JPS63185970A - 2h-1,4-benzoxazin-3(4h)-one derivative - Google Patents

Abstract

NEW MATERIAL:A 2H-1,4-benzoxazin-3(4H)-one derivative shown by formula I (R<1> is 3-iodo-2-propynyloxy or 3-iodo-2-propynyl; R<2> is H, halogen, lower alkyl, acyloxy or NO2). EXAMPLE:4-(3-Iodo-2-propynyloxy)-2H-1,4-benzoxazin-3(4H)-one. USE:An antifungal agent showing extremely strong antifungal activity effective for treating and preventing superficial mycosis. PREPARATION:A compound shown by formula II is reacted with 3-bromo-1- iodo-propyne or a compound shown by formula III is reacted with iodine in the presence of a base to give a compound shown by formula I (Ia, Ib).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides 2H-1,4-benzoxazine-3 ( 4H)-one derivatives.

[Conventional technology]

Herobrodin with 3-iodo-2-propynyl group (
The compound represented by the following structural formula) has strong antifungal activity and is used clinically as a treatment for athlete's foot.

[Problem that the invention attempts to solve]

The present inventors synthesized various compounds having a 3-iodo-2-propynyl group and investigated their antifungal activity, and found a series of compounds exhibiting higher activity than the above-mentioned haloprozin, and completed the present invention. did.

[Means and effects for solving the problems] The present invention has the following features:
It relates to a compound represented by the following general formula (1).

(2) [In the formula, R1 represents a 3-iodo-2-propynyloxy group or a 3-iodo-2-propynyl group.

R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, an acyloxy group or a nitro group. ] In general formula (1), Rz specifically includes a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group,
Propyl group, isopropyl group, butyl group, isobutyl 5
．． 5ee-butyl group, tert-butyl group, acetyloxy group, propionyloxy group, benzoyloxy group,
Examples include four Nido groups.

The compounds of the present invention can be easily produced by the methods shown in [Reaction Formulas-1 and 2] below.

[Reaction formula-1] ([][1,) In formula C, R1 has the same meaning as above. ] That is, the compound of the present invention [■,] is a compound (3-bromo-1-
Iodo-1-propyne [Journal of the American Chemical Society 4 (Journal o
f the llwerican chemical
5ociety), 77 @, 176 (195
5) It can be produced by reacting . This reaction is carried out in the presence of a base in a solvent. Examples of solvents used in this reaction include tetrahydrofuran,
Dioxane, acetonitrile, N,N-dimethylformamide, etc. are preferable, and as the base, for example, water,
Inorganic bases such as potassium oxide, sodium hydroxide, sodium hydride and the like are preferred.

This reaction is preferably carried out at -10 to 100°C, particularly from 0°C to room temperature, with a reaction time of 5 minutes to 10 hours, preferably 5 minutes to 2 hours. Compound [II] and 3-bromo-1
Regarding the usage ratio of -iodo-1-propyne, the latter is usually used in a molar range of 1 to 1.5 times that of the former.

(Reaction formula-2) (11 [] [b'1 [in the formula,
"R2 has the same meaning as above." Furthermore, the above-mentioned compound (Ib) of the present invention can be produced by reacting compound ([1) with iodine in the presence of a base.

Examples of the base include inorganic bases such as potassium hydroxide and sodium hydroxide. The reaction is usually carried out in a mixed solvent of alcohol and water. Examples of the alcohol used include methanol, ethanol, propatool, etc. The reaction temperature is 0 to 50°C, preferably θ°C to room temperature, and the reaction time is 2 to 24 hours, but preferably It is 2 to 12 hours. Compound(
Regarding the proportion of III) and iodine, it is preferable to use 1 to 1.5 times the mole of the former, preferably equimolar moles of the latter.

The compound (II) of [Reaction formula-1] can be prepared, for example, by using an 0-ditrophenol derivative having a substituent R2 (same meaning as above) on the benzene nucleus and ethyl bromoacetate as raw materials, and converting honkanene ( Methods such as acta, chemical forces, and Scandinavian forces (8 acta Ch.
emica 5candinavica)+14
roll.

1214 (1960)).

Moreover, the compound (III) of [Reaction formula-2] can be easily produced according to the following reaction formula.

(m' (V) (III
) [In the formula, R1 has the same meaning as above. ] Compound (IV
) with chloroacetyl chloride is described in JP-A-49-125.
The reaction between compound (V) and 3-bromopropyne may be carried out under the same conditions as described in [Reaction Formula-1] above.

The compound (1) of the present invention exhibits a strong antifungal effect and is particularly effective against superficial mycoses. Therefore, it is usually used in the form of external preparations such as ointments, jellies, creams, powders, solutions, emulsions, or sprays. There is no particular difficulty in formulating these formulations, and they can be formulated according to known methods using excipients suitable for each. Preferred excipients include ointments, jelly formulations, and creams. In the case of pharmaceuticals, animal fats and vegetable fats.

Wax, paraffin, R powder tragacanth, cellulose derivatives, polyethylene glycol, silicone.

Examples include bentonite, silica, talc, zinc oxide, etc., and in the case of powders and sprays, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, chlorofluorohydrocarbon as a propellant base, etc. In the case of solutions and emulsions, water, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol.

N,N-dimethylformamide, cottonseed oil, bed bean oil, corn oil, olive oil, glycerin.

Glycerin formal, polyethylene glycol.

Examples include fatty acid esters of sorbitol.

The concentration of the compound (1) of the present invention in the preparation is 0. A range of 1 to 5% by weight is preferred.

[Example 1] 4-hydroxy-211-1,4-benzoxazine-
5.3 g of 3(4H)-one and 2.1 g of e-potassium hydroxide
was added to N,N-dimethylformamide 64-, stirred well, and 3-bromo-1=iodo-1- was added to N,N-dimethylformamide 64-.
9.4 g of propyne was added dropwise. After stirring at room temperature for 2 hours,
- The solvent was distilled off under reduced pressure. Water was added to the resulting residue, the precipitated crystals were collected by filtration, and recrystallized from chloroform-petroleum ether to give 4-(3-iodo-2-propynyloxy).
5.2 g (yield 49%) of -2H-1,4-benzoxazin-3(4H)-one was obtained. Melting point 122-123℃
.

Elemental analysis: Theoretical value as C++Hs lNOs (
χ): C, 40, 15i 11.2.45; N
, 4.26 Actual value (χ): C, 40, 58i H
,2,70; N, 4.03I Ru Q9” cv
*-': 2180 (C=C), 1665 (C-0
)NMR(DMSO-di)δ: 4.75 (2
H, s, 0-CHz-GO).

4.95 (2H,s,o-CHg-Cs*C)+6
．． 96~7.30 (4tl, *, Ar-omatic
-H) Mass (m/z): 329 (M”) [Example 2] 3.7 g of 8-chloro-4-hydroxy-28-1,4-benzoxazin-3(4H)-one and 3-bromine -1
-Iodo-1-propyne (5.4 g) was reacted in the same manner as in Example 1, and treated with 8-chloro-4-(3-iodo-2-propylene).
4.5 g (yield: 74%) of -propynyloxy)-2H-1,4-benzoxazin-3(4H)-one was obtained. Melting point: 148-150°C.

Elemental analysis: C++H? Theoretical value (χ) for CI I NOx: C, 36,34; H, 1,97; N
, 3.85 Actual value (χ): C, 36, 39; H
, 1,99;
-': 2180 (C=C), 1680 (C-
0)NMR([1M5O-di)δ: 4.90
(2H,s,0-C11t-Co).

4.97 (2H,3,0-CI+!-C=C), 7
．． 20-7. '30 (3H, n+, ^r-omati
c-II) Mass (m/z): 363 (M”) [Example 3] 30 g of 4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one in 320 sd of methanol
and 5N hydroxide) was suspended in a mixed solution of 32% of an aqueous solution of iodine, and 4067 g of iodine was added thereto while stirring while cooling with water. Thereafter, the mixture was stirred at room temperature for 12 hours.

The reaction solution was poured into water and extracted with chloroform. The extract was washed with an aqueous sodium thiosulfate solution, dried, and then the solvent was distilled off. The obtained crystals were separated from chloroform-petroleum ether.
Recrystallize to give 4-(3-iodo-2-propynyl)-2H
-1,4-benzoxazin-3(4H)-one 20.
9 g (yield 42%) was obtained. Melting point 166-171℃,' Elemental analysis: C++Hs t Not theoretical value (χ): C, 42,20i H, 2゜58; N
, 4.47 Actual value (χ): C, 42,03, H,
2,6B, N, 4.27I Rv:gQ"c+
w-': 2180 (CmiC), 1655 (C=
O)NMR(DMSO-da)δ: 4.63
(2H,s,0-CHt-CO).

4.80 (211,s, O-C0-C1lmiC)1
6.96~7.28 (48, m, 8 r-omati
c-H) Mas s (m/z): 3 13
(M') [Examples 4 to 15] The corresponding raw material compounds were treated in the same manner as in Example 3 to obtain the following compounds.

[Reference Example 1] (a) O- to N,N-dimethylformamide 400ad
Nitrophenol 69.5g, ethyl bromoacetate 125g
g and 104 g of potassium carbonate were added thereto, stirred at 80° C. for 2 hours, and then cooled. After filtering off the insoluble matter, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After washing the extract with water and drying, the solvent was distilled off and further vacuum distilled to obtain 96 g of ethyl 0-nitrophenoxyacetate (yield: 85%).

Boiling point: 145-146°C, 10.3 mmHg.

(b) 22.5 g of ethyl o-nitrophenoxyacetate, 100 g of ethanol, and 15.2 g of zinc powder were mixed, and 20 g of an aqueous solution containing 6.2 g of ammonium chloride was added dropwise while stirring at room temperature. After stirring for 3 hours, 200 ml of 2.4N hydrochloric acid was added dropwise while cooling with water. Insoluble materials were collected by filtration and recrystallized from ethanol to give 4-hydroxy-2H.
-1,4-benzoxazin-3(4H)-one 6.2
g (yield 38%) was obtained. Melting point 168-171°C.

[Reference Example 2] Using 6-chloro-2-nitrophenol and ethyl bromoacetate as raw materials, the same procedure as in Reference Example 1 was used to obtain 8-
Chlor-4-hydroxy-2H-1,4-benzoxazin-3(4H)-one was obtained with a yield of 58%. Melting point 2
23-225°C.

[Reference Example 3] To a mixed solution of (a) 1 g of o-aminophenol, 15.5 g of ethylamine, and 500 g of ethyl acetate, 11.3 g of chloroacetyl chloride was added dropwise under water cooling. After stirring at room temperature for 2 hours, the reaction solution was washed with water and the solvent was distilled off. A 0.3N aqueous sodium hydroxide solution 5 (lad) was added to the residue, heated and melted at 80°C, and the precipitated crystals were recrystallized from benzene to give 2H-1,4-benzoxazine-3.
5.6 g (yield 38%) of (4H)-one was obtained. Melting point: 177-178°C.

(b) 2H-1,4-benzoxazine-3(4H)-
After stirring a mixture of 4.5 g of onion, 2.0 g of potassium hydroxide, and 60 g of N,N-dimethylformamide at room temperature for 1 hour, 7.1 g of 3-bromopropyne was added dropwise while cooling with water. The mixture was further stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. Water was added to the resulting residue, and the precipitated crystals were collected by filtration. N, N
Recrystallization from -dimethylformamide-isopropyl ether gave 2.1 g of 4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (yield: 37
%) was obtained. Melting point 123-125°C.

[Reference Examples 4 to 15] The corresponding raw material compounds were treated in the same manner as in Reference Example 3 to obtain the following compounds.

Table 2 cHzc=cH [Formulation example] Compound of Example 1 2.0g white petrolatum 25.0g stearyl alcohol
25.0g Propylene glycol 12.0
g Sodium lauryl sulfate 1.5 g Ethyl oxybenzoate 0.5 g Further, add deionized water to bring the total amount to 100.0 g.

The above mixture was uniformly mixed according to a conventional method to prepare a cream.

[Biological test]

(1) Measurement of Minimum Inhibitory Concentration (MIC) for Various Fungi Using Sabouraud dextrose medium, MIC was determined by the agar plate dilution method according to the standard method of the Japanese Society of Chemotherapy (revised in 1980). The results are shown in Table 3.

Table 3 MIC (μg/-) a) (1): Candida albicans (Candida albicans)
albicans) I F O1060, (II
): Candida tropicalis (Candida t
ropicalis) IFO1633, (III)
j) Trichophyton Rubrum (Trichoph)
yton rubru+w) TR-37, (m:
Arthroderma pambrosegemie (Arthrod)
ersa vanbreuseghes+ii) S
M 7420, (V): Micro-sporum cants SM
8333 As b) Not tested.

(2) Acute toxicity test The test compound was suspended in 0.5% carboxymethyl cellulose solution, and DDY male mice weighing 20-25 g (1
The 50% lethal dose (LDs.) was calculated from the cumulative mortality rate for 7 days after administration. 4th result
Shown in the table.

Table 4 (Effects of the Invention) The compounds of the present invention showed excellent activity in MIC measurement experiments against various fungi, and were also confirmed to have low toxicity in animal experiments.

The compound of the present invention is characterized by excellent effects as an anti-depressant drug.

Claims (3)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R^1 represents a 3-iodo-2-propynyloxy group or a 3-iodo-2-propynyl group. R^2 represents a hydrogen atom, a halogen atom, a lower alkyl group, an acyloxy group, or a nitro group. ] 2H-
1,4-benzoxanth-3(4H)-one derivative. (2) In the general formula [I], R^1 is 3-iodo-
Claim 1 represented by 2-propynyloxy group
Compounds described in Section. (3) In the general formula [I], R^1 is 3-iodo-
The compound according to claim 1, which is represented by a 2-propynyl group.