JPS6133138A - Naphthoquinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R1 is H or lower alkyl; R2 is H, lower alkenyl, phenyl lower alkyl or alkyl which may have OH). EXAMPLE:2(1-Hydroxyethyl)-5,8-dimethoxy-1,4-naphthoquinone. USE:An anti-inflammatory and analgesic agent, remedy for cardiopathy, antiallergic agent, antithrombotic agent, antitumor agent and antimicrobial agent. PREPARATION:(i) A compound expressed by formula II is subjected to the Grignard reaction to give a compound expressed by formula III (R3 is lower alkenyl, phenyl lower alkyl or alkyl), which is then oxidized. (ii) Alternatively, the compound expressed by formula II is reacted with a Grignard reagent prepared from magnesium and a benzyloxyalkyl halide, and the resultant compound expressed by formula IV (R4 is benzyloxyalkyl) is catalytically reduced, debenzylated and further oxidized to afford the aimed compound expressed by formula I (R2 is other than H).

Description

[Detailed description of the invention] Technical field TECHNICAL FIELD The present invention relates to naphthobovine derivatives.

Structure of the Invention The naphthogynoone derivative of the present invention is a novel compound that has not been described in any literature and is represented by the following general formula (1).

[In the formula, R represents a hydrogen atom or a lower alkyl group, and R2 represents a hydrogen atom, a lower alkenyl group, a phenyl lower alkyl group, or an alkyl group that may have a hydroxyl group as a substituent. ] The compound of the present invention represented by the above general formula (1) has anti-inflammatory action, anti-complement action, anti-hypertensive action, heart disease treatment action, anti-allele f- action, platelet aggregation inhibiting action, anti-tumor action, and antibacterial action. It is useful as an anti-inflammatory analgesic, an antihypertensive agent, a heart disease treatment agent, an antiallergic agent, an antithrombotic agent, an antitumor agent, and an antibacterial agent.

In the above general formula (1), the lower alkyl group is:
Examples include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, pyl, isobutyl, butyl, isobutyl, 5lit-butyl, and fttrt-butyl.

Lower alkenyl groups include 1, such as vinyl, allyl, 2
-butenyl, 3-dithenyl, l-methyl-2-'10benyl, 2-besitenyl, 2-to+ttenyl has 2 to 2 carbon atoms
The alkenyl group of 6 can be exemplified.

Examples of the phenyl lower alkyl group include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylbutyl, and phenylsil groups.

Examples of the alkyl group that may have a hydroxyl group as a substituent include unsubstituted alkyl groups having 1 to 20 carbon atoms including the lower alkyl groups mentioned above, such as the lower alkyl groups listed above, pentyl, Beef sil, octyl, nonyl, decyl,
boucidecyl, dodecyl, tetradecyl, he+sadicyl,
Octadecyl eicosyl group, etc. and e.g. Shido0+dimethyl, 2-Hydrobodiethyl, 3-Human0+Sib0pil,
2-dipropyl, 2-hydro-methylethyl, 4-human O+diptyl, 1.4-; human 0
Examples of the above-mentioned alkyl groups having 1 to 2 hydroxyl groups include bovine cystyl, 6-hydrocytyl, and 9-human O+dinonyl.

The compound represented by the above general formula (+) of the present invention can be produced, for example, by the method shown in the following reaction scheme.

Reaction scheme-1 (A) (B) (1a
) [R□ in each formula is the same as above. R3 is a lower alkenyl group,
Represents a phenyl lower alkyl group or an alkyl group. ] According to Reaction Scheme-1, the compound of general formula (B) is obtained by the Chrynisale reaction of the compound of general formula (A>), and then this is oxidized to obtain the compound of general formula (1-a). Invention compounds can be obtained.

The Chrynisale reaction of the compound of the above general formula (, 4) can be carried out according to a conventional method. That is, the reaction is carried out using Chrynisale reagent in a suitable solvent at a temperature of about -20 to 60°C, preferably about 0 to 25°C, and 1 mole of lu+lu or lower alkenyl halogenide and a secondary halide are prepared. About 1.
It can be easily prepared from 1 to 1.2 times the molar amount of magnesium. As the solvent, ordinary ether, tetrahydrofuran, etc. can be used. The amount of the Klinyard reagent used is usually equivalent to 5 times the molar amount of the compound of the general formula (4), preferably the amount that the solvent solution of the compound of the general formula (4) is originally present. The amount at which the yellow color disappears is preferably about 7 to 4 times the molar amount.

The oxidation reaction of the compound of general formula (B) thus obtained is as follows:
For example, Seritzk ammonium nidrad [υ/7/4
)2Ce (No. 3 )6, hereinafter referred to as "CAN"] or a method using AgO in dilute nitric acid. The method using the above CAM is carried out in more detail, for example, in a solvent such as dioxane, acetonitrile, tetrahydrofurazine, dichloromethane, lyoform, ether, etc., based on the equivalent mole of the compound of general formula (B). Using about 5 times the mole, preferably about 2 to 2.5 times the mole of CAM, the temperature is about -20 to 60°C, preferably about 0 to 0.
The test is carried out at 30°C. In addition, the oxidation reaction using Ago in dilute nitric acid can be carried out, for example, in a solvent such as acetoxy, dioxane, tetrahydrofradi, ether, etc.
- The boiling point of the solvent, preferably 0 to 60°C.

In this way, the compound of the present invention of general formula (1-a) can be obtained. In addition, in the method shown in the above reaction scheme-1, the general formula (1
-a) The compound of general formula (7?) used as a synthetic intermediate is:
It is itself a useful compound with various pharmacological activities.

Reaction scheme-2 (A) (C) (D) (lb) [In the formula, R□ is the same as above. R4 is benzyl + sial +
The group and RI represent a human 0+sialic group. According to Reaction Scheme-2, the compound of the present invention of general formula (1b) [general formula (1,) where R2 is an alkyl group having a hydroxyl group as a substituent] is produced. That is, the compound of the general formula (,4) is reacted with a Krinillard reagent prepared from matanesium and a ruhalide in besidyl oxide in the same manner as the Krinillard reaction shown in Reaction Scheme-1 to obtain the compound of the general formula (,4). A compound of C) is obtained, which is then subjected to catalytic reduction and debesidylation reaction to obtain a compound of general formula CD>, and the compound of general formula (D) is then converted into the same compound as shown in Reaction Scheme-1. By subjecting it to an oxidation reaction, the desired general formula Ca
Compound b') is obtained.

The above catalytic reduction reaction (debesidylation reaction) is carried out in accordance with a conventional method using a conventional catalyst such as palladium carposi, pto2, Raney nickel, alcohol, ethyl acetate, N
, N-dimethylformamide, in a solvent such as ether,
This is carried out by adding hydrogen under normal pressure to 3 atmospheres.

Reaction Scheme-3 (A') (E)OR; 0 (lc) [In the formula, R1 represents a lower alkyl group. ]Reaction scheme-3
According to the method, a compound of the present invention [compound of general formula (lc)] in which R2 in general formula (1) is a hydrogen atom is produced.

The reduction reaction of the formyl group of the compound of general formula (A') can be carried out using a conventional reducing agent such as NaBH, Ls 1413%, etc.
Preferably by a conventional method using NaB1ζ, more preferably alcohol, tetrahedral, water, N,
A'-'': The reaction is carried out in a mixed solvent such as methylformamide or the like at about 0 DEG to 30 DEG C.NaBH4 is usually used in an amount of about 1 molar to 2 times the molar amount of the starting compound of general formula (A').

The oxidation reaction of the compound of general formula (E) thus obtained is as follows:
The reaction is carried out in the same manner as shown in Reaction Schemes-1 and -2 above.

Reaction scheme-4 [In the formula, R□ and R2 are the same as above. ] The compound of the present invention of general formula (1) (hyde compound) can be converted into the compound of general formula (F) (hydro compound) by reducing the compound according to a conventional method. This reduction reaction can be carried out using well-known catalysts such as stannous chloride, sodium borohydride, sodium hydride, and sulfide.
This can be carried out in a conventional manner using a catalyst for catalytic hydrogenation. For example, when using stannous chloride, the reaction is carried out at about -20 to 30°C using 5nC-132.2H20 in an amount of 5nC-132.2H20 in a molar amount of 1 to 3 times the amount of compound (1) in an aqueous alcohol acidified with hydrochloric acid. It is done. In the case of sodium borohydride, the reaction is preferably carried out in alcohol with compound (1
) is carried out at about 0 to 30°C using sodium borohydride in an amount of about 1/2 to 3 times the molar amount. In the case of sodium hydrosulfide, it is used in the form of an approximately 10% aqueous solution, and the reaction proceeds in a solvent such as acetate, ether, dioxicate, etc. at a temperature ranging from about 10°C to the boiling point. Furthermore, catalysts for catalytic hydrogenation such as 596 Pd-carbon, PtO
When using 2, etc., the reaction is carried out by hydrogenating them in a solvent such as alcohol, ethyl acetate, dimethylformamide, ether, or sulfate under a pressure of normal pressure to 3 atm using a conventional catalyst. is completed.

In addition, the compound of general formula (7) can be prepared by air oxidation, ferric chloride,
It can be easily oxidized using an oxidizing agent such as silver oxide according to a conventional method to give the compound of the present invention of general formula (1). The above ferric chloride is usually used in the form of an aqueous solution in a molar range of 7 to 20 times the mole of compound (F), and in this case, the reaction is carried out at about 0 to 30°C in a solvent such as tetrahydrofluoride acidified with hydrochloric acid or alcohol. It will be carried out in Further, silver oxide is used in an amount of 7 molar equivalent to 20 times the molar amount of compound (7), and in this case, the reaction is carried out at about 0 to 30°C in a solvent such as ether, acetate, dioxic acid, or tetrahedron.

The target products obtained by each of the above reaction steps can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, and collage. Further, the compounds of the present invention may have optical isomers and geometric isomers, and such isomers are also included within the scope of the present invention.

EXAMPLES Hereinafter, production examples of raw material compounds for producing the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples.

Reference Example 1 Production of 1.4.5.8-tetramethoxy2-naphthalene 2-naphthalene 1.4.5f of 8-tetramethoxy2-naphthalene carboaldihyde was added to 7Qml of ethanol and Dissolved in Tetrahuman 0F35P and cooled on ice with NaBH41f.
Add gradually. After continuing to stir for 30 minutes, the solvent was distilled off, extracted with ethyl acetate, and the solvent was distilled off to obtain a crude product. This is dissolved in dichloromethane, methoxychloride, and IK, and recrystallized by adding hexane to obtain the target compound 4.7f as white crystals.

Melting point 109-110℃ ``H-NMR (CDCe3, TMS) δpp,, =
2.60 (S, IH), :3.88 (8,3H
), 3.90 (S, 37'/), 3.92 (S
, 3H), 3.96 (S, 3H), 4.83
(bs, 2H), 6.80 (8,3H), 6.9
0 (S, iH) Reference example 2 2-(4-besidyl group-human 0+side group)
-Production of sinaphthalene in 1,4,5,8-tetrameth 1.4.5.8-Tetrameth, 2-naphthalene carbide 5f is dissolved in tetramethane, 0fura:/100d, and this solution is Magnesium 1.3f, 3-be, 7.
; Klinyard reagent prepared from 12.5F pyrubromide and 12.5F ether was slowly added under water cooling. After continued stirring for 10 minutes, the reaction solution was transferred to a saturated aqueous acinanium chloride solution and extracted with ethyl acetate. The crude product obtained by drying and concentrating the organic layer was subjected to silica gel chromatography (developing solvent: ethyl acetate: n-
Purification was carried out using a 3:'4) method to obtain 6.659 (86) of the target compound as an oil.

"H-NMR (CDCe3, TMS) δpp ae 7.30 (s, 5H), 7.00 (S
, lH), 6.77 (8,2H), 5.21 Cm,
IH), 4.50 (S, 2[), 3-90 (s
, 6H), 3.85 (s, 3H), 3.70
(s, 3H), 3.53 (t, J=5.7H
z, 2H), 3-28Cd, J=3.5Hz
, 1#), 1.6-2.1 (m, 4H) Reference example 3 2-(1,4-,; human 0 bovine diptyl) -1,4,5
, 8-Tetramethocinaphthalene Compound 6.50f obtained in Reference Example 2 was mixed with ethyl acetate.

The product was dissolved in a mixed solvent of 180 g of dimethylformamide and 50 g of dimethylformamide, 100 g of 5-thipalladium on carbon was added thereto, and hydrogenated at room temperature and pressure for 24 hours.

After filtering the reaction solution, it was concentrated and treated with silica talc 0.0% silica (developing solvent: chloroform:methanol = 20:1).
Purification was performed to obtain the target compound 3.95F (77%) as white crystals.

Melting point 113-118℃ H-NMR (CDCe3, TMS) ?-00 (s, IH>, 6.80 (s, 2H
), 5.21 Cm, IH), 3-91 (s,
6H), 3-87 Cs, 3H), 3.71 (
s, 3H), 3-67 (t, J=4.7Hz
, 2H"), 3, 1 (brs, , IH),
2.1 (brs-, I H>, 1.6~2.0 (m
, 4H) Example 1 Production of 2-(l-human 0+diethyl)-5,8-dimethoxy, 1,4-naphthalene and 2-naphthalene (1) Dissolve 3t of carbaldide in 50m of THE,
Clinillard's reagent prepared with 4.25 f of methyl iodide, 750,119 mcnesium and 35 mA' of ethyl ether was slowly added to this solution under water cooling.

After continuing to stir for 10 minutes, the reaction solution was transferred to a saturated aqueous solution and extracted with ethyl acetate. The crude product obtained by drying and concentrating the organic layer was mixed with silica talc 0.
Developing solvent ether:n-to+sashi-2:l~3:l)
2-(l-human 0+diethyl") -1
,4,5,8-titrameth+sinaphthalene 2.60fC
B2%) is obtained as white crystals.

(2) Dissolve 2.60 t of the compound obtained in (1) above in 720 tnl of dichloromethane, add a solution prepared by dissolving sesilisquasimonium nitrate CCAN) 121 in 20 mJ of water, and vigorously stir at room temperature for 5 minutes. Stir. The reaction solution was extracted with dichloromethane, the organic layer was dried, and after concentration, silica gel column chromatography (developing solvent: 00 form: ethyl acetate: methanol - 10:1 o:t
) to obtain the target compound 1.18r. The physical properties of this product are shown in Table 1 below.

Using appropriate starting materials, the compounds of Examples 4 to 8 and 12 to 14 shown in Table 1 below are obtained in the same manner as above.

Example 2 2-(1,4-,:hydro+cydutyl')-5,8
- Jishido 0 Beef Sea 1.4 - Nando + Noshi Production Reference Example 3
Compound 3.58f was dissolved in 30 ml of Zigolmetase,
Into this solution was added sericac7inium: )5-t (CA
M) Add a solution of 16.1 tt dissolved in 3 C1 t of water and stir vigorously for 5 minutes at room temperature.

Extract the reaction solution with a jig filter, dry the organic layer,
After concentration, silica gel chromatography (developing solvent chloroform: ethyl acetate: methanol = 10:10:1
) K and purified 1r target compound 150W (4.7%
). The physical properties of this product are shown in Table 1.

Examples shown in Table 1 in the same manner as above using appropriate starting materials! , 9, io and l! Get a variety of products.

Example 3 2-Shidoro beef dimethyl-5.8-dimeth + sea 1.4-
Manufacture of Naphthonomin “6 liters of the compound of Reference Example 1 and 12 tons of silver oxide were mixed with 1 ton of dioxane.
24 m/6N nitric acid was slowly added to the suspended solution at room temperature. After stirring for 15 minutes, transfer to water and extract with a jig filter. After drying and concentrating the organic layer, the crude product was dissolved in silica talc 0.
Purification with ether:n-to-cow-soak-1:1 to 2:1 and then ethyl acetate) yielded 2.5 y (47%) of the target compound.
is obtained as red-yellow crystals. The physical properties of this product are shown in Table 1.

The compound of Example 2 can be obtained by the same operation as above.

Examples 4 to 14 Each compound shown in Table 1 below is obtained in the same manner as in any of Examples 1 to 3 above.

Table 1

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a hydrogen atom or a lower alkyl group, and R_2
represents a hydrogen atom, a lower alkenyl group, a phenyl lower alkyl group, or an alkyl group that may have a hydroxyl group as a substituent. ] A naphthoquinone derivative represented by