JPS62228049A - 1-(cyanomethyl)fulvene compound and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are H, alkyl, cycloalkyl, alkenyl, aryl or R<1> and R<2> together form polymethylene). EXAMPLE:6,6-Tetramethylene-1-(cyanomethyl)fulvene. USE:A carcinostatic agent exhibiting strong antitumor activity. PREPARATION:The compound of formula I can be produced by reacting 7- methylenebicyclo[2,2,1]hept-5-en-2-one of formula II with an acidic reagent (e.g. phosphorus trichloride, thionyl chloride) in a solvent such as ether at -100-+100 deg.C or at room temperature for convenience. The amount of the acidic reagent is 1 equivalent or excess.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (1) 0, where R1 and R2 are hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, or an aryol group; R1 and R
Z can be taken together to form a polymethylene group. The present invention relates to 1-(cyanomethyl)fulhenes represented by the following formula and a method for producing the same. The substance represented by the general formula (r) is a new compound and has strong antitumor activity.

[Conventional technology]

At present, when no truly effective cancer chemotherapeutic agent has been invented yet, the development of anticancer agents with novel structures is also a social need.

[Problem that the invention seeks to solve]

The present inventors aimed to develop a novel anticancer drug, and as a step toward this goal, they made earnest efforts to search for a strong anti-aim active substance. As a result, they found that CI-(5
-methylene-1,3-cyclopentagenyl)] acetonitrile (common name is 1-(cyanomethyl)fulpene, the common name is used herein) has a strong antitumor activity; They discovered a manufacturing method and completed the present invention.

[Means for solving problems]

The 1-(cyanomethyl)fulpene represented by the general formula (1) of the present invention is 7 represented by the following general formula (n).
-Alkylidenebicyclo(2,2゜1)hept-5-en-2-one It can be obtained by reacting oxime under acidic conditions.

Edge jl [In the formula, R1 and RZ represent the same meanings as above. ] The compound represented by the general formula (n) as a raw material can be synthesized from the corresponding 7-alkylidenebicyclo[2゜2.1]hept-5-en-2-one (III) (see reference side below) . In addition, (fir) is a compound that can be easily synthesized by the method developed by the present inventors (Japanese Patent Laid-Open No. 5
5-124780).

The step from the general formula (■) to H) is the process from the general formula (I+
) 7-AlkylidenebicycloC2,2,
1) Hept-5-en-2-one oxime is reacted under acidic conditions. The reaction is preferably carried out in a solvent that does not directly participate in the reaction, for example,
Dichloromethane, chloro17form, carbon tetrachloride, pentane, hexane, cyclohexane, Hensen, 1 toluene,
Chirenlene, ether, tetrahydrofuran, di-1-
Examples include san, dimethoxyethane, and the like. The reaction temperature ranges from -100°C to 100°C, but it is convenient to carry out the reaction at room temperature.

As the acidic reagent 1 used in this step, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, acetyl chloride, mesyl chloride, tosyl chloride, etc. can be used. It is appropriate to use an equivalent amount, but there is no harm in using an excess amount.

Examples of the substituents R1 and R1 of the compounds represented by the general formulas (I) and (TI) of the present invention include hydrogen, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, Examples include straight chain or branched chain substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms such as octyl group, nonyl group, and decyl group. An alkenyl group refers to an alkenyl group having 2 to 10 carbon atoms, such as a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, a 2-phenylvinyl group, etc. and positional isomers. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Oryl group includes phenyl group, halophenyl group, tolyl group, ethylphenyl group, furobylphenyl group, gysylyl group, phenyl group, nitrophenyl group, naphthyl group, pyridyl group, pyrrolyl group, chenyl group, furyl group, etc. I can give an example.

Examples of the polymethylene group formed by R1 and R2 include a dimethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, and the like.

The compound of the present invention represented by the general formula (1) showed a strong inhibitory effect in an in vitro growth inhibition test using mouse leukemia cells P388 (see test side below).

Hereinafter, the present invention will be explained in more detail with reference to Examples, Reference Examples, and Test Examples.

Reference example 1 7-cyclopentylidene bicycloC2,2,1)hept-5-ene-2-one 429■ (2°47m-m01)
was dissolved in ethanol (5 ml) and lysine (5 ml). Among these, hydroxylamine hydrochloride 265
w (3,70 mmo ) was added thereto, and the mixture was heated under reflux for 3 hours. Add water (50ml) and add ether (25ml x 3)
Extracted with. The extract was washed with water (20 ml x 3) and dried over anhydrous magnesium sulfate. Inorganic substances were filtered off, and the solvent was distilled off under reduced pressure. The residue was separated and purified by column chromatography (silica gel, hexane; ether-3; 1) to obtain 7-cyclopentylidenebicycloC2,2°1]hept-5-en-2-one oxime 261. This was a mixture of syn-oxime and anti-oxime in a ratio of about 1:IO.

Yield 55.9%.

TR (neat): 3270, 2940°1430.9
40,735co+-'.

NMR (CDC1t): δ 1.33-2.66 (10
H, m), 3.35 (L H, broads)
, 3.65 (I H, m) , 6.23
(IH.

dd, J=3Hz, 6Hz), 6.47(LH, dd,
J = 3Hz, 6Hz).

9.40 (IH, s).

145 (58%), 131 (48%).

91 (63%).

Reference Example 2 As a starting material, 7-cyclohexylidenebicyclo(2
,2,1) hept-5-en-2-one 312■(1,
66mmo
) Heb-5-en-2-one oxime 337■ was obtained. Yield lOO%.

TR (neat): 3270.2950°1450.9
40,740cm-'.

NMR (CDCIs): δ 1.49 (6H.

m), 2.06 (4H, m>, 2.15 (IH.

d, J-10Hz), 2.43 (IH.

dd, J=2Hz, 10Hz), 3.56(IH,
m), 3.83 and 4.57 (total IH, each m)
, 6.27 (IH, dd.

J=2Hz, 4Hz), 6.52 (IH.

dd, J=2Hz, 4Hz).

MS m/i: 203 (M′″, 18%).

186 (100%), 118 (44%).

117 (31%), 91 (46%), 83 (4
9%).

Reference Example 3 As a starting material, 7-cyclohebutylidenebicyclo(2
,2,1) hept-5-en-2-one 1.027 g
(5,08mmo
2,1) Hept-5-en-2-one oxime 933
I got ■.

This was an isomer mixture of syn-oxime and anti-oxime in a ratio of about 1:4.5.

Yield 84.7%.

TR (neat): 3250, 2930°16B5.1
440,930,730 cm-'.

NMR (CDCI3): δ 1.4B (8H.

m), 2.0-2.63 (6H, m), 3.53 (I
H, m), 3.80 and 4.55 (together Ill, each m), 6.28 (IH, dd.

, 1=3Hz, 6Hz), 6.52 (IH.

dd, J=3Hz, 6Hz), 7.82 (IH, s).

Reference Example 4 As a starting material, 7-cyclobutylidene bicyclo(2,
2,1) Hept-5-en-2-one 140+w (0
, 875mmo 1) was carried out in the same manner as in Reference Example 1, and 7-cyclobutylidenebicyclo(2,2,1)
104.2 ml of hept-5-en-2-one oxime was obtained. Yield 68.1%.

This was a 1:6.7 isomer mixture of syn-oxime and anti-oxime.

IR (neat): 3250.2920°1420,
735 (Jl-True.

NMR (CDCI, ): δ 1.8B (2H.

quartet, J=4Hz), 2.13-2.77
(6H, m), 3.30 (IH, m).

3.58 and 4.28 (together II (, each m).

6.23 (IH, dd, J=2Hz, 4Hz>.

6.47 (IH, dd, J=2Hz, 4TIz).

8.73 (IH, broads).

MS m/B: 175 (M”, 21%).

15B (100%), 147 (52%).

130 (64%), 117 (75%).

103 (92%), 91 (58%), 77 (49%)
).

Reference Example 5 As a starting material, 7-ophthyridine bicyclo(2,2,
1) Hept-5-en-2-one 346■ (1,59m
7-mol) was used in the same manner as in Reference Example 1.
Oftyridine bicycloC2,2,1)hept-5-en-2-one oxime 210■ was obtained. This thing is sy
It was an isomer mixture of n-oxime and anti-oxime, and the ratio was about 1:4.5. Yield 56.6%
.

IR (neat): 3250, 2940°1460.9
55.735cm-'.

NMR (CDCI, ): δ 0.67-1.55 (13
H, m), 1.63-2.63 (4H.

m), 3.27 and 3.80 (together Ill.

m), 3.55 (1) [, m), 4.8 respectively
0 and 4.83 (total IH, each t, J-7Hz
) 6.30 (IH, m), 6.82 (I H, rr+
), 7.85 (I H, m).

MS m/z: 234 (M”+1.5%).

233 (M”, 24%), 216 (53%).

148 (45%), 134 (64%).

131 (63%), 119 (59%).

11B (93%), +17 (58%).

105 (49%), 92 (52%), 91 (100
%), 79 (48%), 41 (47%).

Reference Example 6 As a starting material, 7-(4-propyl)benzylidenebicyclo(2,2,1)hept-5-en-2-one 37
Reference Example 1 except that 2g (1,56mmo +) was used.
In the same manner as above, 7-(4-propyl)benzylidenebicyclo(2,2,1)hept-5-en-2-one oxime 342■ was obtained. Yield 86.6%.

IR (neat): 3250. 2975°294
5, 1470. 750C11-'.

NMR (CDC1,): δ 0.95 (
3H.

t, J=6Hz), 1.63 (2H, m)
.

2.48 (2H, t, J=8Hz), 2.
55 (2H, d, J=IHz), 3.42 and 3.93
(Total IH, each m), 3.67 and 4, 22 and 4
．． 41 and 4.97 (both IH).

m), 5.88 (IH, m), 6.38 respectively
(IH, dd, J=2Hz, 4Hz).

6.57 (IH, dd, J = 2Hz, 4
Hz).

7.17 (4H, s), 8.00 (LH,
broadS).

MS m/z: 254 (M"+1. 10%).

stomach 25300%), 236 (92%).

210 (97%), 167 (100%).

165 (91%), 153 (71%).

152 (68%).

Example 1 7-cyclopentylidenebicyclo(2,2,1)hept-5-en-2-one oxime 47cm (0,25mm
ol) was dissolved in anhydrous ether (2 ml) and cooled to -78°C. In this solution, thionyl chloride 97+w (0
, 72 mmo I) in anhydrous ether (2 ml) was added dropwise. After stirring at -78°C for 2 hours, saturated sodium bicarbonate water (10ml) was added, and ether (lomlx
3). The extract was washed with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. Inorganic substances were filtered off, and the solvent was distilled off under reduced pressure. The residue was separated and purified by column chromatography (silica gel, hexane:ether-5:l) to obtain 10 6,6-tetramethylene=1-(cyanomethyl)fulvene.

Yield 23%.

TR (neat): 2980, 2270°1635
．． 1420,830,760°650 (J-'.

NMR (CDCl2): δ 1.80 (4H.

m), 2.82 (4H, m), 3.57 (2H.

s), 6.113-6.65 (3H, m>.

MS m/z: 172 (M”+1.14%).

171 (M”, 98%), 144 (100%),
143 (43%), 131 (77%).

129 (76%), 116 (68%).

115 (44%).

Example 2 7-cyclopentylidene bicyclo(2,2,1)hept-5-en-2-one oxime 57cm (0,30mm
o ]) in anhydrous ether (2 ml), -20
Cooled to ℃. Thionyl chloride 91N (0.67mmo
A solution of I) in anhydrous ether (1 ml) was added dropwise. -2
Stirred at 0'C for 1 hour. Saturated sodium bicarbonate water (
10 ml) was added and extracted with ether (10 ml x 3). After washing with saturated brine (10ml), it was dried over anhydrous magnesium sulfate. The f′jI medium was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel, hexane:
Separation and purification with ether = 5 + 1) gave 12 parts of 6,6-titramethylene-1-(cyanomethyl)fulvene. Yield 23%.

Example 3 7-Cyclopentylidene bicyclo[2,2,13hept-5-en-2-one oxime 45cm (0,24mm
o + ) was dissolved in anhydrous ether (2 ml). A solution of 91 μm (0.67 mmol) of thionyl chloride in anhydrous ether (2 ml) was added. After stirring at room temperature for 15 minutes, saturated aqueous sodium bicarbonate (10 ml) was added. It was extracted with ether (10 ml x 3), and the extract was washed with saturated brine (10 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was separated and purified by column chromatography (silica gel, hexane:ether-5:1) to obtain 9 parts of 6,6-titramethylene-1-(cyanomethyl)fulvene. Yield 22%.

Example 4 As a starting material, 7-cycloptylidene bicycloC2,
2,1) Hept-5-en-2-one oxime 67. O
The same procedure as in Example 3 was carried out except that Ow (0,383 mmo I) was used to obtain 8.58 µ of 6,6-drimethylene-1-(cyanomethyl)fulvene. Yield 16.3%
.

I R(KB r) = 2970. 2930°2
250 cII-'.

NMR (CDCIs): δ 2.23 (2H.

quartet J=5Hz), 3.20 (4
H.

t, J=5Hz), 3.48 (21-1s
).

6.17-6.57 (3H, m).

MS m/z: 1 57 (M',
49%).

129 (40%), 102 (100%).

Example 5 As a starting material, 7-cyclohexylidenebicyclo(2
, 2,1) 24.2 µ of hept-5-en-2-one-1-(cyanomethyl)fulvene were obtained.

Yield 38.5%.

Yellow solid (solidified after being left in the refrigerator) TR (neat
):2940, 2870°2255, 1615. 1
445. 1350°760C11-'.

NMR (CDCIs): δ 1.73
(6+1゜m), 2.65 (4H, m),
3.70 (2H.

s), 6.30 (IH, dd, J=2Hz
.

4Hz), 6.60 (2H, m>.

MS m/z: 186 (M'+1.1
6%).

185 (M”, 75%), 15B (39%).

129 (41%), 117 (100%).

115 (39%).

Example 6 7-cyclohebutylidene bicyclo(2
,2,1) Hept-5-en-2-one oxime 75.
The same procedure as in Example 3 was carried out except that 8+ng (0,349mmo +) was used, and 6,6-hexamethylene-1-
(Cyanomethyl)fulvene 28.5 μm was obtained. Yield 41
．． 0%.

IR (KBr): 2930, 2250°1600.8
25,740,640 cm-'.

NMR (CDCl2): δ 1.08-1.92 (8H
, m), 2.75 (2H, m).

3.63 (2H, s), 6.28 (IH, m).

6.53 (2H, m).

MS m/z: 200 (M”+1.7%).

199 (M”, 42%), 131 (30%).

129 (28%), 117 (100%).

116 (31%), 115 (30%).

91 (34%).

Example 7 Twocyclohebutylidenebicyclo(2,2,1)hept-5-ene-nione oxime 74.78 mg (0
, 345 mmol) was dissolved in anhydrous ether (5 ml) and 143 μm (0,687 mmol) of phosphorus pentachloride was added in one portion. After stirring at room temperature for 30 minutes, water (10ml
) and extracted with ether (10ml x 3). The extract was washed with saturated brine (10ml) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica sol, hexane:ether-9:1) to obtain 6,6-hexane. Yield = t%.

Example 8 7-Oftyridinebicyclo(2,2,1)hept-5-
En-2-one oxime 70■ (0.30mm o
) was dissolved in anhydrous ether (2 ml). Thionyl chloride 121■ (0,896m-mo+) was cooled with water,
It was dissolved in anhydrous ether (2ml) and added. After stirring at room temperature for 15 minutes, saturated aqueous sodium bicarbonate (10 ml) was added. It was extracted with ether (10 ml x 3), and the extract was washed with saturated brine (10 ml).

After drying over anhydrous magnesium sulfate, inorganic substances were filtered off, and the solvent was distilled off under reduced pressure. The residue was separated and purified by column chromatography (silica gel, hexane:ether = 9:1), and 6-hebutyl-1-(cyanomethyl)fulhen 2
8.4■ was obtained. This was a two isomeric γIL compound (approximately 2:1) with respect to the substituent at position 6. Yield 44
,1%.

IR (neat): 2940, 2250° 2205 (2
)-1°NMR (CDCis): δ 0.67-1.80 (13
H, m), 2.33-2.70 (2H.

m), 3.50 and 3.63 (2H in a hurry.

s), 6.06 to 6.83 (3H, m) respectively.

MS m/z: 216 (M”+1.11%)
.

2] 5 (M”, 24%), 131 (100%), 117 (70%), 9I (32%).

Example 9 Same as Example 8 except that 7-(4-propyl)benzylidenebicycloC2,2,1)hept-5-en-2-one oxime 73w (0,289 mmo 1) was used as the starting material. 13.7 µ of 6-(4-propyl)phenyl-1-(cyanomethyl)fulvene was obtained. Yield 20.2%.

This was a mixture of two isomers regarding the exonic double bond.

IR (neat): 2950, 2250°1515,
740cs*-'.

NMR (CDCIs): δ 0.97 (3) (.

t, J=6Hz), 1.67 (2H, m).

2.62 (2H,t, J-61(z), 3.1
7 and 3.63 (2H in total, m each).

6.27 and 6.53 (total LH, each m).

6.43 and 6.68 (total IH, each m).

6.55 and 6.70 (total IH, each m).

7.1 to 7.6 (4H in total, m each).

7.15 and 7.47 (together IH, each S).

MS m/z: 236 (M”+1.15%).

235 (M”, 66%), 206 (58%),
192 (100%), 165 (67%),
152 (53%).

Test Example I Goburi (Jψ1 mackerel disease founder □388) 1 cultured mouse lymphocytic leukemia cells (P388)
5X1 in RPMI-1640 medium supplemented with % live fetal serum.
The compound of the present invention, 40 to 3.3X
The cells were cultured at 37°C for 49 hours in the presence of 10-"8g/m+. The number of floating cells was counted using a Coulter counter. A dose-response curve was created based on the growth inhibition rate compared to the sample without the addition of the compound, and the IC50 was determined. I asked for it.

The results are shown in Table 1.

As a solvent for the compound, 0.5-10-4% acetone or T) MSO coexisted, but 0.5% acetone or r)
The growth inhibition rate in the presence of MSO was less than 10%.

S dog 1> Mouse, Rin! Ihi using yesterday η good voice danen
Compound IIC50 (
11/verb) Procedural amendment (Kuguan) Commissioner of the Patent Office Black 1) Mr. Ming Xiong 1, Indication of the case Patent Application No. 48447 filed in 1988 2, Title of the invention 3, “Invention” in the specification of the person making the amendment Column 5, "Detailed explanation of the structure of the present invention", content of amendment (11) Corrected to the structural formula on page 27, line 2 of the specification of the present application.

that's all

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, or an aryl group, and R^
1 and R^2 can be combined to form a polymethylene group. ] A 1-(cyanomethyl)fulvene derivative represented by: (2) 7-methylenebicyclo[2.2.1]hept-5-en-2-one oxime represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ is characterized by treatment with an acidic reagent. Method for producing 1-(cyanomethyl)fulvenes represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. is a group, R
^1 and R^2 can be combined to form a polymethylene group. ].