JPS60142936A - Substituted phenyl derivative, its preparation, and remedy containing it - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is H, alkyl, alkoxy, alkenyl, etc.; R<2> is H, or CH3; R<3> is hydroxymethyl, carboxyl, carboxymethyl, etc.; R<4> is H, halogen, or alkyl; X is CH2O, CH2S, CH2NH, CH2NR<5> (R<5> is alkyl, or phenyl), CONR<5>, etc.; n is 0-2; bond containing dotted line is double bond, or single bond], its salt, or its acid addition salt. EXAMPLE:O-(P-Amylcinnamyl) salicylic acid. USE:A leulotriene antagonist, phospholipase inhibitor, and 5alpha-reductase inhibitor. PREPARATION:For example, a compound shown by the formula II is reacted with a (thiol)phenol derivative or aniline derivative shown by the formula III (Y is O, S, or NR<6>; R<6> is H or R<5>) in an inert organic solvent at room temperature -80 deg.C, to give a compound shown by the formula I where X is CH2O, CH2S, CH2NG, or CH2NR<5>.

Description

[Detailed description of the invention]

The present invention relates to novel substituted phenyl rust conductors. More specifically, the present invention relates to novel substituted phenyl derivatives having leukotriene antagonistic activity, phospholipase inhibitory activity, and 5α-reductase inhibitory activity, methods for producing the same, and pharmaceuticals containing these as active ingredients. Prostaglandin
, hereinafter abbreviated as PC. ) Several important discoveries have been made in the field of research over the past few years. Therefore, there has been a major change in the flow of PG research and development in recent years, and among the newly discovered and newly determined PG families, PG endo' is one with particularly strong and unique biological activity. PG endoperoxides (i.e. Pco2 and PGH2), thromboxane A2 (Thr
omboxane A2, hereinafter abbreviated as TXA2. )
, prostacyclin
, PGI1) and leukotrienes C, D and E (hereinafter referred to as LTC, LTD and LTE, respectively)
It is abbreviated as ) etc. In addition to these compounds, the entire PG family, which includes various PGs that have already been well-known, are biosynthesized in vivo using arachidonic acid as a common parent, so the entire metabolic pathway starting from arachidonic acid is Arachitonic acid cascade)” (A
rachidonate cascade). For detailed explanations of each route and pharmacological properties of each product, see Medical History, 114°378 (1980),
114.462 (1980), Ibid. 114.866 (1980), same, Jin 929 (1980)
), Modern Medicine, 12,909 (1980), 12.
1029 (1980), 12.1065 (1980)
) and same. 12.1105 (1980), etc. Cyclooxygenase acts on arachidonic acid cascade clay and arachidonic acid to produce various PGs such as prostaglandin F2a (hereinafter P
It is abbreviated as C-F2a. ) Lipoxygenase acts on the pathway leading to prostaglandin E2 (hereinafter abbreviated as PGE2), PGI2, TxA2, etc. and arachidonic acid to produce hyde-90 peroxyeicosatetraenoic acid)
' (bydroperoxy-eicosatetr
aenoic acid, hereinafter abbreviated as HPETE. ), then hydroxyeicosat, etraen
oic acid. Hereinafter, it will be abbreviated as HETE. ) or the route leading to leukotrienes. Since the former route is already well known, we will not discuss it in detail here. For details, 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 Scheme I. Arachidonic acid is metabolized by the well-known pathway, ie, PG/doper oxide, and also by lipoxygenase, which enters 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 1-HPETE, respectively.
5-HPETE is produced. HPETE of cholera is produced by converting hydrogen peroxide groups into hydroxyl groups by peroxidase.5. -1 (ETE, 12
-HETE or 15-HETE. Furthermore, among these HPETEs, 5-HPETE is converted to LTA4 by being dehydrated. Furthermore, LTA 4 is enzymatically converted to leukotriene B4 (hereinafter abbreviated as LTB4) and glutathione-S.
-) Converted to LTC4 by transferase. And L T C 4 is γ-glutamyl trans A
Converted to LTD4 by butidase. LTD441
Furthermore, it has recently been revealed that it is metabolized to LTE4 [Biochern-Biopbys-Res.
-Commun-, look up. 1266 (1979) and Prostag1andin
s+19(5)+645 (1980)]. On the other hand, when talking about SRS, SRS is SlowR
It is an abbreviation of ``eacting Subst, ance'', and this name was used by Feldherg et al. for the substance released when cobra venom is injected into the lungs or cobra venom is incubated with egg yolk. It has been reported that the effect is long-lasting [J-Physiol-+±1. 187 (1938)]. Furthermore, Kellayay et al. sensitized the lungs of sensitized guinea pigs with antigen during perfusion, resulting in SF (S-A (Slow R
acting Substance of Ana. p
C Quan, who showed for the first time that SRS-A and allergic reactions were released.
t, J & p- Phvsiol-, 30, 121 (
1940)). In addition, Brocklehurst has shown that when an antigen is applied to a surgically instilled lung section of a patient with bronchial asthma for whom a specific antigen is known, histamine and SRS are produced.
-A is released and strongly contracts the bronchial muscles, and this contraction is not relieved by antihistamines, making SRS-A an important bronchial constrictor during asthma attacks.
constrictor) [Pr
oF. r-Allergy, 6. 539 (1962
)reference〕. Subsequently, SBS-
A constricts the bronchial ring in a normal person [Int, -A
rch. Allergy Al)T)1-Immunol-,
38, 217 (1970)], rat SR
When S-A is intravenously injected into guinea pigs, an increase in pulmonary airway resistance is observed [J-Clin, Invest, +53,
1679 (1974)]; when Sf (S-A) is injected into the cervix of guinea pigs, rats, and monkeys, the permeability of blood vessels is reduced by 7.
Advances in Imtnuno
lO)zy+10, 105 (1969), J, Allp
rgy Clip-Immunol-, 6 2 1,
3 7 1 (1978), PrOstsg]. and
Ins+±9 (5), 779 (1980), etc.] There have been many reports. As mentioned above, SRS is a calcium ionophore (calcium ionophore) that is released due to the immune response and is called SRS-A.
Substances that are released without an immune response such as treatment with ionophores are classified as SRS and Class 2M, 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 LTC;4 and LTD4 are the same substances as S)Is or SRS-A, and therefore the pharmacological properties of these leukotrienes are similar to those of SRS-A.
Or C Proc, Natl., which can be considered in place of the pharmacological properties of SRS-A. Acad-Sc
i-USA, ys, 427s (+979), Bioch
em-Biophys-Res. Commun-, 91.1266 (1979), Pro
c- Natl-Acad, Sci-USA, 77,
2014 (1980), Nature. 285, 104 (1980)]. Based on the results of many studies such as these, various leukotrienes (LTC4, L'I'D4, LTE 4, and leukotrienes whose structures may be determined in the future) are currently biosynthesized from arachidonic acid via LTA4. is considered to be an important factor involved in the development of allergic tracheal and bronchial or pulmonary diseases, allergic shock, and various types of allergic inflammation. Therefore, by suppressing these leukotrienes, allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shock, and various allergic diseases can be prevented in mammals including humans, especially humans. It is effective in the prevention and/or treatment of. In addition, arachidonic substances are phospholipase (phoI3ph
-olipase), but a closer look shows that there are two routes as shown in Scheme 11: (1) phosphatidyl malin (ptl
(2) Pathway in which phospholipase A2 acts on phos'phatidyl choline
1,2-diglyceride (1,2-diglyceride) is produced by the action of phospholipase C on 1,2-diglyceride (1,2-diglyceride).
glycericlelipase), then monoglycerite tri, e-se (rnonoglyceridel)
, 1pase) is generally thought to be released (Chemistry and Biology 21, 154 (1983)
)reference). The liberated arachidonic acid is further processed by two routes: (1) cyclooxygenase (cvclooxygenase);
ase) metabolic pathway, prostaglandin (PG)
and thromboxane A2 (TXA2), or (2) lipoxygenase (1j
, poxygenase) metabolic pathway, SFtS-
A(Slow Reacting(5ubstance)
s of anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriacetate B4
It is known that it is metabolized into physiologically active substances such as (Laukotriene B4) [Chemistry and Biology 21
．． ．． 154 (1983) @ Teru]. These metabolites include, for example, TXA2, which is a substance with strong platelet aggregation and vasoconstriction; 5) (S-
A is a chemical mediator of asthma]
LTB 4 is a chemical mediator of inflammation such as gout;
Furthermore, pG is known to be a chemical mediator that has vasodilatory effects, carcinogenic effects, thermogenic effects, and leukocyte migration effects in inflammation [Metabolism 20.317 (1983
), The Lancet 1122 (1982) Edited by Makoto Katori et al. Prostaglandin (197B) 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. The inventors have carried out extensive research to find compounds that antagonize leukotrienes or inhibit phospholipases (phospholipase A2 and/or phospholipase C) and have found that certain carboxamide derivatives achieve this purpose. They have already filed a patent application (see specification of % Application No. 58-203632). This time, the present inventors have succeeded in converting the 100NF (- group) in the previously proposed carboxamide derivatives to other groups to create these new compounds (compounds represented by the general formula (1) described below). The present invention has been completed based on the discovery that the pharmacological action of the compound can be enhanced or improved.The compound of the present invention strongly inhibits phospholipase and suppresses the release of arachidonic acid from phospholipids, so it is effective in mammals including humans. It is particularly effective in the prevention and/or treatment of diseases caused by arachito9anoic acid metabolites 1 such as TXA2, PG, and leukotrienes in humans. Examples of target diseases include allergies caused by the above-mentioned leukotrienes. These include various sexual diseases 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 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 is present in the endoplasmic reticulum and diaphragm,
Converts ingested testosterone into the active form of 5α-
This active form of 5 (Y-dihydrotestosterone) causes cell proliferation by binding to intracellular receptors.
If this effect is reversed, it is said to lead to the onset of prostatic hyperplasia, alopecia, or sitting ulcers. For example, in the case of benign prostatic hyperplasia, conventionally, as drug therapy, estrogen agents, which are female hormones, and gestagen agents, which have anti-androgen effects, have been used. However, in both cases, the original hormonal effects remain as side effects, so it was difficult to say that sufficient treatment was being provided. Of course, the compound of the present invention does not have any hormone-specific effects, and moreover, it strongly inhibits 5α-reductase, suppresses the increase in 5α-dihydrotestosterone, and suppresses cell proliferation. In particular, it can effectively prevent and/or treat benign prostatic hyperplasia, alopecia, and sitting pain in humans. The present invention is based on the general formula [wherein R is (1) a hydrogen atom, (11) a straight or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, and (Ill) a straight chain having 2 to 15 carbon atoms. A chain or branched alkenyl group or a straight or branched alkenyloxy group having 3 to 15 carbon atoms, or (IVI 2 to 15 carbon atoms)
A straight or branched alkynyl group or a carbon number of 3 to 1
5 represents a linear or branched alkynyloxy group,
2 R represents a hydrogen atom or a methyl group, and R is a hydroxymethyl group, a carboxyl group, a carboxymethyl group, a straight chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a straight chain having 3 to 7 carbon atoms. or represents a branched alkoxycarbonylmethyl group, R represents a hydrogen atom, a halogen atom, or a straight or branched alkyl group having 1 to 4 carbon atoms, or has the formula -CH20-, -GH2S-1
-CH2NH-, -CH2NR-, -CO-8-, -c
represents a group represented by o-NR- or -co-cH2- (in the formula, R represents a straight or branched alkyl group having 1 to 4 carbon atoms or a phenyl group), and R represents 0.1 or 2, and the symbol = represents a double bond (E, 2 or E
Z mixture) or a single bond. The present invention relates to substituted phenyl derivatives represented by the above, non-toxic salts and acid addition salts thereof, methods for producing them, and pharmaceuticals containing them as active ingredients. In the general formula (11), the alkyl group in the linear or branched alkyl group having 1 to 15 carbon atoms or the alkoxy group represented by R is a methyl group, an ethyl group, a propyl group, a butyl group, and a methyl group. , hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group,
Examples include tridecyl group, tetradecyl group, pentadecyl group, and isomers thereof. Preferred groups as R include linear or branched alkyl groups or alkoxy groups having 1 to 8 carbon atoms, and particularly preferred groups include Ru is a methyl group (amyl group) or a methyloxy group. In general formula (1), the alkenyl group in the straight chain or branched alkenyl group having 2 to 15 carbon atoms or the straight chain or branched alkenyloxy group having 3 to 15 carbon atoms represented by R is ethynyl Group, pro is nyl group, ethynyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group,
Examples thereof include a nonenyl group, a decenyl group, an undecenyl group, a tothycenyl group, a tothycenyl group, a tetradecenyl group, a ntadecenyl group, and isomers thereof. In the general formula O), the alkynyl group in the straight chain or branched alkynyl group having 2 to 15 carbon atoms or the straight chain or branched alkynyloxy group having 3 to 15 carbon atoms represented by R is an ethynyl group. , propynyl group, butynyl group, pentynyl group, hexynyl group, hezotinyl group, octenyl group, phenyl group, decynyl group, randecynyl group, dotesynyl group, tridecynyl group, tetradecynyl group, pentadecynyl group, and isomers thereof. However, when R represents an alkenyloxy group or an alkynyloxy group, there is a double bond or triple bond between carbon atoms other than the carbon atoms adjacent to the oxygen atom. It is also preferred when R1 represents a hydrogen atom. R may be substituted at any position on the Hensen ring, but the preferred position is the e position. In the general formula (11, in R, a straight chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms and a straight chain or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms has 1 to 5 carbon atoms. Examples of the straight-chain or branched alkyl group include a methyl group, an ethyl group, a propyl group, a methyl group, an R-methyl group, and isomers thereof, and any group is preferable. 3. R or a hydroxymethyl group , a carboxyl group, or a carboxymethyl group. In the general formula (1), the linear or branched alkyl group having 1 to 4 carbon atoms represented by R includes a methyl group, an ethyl group, a propyl group, butyl group, and isomers thereof. In the general formula (11), examples of the halogen atom represented by R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. It is also preferable that R represents a hydrogen atom. R and R may be substituted at any position on the ring, with the preferred position of H being the ortho position, and the preferred position of H being the meta or para position.General formula (11 Among them, the linear or branched alkyl group having 1 to 4 carbon atoms represented by R in X includes a methyl group, an ethyl group, a propyl group, a methyl group, and isomers thereof. Preferably. 5. It is also preferable when R represents a phenyl group. The compound of the present invention represented by the general formula (1) may have isomers, especially when the symbols = represent a double bond,
Due to this double bond E or Z, when the symbol = represents a single bond and R represents a methyl group, the carbon atom to which this methyl group is bonded becomes an asymmetric carbon, and isomers exist. Furthermore, isomers may occur when each substituent in general formula (1) represents a branched alkyl group or alkylene group, or when it contains a double bond. The present invention also includes all these individual isomers and mixtures thereof. Until now, patent applications containing compounds having chemical structures similar to the compounds of the present invention have been filed, but 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 the fact that the present invention is included in this invention does not mean that the present invention is included in the scope of the invention. There is no description suggesting that it is antagonistic to leukotrienes, which is one of the leukotrienes.
No. 7-106651 also discloses a similar compound, but the compound of the present invention is not included here either. Moreover, although the above-mentioned published specification mentions 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. Furthermore, the t14+J2 applications do not describe the use as a phospholipase inhibitor or 5α-reductase inhibitor as in the present invention, and do not describe the use as an antithrombotic agent, prophylaxis against benign prostatic hyperplasia, alopecia, and sitting pain. In the present invention, the use as a treatment is discovered for the first time, and the present invention cannot be easily deduced from these prior art. , -GH2S
−. A compound represented by the general formula (11) representing a group represented by -0H2NH- or -0H2NR' (wherein, R5 has the same meaning as above), that is, general formula 1 [wherein, Y is 10-1] -8- or -NR- (wherein R
represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group. ), and other symbols have the same meanings as above.1-0] Compounds represented by the general formula (in which 1 base is

The symbol [ has the same meaning as above. ) and a compound represented by the general formula (in the formula, all symbols have the same meanings as above). In this reaction, when the compound represented by the general formula (III) is a phenol or thiophenol derivative,
Inert organic solvents, such as tetrahydrofuran (THF)
, diethyl ether, methylene chloride, chloroform, carbon tetrachloride, intane, hexane, benzene, toluene,
Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphatamide (H
MPA) in the presence of a base such as sodium hydride, potassium carbonate, triethylamine, male lysine at room temperature to 80°C. When the compound represented by the general formula (III) is an aniline derivative, it is prepared at room temperature to 80°C in the above-mentioned inert organic solvent or without a solvent and optionally in the presence of a tertiary amine such as triethylamine.
It will be held in x A compound represented by the general formula (11) representing a group represented by the formula -GO-8-Mataha-Co-NFC (in the formula, R represents the same meaning as above), that is, the general formula R1 [in the formula, Y' represents a group represented by -S- or -NR5- (in the formula, R5 has the same meaning as above), and other symbols have the same meanings as above.] The compound represented by Produced by reacting a compound represented by the formula (in which all symbols have the same meanings as above) with a compound represented by general formula (in the formula, all symbols have the same meanings as above). This reaction is a known reaction, for example, an inert organic solvent,
For example, the reaction is carried out in methylene chloride, chloroform, or tetrahydrofuran in the presence of a tertiary amine such as triethylamine or pyridine at a temperature of -20°C to 40°C. Preferably in methylene chloride in the presence of triethylamine,
It is carried out at 0°C to room temperature. General formula (where X represents a group represented by the formula -CO-CH2-)
1), that is, the compound represented by the general formula (in the formula -1, all symbols have the same meanings as above), the compound represented by the general formula (IV) and the general formula [in the formula, R Bar C00C(OH3)3. -CH2COO
C(CH3)3 or -0H20THP (wherein, TH
P represents a tetrahydroran-2-yl group. ), and R has the same meaning as above. ] was reacted to obtain a compound represented by the general formula (in the formula, all °C symbols have the same meanings as above. (wherein, R3h represents a group represented by -000) L-at-t2coon or -CH2QH, and the others have the same meanings as above.), and further the desired b Niyori, R car C0OH maf,: When H-CH2COOH represents a group, a compound represented by the general formula (IC) can be produced by subjecting it to the esterification reaction described below. The reaction between the compound represented by the general formula (IV) and the compound represented by the general formula (Vl) is carried out by first adding the compound represented by the general formula (Vl) to an inert organic solvent such as THF, ethyl ether, antane, etc. , hexane, toluene, in HMPA, from -78°C to room temperature, preferably -78°C.
By reaction with a suitable lithiation agent, e.g. lithium diimpropylamide, at a temperature between 0.degree.
) is used as a lithium derivative of the compound represented by formula (IV), and then this derivative is reacted with a compound represented by general formula (IV) 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, J ethyl ether,
Treatment with an acid, e.g. an inorganic acid such as hydrochloric acid or an organic acid such as 7)-toluenesulfonic acid, trifluoroacetic acid, in hexane, benzene, toluene or without solvent at room temperature to reflux temperature. As a result, it is converted into a compound represented by the general formula (IC-α). The compound represented by the general formula (lI) used as a starting material can be produced, for example, according to the following reaction. (X)' (XI) Briefly describing each of the above reactions, the esterification is carried out at 0°C using a diethyl ether solution of diazomethane in an inert organic solvent such as ethyl acetate. Reductions are carried out in inert organic solvents such as THF, diethyl ether, toluene, with reducing agents such as diisobutylaluminum rhamno-hydride or lithium aluminum hybilite 9, from -78 °C to the reflux temperature of the solvent. Chlorination is carried out using thionyl chloride, 7)-) luenesulfonyl chloride, etc. in an inert organic solvent such as methylene chloride in the presence of a tertiary amine such as triethylamine from 0°C. React at 50°C or use methanesulfonyl chloride in the presence of 2.4.6-collidine and lithium chloride in chloroform to
C J-o-c-, 36, 30 reacted at room temperature from °C
44 (1971)]. For the compound represented by the general formula (1) used as a starting material, a carboxylic acid represented by the general formula (■) is prepared by adding the carboxylic acid represented by the general formula (■) in an inert organic solvent such as methylene chloride, tetrahydrofuran, or without a solvent at a temperature ranging from -40°C to room temperature. It is produced by reacting with thionyl chloride or oxalic acid chloride. It is preferably carried out using oxalic acid chloride without a solvent at room temperature. General formulas (m), (V) and ( Vl
) are all known compounds, or
Alternatively, it 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 Japanese Patent Application No. 58-203632 or an obvious analogous method thereof. Furthermore, according to the present invention, a compound represented by the general formula (11) in which R represents a carboxyl group or a carboxymethyl group and other symbols have the same meanings as above, R represents an alkoxycarbonyl group or an alkoxycarbonylmethyl group, respectively. It can also be obtained by subjecting a compound represented by the general formula (1) in which the expressions and other symbols have the same meanings as above to a saponification reaction.The saponification reaction is a known reaction, and for example, compounds that are miscible with water can be obtained. an alkaline substance such as sodium hydroxide, potassium hydroxide, in a solvent such as methanol, ethanol, THF;
Using an aqueous solution such as lithium hydroxide, from 0℃ to 50℃
temperature, preferably room temperature. In addition, a compound represented by the general formula (Il) in which R is an alkoxycarbonyl group, where R represents an alkoxycarbonylmethyl group, and other symbols have the same meanings as above, each R represents a carboxyl group or a carboxymethyl group, and other symbols have the same meanings as above. General formula (1
) can also be obtained by subjecting the compound represented by formula to an esterification reaction. The esterification reaction is a known reaction, for example using a suitable diazoalkane in diethyl ether, ethyl acetate or methylene chloride, at temperatures ranging from -10°C to room temperature, preferably at 0°C.
C. or using the corresponding alcohol and dicyclohexylcarbodiimide in the presence of a base such as pyridine in an inert organic solvent such as methylene chloride at temperatures from room temperature to 50.degree. 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. A giant monkey. Purification may be carried out after each reaction or after the completion of several reactions (... Salts and acid addition salts are preferably non-toxic. Here, non-toxic salts and acid addition salts are is relatively harmless to animal tissue, and when used in the amount necessary for treatment, the effective pharmacological properties of the compound represented by general formula (1) may be due to side effects caused by its anions or cations. It refers to salts consisting of intact anions or cations. It is also preferred that the salts and addition salts are water-soluble. Suitable salts include, for example, salts of alkali metals such as sodium or potassium, calcium or These include salts of alkaline earth metals such as magnesium, ammonium salts and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include Examples include amines that can theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups, which may be the same or different when one or more hydrogen atoms are replaced. , for example, carbon number 1-6
alkyl groups, and hydroxyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclothylamine salts, benzylamine salts, phenethylamine salts, pi-lysine salts, and monoethanolamine salts. , organic amine salts such as jetanolamine salt, lysine salt, and arginine salt. Suitable acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoic acid. salt,
Examples include organic acid salts such as citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and isethionate. The salt of the substituted phenyl-conductor represented by the general formula (1) can be prepared by adding the acid represented by the general formula (11) to a suitable base, such as an alkali metal or alkaline earth metal hydroxide, in a suitable solvent. Alternatively, it can be obtained by reacting with a carbonate or an organic amine.The acid addition salt of the substituted phenyl vj4 represented by the general formula (1) can be obtained by adding the compound represented by the general formula (1) by a known method, for example, using an appropriate solvent. Among them, suitable acids, such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, or acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethane It can be obtained by reacting with an organic acid such as sulfonic acid, Hanzensulfonic acid, toluenesulfonic acid, or isethionic acid.As mentioned above, the compound of the present invention has leukotriene antagonistic activity, phospholipase inhibitory activity, and 5α-reductase inhibitory effect. However, in laboratory experiments, for example, the compounds of the present invention showed the following effects on LTD4, and the compounds of the present invention showed the effects on phosphoIJ)R-zeA2 as shown in the table below. showed an inhibitory effect. The compounds of the present invention exhibited inhibitory effects on 5α-reductase as shown in the table below. The appetizer inhibition rate shows the value at 2rrLM concentration of the compound of the present invention. The antagonistic effect of the compound of the present invention on LTD4 was measured by the following experimental method. The ileum (3 cm) removed from a male guinea pig weighing 300 to 400 g was heated at 37°C, Tvrode solution, and oxygen (95%
%)-carbon dioxide (5%) mixed gas, and after stabilizing for about 30 minutes, LTD 4 was
The compound of the present invention was added at a concentration of 0.017ml, and the shrinkage height was measured by changing the concentration of the compound of the present invention based on the shrinkage at this time, and the engineering C5o value was calculated from this. The inhibitory effect of the compounds of the present invention on phosphorinoξ-ase A2 can be determined by using a modified 5hakir method using L-β- as a substrate.
[1-C]-Arachitonyl-α'-stearoyl-phos-7-acylcholine was measured using t'-SeA2, a phosphoryl obtained from guinea pig lung, as the enzyme [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 fraction, with reference to the method of J. Shimazaki et al. 5α-reductase activity was measured using 0.09 MHepes (T)H7,4), 0.2
2M sucrose, 5% IQM NADPH 15μM [4
-0] Testolone, 5α-reductase, and the metal compound of the present invention were used to react at 37° C. for 60 minutes. The reaction was stopped with chloroform-methanol (,/2), and after centrifugation, the supernatant was spotted on a silica gel thin layer plate and chloroform-methanol-acetic acid (
99,2: 0.6: 0.2),
The radioactivity of the generated dihydrotestosterone was measured using a TLC scanner, and the enzyme activity inhibition was calculated [E
ndocrinoL Japan,, 18 r 17
9 (1971)]. In dairy animals including humans, especially humans, suppressing leukotrienes can prevent allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shock, 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, by inhibiting phospholipases (phospholipase A2 and/or phosphorinoξ-ase C).
For example, it is effective in preventing and/or treating thrombosis caused by damage to the endothelium or intima of the brain or coronary arteries, and various inflammations such as arthritis and rheumatism. Furthermore, inhibiting 5α-reductase can prevent benign prostatic hyperplasia, alopecia, and acne.
or effective for treatment. To use the substituted phenyl derivatives represented by general formula (1) or their non-toxic salts or acid addition salts for the above-mentioned purposes (as leukotriene antagonists, phospholipase inhibitors or 5α-reductase inhibitors), each of the following: It is usually administered systemically or locally, orally or parenterally. Dosage depends on age, body weight, symptoms, therapeutic effect, administration method,
Although it varies depending on the treatment time etc., it is usually lIn9 to Ig per adult, preferably 20 m2 to 2.
00rn9, administered orally once to several times a day, or 100μ of each at a time per adult.
It is administered parenterally in the range of 1 to 100 g, preferably 1 to 10 g, 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 a smaller amount 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, sucrose, human 90xypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. , mixed with magnesium aluminate metasilicate. The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and pigeon-breakers such as cellulose calcium gluconate, in accordance with conventional methods. For tablets or pills, white M, gelatin,
It may be coated with a film of a gastric or enteric substance such as hydroxypropyl cellulose or hydroxypropyl methylcellulose phthalate, or it may be coated with two or more layers. Also included are capsules of ingestible 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, and POLYTSU 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 disinfectants or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use. Other compositions for parenteral administration include topical solutions, liniments such as ointments, containing one or more active substances and formulated in a manner known per se, for rectal administration. Includes suppositories and 4-touch saris for intravaginal administration. Among the compounds of the present invention represented by the general formula (1), preferred compounds include 0-cinnamylsalicylic acid, 0-(7)-amylcinnamyl)salicylic acid, (J-(
p-pentyloxycinnamyl) thiolic acid, 2-(
Cinnamyloxy)benzyl alcohol, 2-CP-amylcinnamyloxy)benzyl alcohol, 2-Cp
-A cinnamyloxy)benzyl alcohol, 2-(cinnamylthio)benzoic acid, 2-(p-amylcinnamylthio)benzoic acid, 2-(ρ
-R-methyloxycinnamylthio)benzoic acid, 2-(cinnamylthio)benzyl alcohol, 2-<p-amylcinnamylthio)hensyl alcohol, 2-(p--!
Nteroxycinnamylthio)handyl alcohol, N-cinnamylanthranilic acid, 1'J-(p-amylcinnamyl)anthranilic acid, N
-<p=nteroxycinnamyl)anthranilic acid, 2
-(cinnamylamino)benzyl alcohol, 2-CP
-amylcinnamylamino)benzyl alcohol, 2-(7)--! S-(cinnamoyl)thiosalicylic acid, 5-(7)-amylcinnamoyl)thiosalicylic acid, 3-(P-interoxycinnamyl)thiosalicylic acid, 2-(cinnamoylthio)hen sil alcohol, 2-
<p-amylcinnamoylthio)benzyl alcohol,
2-(ρ-pentyloxycinnamoylthio)benzyl alcohol, N-cinnamoyl-N-phenylanthranilic acid, N-
(p-amylcinnamoyl)-N-phenylanthranilic acid, N-Cp--'! cinnamoyl)-N-phenylanthranilic acid, 2-(N-cinnamoyl-N-phenylamino)hencyl alcohol, 2-CN-CP-amylcinnamoyl)-N-phenylaminocohencyl alcohol, 2 -CN-CP- (teroxycinnamoyl) -N-
Phenylaminocobenzyl alcohol, N-cinnamoyl-N-methylanthranilic acid, N-(P-amylcinnamoyl)-N-methylanthranilic acid, N-(p--enthyloxycinnamoyl)-N-methylanthranilic acid acid, 2-(N-cinnamoyl-N-methylamino)-;ndyl alcohol, 2-CN-CP-amylcinnamoyl)-N-methylaminocobenzyl alcohol, 2-[N-(ar'! Oxycinnamoyl) −
N-methylaminocobenzyl alcohol, 2-(cinnamoylmethyl)benzoic acid, 2-(p-amylcinnamoylmethyl 01benzoic acid, 21p--!antyloxycinnamoyl methane)> Benzoic acid, 2-(cinnamoyl Methylenhanzyl alcohol, 2-(7)-7
Examples include milcinnamoylmethyl)hensyl alcohol, 2-CP-'ethyloxycinnamoylmethyl)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.
The present invention is not limited to these examples. In addition, 1'-TLCJ, l'-IH in Reference Examples and Examples
J, [NMI (J and MsJ symbols are
"Thin layer chromatography", "Infrared absorption chromatography", "
"nuclear magnetic resonance spectral" and "mass spectrometry"
The proportion of solvent described in the section of separation by chromatography indicates the volume ratio, [The solvent in parentheses of [TLCJ] indicates the developing solvent, and l'-IRJ is measured by the liquid film method unless otherwise specified. However, [N M RJ is measured using a deuterated chloroform (CDC13) solution unless otherwise specified. Reference Example I P-amyl cinnamyl alcohol ρ-amyl cinnamic acid dissolved in ethyl acetate 5H (patent application 1973)
Compound described in Reference Example 2 of Specification No. 8-203632) 4
A solution of diazomethane in diethyl ether was added to the mixture at 0° C. with stirring until no more foaming occurred, and 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 heated at -78°C under an argon atmosphere.
A 901.76M solution of diisobutylaluminum hydride 26-a/ dissolved in toluene was slowly added thereto, and the mixture was stirred at -78°C for 5 minutes and then at 0°C for 30 minutes. Next, methanol was added dropwise at 0°C until no foaming occurred, and
After stirring for 5 minutes at ℃, add 1.21r of water at 0℃.
tl was slowly added and the mixture was stirred vigorously for 1 hour at room temperature. The precipitated white crystals were separated in a furnace, the filtrate was concentrated under reduced pressure, and water was removed by azeotroping with toluene to obtain the title compound 387■ having the following physical properties as a crude product (pale yellow solid). . TLC (ethyl acetate: cyclohexane = 1:2): Rf
Mi0.34: NMR: δ = 7.29 (2H1 self), 7.10 (2H,
d), 6.58 (IH, d), 6.18 (l) (, dt
), 4.16 (2H. d), 2.58 (28, t), 2.30 (1 genus 5),
1. 18-1.10 (6H, m), 0.87 (3H,
t): MS near rL/Z=204(M), 191.1
61.147.133.105.91゜Reference Example 2 p-amylcinnamyl chloride Alcohol compound (produced in Reference Example 1) 102Q dissolved in 0.5 parts of dry chloroform under an argon atmosphere
? 72 μl of IC12,4,6-:I lysine and 21 drops of lithium chloride dissolved in 1.5 mA of dry dimethylformamide were added and the mixture was cooled to 00C. 43 μl of methanesulfonyl chloride was added thereto, and the mixture was stirred at 0°C for 15 hours and then at room temperature overnight. 10 d of water was added to the reaction mixture, and diethyl ether and n--'enthane (1:1) were added. ), the extract was washed sequentially with saturated copper nitrate (ml aqueous solution), water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound 100In9 having the following physical properties. NMR: δ = 7.30 (21-1, cL), 7.12 (
2H, d), 662 (IH, d), 6.24 (LH, d
i), 4.20 (2H. d), 2.58 (2,H,t), 1.80-1.1
0 (5) (. m), o, 57 (3H, t): MS: m/Z = 222 (M), 187.165.12
9.117.71.43゜Example 1 O-(p-amylcinnamyl)salicylic acid methyl ester Dried tetrahydrofuran 0.24 in an alkone atmosphere
(hydrogenated suspension) IJium (content 264%) 1
1.50 ml of salicylic acid methyl ester dissolved in 0.2 mt of dry tetrahydrofuran was slowly added to 1.3~ at room temperature, and after stirring at the same temperature for 5 minutes, about 5 ml of dry dimethylformamide was added, and then 5 ml of dry tetrahydrofuran was added. Add 67 da of cinnamyl chloride compound (manufactured in a reference example) dissolved in 0.3 to 50 °C.
The mixture was stirred at 80° C. for 2 hours and then at 80° C. for 3 hours, and then cooled to room temperature. 5 ml of water was added to the reaction mixture, and the mixture was 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 (eluent: chloroform:cyclohexane=1→3:2) to obtain the title compound 87■ having the following physical properties. TLC (ethyl acetate: cyclohexane = 1:10): R
f snow 0.23: NMR: δ = 7.79 (IH, d(t), 7.40 (I
H, dt), 7.30 (2H, d), 7.10 (2H,
d), 6,98 (IH, d), 6.93 (IH, di)
, 6.76 (IH. d), 6.32 CIH, d, 4.74 (2H, rid
), 3-” 5 (3H,z )′, 2.5’6 (2H
, t), 1. ．． 80-1.10 (6H, m), 0.84
(3H, t); MS: m/Z=338CM+), 30
7.187.131.129.117.115.71.
43゜Example 2 N-(p-amyl cinnamyl) anthranilic acid methyl ester Under an argon atmosphere, a mixture of 180 ~ cinnamyl chloride compound (produced in Reference Example 2) and anthranilic acid methyl ester (366 ml; 1) was heated at 40'C. It solidified after stirring for 1 hour. Diethyl ether 501r in solid matter
Ll and 20 WLl of a saturated aqueous sodium bicarbonate solution were added and dissolved, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:cyclohexane=5→1:2) to obtain 95 mg of the title compound having the following physical properties. TLC (chloroform: cyclohexane = 1:2): R
f=0.24; NMR: δ=7.92 (IH, dd), 8.10-7.
70 (IH, br), 7.45-7.20 (IH, m)
, 7.2s (2H, d), 7.08 (-2H, Li-)
, 6.70 (IH, cl), 6.67 (IH, t), 6
．． 6o (IH, d), 6.22 (IH. dt), 3.98 (2Ht'), 3.82 (3H, r
), 2.56 (2H, t), 1.80-1.10 (6H
, m), 0.87 (3H, t): - IJS: mAZ-337 (M''), 312.31
'0,306.304.278.266.248.23
4.202,187, 117.71.43° The following compound was obtained in the same manner as in Example 2. (α) J-Cinnamyl anthranilic acid methyl ester starting material cinnamyl chloride and anthranilic acid methyl ester: TLC (chloroform:cyclohexane-1:x): R
f=0.34; NMR: δ=7.93 (IH, dd-), 8.10-7
．． 70 (IH, br), 7.60-7.00 (6H,
m), 6.72 (IH, d), 6.68 (IH, t),
6.64 (11-1, d), 6.28 (IH2dt),
4.03 (2H,t), 3.87 (3) 1°S)
; MS: m/Z=267 (M), 252.234.20
8.206.132, ]17.115.91゜Example 3 S-(ρ-amylcinnamoyl)thiosalicylic acid 1 d of oxalic acid chloride was added to 1511 ng of p-amylcinnamic acid, stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The acid chloride was obtained. Thiosalicylic acid 106 dissolved in methylene chloride IWLl
# and triethylamine 139■, methylene chloride 1-
Acid chloride (prepared above) dissolved in water was added dropwise under water cooling, and the mixture was stirred at room temperature for 1 hour. 3 d 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 roohexane to obtain the title compound 1501119 as a pale yellow solid having the following physical properties. TLG (ethylacetate A/:W-hexane=1:t):Rf
-0,3: NMR: δ-8,04(IH, d(t), 7.68(I
H, d), 7.8-7.4 (4H, m), 7.3-7.
15 (2H, d), 6.78 (IH, d): IR (KBr method) Niji = 1680.1610.156o
, 1475.1410 cm-': MS: m/Z-354 (M), 332.294.21
8.201.161° The following compound was obtained in the same manner as in Example 3. (αl N-(7'-amylcinnamoyl)-N-phenylanthranilic acid Starting materials: p-amylcinnamic acid 1201n9 and N-phenylanthranilic acid 11'19; Purification method Nisilica gel column chromatography (ethyl acetate: n-hexane) -1:4): Yield: 172■: TLC (ethyl acetate: FL-hexane = 2:1): Rf
-0,2: NMR: δ=s, oo(1)1. br), 7.73(I
H, d), 7.6-7.0 (12H, 7W), 6.4 (
IH, hr); Engineering R Niji = 1715.1690, 16
40.159o, 1485cm :MS:m/Z-41
3,369,218,213,201,195,161
゜(hIN-CP-amylcinnamoyl)-N-methylanthranilic acid Starting material 2p-amylcinnamic acid 109ml;' and N-methyk77) Shell acid methyl ester 165■: Purification method Nisilica gel column chromatography (cyclohexane: Ether acetate dried 2:1): Yield: 130■: NMR: δ-8,04 (IH, dd), 7.66uH,
d), 7.57 (2H, ds, 7.3 (IH, dd),
7.20 (2H. d), 7.06 (2H, d), 6.10 (IH, d). 3.82 (3H,,?), 3.34 (3H, #),
2.55(2H,t), 1.6-1.2(6)(,
m), 0.86(3)(,m): MS: m/Z=365(M), 334.306.20
1.165.144.131°(C12-[N-(P-amylcinnamoyl)-N-
Methylaminocohensyl alcohol Starting materials 2p-amylcinnamic acid 218~ and 2-(methylamine)benzyl alcohol 137rn9; Purification method Nisilica gel column chromatography (cyclohexane: ethyl acetate - 5:1): Yield = 150~; TLC (yChlohexane:ethyl acetate=2:1):Rf
-0,12; NMR: δ = 7.7-7.0 (9H, m), 6.1 (I
H, d) -4,64 (2H, s'), 3.32 (3H,
Q, 2.54 (2H.t), 1.55 (2H,m), 1.4-1.2 (4
H,? lL), 0.85 (3t(,t): ■R Niji = 3400.292 Q, 2850.1735
．． 1650.1600.1370.1240.1040
cm. MS: m/Z=337CM), 306, 201, 17
6.161.144.136.131,119,115
゜Example 4 O-(7'-7milcinnamyl) salicyl lu! and its sodium salt Tetrahydrofuran-methanol (1:1) mixture 2
．． 5 ml of 1N sodium hydroxide aqueous solution Q was added to 85~ of the methyl ester compound (produced in Example 1) dissolved in 0.0 ml of the methyl ester compound (produced in Example 1), and the mixture was stirred at room temperature for 24 hours. 10 ml of water and 1.0 d of 1N hydrochloric acid were added to the reaction mixture, 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 subjected to silica gel column chromatography (elution solvent,
Purification with chloroform:cyclohexane (5:1→chloroform only) gave 60 μm of the title compound (free acid) having the following physical properties as a colorless solid. TLC (ethyl acetate:cyclohexane=t:2):Rf
-0,20: NMR: δ = 8.19 (IH, CLcL), 7.54 (
11(, (it), 7.34(2H,d), 7.25
-7.00 (41 (1 m>, 6,78 (1) L, d),
6.34(1)1. tt>, 4.91 (2H. d), 2.59 (2H, t), 1.80-1.10 (6
H. nL), 0.88(3)i, t): IR (KBr method) Niji-2960, 2930, 2850
, 1695, 1670, 1600, 1570, 1505
,1490,1460,1440,1410,1380
,1310,1290,1260%1160.1085
．． 985,-i. 750 cIrL tube MS near 7&/Z=324CM), 306.2'80
,278,253°249.235.22″1・,2o
c+, 187.117.71.43゜Dissolve the free acid obtained above in methanol 1-2-, add 185 μl of a 1N aqueous sodium hydroxide solution, concentrate under reduced pressure, and further azeotropically with a mixture of toluene and ethanol. The water was removed and the mixture was sufficiently dried with phosphorus pentoxide to obtain the title compound (sodium salt) 64~ as a colorless solid having the following physical properties ◇ NMR (CD30D merging): δ = 7.38 (IH, dd
), 7,32(2)I, d), 7.21(1)(
, cLt ), 7.10 (21 (. d), 6.98 (IH, cL), 6.88 (IH, t
), 6.73 (IH, d), 6.41 (IH, d
, t ), 4.73czH, dd), 2.57 (2H,
t), 1.60 (2) (. WL), 1.45-1.20 (4H, rrL), 0.8
9(3)(,t). The following compound was obtained in the same manner as in Example 4. (αl N-(P-amylcinnamyl)anthranilic acid and its sodium salt Starting material: Methyl ester compound 9 prepared in Example 2
5m! 7: Yield [acid] 285 ~; TLG [acid] = (ethyl acetate: cyclohexane = 1:4
): Rf = 0.20: NMR ['acid]: δ = 10.0O-8.00 (2H, b
r), s, oo (xH. dc?), 7.50-7.2 ('L H,i), 7.
19 (2H. d,), 7.10 (2H, ('), 6.73 (IH,
(t'), 6.69 (IH, i ), 6.60 (IH,
d), 622 (IH, dt), 4.04 (2H, d),
2.58 (2H. t), 1.80-1.10 (6H, m), 0.88 (3
H, t>IR [acid] (KBr method) = 3380.2
970,2920.2850.1655.1570.1
510.1450.1440.1405.1320.1
240.1155, -1. 1100.1035.960.745cm. MS [acid], Hm/Z = 323 (M+), 305.27
8.252, to 234.202.187.161.1
17.71.43: NMR [salt] (CD30D solution):
δ-7,85 (IH, dd), 7.26C2H, d),
7.16 (tH, dt), 7.06 (2H, d), 6.
66 (II (, d), 6.60 (IH, d) 6.52 (
IH, t ), 6.30 (IH, di), 3.94 (2
H, dg), 2.55 (2H, t), 1°58 (2H. In), 1.45-1.15 (48, r + Q, 0.88
(3H,t): Salt form: colorless solid. (b) N-cinnamyl anthranilic acid starting material: methyl ester compound produced in Example 2 (α) (however, only saponification reaction was performed): TLC (ethyl acetate: cyclohexane = 1:2): Rf
=0.36: NMR (CD30D+dimethylsulfoxide-d6 solution): δ-7,85 (LH, dd), 7.50-7.00
(6H, m'), 6.74 (11-(,''), 6.62
(IH, L:L), 6.57 (IH, (tt), 6.1
9 (IH, di), 3.98 (2H, ct): MS: m/Z-253 (M), 235.208.13
2.117.91: Acid form: pale yellow solid. (CIN-(7'-amylcinnamoyl)-N-phenylanthranilic acid sodium salt starting material: anthranilic acid prepared in Example 3 (α);
(However, only the salt formation reaction was performed.) Form of salt: pale yellow solid. (d) N-(71)-amylcinnamoyl)-N-methylanthranilic acid and its sodium salt Starting material: Methyl ester compound prepared in Example 3(b) 1301n9: Yield [acid]: 93 drops; NMR [ acid]: δ-13,15(IH,"), 7.7-
7.0 (8H, m), 6.80 (IH, cL), 3.3
4 (3H, s), 2.52 (2H, t), 1.53
(2H, yx,), 1.4-1.2 (4H, 7W),
0.84 (3H, m>: IR [acid] (KBr method) =
3450.2930.2850.1710.1640.
1580.1380.1240-1°α. MS [acid] 2m/Z=351(M), 306.201
．． 151.131.115° Salt form: white solid. Reference example 3 2-([1-(7)-amylcinnamoyl)-1-t
ert-cytoxycarbonylcomethyl)benzoic acid ter
t-Butyl ester Under a nitrogen atmosphere, 1.8 ml of a 1.6M solution of rubyl lithium dissolved in ruhexane was added dropwise to 400 µj of diisopropylamine dissolved in 7 ml of tetrahydrofuran at room temperature, and stirred at the same temperature for 20 minutes to dissolve the lithium. A diimpropylamide solution was obtained. This solution was cooled to -78°C, 292 μm of 2-(tert-cytoxycarbonylmethyl)benzoic acid tert-butyl ester was added at the same temperature, and after stirring for 30 minutes, p-amyl dissolved in tetrahydrofuran 2- Cinnamoyl chloride was prepared as the acid chloride in Example 3. )236.5m
After stirring for 30 minutes at -78°C, 21 (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 purified by silica gel column chromatography (elution solvent, ethyl acetate: rL-hexane = 1
:9) to obtain the title compound 16 having the following physical properties:
I got 5 ■. NMR: δ = 12.5 (IH, hx), 8.03 (IH
, q), 7.60-7.20 (9H, ya), 6.2
5 (IH, +7), 1.62 (2H, m), 1-45 (
18H, m), 1.32 (4H. -m), 0.88 (3H, t)'. IR Niji=2725.1650.1630.1595c
m. The following compound was obtained in the same manner as in Reference Example 3. (αl 2-[(1-cinnamoyl-1-tert-butoxycarbonyl)methyl]benzoic acid tert-butyl ester Starting material: 17-(tert-butoxycarbonylmethyl)benzoic acid tert-butylnistyl 292
Cinnamoyl chloride P167.5m9: Purification method Nisilica gel column chromatography (elution solvent, ethyl acetate: rL-hexane = 3:97): Yield = 140 ~
; NMR: δ=12.5 (IH,b!>, 7.60-7.
20 (9H, m), 6.25 (IH, q), 1.45 (
9H, #): Engineering R Niji = 2730.1650.163
0.1595cm. Example 5 120 Da of the tert-butyl ester compound (produced in Reference Example 3) dissolved in 2-(p-amylcinnamoylmethyl)benzoic acid/trifluoroacetic acid 1- was stirred at room temperature for 2 hours and then depressurized. Concentrated. Benzene 3rR1 was added to the obtained residue 1, refluxed for 30 minutes, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: 1=1 hexane) to obtain the title compound 40 as a white solid having the following physical properties. TLO (ethyl acetate: rL-hexane = 1:1) diRf
-0,36: NMR: δ = 8.08 (IH, (1), 7.7-7.1
5 (9H, m'), 6.79 (IH, d), 4.37
(2H,z), 2.62-(2HtAt), 1.62(
2H, F7L), 1.31 (4H. m), 0.89 (3H, t): IFt (KBr method) Niji-3200-2400, 169
o, 16o5ctrt-1: Ms: m/z-336 (M), 318.261.20
1° The following compound was obtained in the same manner as in Example 5. (α)2-(cinnamoylmethyl)benzoic acid starting material:
1 ert-butyl ester compound XOOII kg produced in Reference Example 5 (α): Purification method: Silica gel column chromatography (elution solvent, ethyl acetate nidohexane = 1:1): Yield = 30 ■: TLC (ethyl acetate: n-hexane: /-1: 1
): Rf 0.19; NMR 2 δ-8-07 (IH, q), 7.65 (IH,
c'), 7.6-7.2 (9H, m), c;, 53 (x
H * j), 4438 (2H, z): IH (KBr method) Niji-3200-2400, 1695
, 161o, 1575 cIIt: MS:m/Z-266,248,238,220,13
1,118°103%77: Two-white powder in shape. Example 6 2-(N-(p-amylcinnamoyl)-N-methylaminocobenzyl alcohol 5g, cellulose calcium gluconate (disintegrant) 200~, magnesium stearate (lubricant) 100■ and microcrystalline cellulose 5.7 g was mixed and tableted in a conventional manner to obtain 100 tablets containing 50 μ of active ingredient in each tablet. (3 others) Continued from page 1 ■ Int, C1,' Identification symbol Office docket numbering procedure amendment C-) Date: 70, 1981 1. Display of case Relationship to patent application No. 245562 of 1988 Patent applicant name Ono Pharmaceutical Co., Ltd. Kasumigaseki Building Post Office P.O. 49th month March 7, 1980 (Shipping date° June 1983)
(Mon. 27th) 6. Number of inventions increased by amendment 0 7. Column 8 for detailed explanation of the invention in the specification subject to amendment, Contents of amendment, page 17, line 1, page 17, line 1, Page 22 7
Correct the "scheme" in the second line to "reaction process formula". The "diagram" in the first line of page 24 is corrected to "reaction process formula".

Claims (1)

[Scope of Claims] l) General formula [wherein R is (1) a hydrogen atom (II) a straight or branched alkyl group or an alkoxy group having 1 to 15 carbon atoms, Trill having 2 to 15 carbon atoms; Straight chain or branched alkenyl group or straight chain or branched alkenyloxy group having 3 to 15 carbon atoms, or (1v) straight chain or branched alkynyl group having 2 to 15 carbon atoms or 3 carbon atoms ~15
represents a straight-chain or branched alkynyloxy group, R
represents a hydrogen atom or a methyl group, R is a hydroxymethyl group, a carboxyl group, a carboxymethyl group, a straight or branched alkoxycarbonyl group having 2 to 6 carbon atoms,
Alternatively, it represents a straight chain or branched chain alkoxycarbonylmethyl group having 3 to 7 carbon atoms, R represents a hydrogen atom, a halogen atom, or a straight chain or branched chain alkyl group having 1 to 4 carbon atoms, and x represents a straight chain or branched chain alkyl group having 1 to 4 carbon atoms. Formula -CH20-, -CH2S-, -
CH2NH-, -CH2NR-, -GO-8-, -GO
-NR- or -co-CH2- (wherein R is 1 carbon number
~4 linear or branched alkyl group or phenyl group. ) represents a group represented by 0.1 or 2, and the symbol =: represents a double bond (E, A or E
Z mixture) or a single bond. ] Substituted phenyl derivatives, non-toxic salts thereof, or non-toxic acid addition salts thereof. 2) The derivative according to claim 1, wherein R is a hydrogen atom. 3) The derivative according to claim 1, wherein R is a linear or branched alkyl group or alkoxy group having 1 to 15 carbon atoms. 4) The derivative according to claim 3, wherein R1 is a linear or monobranched alkyl group or alkoxy group having 1 to 8 carbon atoms. 5) The derivative according to claim 1, wherein R is a linear or branched alkenyl group having 2 to 15 carbon atoms or a linear or branched alkenyloxy group having 3 to 15 carbon atoms. 5) The derivative according to claim 1, wherein R is a linear or branched alkynyl group having 2 to 15 carbon atoms or a linear or branched alkynyloxy group having 3 to 15 carbon atoms. 7) The derivative according to any one of claims 1 to 6, wherein R is a hydroxymethyl group. 8) The derivative according to any one of claims 1 to 6, wherein R is a carboxyl group or a linear or branched alkoxycarbonyl group having 2 to 6 carbon atoms. 9) The derivative according to any one of claims 1 to 6, wherein R is a carboxymethyl group or a linear or branched alkoxycarbonylmethyl group having 3 to 7 carbon atoms. 10) X is the formula -CH20-, -CH2S-, -CH2N
Any one of claims 1 to 9 which represents a group represented by H- or -0H2NR- (wherein R has the same meaning as described in claim 1) Derivatives as described. 11) x is of the formula -GO-8-, -00-NR--1 Taha-
The compound according to any one of claims 1 to 9, which represents a group represented by CO-CH2- (in the formula, R has the same meaning as described in claim 1). derivative. 12) The derivative according to claim 1, wherein the compound is o-<p-amylcinnamyl)salicylic acid, its sodium salt, or its methyl ester. 13) The derivative according to claim 1, wherein the compound is N-cinnamyl anthranilic acid, its sodium salt, or its methyl ester. 14) The derivative according to claim 1, wherein the compound is N-(, p-amylcinnamyl)anthranilic acid, its sodium salt, or its methyl ester. 15) The derivative according to claim 1, wherein the compound is 8-(7)-amylcinnamoyl)thiosalicylic acid, its sodium salt, or its methyl ester. 16) The compound is N-(7)-amylcinnamoyl)-N
-phenylanthranilic acid or its sodium salt,
or a methyl ester thereof. 17) The compound is N-(7)-amylcinnamoyl)-
N-methylanthranilic acid or its sodium salt,
or a methyl ester thereof. 18) The derivative according to claim 1, wherein the compound is 2-CN-(p-amylcinnamoyl)-N-methylamine]pen:)/L/alcohol. 19) The derivative according to claim 1, wherein the compound is 2-(cinnamoylmethyl)benzoic acid, its sodium salt, or its methyl ester. 20) The derivative according to claim 1, which is a compound 2-(7+-amylcinnamoylmethyl)benzoic acid, IJium salt, or a methyl ester thereof. 21) General formula [wherein R is (1) a hydrogen atom, (lil a straight chain or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, (illll a straight chain or branched chain having 2 to 15 carbon atoms) chain alkenyl group or straight chain or branched chain alkenyloxy group having 3 to 15 carbon atoms, or (lvl 2 to 15 carbon atoms)
A straight or branched alkynyl group or a carbon number of 3 to 1
5 represents a linear or branched alkynyloxy group,
R represents a hydrogen atom or a methyl group, R represents 0.1 or 2, and the symbol == represents a double bond (Dan, I or a mixture of I and S) or a single bond. ] and the general formula [wherein, Y is 10-1-8- or -NR- (wherein, R
represents a hydrogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms, or a phenyl group. ), R represents a hydroxymethyl group, a carboxyl group, a carboxymethyl group, a straight chain or branched alkoxycarbonyl group having 2 to 6 carbon atoms, or a straight chain or branched chain having 3 to 7 carbon atoms. represents the alkoxycarbonylmethyl group of the chain,
R represents a hydrogen atom, a halogen atom, or a straight or branched alkyl group having 1 to 4 carbon atoms. ] A method for producing a compound represented by the general formula (in the formula, all symbols have the same meanings as above), which comprises reacting the compound represented by: 22) A compound represented by the general formula (in which all symbols have the same meanings as described in claim 21) and a compound represented by the general formula (wherein Y' is -8- or -NR5- (formula (wherein, R5 represents a linear or branched alkyl group having 1 to 4 carbon atoms or a phenyl group), and R3 and R4 have the same meanings as in claim 211. 23) A method for producing a compound represented by the general formula (in which all symbols have the same meanings as above), characterized by reacting a compound represented by the general formula [wherein R is -cooc] (aH3)3, -aH2coo
C(aH3)3 or 10H20THP (wherein, THP
represents a tetrahydro-80 biran-2-yl group. ), and other symbols refer to the second claim.
It has the same meaning as described in Section 1. ] The compound represented by is treated with an acid to form a compound represented by the general formula (wherein R represents a group represented by GOOH, -CHCOOHmat, or CHOH2, and the others have the same meanings as above). Compound, and optionally 3b. When R represents a group represented by -〇〇OH or -CH2C00H, a patent characterized in that it is subjected to an esterification reaction (in the formula, all symbols have the same meaning as described in claim 21). A method for producing a compound represented by: 24) General formula [wherein R is (1) a hydrogen atom, (11) a straight chain or branched alkyl group or alkoxy group having 1 to 15 carbon atoms, (iill a straight chain or branched chain having 2 to 15 carbon atoms) A branched alkenyl group or a straight or branched alkenyloxy group having 3 to 15 carbon atoms, or (M a straight or branched alkynyl group having 2 to 15 carbon atoms or a straight chain having 3 to 15 carbon atoms) or represents a branched alkynyl group, R represents a hydrogen atom or a methyl group, R represents a hydroxymethyl group, a carboxyl group, a carboxymethyl group, a straight or branched alkoxy group having 2 to 6 carbon atoms. carbonyl group,
Alternatively, R represents a straight-chain or branched alkylmethyl group having 3 to 7 carbon atoms, R represents a hydrogen atom, a halogen atom, or a straight-chain or branched alkyl group having 1 to 4 carbon atoms; Formula -CH20-, -CH2S-1-
CH2NH-, -GH2NR-, -CO-8-, -Co
-NR- or -GO-CH2- (wherein R is 1 carbon number
~4 linear or branched alkyl group or phenyl group. ), R represents 0.1 or 2, and symbol 2 represents a double bond (Dan, A or EZ
- represents a mixture) or a single bond. ] A leukotriene antagonist characterized by containing a substituted phenyl derivative represented by the following, a non-toxic salt thereof, or a non-toxic acid addition salt thereof as an active ingredient. 25) Substituted phenyl derivatives represented by the general formula (in which all symbols have the same meanings as described in claim 24),
Its non-toxic salt or its non-toxic acid addition salt as an active ingredient.
- A phospholipase inhibitor comprising: 26) Substituted phenyl derivatives represented by the general formula (in which all symbols have the same meanings as described in claim 24),
A 5α-reductase inhibitor comprising a non-toxic salt thereof or a non-toxic acid addition salt thereof as an active ingredient.