JPS60142941A - Ketone compound, its preparation, and drug containing it as active ingredient - Google Patents

Abstract

NEW MATERIAL:A ketone compound shown by the formula I [R<1> is 3-22C alkyl, alkoxy, alkenyl or alkenyloxy; R<2> and R<2>' are H, or 1-15C alkyl; X is group shown by the formula NR<5> (R<5> is H, or 1-4C alkyl), S, O, or methylene; R<3> is COOR<6>, CH2COOR<6>, OCH2COOR<6> (R<6> is H, or 1-4C alkyl), or hydroxyl group; R<4> is H, halogen, 1-4C alkyl, alkoxy, group shown by the formula COOR<7> (R<7> is H, or 1-4C alkyl), hydroxyl group, etc.; n is 0-2; dotted line parts are single bond, or double bond, with the proviso that they are not double bond when R<1> is alkoxy or alkenyloxy] or its nonpoisonous salt. EXAMPLE:N-(9Z,12Z-Octadecadienoyl)anthranillic acid. USE:Having antagonizing action on leukotriene, inhibitory action on phospholipase, and inhibitory action on 5alpha-reductase, and useful as a drug. PREPARATION:A compound shown by the formula II is reacted with a compound shown by the formula III to give a compound shown by the formula I .

Description

[Detailed description of the invention] The present invention relates to novel ketone compounds.

More specifically, the present invention relates to novel ketone compounds having leukotriene antagonism, phospholipase inhibition, and 5α-reductase inhibition, methods for producing the same, and pharmaceuticals containing these as active ingredients.

Prostaglandins (Prosta, qlandin,
Hereinafter, it will be abbreviated as PG. ) Several important discoveries have been made at Atsui in the past few years in the area of research and death. Therefore, there have been major changes in the flow of PG research and development in recent years. Newly discovered or newly determined PC
Among the members of the family, PG tncloperoxide has particularly strong and unique proboscis activity.

i.e. Pco2 and PGH2), thromboxane A2
(TromboxarLe A2, hereinafter abbreviated as TXA2), prostacyclin' (Proztac
yclin (PCI)) and leukotrienes C, D, and E (hereinafter abbreviated as LTC, LTD, and LTE, respectively). In addition to these compounds, all members of the PG family, including various types of PC 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 It is called the arachidonic acid cascade. For a detailed explanation of each pathway and the pharmacological properties of each product, see History of Medicine, 114°378 (1980
), 114, 462 (1980), 1 Sat., 86
6 (19,80), 114,929 (1980),
Modern Medicine, 12, 909 (1980).

12.1029 (1980'), 12.10'
65 (1980) and same, 12, 1105 (1980)
etc. are listed.

In the arachidonic acid cascade, cyclooxygenase acts on arachidonic acid to produce various PGs such as prostaglandin F2ct (hereinafter abbreviated as p (7F'2a)) and prostaglandin E via Pco2 and PGH2.
2 (hereinafter abbreviated as PGE2).

Lipoxygenase acts on the pathway leading to PGI2, TXA2, etc. and arachidonic acid to produce hydronoξ-oxyeicosatetraenoic acid (hydroξ-oxyeicosatetraenoic acid).
-eicozatetraenoic acid, hereinafter abbreviated as HPETE. ) via Hydroxyeicosatetraenoitsukuashitsu F#
ozatetraenoicacid, hereinafter HETE
It is abbreviated as ) or the route leading to leukotrienes.

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

Please refer to the publication by Kodansha.

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

Arachidonic acid is metabolized by a well-known pathway, that is, via PG endoperoxide, or by a completely different pathway by lipoxygenase. That is, arachidonic acid and lipoxygenase, e.g.
-Lipoxygenase.

12-lipoxygenase or 15-lipoxygenase acts to produce 5-HPETE and 12-HPE, respectively.
TE or 15-HPETE is produced.

In these HPETEs, hydrogen peroxide groups are converted to hydroxyl by peroxidase, resulting in 5-HETK, 12-H
Converted to ETE or 15-HETE.

In addition, -5-HPETE among these) IPETE
is converted to LTA4 by dehydration.

In general, LTA4 is enzymatically converted to leukotriene B4 (hereinafter abbreviated as -LTB4) and also to glutathione-8-
) Converted to -LTC4 by transferase.

Then, LTG4 is converted to LTD by γ-daltamyl transpeptidase. LTD4 is further LT
It has recently been revealed that it is metabolized to E4 (B
iochem, Biophyz, Rat, Oomm
u, n,.

91.1266 (1979) and Proztaglan
dinz.

See L. (5), 645 (1980)].

On the other hand, when talking about SR8, SR8 is Slow
It is an abbreviation of Rgacting F3uhztancg, and this name was used by FeLd, Atrg, and others for the substance liberated when cobra venom pulmonary flow or copra venom was incubated with egg yolk. It has been reported that the effect lasts for a long time (J, Phyziol.
94.187 (1938)].

Furthermore, Ketlaway et al. sensitized the lungs of sensitized guinea pigs with an antigen during perfusion, resulting in SR8-A (SZOWRgact).
inlStLbztancg of Anaphyla
xis) was released, and showed for the first time the relationship between 5R8-A and allergic reactions [Qlant, J'
, Ex:p, Phyzinl,.

Q 121 (1940)]. Also f3rackLg
When htLrrtt is exposed to a lung section surgically removed from a patient with bronchial asthma whose specific antigen is known, histamine and 5R8-A are released, strongly contracting the bronchial muscles, and this contraction can be slowed down by antihistamines! This suggests that 5R3-A is an important bronchoconstrictor during asthma attacks [Progr., Allergy, 6].
See ゜539 (1962)]. Subsequently, 5R8-A obtained from human lung tissue fragments constricts normal human bronchial rings [In, t, Arch, Allergy A
ppl.

See Immanol, 38.217 (1970)]
, intravenous injection of rat 5R8-A into guinea pigs increases pulmonary airway resistance [J, Gli, Inv.
est,.

53.1679 (1,974)), 5R3-A restores vascular permeability when injected into the skin of guinea pigs, rats, and monkeys [Advances irLImyn
ttnology.

10, 105 (1969), J. Allergy
C11n.

Imynu, nol., 621.371 (1978)
, prosta-grandinz, 19 (5),
779 (19-80) 4] and many other reports.

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

Furthermore, LTC and LTD4 are SR8 or 5
It has become clear that they are the same substances as R3-A, and therefore the pharmacological properties of these leukotrienes can be considered interchangeably with those of SR8 or 5R8-A.CProc, Natl, Acact.

Sci, USA, 76, 4275 (1979), f
3iocn em.

Biophys, Rts, Gommu, n, 91
．． 1266 (1979), Proc, NatL, A
cad, Sci, USA, 77, 2014 (198
0L Natu, re, 285, 104 (1980)].

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

Therefore, by suppressing these leukotrienes, allergic tracheal and bronchial diseases such as asthma, allergic lung diseases, allergic shock, and various allergic diseases in mammals including humans, especially humans, can be prevented. Effective for prevention and/or treatment.

Furthermore, arachito-nine acid is released from phospholipids by the action of phospholipase (phosp-olipase), but if we look closely, we can see that there are two routes as shown in the diagram (■), namely (1) phosphatidylcholine (phosp-olipase).
The pathway in which phospholipase A2 acts on (2) phosphatidyl inosit (phospholipase A2)
ol), phospholipase C acts on 1,2-diglyceride <
Lyceridelipase), then monoglyceride lipase (morLogtycerid, 111i
-pazt) 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 (cyclooxygenase);
aze) metabolic pathway, prostaglandin (PGl)
or (2) lipoxygenase (LI).
poxygerLasg) metabolic pathway, SR8-A
(Slow Reacting 5LLhztαnct
s of Anαphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriene B4
(LeLLkotrierLg R4) is known to be metabolized into a physiologically active substance [Chemistry and Biology 21
, 154 (1983)].

These metabolites are 1. For example, TXA2 is a substance with strong platelet aggregation and vasoconstriction effects, and 5R8-A
is a chemical mediator of asthma.
LTB4 is known to be a chemical mediator of inflammation such as gout, and PG is a chemical mediator that has vasodilatory, carcinogenic, thermogenic, and leukocyte migration effects in inflammation. Teishi Metabolism 20, 317 (1983)
, TAg Lancet 1122 (1982), Prostaglandins (1978) edited by Makoto Katori et al., Kodansha].

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

We have proposed compounds that antagonize leukotrienes, or phospholipases (phospho-IJ, t'-ase A2 and/or
In order to find a compound that inhibits phospholipase C), as a result of extensive research, it was discovered that a ketone compound represented by the general formula (T) described below achieves the purpose, and the present invention was completed.

The compound of the present invention strongly inhibits phospholipase and suppresses the release of arachidonic acid from phospholipids, thereby preventing diseases caused by arachidonic acid metabolites such as TXA2 and PG-leukotriene in mammals including humans, especially humans. and/or therapeutically effective.

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 1, 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 exists in the endoplasmic reticulum and nucleic acids, and converts testosterone ingested into one target tissue into the active form of 5α-reductase.
It has the effect of converting into dihydrotestosterone, and this active form of 5α-dihydrotestosterone causes cell proliferation by binding to intracellular receptors, and when this effect is reversed, it can cause benign prostatic hyperplasia, alopecia, and acne. It is said to cause the onset of the disease.

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 has hormone-specific effects, and moreover, it strongly inhibits 5α-reductase, suppresses the increase in 5α-dihydrotestosterone, and suppresses cell proliferation. It effectively prevents and/or treats benign prostatic hyperplasia, alopecia, and erectile dysfunction.

The present invention is based on the general formula m [wherein R1 represents a linear or branched alkyl group, alkoxy group, alkenyl group, or alkenyloxy group having 3 to 22 carbon atoms, and R2 and R2' each independently, represents a hydrogen atom or a linear or branched alkyl group having 1 to 15 carbon atoms, and the symbol X represents the formula NR5 (in the formula, R
5 represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms. ), a sulfur atom, an oxygen atom or a methylene group, and R3 is of the formula C00R6
, CH2C00R6 or 0CH2GOOR6 (in each formula, R6 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), and R4 represents a hydrogen atom or a halogen atom. , carbon number 1~
A straight-chain or branched alkyl group or alkoxy group of 4, a group represented by the formula GOOR7 (wherein R7 represents a hydrogen atom or a straight-chain or branched alkyl group having a carbon number of] to 4) , represents a hydroxyl group or a nitro group, and L is Ol
It represents l or 2, and the symbol = represents a single or double bond (
winter, each or 'su mixture). However, when R1 is a calkoxy group or an alkenyloxy group, the symbol = does not represent a double bond. ] The present invention relates to ketone compounds and non-toxic salts thereof, methods for producing them, and pharmaceuticals containing them as active ingredients.

The alkenyl group in the general formula (11) is a linear or branched alkenyl group having 3 to 22 carbon atoms or an alkenyloxy group represented by R1; Hexenyl group, hexagenyl group, hexenyl group, heptagenyl group, hexagenyl group.

octenyl group, octagenyl group, octagenyl group,
Nonenyl group, nonajenyl group, nonajenyl group, nonatetraenyl group, decenyl group, decagenyl group, decagenyl group, decatetrae=74- undecenyl group, undecajenyl group, undecajenyl group, undecatetraenyl group, undecatetraenyl group, dodecenyl group, dodecajenyl group, 1 decatrienyl group, dodecatetraenyl group, tridecatrienyl group, tridecenyl group, tridecagenyl group, tridecatrienyl group, tridecatetraenyl group, tridecatrienyl group, tridecahexaenyl group-tetradecenyl group.

Tetradecagenyl group, Tetradecagenyl group, Tetradecatetraenyl group, Tetradeca is a ntaenyl group, Tetradecahexaenyl group, -! ! ntadecenyl group, bancdecajenyl group, hantadecatrienyl group, hantadecatetraenyl group, hantateca intaenyl group, intatecahexaenyl group, intertadecaheptaenyl group, hexadecenyl group.

hexadecagenyl group, hexadecagenyl group, hexadecatetraenyl group, hexadeca-ntaenyl group, hexadecahexaenyl group, hexadecaheptaenyl group, heptadecenyl group, heptadecagenyl group, hexadecagenyl group, heptadeca Tetraenyl group, -butadecaRntaenyl group.

heptadecahexaenyl group, heptadecaheptaenyl group, heptadecaoctaenyl group, octadecenyl group, octadecagenyl group, ophtadetrienyl group, octadecatetraenyl group, octadecabentaenyl group, octadecahexaenyl group, octadecaheptaenyl group group, octadecaoctaenyl group, nonadecenyl group, nonadecagenyl group, nonadecagenyl group, nonadecatetraenyl group, nonadecabentaenyl group, nonadecahexaenyl group,
nonadecatetraenyl group, nonadecatetraenyl group, nonatecanonaenyl group, eicosenyl group, eicosagenyl group, eicosagenyl group, eicosatetraenyl group,
Eicosa is an antaenyl group, an eicosahexaenyl group, an eicosaheptaenyl group, an eicosaoctaenyl group, an eicosagenyl group, a heneeicosenyl group, a heneeicozagenyl group, a heneeicosatrienyl group - a heneeicosatetonyl group, a heneeicosaRntaenyl group group, heneeicosahexaenyl group, heneeicosaheptaenyl group, heneeicosaoctaenyl group, heneeicosanonaenyl group,
Examples include a heneeicosatecaenyl group and isomeric groups thereof, and preferred groups for R1 include a heptadecagenyl group, a heptadecagenyl group, a dimethylhebutagenyl group, and an isobutenyl group.

However, when R1 represents an alkenyloxy group, it has a double bond between carbon atoms other than the carbon atoms adjacent to the oxygen atom.

In the general formula (1), the linear or branched alkyl group having 3 to 22 carbon atoms or the noalkyl group in the alkoxy group represented by R1 is a propyl group or a butyl group.

is a methyl group, hexyl group, heptyl group, octyl group, nonyl group - decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, hantadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group - Examples include heneicosyl group, tridecyl group and isomer groups thereof, and preferred groups include:
Loopdel group - lunonyl group, fL-decyl group -n -
) +) decyl group, nd-d tadecyl group, and ruhebutadecyl group.

General formula (-R2 and R2/ in Il have 1 to 1 carbon atoms)
Examples of the straight chain or branched chain alkyl group of 15 include a methyl group, an ethyl group, a pro♂ group, a methyl group, a methyl group, a hexyl group, a heptyl group, and an octyl group.

Nonyl group, decyl group, undecyl group, dodecyl group, tritesyl group, tetradecyl group, hantadecyl group.

and their isomeric groups, including R2 and R2/
Each preferred group includes a methyl group and a roudecyl group. It is also preferable that R2 and R2/ each represent a hydrogen atom.

In the general formula (11, the halogen atom represented by R4 is:
Examples include fluorine atom, chlorine atom, bromine atom and iodine atom.

Preferred atoms for R4° include a hydrogen atom and a chlorine atom.

In the general formula (1), the alkyl group in the linear or branched alkyl group having 1 to 4 carbon atoms or the alkoxy group represented by R4 includes methyl group, ethyl group, propyl group, butyl group, and isomers thereof. Examples include body groups.

In the general formula (Il), the linear or branched alkyl group having 1 to 4 carbon atoms represented by R5, R6, and R7 include a methyl group, an ethyl group, a propyl group, a butyl group, and a stiff isomer group. Can be mentioned.

R5 is preferably a hydrogen atom, and R6 and R7 are preferably a hydrogen atom, a methyl group, or an ethyl group.

The compound of the present invention represented by the general formula (1) may have isomers, and in particular, when the symbol = represents a double bond, the name or wife of this double bond may be used to indicate whether the symbol is a single bond or not. When R2 and/or haR2' is an alkyl group, the carbon to which this alkyl group is bonded is an asymmetric carbon, and isomers exist.

Further, the general formula (alkyl in each substituent in Il,
Alkylene, alkenyl and h/mata by branching of the alkenylene moiety and double bonds of the alkenyl and/or alkenylene moiety.

Isomers are generated in the same manner as above. The present invention is.

It includes all these isomers and mixtures thereof.

According to the present invention, compounds represented by the general formula (IJ), wherein Y represents the formula NR5 (wherein R5 represents the same meaning as above), a sulfur atom or an oxygen atom; The compound represented by the general formula [wherein all symbols have the same meanings as above] and the general formula [in the formula, All symbols have the same meanings as above.] It can be produced by reacting the compounds shown below.

This reaction is a known reaction. It will be held in It is preferably carried out in methylene chloride in the presence of triethylamine or pyridine at o'c to room temperature.

The compound represented by the general formula (IIJ) is a known compound. For example, a compound in which R3 is a carboxy group at the 2-position, R4 is a chlorine atom at the 5-position, and Y is an amine group is 4-chloroanthranilic acid. A compound in which R3 is a carboxy group at the 2-position, -R4 is a hydrogen atom, and Y is an oxygen atom is salicylic acid, and both of these are commercially available.

Furthermore, according to the present invention, among the compounds represented by the general formula (11), the compound represented by the general formula [wherein all symbols have the same meanings as above] is the compound represented by the general formula [wherein, It represents a tert-butyl group, and all other symbols have the same meanings as above.] It can be produced by treating the compound represented by the following with an acid and then esterifying if necessary.

This treatment reaction is carried out, for example, using strong PIl (hydrochloric acid, 711-)luenesulfonic acid, trifluoroic acid, etc.) in an inert organic solvent (tetrachloroethane, benzene, toluene, etc.) or without a solvent, and refluxing from room temperature. It is done at temperature.

The compound represented by the general formula (IV) is a compound represented by the general formula CTi) and the general formula [where all symbols have the same meanings as above. ] It can be produced by reacting the compounds shown below.

This reaction can be carried out, for example, by using a compound represented by the general formula (Vl) in an inert organic solvent (tetrahydrofuran, ethyl ether,
React with a lithiation agent (lithium diisopropylamide, etc.) at a temperature of -78°C to 0°C in pentane, hexane, benzene, toluene, hexamethyltetramine, etc.),
This is carried out by reacting this with a compound represented by the general formula (III) in the above-mentioned inert organic solvent at -78°C to room temperature.

The esterification is carried out, for example, in an alkanol having a corresponding alkyl group in the presence of an acid ((P-)luenesulfonic acid, hydrochloric acid, hydrogen chloride gas, etc.) at a temperature of 0°C to 40°C. Of course, in addition to the above-mentioned alkanol, an organic solvent (such as tetrahydrofuran, methylene chloride, etc.) that does not participate in the reaction may be added.

The compound represented by the general formula (■) is known per se or can be produced by a known method.

The compound represented by the general formula (Ill) is produced by converting a carboxylic acid represented by the general formula (in which all symbols have the same meanings as above) into an acid chloride.

The reaction of converting a carboxylic acid to an acid chloride is well known and uses an inert organic solvent (methylene chloride).

chloride (such as tetrahydrofuran) or without solvent.
thionyl chloride, oxalyl chloride, ethyl chloroformate, etc.) at a temperature of -40°C to 30°C. It is preferably carried out using oxalyl chloride in the absence of a solvent at room temperature.

Is the carboxylic acid represented by the general formula (IV) known per se (for example, -linoleic acid, 3-ethoxypropionic acid, etc. are available as commercial products)?

Alternatively, it can be produced by a known method.

An example of the manufacturing method is shown in the diagram.

Diagram■ （C）↓ (J IO In the diagram ■, each symbol represents the following meaning.

R8 - Any available carbon chain alkyl or alkenyl group.

R8' - an alkyl group corresponding to R8.

R9, R12 - hydrogen atom or alkyl group having 1 to 4 carbon atoms.

RIO - hydrogen atom or alkyl group having 1 to 15 carbon atoms.

R11 - single bond or alkylene group having 1 to 20 carbon atoms.

Each step in the diagram ① is a well-known reaction, but to explain briefly, the step (zl is a reduction reaction). Use lithium aluminum hydride to react at a temperature of -78°C or use lithium aluminum hydride to react at a temperature of 0°C.
C to reflux temperature.

Step (hl is W*ttLg reaction, for example, an inert organic solvent (ethyl ether, tetrahedral 90 furan).

The reaction is carried out at 8° C. to room temperature using a Wittig reagent such as phosphorane represented by the general formula (■) in chloroform, benzene) in the presence of hexamethylphosphaamide if necessary.

Step (C) is a saponification reaction, for example, using an aqueous solution of an alkaline substance (potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.) in an organic solvent (tetrahydrofuran, methanol, ethanol, etc.) that is miscible with water. ,0°C
It is carried out at a temperature of ~40°C.

Of course, this step is unnecessary if R12 is a hydrogen atom.

Step (d) is a reduction reaction, for example, in a hydrogen atmosphere in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.) in the presence of a catalyst (palladium-carbon, palladium, platinum black, nickel, etc.) at 0°C to 40°C. It is carried out at a temperature of

This series of reactions may of course be started from each available compound, and if step Kl is not necessary, one step may be omitted (or step < CI and step (dl) may be performed in the reverse order. By repeating these steps as many times as necessary, a carboxylic acid having any carbon chain or double bond at any position can be obtained.

Also, instead of the compound represented by the general formula -, the compound represented by the general formula [wherein all symbols have the same meanings as above]. ] When using a ketone represented by the general formula [In the formula, all symbols have the same meanings as above. ] can be obtained.

Alternatively, instead of the Wittig reaction in this series of steps, the Perkin or Depner reaction [for example, using malonic acid or its ester in the presence of biR-lysine and using a tertiary amine (pyridine, etc.) as a solvent, at 100°C to reflux. Do it at temperature. ] may be used.

Furthermore, within the range represented by the general formula (Il), there are several methods for producing another group of compounds from a specific group of compounds, such as (1) esterification, (2) saponification, (3) ) Catalytic reduction, (4) OH→R6 conversion.

List each of these in the diagram below. Each symbol in the diagram (■) represents the following meaning, and the other symbols represent the same meanings as above.

Hla - Straight chain or branched alkyl group having 3 to 22 carbon atoms.

R3a - Formula Coo)l, 0H2COOHt t, :M
0GH2G008 The group shown.

R3h complete set C00I (6, CHGOOR6 or 0CH
A group represented by GOOR622.

Diagram Formula ■ (1) Esterification ↓ ↑ (2) Saponification (1) Esterification ↓ ↑ (2) Kenichi ↓ (3) Catalytic reduction ↓ (4) OH-+ Each step in the conversion scheme ■ of 001-12GOQR6 The outline is as follows.

(1) Esterification - carried out, for example, in the presence of an acid (7)-) luenesulfonic acid, hydrochloric acid, hydrogen chloride gas, etc., in an alkanol having the corresponding alkyl group, at a temperature of 0°C to 40°C. Of course, in addition to the above-mentioned alkanol, an organic solvent (such as tetrahydrofuran or styrene chloride) that does not participate in the reaction may be added.

(2) Saponification - For example, using an aqueous solution of an alkaline substance (potassium hydroxide, lithium hydroxide, lithium hydroxide, etc.) in a water-miscible solvent (ethanol, methanol, tetrahydrofuran, etc.) at 00C. It is carried out at a temperature of ~80°C.

(3) Catalytic reduction - For example, in a hydrogen atmosphere, in an organic solvent (methanol, ethanol, tetrahydrofuran, etc.), in the presence of a catalyst ( ) ξ radium-carbon, no ξ radium, platinum black, nickel, etc.), 0°C to 40°C be carried out at a temperature of

(4) Conversion of OH-+0CR2GOOR6 - For example, in an inert organic solvent (tetrahydrofuran, methylene chloride, methyl ethyl ketone, etc.) using a reagent such as alkoxycarbonylpropylene, in the presence of a base (potassium carbonate, etc.), if necessary. Perform at room temperature to reflux temperature in the presence of sodium iodide.

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, washing, recrystallization, etc. can do.

Purification may be performed for each reaction or after completion of several reactions.

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

The compounds of the present invention exhibited antagonistic effects against -LTD4 as shown in the table below.

The compound of the present invention is resistant to phospholipase A2.

It showed inhibitory effects as shown in the table below.

The compounds of the present invention are effective against 5α-reductase.

It showed inhibitory effects as shown in the table below.

(2) Inhibition rate shows the value at 2mM concentration of the compound of the present invention.

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

The ileum (3 cm) removed from a male guinea pig weighing 300-400.9 cm was heated at 37°C, Tyrode's solution, and oxygen (9 cm).
5%) - carbon dioxide (5% λ) was suspended in a magnuk tube with mixed gas aeration and stabilized for about 30 minutes17) Qi LTD
was added at a concentration of 10-'l/ml, and with respect to the shrinkage at this time, the concentration of the compound of the present invention was varied, the shrinkage height was measured, and the engineering C5o value was calculated from this.

The inhibitory effect of the compounds of the present invention on phospholipase A2 can be demonstrated by a modified Sh, akir method using L-β as a substrate.
-[1-"C]-arachitonyl-α-stearoylphosphatidylcholine was measured using phospholipase A2 obtained from guinea pig lungs [Al σ1.Biochem, 114.67 (1981
)reference〕.

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-reductor senoactivity measurement C, 0.09 MHtpes (pH 7,4)-022M
Sucrose, 5X10-3MNADPH 15μM [4-14
G] One reaction was carried out at 37° C. for 60 minutes using a mixture of testolone, 5α-reductase and the compound of the present invention. To stop the reaction, 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) to determine the radioactivity of the generated dihydrotestosterone. T L Gx
After measurement, enzyme activity inhibition 1 was calculated (3ncLo'cγ1nol).

Japan, '18, 179 (1971)].

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

Moreover, it is preferable that the salt is water-soluble.

Suitable salts include, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts, and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include, for example, amines 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, e.g.
-6 alkyl groups, and human90xyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclomethylamine salts, benzylamine salts, phenethylamine salts.

Examples of organic amine salts include lysine salts, monoethanolamine salts, jetanolamine salts, lysine salts, and arginine salts.

The salt of the ketone compound represented by the general formula (I) is a salt of the ketone compound represented by the general formula (I).
It can be obtained by a known method, for example, by reacting the acid represented by No. 11 with a suitable base such as an alkali metal or alkaline earth metal hydroxide or carbonate or an organic amine in a suitable solvent.

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 shock, and various allergic diseases. / or therapeutically effective and also phospholipase (phospholipase A2 and/or phospholipase C)
) to prevent diseases caused by arachidonic acid metabolites including the above-mentioned leukotrienes, such as thrombosis due to damage to the endothelium and intima of the brain and coronary arteries, and various inflammations such as arthritis and rheumatism. and/or therapeutically effective. Furthermore, inhibition of 5α-reductase is effective for the prevention and/or treatment of prostatic hyperplasia, alopecia, and acne scars.

In order to use the ketone compounds of the general formula (Il) or their non-toxic salts for the above purposes (as leukotriene antagonists, phosphorynoξ-ase inhibitors or 5α-reductase inhibitors), for each, usually systemic or administered topically orally or parenterally.Dosage is determined by age,
Although it varies depending on body weight, symptoms, therapeutic effects, administration method, processing time, etc., the dose is usually 1 to 1 dah for each dose per adult.
1. ? , preferably in the range of 209 to 200 cm, 1 day per day
Orally administered once to several times or per adult,
Each dose is administered parenterally in the range of 100 μg to 1 oomg, preferably ITn9 to 10In9, once to several times a day. Of course, as mentioned above, the dosage varies depending on various conditions, so there may be cases in which a smaller amount than the above-mentioned dosage range is sufficient, and there may be cases in which it is necessary to administer beyond the above-mentioned dosage range.

Solid compositions for oral administration according to the invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances may be present in a small amount (and one inert diluent, such as lactose, mannitol, butosucrose, human 90-xyprogylcellulose, microcrystalline cellulose).

Mixed with starch, polyvinylpyrrolidone, magnesium aluminate metasilicate. The compositions may contain additives other than inert diluents, such as lubricants such as magnesium stearate and disintegrants such as fibrin calcium gluconate, in accordance with conventional methods. Tablets or pills may be coated with a film of gastric or enteric substances such as sucrose, gelatin, human 90-xypropyl cellulose, human 80-xypropyl methylcellulose phthalate, or coated with two or more layers. You can.

Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, e.g. Contains water and ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
Fragrances May contain 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 and suspensions.

Includes emulsifying agents. 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, sF Lysolite 8O, gum arabic, and sodium alginate. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These may be sterilized, for example, by filtration through a bacteria-retaining filter, 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, which contain one or more active substances and may be formulated in a manner known per se, include topical solutions, liniments such as creams, and for intravenous administration. suppositories and issaries for intracavitary administration.

Among the compounds of the present invention represented by general formula (I), preferred compounds include N-(2-hebutenoyl)anthranilic acid, N-(2-
Dogsenoyl)anthranilic acid, N-(2-)lidecenoyl)anthranilic acid, N-(2-hexadecenoyl)
Anthranilic acid, N-(2-octadecenoyl)anthranilic acid, N-(2-eicosenoyl)anthranilic acid.

N-(2,11,14-eicosatrienoyl)anthranilic acid, N-(2,8,11,14-eicosatrienoyl)anthranilic acid, N-(5,9-dimethyl-2,4,8- decatrienoyl)anthranilic acid, N-(5-methyl-2,4-hexagenoyl)anthranilic acid, 4-chloro-N-(2-hebutenoyl)anthranilic acid, 4-chloro-N-(2-dodecyl)anthranilic acid, ) 7notranilic acid, 4-chloro-N-(2-)IJdecenoyl)anthranilic acid.

4-Rio-N-(2-hexadecenoyl)anthranilic acid, 4-chloro-N-(2-octadecenoyl)anthranilic acid.

4-chloro-N-(2-eicosenoyl)anthranilic acid, 4-chloro-N-(2,11,14-eicosatrienoyl)anthranilic acid.

4-chloro-N-(2,8,11,14-eicosatetraenoyl)anthranilic acid, 4-chloro-N-(5,9-dimethyl-2,4,8-decatrienoyl)anthranilic acid, 4-chloro -N-(5-methyl-2,4-hexagenoyl)anthranilic acid, 5-(2-hebutenoyl)thiosalicylic acid, 5-(2-
)'decenoyl)thiosalicylic acid, 5-(2-tridecenoyl)thiosalicylic acid, 5-(2-hexadecenoyl)thiosalicylic acid.

5-(2-octadecenoyl)thiosalicylic acid, 5-(
2-eicosenoyl)thiosalicylic acid, S-(2,11
, 14-eicosatrienoyl)thiosalicylic acid, S-(2,8,11,14-eicosatrienoyl)thiosalicylic acid, 5-(5,9-dimethyl-2,4,8-decatrienoyl)thiosalicylic acid, 5 -(5-methyl-2,4-hexagenoyl)thiosalicylic acid.

4-chloro-8-(2-hebutenoyl)thiosalicylic acid.

4-chloro-8-(2-dodecenoyl)thiosalicylic acid, 4-chloro-3-(2-)lidecenoyl)thiosalicylic acid, 4-chloro-8-(2-hexadecenoyl)thiosalicylic acid, 4-chloro-8- (2-octadecenoyl)thiosalicylic acid, 4-chloro-8-(2-eicosenoyl)thiosalicylic acid, 4-chloro-3-(2,11,14-eicosatrienoyl)thiosalicylic acid, 4-chloro-8-(2 , 8,11,14-eicosatetraenoyl)thiosalicylic acid.

4-chloro-8-(5,9-dimethyl-2,4,8-decatrienoyl)thiosalicylic acid, 4-chloro-8-(5-methyl-2,4-hexagenoyl)thiosalicylic acid, 0-(2- Hebutenoyl) salicylic acid.

0-(2-dodecenoyl)salicylic acid, 0-(2-tridecenoyl)salicylic acid.

0-(2-hexadecenoyl)salicylic acid, 〇-(2-
octadecenoyl) salicylic acid.

〇-(2-eicosenoyl)salicylic acid, 0-(2,
11,14-eicosatrienoyl)salicylic acid, 0-(2,8,11,14-eicosatrienoyl)salicylic acid, 0-(5,9-dimethyl-2,4,8-decatrienoyl)salicylic acid.

o -, (5-methyl-2,4-hexagenoyl) salicylic acid, 4-chloro, -o-(2-hebutenoyl) t IJ
cylic acid, 4-chloro-0-(2-dodecenoyl)salicylic acid.

4-chloro-0-(2-)lidecenoyl)salicylic acid, 4-chloro-0-(2-hexadecenoyl)salicylic acid, 4-chloro-0-(2-octadecenoyl)salicylic acid, 4-chloro-0-(2- Eicosenoyl> f IJ
-F-ruic acid, 4-chloro-0-(2,11,14-eicosatrienoyl)salicylic acid, 4-chloro-0-(2,8,11,14-eicosatrienoyl)salicylic acid, 4-chloro -0-(5,9-dimethyl-2,4,8-decatrienoyl)salicylic acid, -4-chloro-0-(5-methyl-2,4-hexagenoyl)salicylic acid.

N-(2-methyl-2-tridecenoyl)andranilic acid.

N-(3-methyl-2-tridecenoyl)anthranilic acid, N-(3-decyl-2-tridecenoyl)anthranilic acid, N-(2-methyl-2-octadecenoyl)anthranilic acid.

N,-(3-methyl-2-octadecenoyl)anthranilic acid.

N-(3-decyl-2-octadecenoyl)anthranilic acid.

4-chloro-(2-methyl-2-tridecenoyl)anthranilic acid, 4-chloro-(3-methyl-2-tridecenoyl)anthranilic acid, 4-chloro-(3-decyl-2-tridecenoyl)anthranilic acid.

4-chloro-(2-methyl-2-octadecenoyl)anthranilic acid.

4-chloro-(3-methyl-2-octadecenoyl)anthranilic acid.

4-chloro-(3-decyl-2-octadecenoyl)anthranilic acid, N-(9,12-octadecagenoyl)anthranilic acid.

N-(5,8,11-octadecatrienoyl)anthranilic acid.

4-chloro-N-(9,12-octadecagenoyl)
Anthranilic acid, and 4-chloro-N-(5,8,11-octadecatrienoyl)anthranilic acid and the corresponding methyl esters, ethyl esters and non-toxic salts of these acids.

Hereinafter, the present invention will be explained in detail with reference to reference examples and examples.
The present invention is not limited to these examples. Note that [TLCJ-[IRJ, “N
The symbols MRJ and [MSJ represent "thin layer chromatography,""infrared absorption spectroscopy,""nuclear magnetic resonance spectrometry," and "mass spectrometry," respectively, and are listed in the section on separation by chromatography. The proportion of the solvent indicates the volume ratio -1'-TLCJ The solvent in parentheses indicates the developing solvent +l'-IRJ is defined as KBr tablet 4 unless otherwise specified, and l'-NMRJ is Unless otherwise specified, measurements are made using heavy chloroform (CDC13) solution.

Reference Example 1 Ethyl γ-lyrunaldehydolinoleate 2.41! was dissolved in 30 ml of anhydrous toluene, cooled to -78°C, and DIBAL (:) isobutylaluminum hydride: 25% toluene solution)
After slowly dropping 5 mJ, ethyl ether was added and the temperature was raised to room temperature. The reaction solution was washed successively with an aqueous sodium hydrogen tartrate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane:ethyl acetate-5
The title compound 2 was purified with 0:1) and has the following physical properties.
I got ゜I.

TLC: Rf=0.65 (cyclohexane:ethyl acetate=3:1).

MS near FL/Z, = 262 (M”), 191.164
．． 150ONMB: δ = 9.78 (t, IH), 5.4
0 (m, 6H), 2.80 (m, 4H), 2.42 (t
tt, 2H), 1.90-2.20 (m, 4H)
, 1.20-1.80 (771,, l0H), o, ss
(m, 3H).

Reference Example 1 (α) Linolaldehyde Ethyl linoleate 3.3. ? Using the same procedure as in Reference Example 1, the title compound 3.0.9 was obtained.

Reference Example 2 Methyl 2E, 8Z, 112,142-eicosatetraenoate 2.09% of the aldehyde produced in Reference Example 1 was dissolved in 30d of chloroform, 2.4g of methoxycarbonylmethylidene triphenylphosphorane was added, and the mixture was refluxed for 3 hours. did.

After the reaction, the reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (cyclohexane:ethyl acetate = 3:1) to obtain 1.9 g of the title compound having the following physical properties.

TLC: Rf=0.59 (cyclohexane:ethyl acetate=3:1).

MS knee/z, -318 (M+), 287-259.1
50°NMR (ODO13): δ-6,41(q,2
H), 5.40 (m.

5H), 3.73 (J', 3H), 2.80 (m, 4H
)-1,90~2.4o(m, 131-1), 1.2
0-160 (m, 10H) - 0,90 (7W, 3H).

Reference Example 2 (a) Methyl 2E, 11Z, 14Z-Eicosatrienoate Reference Example] Using 3.0 g of the compound produced in (α), the title compound having the following physical properties was obtained by the same procedure as in Reference Example 2. 3.1 g was obtained. In addition, for purification, silica gel column chromatography (cyclohexane: ethyl acetate = 20
:1) was used.

TLC: Rf=0.72 (cyclohexane:ethyl acetate=4:1).

MS: m/z, = 320 (M''), 28
8-260°NMR: δ-6,41 (q, 2H), 5.
36 (m, 4H), 3.70 (, r, 3H) = 2.7
4 (m, 2H,), 1.80-2.50 (m, 6H),
1.3 (yn, 16H), 0.88 (m, 3H)
.

Reference Example 2 (h) The title compound 366I having the following physical properties was obtained in the same manner as in Reference Example 2 using 3.9 g of methylpentanal 2-octenoate.

MS: yt/Z = 142 CM”),
126,113-111.86-87°NMR: δ-7,00 (dt, IH), 5.84 (dt
, IH).

3.72 (-?, 3H), 2.2 (F7!, 2H), 1
．． 20-1.60 (m, 4H), 0.91 (t, 3H
).

Reference Example 2 (C) 2-Methyl todecenoate C9H19/\/■OCH3 Using 4.4 g of octanal, 3.1 g of the title compound having the following physical properties was obtained in the same manner as in Reference Example 2. .

MS-Cisse 212 (M”), 180, 138, 113
゜87゜NMR: δ-6,98(dt, 1)(), 5.82(
dt, IH).

3.72 (J, 3H), 2.20 (fi, 2H), 1.
26(m, 14H)-0,87(t, 3H).

Reference Example 2(d) 5.9-dimethyl-2-dimethyl (dimethyl 8-decatripentaenoate 3.7-dimethylocta2,6-dininaldehy) 4
．． 111 and the same operation as in Reference Example 2, 4.2 g of the title compound having the following physical property values was obtained.

MS: m/z, = 208 (M”), 19
3,177.165°140.125.81.69°NMR: δ=7.61Cdd, IH), 6.00(d,
, IH), 5.80 (dd, IH), 5.10 (-1"
, IH), 3.73 (#, 3H), 2.20 (yn, 4
H).

1.90 (m, 3H), 1.68 (t, 38), 1.6
1 (j', 38).

Reference Example 2(e) Using 3.8 g of methyl 3-methyl-2-butynal 5-methyl-2E, 4-hexadienoate.

By the same operation as in Reference Example 2, the title compound 3.8I! having the following physical properties was obtained. I got it.

NMR: δ-7,00 (dd, IH), 5.99 ((f
, IH), 5.75Cd, IH)-3,73(J?, 3
H), 1.89 (J, 3H), 1.87 (S, 3) ()
.

Reference Example 2V1 Same as Reference Example 2 using 2.21 ethylhexadecanal 2-methyl-2-octadecenoate and 5 g of 1-ethoxycarbonylethylidene triphenylphosphorane (instead of methoxycarbonyltriphenylphosphorane). By this operation, the title compound 2 having the following physical properties was obtained.
．． OMS obtained 9g: m/;1 = 324 (M''), 27
9,278.141°NMR: δ-6,75(ya,
1) l) -4,17(q, 2B), 2.10(t, 2
H), 1.80 (j, 3H), 1.20-1.40 (
Town 29H)-0,86(t,3)1).

Reference Example 2 (g) Methyl 2-decyl-2-tridecenoate C1oH2□ Didecylketone 15. The title compound 108■ was obtained in the same manner as in Reference Example 2 using Sl. Note that silica gel column chromatography (hexane:ethyl acetate-40:1) was used for purification.

Reference example 2 3-methyl-2F, methyl methyl Z-octadecenoate
Using pentadecyl ketone 2.59.

The title compound 288 was obtained by the same operation as in Reference Example 2. Note that silica gel column chromatography was used for the purification pressure.

Reference Example 3 2E, 8Z, 11Z, -14Z-eicosatetraenoic acid The ester 1.99 produced in Reference Example 2 was converted into T)IF(40
+ul)-methanol (40ml), y) was dissolved in the mixed solution, 7.54ml of 4N potassium hydroxide aqueous solution was added, stirred at room temperature for 4 hours, adjusted to pH 3 with hydrochloric acid, and then extracted with ethyl ether. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethanol-40:1) to obtain 1.0 g of the title compound having the following physical properties.

TLG: Rf=0.34 (cyclohexane:ethyl acetate=4:1).

MS: m/z = 304 (M''), 2
59,247°244.206,150°NMR: δ-6,75 acid 5H), 2.80 (77!, 4H)-1,80-2.3
0 (m, 6), 1.20-1.40 (m.

10H), 0.88 (++t, 3H).

Reference Example 3 (a) 2E, l 1z, 14z-Process 4j) IJ F acid Reference Example 2 (Using 3.1 g of the compound produced in Gradient, a compound having the following physical property values was prepared in the same manner as in Reference Example 3. Title compound 1.
Got 911. Note that silica gel column chromatography (methylene chloride:ethanol = 40:1) was used for purification.

TLG: Rf=0.22 (methylene chloride; ethanol=40:1).

MS: m/z=306.261, 179.165°NM
R: δ=6.48 (q, 2H'), 5.38 (m.

4H), 2.78 (m, 28), 1.80-2°40 (
m, 6H)-1,32(m, 16H).

0.88 (m, 3H).

Reference Example 3 (b) 2-Octenoic acid 7/\Q' 3.2 g of the title compound having the same value as above were obtained. Silica gel column chromatography (hexane:ethyl acetate-5:1) was used for purification.

MS: m/Z, -129,128 (M”), 1
10.99.88.73°NMR: δ-7,67(dt, IH)-5,83Cd-
t, IH), 2.2(yn, 2H), 1.20-1.
60 (m, 4H), 0.90 (t, 3H).

Reference example 3 (C) 2-dodecenoic acid n-(/c, Hl 9ha, coo.

Using 3.1 g of the compound produced in Reference Example 2(C), 28 g of the title compound having the following physical property values was obtained by the same operation as in Reference Example 3. In addition, silica gel column chromatography (hexane: ethyl acetate = 5: 1) was used for purification.
was used.

MS m/z = 198 (M+), 180,16
2-138°73°NMR: δ-7,67 (dt, IH), 5.86 (dt
,1)().

2.24 (FW, 2H), 1.28Cm, 14H) -□
, H(t, 3H).

Reference Example 3(d) 5.9-Dimethyl-2, 4, 8-decato IJ Enenoic acid Compound 42I prepared in Reference Example 2(d) was used.

By the same operation as in Reference Example 3, 3.7 g of the title compound having the following physical properties was obtained. In addition, for purification (Ma71 Tsukagel column chromatography (hexane: ethyl acetate = 5
:1) was used.

M S +, m /z, = 194 ('''')
, 179.151.126.111.81, 69°NMR: +5 = 7.70 (cLd, -1 to 1), 6
．． 05 ((i, 1) (), 5.80 (cL, IH),
5.10 (m, IH).

2.18(fi,4H), 1.91(,r,3H)-1
, 68 (s, 3l-1), t, 6x (t, 3H).

5 Reference Example 3 (e) 5-Methyl-2, 4-hexadienoic acid Reference Example 2 (e)
Compound prepared in 3.8. ! Using i', the title compound 3. having the following physical property values was obtained by the same operation as in Reference Example 3.
3g was obtained. Note that silica gel column chromatography (hexane:ethyl acetate = 5:1) was used for purification.

MS: m/2=126(M”), 111.81°NMR
: δ-7,67(dd, IHn, 6.0'3((7,
IH) -5,74 (d, IH), 1.88 (J', 6H
).

Reference Example 3V) 2-Methyl-2-octadecenoic acid Reference Example 2 (using compound 2.911 produced in 7+,
By the same operation as in Reference Example 3, the title compound 2.39 having the following physical properties was obtained. Note that the recrystallization method (benzene) is used for purification.

MS: m/2=296(''), 278,250,214
゜210.87゜NMR: δ=6.94 (m, 1)i), 2.16
(t, 2H)-1,84(,?, 3H), 1.20~1
．． 40 (m, 26H), 0.88 (t, 3H).

Reference example 3ω) 2-danru-2-tridecenoic acid Reference Example 2 (using Compound 108~ produced in !7+).

By the same operation as in Reference Example 3, the title compound 59■ having the following physical properties was obtained. In addition, the recrystallization method (benzene-hexane) was used for purification.

MS Near 7L/Z=352(M”)-292,211,
166°NMR: δ=5.83 (#, IH), 2.60
(m, 2H), 2.15 (m, 2H), 1.20-1.
50 (FW, 32H), o, 5s (t, 6H).

Reference Example 3 (h) 3-Methyl-2■-octadecenoic acid Compound 288rn9 produced in Reference Example 2 was used in the same manner as in Reference Example 3 to obtain the title compound 96rn9 having the following physical properties. Note that a recrystallization method (hexane-hydrogen) was used for purification.

MS: m//? ,,=296(M+),2
78,236-100°NMR: δ=5.68(j, I
H), 2.16 (t, 2H), 2.16 (d, 3H
), 1.50 (t, 2H), 1.26 (J, 24H),
0.88(t, 3)().

Example I N-(9Z, 122-octadecagenoyl)anthranilic acid and its sodium salt 1.5- of oxalyl chloride was added to 605 my of linoleic acid, and after being allowed to stand at room temperature for 1 hour, the solution was concentrated under reduced pressure. 3ml of anthranilic acid 296■ and triethylamine 4361n9
was added dropwise to a solution of methylene chloride (3 ml) under water cooling. Stirred overnight at room temperature, diluted hydrochloric acid was added, and then extracted with ethyl acetate. The extract was washed 11 times with diluted hydrochloric acid and water, and then diluted with anhydrous sulfuric acid). It was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 550 ml of the title compound [acid] having the following physical properties.

TLO: Rf=0.4 (ethyl acetate:hexane=11)
.

MS: rIL/z = 399 (M+), 381,262° IR (liquid film method) rainbow = 1690.1680.1615° 1590 cm.

NMR: δ=8.76 (dd,'IH), 8.0
9 (dd, IH).

7.58 (d-t, IH), 7.10 (jt, IH),
5.25-5.50 (rn, 4H).

The obtained acid was dissolved in methanol, an equivalent amount of a 1N sodium hydroxide solution was added, and the mixture was concentrated under reduced pressure to obtain the corresponding sodium salt.

Example 1 (α) Rhenoyl)anthranilic acid and its sodium salt The title compound [acid] having the following physical property values was produced by the same procedure as in Example 1 using Compounds 265 to 265 produced in Reference Example 3 and anthranilic acid 119rn9. Obtained 80m2. For purification, silica gel column chromatography (
Ethyl acetate:hexane=1:10) was used. The sodium salt was similarly prepared.

TLC [acid]: l-1/=0.2 (ethyl acetate:
Hexane = 1-1).

MS (acid): rrL//2=423,405,294.
286°258°IR [salt] (KBr) Niji = 1665.1.615-1
580.1500.1435cm.

NMR [salt] (CI) C13+CD30D): δ=8.
28 (ct, LH) - 7,90 (d, LH), 7.13
(t, lH), 6.6-6.9 (771, 2H), 5.
68Cd, IH)-5,2-5.6Cm, 6H).

Example 1(b) N-(2shi 112,147L-eicosatrienoi)
L/) Anthranilic acid and its sodium salt Reference example 3
Using 3901 ng of the compound produced in (α) and 174 to 174 anthranilic acids, 120 m9 of the title compound [acid] having the following physical property values was obtained by the same operation as in Example 1. For purification, silica gel column chromatography (
Ethyl acetate:hexane-1:10) was used. The sodium salt was similarly prepared.

TLC (acid'): Rj = 0.2 (ethyl acetate: hexane = 1; 1) MS (acid) -7at/!J-425,407,288,
260゜200゜IJ acid] (film method) Niji = 1680.1600゜158
0.1520 cWL-NMR [acid] (CDC13): δ = 8.84 (d, I
H), 8.13 (d, IH), 7.61 (+!, LH)
.

7.12(t,1)(),? ,00(jt,1)(),
6.0OCd, IH), 5.2-5.5 (m, 4H).

Example 1 tC+ N-(2E-hebutenoyl)anthranilic acid and its sodium salt Using the compound 1281n9 produced in Reference Example 3(h) and anthranilic acid 137~, the following physical property values were obtained by the same operation as in Example 1. The title compound [acid] having 83rn
I got a 9. The sodium salt was similarly prepared.

MS (acid): m/Z = 247 CM''),
190,137°119.111°IR [acid] (liquid film method) Niji = 3500-2500.29
60°2930.2860.1690.1640.15
80.1520- 1440.1380. 1220-
980cm.

NMR (acid) (CDC13): δ=8.7Hd, IH)
, 8.07 (d, LH), 7.50 (t, IH), 7.
C7 (t.

IJ-6,95 (dt, IH), 5.98 (d, IH)
, 2.24 (q, 2H), 1.3-1.6 (m, 4H)
.

0.92 (t, 3H).

Example 1(d) N-(2E-dodecenoyl)anthranilic acid and its sodium salt Using compounds 198~ and anthranilic acid 137~ produced in Reference Example 3(C), the following procedure was carried out in the same manner as in Example 1. The title compound [acid] 184Iv having physical properties was obtained. The sodium salt was similarly prepared.

MS (acid): m/z, = 317 (M''),
190.181-14L 137.119゜IR (acid) (KBr) nitrogen = 3450.3120.29
40.2860.1705.1690.1640.16
10.1590.1530.1450.1230cII
L.

NMR [acid]: δ = 8.84 (d, IH), 8.13 (
d, IH), 7.61 (t, IH), 7.12 (t, I
H), 7.00 (dt, IH), 6.00 (C4,1)
(), 2.37 (ql 2H), 1.50 (m, 2H)
, 1.28 (m, 12H), o, ss (!, 3H).

Example 1(e) N-(5,9-dimethyl-2!J 4,8-decatrienoyl)anthranilic acid and its nato Reference Example 3(d
) Compound 87rn9 and anthranilic acid 6
Using 61n9, the title compound [acid] 601n9 having the following physical property values was obtained by the same operation as in Example 1. The sodium salt was similarly prepared.

MS [acid] Near 7E/2 = 313 (M”), 2
98.245°230.226,212,177.13
7゜IR [acid] (liquid film method) Niji-3400-2600-
2950.1680.161L 1580.1520.
1445.1230.1160 儂.

NMR [acid]: δ = 8.90 (j, IH), 8.16 (
d, IH), 5.9-6.2 (-2H), 5.12 (j
, IH), 2.18 (S, 4H) - 1,93 (J', 3
H), 1.5-1.8 (m, 6) 1).

Example IV) N-(5-Methyl-2J4-hexagenoyl)anthranilic acid and its sodium salt The same procedure as in Example 1 was carried out using the compound 86■ produced in Reference Example 3(e) and anthranilic acid 107■. The title compound [acid] 125■ having the following physical properties was obtained. Note that silica gel column chromatography was used for purification. The sodium salt was similarly prepared.

MS [acid]: Machi'Z, = 245 (M"), 230, 21
2゜146.137,109゜IR [acid] (KBr) Niji-3450,2970
,1690°1660.1600.1580.1520
．． 1445.1350.1290.1230cm ON
MR [acid]: δ-8,91 (d, IH), 8.17 (d
, IH), 7.74Cd, 1B), 7.64(d, tH
), 7.14 (d, 1) 1), 6.09 (d, IH),
6.00 (d, IH), 1.94 (s, 3H).

1.91 (-?, 3H), Example 1 (!I) N-(bi-tridecenoyl)anthranilic acid and its sodium salt 2-) lysosenic acid 349 daohabi anthranilic acid 22
Using 5 inches, 150 pieces of the title compound [acid] having the following physical properties were obtained by the same operation as in Example 1. Note that silica gel column chromatography (ethyl acetate:hexane=1:10) was used for purification. The sodium salt was similarly prepared.

TLO [acid]: Rf=0.6 (ethyl acetate:hexane=2:1).

MS (acid): m/z-331,313,195,137
゜IR [acid] (KBr) Nizi-1680, 1675, 1
630°1600.1580cm.

NMR [acid] C0DOI 3): δ-8,83Cd
, IH).

8.13 (dd, 1B), 7.5o (dt, IH)
, 7.10 (t, IH), 7.00 (d4.1H), 5
．． 99(d, IH).

Example 1 (l) N-(2-hexadecanoyl)anthranilic acid and its sodium salt U()
The title compound [acid] 126IIQ having the following physical properties was obtained by the same operation as in Example 1 using 62 Da. Note that silica gel column chromatography (ethyl acetate:hexane-1:10) was used for purification. The monosodium salt was similarly prepared at °C.

TLG [醗]: Rf-0,6 (acetic acid-ethyl:hexane-1:1).

MS [acid]: WL cold-373,355,237,200
゜190.179゜IR (acid) (KBr) nitrogen = 1690.1675: 1
630.1600.158044520cm -NMR
[Acid] (CDOAt3): δ-8,83 (d, IH),
812((Ld, 1B), 7.60(tit, IH
), 7.10 (t, IH), 6.99 (dt, 1)
1), 5.98 (d, IH).

Implementation, Example 1 (4-chloro-N-(2,112.14-4-eicosatrienoyl)anthranilic acid and its sodium salt G/ Compound 300 prepared in Reference Example 3 (α) and 4-chloro Using anthranilic acid 169■, the title compound [acid] 9 having the following physical properties was obtained by the same procedure as in Example 1.
I got 2 ■. Note that silica gel column chromatography (ethyl acetate:hexane-1:10) was used for purification. The sodium salt was similarly prepared.

TLC (acid): Rf-0,2 (ethylacetate N:hexane-2:1).

MS [acid]: ya/Z-461,459,443,44
1゜288.260゜IR (acid) (KBr) Nizi-1700, 1680-16
30,1600,1570cm.

NMR [acid] (cpcz 3): δ-8,92(t
L, IH).

8.03(d, II(), 7.07(dd, IH
).

6.99C (Lt, IH), s, 96 (d, IH),
5.2-5.5 (m, 4H).

Example 10) Using N-(2E-octadecenoyl)anthranilic acid and its sodium salt 2E-octadecenoic acid 145In9 and anthranilic acid 105Da, the title compound [acid] having the following physical property values was obtained by the same operation as in Example 1. 59Tn9 was obtained.

The sodium salt was similarly prepared.

TLU (acid 1: Rf-0□3 (ethyl acetate: hexane-
2:l).

MS[acid]nid'2 = 401.383,265,1
90°137.120°II ([acid] (KBr)nid = 3120.2930-2
850.1700.16IIS・)-1640,160
5-1585, 1530, 1450, 1385, 129
5,1220,965cm.

NMR [acid') (CDC13): δ-11,0O (t,
1) (), 8.83 (d, IH), 8.12 (d, I
H).

7.6o (t, IH), 7.11 (t, 1l-1).

7.00 (dt, 11 (), 5.98 (d, IH).

2.26 (m, 2H), 1.50 (yW, 2H), 1.
15-1.40 (m, 24H) - 0.88 (t.

3H).

Example 1 (n) 4-chloro-N-(2■-octadecenoyl)anthranilic acid and its sodium salt C/ By the same operation as in Example 1 using 410 m9 of 2EZ-octadecenoic acid and 250 m9 4-chloroanthranilic acid. Title compound [acid] 216 having the following physical property values
I got ■. Note that silica gel column chromatography (ethyl acetate:hexane=1:4) was used for purification. The sodium salt was similarly prepared.

TLC (acid:): FIf=0.3 <Ethyl acetate:
Hexane-1:l).

MS [acid]: m/z-43s, 417,265,213
゜198.180゜IR (acid) (KBrC1/=1700.1665.16
00-1565crIL.

NMR [acid'] (C; DO/3): δ-8,94 (d,
IH), 8.04Cd, IH), r, Os<dd, IH
), 7.01 (dt, IH), 5.96 (d, 1.8
).

Example 1 (tI S-(2E-eicosenoyl)thiosalicylic acid Using 2E-eicosenoic acid 147~ and thiosalicylic acid 73~, the title compound [acid] having the following physical property values was produced by the same operation as in Example 1. 11°■ was obtained.The recrystallization method (-\xane) was used for purification.

TLG [acid:]: Rf-0,40 (ethyl acetate:hexane=1:1).

MS [acid): m/,,=446.428-293,13
6゜IR[acid](KBr)nid = 1690.1670.
1625cm.

NMJ acid) (13Cδ-8,06 (d, IH) in CD,
7.45-7.70 (m, 3H), 7. QQ(d
t.

1) (), 6.18 (d, IH).

Example 1 (ml 4-chloro-N-(2-methyl-2-octadecenoyl)anthranilic acid (J) Using the compound 273m? prepared in Reference Example 3vl and 4-chloroanthranyl l[137m9, Example 1 and By similar operations, the title compound 18 having the following physical properties was obtained.
I got 5rny. For purification, recrystallization method (hexane-
ethyl acetate) was used.

TLC: Rf=0.3 (ethyl acetate:hexane=1:
1) cMS: m/z, = 449,43
1.279.16], 109°IF ((KBr) Niji=
1680.1670.1620.159 (1,1565
crIL-'.

NMR (GDO13+CI)30D): δ=8.84(
IH, d), 8.03 (11-1, d), 7.05 (
IH, dc? ), 6.63 (IH, t).

Example 1 (fL) 0-(2E-eicosenoic acid) salicylic acid The title compound having the following physical properties was prepared by the same procedure as in Example 1 using 136 μl of 2E-eipsenoic acid and 60.5 μl of salicylic acid. I got 87m.

□ For purification, silica gel column chromatography (hexane: ethyl acetate = 10:1) was used.

TLC: Rf=0.30 (ethyl acetate:hexane-
1:2).

MS-S'z, -413,412,293-120°IR (Kt3r) Niji=1720.1685.1640
．． 1600cIrL O NMR: δ = 8.07 (dcM, IH), 7.61 (d
t, IH), 7.10-7.40Cm, 3H)-6,0
7(d, IH).

Example 1 (O) 4-chloro-N-(3-decyl-2-tridecenoyl)
Anthranilic acid C,l Using Compounds 59 to 1 produced in Reference Example 3(g) and 28.8 mg of 4-chloroanthranilic acid, the title compound 28Da having the following physical properties was obtained by the same operation as in Example 1. Ta. In addition, pre-ξ latex TLO (methylene chloride:methanol=100:15) was used for purification.

TLG: 1 (f-0,30 (ethyl acetate:hexane-2:l).

MSS dichroic color 507.505-488.335,264
, IR(KBr) Niji=17,00.1665.162
5, □NMR: δ=8.91 (d, 1H)-s, o
O(d, quality.

7.02Cd(t, 1l(), 5.67(#, IH5
'.

2.68 (t, 2H), 2.16 (t, 2H) a' Example 1 (p) 4. . -N-(3-1fv-2"EZ Le,.

Reference Example 3 Using compound 96 and 4-chloroanthranil #55 and #19, the title compound 40 having the following physical properties was obtained by the same procedure as in Example 1. Note that recrystallization method (hexane) was used for purification.

TLC: Rf=0.30 (ethyl acetate:hexane #
2:l).

MS: m/2. =451-449,432-279,1
71°IR (KBr) Niji = 1690, 1675,]!
540°l NMR (CDC713+GD30D):'δ='8:'
88 (d, i HLs, oou, ui),'z,
, o,'z<ttd, IH), 5.74(j, tH
). , Example 1 (qI N-(3E-eicosenoic anthranilic acid and its sodium salt 000) 1(Nα) Example 1 By the same operation as above, the title compound [acid] 1409 having the following physical properties was obtained.

The recrystallization method (hexane) was used for purification. The sodium salt was similarly prepared.

TLG (acid): Rf-0,5 (ethyl acetate:hexane=1:1).

MS [acid] to 2m = 429,411,293,200.
137,120゜IR [acid] di-1690,1680,1640,16
00゜1585.1510cIrL O NMJ acid]: δ-8,83(LH,d), 812(i
H.

dd), 7.60 (l) l, ds, 7.10 (IH,
t)'.

6.99 (LH, dt), 5.98 (IH, d).

Example 1 ('-1 4-chloro-N-(2E-eicosenoic acid) anthranilic acid and its sodium salt 2-eicosenoic acid 216 ~ and anthranilic acid 12
The title compound [acid] 84 having the following physical property values was obtained by the same operation as in Example 1 using 0m9. Note that a recrystallization method (hexane:ethyl acetate=1:2) was used for purification. The sodium salt was similarly prepared.

TI, QC acid,]: Hf-0,2 (ethyl acetate:hexane-1:1).

MS (acid'): m/2. =463.445.293
,173゜171゜IR [acid] di = 1685-1665.1630.15
95.1570.1520cm.

NMR [acid] (CDC13+CD301J): δ=8B
7 (I H, d).

8.02CIH, d), 7.04 (lH, dd), 6.
97 (LH, dt), 5.96 (IH, d-).

Example 2 5 g of N-(2-dodecenoyl)anthranilic acid, 200 Da of fiber element calcium gluconate (disintegrating agent), 100 ~ 100 of magnesium stearate (lubricant), and 4.79 kg of microcrystalline cellulose were mixed in a conventional manner and pounded. 100 tablets containing 50 μl of active ingredient in each tablet were obtained.

Continuation of page 1 ■Int, CI,' Identification symbol Agency F C12N 9/99 serial number 14′.

Procedural Amendment (Date of April 1985 1, Case Indication 1988 Patent Application No. 245561 Minimum ('1) Relationship with Special R1 Applicant Name Ono Pharmaceutical Co., Ltd. Kasumigaseki Building Post Office I Box No. 49 June 1, 1980 [1 (Shipping date: 3, 1982)
Month 270) 6 Number of inventions increased by amendment 0 7, Column 8 for detailed explanation of the invention in the specification subject to amendment, 2nd line from the bottom of page 14 of the specification of the contents of the amendment, 1st line from the bottom of page 15 of the specification , line 11 on page 20, lines 4 and 5 on page 68, bottom line (two places) on page 42, and line 1 on page 46.
Correct "scheme" to "reaction process formula".

The "diagram" in the first line of page 22 is corrected to "reaction process formula".

Claims (1)

[Scope of Claims] 1) General formula [wherein R1 represents a linear or branched alkyl group, alkoxy group, alkenyl group or alkenyloxy group having 3 to 22 carbon atoms, R2 and R2/ each independently represents a hydrogen atom or a straight or branched alkyl group having 1 to 15 carbon atoms, and the symbol X represents the formula NR5 (in the formula, R5
represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms. ), a sulfur atom, an oxygen atom, or a methylene group.
, CHGOOR6 or 0CR2GOOR6 (in each formula
R6 represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms. ) or a hydroxyl group, -R4 is a hydrogen atom, a halogen atom, and has 1 to 4 carbon atoms.
straight-chain or branched alkyl or alkoxy groups,
Formula C00R7 (wherein, R7 is a hydrogen atom or has 1 carbon number
~4 linear or branched alkyl group. ) represents a hydroxyl group or a nitro group, where l is 0.1
or 2, where the symbol d represents a single bond or a double bond (E
, Z or EZ mixture). However, when R1 is an alkoxy group or an alkenyloxy group, the symbol 2 does not represent a double bond. ] or a non-toxic salt thereof. 2) The compound according to claim 1, wherein R1 is a linear or branched alkyl group or alkenyl group having 3 to 22 carbon atoms. 3) The compound according to claim 1 or 2, wherein R' is an n-1 thyl group, a lunonyl group, a rudecyl group, a yt-17decyl group, an n-<ntadecyl group, or a ruhebutadecyl group. . 4) The compound according to claim 1, wherein R1 is a linear or branched alkenyl group or alkenyloxy group having 3 to 22 carbon atoms. 5) The compound according to claim 1 or 4, wherein R1 is a hebutadecagenyl group, a heptadecatrienyl group, a dimethylhebutadecagenyl group, or an isozotenyl group. 6) R and R2' are each independently a hydrogen atom,
Claim 1 which is a methyl group or a roudecyl group
A compound according to any one of Items 1 to 5. 7) The compound according to any one of claims 1 to 6, wherein the symbol X is an imino group, a sulfur atom, or an oxygen atom. 8) R3 is a carboxy group or a methyl ester thereof,
A compound according to any one of claims 1 to 7, which is an ethyl ester or a non-toxic salt. 9) The compound according to any one of claims 1 to 8, wherein R4 is a hydrogen atom or a halogen atom. 10) The compound according to claim 1, which is N-(9Z, 12z-octadecajenoyl)anthranilic acid or its sodium salt. 11) N-(2E, 8Z, 11z, 14z-4'l:I
The compound according to claim 1, which is (satetranoyl)anthranilic acid or its sodium salt. 12) The compound according to claim 1, which is N-(2E, 11Z, 142-octadecajenoyl)anthranilic acid or its sodium salt. The compound according to claim 1, which is 131N-(2E-hebutenoyl)anthranilic acid or its sodium salt. 14) Claim 1 which is N'-(2E-decenoyl)anthranilic acid or its IJium salt
Compounds described in Section. 15) N-(5,9-dimethyl-2E,4E,8-
The compound according to claim 1, which is decatrienoyl)anthranilic acid or its sodium salt. 16) The compound according to claim 1, which is N-(5-methyl-2E,4-hexadienoyl)anthranilic acid or its sodium salt. 17) The compound according to claim 1, which is N-(2E-)lidecenoyl)anthranilic acid or its sodium salt. 18) Claim 1 which is N-(2E-hexadecanoyl)anthranilic acid or its salt
Compounds described in Section. 19) The compound according to claim 1, which is 4-oo-N-(2E, 11Z, 14z-octagenoyl)anthranilic acid or its sodium salt. 20) Claim 1 which is N-(2E-octadecenoyl)anthranilic acid or its salt
Compounds described in Section. 21) 4-chloro-N-(2EZ-octadecenoyl)
The compound according to claim 1, which is anthranilic acid or its sodium salt. 22) The compound according to claim 1, which is S-(2E-eicosenoyl)thiosalicylic acid. 23) The compound according to claim 1, which is 4-chloro-N-(2-methyl-2-octadecenoyl)anthranilic acid. 24) The compound according to claim 1, which is O-(2E-eicosenoyl)salicylic acid. 25) The compound according to claim 1, which is 4-chloro-N-(3-decyl-2-tridecenoyl)anthranilic acid. 26) Claim 1 which is 4-chloro-N-(3-methyl-2EZ-octadecenoyl)anthranilic acid
Compounds described in Section. 27) The compound according to claim 1, which is a N-(bi-eicosenoyl)anthranilic acid or its salt. 28) The compound according to claim 1, which is 4-chloro-N-(2E-eicosenoyl)anthranilic acid or its sodium salt. 29) General formula [wherein R represents a linear or branched alkyl group, alkoxy group, alkenyl group or alkenyloxy group having 3 to 22 carbon atoms, and R2 and R2/ each independently represent a hydrogen atom or represents a straight or branched alkyl group having 1 to 15 carbon atoms, and ru represents 0.1 or 2;
The symbol rich represents a single bond or a double bond (E, Z or ``mixture''). However, when R1 is an alkoxy group or an alkenyloxy group, the symbol = does not represent a double bond. A compound represented by the general formula [wherein the symbol Y is a group represented by the formula NR5 (wherein R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms], It represents a sulfur atom or an oxygen rx atom, and the formula R3 is GOOR6, OHGOOf (6 or 0
CR2GOOR6 (In each formula, R6 represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms.)
represents a group or a hydrogen group, R4 is a hydrogen atom,
・・・Rogen atom, linear or branched alkyl group or alkoxy group having 1 to 4 carbon atoms, formula cooR7 (in the formula, R
7 represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms. ) represents a hydroxyl group or a nitro group. [In the formula, all symbols have the same meanings as above. ] A method for producing a ketone compound or a non-toxic salt thereof. 30) General formula [In the formula, 〉 represents a butyl group, and other symbols have the same meanings as described in claim 27. [In the formula, all symbols have the same meanings as above.] [In the formula, all symbols have the same meanings as above. ] A method for producing a compound represented by. 31) General formula [wherein R1 represents a linear or branched alkyl group, alkoxy group, alkenyl group, or alkenyloxy group having 3 to 22 carbon atoms, and R2 and R2' each independently represent a hydrogen atom Or represents a straight chain or branched alkyl group having 1 to 15 carbon atoms. represents a group represented by the symbol or 2NR5 (wherein R5 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms), a sulfur atom, an oxygen atom, or a methylene group, and R3 represents a group represented by the formula cooR'i, C, H2GOOR6 or 0CH2GOOR6 (in each formula, R6 represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms) or a hydroxyl group; R4 represents hydrogen; Atom, halogen atom, straight-chain or branched alkyl group having 1 to 4 carbon atoms, or alkoxy group 1 Formula GOOR7 (wherein R7 is a hydrogen atom, or a straight-chain or branched alkyl group having 1 to 4 carbon atoms) represents a group represented by ), a hydroxyl group or a nitro group, n represents 0.1 or 2,
The symbol = represents a single or double bond (E, winter or U mixture). However, when R1 is an alkoxy group or an alkenyloxy group, the symbol = does not represent a double bond. ] A leukotriene antagonist characterized by containing a ketone compound or a non-toxic salt thereof as an active ingredient. 32) General formula [In the formula, all symbols have the same meaning as described in claim 31. ] A phospholipase inhibitor characterized by containing a ketone compound represented by the following or a non-toxic salt thereof as an active ingredient. [In the formula, all symbols have the same meanings as described in claim 31. ] A 5α-reductase inhibitor containing a ketone compound or a non-toxic salt thereof as an active ingredient.