JPH0419982B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides antagonism to leukotrienes,
The present invention relates to a novel substituted phenyl derivative having phospholipase inhibitory activity and further 5α-reductase inhibitory activity. Prostaglandin (PG)
It is abbreviated as ) In the field of research, several important discoveries have been made one after another over the past few years, and therefore the flow of PG research and development has also undergone major changes in recent years. Among the newly discovered and newly characterized PG families, PG endoperoxides (i.e., PGG ₂ and PGH ₂ ), thromboxane A ₂ , have particularly potent and unique biological activities.
(ThromboxaneA ₂ , hereinafter abbreviated as TX A ₂ ),
Prostacyclin (i.e.
PGI ₂ ) and leukotrienes C, D and E (hereinafter abbreviated as LTC, LTD and LTE, respectively). In addition to these compounds,
All of the PG families, including various PGs that have been well known, are biosynthesized in vivo using a common parent substance, so the entire metabolic pathway starting from arachidonic acid is the arachidonic acid cascade. )It is called. For a detailed explanation of each pathway and the pharmacological properties of each product, see History of Medicine, 114 , 378.
(1980), 144 , 462 (1980), 114 , 866
(1980), 114 , 929 (1980), Modern Medicine, 12 ,
909 (1980), 12 , 1029 (1980), 12 , 1065
(1980) and Ibid., 12 , 1105 (1980), etc. In the arachidonic acid cascade, cyclooxygenase acts on arachidonic acid to generate PGG ₂ and further
Through PGH ₂ , various PGs, such as prostaglandin F ₂ 〓 (hereinafter abbreviated as PGF ₂ 〓), prostaglandin E ₂ (hereinafter abbreviated as PGE ₂ ), PGI ₂ , TXA ₂
etc., and lipoxygenase acts on arachidonic acid to produce hydroperoxyeicosatetraenoic acid (hereinafter referred to as hydroperoxyeicosatetraenoic acid).
Abbreviated as HPETE. ) to hydroxyeicosatetraenoic acid (hereinafter abbreviated as HETE) or leukotrienes. Since the former route is already well known, we will not discuss it in detail here. For details, please refer to Prostaglandin (1978), edited by Shin Katori et al., published by Kodansha. Regarding the latter route, it is known that various compounds are produced by the route shown in the reaction scheme. Arachidonic acid is metabolized by a well-known pathway, that is, via PG endoperoxide, and is also metabolized by lipoxygenase in a completely different pathway. That is, lipoxygenase such as 5-lipoxygenase, 12-lipoxygenase or 15-lipoxygenase acts on arachidonic acid to produce 5-HPETE,
12-HPETE or 15-HPETE is produced. These HPETEs are produced by converting hydrogen peroxide groups into hydroxyl groups by peroxidase, resulting in 5-
Converted to HETE, 12-HETE or 15-HETE. Also, among these HPETEs, 5-
HPETE is converted to LTA ₄ by being dehydrated. Furthermore, LTA ₄ is enzymatically converted to leukotriene B ₄
(hereinafter abbreviated as LTB ₄ ) and LTC ₄ by glutathione-S-transferase. LTC ₄ is then converted to LTD ₄ by γ-glutamyl transpeptidase. It has recently become clear that LTD ₄ is also replaced by LTE ₄ [Biochem.Biophys.Res.Commun., 91 ,
1266 (1979) and Prostaglandins, 19 (5), 645
(1980)]. On the other hand, when talking about SRS, SRS is Slow
This name is an abbreviation for Reacting Substance.
Pulmonary perfusion of cobra venom, or cobra venom, was used by Feldberg et al. for a substance liberated when incubated with egg yolk; this substance slowly constricts the isolated guinea pig ileum, and its action lasts for a long time. It has been reported [J.Physiol., 94 , 187
(1938)]. Furthermore, Kellaway et al. sensitized SRS-A (Slow
Reacting Substance of Anaphylaxis) was shown to be released, and the relationship between SRS-A and allergic reactions was shown for the first time [Quant.J.Exp.Phvsiol.
30, 121 (1940)]. Brocklehurst also reported that when an antigen was applied to a surgically removed lung section from a patient with bronchial asthma for whom a specific antigen was known, histamine and SRS-A were released, causing strong contraction of the bronchial muscles.
This contraction was not alleviated by antihistamines, suggesting that SRS-A is an important bronchoconstrictor during asthma attacks [see Progr. Allergy, 6 , 539 (1962)].
Subsequently, SPS-A obtained from human lung tissue fragments contracted the bronchial muscle rings in normal humans [Int.Arch.
See Allergy Appl. Immunol., 38, 217 (1970)],
When rat SRS-A is intravenously injected into guinea pigs, an increase in pulmonary airway resistance is observed [J.Clin.Invest., 53 ,
1679 (1974)]; intradermal injection of SRS-A in guinea pigs, rats, and monkeys increases vascular permeability [Advances in Immunology, 10 , 105
(1969), J. Allergy Clin. Immunol., 621 , 371
(1978), Prostaglandins, 19 (5), 779 (1980), etc.]. As mentioned above, SRS is divided into two types: SRS-A, which is released due to immune reaction, and SRS, which is released without immune reaction, such as calcium ionophore treatment. However, there are many similarities between the two, and it is thought that there is a strong possibility that they are the same substance. Furthermore, it has become clear that LTC ₄ and LTD ₄ are the same substances as SRS or SRS-A, and therefore the pharmacological properties of these leukotrienes are
It can be considered in place of the pharmacological properties of SRS or SRS-A [Proc.Natl.Acad.Sci.USA,
76, 4275 (1979), Biochem.Biophys.Res.
Commun., 91 , 1266 (1979), Proc. Natl. Acad.
Sci.USA, 77 , 2014 (1980), Nature, 285 , 104
(1980)]. Based on these many research results, various leukotrienes (LTC ₄ , LTD ₄ , LTE ₄ , and leukotrienes whose structures may be determined in the future), which are biosynthesized from arachidonic acid via LTA ₄ , and allergy It is considered to be an important factor involved in the development of tracheal and bronchial or pulmonary diseases, allergic shock, and various types of allergic inflammation. Therefore, by suppressing these leukotrienes, allergic tracheal and bronchial diseases in mammals including humans, especially humans, such as asthma, allergic lung diseases, allergic shots, and various allergic diseases can be cured. prevention and/or
or effective for treatment. In addition, arachidonic compounds are released from phospholipids by the action of phospholipase, but a closer look shows that there are two routes as shown in the reaction scheme: (1) phosphatidyl
( ₂ ) Phospholipase C acts on phosphatidyl inositol to produce 1,2-diglyceride (1,2-diglyceride).
It is generally thought that a pathway in which 2-diglyceride is produced, which is then released by the action of diglyceride lipase and then monoglyceride lipase [Chemistry and Biology 21 ,
154 (1983)]. The liberated arachidonic acid is further converted into physiologically active substances such as prostaglandin (PG) and thromboxane A ₂ (TXA ₂ ) through two pathways: (1) the cyclooxygenase metabolic pathway; or (2) via the lipoxygenase alternative pathway.
SRS-A (Slow Reacting Substances of
Anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriene _B4 (Leukotriene
It is known that it is metabolized into physiologically active substances such as B ₄ ) [see Chemistry and Biology 21, 154 (1983)]. These metabolites include, for example, TXA ₂ , which is a substance with strong platelet aggregation and vasoconstriction effects, SRS-A, which is a chemical mediator of asthma, and LTB ₄ , which is a substance that has inflammatory effects such as gout. It is known that PG is a chemical mediator that has vasodilatory effects, analgesic effects, fever effects, and leukocyte migration effects in inflammation [Metabolism 20, 317 (1983), See Lancet 1122 (1982), Prostaglandins (1978) edited by Shin Katori et al., Kodansha]. In this way, arachidonic acid is converted and metabolized into chemical mediators that play physiologically important roles in living organisms, but an imbalance in these mediators causes a number of diseases. We have proposed compounds that antagonize leukotrienes, or phospholipases (phospholipase A ₂
As a result of extensive research to find compounds that inhibit phospholipase C) and/or phospholipase C),
It has been found that a certain carboxamide derivative achieves this purpose, and a patent application has already been filed (see Japanese Patent Application No. 58-203632 (Japanese Patent Application Laid-open No. 60-97946)). This time, the present inventors replaced the -CONH- group in the previously proposed carboxamide derivatives with another group, thereby achieving the properties of these new compounds (compounds represented by the general formula () below). The present invention was completed based on the discovery that pharmacological effects are enhanced or improved. The compounds of the present invention strongly inhibit phospholipase and suppress the release of arachidonic acid from phospholipids, thereby preventing diseases caused by arachidonic acid metabolites such as TXA ₂ , 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) and Pharmacy 34, 167 (1983)]. Furthermore, the compound of the present invention has been found to have the following 5α-reductase inhibitory action in addition to its uses as a leukotriene antagonist and phospholipase inhibitor as described above. 5α-reductase exists in the endoplasmic reticulum and nucleic acids, and has the function of converting testosterone ingested into target tissues into active 5α-dihydrotestosterone. When it binds to the body, it causes cell proliferation, and when this effect is enhanced, it is said to lead to the onset of prostatic hyperplasia, alopecia, and acne. 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, it was difficult to say that sufficient treatment was being carried out because the original hormonal effect did not remain as a side effect. Of course, the compound of the present invention does not have any action specific to hormones, 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 acne in humans. The present invention is based on the general formula [In the formula, R ¹ represents (i) a hydrogen atom or (ii) a linear or branched alkyl group having 1 to 10 carbon atoms, R ² represents a hydrogen atom, and R ³ represents a hydroxymethyl group, a carboxyl group, group or a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms, R ⁴ represents a hydrogen atom, and X has the formula -CH ₂ O-, -CH ₂ S-, -CH ₂ NH-, -CO-S-, -CO- ^NR5- or -CO- _CH2- (wherein, ^R5 represents a straight or branched alkyl group having 1 to 4 carbon atoms or a phenyl group).
represents a group represented by, n represents 1, and the symbol 〓
represents a double bond (E, Z or EZ mixture). The present invention relates to substituted phenyl derivatives represented by the following formulas, non-toxic salts thereof, and non-toxic acid addition salts thereof. In the general formula (), the linear or branched alkyl group having 1 to 10 carbon atoms represented by R ¹ is a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group. group, nonyl group, decyl group, and isomers thereof. Preferred groups as R ¹ include groups having 1 to 1 carbon atoms.
8 straight or branched alkyl groups,
A particularly preferred group is an n-pentyl group (amyl group). It is also preferred when R ¹ represents a hydrogen atom. Although R ¹ may be substituted at any position on the benzene ring, the preferred position is the para position. In the general formula (), the straight chain or branched alkyl group having 1 to 5 carbon atoms in the straight chain or branched chain alkoxycarbonyl group having 2 to 6 carbon atoms in R ³ is a methyl group, ethyl group, propyl group, butyl group, pentyl group, and isomers thereof, and any group is preferable. It is also preferable that R ³ represents a hydroxymethyl group or a carboxyl group. Although R ³ may be substituted at any position on the benzene ring, the preferred position of R ³ is the ortho position. In the general formula (), R ⁵ in X represents 1 carbon number
~4 straight chain or branched alkyl group,
Examples include methyl group, ethyl group, propyl group, butyl group, and isomers thereof, and any group is preferable. It is also preferred when R ⁵ represents a phenyl group. The compound of the present invention represented by the general formula () may have isomers, particularly due to the double bond E or Z represented by the symbol 〓. Furthermore, isomers may also occur when each substituent in the general formula () represents a branched alkyl group or alkylene group. The present invention also includes all these individual isomers and mixtures thereof. Although several patent applications containing compounds having chemical structures similar to the compounds of the present invention have been filed so far, the present invention cannot be easily inferred from these patent applications. For example, JP-A-50-135047 broadly discloses N-(substituted cinnamoyl)anthranilic acid derivatives, but this invention does not include the present invention at all, and moreover, it does not meet the purpose of the present invention. There is no description that suggests that it is antagonizing one of the leukotrienes. Also, JP-A-57
-106651 also discloses a similar compound, but this also does not include the compound of the present invention at all. Furthermore, although the above-mentioned publication specifies inhibition of leukotriene biosynthesis as an objective, this objective is achieved by selectively inhibiting 5-lipoxygenase as the 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 as a phospholipase inhibitor or 5α-reductase inhibitor like the present invention, and they are used as an antithrombotic agent, for prostatic hyperplasia, alopecia, and acne. The preventive and therapeutic uses were discovered for the first time in the present invention, and the present invention cannot be easily inferred from these prior art. According to the invention, X has the formula _-CH2O -- _CH2S-
or a compound represented by the general formula () representing a group represented by -CH ₂ NH-, that is, a compound represented by the general formula [In the formula, Y represents a group represented by -O-, -S- or -NH-, and the other symbols have the same meanings as above. ] The compound represented by the general formula (In the formula, all symbols have the same meanings as above.) Compounds represented by and general formula (In the formula, all symbols have the same meanings as above.) It can be produced by reacting a compound represented by the following. When the compound represented by the general formula () is a phenol or thiophenol derivative, this reaction can be carried out using an inert organic solvent such as tetrahydrofuran (THF), diethyl ether, methylene chloride, chloroform, carbon tetrachloride, pentane, Hexane, benzene, toluene, dimethylformamide, (DMF), dimethyl sulfoxide (DMSO),
in hexamethylphosphamide (HMPA) in the presence of a base such as sodium hydride, potassium carbonate, triethylamine, pyridine from room temperature to 80°C.
It is carried out at ℃. When the compound represented by the general formula () is a derivative of aniline, in an inert organic solvent as described above or without a solvent, if necessary in the presence of a tertiary amine such as triethylamine,
It is carried out at room temperature to 80°C. X is of the formula -CO-S- or -CO-NR ⁵ (wherein,
R ⁵ has the same meaning as above. ) A compound represented by the general formula () representing a group represented by the general formula (), that is, a general formula [In the formula, Y' is -S- or -NR ⁵ - (in the formula, R ⁵
has the same meaning as above. ) represents a group, and other symbols have the same meanings as above. ] The compound represented by the general formula (In the formula, all symbols have the same meanings as above.) Compounds represented by and general formula (In the formula, all symbols have the same meanings as above.) It can be produced by reacting the compound shown below. This reaction is a known reaction, for example, in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, in the presence of a tertiary amine such as triethylamine, pyridine, etc., at -20°C to 40°C.
It is carried out at a temperature of Preferably it is carried out in methylene chloride in the presence of triethylamine at 0°C to room temperature. Compounds represented by the general formula () in which X represents a group represented by the formula -CO-CH ₂ -, that is, the general formula (In the formula, all symbols have the same meanings as above.) The compound represented by the formula () is the compound represented by the general formula () and the general formula [In the formula, R ^3a is −COOC(CH ₃ ) ₃ or −
CH ₂ OTHP (where THP is tetrahydropyran-
Represents a 2-yl group. ) represents a group represented by
R ⁴ has the same meaning as above. ] By reacting the compound represented by the general formula (In the formula, all symbols have the same meanings as above.) A compound represented by (In the formula, R ^3b represents a group represented by -COOH or -CH ₂ OH, and the others have the same meanings as above.), and if desired, R ^3b represents a group represented by -COOH. In the case where the compound is represented by the general formula (IC), a compound represented by the general formula (IC) can be produced by subjecting it to the esterification reaction described below. Compounds represented by general formula () and general formula ()
The reaction with the compound represented by is first carried out using the general formula ()
The compound represented by is dissolved in an inert organic solvent, e.g.
THF, diethyl ether, pentane, hexane,
Lithium derivatives of compounds of general formula () are prepared by reaction with a suitable lithiation agent, such as lithium diisopropylamide, in benzene, toluene, HMPA at a temperature of -78°C to room temperature, preferably -78°C to 0°C. The reaction is then carried out by reacting this derivative with a compound represented by the general formula () in the above-mentioned inert organic solvent at a temperature ranging from -78°C to room temperature. The compound represented by the general formula () can be prepared using an inert organic solvent such as lower alkanol, THF, diethyl ether, pentane, hexane, benzene,
The general formula (C-
It is converted to the compound shown in a). The compound represented by the general formula () used as a starting material can be produced, for example, according to the following reaction. Briefly explaining each of the above reactions, esterification is carried out using a diethyl ether solution of diazomethane in an inert organic solvent such as ethyl acetate at 0°C.
It will be held in The reduction is carried out using a reducing agent such as diisobutyl aluminum hydride or lithium aluminum hydride in an inert organic solvent such as THF, diethyl ether, toluene, from -78°C to the reflux temperature of the solvent. Chlorination can be carried out using thionyl chloride, p-toluenesulfonyl chloride, etc. in an inert organic solvent such as methylene chloride in the presence of a tertiary amine such as triethylamine at 0°C to 50°C, or The reaction is carried out using methanesulfonyl chloride in the presence of 2,4,6-collidine and lithium chloride in chloroform at temperatures ranging from 0°C to room temperature [see JOC, 36, 3044 (1971)]. The compound represented by the general formula () used as a starting material is prepared by converting the carboxylic acid represented by the general formula () to thionyl chloride in an inert organic solvent such as methylene chloride, tetrahydrofuran, or without solvent at -40°C to room temperature. Alternatively, it is produced by reacting with oxalyl chloride. Preferably, this is carried out using oxalyl chloride without a solvent at room temperature. General formula () used as starting material,
The compounds represented by () and () are both known compounds, or can be produced from known compounds by known methods. The carboxylic acid represented by the general formula () used as a starting material can be produced by the method described in JP-A-60-97946 or an obvious analogous method thereof. Furthermore, according to the present invention, a compound represented by the general formula () in which R ³ represents a carboxyl group and other symbols have the same meanings as above, R ³ represents an alkoxycarbonyl group and the other symbols have the same meanings as above. It can also be obtained by subjecting a compound represented by the general formula () having the same meaning to a saponification reaction. The saponification reaction is a well-known reaction, for example, using a water-miscible solvent such as methanol, ethanol,
It is carried out using an aqueous solution of an alkaline substance such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. in THF at a temperature of from 0°C to 50°C, preferably at room temperature. Further, R ³ represents an alkoxycarbonyl group,
A compound represented by the general formula () in which other symbols have the same meanings as above is a compound represented by the general formula () in which R ³ represents a carboxyl group and other symbols have the same meanings as above. It can also be obtained by attaching it to The esterification reaction is a known reaction and is carried out, for example, using a suitable diazoalkane in diethyl ether, ethyl acetate or methylene chloride at temperatures ranging from -10°C to room temperature, preferably 0°C; 50 from room temperature using the corresponding alcohol and dicyclohexylcarbodiimide in the presence of a base such as pyridine in an active organic solvent.
It is carried out at a temperature of °C. The reaction product can be purified by conventional purification methods, 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. It can be purified by Purification may be performed for each reaction or after completion of several reactions. 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 the general formula () has effective pharmacological properties. It means a salt consisting of an anion or cation that is not impaired by the 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, and are selected from, for example, alkyl groups having 1 to 6 carbon atoms 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, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts. Examples include organic amine salts such as , lysine salt, and arginine salt. Suitable acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,
Inorganic acid salts such as nitrates, or acetates, lactates, tartrates, benzoates, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, isethionates. Examples include organic acid salts. The salt of the substituted phenyl derivative represented by the general formula () can be prepared by adding the acid represented by the general formula () to a suitable base such as an alkali metal or alkaline earth metal hydroxide or carbonic acid in a suitable solvent. Obtained by reaction with salts or organic amines. Acid addition salts of substituted phenyl derivatives represented by the general formula () can be prepared by adding the compound represented by the general formula () to a suitable acid such as hydrochloric acid, hydrobromic acid, iodide acid, etc. in a suitable solvent. Inorganic acids such as hydrogen acid, sulfuric acid, phosphoric acid, nitric acid, or acetic acid, lactic acid,
It is obtained by reaction with organic acids such as tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid. As mentioned above, the compounds of the present invention have leukotriene antagonism, phospholipase inhibition and 5α-
It has a reductase inhibitory effect, and in laboratory experiments, for example, it has shown the following effects. The compounds of the present invention exhibited antagonistic effects against LTD ₄ as shown in the table below. [Table] The compounds of the present invention have the following effects on phospholipase A ₂ :
The table below shows the inhibitory effects. [Table] The compound of the present invention has the following effects on 5α-reductase:
It showed inhibitory effects as shown in the table below. [Table] Shows the values.
The antagonistic effect of the compounds of the present invention on LTD ₄ was determined by the following experimental method. The ileum (3 cm) removed from a male guinea pig weighing 300-400 g was incubated at 37°C in Tyrode's solution and oxygen (95%).
- Suspended in a Magnus tube vented with a mixture of carbon dioxide (5%) and stabilized for approximately 30 minutes, the LTD ₄
The compound of the present invention was added at a concentration of 10 ^-9 g/ml, and the contraction height was measured by changing the concentration of the compound of the present invention based on the contraction at this time, and the IC ₅₀ value was calculated from this. The inhibitory effect of the compounds of the present invention on phospholipase _A2 was determined by a modified Shakir method using L-β-[ ^1-14C ]-arachidonyl-α'-stearoyl-phosphatidylcholine as the substrate and guinea pig as the enzyme. It was measured using phospholipase A ₂ obtained from lungs [see Anal.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 fractions with reference to the method of J. Shimazaki et al. 5α-reductase activity was measured using 0.09M HePes (PH7.4), 0.22M
The reaction was carried out at 37° C. for 60 minutes using a mixture of sucrose, 5× ^{10 −3} M NADPH, 5 μM [4- ¹⁴ C] testolone, 5α-reductase, and the compound of the present invention. Stop the reaction with chloroform-methanol (1/2)
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).
The radioactivity of the generated dihydrotestosterone
Measurement was performed using a TLC scanner, and enzyme activity inhibition was calculated [Endocrinol, Japon., 18, 179 (1971)]
reference〕. In mammals including humans, especially humans, by suppressing leukotrienes, it is possible to prevent allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shots, and various allergic diseases. and/or is effective in the treatment of diseases caused by arachidonic acid metabolites, including the above-mentioned leukotrienes, such as thrombosis of the brain and coronary arteries, by inhibiting phospholipases (phospholipase _A2 and/or phospholipase C). It is effective in preventing and/or treating thrombosis caused by damage to the endothelium or intima, and various inflammations such as arthritis and rheumatism. moreover
Inhibiting 5α-reductase is effective in preventing and/or treating benign prostatic hyperplasia, alopecia, and acne. Substituted phenyl derivatives of general formula () or their non-toxic salts or acid addition salts for the above purposes (as leukotriene antagonists, phospholipase inhibitors or 5α-reductase inhibitors)
For use, each is usually administered systemically or locally, orally or parenterally. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, processing time, etc., but is usually 1 mg to 1 g, preferably 20 mg to 200 mg, per adult.
mg, administered orally once to several times a day, or each once per adult.
It is administered parenterally in the range of 100 μg to 100 mg, preferably 1 mg to 10 mg, 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 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, dextrose, hydroxypropyl cellulose, microcrystalline cellulose, starch,
Polyvinylpyrrolidone is mixed with magnesium aluminate metasilicate. The compositions may contain additives other than inert diluents in conventional manner, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate. Tablets or pills may be coated with a film of gastric or enteric substances such as white sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, 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 include commonly used inert diluents, such as purified water. , including ethanol. In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, 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 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 suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of sterilizing agents, 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:
Includes topical solutions, liniments such as lozenges, suppositories for intrarectal administration and pettu saris for intravaginal administration, containing one or more active substances and formulated in a manner known per se. . Among the compounds of the present invention represented by the general formula (), preferred compounds include O-cinnamyl salicylic acid, O-(p-amyl cinnamyl) salicylic acid, 2-(cinnamyloxy)benzyl alcohol, 2-(p-amyl cinnamyl) oxy)benzyl alcohol, 2-(cinnamylthio)benzoic acid, 2-(p-amylcinnamylthio)benzoic acid, 2-(cinnamylthio)benzyl alcohol, 2-(p-amylcinnamylthio)benzyl alcohol, N-( Cinnamyl anthranilic acid, N-(p-amylcinnamyl)anthranilic acid, 2-(cinnamylamino)benzyl alcohol, 2-(p-amylcinnamylamino)benzyl alcohol, S-(cinnamoyl)thiosalicylic acid, S-(p -amylcinnamoyl)thiosalicylic acid, 2-(cinnamoylthio)benzyl alcohol, 2-(p-amylcinnamoylthio)benzyl alcohol, 2-(p-pentyloxycinnamoylthio)
Benzyl alcohol, N-cinnamoyl-N-phenylanthranilic acid, N-(p-amylcinnamoyl)-N-phenylanthranilic acid, 2-(N-cinnamoyl-N-phenylamino)
Benzyl alcohol, 2-[N-(p-amylcinnamoyl)-N-phenylamino]benzyl alcohol, N-cinnamoyl-N-methylanthranilic acid, N-(p-amylcinnamoyl)-N-methylanthranilic acid, 2 -(N-cinnamoyl-N-methylamino)
Benzyl alcohol, 2[N-(p-amylcinnamoyl)-N-methylamino]benzyl alcohol, 2-(cinnamoylmethyl)benzoic acid, 2-(p-amylcinnamoylmethyl)benzoic acid, 2-(cinnamoylmethyl)benzoic acid Examples thereof include moylmethyl)benzyl alcohol, 2-(p-amylcinnamoylmethyl)benzyl alcohol, acid addition salts thereof, and methyl esters thereof. Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, the symbols "TLC", "IR", "NMR" and "MS" in Reference Examples and Examples respectively refer to "thin layer chromatography", "infrared absorption spectrum", "nuclear magnetic resonance spectrum", and "nuclear magnetic resonance spectrum". "Mass spectrometry" stands for chromatographic separation, and the percentage of solvent listed in the section for separation by chromatography indicates the volume ratio, the solvent in the bracket of "TLC" indicates the developing solvent, and "IR" indicates a special description. If there is no such thing, it is measured using the liquid film method, and unless otherwise specified, "NMR" is measured using a deuterated chloroform (CDCl ₃ ) solution. Reference example 1 p-amyl cinnamyl alcohol A diethyl ether solution of diazomethane was added to 400 mg of p-amylcinnamic acid (compound described in Reference Example 2 of Japanese Patent Application No. 58-203632) dissolved in 5 ml of ethyl acetate while stirring at 0°C until no more foaming occurred. The mixture was stirred at the same temperature for 10 minutes and concentrated under reduced pressure. The residue was dissolved in 10 ml of dry toluene and a 1.76 M solution of diisobutylaluminum hydride in toluene at −78 °C under an argon atmosphere.
Add 2.6 ml slowly and stir at -78℃ for 5 minutes and then at 0℃ for 30 minutes.Next, add methanol dropwise at 0℃ until no more foaming occurs, stir at 0℃ for 5 minutes, then further at 0℃. 1.2 ml of water was slowly added and stirred vigorously at room temperature for 1 hour. The precipitated white crystals were separated, the liquid was concentrated under reduced pressure, and water was removed by azeotroping with toluene to obtain 387 mg of the title compound as a crude product (pale yellow solid) having the following physical properties. TLC (ethyl acetate: cyclohexane = 1:2):
Rf=0.34; NMR: δ7.29 (2H, d), 7.10 (2H, d), 6.58
(1H, d), 6.18 (1H, dt), 4.16 (2H, d)
2.58 (2H, t), 2, 30 (1H, s), 1.18−
1.10 (6H, m), 0.87 (3H, t); MS: m/Z=204 (M ⁺ ), 191, 161, 147, 133,
105, 91. Reference example 2 p-amyl cinnamyl chloride Under an argon atmosphere, 72μ of 2,4,6-collidine and 21mg of lithium chloride dissolved in 1.5ml of dry dimethylformamide were added to 102mg of the alcohol compound (produced in Reference Example 1) dissolved in 0.5ml of dry chloroform. Cooled to ℃. 43μ of methanesulfonyl chloride was slowly added thereto, and the mixture was stirred at 0°C for 1.5 hours and then at room temperature overnight. Add 10 ml of water to the reaction mixture and add 50 ml of a mixture of diethyl ether and n-pentane (1:1).
The extract was washed successively with a saturated aqueous copper nitrate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 100 mg of the title compound having the following physical properties. NMR: δ=7.30 (2H, d), 7.12 (2H, d), 6.62
(1H, d), 6.24 (1H, dt), 4.20 (2H, d),
2.58 (2H, t), 1.80−1.10 (6H, m), 0.87
(3H, t); MS: m/Z=222 (M ⁺ ), 187, 165, 129, 117,
71, 43. Example 1 O-(p-amylcinnamyl)salicylic acid methyl ester Dry tetrahydrofuran under argon atmosphere
Sodium hydride suspended in 0.2 ml (content: 64
%), 50 mg of salicylic acid methyl ester dissolved in 0.2 ml of dry tetrahydrofuran was slowly added at room temperature, stirred at the same temperature for 5 minutes, then about 0.5 ml of dry dimethylformamide was added, and thinner dissolved in 0.3 ml of dry tetrahydrofuran was added. Milk chloride compound (manufactured in Reference Example 2) 67
After stirring at 50°C for 2 hours and then at 80°C for 3 hours, the mixture was cooled to room temperature. Add 5 liters of water to the reaction mixture
ml and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform:cyclohexane=1:1→3:2) to obtain 87 mg of the title compound having the following physical properties. TLC (ethyl acetate: cyclohexane = 1:10):
Rf=0.23; NMR: δ=7.79 (1H, dd), 7.40 (1H, dt), 7.30
(2H, d), 7.10 (2H, d), 6.98 (1H, d),
6.93 (1H, dt), 6.76 (1H, d), 6.32 (1H,
dt), 4.74 (2H, dd), 3.85 (3H, s), 2.56
(2H, t), 1.80−1.10 (6H, m), 0.84 (3H,
t); MS: m/Z=338 (M ⁺ ), 307, 187, 131, 129,
117, 115, 71, 43. Example 2 N-(p-amylcinnamyl)anthranilic acid methyl ester Under an argon atmosphere, a mixture of 180 mg of cinnamyl chloride compound (produced in Reference Example 2) and 366 mg of anthranilic acid methyl ester was stirred at 40° C. for 1 hour and solidified. 50 ml of diethyl ether and 20 ml of a saturated aqueous sodium bicarbonate solution were added to dissolve the solid, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent, chloroform:cyclohexane = 1:5 →
1:2) to obtain 95 mg of the title compound having the following physical properties. TLC (chloroform: cyclohexane = 1:
2): Rf=0.24; NMR: δ=7.92 (1H, dd), 8.10−7.70 (1H,
br), 7.45−7.20 (1H, m), 7.23 (2H, d),
7.08 (2H, d), 6.70 (1H, d), 6.67 (1H,
t), 6.60 (1H, d), 6.22 (1H, dt), 3.98
(2H, t), 3.82 (3H, s), 2.56 (2H, t),
1.80−1.10 (3H, m), 0.87 (3H, t); MS: m/Z=337 (M ⁺ ), 312, 310, 306, 304,
278, 266, 248, 234, 202, 187, 117, 71,
43. The following compound was obtained in the same manner as in Example 2. (a) N-cinnamyl anthranilic acid methyl ester Starting materials: cinnamyl chloride and anthranilic acid methyl ester; TLC (chloroform: cyclohexane = 1:
1): Rf=0.34; NMR: δ=7.93 (1H, dd), 8.10−7.70 (1H,
br), 7.60−7.00 (6H, m), 6.72 (1H, d),
6.68 (1H, t), 6.64 (1H, d), 6.28 (1H,
dt), 4.03 (2H, t), 3.87 (3H, s); MS: m/Z=267 (M ⁺ ), 252, 234, 208, 206,
132, 117, 115, 91. Example 3 S-(p-amylcinnamoyl)thiosalicylic acid 1 ml of oxalic acid chloride was added to 151 mg of p-amylcinnamic acid, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain acid chloride. Thiosalicylic acid dissolved in 1 ml of methylene chloride
Acid chloride (prepared above) dissolved in 1 ml of methylene chloride was added dropwise to 106 mg of triethylamine and 139 mg of triethylamine under ice cooling, and the mixture was stirred at room temperature for 1 hour. 3 ml of 1N hydrochloric acid was added to the reaction mixture, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a solid. The obtained solid was washed with n-hexane to obtain 150 mg of the title compound as a pale yellow solid having the following physical properties. TLC (ethyl acetate: n-hexane = 1:1): Rf
= 0.3; NMR: δ = 8.04 (1H, dd), 7.68 (1H, d), 7.8
−7.4 (4H, m), 7.3−7.15 (2H, d), 6.78
(1H, d); IR (KBr method): ν=1680, 1610, 1560, 1475,
1410cm ^-1 ; MS: m/Z=354 (M ⁺ ), 332, 294, 218, 201,
161. The following compound was obtained in the same manner as in Example 3. (a) N-(p-amylcinnamoyl)-N-phenylanthranilic acid Starting materials: 120 mg of p-amylcinnamic acid and 117 mg of N-phenylanthranilic acid; Purification method: Silica gel column chromatography (ethyl acetate: n-hexane = 1:4); Yield: 172 mg; TLC (ethyl acetate: n-hexane) -hexane=2:1); Rf
= 0.2; NMR: δ = 8.00 (1H, br), 7.73 (1H, d), 7.6
−7.0 (12H, m), 6.4 (1H, br); IR: ν=1715, 1690, 1640, 1590, 1485 cm ^-1 ; MS: m/Z=413, 369, 218, 213, 201, 195,
161. (b) N-(p-amylcinnamoyl)-N-methylanthranilic acid Starting materials: 109 mg of p-amylcinnamic acid and 165 mg of N-methylanthranilic acid methyl ester; Purification method: Silica gel column chromatography (cyclohexane: ethyl acetate = 2:1); Yield: 130 mg; NMR: δ = 8.03 (1H , dd), 7.66 (1H, d), 7.57
(2H, dt), 7.3 (1H, dd), 7.20 (2H, d),
7.06 (2H, d), 6.10 (1H, d), 3.82 (3H,
s), 3.34 (3H, s), 2.55 (2H, t), 1.6−
1.2 (6H, m), 0.86 (3H, m); MS: m/Z = 365 (M ⁺ ), 334, 306, 201, 165,
144, 131. (c) 2-[N-(p-amylcinnamoyl)-N-
Methylamino] benzyl alcohol Starting materials: 218 mg of p-amylcinnamic acid and 137 mg of 2-(methylamino)benzyl alcohol; Purification method: Silica gel column chromatography (cyclohexane: ethyl acetate = 5.1); Yield: 150 mg; TLC (cyclohexane: ethyl acetate = 2) :1)
Rf=0.12; NMR: δ=7.7−7.0 (9H, m), 6.1 (1H, d),
4.64 (2H, s), 3.32 (3H, s), 2.54 (2H,
t), 1.55 (2H, m), 1.4-1.2 (4H, m),
0.85 (3H, t); IR: ν=3400, 2920, 2850, 1735, 1650, 1600,
1370, 1240, 1240, 1040cm ^-1 ; MS: m/Z=337 (M ⁺ ), 306, 201, 176, 161,
144, 136, 131, 119, 115. Example 4 O-(p-amylcinnamyl)salicylic acid and its sodium salt To 85 mg of the methyl ester compound (produced in Example 1) dissolved in 2.0 ml of a mixture of tetrahydrofuran and methanol (1:1), 0.5 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 24 hours. Add 10ml of water and 1.0ml of 1N hydrochloric acid to the reaction mixture.
was added 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 residue was subjected to silica gel column chromatography (elution solvent, chloroform:
The residue was purified with cyclohexane (5:1 → chloroform only) to obtain 60 mg of the title compound (free acid) as a colorless solid having the following physical properties. TLC (ethyl acetate: cyclohexane = 1:2):
Rf=0.20; NMR: δ=8.19 (1H, dd), 7.54 (1H, dt), 7.34
(2H, d), 7.25−7.00 (4H, m), 6.78 (1H,
d), 6,34 (1H, dt), 4.91 (2H, d), 2.59
(2H, t), 1.80−1.10 (6H, m), 0.88 (3H,
t); IR (KBr method): ν=2960, 2930, 2850, 1695,
1670, 1600, 1570, 1505, 1490, 1460,
1440, 1410, 1380, 1310, 1290, 1260,
1160, 1085, 985, 750 cm ^-1 ; MS: m/Z=324 (M ⁺ ), 306, 280, 278, 253,
249, 235, 221, 209, 187, 117, 71, 43. Add the free acid obtained above to methanol 1-2
ml, 1N aqueous sodium hydroxide solution
185μ was added, concentrated under reduced pressure, azeotroped with a mixture of toluene and ethanol to remove water, and thoroughly dried over phosphorus pentoxide to obtain 64mg of the title compound (sodium salt) as a colorless solid having the following physical properties. obtained as. NMR (CD ₃ OD solution): δ = 7.38 (1H, dd), 7.32
(2H, d), 7.21 (1H, dt), 7.10 (2H, d),
6.98 (1H, d), 6.88 (1H, t), 6.73 (1H,
d), 6.41 (1H, dt), 4.73 (2H, dd), 2.57
(2H, t), 1.60 (2H, m), 1.45−1.20 (4H,
m), 0.89 (3H, t). The following compound was obtained in the same manner as in Example 4. (a) N-(p-amylcinnamyl)anthranilic acid and its sodium salt Starting material: 95 mg of the methyl ester compound prepared in Example 2; Yield [acid]: 85 mg; TLC [acid]: (ethyl acetate: cyclohexane = 1:
4): Rf=0.20; NMR [acid]: δ=10.00−8.00 (2H, br), 8.00
(1H, dd), 7.50−7.2 (1H, m) 7.19 (2H,
d), 7.10 (2H, d), 6.73 (1H, d), 6.69
(1H, t), 6.60 (1H, d), 6.22 (1H, dt),
4.04 (2H, d), 2.58 (2H, t), 1.80−1.10
(6H, m), 0.88 (3H, t); IR [acid] (KBr method): ν = 3380, 1970, 2920,
2850, 1655, 1570, 1510, 1450, 1440,
1405, 1320, 1240, 1155, 1100, 1035, 960,
745cm ^-1 ; MS [acid]: m/Z = 323 (M ⁺ ), 305, 278, 252,
234, 202, 187, 161, 117, 71, 43; NMR [salt] (CD ₃ OD solution): δ = 7.85 (1H, dd),
7.26 (2H, d), 7.16 (1H, dt), 7.06 (2H,
d), 6.66 (1H, d), 6.60 (1H, d) 6.52
(1H, t), 6.30 (1H, dt), 3.94 (2H, dd),
2.55 (2H, t), 1.58 (2H, m), 1.45−1.15
(4H, m), 0.88 (3H, t); Form of salt: colorless solid. (b) N-cinnamyl anthranilic acid Starting material: methyl ester compound produced in Example 2(a) (however, only saponification reaction was performed); TLC (ethyl acetate: cyclohexane = 1:2):
Rf=0.36 NMR ( _CD3OD +dimethylsulfoxide- _d6 solution): δ=7.90 (1H, dd), 7.50-7.00 (6H,
m), 6.74 (1H, d), 6.62 (1H, d), 6.57
(1H, dt), 6.19 (1H, dt), 3.98 (2H, d); MS: m/Z=253 (M ⁺ ), 235, 208, 132, 117,
91; Acid form: pale yellow solid. (c) N-(p-amylcinnamoyl)-N-phenylanthranilic acid sodium salt Starting material: Anthranilic acid prepared in Example 3(a); (However, only the salt-forming reaction was performed.) Form of salt: Pale yellow solid (d) N-(p-amylcinnamoyl)-N- Methylanthranilic acid and its sodium salt Starting material: 130 mg of the methyl ester compound prepared in Example 3(b); Yield [acid]: 93 mg; NMR [acid]: δ = 8.15 (1H, d), 7.7-7.0 (8H,
m), 6.80 (1H, d), 3.34 (3H, s), 2.52
(2H, t), 1.53 (2H, m), 1.4−1.2 (4H,
m), 0.84 (3H, m); IR [acid] (KRr method): ν = 3450, 2930, 2850,
1710, 1640, 1580, 1380, 1240 cm ^-1 ; MS [acid]: m/Z = 351 (M ⁺ ), 306, 201, 151,
131, 115. Salt form: white solid. Reference example 3 2-{[1-(p-amylcinnamoyl)-1-
tert-butoxycarbonyl]methylbenzoic acid
tert-butyl ester Diisopropylamine was prepared by dissolving 1.8 ml of a 1.6M solution of n-butyllithium in n-hexane in 7 ml of tetrahydrofuran under a nitrogen atmosphere.
It was added dropwise to 400μ at room temperature and stirred at the same temperature for 20 minutes to obtain a lithium diisopropylamide solution.
This solution was cooled to -78°C, 292 mg of 2-(tert-butoxycarbonylmethyl)benzoic acid tert-butyl ester was added at the same temperature, and after stirring for 30 minutes,
236.5 mg of p-amylcinnamoyl chloride (produced as acid chloride in Example 3) dissolved in 2 ml of tetrahydrofuran was slowly added dropwise at -78°C, stirred for 30 minutes, then 2N hydrochloric acid was added and the temperature was raised to room temperature. . The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent, ethyl acetate: n-hexane =
1:9) to obtain 165 mg of the title compound having the following physical properties. NMR: δ=12.5 (1H, bs), 8.03 (1H, q), 7.60
−7.20 (9H, m), 6.25 (1H, q), 1.62 (2H,
m), 1.45 (18H, m), 1.32 (4H, m), 0.88
(3H, t); IR: ν=2725, 1650, 1630, 159 ^{cm -1} . The following compound was obtained in the same manner as in Reference Example 3. (a) 2-[(1-cinnamoyl-1-tert-butoxycarbonyl)methyl]benzoic acid tert-butyl ester Starting materials: 292 mg of o-(tert-butoxycarbonylmethyl)benzoic acid tert-butyl ester and 167.5 mg of cinnamoyl chloride; Purification method: Silica gel column chromatography (elution solvent: ethyl acetate; n-hexane)
3.97); Yield: 140 mg; NMR: δ = 12.5 (1H, bs), 7.60−7.20 (9H,
m), 6.25 (1H, q), 1.45 (9H, s); IR: ν=2730, 1650, 1630, 1595 ^{cm -1} . Example 5 2-(p-amylcinnamoylmethyl)benzoic acid 120 mg of the tert-butyl ester compound (produced in Reference Example 3) dissolved in 1 ml of trifluoroacetic acid was stirred at room temperature for 2 hours and then concentrated under reduced pressure. 3 ml of benzene was added to the resulting residue, refluxed for 30 minutes, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate:n-hexane=1:1) to obtain 40 mg of the title compound as a white solid having the following physical properties. TLC (ethyl acetate: n-hexane = 1:1): Rf
= 0.36; NMR: δ = 8.08 (1H, q), 7.7−7.15 (9H, m),
6.79 (1H, d), 4.37 (2H, s), 2.62 (2H,
bt), 1.62 (2H, m), 1,31 (4H, m), 0.89
(3H, t); IR (KBr method): ν=3200−2400, 1690, 1605cm
^-1 ; MS: m/Z=336 (M ⁺ ), 318, 261, 201. The following compound was obtained in the same manner as in Example 5. (a) 2-(cinnamoylmethyl)benzoic acid Starting material: 100 mg of the tert-butyl ester compound produced in Reference Example 5(a); Purification method: Silica gel column chromatography (elution solvent: ethyl acetate: n-hexane = 1:
1); Yield: 30 mg; TLC (ethyl acetate: hexane = 1:1): Rf =
0.19; NMR: δ = 8.07 (1H, q), 7.65 (1H, d), 7.6
−7.2 (9H, m), 6.83 (1H, d), 4.38 (2H,
s); IR (KBr method): ν=3200−2400, 1695, 1610,
1575cm ^-1 ; MS: m/Z=266, 248, 238, 220, 131, 118,
103,77; Shape: white powder. Reference Example 4 2 [N-(p-amylcinnamoyl)-N-methylamino]benzyl alcohol 5g, cellulose calcium gluconate (disintegrant) 200mg, magnesium stearate (lubricant) 100mg and microcrystalline cellulose 5.7g. Mix and tablet by conventional method, 1
100 tablets with 50 mg of active ingredient in the tablet were obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents (i) a hydrogen atom or (ii) a straight or branched alkyl group having 1 to 10 carbon atoms, R ² represents a hydrogen atom, and R ³ represents a hydroxymethyl group, a carboxyl group, group or a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms, R ⁴ represents a hydrogen atom, and X has the formula -CH ₂ O-, -CH ₂ S-, -CH ₂ NH-, -CO-S-, -CO- ^NR5- or -CO- _CH2- (wherein, ^R5 represents a straight or branched alkyl group having 1 to 4 carbon atoms or a phenyl group).
represents a group represented by, n represents 1, and the symbol 〓
represents a double bond (E, Z or EZ mixture). ] A substituted phenyl derivative, a non-toxic salt thereof, or a non-toxic acid addition salt thereof. 2. The derivative according to claim 1, wherein R ¹ is a hydrogen atom. 3. The derivative according to claim 1, wherein ^R1 is a linear or branched alkyl group having 1 to 10 carbon atoms. 4. The derivative according to claim 3, wherein R ¹ is a linear or branched alkyl group having 1 to 8 carbon atoms. 5. The derivative according to any one of claims 1 to 4, wherein R ³ is a hydroxymethyl group. 6. The derivative according to any one of claims 1 to 4, wherein ^R3 is a carboxyl group or a straight or branched alkoxycarbonyl group having 2 to 6 carbon atoms. 7 X is the formula -CH ₂ O-, -CH ₂ S- or -
The derivative according to any one of claims 1 to 6, which represents a group represented by CH ₂ NH-. 8 X is the formula -CO-S-, -CO-NR ⁵ - or -
Any one of claims 1 to 6 which represents a group represented by CO-CH ₂ - (in the formula, R ⁵ has the same meaning as described in claim 1) Derivatives as described. 9. The derivative according to claim 1, wherein the compound is O-(p-amylcinnamyl)salicylic acid, its sodium salt, or its methyl ester. 10 The compound is N-cinnamyl anthranilic acid,
The derivative according to claim 1, which is a sodium salt thereof, or a methyl ester thereof. 11. The derivative according to claim 1, wherein the compound is N-(p-amylcinnamyl)anthranilic acid, its sodium salt, or its methyl ester. 12 The compound is S-(p-amylcinnamoyl)
Claim 1, which is thiosalicylic acid, its sodium salt, or its methyl ester
Derivatives described in Section. 13 The compound is N-(p-amylcinnamoyl)-
The derivative according to claim 1, which is N-phenylanthranilic acid, its sodium salt, or its methyl ester. 14 The compound is N-(p-amylcinnamoyl)-
The derivative according to claim 1, which is N-methylanthranilic acid, its sodium salt, or its methyl ester. 15. The derivative according to claim 1, wherein the compound is 2-[N-(p-amylcinnamoyl)-N-methylamino]benzyl alcohol. 16. The derivative according to claim 1, wherein the compound is 2-(cinnamoylmethyl)benzoic acid, its sodium salt, or its methyl ester. 17 Claim 1, wherein the compound is 2-(p-amylcinnamoylmethyl)benzoic acid, its sodium salt, or its methyl ester
Derivatives described in Section.