saturated saline, and anhydrous 4ifJQ! Dry with magnesium, concentrate under reduced pressure, purify by vacuum distillation,
The title compound-13F having the following physical properties was obtained.

bp: 147°C/12saHI.

MS: m/Zhi 176 (M), 147.133.120
．． 119°NMR: δ-9,93 (-f', IH), 7
．． 76(d, 2H), 7.29<d, 2H), 7.63
(t, 2H), 1.40-1.70 (771, 2H),
0.85 (yK, 3H).

Reference f! I 31α) The title compound 103I having the following physical property values was obtained by the same operation as in Reference Example 3 using p-benzthylbenzaldehyde imptilbe/ze/1211.
I got it. Note that vacuum distillation was used for purification.

AF: 125°C/2 axes 1HJF.

MS:”/Z-162(M), 120,115.91
°NMR: δ-9,99 (JP, IH), 7.80 (d
, 2H), 7.30 (4,2l-1), 2.54 (d,
2H), 1.90 (FIL.

IH), 0.89 (tL, 6H), Reference Example 3 (AI P-isotylbenzaldehyde isomethylbenzaldehyde y132II was used, and the title I having the following physical property values was obtained by the same operation as in Reference Example 3. 79 g of acetic acid was obtained. Vacuum distillation was used for Kozuura.

MS: m/Z-176CM), 133.131.12
0,92.91°NMR: δ-9,93 (I*IH), 7.8 (llt
, 2H), 7.34 ('', 2H), 2.70 (FIL
, 2) 1), 1.54 (m.

2H), 0.96 (IZ, 6H).

Reference Example 3 (C) The title compound 61.9 having the following physical properties was obtained in the same manner as in Reference Example 3 using 120 g of p-cyclohexyl/saldehyde 8 cyclohexylbenzene. Note that vacuum distillation was used for purification.

NM) 1: δ-9,93 (J', IH), 7. s(t
, 2H), 7,33(d, 2H), 2.40-2.6
0(m, IH), 1.60-1.90(m, 5)i)
, 1.10-1.50 (m, 5H).

Reference Example 3(d) P-Hebutylbenzaldehyde'-07H15 Using heptylinyne 1301, the title compound having the following physical property values 65.9 was prepared in the same manner as in Reference Example 3.
I got it. Note that vacuum distillation was used for purification.

HP: 115℃15IIIHI! .

MS: m/Z-204 (M), 175, 161, 12
0,92.91°NMR: δ-9,76 (#, IH), 7.78 (d, 2
H), 7,31('', 2H), 2.65(t, 2H),
1.40-1.70 (m+2H), 1.27 (m,
8) (), o, 84 ('', 3H).

Reference Example 3 (g) P-decylbenzaldehyde C10H21 The title compound 65II having the following physical properties was obtained by the same operation as in Reference Example 3 using 134 g of decylbenzene.

TmG: Rf-0,53 (cyclohexa/:ethyl acetate-1:9).

NMR: δ-9,76 (J, IH), 7.40 ("",
4) 1), 2.70 (', 2H), 0.88 (m,
3H).

Reference example 4 p-amylcinnamic acid Compound 5.88I produced in Reference Example 3! Chloroho.

Dissolved in 150ml of lumen, added 16.79tt of methoxycarbonylmethylithene triphenyl phosphoraf,
The mixture was refluxed for 30 minutes. After cooling to room temperature, concentrate under reduced pressure.
The residue was purified by silica gel column chromatography (methylene chloride dichlorohexane = 2:3). The obtained methyl ester was converted into tetrahydro7(70ral)-
It was dissolved in a mixed solution of methanol (30-), added with 50 n of 2N aqueous potassium hydroxide solution, stirred overnight at room temperature, added with 500 at of water, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound 6.44II having the following physical properties.

MS: m/Z-218 (M), 175.161.14
4.115°NMR: δ=8.50 (J, IH), 7.
78 (4, IH), 7.47 (d, 2H), 7.21 (
cl, 2H), 6.40 (d.

IH), 2.63 (t, 2H), 1.40-1.80 (
Folding screen.

2H), 1.10-1.45 (771,4H), 0.8
8 (t.

3H).

Reference Example 5 P-ingutyl cinnamic acid-a4H7 Reference g 8.9 g of the compound produced in AJ3 (α) was bathed in pyridine 451117, bilysine ld and malonic acid 5.71I were added, and the mixture was heated to 120°C. Time reacted. The reaction solution was allowed to cool to room temperature, water was added, the mixture was acidified with hydrochloric acid, and filtered. This was recrystallized from a mixed solution of hexane-ba/yne to obtain the title compound 1 having the following physical properties.
0.7g was obtained.

- MS: m/Z=204 (M), 161.144.11
5°NMR: δ = 7.80 (d, IH), 7.48 (d
, 2H), 7,18(tL, 2H), 6.42('', I
H), 2.50 (d.

2H), 1.84 (771, IH), 0.90 ((Z,
6H).

Reference Example 5 (α) p-ino is cinnamic acid The title compound 2.9II having the following physical property values was obtained by the same operation as in Reference Example 5 using 2.7 g of the compound produced in Reference Example 3 (α). Ta. In addition, the recrystallization method (rL-
Hexane-benzene) was used.

MS: m/Z=218(M), 151.144,11
5 NMR: δ-7,8Q(ct, 1)I), 7.4
8 (d, 2H), 7.22 (d, 2H), 6.40 (
d-, IH), 2°63 (t.

2H), 1.40-1.80('', 3H), 0.92
(t.

6l-1).

Reference Example 5 (h) P-cyclohexylcinnamic acid The title compound 3. having the following physical property values was obtained by the same procedure as in Reference Example 5 using 8.6 g of the compound produced in Reference Example 3 (C). Obtained Og. Note that a recrystallization method (chloroform) was used for purification.

NMR: δ-7,8Q (d, IH), 7.48 (d,
2H), 7.26 (d, 2H), 7.22 (d, 2H)
), 6.43 (d.

IH), 2.40-2.80 (rn, IH), 1
．． 60-2.00 (4,5H), 1.20-1.60 (
m, 5H).

Reference Example 5 (C) P-heptylcinnamic acid Reference Example 3 ((9.0 g of the title compound having the following physical property values was obtained by the same operation as in Reference Example 5 using Compound 8.7I produced by Ll.

143:mlZ-246CM), 161.144.1
15°NMR: δ = 7.80 (d, IH), 6.41 (
cL, IH), 2.63 (t, 2H), 1.40-1.
70 (771, 2H), 1.30 (m, 8H), 0.8
6 (F7L, 3H).

Reference Example 5 (d) p-decylcinnamic acid Using 1.3 g of the compound produced in Reference Example 3 (C), 1.2 g of the title compound having the following physical property values was obtained by the same procedure as in Reference Example 5. Ta.

TLG: Hf=0°55 (chloroform:methanol-
1:9).

MS two doors/Z=288CM), 161°■R Niji=3
400-2300.1680.1620.1605.1
460.1425.1310.1290.1225.1
180.980cm-”.

NMR: δ-7,88 (d, IH), 7.33L9.
4l-1), 6.39 (cz, tH), 2.63 (t,
2) (), 0.87 (m, a) (t.

Reference Example 6 p-Amyl acetophenone 8.6 g of aluminum chloride was suspended in 60 m/m of carbon tetrachloride, and 4.6 ml of acetyl chloride was added dropwise.
The mixture was cooled with ice, and a solution of 8 g of amylbenzea dissolved in 3 Q ml of carbon tetrachloride was added dropwise. After stirring the reaction solution for 2 hours, it was poured into ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated sodium chloride water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The concentrate was purified by distillation to obtain 6.6 g of the title compound having the following physical properties.

MS: nL/Z=190CM), 185.133°N
MR: δ-7,88 (ct, 2H), 7.25 (li,
2) 1), 2.64 (1!, 2H), 2.55 (2,
3H), 1,40-1.80 (m, 2H), 1.20
~1.40 (1,4H), 0.87 (t, 3)1).

Reference Example 7 P-A, Milutimethylcinnamic acid Compound 6.61 produced in Reference Example 6 was dissolved in 50 ml of toluene.
14 g of methoxycarbonyl triphenyl phosphorane was added thereto, and the mixture was heated under reflux for 48 hours. After the reaction, the reaction was allowed to cool, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.6 g of methyl ester of the title compound.
I got it. This was mixed with methanol-tetrahydrofuran (1:
Dissolve in the mixture of 1) and add 12 mJ of 5N potassium wedzide.
was added for hydrolysis, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.

The residue was purified by silica gel column chromatography.
280 mg of the title compound having the following physical properties was obtained.

MS: m/Z-232tM), 214.175.15
8°NMR: δ=7.32L9,2H), 6.18(d
, IH), 2.64 ('+ 2H), 2.62 (d, 3
H), 1.64 (m.

2H), 1.30-1.40('', 4H), 0.90(
t, 3H).

Reference example 8 3-Hebutyldecyl cinnamic acid Phenyl hebutyldecyl ke) y6JF.

The mixture was dissolved in Roform 30+J, methoxycarbonyl methylidene triphenylphosphora/12.51 was added, and the mixture was heated under reflux for 72 hours. After the reaction, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (rL-hexane:ethyl acetate = 40:1), and the obtained methyl ester was dissolved in ethanol-tetrahydrofura/.
Hydrolysis using an aqueous potassium hydroxide solution and purification by recrystallization gave the title compound 430■ having the following physical properties.

MS Near 1L/Z-358CM 398.175.1
62°NMR: δ-7,40 (771,5H), 6.0
6 (J', IH), 3.12 (t, 2H), 1.20-
1.40 (m, 26H), 0.87 (t, 3H) 0 Reference Example 9 p-Hydroxycinnamic acid methyl ester 1-1 p-Hydroxycinnamic acid (produced in Reference Example 4) 25I
! was dissolved in 2001 rL of methanol, hydrogen chloride gas was bubbled in for 30 minutes under water cooling, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane:ethyl acetate=10:1) to obtain 26 g of the title compound having the following physical properties.

MS: m/Z=178 (M), 147.119.91
°NM)t:δ=6.88-7.48(ctct, 4
H), 6.30-7.85 (9,2H), 3.80 (#
, 3H).

- Reference Example 10 1.04 g of sodium p-octyloxycinnamate hydride was suspended in 151 dK of anhydrous tetrahydrofuran, cooled on ice, and a solution of compound 4.5S prepared in Reference Example 9 dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise, and then Anhydrous dimethylformamide IQm
Added l. Add 5.8g of octyl bromide to this reaction solution.
A solution of was dissolved in anhydrous tetrahydrofura/10IIIJ was added, and the mixture was refluxed for 4 hours.

After the reaction, 50 uJ of ether and 50+/ml of water were added, and the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a mixture of tetrahydrofuran (3Qm/) and methanol (30ml), 15d of a 4N aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours.

After the reaction, water, ether and 5 m/ml of concentrated hydrochloric acid were added, and the ether layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization using Yinying to obtain 3.0 g of the title compound having the following physical properties.

MS two doors/Z-276 (M), 258.164.14
7°NMR: δ = 7.20 (dd, 4H), 7.00 (
9,2H), 3.98(t,2H), 1.60-1.9
0 (m, 2H), 1.20-1.60 (7FL, 10H
), 0.87 (t, 3H).

Reference Example] 1 2-rN-(7)-amylcinnamoyl)aminocophenol P-amylcinnamoic acid (produced in Reference Example 4) was added with 1d of oxalyl chloride, and was incubated at room temperature for 1 hour. After that, the mixture was concentrated under reduced pressure, and chloroform 2- was added.

This is O-aminophenol 1621n9 and triethylamine 142 and loloform 4#+7! The mixture was poured into a solution dissolved in water under ice cooling, stirred at the same temperature for 1 hour, water was added, extracted with ethyl acetate, and concentrated under reduced pressure. Methanol was added to the residue, insoluble matter was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: luhexa:/=1:4), which had the following physical properties. The title compound 69IR9 was obtained.

TI, C: Rf-0,60 (ethyl acetate:rL-hexane-1=2).

MS: m/Z-309 (M), 201.131° engineering R
Niji-1650, 1620, 1600cm-'.

NMR: δ-9,33 (ε, IH), 7.77 (d,
l) I'), 7.76 (yttH), 7.00-7.5
0 (FIL, 7H), 6.85tdt*tH),
6.57 (d, IH).

Example I N-(7'-1 milci/namoyl)orthanylate p-amylcinnamic acid #! (Produced in Reference Example 4.) Add 1 d of oxalyl chloride to 100 IQ, stir at room temperature for 1 hour, concentrate under reduced pressure, and add 1 ml of methine chloride. This common solution was cooled on ice, and 79 μl of orthanyl acid was added. A methine chloride/solution (1 ml) containing 92 Da and triethylamine was added and stirred overnight at room temperature.

After the reaction, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate.

The extract was washed successively with diluted hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 551 ng of the title compound having the following physical properties.

TLC: Rf day 0.1 (ethyl acetate).

IR Niji = 1660.1630.1610.1595
CFILONMH: δ=8.42 (cL, IH), 7.
88 (ct, IH), 7.68 (d, IH), 7.10
-7.55 (F71.7) (), 6.63 (cL, IH
).

Example 1 (α) Using the compound 110111& produced in Reference Example 4 and 77 da of 3-hydroxyanthranilic acid (1), the title compound 52 da was obtained by the same procedure as in Example 1 having the following physical property values.

In addition, silica gel column chromatography (ethyl acetate:Ruhexane-1:2) was used for purification.

TLC: Rf = 0.2 (ethyl acetate) MS: m/Z = 353 (M), 335.317.28
9.201°IR (liquid film method) Niji = 1720.1680
, 1620.1600cR-1°NMR (GDC13+-CD30D): δ-6,90
-7,70 (m, 8H), 6.30-6.65 (rn,
IH).

Example 1 (h) The title compound 701119 having the following physical properties was obtained by the same procedure as in Example 1 using 170 da of the compound prepared in Reference Example 4 and 100 da of 2-aminothiophenol. In addition, silica gel column chromatography (cyclohexa/:ethyl acetate-5=1) was used for purification.

TLG: Rf-0,7 (cyclohexene:ethyl acetate=
3:1).

MS: m/Z-325 (M), 323.306.29
0.266.201.161°NMll: δ-8,49 (d, IH), 8.10 (-?
, IH), 7.63tds iH), 7.47(d, 2
H), 7.21 (114°2H), 7.1-7.4 (m
, 2H), 6.98 (t.

IH), 6.19 (d, IH), 2.64 (t, 2H)
1.65 (rn, 2H), 1.32 (m, 4) 1), 0
．． 9, (tl 3H).

Example 1 (C) The title compound 164~ having the following physical properties was obtained in the same manner as in Example 1 using Compound 172* produced in Reference Example 4 and 4-nitroanthranilic acid 1434.

Note that purification was performed by recrystallization method (ethyl acetate).

TLC: Rf=0.1 (ethyl acetate) 0MS near 71/
Z-382CM), 364.201.161.152
a engineering R: υ = 1710.1670.1615.159
5cWL.

NMR (CDC13+CD30D): δ-9,73(d
, IH), 8.28 (d, IH), 7.90 (dd, I
H), 7.76u, iH), 7.15-7.60 (77
! , 4H), 6.54(d, IH).

Example 1(d) The title compound 130■ having the following physical properties was obtained by the same operation as in Example 1 using Compounds 130~ produced in Reference Example 4 and 4-chloroa/tranyl acid 102■.

Note that a recrystallization method (ethyl acetate:rL-hexane-1:1) was used for purification.

TLC: R/-0,2 (ethyl acetate) OMS: tn
/Z-371(M), 353,201゜Work R Niji =
1705.1670, 1600.1570cInONM
R (CDG13+CD30D): δ-8,49(',
IH).

8.05('', IH), 7.73Ld, IH), 7.1
5-7.55 (Tn, 4H), '7. o7(aa.

IH), 6.56 (d, IH).

Conventional Flow Example 1 (C) The title compound 172~ having the following physical properties was obtained by the same procedure as in Example 1 using Compound 170da prepared in Reference Example 4 and 5-methylanthranyl fi118. Note that a recrystallization method (ethyl acetate-ruhexane) was used for purification.

TLCt:)1/=0.30 (Ethyl acetate:n-hexane7=1:1)■R Niji=1680.1620.1
590.1520 (Mll-'.

NMR: δ = 8.77 (d, IH), 7.96 (”
, IH), 7.75 (dttH), 7.43 (dd, I
H), 7.15-7.55 (yx, 4H), 6.55 (
d, IH), 2.38 ('13H).

Example 1σ) The title compound 170 having the following physical property values was obtained by the same operation as in Example 1 using Compound 150In9 produced in Reference Example 4 and 5-chloroanthranilic acid 1181119.
F#g was obtained.

TLC:) 17-0.30 (ethyl acetate).

MS: m/Z=371.353.201.144゜Work R
:υ =1680.1620.1600.1580.1
510cIrL-1°NMR (CDC13+CD30D): δ-8,75(d
,,IH), 8.08(d,iH), 7.72('',4
H), 7.50<ctcLtIH), 7.15-7.6
0 (F7L, 4H), 6.55 (d, IH).

Example 1 (g) -(ρ-Amylcinnamoyl)-3-chloroanthranilic acid The following procedure was carried out in the same manner as in Example 1 using the compound 165■ produced in Reference Example 4 and 3-chloroanthranilic acid 135η. Title compound vlJ1351%' having physical properties
I got it.

TLC: Hf=0.30 (ethyl acetate).

MS Near FL/Z=371.353.336.2010
Engineering Rniji = 1690, 1655.1620.1510c
m.

NMR (CDC13+CD30D): δ=7.89(
d, d, IH), 7.72 (d, IH), 7.62 (”
, IH), 7.40-7.55 (FW, 2H), 7.
15-7.30 (rILt3H).

Example 1 (A) Compound 138 da and 2-amino- produced in Reference Example 4
The title compound 130Fn having the following physical properties was obtained by the same operation as in Example 1 using 4-nitrophenol 979.
I got a 9. In addition, for purification, recrystallization method (rhexane-
Ethyl acetate was used.

TL (3: Rf=0.60 (ethyl acetate:rL-hexa7=1=1).

MS: m/Z=354,201.131゜Work R Niji =
1670.1620.1595.1540cm-1°N
MR (GDC; 733 + GD301): δ-8,7
5 (d, IH), 7.93 (dd, 1) Shun, 7.75
('', lH)・7.45,7.55(m, 2t()
, 7.15-7.30 (4,2H), 6.95 (L:t
, IH), 6,64(d, IH).

Example 4 (Ll) Using the compound 125■ produced in Reference Example 4 and 2-aminobenzotrifluoride 92■, the title compound 55■ having the following physical property values was obtained by the same procedure as in Example 1. Note that the &ma recrystallization method (n-hexane) was used for purification.

TLC: Rf 0.40 (ethyl acetate:Ruhexane=1:1).

MS: yrL/Z=361.342.304.25
6.201.144.131゜IR Niji=1660.1625.1590.1530(
:rrL.

NMR: δ-8,75 (d, IH), 7.74 (d,
IH), 7.4-7.7 km, 4H), 7.
15-7.30 (m, 3H), 6.47 (17,1[)
.

Example 10) The title compounds 65 to 65 having the following physical properties were prepared in the same manner as in Example 1 using Compound 128da produced in Reference Example 4 and 3,5-cycloa/tranilic acid 1211n9.
I got it. Note that a recrystallization method (n-hexane-ethyl acetate) was used for the purification.

TLC: Rf-0,20 (ethyl acetate).

MS:ya/Z-407,405,389,387,3
32,330,218,201,189,187゜Work R
Niji-1700, 1645, 1615, 1600α U NMR (CDC13+CD30D): δ=7.86
”, IH), 7.69 (d, IH), 7.61 (dt
lH), 7.15-7.55 C'n, 4H), 6.
60 (d.

IH).

Example 1 (k) 3-CN-(p-amylcinnamoyl)aminosalicylic acid Using 150 Ing of the compound produced in Reference Example 4 and 105~ of 3-aminosalicylic acid, the following physical properties were obtained by the same operation as in Example 1. The title compound 67Fng was obtained. Note that Preparatize TL, C (ethyl acetate:methanol = 4:1) was used as the precipitate.

TLC: Rj-0,30 (ethyl acetate: methanol
:1).

MS:”/Z=353(M), 309.290.20
1゜Work R Niji-1650, 1620, 1600, 152
0cm.

NMJUD3QD): δ=8.20d-d, IH),
7.63L””.

IH), 7.4HcL, IH), 7.15-7.55 (
m, 4H), 6.92 (d, 11(), 6.76 (ie
IH).

Example 1 (4) 2-[N-(J[+-amylcinnamoyl)aminocoterephthalic acid] Same as Example 1 using compounds 170 to 2-aminoterephthalic acid prepared in Reference Example 4 and 141 da of 2-aminoterephthalic acid. By this operation, the title compound 891Rg having the following physical properties was obtained.

TLO: Rf=0.20<ethyl acetate:ruhexane-
1:1).

MS: m/Z-365, 347, 219, 144, 13
7,131°14MR: δ-=8.88 (d, 1) 8.15 (d
t, IH), 7.62 (dt, IH included 7.1-7.6
(m, 4) (), 7.12 (t, IH), 6.56
(tL, IH).

Example 1 (N-(7'-amylcinnamoyl)-4-methoxyanthranilic acid) The following procedure was carried out in the same manner as in Example 1 using the compound 218 d prepared in Reference Example 4 and 250 d of 4-methoxyanthranilic acid. The title compound 225■ having the physical property values was obtained.For purification, silica gel column chromatography (
Chloroform:methanol=40:1) was used.

TLO: 1 (f=0.56 (ethyl acetate:methanol≠
10:1).

MS: m/Z-367 (M), 349.292.20
1.167.161.144.131.115.43°IR Niji=3100.2930.2860.1680.
1610.1585.1525.1460.1395.
1335.1220.1140°1035.1005.
970 cFIL.

NM) ((CD30D): δ=8.29Ld, IH)
, 8.02 (d.

IH), 7.61(d, IHn, 7.51('',
2H) 7.19 (d, 2HJ, 6.57 (d, lH)
, 6.62('', IH', 3.83(-', 3H), 2
．． 61 (t, 2H), 1.61 (Fll, 2H), 1.
20-1.45 (rrL, 4H), 0.89 Lt
, 3) 1).

Example 1 (1) The title compound 230η having the following physical property values was obtained by the same procedure as in Example 1 using Compound 239■ prepared in Reference Example 5 and 4-chloroanthranilic acid 201~.

For purification, a recrystallization method (rL-hexane: ethyl acetate 10:1) was used.

MS two doors/Z= 359.357.340.187゜I
R Niji = 1700.1670.1600.1570.1
500cIrLO N to R (CDOI3+CD30D): δ=8.93(
d, IH), 8.03 (cl, IH), 7.73 (ld
, IH), 7.1-7.6 (m, 4H), 7.07 (d
d, IH), 6,55 (dt IH).

Example 1 (0) 4-chloro-N-(7'-isoityrsinnamoyl)
The title compound 227~ having the following physical property values was obtained by the same procedure as in Example 1 using Compound 211■ produced in Anthranilic Acid Reference Example 5 (α) and 4-chloroanthranyl #R166~.
I got it. Note that a recrystallization method (Rhexa/-ethyl acetate) was used for purification.

'I'LC: R7-0.20 (ethyl acetate #: n-hex f
7=2:1).

MS: m/Z-374, 372, 353, 201°IR
:υ巳1700.1670.1600α.

NMR(GDO13+(jD30Dn: 6 days 8.95(
d, IH), 8.03 (d, IH) h7.70Ld,
IH), 7.1-7.5L”, 4H), 7.06((Z
d, IH), 6.55 ('', IH).

Example 1 (P) 206 mg of the title compound having the following physical properties was obtained by the same procedure as in Example 1 using Compounds 219 to 219 prepared in Reference Example 5 (h) and 164 μl of 4-chloroa/tranyl acid.
I got it. Note that a recrystallization method (ethyl acetate) was used for purification.

TLO: Rf-0,20 with vinegar, n-hex-2: 1).

MS: m/Z-385, 383, 365, 213° Engineering R Niji is 1700.1670.1625.1600.
1580cIIL O NMR (GDGJ3+CD3(JD): δ-8,89(
d, IH), 8. o3(d, IH included 7.89(d, 1
)1), 7.2-7.6 (m, 4H), 7.06 (dd
, IH), 6.55(d, IH),.

Example 1 (q) Using 275 rng of the compound prepared in Reference Example 7 and 305 ml of 4-chloroanthranilic acid, the title compound 72~ having the following physical properties was obtained by the same operation as in Example 1. Note that a recrystallization method was used for purification.

TLG:I:11 0.20 (ethyl acetate).

MS: m/Z-385, 367, 215, 145, 11
5,43゜IH Niji-3150, 2930, 2860,
1690, 1675, 1600, 1580, 1510,
1415, 1380, 1190, 1145, 1°110
0.915 CIl! O NMR: δ-11,00 (J', 1) 1), 8.80 (
d, IH), 8.02 (d, 1) 1), 7.41 (d
, 2H), 7.19 (d, 2) 1), 7.05 (ctd
, IH), 6.16(#,1)(), 3.50(#,I
H), 2.64 ('', 3H), 2.62 (t, 2H),
1.62 (71t, 2H), 1.20-1.45 (7
'L, 4H) 0.89 (t, 3H).

Example 1(r) The title compound 71 da having the following physical property values was obtained by the same operation as in Example 1 using the compound 155 da produced in Reference Example 4 and 4-fluoroanthranyl fi100 #. Note that a recrystallization method was used for purification.

TLC: R7-0,20 (ethyl acetate.

MS: m/Z=355.337.310.201.14
5, 131.115.43゜R Niji -3110, 2930, 2860, 1710
, 1675, 1605, 1525, 1450, 1430
,1390,1340,1280,1210,1130
,1005,990,970,905,810clIL
a NMR: δ-11,32 (JP, IH), 8.71 (”
, IH).

8.16 (dd, IH), 7.75 (d, IH), 7.
48 (ct* 2H), 7.18 (tL, 2H), 6.
81 (F71.IH), 6.53 (d, IH), 4.4
0('t IH), 2.61(t, 2H), 1.60(
77L, 2) 1), 1.20-1.45 (m, 4H) 0
．． 88(t,3)1).

Example 1 (J'1 4-Chloro-N-(P-hebutylcinnamoylphanthranilic acid) Example 1 using the compound 184 da produced in Reference Example 5 (C) and 129 da of 4-chloroanthranilic acid The title compound 1451v having the following physical property values was obtained by the same operation as
I got it. In addition, the recrystallization method (ethyl acetate-luhexane) was used for M product.

TLG: R7-0,20 (ethyl acetate: ruhexa/-
2:1).

MS: m/Z-401, 399, 381, 229, 18
9,144,131゜Engine R Niji-1700, 1670, 1600, 1570,
1520, 1505.

NMR: δ-9,00 (tL, IH), 8.05 (d,
1) l), 7.75 (d, IH), 7.15-7.5
5 (FIL, 4H) 7.10 (dd, IH), 6.
53(d, IH).

Example 1(t) 4-chloro-N-(7'-7'silcinnamoyl)anthranilic acid C/ Compounds 1821Ni and 4 produced in Reference Example 5(d)
- Using chloroanthranilic acid 1099 (.), the title compound 13 having the following physical properties was obtained by the same procedure as in Example 1.
I got 3 ■. Note that a recrystallization method (methanol) was used for purification.

TLC: R7-0,30 (ethyl acetate:F&-hexane-2=1).

MS Near 71/Z-443, 441, 423, 296,
271゜IR Niji-1700, 1670, 1595, 1
565,1510 硼 NMR: δ-8,9H (d, tH), 8.07 ('', I
H), 7.76Ld, IH), 7.15-7.6 OL
71L, 4H) 7.11 (dd, IH), 6.5
4(”, IH).

Example 1 (W) Manufactured with reference vivU10 (1 snout, 19111#9
The title compound 150Isg having the following physical properties was obtained by the same procedure as in Example 1 using 119Isg of oyohi 4-chloroanthranilic acid. In addition, recrystallization method (n-
Hexane) was used.

TLC: R/da 0.20 (ethyl acetate:ruhexane zero 1=1).

MS Two Raku/Z-429, 411, 299, 259, 14
7゜IR rainbow 1680.1660.1590.156
5.1500cIfL.

NMR (GDGJ3+GD30D): δ-8,9H (
', IH), 8.02td, tH), 7.66(d, I
H), 7.4-7.6 (m, 2H), 7.04Ldct
, 1) 1), 6.8-7.0 (also 2H), 6.44
(', 1 to -1).

Example 1←) Using the compound 154 da produced in Reference Example 8 and 74 da of 4-chloroanthranilic acid, the title compound 100■ having the following physical properties was obtained by the same operation as in Example 1. Note that a recrystallization method (ethyl acetate-ruhexane) was used for purification.

TLO: Hf=0.20 (ethyl acetate: rL-hexa/
=2:1).

MS: m/Z = 511,493.341 engineering R Niji = 16
90.1670.1620.1595.1565.15
10c/rL.

NMR (CIX; l!3 + GD30D): δF8.6
9('', IH), 7.89(d, 1)(), 7.15-
7.40 L m, 5H), 6.96 (ctd, I
H), 5.9J', IH).

Example 1 (W) 1.13 g of the compound produced in Reference Example 4 and Reference Example 2
The title compound 54'7I having the following physical property values was obtained by the same operation as in Example 1 using Compound 1.09# prepared in
I got n9. Note that silica gel column chromatography (ethyl acetate-ruhexane) was used for purification.

TLC: Rf-0,40 (ethyl acetate=f&-hexane=1:2).

MS: m/Z=351 (M), 201.151.13
1゜NM) 1: δ=12.96 (JI, IH), 8
．． 77ud, IH), 8.02 (♂, IH included 7.7
4Ld, IH), 7.48 (lK, 3H), 7.20 (
'? 2H), 6.94 (t, IH), 6.56 (d
, IH), 2.64 (t, 2H), 2.63 (J'
, 3H), 1.10-1.80 on the door, 6H), 0.
90 (t, 3H).

Example 2 Under an argon atmosphere, 0.16#IJ? was slowly added at 0°C and stirred for 5 minutes. An anhydrous chloroform solution (3d) of Compound 113da prepared in Reference Example 11 was slowly added to this at 0°C, and the mixture was stirred at the same temperature for 30 minutes and then at the lowest temperature for 1 hour.

After the reaction, ethyl acetate and dilute hydrochloric acid were added, the layers were separated, and the organic layer was washed successively with water, an aqueous sodium bicarbonate solution, and Juri saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate: cyclohexane = 2 = 5) to obtain the title compound 106 having the following physical properties.

Tl, (3: k'lf = 0.25 L vinegar ["chill:
cyclohexane = 1:2).

MS: m/Z=445CM), 416.400.37
4.290.245.227.201.131,''15
．． 43゜■)tniji+3310.2980.2950.
2920.2850.1685.1630.1605.
1525.1480.1445.1340°1275.
1255.1185.1160.1105.1050.
1030.970cWLONMI(: δ -8,64
L-? , 1) 1), 8.36 (a, IH n, 7.74
(d, IH), 7.48u, 2H), 7.18 (d, 2
H), 7-15-7.30 (nL, 20H) 7.0
6 (t, IH), 6.55 (d, 1) 1 n, 4.13
(fi, 4H), 2.62 (t, 2H), 1.62Lm
, 2'l), 1.34 L tL t , 16 H
), 1.20-1.50 (fi, 4H), 0.89 (t
, 3H).

Example 3 1 ml of oxalylchloride F# was added to 109 ml of P-amylcinnamic acid (produced in Reference Example 4), stirred at room temperature for 1 hour, concentrated under reduced pressure, and 1 ml of methylene chloride was added.

This solution was cooled on ice, and 4-hydroxyanthranyl@77
IV.) A mixture of 0.214 ml of ethylamine and 2 d of chloroform was added, stirred at the same temperature for 30 minutes and at room temperature for 1 hour and 30 minutes, poured into 20 d of 0.5N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in a mixture of methanol (L2.5+d)-tetrahydrofuran (2,5a/), 2d of a 1N aqueous sodium hydroxide solution was added, and the mixture was allowed to stand overnight.

After the reaction, 3 ml of 1N hydrochloric acid and 10 + tj of water were added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column chromatography (chloroform:methanol=10:1) to obtain the title compound 58 having the following physical properties.

TLO: R7 = 0.23 (chloroform: methanol =
10:1).

MS:yx/Z=353LM), 335.309.2
78.2θ1.161.131.115.43°IR Niji -3100,2930,2860,1660
゜1605.1550.1450.1410.1325
．． 1250.1145.1000.975.870.7
70α.

NMR(01)Gl3+CD3oD): δ=8.
24 (lt, IH), 7.49 ('', 2H), 7.20
(d, 2) 1), 6.60 (d, IH), 6.56 (d
d, IH), 2.64 (t, 2H), 1.64 (m, 2
H), 1.20-1.45 (711,4H), 0.90
(t, 3H).

Example 4 6-acetyl-2-[N-(7'-amylcinnamoyl)aminocophenoxyacetic acid methyl ester Example 1 Compounds 305~ produced in Japan were dissolved in 710ml of methyl ethyl ketone, and 260ml of sodium iodide, 2- , / lomoacetic acid methyl ester 0.83 ml, and potassium carbonate 73
11 ng of the mixture was added, and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature and filtered, and the filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:rL-hexane-1:5) to obtain the title compound vIJ285■ having the following physical properties. -hexane-1=3).

MS: m/z-423CM), 397.392.36
6.364.351.334.223.201.144
．． 131.115°NMI (: δ-9,84(-', 1)(), 8.76
(dd, IH), 7.75 (d, IH),? ,52L
d, 2H), 7.35 (44, IH), 7.20 (',
1) (), 7.18 ('', 28), 6.75 (',
1) (), 4.62 (ε, 2H), 3.84 (J',
3H), 2.63(i', 2)1), 2°60LJ'
, 3)1), 1.62Lm, 2)1), 1.20-1
．． 45 (FFL, 4H), 0.88 (t, 3H)
.

Example 5 280 Ing of the compound produced in Example 4 was dissolved in methanol (
3a11 was dissolved in a mixture of tetrahydrofuran (3a/), 211Il of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature all day and night. After that, 3D of 1N hydrochloric acid and 15R1 of water were added, 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 a recrystallization method (ethyl acetate-ruhexane) to obtain the title compound 131■ having the physical properties shown in J.

'rt, c: Rf-o, 3ot acetate ethyl: methano-A
/M5: 19 MS: m/Z-409 (M), 39
1.351.334.259.209.201° Engineering R Niji Snow 3270.3120.2930.2850.
1740.1680.1660.1615.1600.
1540.1435.1410, ~1350.1270
．． 1160.1120.1050.975CIllllI NMR: δ -9,70L&, 1l-1), 8.70(
d, LH), 7, 'lOt', IH), 7.00-7.
55tm, 6)1).

6.65 (d, IH), 4.3J#, 2) 1), 2.5
7tyt 3H), 2.55(t, 2H), 1.56(
m, 2l-1), 1.20-1.45 (m, 4H),
0.87 (t, 3H).

Example 6 Compound 85 prepared in Example 1 (gradient) was dissolved in methanol 5
m7! Dissolved in 1 N aqueous sodium chloride solution 0,
23 ml was added, concentrated under reduced pressure, and dried in a desiccator to obtain the title compound 86η having the following physical properties.

NM) 1(CD30D): δ=821H(t, IH)
, 7.62L11', In-1).

7.53('', 2H, 7.2H'', 2)1), 7.
00 (d, IH), 6.87-7.12 (m, 3
H), 4.44 (#, 2H), 2.63 (t, 21
(), 1.64 (m, 2) 1), 1.25-1.45
Lm, 4H), 0.90 (t, 3H).

Example 7 The same operations as in Example 6 were carried out, and Examples 1(C) and 1(
d), 1(e), 1(force, 1(fl, 1(1),
1(r), 1 (rL+, 1(0), 1(p), 1
The corresponding sodium salts of compounds (S), 1(t;, 1(9) and 3) were prepared.

The monosodium salt of the compound of Example 1 (1) was produced.

Example 8 N-(P-amylcinnamoyl)orthanilic acid 5.9.
Cellulose calcium gluconate (disintegrant) 200Ing,
100 μl of magnesium stearate (lubricant) and 4.7 μl of microcrystalline cellulose were mixed in a conventional manner and compressed to give 100 tablets containing 50 μl of active ingredient in each tablet.

Claims (1)

[Scope of Claims] [In the formula, R is (1) a straight-chain or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, a straight-chain or branched alkenyl group having 2 to 15 carbon atoms, or represents an alkenyloxy group, (1) an unsubstituted phenyl group or benzyl group, or a hydrogen atom, or (ili) a cycloalkyl group having 4 to 7 carbon atoms, and R and R are each independently , represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 20 carbon atoms, and R is a (11 carboxy group, carboxymethyl group, or carboxymethoxy group, or a straight-chain or branched chain having 2 to 6 carbon atoms) an alkoxycarbonyl group or a linear or branched alkoxycarbonylmethyl group having 3)7 carbon atoms represents an alkoxycarbonylmethoxy group or a hydroxyl group, or (
Ill represents a mercapto group, a sulfo group, a jetoxyphosphonoyl group, or an acetyl group, and R4 and R5 each independently represent a hydrogen atom, a halogen atom, or a carbon number of 1 to 4.
straight-chain or branched alkyl or alkoxy groups,
Represents a carboxyl group, a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms, a hydroxyl group or a nitro group,
LE represents 0, 1 or 2, and the symbol == represents a double bond (star, ヱ or EZ mixture) or a single bond. However, R or the above (11Fr: R4 and R if applicable)
are not hydrogen atoms at the same time. ] An aniline derivative or a non-toxic salt thereof. 2) The compound according to claim 1, wherein the symbol = represents a double bond, and 1 is 1. 3) The compound according to claim 1 or 2, wherein R is an amyl group. 4) R is a carboxy group, a carboxymethyl group, a dimethoxy group in a carboxyl group, a methoxycarbonyl group. Claims 1 and 2 are methoxycarbonylmethyl groups, methoxycarbonylmethoxy groups, or hydroxyl groups.
A compound according to item 3 or item 3. 5) The compound according to claim 1, 2, 3 or 4, wherein R is a halogen atom or a nitro group. 6) The compound according to claim 1, 2, 3 or 4, wherein R is a carboxy group or a hydroxyl group. 7) The compound according to claim 1, 2, 3, or 4, wherein I-i is a methyl group, a methoxy group, or an acetyl group. 8) A compound according to claim 1, 2 or 3, wherein R is a sulfo group, a mercapto group, a trifluoromethyl group, a jetoxyphosphonoyl group or an acetyl group. 9) R and R are The compound according to claim 1, 2, 3, or 8, wherein both are hydrogen atoms. 10) R is an isobutyl group or an isopentyl group. 3. The compound according to claim 1 or 2, which is a heptyl group, decyl group, octyloxy group or cyclohexyl group. 11) The compound according to claim 1, 2 or 10, wherein R is a carboxy group or a methoxycarbonyl group. 12) Claim 1, in which R is a halogen atom;
A compound according to item 2, item 10 or item 11. 13) The compound according to claim 1, which is N-Cp-amylcinnamoyl)orthanyl acid. 14) The compound according to claim 1, which is N -CP-amylcinnamoyl)-3-hydroxyanthranilic acid. 15) The compound according to claim 1, which is z-CN-<p-amylcinnamoylamino]thiophenol. 16) The compound according to claim 1, which is N-(P-amylcinnamoyl)-4-nitroanthranilic acid or its sodium salt. 17) The compound according to claim 1, which is N-(P-amylcinnamoyl)-4-chloroa/tranilic acid or its sodium salt. 1B) The compound according to claim 1, which is N-CP-amylcinnamoyl)-5-methyla/tranyl acid or its sodium salt. 19) The compound according to claim 1, which is N -CP-amylcinnamoyl)-5-chloroanthranilic acid or its sodium salt. 20) The compound according to claim 1, which is N-(7)-amylcinnamoyl)-3-chloroa/tranilic acid or its sodium salt. 21) Claim 1 which is 2-(N-(7)-amylcinnamoyl)7mi/)-4-ditrophenol
Compounds described in Section. 22) When 2-(N-CP-amylcinnamoyl)amino]ha/citrifluoride, g'f is the compound according to claim 1. 23) N-(p-alcyl/namoyl)- The compound according to claim 1, which is 3,5-dichloroanthranilic acid. 24) The compound according to claim 1, which is a-(N-(7)-7milcinnamoyl)aminocosalicylic acid. 25) The compound according to claim 1, which is 2-CN-(p-amylcinnamoyl)aminocoterephthalic acid or its sodium salt. 26) The compound according to claim 1, which is N-(p-amylcinnamoyl)-4-methoxyanthranilic acid or its sodium salt. 27) Compound 028)-1chloro-N of claim 1 which is 4-chloro-N-(7)-isobutylcy/namoyl)anthranilic acid or its sodium salt
-(7)-isoityrsinnamoyl)anthranilic acid or its sodium salt 29) 4-chloro-N-(7)-cyclo-
! The compound according to claim 1, which is anthranilic acid or its sodium salt. 30) The compound according to claim 1, which is N-(71-amyl-3-methylcinnamoyl)-4-chlorotetraanthranilic acid or its sodium salt. 31) The compound according to claim 1, which is N-Cp-amylcinnamoyl)-4-fluoroanthranilic acid or its sodium salt. 32) The compound according to claim 1, which is 4-chloro-N-(7)-hebutylcinnamoyl)anthranilic acid or its sodium salt. 33) The compound according to claim 1, which is 4-chloro-N-(p-decylcinnamoyl)anthranilic acid or its sodium salt. 34) The compound according to claim 1, which is 4-chloro-N-(7)-octyloxycinnamoyl)anthranilic acid. 35) Special wfI which is 4-chloro-N-(3-nitadecyl/namoyl)anthranilic acid! A compound according to item 1 of the W-end range. 36) The compound according to claim 1, which is 6-acetyl-27r N -(p-amylcinnamoyl)aminocophenol. 37) The compound according to claim 1, which is 2-(P-amylcinnamoyl)aminophenyl diethyl phosphate. 38) The compound according to claim 1, which is N-(p-amylcinnamoyl)-4-hydroxyanthranilic acid or its sodium salt. 39) The compound according to claim 1 which is 6-acetyl-2-(N-(p-amylcinnamoyl)aminocophenoquinicacetic acid or its methyl ester. 40) (11 General formula [wherein, R represents (1) a straight chain or branched chain alkyl group or alkoxy group having 1 to 15 carbon atoms, a straight chain or branched chain alkenyl group or alkenyloxy group having 2 to 15 carbon atoms, or (i) represents an unsubstituted phenyl group or indyl group, a hydrogen atom, or (Ill) represents a cycloalkyl group having 4 to 7 carbon atoms;
each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms, R represents 0.1 or 2, and the symbol =: represents a double bond (F, Z or 1 mixture) or a single bond. ] Acid chloride represented by the general formula [wherein R is (1) a carboxy group, a carboxymethyl group, a carboxymethoxy group, a straight chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a carbon Represents a linear or branched alkoxycarbonylmethyl group, alkoxycarbonylmethoxy group, or hydroxyl group of numbers 3 to 7, or (Ill represents a mercapto group, sulfo group, jetoxyphosphonoyl group, or acetyl group, R and R Each independently represents a hydrogen atom, a halogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, an alkoxy group, a carboxy group, a straight-chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms. 1 represents a hydroxyl group, a hydroxyl group, or a nitro group.However, when R falls under (1) above, R and R must not be hydrogen atoms at the same time. or the general formula % [In the formula, H and R each have the same meaning as H and R above, but may also be a hydrogen atom, and other symbols are the same as above. [In the formula, R represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, and X and X each represent a halogen. represents an atom.] [In the formula, all symbols are as above. 41) General formula [wherein R is (1) a linear or branched alkyl group having 1 to 15 carbon atoms or It represents an alkoxy group, a linear or branched alkenyl group or alkenyloxy group having 2 to 15 carbon atoms, (represents an unsubstituted phenyl group or benzyl group with Ml, or a hydrogen atom, or (11+1 carbon number 4 ~7 cycloalkyl group 22', R and R each independently represent a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms, and H is (1) a carboxy group. Methyl group, or carboxymethoxy group, or straight-chain or branched-chain alkoxycarbonyl group having 2 to 6 carbon atoms, or straight-chain or branched-chain alkoxycarbonylmethyl group having 3 to 7 carbon atoms, or alkoxycarbonylmethoxy group , or represents a hydroxyl group, or (
n) Represents a mercapto group, a sulfo group, a jetoxyphosphonoyl group, or an acetyl group, and R4 and R5 are each independently a hydrogen atom, an atom, and a carbon number of 1 to
4 represents a straight-chain or branched alkyl group, alkoxy group, carboxy group, a straight-chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms, a hydroxyl group, or 1 nitro group; , 1 or 2, and the symbol =- represents a double bond, a double bond, a compound or a mixture), or a single bond. However, if R falls under (1) above, R4 and R5 shall not be hydrogen atoms at the same time.0] A leukotriene antagonist containing an aniline visiting conductor or a non-toxic salt thereof as an active ingredient. 42) General formula [In the formula, all symbols have the same meanings as in claim 41. ] A phospholipase inhibitor characterized by containing an aniline visiting conductor or a non-toxic salt thereof as an active ingredient. 43) General formula [In the formula, all symbols have the same meaning as in claim 41 of the watch. ] A 5α-reductase inhibitor characterized by containing an aniline visiting conductor or a non-toxic salt thereof as an active ingredient.