WO2001089504A1 - Tropolone derivatives and pharmaceutical compositions - Google Patents

Abstract

Excellent 12-lipoxygenase inhibitors containing as the active ingredient tropolone derivatives of the general formula (1) or salts thereof. In said formula wherein R1 is hydrogen or optionally substituted C¿3-10? alkenyl; R?2¿ is hydrogen, C¿1-6? alkyl, optionally substituted C3-10 alkenyl, or alkynyl; R?3¿ is hydrogen; R4 is hydrogen or C¿1-6? alkyl; and R?5¿ is hydrogen or a group of the general formula (2): -(CH¿2?)nNR?6R7¿ (wherein n is an integer of 1 to 6; and R?6 and R7¿ are each independently hydrogen, alkyl, or aralkyl, or alternatively R?6 and R7¿ together with the nitrogen atom adjacent thereto may represent optionally substituted 5- or 6-membered cyclic amino), with the proviso that the compound wherein R?1, R2, R3, R4 and R5¿ are simultaneously hydrogen is excepted.

Description

 Specification

 Technical field of borolone derivatives and pharmaceuticals

 The present invention relates to a 12-lipoxygenase inhibitor containing a tropolone derivative or a salt thereof as an active ingredient, and a novel tropolone derivative and a salt thereof. Background art

Lipoxygenase is an oxygenase that adds one molecule of oxygen to unsaturated fatty acids to produce its hydroperoxide derivative. The produced hydroperoxide derivative is further metabolized and converted to eicosanoids having various physiological activities. Generally, 5-, 12-, and 15-lipoxygenases are distinguished depending on the number of carbon atoms counted from the carboxyl carbon of arachidonic acid. 12-Lipoxygenase adds oxygen to the C-12 position of arachidonic acid to produce 12-hydroxyperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE). Its activity has been found in various tissues such as platelets, leukocytes, lymphocytes, and smooth muscle. 12-HPETE is reduced to give the hydroxy form (12-HETE), and is also converted to heptoxylin (HXA ₃ , HXB ₃ ). The role of these products in various diseases has been rapidly elucidated in recent years.

When tissues are stimulated in some way, phospholipase releases arachidonic acid from cell membrane lipids. 12-HETE, which is produced from 12-HPBTE generated by arachidonic acid by 12-lipoxygenase, increases leukocyte chemotaxis, platelet aggregation, and smooth muscle cell migration, and increases arteriosclerosis. It is said to be involved in many disease states such as adult diseases such as heart disease and allergic disease [eg, Tada et al., Cardiovascular Research 21 (8), 551-558 (1987); Muroda et al. Watanabe et al., J. Neurochem., 50 (4), 1145-1150 (1988); Hammar strom, S. et al., Therapeutics 13 (6), 785-788 (1984); al. Proc. Natl. Acad. Sci, USA, 72, 5130 (1975), etc.], and their overproduction is regarded as a problem. If inhibition of the activity of the Li Pokishigenaze, I ² - - 1 ² which catalyzes a reaction from Araki Don acid produces 12-HPETE metabolites (eg, 12-HETE) in re epoxy Genaze and a This suppresses the overproduction of It can be used as a prophylactic or therapeutic agent for diseases caused by metabolites of 12-lipoxygenase (eg, 12-HETE). It is also known that subcutaneous administration of 12-HPETE causes pain (1999 National Neurological Society).

 Until now, various trobolone derivatives have been known. For example, International Publication No. W09900366 describes that 7- (4-phenylbiperazinomethinole) troborone is useful for pollakiuria and urinary incontinence. Japanese Patent Publication No. 57-50934 discloses a method for producing a troborone derivative having a double bond in a side chain, which has an insecticidal, antifungal and antibacterial activity. Japanese Patent Application Laid-Open No. 60-228414 discloses that trobolone and its derivative have 12-lipoxygenase inhibitory activity and are useful as agents for preventing or treating diseases caused by 12-lipoxygenase metabolites. It has been disclosed. However, the trobolone derivative according to claim 1 of the present invention, including 4-isopropylpyro; ^ -lone (generic name: hinokitiol), is said to have a 12-lipoxygenase inhibitory activity. Description o Disclosure of the invention

 An object of the present invention is to provide an excellent selective inhibitor of 12-lipoxygenase and a novel compound useful as a medicament.

 In order to achieve the above object, the present inventors have found that, in the process of synthesizing and examining various compounds, the compound represented by the following general formula (1) has an excellent 12-lipoxygenase inhibitory action. And completed the present invention.

で表される トロボロン誘導体 （以下、 本化合物と称する） 又はその 塩を有効成分と して含有する 12-リポキシゲナーゼ阻害剤に関する。 The present invention provides the following general formula (1)

The present invention relates to a 12-lipoxygenase inhibitor comprising, as an active ingredient, a trobolone derivative (hereinafter, referred to as the present compound) represented by the formula

In the formula, R ¹ represents a hydrogen atom or an optionally substituted phenol having 3 to 10 carbon atoms;

R ² represents a hydrogen atom, an alkyl having 1 to 6 carbons, an alkenyl having 3 to 10 carbons which may be substituted or an anorecynole having 3 to 10 carbons which may be substituted;

R ³ represents a hydrogen atom;

R ⁴ represents a hydrogen atom or an alkyl having 1 to 6 carbons;

R ⁵ is a hydrogen atom or the following general formula (2)

-(CHJ _n NR ⁶ R ⁷ (2)

(11 represents an integer of 1 to 6, R ^e and R ⁷ are the same or different and are adjacent to each other by a hydrogen atom, an alkyl having 1 to 6 carbon atoms or an aralkyl having 6 to 12 carbon atoms, or R ^e R ⁷ Together with the nitrogen atom, it represents one or more NR ^e R ⁷ and may represent a 5- or 6-membered cyclic amino which may be substituted, and such a cyclic amino group may further include a nitrogen atom, an oxygen atom or And may have a sulfur atom.).

However, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ exclude compounds that are simultaneously hydrogen atoms.

式中、 R ^{1 1}は、 置換されていて もよい炭素数 3 -10のァルケ ノレ を表し ； Further, the present invention relates to a troborone derivative (hereinafter, referred to as the compound of the present invention) represented by the following general formula (1a), (lb) or (1c) or a salt thereof.

In the formula, R ¹¹ represents an optionally substituted arylalkyl having 3-10 carbon atoms;

R ^{2 1,} R ^{4 1} is either one represents an alkyl of 1-6 carbon atoms, the other person is a hydrogen atom.

Wherein, R ^{2 2} is R 5 2 represents an alkyl have 6 carbon atoms, the following one general formula (2 b)

(CH ₂ ) _n NR, 6,2 ■ R _D 72

 (2b)

(N represents an integer of 1-6 carbon atoms, R ^{6 2,} R ^{7 2} are the same or different and each Wakashi hydrogen atom Ku represents Ararukiru, or R ^{6 2,} nitrogen atoms R ^{7 2} are you adjacent Represents a 5- to 6-membered cyclic amino, which may be substituted with alkyl, and is a NR ⁶ R ^7. Such a cyclic amino group is a nitrogen atom as a ring-constituting atom. May be included.).

式中、 R ^{2 3}は、 炭素数 4 - 10のァルケ-ル又はアルキニルを表す, 一般式 （ 1 ) で表される化合物及びその塩 （本化合物） は、 優れ た 12-リ ポキシゲナーゼ選択的阻害作用を有する。 本化合物の中に は、 公知の化合物も含まれるが、 トロボロ ン及び 3-ィ ソプロ ビル ト ロボロ ン以外の化合物が優れた 12-リ ポキシゲナーゼ選択的阻害活 性を有するこ とは、 本発明者らが初めて見いだしたものである。 ま た、 一般式 （ l a)、 .（ l b ) 又は l c ) で表される ト ロボロ ン誘 導体及びその塩 （本発明化合物） は、 文献未記載の新規化合物であ る。

Wherein, R ^{2 3,} the number 4 carbon - Aruke of 10 - represents the le or alkynyl, the compound represented by the general formula (1) and salts thereof (the compound), excellent 12-Li Pokishigenaze selective inhibition Has an action. This compound includes known compounds, but compounds other than troborone and 3-isoprovir troborone have excellent 12-lipoxygenase selective inhibitory activity. The present inventors have found for the first time that they have the property. Further, the boroborone derivative represented by the general formula (la),. (Lb) or lc) and a salt thereof (the compound of the present invention) are novel compounds not described in the literature.

 The structural feature of the compound (la) is that the 3-position of the toroborone skeleton is alkenyl, one of the 4-position and 6-position is alkyl, and the other is a hydrogen atom.

 The structural feature of the compound (1b) is that the 4-position of the toroborone skeleton is an alkyl and the 7-position is an aminoalkyl group represented by the formula (2b).

 The structural feature of the compound (1c) is that the 4-position of the tropolone skeleton is alkenyl or alkyl having 4 to 10 carbon atoms.

 Hereinafter, the present invention will be described in detail.

 The definition of each substituent used in this specification is as follows.

“Alkyl” is a straight or branched chain having 1 to 6 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutynole, sec-butynole Tert-butyl, n-pentynole, isopentyl, n-hexyl, isohexyl and the like. In particular, those having 1 to 4 carbon atoms are preferred. R ^2, R ^{2 1} or by a R ^{2 3,} arbitrary I Sopuro pill preferred especially.

“Alkenyl” includes straight-chain or branched-chain C 3-10 carbon atoms such as aryl, propyl, isopropenyl, butyr, isotbutinole, and pentenyl. Nore, Isopentenino, Hexenole, Isohexenyl and the like. In particular, those with 3-7 carbon atoms are preferred. Such alkenyl may have the alkylene moiety substituted with fuel. It is an R ² or R ^{2 3,} in particular having an unsaturated bond at the 1-position, Aruke - Le or alkynyl preferred arbitrariness.

"Archiel j is a straight or branched chain having 3 to 10 carbon atoms, such as n-butyninole, n-pentininole, n-hexyl, and isohexyl. Shells and the like can be mentioned. In particular, those with 3 to .7 carbon atoms are preferred. ' Such alkynyl may be substituted with hydroxy and / or alkyl. It is an R ² or R ^{2 3,} having an unsaturated bond, especially 1-position, preferred alkenyl or Arukieru arbitrarily.

 An “aralkyl” is a compound in which the alkyl portion is a straight or branched chain having 1 to 4 carbon atoms and the aralkyl portion is 6 to 12 carbon atoms (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenyl) and, for example, benzyl, phenylene, 1-phenyl / reethyl, 3-phenylpropyl, 2-phenylpropyl and the like. Of these, those having 7 to 10 carbon atoms are preferred, and benzyl or 1-phenyl-ethyl is particularly preferred.

 Examples of the optionally substituted 5- to 6-membered “cyclic amino” include pyrrolidino, piperidino, piperazino, morpholino and the like. Examples of the substituent of the cyclic amino include the aforementioned alkyl and aralkyl.

In the formula (la), R ¹¹ is an optionally substituted carbon atom having 3 to 7 carbon atoms, and ^one of R 21 and R ⁴ ] is an alkyl group having 1 to 3 carbon atoms. , and the other is laid like is collected by Roboro emissions derived thereof or a salt thereof is a hydrogen atom, in the formula (lb), R ^{2 2} is an alkyl of 1-3 carbon atoms, R ^{5 2} force S 1-Fueniruechirua Mi Roh methyl or lay preferred is 4-Mechirubiperajino methyl, in formula (1 c), R ^{2 3} has an unsaturated bond at position 1, also alkenyl having 4 -10 carbon alkynyl, among them the number of carbon atoms 7-10 alkenyl or alkynyl are preferred.

 In particular, the following compounds are preferred.

 4 1—Hepti 2 / Le) Troboron,

 4--cis-hepte-nore) Toroboron,

4-1-Trans-Heptur) Toroboron,

3 1 1 1 1)

3 1, 1 dimethino rea) 1 4 1 Isopropyl propyl boron 3-(1, 1-dimethyl linole) 1 6-isopropyl troborone, 3-(1-etchinore 1 2-propenile) 1 6-isopropy / retropolone,

 3-(1 —ethyl 1 2 —propionyl) 1 4 1-isopropylpropyl tropolone,

 3 — Aryl 4 — Methinole Toroborone,

 3—Ari Nore 6—Methyl Troboron,

 3-(1, 1-Dimethylaryl) 1-4-methyltroborone.

 3 — (1, 1-dimethylarinole)-1-6 — methyl troborone,

 3 — Aryl 1 4 1 Isopro Pinole Tropolon,

 3 — Allyl 6 — Sopropyl Trobolone,

 7-(4—Metinorebiperazinizolemethinole)

 7- [1 (R) -methyl-benzylaminomethyl] hinokitiol, 7- (1-methyl-benzylaminomethyl) hinokitiol, 7- (N, N-dibenzylaminomethyl) hinokitiol,

 3 — (1 — feninole 2 — pourininole) 1 4 — methinole toroborone, 7 — (1 1 feninole 2 — pourininole) 1 4 — methinole toroborone, 3 — (1 — ェ1-methyl tropolone and 7- (1—ethinole 2—propion / re) 1-4-methyl tropolone

 Examples of the “salt” include an inorganic acid salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, and the like. , Maleic acid, succinic acid, methansnoleonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, and other organic acid salts, sodium salts, potassium chloride, etc. And alkaline earth metal salts such as calcium salts.

 The present compound includes keto-enol tautomers and cis-trans isomers, and each isomer and a mixture thereof are also included in the present invention.

"12-lipoxygenase inhibitors" are polyvalent non-valent agents such as arachidonic acid. Diseases caused by abnormal increase in enzyme activity by inhibiting the catalytic activity of 12-lipoxygenase using saturated fatty acids as a substrate, such as arteriosclerosis, ischemic heart disease, circulatory diseases such as cerebral vasospasm, psoriasis, Allergic diseases such as nephritis · Compounds useful for the prevention and treatment of inflammatory diseases, cancer metastasis, pain, etc.

Manufacturing method A

 Compound (1a) and the present compound similar thereto can be produced according to the following reaction formula.

(3) (31) ^(la)

(Wherein, R ^{1 1} R ^{2 1} and R ^{4 1} are as defined above. R are shorted with a dislocation R

X represents an alkenyl group to be ¹ and halogen. )

 Examples of the halogen include chlorine, bromine, and iodine. First step

The compound (31) is produced by reacting the compound (3) with a halogen compound (RX) in a suitable solvent in the presence of a base at about 20 to 150 ° C. Examples of the reaction solvent include polar solvents such as acetate-tolyl, N, N-dimethylformamide (DMF), getyl ether, tetrahydrofuran (THF), and dioxane. Such ether solvents, hydrocarbons such as benzene, toluene, etc .; System solvents, halogenated hydrocarbons such as methylene chloride, and clog form, or a mixed solvent thereof can be used. . Examples of the base include alkali carbonates such as potassium carbonate, sodium carbonate, silver carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and sodium methylate. Organic tertiary amines such as metal compounds, triethylamine, and triethylenediamine can be used. The amount of the base to be used is 1- to 2-fold the molar amount of the compound (3). The amount of the halogen compound to be used in the compound (3) is preferably in the range of 1 to 10 times by mol. More preferably, it is 1 to 3 moles. The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 24 hours.

Second step

 Compound (1a) is produced by subjecting compound (31) to a Claisen rearrangement reaction. That is, the compound (31) is usually used without a solvent or in a solvent at 50 to 250 ° C, preferably 100 to 220 ° C for 30 minutes to 48 hours, preferably 30 minutes to 24 hours, if necessary. The rearrangement reaction proceeds by heating in a sealed tube. Examples of the solvent include polar solvents such as acetonitril, Ν, Ν-dimethylformamide (DMF), ether solvents such as getyl ether, tetrahydrofuran, and dioxane; benzene; Hydrocarbon solvents such as toluene and xylene, halogenated hydrocarbons such as methylene chloride and chloroform, Ν, Ν-dimethylaniline, diphenyl ether, 1,2,3,4-tetramethylbenzene And the like, or a mixed solvent thereof can be used.

Manufacturing method Β

 Among the compounds (lb), the compound (lb-1) in which n is an integer of 1 and the similar compounds are obtained by subjecting compound (4) to compound (5) according to the following reaction formula. It can be produced by subjecting to an arsenic reaction.

(Wherein, R ^{2 2,} R ^{6 2} and R ^{7 2} are as defined above.)

That is, compound (4) and compound (5) are dissolved in a suitable solvent in the presence of formaldehydes at a temperature from 0 ° C. to the boiling point of the solvent used, preferably about 10 to 100 ° C. Minutes to 48 hours to react and condense, then treat with acid. Examples of the reaction solvent include water, alcohols such as methanol, ethanol, propanol, and butanol, dioxane, and Ether solvents such as trahydrofuran and the like, Ν, Ν-dimethylformamide dimethyl sulfoxide, sulfolane, pyridine, etc.) can be used. Compound (5) may be used in the form of a salt. Examples of such a salt include an inorganic acid salt with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, etc., oxalic acid carbonate, tartaric acid, acetic acid And organic acid salts such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, etc. Examples of the formaldehyde include those having an action equivalent to that of formaldehyde during the Mannich reaction. For example, there may be mentioned formaldehyde, paraformaldehyde, honolemarin, methyla.onele, ethylanole, piperidinomethylinolephthalimid, hexamethylenetetramine, etc. <Compound (5) is compound (4) 1) to 50 equivalents per 1) Production method C

 Among the compounds (lb), the compound (lb-2) in which n is an integer of 2 to 6 and a compound similar thereto are obtained by reacting the compound (4) with the compound (52) according to the following reaction formula. It can be manufactured by doing so.

(Wherein, R ^{2 2,} R ^{6 2} and R ^{7 2} are defined as above and m is 2 -. 6 integers, X ¹ is a leaving group.)

Examples of the leaving group include a halogen and a methanesulfonyloxy group. This reaction, t ¾ in this transgression carried out in the same manner as in the production method A (JA Bartrop, J. Chem. So p.958, see 1946) ₀

Manufacturing method D

Among the compounds (1 c), Ku Wakashi alkenyl represented by R ^{2 3} are alkyl - the compound having an unsaturated bond at the 1-position of the Le (1 c one 1) and the compounds similar to this, the following It can be manufactured according to the reaction formula ₍

(Wherein, X is as defined above. M represents a leaving group, R ^Q is 'represent two smaller alkyl yo Risumi prime, R ^{2 3'} R ^{2 3} is an unsaturated bond at the 1-position Represents an alkenyl or an alkyl having

 Represents double picking or. )

 Compound (6) is reacted with compound (7) in a solvent in the presence of a catalyst at about 20 to 150 ° C. to produce compound (1c-11). Examples of the leaving group include anoalkyltin, boron alkali, zinc zinc, and the like.Examples of the reaction solvent include acetonitril, N, N-dimethylforma Polar solvents such as amide (DMF), ether solvents such as jet ether, tetrahydrofuran, and dioxane; hydrocarbon solvents such as benzene and toluene; triethylamine; piperidine Basic solvents or mixed solvents thereof can be used. As the catalyst, a palladium catalyst such as dichloromethane (triphenylphosphine) palladium or the like, or a metal halide such as copper iodide or copper bromide can be used. The reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but is usually about 30 minutes to 48 hours. The amount of the compound (7) to be used relative to the compound (6) is preferably in the range of 1 to 10 moles, more preferably 1 to 3 moles. The amount of the catalyst used for the compound (6) is preferably in the range of 0.1 to 2 moles (M. G. Banwell, et al., J. Chem. Soc., Chem. Comm. (10) p. 616, 1989).

The other compound (1) can be produced by a known method (for example, JP-A-57-50934) or a method analogous thereto. The compound (1) thus produced can be obtained by a means known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, fractionation, and mouth chromatography. Can be isolated and purified. For the starting compound (3), the starting compound (4), the starting compound (5) and the starting compound (52), commercially available ones can be used, or known methods (WT Brandy, JP Hieble, J. Am. It can be manufactured according to Chem. Soc., 94, 4278 (1972) and WT Brandy, Synthesis, 1971, 415).

 The 4-halogenotropolone of the starting compound (6) can be produced according to Synthesis, 165 (1981); Tetrahedron Letters, 2 ±, 449 (1980) R ΐ Tetrahedron, 2 ±, 1673 (1965) .

 The salt of the present compound (1) can be produced by a method known per se. For example, the hydrochloric acid 本 of the present compound (1) is obtained by treating the present compound (1) with an alcohol solution of hydrogen chloride or ethyl ether solution and collecting the precipitated crystals by filtration, or concentrating the solution if no crystals are precipitated. It can be obtained by filtering out the crystals after precipitation.

 When the compound is administered as a medicament, the compound is used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5% to 90%. % As a pharmaceutical composition containing the composition.

 As the carrier, one or more solid, semi-solid or liquid diluents, fillers, and other prescription auxiliaries are used. Preferably, the pharmaceutical compositions are administered in dosage unit form. The present compound can be used as a liquid preparation (eg, an injection for intravenous administration, a bladder infusion, a capsule for oral administration) in addition to a solid preparation. The pharmaceutical composition can be administered in a tissue, orally, topically (eg, transdermally), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. For example, oral administration is preferred.

When a 12-lipoxygenase inhibitor is administered, for example, as a therapeutic agent for arteriosclerosis, the dose should be adjusted in consideration of the patient's condition such as age, weight, nature of the disease, severity, etc., and the route of administration. Usually, the amount of the active ingredient of the present invention for an adult is in the range of 1 tng to 1,000 mg per day for oral administration, preferably 1 mg for an adult. ~ 500 mg No adult range. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. In general, they can be administered once or several times a day. The same dosage as described above can be used as a prophylactic / therapeutic agent for other diseases. BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described in more detail with reference to Reference Examples (Examples of production of starting compounds or known compounds), Examples (Examples of the present invention!), Preparation Examples, and Test Examples. It is not limited to these.

Reference example 1

 2-ary rotrobon

 1.22 g of troborone was dissolved in 12 ral of THF, 2.52 g of arylene iodide and 4.13 g of silver carbonate were added, and the mixture was refluxed overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain 1.0 g of the desired compound as an oil. Was.

Reference example 2

 2 — (3,3-Dimethylaryloxy) tropone

 0.91 g of the target compound was obtained as an oily substance in the same manner as in Reference Example 1 using 1.22 g of boroborone and 1.49 g of 3,3,3-dimethylarinole bromide.

Reference example 3

 3 — Arinore Tropolon

 0.49 g of 2-aryloxytropone obtained in Reference Example 1 was dissolved in 10 ml of xylene and refluxed for 3 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate 5: 1) to obtain 0.37 g of the objective oil.

Elemental analysis value C ₁₀ H _l 0 0 ₂

 Theoretical value C: 74.06 H: 6.21

 Found C: 74.35 H: 5.93

^-RCCDCla) δ 3.60 (2Η, d), 5.11-5.21 (2H, m), 5.94-6.10 (1H, m), 6.96-7.52 (4H, m), 9.45 (1H, br) Reference example 4

 2 — (3,3—Dimethylaryloxy) 1-4 — Isopropyl tropone and 2 — (3,3 — Dimethylaryloxy) 1 6 — Isopropyl tropone

Human Nokichioru 0. 7 g, to obtain a mixture 523. 8 mg of O Ri objective compound produced in Referential Example 1 using bromide Jimechiruari Le 0. 76 _g.

Reference example 5

 2 — (2 — pentenoyl) 1-4 isopropyl chloride and 2 — (2 — pentenoyl) 1 6-isopropyl chloride

 The same procedure as in Reference Example 1 was carried out using 0.7 g of Hinoki chionore and 0.76 g of 1-bromo-2-pentene to obtain 272.6 mg of a mixture of the target compound. Reference example 6

 2 — arynoroxy-4 methyl tropone and 2 — aryroxy 6-methyl tropone

 Using 0.30 g of 4-methyltroborone and 0.32 g of aryl bromide, 265.6 mg of a mixture of the target compound was obtained in the same manner as in Reference Example 1.

Reference Example 7

 2— (3,3-Dimethylarinoleoxy) -1-methyltropone and 2- (3,3-Dimethylarinoleoxy) -16-methyltropone

 The same operation as in Reference Example 1 was carried out using 50 mg of 4-methyltroborone and 65.6 rag of 3,3,3-dimethylarinyl bromide to obtain 49.4 mg of a mixture of the target compound.

Reference Example 8

 2 — arynoroxy 4 — isopropyl tropone and 2 — aryoxy 6 — isopropyl tropone

 Using the same procedure as in Reference Example 1 using 1.0 g of hinokitiol and 0.88 g of _3,3-dimethylbromide, 548.4 mg of a mixture of the target compound was obtained. Reference Example 9

 3-(1, 1 —dimethylarinole) troborone

2- (3,3-dimethylaryloxy) tropone obtained in Reference Example 2 Using 0.86 g and operating in the same manner as in Reference Example 3, 0.17 g of the desired compound was obtained as an oil.

Elemental analysis value C _l2 H _M 0 ₂

 Theoretical value C: 75.76 H: 7.42

 Measured value C: 76.00 H: 7.22

 d-NMRiCDCla) 6: 1.54 (6H, s), 4.96-5.06 (2H, m), 6.23 (1H, dd), 6.95-7.29 (3H, m), 7.72 (1H, d), 9.96 (1H, br) )

Example 1

 4 One (1—Heptul) Trobolone

Under an argon stream, 4-promotropoloneg, 1-heptin 0.72 g, tetra (tetraphenylphosphine) palladium 116 mg, copper (I) bromide 43 mg, and triethylamine 20 mg in THF 10 ml Dissolved and refluxed overnight. After filtering off the insolubles and concentrating the filtrate, the residue was subjected to silica gel column chromatography (CHCl ₃ : MeOH = 100: 1) and treated with n-hexane to obtain 0.60 g of the desired compound. Was. Melting point 34-35 ° C

Elemental analysis C ₁₄ H ₁₆ 0 ₂ and to

 Theoretical value C: 77.75 H: 7.46

 Observed value C: 77.76 H: 7.44

- noodles _{(CDC1 3) δ: 0.93 (} 3H, t), 1.35-1.66 (6H, m), 2.43 (2H, t), 7.08-7.42 (4H, m)

Example 2

 4 — (1 — cis-heptur) Toroboron

0.49 g of 4- (1-heptyl) tropolone was dissolved in 10 ml of ethanol, 150 mg of a Lindlar catalyst and 0.2 ml of quinoline were added, and hydrogenation was carried out overnight at normal pressure and room temperature. After filtering off the catalyst and concentrating the filtrate, the residue was subjected to silica gel column chromatography (CHCl ₃ : MeOH = 200: 1) to obtain 0.38 g of the desired compound as an oil.

As the elemental analysis C ₁₄ H ₁₈ 0 ₂

 Theory C. 77.03 H: 8.31

Measured value C: 76.71 H: 8.55 -顧_{(CDC1 3) S: 0.88 (} 3Η, t), 1.24-1.65 (6H, m), 2.21-2.33 (2H, m),

5.77-5.90 (IH, m), 6.42 (IH, m), 7.21-7.30 (4H, m)

Example 3

 4-(1 — Trans-Heptur) Toroboron

0.5 g of 4-bromotropolone is dissolved in 5 tnl of dioxane, and 1-trans-heptene ninole trimethinole tin [Tetrahedron Letters, 32, 7647 (1991)] l, 30 g, di (triphenylphosphine) B) Dichloropalladium (175 mg) was added, and the mixture was refluxed for 4 hours. Water and ethyl acetate were added to the reaction solution, insolubles were filtered off, and the organic layer was separated. The organic layer was washed with a 10% aqueous solution of lithium fluoride and water, dried over magnesium sulfate and concentrated, and the residue was subjected to silica gel chromatography (CHCl ₃ : MeOH = 200: 1). 0.19 g of the desired compound was obtained as an oil.

As the elemental analysis C ₁₄ H ₁₈ 0 ₂

 Theoretical value C: 77.03 H: 8.31

 Measured value C: 77.01 H: 8.12

_{'H-NMR (CDC1 3)} δ: 0.91 (3Η, t), 1.26-1.53 (6Η, m), 2.21-2.31 (2Η, m),

6.31-6.50 (2Η, m), 6.99-7.46 (4Η, m)

Example 4

 3 — (1, 1-Dimethylarinole) 1 4-Isopropylpyrrololone and 3 — (1, 1-Dimethylarinole) 1 6 —Isopropyl pyrroloborone 2_ (3, 3-Dimethylaryloxy) -4-dipropynoletropone and 2- (3,3-dimethylaryloxy) -6-diisopropylpropyltone 52 g were obtained in the same manner as in Reference Example 3 to obtain the desired compound. Was obtained as an oil (0.24 g).

-Leave (CDC1 ₃ ) δ: 1.27 (6Η, d), 1.53 (6H, s), 2.87 (m, IH), 4.97-

5.04 (m, IH), 6.17-6.28 (m, IH), 6, 86-6.92 (m, IH), 7.26-7.28 (m, IH),

7.60-7.64 (m, IH)

Example 5

3-(1 1 ethyl 1 2 — Propaninole) 1 6 — Isopro pill Tropolo _ In the same manner as in Reference Example 3, 0.34 g of 2- (2-pentenoyl) -4-ysopropyl tropone and 2- (2-pentenoyl) -6-isopropylpropyl tropone obtained in Reference Example 5 were used. The reaction was followed by post-treatment, and the residue was subjected to silica gel column chromatography, and the fraction eluted earlier was concentrated to give the target compound as an oil (0.28 g).

- image _{(CDC1 3) 5: 0.90 (} 3Η, t), 1.27 (6H, d), 1.64-1.84 (2Η, m), 2.88 (111, m), 4.05 (IH, q), 5.09-6.02 (1H , m), 6.91-6.95 (IH, m), 7.30-7.34 (2H, m)

Example 6

 3 — (1 —ethyl 1 2 —propininole) 1 6 —isopro pinole and tropolone 3 _ (1 —etinole 2 —propininole) 1 4 1-isopropinole

 The post-fraction of Example 5 was concentrated to obtain 0.20 g of the desired compound as an oily mixture.

'Η-band R (CDC1 ₃ ) δ: 0.86-1.01 (3Η, m), 1.21-1.28 (6Η, m), 1.43- 2.14 (2H, m), 2.83-3.51 (IH, m), 4.01-4.17 (1H, m), 4, 93-5.13 (2H, m), 5.90-6.39 (IH, m), 6.92-7.34 (3H, m)

Example 7

 3—aryl-1 4—methyltroborone and 3—aryl-1 6—methyltroborone

 265.6 mg of 2-aryloxy-4-methyltropone and 2-aryloxy-6-methyltropone obtained in Reference Example 6 were treated in the same manner as in Reference Example 3 to give an oil, and 12.lmg of the target compound was obtained as a mixture. Obtained.

-Face (CDC1 ₃ ) δ: 1.72 (3H, s), 2.19-2.32 (2H, m), 4, 99-5.03 (IH, m), 6.15-6.28 (IH, m), 6.89-6.91 (IH, m), 7.25-7.29 (IH, m), 7, 59- 7, 63 (IH, m)

Example 8

 3-(1, 1-dimethinorea linole)-1-4-methyl / letropolone and 3-(1, 1-dimethinorea rilole)-6-methylthioborone

2- (3,3-dimethylaryloxy) -4-methyl methyl obtained in Reference Example 7 In the same manner as in Reference Example 3, 19.4 mg of the target compound was obtained as an oily mixture by operating on ropone and 2- (3,3-dimethylaryloleoxy) -6-methyltropone 49.4 mg in the same manner as in Reference Example 3.

-Marauder R (CDC1 ₃ ) 6: 1.53 (6Η, s), 1.71 (3H, s), 4.98-5.03 (IH, m), 6.21-6.28 (IH, m), 6.89-6.92 (IH, m), 7.26-7.28 (IH, m), 7.61- 7.64 (1H, m)

Example 9 '

 3 — Aryl 4 — Isopropinoletropolone and 3 — Arinole 6 — Tip mouth Pinoletropone

 In the same manner as in Reference Example 3, 0.82 g of 2-aryloxy_4—isopropyl tropone and 2-aryloxy-6-isopropylpropyl tropone obtained in Reference Example 8 were treated in the same manner as in Reference Example 3 to obtain 0.67 g of an oily mixture. I got it. 6 tnl of THF, 0.62 ml of acetic anhydride, 1.83 ml of triethylamine, and 4-dimethylaminopyridine (0.20 g) were added to the oily substance, and the mixture was stirred at room temperature for 22 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was subjected to 2-acetoxy- by preparative liquid column chromatography. 3-Arino-4-pyroxypropyl tropone and 2-acetoxy-3-aryl-6-pyroxypropyl mouth were collected. 5 ml of water, 5 ml of THF and 54.mg of anhydrous lithium hydroxide were added to each 2-acetoxy compound, and the mixture was stirred at room temperature for 25 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1). 4), the target compound 3-aryl-4-isopropyl propyl borolone 96.lmg and 3-aryl-6-isopropyl propyl boroborone 96.Img were each converted into an oil. Obtained.

 3 — Ari Nolay 4 Isoprop Pil Trobolone

lH - hide _{(CDC1 3) δ 1.20 (6Η} , d), 2.82 (IH, m), 3.75 (2H, d), 4.93- 5.06 (2H, m), 5.95-6.05 (IH, m), 7.03-7.06 (IH, m), 7.18-7.28 (2H, m) 3 —Alinore 6 —Sopro Pinole Tropolon

lH-NMR (CDCl ₃ ) 5: 1.20 (6Η, d), 2.82 (IH, m), 3.50 (2H, d), 5.04- 5.11 (2H, m), 5.87-5.98 (IH, m), 6.84- 6.94 (IH, m), 7.24-7.26 (IH, ra), 7.31-7.34 (1H, m)

Example 10

 7-(4-Mechinorepidurajunoremechinore)

Hinokitiol (0.50 g) was dissolved in methanol ( ⁵ ml), N-methylpyrazine (0.59 g) and acetic acid (0.21 ml) were added, and the mixture was stirred at 60 ° C. for 30 minutes. 0.32 ml of 37% formaldehyde was added to the reaction solution, and the mixture was further refluxed for 4 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with a black hole form. The organic layer was dried over anhydrous magnesium sulfate, after滤過, the solvent was concentrated, _c ^l H the residue to obtain the desired compound 0.65g recrystallized from acetic Echiru -瞧_{(CDC1 3) δ: 1.28 (} 6Η, d), 2.31 (3Η, s), 2.51-2.60 (8Η, m), 2.90 (1Η, m), 3.71 (2Η, s), 6.96-7.00 (1Η, m), 7.27-7.32 (111, m) , 7.73-7.77 (IH, m)

Example 1 1

 7 — Pyrrolidurmethylhinokitiol

 The residue obtained by the same procedure as in Example 10 using 0.50 g of hinokitiol and 0.26 g of pyrrolidine was applied to silica gel column chromatography (ethyl acetate: n-hexane = 1: 4). This gave 0.54 g of the desired compound.

_{- NMR (CDC1 3) δ:} 1.28 (6Η, d), 1.63 - 1.97 (4H, m), 2.46 - 2.60 (4H, m),

2.89 (1H, m), 3.82 (211, s), 6.90-7.03 (1H, m), 7.31-7.34 (IH, m),

7.68-7.80 (1H, m)

Example 1 2

 7 ー Pipette Gino

 The same procedure as in Example 10 was carried out using 0.5 g of hinokitiol and 0.31 g of piperidine to obtain 0.55 g of the target compound.

'H-NMRiCDClj) 6: 1.26 (6Η, d), 1.39-1.78 (6H, m), 2.37-2.61 (4H, m), 2.89 (lH, m), 3.69 (2H, s), 6.90-7.02 ( 1H, m), '7.2 g 7.31 (IH, ra), 7.72-7.84 (IH, m)

Example 13

 7-(4 Benzylpidragel methyl)

 The same procedure as in Example 11 was carried out using 0.70 g of hinokitiol and 0.90 g of 1-benzylpiperazine to obtain 0.94 g of the target compound.

lH - thigh _{(CDC1 3) δ 1.27 (6Η} , d), 1.62-1.66 (4Η, ra), 2.11 (IH, m),

2.52-2.56 (4H, m), 2.86-2.91 (2H, m), _3.06-3.10 (1H, m), 3.65 (2H, s), 6.94-6.98 (IH, m), 7.13-7.31 (6H , m), 7.71-7.75 (IH, m)

Example 14

7-(4 _ Benzinore Piberi Gino Mechinore)

 The same procedure as in Example 10 was carried out using 0.70 g of hinokionore and 0.90 g of 4-benzinolepiperidine to obtain 0.71 g of the desired compound.

lH-NMR (CDCl ₃ ) δ: 1.27 (6H, d), 2.52-2.57 (8H, m), 2.89 (1H, m), 3.53 (2H, s), 3.70 (2H, s), 6.95-6.99 ( 1H, m), 7.25-7.37 (6H, m), 7.73-7.77 (IH, ra)

Example 15 '

 7-C 1-(R) —methyl-benzylaminomethyl] Example using 0.70 g of hinokitiol and 0.49 g of (R) -α-methinobenzoylamine, and the same operation as in 1. Thus, 0.53 g of the target compound was obtained.

- Anonymous _{(CDC1 3) δ: 1.27 (} 6Η, d), 1.59 (3H, d), 2.89 (IH, m), 3.77-

3.91 (4H, m), 6.90-6.93 (IH, m), 7.23-7.37 (6H, m), 7.46-7.50 (IH, m)

 7-(1-methylbenz / rareminomethyl) hinokitiol

 The same procedure as in Example 11 was carried out using 0.55 g of hinokitiol and 0.49 g of α-methylbenzylamine to obtain 0.53 g of the desired compound.

6 ： 1.27 (6Η, d) , 1.59 (3Η, d) , 2.89(lH,m), 3.77- 3.91 (4H, m) , 6.90-6.93 (IH, m) , 7.23-7.37 (6H, m) , 7.46-7.50 (IH, m) 実施例 1 7

6: 1.27 (6Η, d), 1.59 (3Η, d), 2.89 (lH, m), 3.77-3.91 (4H, m), 6.90-6.93 (IH, m), 7.23-7.37 (6H, m), 7.46-7.50 (IH, m) Example 17

7-(N, N-dipendinoleaminomethyl) hinokitiol JP01 / 04362

Morpholine (3191), acetic acid (209 μ1) and formaldehyde (37%, 274 μ1) were added to methanol (5 ml), and hinokitiol (500 mg) was added. The mixture was stirred at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate, and extracted with a black hole form. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of the target compound. The crude product was purified by silica gel chromatography (chloroform: methanol = 70: 1) to obtain 1.lg of the desired compound.

- Luo _{(90MHz, CDC1 3) δ:} 1.26 (d, J = 6.7Hz, 6H), 2.77-3.15 (m, 1H), 3.63 (m, 2H), 3.78 (m, 4H), 6, 98 - 8.19 (m, 13H)

Example 18

 7 — Monoreho Rino Me Chino Leh

 Moglefolin (319 μl), acetic acid (209 μl), and formaldehyde (37%, 274 μl) were added to a solution of cypress (500 mg) in methanol (5 ml). The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with a cross-linked form.The obtained organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to obtain a crude product of the target compound, which was purified by silica gel column chromatography (form: form: metanol = 50: 1). This gave 455.8 mg of the desired compound.

 -Sat (300MHz, CDC) 8: 1.22 (d, J = 7.5Hz, 6H), 2.47-2.50 (m, 4H), 2.90 (septet, J = 7.5Hz, 1H), 3.64 (s, 2H), 3.67 -3.70 (m, 4H), 6.92-6.96 (m, 1H), 7.24-7.27 (m, 1H), 7.71-7.75 (m, 1H)

_{IR (CHC1 3): 3458,} 3020, 2968, 1612, 1475, 1398, 1250cm- 1 'M / S (70 eV): m / z 263 (M +, 7)

And a _{HRMS (70 eV) C 16 H} 21 N0 3,

( ⁺ ): Calculated value: 263.1521, measured value: 263.1512

Example 19

3-(1 1 feninole 2 — Propaninole) 1 4 — meth / letropolone and 3 — (1 — feninore 1 2 — proben / re) 1 6 — methinele tropolon N Under a nitrogen stream, a suspension of sodium hydride (60% in oil, 17.7 mg) in N, N-dimethylformamide (lml) was added at 0 ° C to 4-methyl tropolone ( A solution of 50 mg) in N, N-dimethylformamide (lml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Cinnamyl bromide (67 μl) was added dropwise to the reaction solution at 0 ° C, and the mixture was stirred at 75 ° C for 2 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to preparative TLC (ethyl acetate: hexane = 1: 1). ) And purified by 2 — (3 — phne / ray 2 — propynoleoxy) -1- 3-methyl, phthalone and 2- — (3 — phne-nore 2 — probeninoleoxy) 1 6 — meth Tinoretrobon was obtained as a mixture of two isomers (19.3 mg). A solution of this mixture (19 rag) in xylene (5 ml) was heated to reflux at 150 ° C. for 24 hours. After evaporating the solvent, the obtained mixture was purified by preparative TLC (ethyl acetate: hexane = 1: 1) to obtain the desired compound (19 tng) as a mixture of two isomers.

lH-NMR (270 Hz, CDC1 3) δ: 1.71 (s, 3H), 3.76 (m, 1H), 5.00-

5.03 (m, 1H), 6.25-6.31 (m, 1H), 6.85-6.89 (m, 1H), 7.26-7.35 (m, 6H), 7.59-7.61 (m, 1H),

Example 20

 3-(1 チ チ 2 2-— ぺ レ) 1 4 メ

3 — (1 — Echinore 1 2 — Prognore) 1 6 — Metinole Tropolon

 Using 1-bromo-2-pentene (55 1) in place of cinnaminolebromide, the target compound was prepared as a mixture of two isomers in the same manner as in Example 19.

(20 mg).

IH-NMR (270 Hz, CDC1 3) 6: 1.19 (t, J = 6.9Hz, 3H), 1.71 (s, 3H),

2.09 (m, 2H), 3.84 (m, 1H), 4.98-5.03 (m, 1H), 6.21-6.28 (m, 1H),

6.89-6.92 (m, 1H), 7.26-7.28 (m, 1H), 7.59-7.62 (m, 1H)

MS (FAB): m / Z 205 (M + l, 100)

Formulation Example 1

100 g of calcium silicate (trade name: Flowlite) is stirred with a granulator (bath). (VG -01, manufactured by Parec), and 50 g of the compound of Example 7 is added thereto, and dispersed and mixed. Next, a predetermined amount of a 5% aqueous solution of hydroxypropylcellulose (trade name: HPC-L) is added, granulated, and dried by a fluidized-bed granulator / dryer (STREA _: manufactured by Bowrec). The granules are sized by a granulator (Komill: Parek). To the resulting intermediate 160g, lactose (trade name: Dairaku toast) 7 ⁷⁵ g, Ke I acid Kanoreshiumu 10g, C C-Ca (quotient mouth name:!? ECG-505) 50g and Magunei steer-phosphate Pour 5 g of the rubber into a blender (Bore Container Mixer MC20: Kotopi Giken), mix it, and use a rotary tableting machine (Collect 12HUK: made by Kikusui) to reduce the diameter to 8 mm and 200 mg / tablet. Mold to obtain tablets containing 10 mg of the compound of Example 7.

Formulation Example 2

 150 g of magnesium metasilicate aluminate (trade name: Neusilin) was charged into a stirring granulator (Pachicarda Lanulator VG-01 type: manufactured by Parec), and 50 g of the compound of Example 7 was added. Disperse 'mix. Next, a predetermined amount of a 5% aqueous solution of hydroxypropyl cellulose 2910 (trade name: TC-5R) is added, granulated, and dried by a fluidized bed granulating dryer (STREA: manufactured by Bowrec). Then, sizing is performed with a crushing / sizing machine (comil: manufactured by Bauretsu). To 210 g of the obtained intermediate, 790 g of t-lactose (trade name: lactose) is put into a mixer (Borecontainer Mixer MC20: Kotopi Giken), and after mixing, a capsule filling device (capsule filler: 200 mg was filled into the No. 1 capsule with Shiono Gikuoli Caps Co., Ltd.) to obtain a forcepsel containing the compound lOtng of Example 7. Test example 1

Inhibitory effect on 12-lipoxygenase

1. Preparation of enzyme

Human platelet 12-lipoxygenase preparations include hexahistidine-binding protein expression plasmid pQE-32 and human erythroleukemia cell 12-lipoxygenase (platelet-type) mRNA. The enzyme cDNA, which was prepared by reverse transcription of the enzyme, was incorporated, and six amino acids were added to the amino terminal of the enzyme protein. Recombinant 12-lipoxygenase to which a stidine residue was added was expressed in Escherichia coli, and purified to homogeneity using Ni ²⁺ -ditritriacetate agarose chromatography [Nakamura, M., et al. al, J. Hisochem. Cytochem. 43, 237-244 (1955)] ₀ Porcine leukocyte 12-lipoxygenase is a plasmid vector of the porcine leukocyte 12-lipoxygenase (leukocyte type) PKK223. -Expressed in Escherichia coli, the obtained recombinant enzyme was homogenized using ammonium sulfate fractionation, gel filtration, anion exchange chromatography, and immunoaffinity chromatography. Purified. For human leukocyte 5-lipoxygenase, a centrifuged supernatant of human leukocytes at 105,000 xg was used as an enzyme preparation. For 15-lipoxygenase, a centrifugal supernatant of 105,000 _X g of egret reticulocytes was partially purified by ammonium sulfate fractionation. Cyclooxygenase-1 (hereinafter abbreviated as C0X-1) is an enzyme preparation that has been solubilized with l% Triton X-100 from hemi seminal vesicle gland microsomes, and cyclooxygenase-2 (hereinafter C0X-1) is used. -2) was expressed in insect cells using paculovirus and solubilized with 45 mM octyl glucoside.

2.Enzyme activity measurement method

 (1) Method using radiolabeled arachidonic acid

For each enzyme, standard reaction solutions were prepared as follows. The enzymatic reaction was performed using a light-shielded test tube. For 12- and 15-lipoxygenase, a reaction solution containing 50m Tris-HCl buffer (pH 7.4) and 0.01% Tween 20 (Nacalai Tesque), and for 5-lipoxygenase, 50mM phosphoric acid buffer. Reaction solution containing 2 mM CaCl ₂ and 2 mM ATP (Wako Pure Chemical Industries, Ltd.), C0X-1 and C0X-2 are 100 mM Tris-HCl buffer (pH 8.0), 2 μ) (Sigma), a reaction solution containing 5 mM triptophan (Katayama Chemical) was used.A test compound or a control compound, troborone (hereinafter, referred to as compound A) or 3-methoxide A 5 l ethanol solution of roborone (hereinafter referred to as compound B) and the enzyme were added to the reaction solution, and the mixture was pre-incubated for 5 minutes at room temperature, and then 25 [1- ^H C] arachidonic acid (Amersham) International) to start the reaction with a total volume of 200 μl. Started. The amount of each enzyme used was 2.5 nmol / tnin.The amount of enzyme used was _c- , 12-, and 15-lipoxygenase at 30 ° C, C0X-1 and C0X-2 at 24 ° C for 1 minute each. The reaction was performed. After the reaction was stopped by adding 101 of 0.2M citrate, the product was extracted by adding 0.3 ml of a mixture of ether / methanol / 0.2M citrate (30: 4: 1.v / v). The products were separated by thin-layer chromatography using a developing solvent of getyl ether / petroleum ether / acetic acid (85: 15: 0.l (v / v)). For quantification of reaction products, use Bio-Image Analyzer-BAS 2000 (Fuji Photo Film Co., Ltd.) on a silica gel plate for thin-layer chromatography (silica gel 60 Fzi4 / Merck). Was measured for radioactivity. As a control, ethanol alone was added instead of the test compound, and the measurement was performed. The relative enzyme activity was calculated with the control activity taken as 100%.

(2) Method using an absorbance meter

Add the test compound and human platelet 12-lipoxygenase to 50 mM Tris-HCl buffer (pH 7.4) containing 0.03% Tween 20, and incubate for 5 minutes at room temperature. An acid (Nu-Chck Prep) was added to carry out the reaction at 30 ° C in a total volume of 1 ml. The increase in 240 mm absorption was continuously measured with a spectrophotometer (Beckman DU640), and the amount of product was calculated using a molecular extinction coefficient of 22,000. The results are shown in Table 1.

Lipoxygenase inhibitory activity

ic ₅₀ (A)

Compound human platelets

 15-LO 5-LO COX-1 COX-2 Example 1 0.34 39 19 7.6〉 100〉 100 Example 2 0.136 31 5.5 7.8> 100> 100 Example 3 0.21 11 11 3.1〉 100 MOO Example 5 0.01 0.17 ndndndnd Example 1 7 0.5 8> 100 45> 100> 100 o

Hinokichio / re 0.15 MOO 17〉 100〉 100 Reference Example 3 0.3 40〉 100 12〉 100〉 100 Reference Example 9 0.5 20> 100 17〉 100〉 100 Reference compound A 2.3 17 50 35〉 100> 100 Compound B 3〉 100 ndndndnd

LO: lipoxygenase; COX: cyclooxygenase; η · d .: not determined

 As is evident from the above table, the present compound has an extremely low concentration compared to troborone and 3-methoxytroborone which are known to have 12-lipoxygenase inhibitory activity. It specifically inhibited human platelet 12-lipoxygenase activity. Industrial applicability

 The compound has a very strong inhibitory effect on 12-lipoxygenase and has selectivity for platelet-type 12-lipoxygenase. Therefore, it can be used as a prophylactic / therapeutic agent for diseases caused by metabolites of 12-lipoxygenase. It will also be a useful reagent for analyzing the active centers of two isozymes of 12-lipoxygenase and for elucidating the physiological effects of platelet 12-lipoxygenase, which has not yet been elucidated.

Claims

 The scope of the claims  The following general formula (1)

A 12-lipoxygenase inhibitor comprising, as an active ingredient, a boroborone derivative represented by the formula: or a salt thereof. In the formula, R ¹ represents a hydrogen atom or an optionally substituted alkenyl having 2 to 10 carbon atoms; R ² represents a hydrogen atom, alkyl having 1 to 6 carbons, alkenyl having 2 to 10 carbons which may be substituted or alkynyl having 2 to 10 carbons which may be substituted; R ³ represents a hydrogen atom; R ⁴ represents a hydrogen atom or an alkyl having 6 carbon atoms; R ⁵ is a hydrogen atom or the following general formula (2) -(CH ₂ ) _n NR ° R '(2) (n represents an integer of 1-6, R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom-alkyl having 1-6 carbons or aralkyl having 6-12 carbons, or R ⁶ , Represents an optionally substituted 5- to 6-membered cyclic amino, taken together with the adjacent nitrogen atom at R ^7. Such a cyclic amino group is a nitrogen atom or a ring-forming atom. (It may have an oxygen atom.). However, compounds in which R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are simultaneously hydrogen atoms are excluded. 2. The boroborone derivative or the salt thereof according to claim ¹ , wherein R ¹ , R ³ , R ⁴ , and R ⁵ are a hydrogen atom, and R ² is an optionally substituted alkenyl having 3 to 7 carbon atoms. A 12-lipoxygenase inhibitor comprising, as an active ingredient. 3. R ¹ is an optionally substituted alkenyl or C 3-7 alkenyl or Alkyl, wherein R 2, R ³ , R ⁴ and R ⁵ are hydrogen atoms 12. A 12-lipoxygenase inhibitor comprising the boroborone derivative or the salt thereof according to 1 as an active ingredient. 4. R ¹ is an optionally substituted alkenyl having 3 to 10 carbon atoms, one of R ² and R ⁴ is an alkyl having 1 to 6 carbon atoms and the other is a hydrogen atom, 12. A 12-lipoxygenase inhibitor comprising, as an active ingredient, the tropolone derivative or a salt thereof according to claim 1, wherein R ³ and R ⁵ are water cable atoms. 5. R ¹ _N R ³ and R ⁴ are hydrogen atoms, R ² is alkyl having 6 carbon atoms, and R ⁵ is a compound represented by the general formula (2) -(CH ₂ ) _n NR ⁶ R ⁷ (2) (N R ^e, R ⁷ is as defined above) Toropo Ron derivatives or 12 Li Pokishigena over peptidase inhibitor containing by salt thereof as an active ingredient according to claim 1, wherein a.  6. The following general formula (1a)

Or a salt thereof. In the formula, R ¹¹ represents alkenyl having 3 to 10 carbon atoms which may be substituted; R ^{2 1,} R ^{4 1} is either one represents an alkyl of 1-6 carbon atoms, the other person is a hydrogen atom. 7. R ^{1 1} is Ri alkenyl der good carbon number of 3 -5 be substituted, either one of R ^{2 1,} R ^{4 1} is alkyl having a carbon number of 1-3, on the other hand is a hydrogen atom 7. The tropolone derivative or a salt thereof according to claim 6. 8. The following general formula (1b)

Or a salt thereof. Wherein, R ^{2 2} is an alkyl having a carbon number of 1-6, R ^{5 2,} the following general formula (2 b) -(CH ₂ ) _n NR ⁶² R ⁷² (2b) (N represents an integer of 1-6 carbon atoms, R ^{6 2,} R ^{7 2} are the same or different and each Wakashi hydrogen atom Ku represents Ararukiru, or R ^{6 2,} nitrogen atoms R ^{7 2} are you adjacent Represents a 5- to 6-membered cyclic amino which may be substituted with alkyl, and such a cyclic amino group may further have a nitrogen atom as a ring-constituting atom. .). 9. Ri alkyl der of R ^{2 2} carbon atoms 1- 3, R ^{5 2} force S 2- Hue - Ruechi luer Mi Roh methyl or 4-Mechirubiperajino preparative Roboron derivative or a salt thereof according to claim 8, wherein methyl .  1 0. The following general formula (1 c)

Or a salt thereof. Wherein, R ^{2 3} represents the § / Rekeniru or Anorekininore number 4 -10 atoms, . 1 1 R ^{2 3} is Ku Wakashi alkenyl carbon number 7 10 alkylene - DOO Roboron derivative or a salt thereof in the range 1 0 wherein according a Le.