JPS6112642A - Aromatic unsaturated ketone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R represents OH, lower alkoxyl, (halogen-substituted)phenol or H; m is an integer 0-7, provided that m is an integer 1-7 when R is H; n is 2 or 3; Xs are adjacent to each other and represent OH or lower alkoxyl]. EXAMPLE:1-(3',4'-Dihydroxyphenyl)-3-oxo-1-octene. USE:Medicines having inhibitory action on lipoxygenase and useful as remedies and preventives for allergic diseases, asthma, inflammation, etc. The daily dose is 10-300mg orally administered once - individed several portions. PREPARATION:A compound expressed by formula II is reacted with a novel compound expressed by formula III preferably in a solvent such as 1,2-dimethoxyethane in the presence of non-nucleophilic base such as NaOH at -80 deg.C - room temperature for 2-4hr to obtain the compound expressed by formula I. The novel compound expressed by formula III is obtained by reacting a compound expressed by formula IV with a compound expressed by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a novel aromatic unsaturated ketone derivative having lipoxygenase inhibitory activity.

[Background of prior art/invention]

Riboquingenase is a leukotriene, 5-
It is an enzyme involved in the in vivo synthesis of hydroxyeicosatetraenoic acid (5-HETE).

Therefore, compounds with lipoxygenase inhibitory action are
It is useful for treating and preventing allergies, asthma, inflammation, etc. .

Such lipoxygenase inhibitory substances include CB, B, which is known as caffeic acid and its methyl ester;
A, 1 Main 2, 92 (1984)), but its lipoxygenase inhibitory action cannot be said to be sufficient.

From this point of view, the present inventors have obtained a cloudy compound having even better poxygenase inhibitory action (wherein R is a phenyl or hydrogen atom which may be substituted with a hydroxyl group, a lower alkoxy group or a halogen atom, m is θ~7
If R is a hydrogen atom, m is an integer of 1 to 7.
The present invention was completed by discovering that aromatic unsaturated ketone derivatives represented by the following formula (where n is an integer of 2 or 3, and X represents adjacent hydroxyl groups or lower alkoxy groups) have particularly excellent poxygenase inhibitory effects. I ended up doing it.

[Disclosure of the invention]

The present invention provides an aromatic unsaturated ketone derivative (I).

In this specification, the lower alkoxy group may be linear or branched, such as methoxy, ethoxy, n-propoxy, 1so-propoxy, n-butoxy, 1so
Examples include those having 1 to 4 carbon atoms such as -butoxy.

Examples of the halogen atom as a substituent include chlorine and bromine, with chlorine being particularly preferred.

m represents an integer of 0 to 7, but if R is a hydrogen atom, 3
It is preferably an integer of ~7, and when R is optionally substituted phenyl, an integer of 0~3.

The aromatic unsaturated ketone derivative (I) of the present invention has the following formula:
Produced by reacting the compound (II) represented by the formula (wherein R and m are the same as defined above) with the compound (I [ Ru.

This reaction is usually carried out in a solvent that does not adversely affect the reaction. As the solvent, ether solvents such as tetrahydrofuran, diethyl ether, and dimethoxyethane are preferred;
Among these, tetrahydrofuran is preferred.

This reaction is preferably carried out in the presence of a non-nucleophilic base such as sodium hydride or lithium diisopropylamide. The reaction temperature is usually about -70°C to room temperature, and the reaction time is usually about 2 to 4 hours.

In addition, when the compound (n) and/or (I [I) has a phenolic hydroxyl group, it is preferable to protect the hydroxyl group, and specific examples of protected compounds include methyl ether, , tetrahydropyranyl ether and the like.

Compound (nl) is a new compound, for example with the formula %formula%
Produced by reacting a compound represented by () with a compound represented by the general formula R-(CH2)mC0OH(■) (wherein R has the same meaning as above) or a reactive derivative thereof (ester, etc.) be done.

The reaction is typically carried out under cooling in the presence of a strongly basic metal compound such as n-butyllithium.

Example] Production of −+11:1-(3°,4”-dimethoxyphenyl)-3-oxo-1-octene Sodium hydride (50% mineral oil) under water cooling
0.87 g dry 1,2-dimethoxyethane 70ml
Inside, dimethyl-2-oxoheptylphosphonate) 4
．． 30 ml of 0 g of dry 1,2-dimethoxyethane are added dropwise. After dropping, stirred at room temperature for 1 hour, then -
Cool to 78°C. After cooling, heratolmaldehyde3.
3 ml of 0 g dry 1,2-dimethoxyethane are added dropwise. After dropping, the mixture was stirred at -78°C for 2 hours, and the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off to obtain a crude product. This product was purified by column chromatography [silica gel/hexane:ethyl acetate-3:1] to obtain 1.3 g of the title compound.

IR: Vmax' 1685.1655.980
cm-'NMR: δCDCl3 0.90 (t, J-6Hz, 3H) 1.05-2
．． 0 (m, 6H-)2.61 (t, J=78
2.21) 3.90 (s, 6H) 6.59 (d, J=+6Hz, IH) 6.8 ~
7', 2 (m, 3H) 7.50 (d, J-
16 Hz, l Old Example 1-(21: Preparation of 1-(3′,4′-dihydroxyphenyl)-3-oxo-1-octene (Compound 1) Example 1-(1-( obtained in 11) 3”, 4′-dimethoxyphenyl)-3-okicul-octene 128 mg
is dissolved in 1 ml of dry dichloromethane and cooled to -78°C. After cooling, 1.5 ml of IN boron tribromide-dichloromethane solution was added dropwise, and the temperature was gradually returned to room temperature. After returning to room temperature, the reaction solution was poured into ice water and extracted with ethyl acetate. After washing the ethyl acetate layer with water, drying with magnesium sulfate,
The solvent is distilled off to obtain a crude product. This product was recrystallized from water-ethanol to obtain 60 mg of crystalline title compound.

IR: Vmax 3500.1678.1640
．． 1598.980 cm-'NMR: δCDe1
3 0.90 (m, 3H) 1.1~1.8 (m, 6) 1) 2.60 (t
, J=611z, 28)6.50 (d, J=
=16)1z, I)I)6.7~7.1 ('m
, 3B) 7.43 (d, J-1611z, I
H) 8.99 (s, IH) 9.37 (s, II() Example 2: 1,5-bis(3', 4'~dihydroxydiphenyl)-3-oxo-1-pentene (compound 2) Production Example 1, -11.1-+21, 1,5-bis(3',4'-dihydroxyphenyl)-3-oxo-1-pentene was obtained. Dimethyl-2-oxo-4-(3
',4''-dimethoxyphenyl)butylbosbonate was used.

Reference Example I Nidimethyl-2-oxo-4-(3', 4'
-Production of dimethoxyphenyl)butylbosbonate-50 ml of n-butyl lithium (2,1M hexane solution) cooled to 78°C and 100 ml of tetrahydrofuran
12.4 g of dimethylmethylphosphonate was added dropwise into the solution. ? After cooling, stir at -78°C for 30 minutes. After stirring, methyl-3-(3',4'-dimethoxyphenyl)
-Propionate 2.2.4 g Synthesized from C3', 4''-simethoxycinnamic acid in two steps: (a) Esterification (HCl -CH30H), (bl reduction (Pd/C-
H2)') and 100 ml of tetrahydrofuran are added dropwise. After dropping, the mixture was reacted at -78°C for 22 hours, and the reaction solution was poured into 500 ml of saturated brine, neutralized, extracted with dichloromethane, dried, and concentrated to obtain a crude product. This product was purified by column chromatography [silica gel/hexane:ethyl acetate-1:4] to obtain the title compound 9.
．． Obtain 0g.

Example 3-(11: 1-(3′,4°-bistetrahydrobillanyloxyphenyl)-6-(3″,4″~dimethoxyphenyl)-3-oquine-1-hexene (compound 3) Production Example 1-(According to 11, Ni(3", 4"-bistetrahydrobylanyloquinphenyl)-6-(3", 4")
"-dimethoxyphenyl)-3-oxo-1-hexene was obtained.

However, in place of the Wittig reagent di-reagent dimethyl-oxoheptylphosphonate in Example 1-(1,1), dimethyl-2-oxo-5 obtained by the same method b'= as in Reference Example 1 in Example 2 was used. -(3".

Using 4″-dimethoxyphenyl)pentylphosphonate and instead of veratraldehyde, 3.4-
bistedrahydrobilanyroxyhenzaldehyde (3,
Synthesized from 4-dihydroxybenzaldehyde and dihydropyran) was used.

IR: Vmax 1685.1630.975
cs”NMR: δCDCl3 1.2-2.2 (m, 141()2.4-2.7
(m, 4H) 3.3-4.3 (m, 4H) 3.90 (s, 68) 5.3-5.4 (m, 2B > 6.55 (d, J=16Hz, 1'H )6
．． 6-1.2 (m, 6B) 7.40 (d, J=I6H2,18>Example 3-
12): Production of 1-(3′4+-dihydroxyphenyl-6-(3″,4″-dimethoxyphenyl)-3-oxo-1-hexene) 1-(3′, 4'-bistetrahydrobyranylogycyphenyl)-6-(3", 4"
-dimethoxyphenyl)-3-oxo-1-hexene 1
00 mg was dissolved in 5 ml of anhydrous methanol, and M
Add medium 1, para-toluenesulfonic acid, and stir at the same temperature.
Stir for an hour. After the reaction, add one drop of triethylamine and concentrate to obtain a crude product. This product was subjected to column chromatography [silica gel/hexane:ethyl acetate=1:
1) to obtain 55 mg of the title compound.

IR: Vmax 3500.16B0.1635
．． 975 c+n-'NMR: δD6-DMSO 1,2-1.6 (m, 2H) 2.4-2.7 (m, 4B) 3.85 (s, 6H) 6,'50 (d, J" 1511z, IH)6
．． 6-1.2' (m, 6H).

7.40 (d, J”15H2, IH) 8.70
(s, In) 9.51 (s, LH) Example 4 The following compound was produced according to the above Example 1-, fll, 1-(21) or Reference Example 1.

・Dimethyl-2-oxo-4-(3″,4″-dimethoxyphenyl)butylphosphonate I R: Vmax 1700.1600.1510
cv-'NMR: δCDCl3 2.5-2.8 (m, 4H) 3.10 ('d, J=24Hz, 2H) 3.80
(d, J-12Hz, 68)3.9 (s,
6) 1) 6.6-7.3 (+n, 38)・1,5-bis(3″,4″-dimethoxyphenyl)-3-oxo-1
-Pentene IR: VIaax 1690.1640.980
cm-'NMR: δCDC: 3 2.5 ~ 2.8 (m, 4H) 3.80 (
s+ 68) 3.90 (s, 68) 6.60 (d, J-IBHz, IN) 6.6
~7.2 (m, 68) 7.48 (d,
J-16Hz, It()・1,5-bis(3'
, 4'-dihydroxyphenyl)-3-oxo-1-pentene I R: Vmax 3500.1680.1640
．． 980 cm-'NMR: δD6-DMSO 2,5-2.8 (m, 4H) 6.53 (d, J=16Hz, IH) 6.6-7
．． 2 (m, 6B) 7.40 (d, J=16H2, IH) 8.60 (
s, IH) Translation 75 (s, IH 9.10 (s, IH) 9.36 (s, Iff) Pharmacological experiment 1 Polymorphonuclear leukocytes collected from guinea pigs were used as an enzyme source, and the enzyme and the enzyme were added to the reaction solution. Arachidonic acid treated with 14C and various aromatic unsaturated ketone derivatives (I) at various concentrations are added and reacted for a certain period of time to convert 14C-arachidonic acid to 5-
5-HETE and leukotriene B synthesized by lipoxygenase were separated by thin layer chromatography, and the enzymatic activity was determined by measuring the counts, and ID5o was determined from the enzyme activity inhibition curve. The results are shown in FIG.

Toxicity experiment Regarding the toxicity of the compounds of the present invention to mice, the LDso value is 100 mg/kg or more when administered orally, which is extremely large compared to the administered dose, and the compounds have a wide safety margin.

As described above, aromatic unsaturated ketone derivatives (I) have a boxygenase inhibitory effect and inhibit leukotriene and 5-HETE synthesis in vivo in mammals such as humans, horses, dogs, guinea pigs, mice, and runts. It is considered to be useful as a therapeutic/preventive agent for allergies, asthma, inflammation, etc.

The aromatic unsaturated ketone derivative (.I) is administered orally or parenterally in the form of a pharmaceutical formulation with a suitable and conventional pharmaceutically acceptable carrier.

Pharmaceutical formulations may take conventional forms such as tablets, capsules, powders, half-seals, injections and the like.

For example, when the aromatic unsaturated ketone derivative (1) is orally administered, it is usually administered at a dose of 10 to 300 mg once or several times a day, depending on the age, weight, and/or severity of the medical condition to be treated. Dosage may vary depending on response to treatment.

Pharmaceutical formulation example 1 Compound (1), compound (2) or compound +31 5
0mg Magnesium Stearate 50m'
g Lactose 50 mg Each of the above ingredients was blended to obtain a tablet weighing 150 mg.

[Brief explanation of drawings]

FIG. 1 is a graph showing the enzyme activity inhibitory effect of aromatic unsaturated ketone derivative (I) on 5-lipoxygenase. Procedural amendment (own ship ■, Indication of the case 1982 Patent Application No. 133496 2, Name of the invention Aromatic unsaturated ketone derivative 3, Amendment 1 Relationship to the case Name of the patent originator (name) Co., Ltd. -, )rijuji 4, agent
■541 Address 4-53-3 Hirano-cho, Higashi-ku, Osaka-shi Ni Life Hirano-cho 406 Telephone (06) 227-1156 "Detailed Description of the Invention" column of the specification, Contents of 66 Amendment (1) Specification No. Page 3, 3rd line from the bottom, change “3 to 7” to “1”
Corrected to 7. (2) On page 4 of the same book, in the second line from the bottom, change “-70℃” to “-
Corrected to 80℃. (3) Corrected to the formula % formula % on page 5 of the same book. , (4) Correct the formula % formula % () on page 5 of the same book. (5) Delete "or so J" on page 5 of the same book, line 8 from the bottom. (6) Delete [δCDCl3 J on page 7 of the same book, line 4 from the bottom.
will be corrected to "δCDC13Ds -DMSOJ. (7) We will submit a power of attorney as shown in the attached sheet. 7. Attached documents ill Power of attorney 1 or more copies

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. (provided that when R is a hydrogen atom, m is an integer from 1 to 7, n is 2 or 3, and X is an adjacent hydroxyl group or lower alkoxy group). Ketone derivatives.