JPS61189272A - Imidazole derivative - Google Patents

Abstract

NEW MATERIAL:The imidazole derivative of formula I [R<1> and R<2> are nitrile, CO2R<3> (R<3> is lower alkyl) or CONHR<4> (R<4> is H or beta-hydroxyethyl); n is 0, 1 or 2]. EXAMPLE:2-(1-Methyl-2-methylthio-5-imidazolyl)methylidenemalononitrile. USE:A radiation sensitizer to promote the radiotherapeutic effect to cancer. It has low toxicity and improved sensitizing effect. The activity is improved by the introduction of methylthio group, methylsulfinyl group or methylsulfonyl group to the 2-C atom of imidazole ring, and electron attractive group to the 5-C atom. PREPARATION:The compound of formula I can be produced by the Knoevenagel reaction of the novel aldehyde compound of formula II with active methylene compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel imidazole derivative, and more particularly to a novel vinylimidazole derivative having a radiosensitizing effect in radiotherapy for cancer.

BACKGROUND OF THE INVENTION Hypoxic tumor cells with low radiation sensitivity are present in tumors, and how to deal with these cells is one of the major problems in radiotherapy.

Imidazole derivatives are widely used as antiparasitic agents and antibacterial agents, but they are also used as radiosensitizers to enhance the effects of cancer radiotherapy. Several are known, such as Propatool [misonidazole].

Problems to be Solved by the Invention Conventional radiosensitizers are still far from satisfactory in terms of efficacy and toxicity, and even misonidazole
Although sensitization is 15 to 23 times greater than when irradiated with radiation alone, there is a limit to the amount that can be used in humans, as exceeding a certain amount is toxic to the peripheral nervous system. Currently, new radiosensitizers with less toxicity and greater sensitizing action are desired.

Means for Solving the Problems The present inventor introduced a methylthio group, a methylsulfinyl group, or a methylsulfonyl group into the 2nd carbon position of the imidazole ring, and by introducing an electron-withdrawing vinyl group into the 5th carbon position. The present invention was completed by discovering that a new vinylimidazole derivative having higher activity than minonidazole can be obtained.

The present invention is based on the general formula (1), [wherein R and R represent a nitrile group, C02R"i or 0ONI (R'), and R3 represents a lower argyl group,
Desire represents a hydrogen atom or a β-hydroxyethyl group, and n
indicates 0,1 sun or 2. ] (hereinafter referred to as the compound of the present invention).

In the compound of the present invention, the group represented by the formula H3S-↓(O)n is a methylthio group, a methylsulfinyl group, or a methylsulfonyl group.

The compound of the present invention is produced by the Knoevenagel reaction between a novel altehyde compound represented by formula (2) (hereinafter referred to as an altehyde compound) and a known active methylene compound represented by formula (3), as shown in reaction formula 1 below. (in the formula B1. B2 and n have the same meanings as above).

(0)n(0)n Reaction conditions such as reaction solvent and catalyst can be applied to general Nebenadel reaction conditions (G, Jones).

○rganic Reaction, +5.204
(1967), W.

Leh, nert, Tetrahedron Let
ters, 1970.4723).

Artecht compound is the known 5-methquine carbonyl-1
-Methyl-2-methylthioimidazole.

That is, 5-methoxycarbonyl-1-methyl-2-
Methylthioimidazole is reduced with a metal hydride such as lithium aluminum hydride to give 5-hydroxymethyl-
1-methyl-2-methylthioimidazole is converted, and then the hydroxomethyl group is converted into an aldehyde group using an oxidizing agent such as mancan dioxide. Altehyde compounds whose substituent at carbon position 2 is a methylsulfinyl group can be further oxidized with an oxidizing agent such as sodium metaperiodate, and altehyde compounds whose substituent at carbon position 2 is a methylsulfonyl group can be further oxidized with an oxidizing agent such as sodium metaperiodate. , which can be further oxidized with an oxidizing agent such as sodium metaperiodate or methachloroperbenzoic acid.

On the other hand, the methylsulfinyl group or methylsulfonyl group of the 2-carbon substituent in the compound of the present invention is
-Methylthiovinylimidazole can also be introduced by oxidation in the same manner as above.

51 Examples of the active methylene compound in the present invention include:
Malononitrile, methyl cyanoacetate, ethyl cyanoacetate, 2-cyanoacetamide, 2-noano N-hydroxyethylacetamide, dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate.

Examples include malonic acid di-n-butyl ester, malonic acid diisobutyl ester, malonic acid di-tert-methyl ester, and the like.

Effects of the Invention The imidazole derivative according to the present invention has a strong radiosensitizing effect and is useful as a substance that enhances the effect of radiotherapy for cancer.

EXAMPLES Next, the present invention will be explained in more detail by reference examples, examples, and test examples.

Reference Example 1 Production of 5-hydroxymethyl-1-methyl-2-methyl6-lthioimidazole 5#l Quinocarbonyl-1-methyl-2-methylthioimidazole 10.39 f (55.9 mmot)
To 200 ml of an ether solution was added 1.06 g (28 mmo7) of lithium aluminum hydride at room temperature four times, and the mixture was stirred for 20 minutes. Add the reaction solution to 50% of Rosselle's salt.
The crude product obtained by addition to 2 tons of aqueous solution and extraction with ethyl acetate was recrystallized from ether-petroleum ether to obtain colorless needle crystals 516y (yield: 924%).

m, p, 85-86℃ Elemental analysis C! Theoretical value (%) as 6H, oN20S
C; 45.55 H; 6.37 1,1; 17.7
1 Actual value (%) C; 45.72 H: 6.22
N; 17.87 Reference Example 2 Production of 5-formyl-1-methyl-2-methylthioimidazole 5-hydroquinomethyl-1-methyl-2-methylthioimidazole 7.87 f/ (49.8 mmot).

300 ml chloroform and 66f manganese dioxide
A mixture of 1 (0,727 mot) was heated under reflux for 15 min. After cooling, the manganese dioxide was filtered off and the chloroform was distilled off under reduced pressure. The crude product obtained was recrystallized from ether-petroleum ether to give 748 g of colorless needle crystals (yield: 9
63%).

m, p, 63-64°C Elemental analysis Theoretical value (%) as C6H3N20S C: 4614 H; 5.16 N;
17.93 Actual value (%) C: 46.52 H; 5
19 N; 18.08 Reference Example 3 Production of 5-formyl-1-methyl-2-methylsulfinylimidazole 5-formyl-1-methyl-2-methylthioimidazole 7,48 f/ (47,9 mmot), water 6C1
ml and 95.8 ml (47.9 mmot) of a 0.5 M aqueous sodium metaperiodate solution were reacted at room temperature for 235 hours. After water was distilled off under reduced pressure, the crystals were washed with methylene chloride, and the crude product obtained by distilling off methylene chloride under reduced pressure was subjected to column chromatography (silica gel 1
70 f, benzene, acetone - purified with 9723), recrystallized from ether-petroleum ether, colorless needle crystals 7
．． 96y (yield 966%) was obtained.

m, p, 74-755°C Elemental analysis Theoretical value (%) as C6H3N202S O: 41.85 H: 4.68
N: 16.27 Actual value (%) C; 42.15 H
;4.72 N:16.26 Reference Example 4 Production of 5-formyl-1-methyl-2-methylsulfonylimidazole 5-formyl-1-methyl-2-methylsulfinylimidazole 3.44 f/ (20 mmot), water A mixture of 10 me and 0.5 M (4 degrees metaperiodic acid) .lium aqueous solution 80 me (40 mmot) was heated under reflux for 10 hours. After cooling, Reference Example 3
3.30 y of colorless needle crystals (yield: 8
78%).

m, p, 119.5-121°C Elemental analysis Theoretical value (%) as C6H3N203s C; 38.29 H; 4.28
N: 14.88 actual value (%) O: 38.67 H;
4.25 N; 14.98 Example 1 Production of 2-(1-methyl-2-methylthio-5-imidazolyl)methylidenemalononitrile 5-formyl-1-
Methyl-2-methylthioimidazole 312 mg (
2,0mmo7), malononitrile 145 mf
A mixture of 1 (2,2 mmot) and 10 ml of water was heated under reflux for 20 minutes. After cooling, the crystals were separated from P and recrystallized from hexane-ethyl acetate to give 400 yellow needle-shaped crystals.
mq (yield 98.0%) was obtained.

m, p, 208-209℃ Elemental analysis Theoretical value (%) as C9H3N4S O; 52.93 H; 3.95
N; 2743 actual value (%) C; 53.01 H;
4.13 N; 27.74 Example 2 Using 5-formyl-1-methyl-102-2-methylsulfinylimidazole in place of 5-formyl-1-methyl-2-methylthioimidazole, Example 1
2-(1-methyl-2-methylsulfinyl-5-imidazolyl)methylidenemalononi l-I
I got J. Pale yellow needle crystals (recrystallized from hexane-ethyl acetate) m, p, 158.5-160°C Yield 926% Elemental analysis Theoretical value as C9H3N40S (%) O: 49.08 H: 5.66
N: 25.44 Actual value (%) C: 49.21 H
;3.81 N;25.54 Example 3 Treated in the same manner as in Example 1, using 5-formyl-1-methyl-2-methylsulfonylimidazole instead of 5-formyl-1-methyl-2-methylthioimidazole. 2-(1-methyl-2-methylsulfonyl-5-imidazolyl)methylitenemalonitrile was obtained.

Pale yellow needle crystals (recrystallized from hexane-ethyl acetate) m,
p, 183-184℃ Yield 941% Elemental analysis Theoretical value (%) as C9H3N40□S C: 45.76) 3.41
N: 23.72 Actual value (%) C: 45.7B H
; 3.43 N; 23.95 Using 7-anoacetic acid ethyl ester, 2-cyanoacetamide or N-hydroxyethyl-2-cyanoacetamide instead of malononitrile, Example 1, Example 2 or Example 6. The following compound was obtained by the same treatment.

Example 4 2-(1-methyl-2-methylthio-5-imidazolyl) methylidenecyanoacetic acid ethyl ester yellow needle crystals (recrystallized from hexane-ethyl acetate) m, p, 133~
134℃ Yield 896% Elemental analysis Theoretical value as CllHI3N302S (
%) C: 52.57 H; 5.21 N; 16
．． 72 Actual value (%) C; 52.79 H; 5.0
9 N; 17.01 Example 5 2- (1-mey-ru 2-methylsulfinyl-
5-imidazolyl) methylidenecyanoacetic acid ethyl ester pale yellow needle crystals (recrystallized from hexane-ethyl acetate) m,
p, 112.5-114℃ Yield 926% Elemental analysis Theoretical value (%) as 011H13N303S
O; 49.43 H; 4.90 N; 15.7
2 Actual value (%) O; 49.43 H; 4.95
N; 15.88 Example 6 2-(+-methyl-2-methylsulfonyl-5-imidazolyl) methylidenecyanoacetic acid ethyl ester colorless needle crystals (recrystallized from hexane-ethyl acetate) m, p
, 116-117℃ Yield 941% Elemental analysis CllHI3N304S, theoretical value (%
) C: 46.64 H: 4.65 N; 14.
83 Actual value (%) c; 46. ss H; 4.4M
N; 14.93 Example 7 2-(1-methyl-2-methylthio-5-imidazolyl) methylidene-2-cyanoacetamide yellow needles (recrystallized from ethanol) 'm, p, 227-228°C Yield 93.9% Elemental analysis Theoretical value as C9H1oN40S (%)
O; 4864 H; 4.53 N; 25.21 actual value (%) C; 48.53 H: 4.66 N
;25.10 Example 8 2-(1-MeF-2-methylsulfinyl-5-
(imidazolyl) methylidene-2-cyanoacetamide pale yellow needle crystals (recrystallized from ethanol) m, p, 26
4-265℃ Yield 81.1% Elemental analysis Theoretical value as C9H1oN・402S (%
) C; 45.37 H; 4.23 N; 23.
51 Actual value (%) C: 45.48 H; 4.21
N; 23.50 Example 9 2-(1-methyl-2-; l-methylsulfonyl-5-imidazolyl) methylitene-2-7 anoacetate pale yellow needle crystals (recrystallized from ethanol) m, p, 262
~266℃ Yield 931% Elemental analysis Theoretical value (%) as C9H1oN403S
O; 42.51 H; 3.96 N; 22.0
3 Actual value (%) O; 42.55 H; 3.93
N; 21.92 Example 1O N-(2-hydroxyethyl)-2-(+-methyl-2
-Methylthio-5-imidazolyl) methylten-2-ene anoacetamide yellow needle crystals (recrystallized from ethanol) m, p, 199-201°C Yield 391% Elemental analysis CII HI3 Theoretical value (%) as N402S c: 4q61 H; 5.30 N; 21.
04 Actual value (%) O; 49.60 H; 5.25
N; 213s Example 11 N-(2-hydroquinoethyl)-2-(1-methyl-2
-Methylsulfinyl-5-imidazolyl) methylthene-2-7 anoacetamide pale yellow flakes (recrystallized from ethanol) m, p, 464-166°C Yield 62.2% Elemental analysis Theoretical value as C1°H14N403S (%)
) C:46. BOH; 5.00 N; 19.85
Actual value (%) C: 46.86 H; 5.03
N; 1964 Example 12 N-(2-hydroxyethyl)-2-(1-methyl-2
-Methylsulfonyl-5-imidazolyl)methylthene-
2-Anoacetamide pale yellow needle crystals (recrystallized from ethanol) m, p,
180-182℃ Yield 80? % Elemental analysis CIIH] Theoretical value as 4N404S (
%) O; 44.29 H; 4.73 N; 18
．． 78 Actual value (%) O; 44.16 H; 4.7
2 N; 18.73 Example 16 Production of 2-(1-methyl-2-methylthio-5-imidazolyl)methylidenemalonic acid dimethyl ester 5-formyl-1-methyl-2-methylthioimidazole 512 mg (2,0 mmo7 ), dimethyl malonate/l/264 mg (2, Dmmot),
A mixture of 6,8 rq (0,08 mmot) of piperidine, 24 mg (0,4 mmo/: ) of acetic acid and 2 ml of benzene was heated under reflux for 65 hours. After cooling, it was purified by column chromatography (silica gel 152, benzene:acetone-99:1) and recrystallized from hexane-ethyl acetate to give 43 smg of pale yellow needles (
A yield of 81.1%) was obtained.

m, p, 91-92℃ Elemental analysis C11HI4N204B as theoretical value (%
) C; 48.88 H; 5.22 N; 10.
36 Actual value (%) C; 49.15 H; 5.18
N; 10.40 Example 14 Production of 2-(1-methyl-2-methylsulfinyl-5-imidazolyl)methylidenemalonic acid dimethyl ester 2-(1-methyl-2-methylthio-5-imidazolyl)methylidenemalon Acid dimethyl ester 297 mg (
1,1 mmot), 6'rnl of methanol and 33 ml of a 0.5 M aqueous solution of sodium metaperiodate.
1 (1,6s rrmol) was reacted at room temperature for 3 days. After distilling off the solvent under reduced pressure, the crystals were washed with methylene chloride, and the crude product obtained by distilling off methylene chloride under reduced pressure was purified by column chromatography (silica gel 10 g benzene:acetone-97:3) and purified with hexane-acetic acid. Recrystallized from ethyl, 230 μg of colorless needle crystals (yield 73.0
%) was obtained.

m, p, 101.5-1025 ℃ Elemental analysis Theoretical value (%) as CIl■14N205S
0; 46.15 H; 4.93 N; 9.78
Actual value (%) C: 46.27 H: 4.87
N: 9.6B In the same manner as in Example 16 or Example 14, the following compound was obtained.

Example 15 2-(1-methyl-2-methylsulfonyl-5-imidazolyl)methylidenemalonic acid 7 methyl ester colorless needle crystals (recrystallized from hexane-ethyl acetate) m, p
, 113.5-114.5℃ Yield 846% Elemental analysis CII H14N206F” as theoretical value (
%) O; 43.71 H; 4.67 N; 9.
27 Actual value (%) O; 43.82 H; 466
N; 9.04 Example 16 2-(1-methyl-2-methylthio-5-imidazolyl)methylidenemalonic acid diethyl ester pale yellow needles (
ether-recrystallized from petroleum ether) m, p, 38
~695℃ Yield 832% Elemental analysis C1, H18N20
Theoretical value (%) as 4S C; 52.33 H; 6
．． 08 N; 9.39 Actual value (%) C; 52.5
5 H; 6.04 N; 9.33 Example 1゛7 2-(1-Methyl-2-methylsulfinyl-5-imidazolyl) methylatenemalonic acid dimethyl ester Colorless oil Yield 939% Elemental analysis 0] Theory as 3H18N2056t value(%
) C: 49.67 H; 5.77 N; 8.9
+ Actual value (%) C; 49.39 H; 5.79
N; 8.72 Example 18 2-(1-methyl-2-methylsulfonyl-5-imidazolyl)methylidenemalonic acid diethyl ester colorless needle crystals (recrystallized from ether-petroleum ether) m,
p, 52-53℃ Yield 841% Elemental analysis Theoretical value (%) as Cl5H18N206S
O; 47.27 H; 5.49 N; 8.45
Actual value (%) O; 47.54 H; 5.41
N; 8.35 Example 19 2-(1-Methyl-2-methylthio-5-imidazolyl) methylidenemalonic acid di-n-propyl ester Pale yellow clear product Yield 982% Elemental analysis Theoretical value as C15H2□N204S ( J)
C; 55.20 H: 6.79 N; 8.58
Actual value (兇) C; 55.18 H: 6.66
N; 8.41 Example 20 2-(1-Methyl-2-methylsulfinyl-5-imidazolyl)methylitenemalonic acid di-n-propyl ester Colorless oil Yield 980% Elemental analysis Theoretical value (%) as Cl5H22N20□S
O;52. /) 2 H; 6.48 N; 8.1
8 Actual value (%) C! ;52.41 H:6.40
N; 8.00 Example 21 2-(1-Methyl-2-methylsulfonyl-5-imidazolyl)methylidenemalonic acid di-n-propyl ester Colorless oil Yield 90.8% Elemental analysis As Cl5H2□N206S Theoretical value(%)
O; 50.27 H; 6.19 N; 7.82
Actual value (%) O'; 50.41 H; 6.06
N; 7.71 Example 22 2-(1-Methyl-2-methylthio-5-imidazolyl) methylidenemalonic acid diisopropyl ester Pale yellow clear product Yield 752% Elemental analysis value 0] Theoretical value as 5H22N204S (%
) C; 55.20 H; /), 79 N; 8.
58 Actual value (%) C; 55.30 H: 6.65
N; 8.38 Example 23 2-(1-Methyl-2-methylsulfinyl-5-imidazolyl) methylitenemalonic acid/isopropyl ester Colorless product yield 877% Elemental analysis Theoretical value as Cl5H2□14□05S (%
)C! ;52. /) 2 H; 6.48 N; 8
．． 18 Actual value (%) C; 52.88 H; 636
N; 7.92 Example 24 2-(1-Methyl-2-methylsulfonyl-5-imidazolyl) methylitenemalonate diisopropyl ester Colorless product yield 824% Elemental analysis Theoretical value (%) as Cl5H22N206S
C: 50.27 H; 6.19 N; 7.82
Actual value (%) O: 50.28 H: 6.06
N; 7.57 Example 25 2-(1-methyl-2-methylthio-5-imidazolyl) methylitenemalonic acid di-n-butyl ester pale yellow oil Yield 890% Elemental analysis Theoretical value as Cl7H26N204S (
%) c; 5760 H; 7.3 q N
; 7.90 Actual value (%) C; 57.65
H; 7.19 N; 7.76 Example 26 2-(1-Methyl-2-methylsulfinyl-5-imidazolyl) methylitenemalonic acid di-n-butyl ester Colorless eraser yield 986% Elemental analysis Theory as C17H26N205S value(%)
O;55. +2 H; 7.07 N; 7.56
Actual value (bulk) O; 54.90 H; 6.94
Nia, 26 Example 27 2-(1-Methyl-2-methylsulfonyl-5-imidazolyl) methylidenemalonic acid di-D-butyl ester Colorless product Yield 907% Elemental analysis Theoretical value (%) as Cl7H28N206S
O; 52.83 H: 6.78 N; 7.25
Actual value (%→C; 53.17 H: 6.66 N
:6.95 Example 28 2-(1-Methyl-2-methylthio-5-imidazolyl) methylitenemalonoic acid di-tert-butyl ester pale yellow oil Yield 110% Elemental analysis Theoretical value (%) as Cl7H26N204s
C; 57.60 H; 7.39 N; 7.90
Actual d1] Value (%) C! ;57.91 H;7.
25 N:B, 0625-Example 29 2-(1-Methyl-2-methylsulfinyl-5-imidazolyl)methylitenemalonic acid di-tert-butyl ester Colorless oil Yield 126% Elemental analysis Theoretical value (%) as C17H26N2o5s
O; 55.12 H; 7.07 N near, 56
Actual value (%) C; 55.11 H; 7.17
N; 7.43 Example 30 2-(1-#f-2-methylsulfonyl-5-imidazolyl)methylitenemalonic acid di-tert-butyl ester Colorless oil Yield 88% Elemental analysis Theoretical value (%) as C17H26N206s
C; 52.83 H; 6.78 N; 7.25
Actual value (%) C; 52.88 H; 6.73
N; 7.25 Test example (a) Experimental method (Chi, eco Murayama et, al.
, Eng. nt, J., Radj, at, Bio.

1983, Vol. 44. N [15,497~
The method of 503'J was followed.

(1) Cells Chinese hamster V79 cells in the exponential growth phase were grown 4x1 in Eagle's minimum essential medium (MEM) supplemented with 10% fetal bovine serum in a carbon dioxide ink bottle at 37°C.
It was used as 1 piece/ml.

(2) Test drug solution Dissolved in dimethyl sulfoxide in an amount to give a final concentration of 0.5%, and then MEM was added to obtain a solution with the desired concentration.

(3) Irradiation experiment Add an equal amount of the test drug solution to 0.5 ml of the cell suspension described in (1), and incubate the container with a mixed gas consisting of 95% nitrogen gas and 5% carbon dioxide for 1 hour at room temperature. The oxygen was blown into the air to create a hypoxic state. This is combined with the bLICo irradiation device (The
ra, tron 780; dose rate approximately 1.5 Gy/
20 Gy of γ-rays were irradiated at room temperature using Cells were then centrifuged, resuspended and diluted to various concentrations in EM 5m7! supplemented with 10% fetal bovine serum and 5% neonatal bovine serum. 10-1 at 37℃ in a Petri dish containing
After incubation in a carbon dioxide incubator for 2 days, the formed colonies were fixed with methanol, stained with Giemsa, and counted visually to determine the number of viable cells.

(b) Results The results are shown in FIGS. 1 to 6. The smaller the number of viable cells for each concentration, the stronger the radiosensitizing effect.

The compound of the present invention was found to have a stronger effect than misonidazole, which was used as a control drug.

[Brief explanation of drawings]

FIG. 1 shows cell viability using the control drug misonidazole. FIG. 2 and FIG. 6 show the cell survival rate when using the compound of the present invention, and A, , B, and C in each figure. D, E and F are respectively Example 2. Example 6゜Example 5. Example 13. The compounds of the present invention obtained in Example 14 and Example 15 are shown. Patent applicant Taisho Pharmaceutical Co., Ltd. Agent Patent attorney Tomi Kitagawa Zozu 1 Ueda drug @concentration Crn chart) Plant detection drug @ Moat (m M) Test drug temperature chart) Procedural amendment (voluntary) Akio I] April 9, 1960 1. Display of the case 1985 Patent Application No. 26576 2. Name of the invention Imidazole derivative 3. Relationship to the person making the amendment Patent applicant address 3-24 Takada, Toshima-ku, Tokyo Address 1: 17
1 Taisho Pharmaceutical Co., Ltd., 6-24-1 Takada, Toshima-ku, Tokyo Telephone: (Tokyo) 985-1111 Name: Patent Attorney (7411) Tomizo Kitagawa 5, Specifications to be amended, Book 6: Details of the amendment Broom book (no changes in content) Z list of attached documents

Claims (1)

[Claims] (1) General formula, ▲Mathematical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^2 are nitrile groups, CO2R^
3 or CONHR^4, R^3 represents a lower alkyl group, R^4 represents a hydrogen atom or a β-hydroxyethyl group, and n represents 0, 1 or 2. ] A compound represented by